MPRO TARGETING ANTIVIRAL COMPOUNDS TECHNICAL FIELD The present disclosure relates to compounds for the treatment of viral infections. In particular, aspects of the invention relate to compounds, compositions, uses and methods for the treatment of one or more coronavirus infection; particularly SARS-CoV-2 (COVID-19). BACKGROUND Coronaviruses (CoVs) are enveloped, positive-strand RNA viruses that infect a wide range of animal hosts, and cause illnesses such as the common cold, severe acute respiratory syndrome (SARS) and the recently identified Middle East respiratory syndrome (MERS). In December 2019 yet another novel coronavirus infection, named SARS-CoV-2, was identified in Wuhan (China). This was rapidly followed by an unprecedented, rapidly spread of the virus across the globe through human-to-human transmission facilitated by international travel. Since this novel coronavirus has only recently been transmitted from animals to the human, or at least has only recently been identified in humans, there is no effective and approved antiviral treatment available. This virus is now commonly known as COVID-19. In analogy to SARS (Severe Acute Respiratory Syndrome) coronavirus (SARS-CoV) and MERS (Middle East Respiratory Syndrome) coronavirus (MERS-CoV), the COVID-19 genome encodes a number of structural and non-structural proteins, including: 3-chymotrypsin-like protease, papain-like protease, helicase, and RNA-dependent RNA polymerase (non-structural); and spike glycoprotein and a variety of accessory proteins (structural). In particular, the non-structural proteins and the spike glycoprotein are considered to be essential for the life cycle of the virus and, therefore, represent potential targets for drug development. For example, the 3-chymotrypsin-like protease (3CL ^pro ), also known as M ^Pro or Nsp5, cleaves viral proteins by hydrolysing the bond following the amino acid glutamine in order to provide a further twelve structural proteins (notated Nsp4 to Nsp16), which include the RNA-dependent RNA polymerase (RdRp, Nsp12) and helicase (Nsp13) which are essential for the virus’ replication machinery. Therefore, if M ^pro is effectively inhibited it could be expected that the infectious cycle of the virus cannot be continued (Wu, F., Zhao, S., Yu, B. et al. A new coronavirus associated with human respiratory disease in China. Nature 579, 265–269 (2020); and Guangdi Li, E. D. Clercq, Therapeutic options for the 2019 novel coronavirus (2019-nCoV).Nature Review Drug Discovery 19(3), 149-150 (2020)). M ^pro is known to be the main protease of coronaviruses. To date there are not enough effective and approved antiviral treatments for COVID-19 available which focus on the inhibition of M ^pro and exhibit pan- / multi-coronavirus activity . It would also be desirable to treat one or more coronavirus infections using the same compound or composition. The present invention has been devised to address at least one of the challenges described above. SUMMARY OF THE INVENTION The present disclosure is directed to compounds and compositions for use in methods, and in corresponding methods, for the treatment of viral infections; particular for the treatment, prevention and/or alleviation of coronavirus infections in a subject. Beneficially, the compounds and compositions of the disclosure may be suitable for the treatment, prevention and/or alleviation of SARS-CoV-2 (COVID-19) infections. In some aspects and embodiments of the disclosure, the compounds and compositions of the disclosure may have utility in the treatment, prevention and/or alleviation of coronavirus infections caused by one or more strain of coronavirus. Suitable coronaviruses include, but are not limited to SARS, MERS, 229E, OC43, HKU1, NL63 and SARS-CoV-2 (COVID-19) or combinations or two, three, four or more thereof. In addition, compounds of the present disclosure may exhibit improved clearance from humans, in use, compared with prior art compounds and/or may be useful in mitigating against drug-drug interactions (DDI) risk, while retaining high potency against COVID-19 and, particularly beneficially, a pan- coronavirus activity. In one aspect of the disclosure, there is provided a compound of Formula (I) including any diastereomers and enantiomers thereof or a pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof: wherein R ¹ may be monocyclic or bicyclic cycloalkyl, heterocycloalkyl, aryl, heteroaryl or combinations thereof, any of which may have one more or substituents, wherein any such monocyclic or bicyclic cycloalkyl, aryl, heteroaryl or combination thereof may be directly connected to the remaining compound (I) or connected via a C ₁ -C ₃ alkylene linker, wherein the alkylene linker may optionally be substituted with one to three R ⁹ ; R ^1’ may be nitrile (CN); R ^1a may be absent, hydrogen, deuterium or C _1-6 alkyl; R ² may be selected from the group consisting of hydrogen; straight or branched C ₁ -C ₆ alkyl; straight or branched C ₁ -C ₆ alkoxy; ( C ₁ -C ₆ alkoxy)-C ₁ -C ₆ alkyl or (C ₁ -C ₆ alkyl)-C ₁ -C ₆ alkoxy, where each alkyl or alkoxy group may be optionally substituted with one to three fluoro, hydroxy, oxo or C ₁ -C ₃ alkoxy; particularly R ² may be hydrogen; R ⁶ may be selected from the group consisting of C ₁ -C ₆ alkyl which is optionally substituted with a cyano or with one to five fluoro; C ₂ -C ₆ alkynyl; and (C ₃ -C ₆ cycloalkyl)-C ₁ -C ₃ alkyl which is optionally substituted with one or two substituents selected from trifluoromethyl and C ₁ -C ₃ alkyl, wherein the C ₁ - C ₃ alkyl is optionally substituted with one to five fluoro; or R ² and R ⁶ taken together with the nitrogen and carbon atoms to which they are attached may form a pyrrolidine or piperidine ring, which is optionally substituted with one to four R ^2a ; R ^2a at each occurrence may be independently selected from the group consisting of fluoro, hydroxy, C ₁ -C ₆ alkyl optionally substituted with one to three fluoro, and C ₁ -C ₆ alkoxy optionally substituted with one to three fluoro; or two R ^2a groups when attached to adjacent carbon atoms and taken together with the carbon atoms to which they are attached form a C ₃ -C ₆ cycloalkyl which is optionally substituted with one to four R ^2b ; or two R ^2a groups when attached to the same carbon and taken together with the carbon to which they are attached form a C ₃ -C ₆ cycloalkyl which is optionally substituted with one to four R ^2b ; R ^2b at each occurrence may be optionally independently selected from fluoro, hydroxy, C ₁ - C ₃ alkyl optionally independently substituted with one to three fluoro or hydroxy, and C ₁ -C ₃ alkoxy optionally independently substituted with one to three fluoro or hydroxy, or two R ^2b groups when attached to the same carbon and taken together with the carbon to which they are attached form a C ₃ - C ₆ cycloalkyl which is optionally substituted with one to four R ⁹ ; R ³ may be selected from the group consisting of straight or branched C ₁ -C ₈ alkyl, straight or branched C ₁ -C ₈ alkoxy, straight or branched (C ₁ -C ₆ alkoxy)-C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, aryl, heteroaryl optionally fused with a 5- or 6-membered heteroaryl or phenyl, (C ₃ -C ₁₂ cycloalkyl)-C ₁ - C ₆ alkyl, C ₃ -C ₁₂ cycloalkoxy, (C ₃ -C ₁₂ cycloalkoxy)-C ₁ -C ₆ alkyl, 4- to 12-membered heterocycloalkyl which is optionally fused with a 5- to 6-membered heteroaryl or phenyl and wherein said heterocycloalkyl comprises one to four heteroatoms independently selected from N, O and S(O)n; (4- to 12-membered heterocycloalkyl)-C ₁ -C ₆ alkyl wherein said heterocycloalkyl moiety comprises one to four heteroatoms independently selected from N, O and S(O)n; C ₆ -C ₁₀ aryl optionally fused with a C4- C ₆ cycloalkyl or a 4- to 7-membered heterocycloalkyl; ( C ₆ -C ₁₀ aryl)-C ₁ -C ₆ alkyl; 5- to 10-membered heteroaryl comprising one to five heteroatoms independently selected from N, O and S, which is optionally fused with a C ₅ -C ₆ cycloalkyl; (5- to 10-membered heteroaryl)-C ₁ -C ₆ alkyl wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S; (C ₆ - C ₁₀ aryl)-(5- to 10-membered heteroaryl)- wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S, (5- to 10-membered heteroaryloxy)-C ₁ -C ₆ alkyl wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S; (5- to 6-membered heteroaryl)-(5- to 6-membered heteroaryl)- wherein each heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; (4- to 7-membered heterocycloalkyl)-(5- to 6-membered heteroaryl)- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n and the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; (5- to 6-membered heteroaryl)-(4- to 7-membered heterocycloalkyl)- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n and the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; wherein each R ³ group is optionally substituted with one to five R ⁴ ; and n at each occurrence is independently selected from 0, 1 and 2; R ⁴ at each occurrence may be independently selected from the group consisting of oxo, halo, hydroxy, cyano, phenyl, benzyl, amino, (C ₁ -C ₆ alkyl)amino optionally substituted with one to five fluoro or with one to three R ⁹ , di(C ₁ -C ₆ alkyl)amino optionally substituted with one to ten fluoro or with one to three R ⁹ , C ₁ -C ₆ alkyl optionally substituted with one to five fluoro or with one to three R ⁹ , (5- to 6- membered heteroaryl)amino- wherein the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S and wherein the heteroaryl is optionally substituted with one to three R ⁹ ; (4- to 7-membered heterocycloalkyl)amino- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n and wherein the heterocycloalkyl is optionally substituted with one to three R ⁹ ; C ₁ -C ₆ alkoxy optionally substituted with one to five fluoro or with one to three R ⁹ ; C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl optionally substituted with one to five fluoro or with one to three R ⁹ ; C ₃ -C ₆ cycloalkyl optionally substituted with one to three fluoro or C ₁ -C ₃ alkyl or R ⁵ ; C ₃ - C ₆ cycloalkyl-C(O)NH- optionally substituted with one to five fluoro or R ⁵ ; 4- to 7-membered heterocycloalkyl-C(O)NH- optionally substituted with one to five fluoro or R ⁵ and wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n; 5- to 6-membered heteroaryl)-C(O)NH- optionally substituted with one to five fluoro or R ⁵ and wherein the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; C ₁ -C ₆ alkyl-C(O)NH- optionally substituted with one to five fluoro or R ⁹ ; C ₁ -C ₆ alkyl-OC(O)NH- optionally substituted with one to five fluoro or R ⁵ ; C ₁ -C ₆ alkyl-NHC(O)NH- optionally substituted with one to five fluoro or R ⁵ ; C ₁ -C ₆ alkyl-S(O)2NH- optionally substituted with one to five fluoro or R ⁵ ; C ₁ - C ₆ alkyl-C(O)- optionally substituted with one to five fluoro or R ⁵ ; C ₁ -C ₆ alkyl-S(O)n- optionally substituted with one to five fluoro or R ⁵ ; and n at each occurrence is independently selected from 0, 1 and 2; R ⁵ may be selected from C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, phenyl, phenoxy, C ₃ -C ₆ cycloalkyl, C ₃ - C ₆ cycloalkoxy, 4- to 7- membered heterocycloalkyl wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n, or a 5- or 6-membered heteroaryl wherein the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; wherein each R ⁵ is optionally independently substituted with one to three R ⁹ ; and n at each occurrence is independently selected from 0, 1 and 2; R ⁹ may be selected from the group consisting of deuterium, oxo, halo, hydroxy, cyano, amino, C ₁ -C ₃ alkyl optionally independently substituted with one to three fluoro or hydroxy, and C ₁ -C ₃ alkyoxy optionally independently substituted with one to three fluoro or hydroxy, and C ₁ -C ₃ alkoxy optionally independently substituted with one to three fluoro or hydroxy. In any aspects and embodiments of this disclosure, the compound is not a compound selected from one or more (e.g. all) of: CPD0077063, CPD0084200, CPD0084205, CPD0084207, CPD0084208, CPD0084209, CPD0084210, CPD0084211, CPD0084212, CPD0084215, CPD0084216, CPD0084217, CPD0084221, CPD0084228, CPD0084231, CPD0084235, CPD0084242, CPD0084248, CPD0084249, CPD0084250, CPD0084252, CPD0084253, CPD0084254, CPD0084301, CPD0084531, CPD0084769, CPD0186407, CPD0186408, CPD0186409, CPD0186410, CPD0186412, CPD0186526, CPD0186529, CPD0186530, CPD0187053, CPD0187106, CPD0187107, CPD0187510, CPD0188058, CPD188059 and CPD0188163. In particular aspects and embodiments of this disclosure, R ¹ does not comprise a lactam (monocyclic) ring. In another aspect there is provided a compound having a chemical structure selected from a structure of Table 1A, Table 1B and/or Table 1C. Also encompassed within the scope of the disclosure is any stereoisomer or mixture of stereoisomers including diastereomers and enantiomers, tautomer, isotopic form, pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof, or combinations thereof of the compounds disclosed herein. In another aspect there is provided a pharmaceutical composition comprising one or more compound according to any aspect of the disclosure, or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers, tautomer, isotopic form, pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof, or combinations thereof, and at least one pharmaceutically acceptable diluent, excipient or carrier. In another aspect there is provided a compound or a pharmaceutical composition as disclosed herein for use in medicine. In another aspect there is provided a method of treatment comprising administration of a therapeutically effective amount of a compound of any aspect or embodiment of the disclosure, or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers, tautomer, isotopic form, pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof, or combinations thereof of the compound, or a composition comprising the compound, to a patient in need thereof. In embodiments, the patient has a viral infection. In another aspect there is provided a method of treating a viral infection, comprising administering one or more compound according to any aspect or embodiment of the disclosure, or a stereoisomer or mixture of stereoisomers including diastereomers and enantiomers, tautomer, isotopic form, pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof, or a composition comprising the compound to a subject in need thereof. According to various aspects and embodiments, the viral infection is coronavirus. In embodiments, the coronavirus is selected form the group consisting: SARS, MERS, 229E, OC43, HKU1, NL63 and SARS- CoV-2 (COVID-19) or combinations or two, three, four or more thereof. According to another aspect of the present invention there is provided a compound of the following formula including any diastereomers and enantiomers, or a pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof: (I), wherein R ¹ is monocyclic or bicyclic cycloalkyl, aryl, heteroaryl or combinations thereof, any of which may have one more or substituents, typically R ¹ may be a five or six membered cycloalkyl or heteroaryl, optionally having one or more substituents, wherein any such monocyclic or bicyclic cycloalkyl, aryl, heteroaryl or combination thereof may be directly connected to the remaining compound (I) or connected via an alkyl linker such as -CH ₂ - or -CH ₂ (CH ₂ )-; R ^1’ is nitrile (CN); R ^1a is absent, hydrogen, deuterium or C _1-6 alkyl (suitably R ^1a may be hydrogen or methyl); R ² is hydrogen; and R ⁶ is selected from the group consisting of C ₁ -C ₆ alkyl which is optionally substituted with a cyano or with one to five fluoro; C ₂ -C ₆ alkynyl; and (C ₃ -C ₆ cycloalkyl)-C ₁ -C ₃ alkyl which is optionally substituted with one to two substituents selected from trifluoromethyl and C ₁ -C ₃ alkyl, and/or optionally substituted with one to five fluoro (preferably, R ⁶ may be CH ₂ -cyclopropyl); or R ² and R ⁶ taken together with the nitrogen and carbon atoms to which they are attached form a pyrrolidine or piperidine ring, which is optionally substituted with one to four R ^2a ; R ^2a at each occurrence may be independently selected from the group consisting of fluoro, hydroxy, C ₁ -C ₆ alkyl optionally substituted with one to three fluoro, and C ₁ -C ₆ alkoxy optionally substituted with one to three fluoro; or two R ^2a groups when attached to adjacent carbons and taken together with the carbons to which they are attached form a fused C ₃ -C ₆ cycloalkyl which is optionally substituted with one to four R ^2b ; or two R ^2a groups when attached to the same carbon and taken together with the carbon to which they are attached form a spiro C ₃ -C ₆ cycloalkyl which is optionally substituted with one to four R ^2b ; R ^2b at each occurrence is optionally independently selected from fluoro, hydroxy, C ₁ -C ₃ alkyl optionally independently substituted with one to three fluoro or hydroxy, and C ₁ -C ₃ alkoxy optionally independently substituted with one to three fluoro or hydroxy; R ³ is selected from the group consisting of C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, (C ₁ -C ₆ alkoxy)-C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, aryl, heteroaryl optionally fused with a 5- or 6-membered heteroaryl or phenyl, (C ₃ - C ₁₂ cycloalkyl)-C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkoxy, (C ₃ -C ₁₂ cycloalkoxy)-C ₁ -C ₆ alkyl, 4- to 12-membered heterocycloalkyl which is optionally fused with a 5- to 6-membered heteroaryl or phenyl and wherein said heterocycloalkyl comprises one to four heteroatoms independently selected from N, O and S(O)n; (4- to 12-membered heterocycloalkyl)-C ₁ -C ₆ alkyl wherein said heterocycloalkyl moiety comprises one to four heteroatoms independently selected from N, O and S(O)n; C ₆ -C ₁₀ aryl optionally fused with a C ₄ -C ₆ cycloalkyl or a 4- to 7-membered heterocycloalkyl; (C ₆ -C ₁₀ aryl)-C ₁ -C ₆ alkyl; 5- to 10-membered heteroaryl comprising one to five heteroatoms independently selected from N, O and S, which is optionally fused with a C ₅ -C ₆ cycloalkyl; (5- to 10-membered heteroaryl)-C ₁ -C ₆ alkyl wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S; (C ₆ -C ₁₀ aryl)-(5- to 10-membered heteroaryl)- wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S, (5- to 10-membered heteroaryloxy)-C ₁ -C ₆ alkyl wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S; (5- to 6-membered heteroaryl)-(5- to 6-membered heteroaryl)- wherein each heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; (4- to 7-membered heterocycloalkyl)-(5- to 6-membered heteroaryl)- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n and the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; (5- to 6-membered heteroaryl)-(4- to 7-membered heterocycloalkyl)- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n and the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; wherein each R ³ group is optionally substituted with one to five R ⁴ ; and n at each occurrence is independently selected from 0, 1 and 2; R ⁴ at each occurrence is independently selected from the group consisting of oxo, halo, hydroxy, cyano, phenyl, benzyl, amino, (C ₁ -C ₆ alkyl)amino optionally substituted with one to five fluoro, di(C ₁ -C ₆ alkyl)amino optionally substituted with one to ten fluoro, C ₁ -C ₆ alkyl optionally substituted with one to five fluoro, (5- to 6-membered heteroaryl)amino- wherein the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; (4- to 7-membered heterocycloalkyl)amino- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n; C ₁ -C ₆ alkoxy optionally substituted with one to five fluoro; C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl optionally substituted with one to five fluoro; C ₃ -C ₆ cycloalkyl optionally substituted with one to three fluoro or C ₁ -C ₃ alkyl; C ₁ -C ₆ alkyl-C(O)NH- optionally substituted with one to five fluoro; C ₁ -C ₆ alkyl-OC(O)NH- optionally substituted with one to five fluoro or with one R ⁵ ; C ₁ - C ₆ alkyl-NHC(O)NH- optionally substituted with one to five fluoro or with one R ⁵ ; C ₁ -C ₆ alkyl-S(O) ₂ NH- optionally substituted with one to five fluoro or with one R ⁵ ; C ₁ -C ₆ alkyl-C(O)- optionally substituted with one to five fluoro or with one R ⁵ ; C ₁ -C ₆ alkyl-S(O)n- optionally substituted with one to five fluoro or with one R ⁵ ; and n at each occurrence is independently selected from 0, 1 and 2; R ⁵ is selected from phenyl, phenoxy, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkoxy, 4- to 7- membered heterocycloalkyl wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n, or a 5- or 6-membered heteroaryl wherein the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; wherein each R ⁵ is optionally independently substituted with one to three halo, C ₁ -C ₃ alkyl and C ₁ -C ₃ alkoxy; and n at each occurrence is independently selected from 0, 1 and 2. In embodiments, R ¹ is selected from the following monocyclic or bicyclic cycloalkyl, aryl, heteroaryl structures: pyridine, δ-lactam, γ-lactam, cyclohexyl, cyclopentyl, δ-lactone, cyclobutyl optionally fused to phenyl, pyrazole, thiazole, triazole, pyridine, cyclopentandiene; and wherein said R ¹ is optionally substituted with C ₁ -C ₃ alkyl which optionally carries one to four heteroatoms independently selected from N, O and S. In embodiments, R ¹ is selected from any one of the following structures:

In embodiments, R ¹ is isoquinoline, quinoline, CH2-δ-lactam, CH2-γ-lactam or CH2-pyridine. In a further embodiment, wherein R ³ is selected from any one of the following structures:

In some particular embodiments, R ³ may have the following structure: wherein R ⁷ is aryl or heteroaryl; and R ⁸ is independently from R ⁷ selected from the group consisting of: C _1-6 alkyl or C _3-6 cycloalkyl optionally comprising one or more heteroatoms, such as N, O and S; particularly N or O; more particularly N. In other embodiments, R ³ is selected from one of the following structures: In another embodiment, R ⁶ and R ² together with the nitrogen and carbon respectively to which they attach, form one of the following structures: In embodiments, R ⁶ and R ² together with the nitrogen and carbon to which they are attached may form one of the following structures: In embodiments, R ^1’ is nitrile. In another embodiment, the compound of formula (I) has the following structures: wherein R ¹ is selected from the group consisting of monocyclic or bicyclic cycloalkyl, aryl, heteroaryl or combinations thereof, as described above. Advantageously, the compounds are useful for the treatment of infections caused by viruses. Beneficially, the viral infection is coronavirus, typically SARS-CoV-2 (COVID-19), SARS, MERS, SARS- CoV-2 (COVID-19) or combinations thereof. Advantageously, the compounds show broad spectrum activity against various viruses such as the ones above. Advantageously, the compounds and structures are inhibitors of the virus-encoded protease M ^pro . In any embodiment, the therapeutic uses of the invention may be in a method comprising administering the compound orally, topically, by inhalation, by intranasal administration, or systemically by intravenous, intraperitoneal, subcutaneous, or intramuscular injection. In various embodiment, the use is in a method comprising administering a compound of formula (I). The methods and/or therapeutic uses of the invention may comprise administering the compound according to formula (I) with one or more additional therapeutic agent. Typically. the one or more additional therapeutic agent is selected from at least one additional antiviral agent. In embodiments, the at least one additional antiviral agent may be selected from an inhibitor of viral RNA-dependent RNA polymerase, an inhibitor of virus-encoded protease that affects processing of a viral RNA-dependent RNA polymerase, an inhibitor of coronavirus binding or release from infected cells, an inhibitor of virus binding to a specific cell surface receptor, an inhibitor of receptor-induced conformational changes in virus spike glycoprotein that are associated with virus entry, or combinations thereof. In any embodiment, administering may comprise administering the compound according to formula (I) simultaneously, sequentially or separately from the one or more additional therapeutic agent. In another aspect there is provided a method of treating or preventing a viral infection in a subject in need thereof, comprising administering to the subject an effective amount of the compound of the following formula or a pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof: wherein the compound is defined according to any aspect and embodiment herein. According to various embodiments of the method, the viral infection is coronavirus, typically SARS- CoV-2 (COVID-19). Beneficially, the compound is an inhibitor of the virus-encoded protease M ^pro . In some suitable embodiments, the method comprises administering the compound orally, topically, by inhalation, by intranasal administration, or systemically by intravenous, intraperitoneal, subcutaneous, or intramuscular injection. In various embodiments, the method may comprises administering a compound of formula (I). In any embodiment, the method may comprise administering the compound according to Formula (I) with one or more additional therapeutic agent. Typically, the compound according to Formula (I) and the one or more additional therapeutic agent are administered simultaneously, sequentially or separately. In embodiments, the one or more additional therapeutic agent is selected from at least one additional antiviral agent. Typically, the one additional antiviral agent is selected from an inhibitor of viral RNA- dependent RNA polymerase, an inhibitor of virus-encoded protease that affects processing of a viral RNA-dependent RNA polymerase, an inhibitor of coronavirus binding or release from infected cells, an inhibitor of virus binding to a specific cell surface receptor, an inhibitor of receptor-induced conformational changes in virus spike glycoprotein that are associated with virus entry, or combinations thereof. In another aspect, there is provided a pharmaceutical composition comprising: an effective amount of the compound of the following formula or a pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof: (I), wherein R ¹ is monocyclic or bicyclic cycloalkyl, aryl, heteroaryl or combinations thereof, any of which may have one more or substituents, typically R ¹ may be a five or six membered cycloalkyl or heteroaryl, optionally having one or more substituents, wherein any such monocyclic or bicyclic cycloalkyl, aryl, heteroaryl or combination thereof may be directly connected to the remaining compound (I) or connected via an alkyl linker such as -CH ₂ - or -CH ₂ (CH ₂ )-; R ^1’ is nitrile (CN); R ^1a is absent, hydrogen, deuterium or C _1-6 alkyl (suitably R ^1a may be hydrogen or methyl); R ² is hydrogen or R ² and R ⁶ taken together with the nitrogen and carbon atoms to which they are attached form a pyrrolidine or piperidine ring, which is optionally substituted with one to four R ^2a ; R ^2a at each occurrence may be independently selected from the group consisting of fluoro, hydroxy, C ₁ -C ₆ alkyl optionally substituted with one to three fluoro, and C ₁ -C ₆ alkoxy optionally substituted with one to three fluoro; or two R ^2a groups when attached to adjacent carbons and taken together with the carbons to which they are attached form a fused C ₃ -C ₆ cycloalkyl which is optionally substituted with one to four R ^2b ; or two R ^2a groups when attached to the same carbon and taken together with the carbon to which they are attached form a spiro C ₃ -C ₆ cycloalkyl which is optionally substituted with one to four R ^2b ; R ^2b at each occurrence is optionally independently selected from fluoro, hydroxy, C ₁ -C ₃ alkyl optionally independently substituted with one to three fluoro or hydroxy, and C ₁ -C ₃ alkoxy optionally independently substituted with one to three fluoro or hydroxy; R ³ is selected from the group consisting of C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, (C ₁ -C ₆ alkoxy)-C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, aryl, heteroaryl optionally fused with a 5- or 6-membered heteroaryl or phenyl, (C ₃ - C ₁₂ cycloalkyl)-C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkoxy, (C ₃ -C ₁₂ cycloalkoxy)-C ₁ -C ₆ alkyl, 4- to 12-membered heterocycloalkyl which is optionally fused with a 5- to 6-membered heteroaryl or phenyl and wherein said heterocycloalkyl comprises one to four heteroatoms independently selected from N, O and S(O)n; (4- to 12-membered heterocycloalkyl)-C ₁ -C ₆ alkyl wherein said heterocycloalkyl moiety comprises one to four heteroatoms independently selected from N, O and S(O)n; C ₆ -C ₁₀ aryl optionally fused with a C ₄ -C ₆ cycloalkyl or a 4- to 7-membered heterocycloalkyl; (C ₆ -C ₁₀ aryl)-C ₁ -C ₆ alkyl; 5- to 10-membered heteroaryl comprising one to five heteroatoms independently selected from N, O and S, which is optionally fused with a C ₅ -C ₆ cycloalkyl; (5- to 10-membered heteroaryl)-C ₁ -C ₆ alkyl wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S; (C ₆ - C ₁₀ aryl)-(5- to 10-membered heteroaryl)- wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S, (5- to 10-membered heteroaryloxy)-C ₁ -C ₆ alkyl wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S; (5- to 6-membered heteroaryl)-(5- to 6-membered heteroaryl)- wherein each heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; (4- to 7-membered heterocycloalkyl)-(5- to 6-membered heteroaryl)- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n and the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; (5- to 6-membered heteroaryl)-(4- to 7-membered heterocycloalkyl)- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n and the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; wherein each R ³ group is optionally substituted with one to five R ⁴ ; and n at each occurrence is independently selected from 0, 1 and 2; R ⁴ at each occurrence may be independently selected from the group consisting of oxo, halo, hydroxy, cyano, phenyl, benzyl, amino, (C ₁ -C ₆ alkyl)amino optionally substituted with one to five fluoro, di(C ₁ -C ₆ alkyl)amino optionally substituted with one to ten fluoro, C ₁ -C ₆ alkyl optionally substituted with one to five fluoro, (5- to 6-membered heteroaryl)amino- wherein the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; (4- to 7-membered heterocycloalkyl)amino- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n; C ₁ -C ₆ alkoxy optionally substituted with one to five fluoro; C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl optionally substituted with one to five fluoro; C ₃ -C ₆ cycloalkyl optionally substituted with one to three fluoro or C ₁ -C ₃ alkyl; C ₁ -C ₆ alkyl-C(O)NH- optionally substituted with one to five fluoro; C ₁ -C ₆ alkyl-OC(O)NH- optionally substituted with one to five fluoro or with one R ⁵ ; C ₁ - C ₆ alkyl-NHC(O)NH- optionally substituted with one to five fluoro or with one R ⁵ ; C ₁ -C ₆ alkyl-S(O) ₂ NH- optionally substituted with one to five fluoro or with one R ⁵ ; C ₁ -C ₆ alkyl-C(O)- optionally substituted with one to five fluoro or with one R ⁵ ; C ₁ -C ₆ alkyl-S(O)n- optionally substituted with one to five fluoro or with one R ⁵ ; and n at each occurrence is independently selected from 0, 1 and 2; R ⁵ is selected from phenyl, phenoxy, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkoxy, 4- to 7- membered heterocycloalkyl wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n, or a 5- or 6-membered heteroaryl wherein the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; wherein each R ⁵ is optionally independently substituted with one to three halo, C ₁ -C ₃ alkyl and C ₁ -C ₃ alkoxy; and n at each occurrence is independently selected from 0, 1 and 2. In embodiments, R ¹ is selected from any one of the following structures:

In embodiments, R ¹ is isoquinoline, quinoline, CH ₂ -δ-lactam, CH ₂ -γ-lactam or CH ₂ -pyridine. In a further embodiment, wherein R ³ is selected from any one of the following structures:

. In some particular embodiments, R ³ may have the following structure: wherein R ⁷ is aryl or heteroaryl; and R ⁸ is independently from R ⁷ selected from the group consisting of: C _1-6 alkyl or C _3-6 cycloalkyl optionally comprising one or more heteroatoms, such as N, O and S; particularly N or O; more particularly N. In embodiments, R ³ is selected from one of the following structures: In another embodiment, R ⁶ and R ² together with the nitrogen and carbon respectively to which they attach, form one of the following structures:

In embodiments, R ⁶ and R ² together with the nitrogen and carbon to which they are attached may form one of the following structures: In embodiments, R ^1’ is nitrile. In another embodiment, the compound of formula (I) has the following structures: wherein R ¹ is selected from the group consisting of monocyclic or bicyclic cycloalkyl, aryl, heteroaryl or combinations thereof, as described above. The pharmaceutically acceptable carrier may be selected from one or more diluent, adjuvant, excipient or vehicle; e.g. an adjuvant may be alum (aluminium hydroxide). In embodiments, the pharmaceutical composition is for use in the treatment or prevention of a viral infection. Typically, the viral infection is coronavirus and especially the viral infection is SARS-CoV-2 (COVID-19). In embodiments, the viral infection may be selected from any coronavirus, such as SARS, MERS, SARS-CoV-2 (COVID-19) or combinations thereof. In embodiments, the pharmaceutical composition is for use in a method comprising administering a pharmaceutical composition comprising a compound of formula (I). In various embodiments of this aspect, the use of the pharmaceutical composition may be in a method comprising administering the pharmaceutical composition comprising a compound according to formula (I) in combination with one or more additional therapeutic agent. Suitably, the administering of the pharmaceutical composition comprising a compound according to formula (I) may be performed simultaneously, sequentially or separately from the one or more additional therapeutic agent. Typically, the one or more additional therapeutic agent is selected from at least one additional antiviral agent. The at least one additional antiviral agent may especially be selected from an inhibitor of viral RNA-dependent RNA polymerase, an inhibitor of virus-encoded protease that affects processing of a viral RNA-dependent RNA polymerase, an inhibitor of coronavirus binding or release from infected cells, an inhibitor of virus binding to a specific cell surface receptor, an inhibitor of receptor-induced conformational changes in virus spike glycoprotein that are associated with virus entry, or combinations thereof. In embodiments the pharmaceutical composition is adapted for administration by a route selected from oral, topical, inhalation, intranasal, or systemically by intravenous, intraperitoneal, subcutaneous, or intramuscular injection. According to another aspect, a method is provided for inhibiting or preventing coronavirus infection such as infection of COVID-19, the method comprising administering a compound according to formula (I) to a subject and/or a cell capable of being infected with or already infected with coronavirus. In another aspect, a compound according to formula (I) provided for use in inhibiting or preventing coronavirus infection coronavirus, wherein the use is in a method comprising administering the compound to a subject and/or a cell capable of being infected with or already infected with coronavirus. Within these aspects, the various features of the compounds, uses and methods set out in relation to any of the above aspects may equally be incorporated within these aspects of the invention. Within the scope of this disclosure it is expressly intended that the various aspects, embodiments, examples and alternatives set out in the preceding paragraphs, in the claims and/or in the following description and drawings, and in particular the individual features thereof, may be taken independently or in any combination. That is, all embodiments and/or features of any embodiment can be combined in any way and/or combination, unless such features are incompatible. More particularly, it is specifically intended that any embodiment of any aspect may form an embodiment of any other aspect, and all such combinations are encompassed within the scope of the invention. The applicant reserves the right to change any originally filed claim or file any new claim accordingly, including the right to amend any originally filed claim to depend from and/or incorporate any feature of any other claim although not originally claimed in that manner. BRIEF DESCRIPTION OF THE DRAWINGS One or more embodiments of the invention will now be described, by way of example only, with reference to the accompanying drawings, in which: Figure 1 is a schematic representation showing COVID-19 viral entry and replication in the cell. One or more embodiments of the invention will now be described, by way of example only, with reference to the accompanying drawings, in which: DETAILED DESCRIPTION Described herein are compounds and compositions (e.g. organic molecules, research tools, pharmaceutical formulations and therapeutics); uses for the compounds and compositions of the invention (in vitro and in vivo); as well as corresponding methods, whether diagnostic, therapeutic or for research applications. The chemical synthesis and biological testing of the compounds of the invention are also described. Beneficially, the compounds, compositions, uses and methods have utility in research towards and/or the treatment of diseases in animals, such as humans. The diseases are in particular viral infections, such as caused by coronavirus, and more specifically COVID-19. However, the compounds may also or alternatively be useful as lead molecules for the selection, screening and development of further derivatives that may have one or more improved beneficial drug property, as desired. Such further selection and screening may be carried out using the proprietary computational evolutionary algorithm described e.g. in the Applicant’s earlier published patent application WO 2011/061548, which is hereby incorporated by reference in its entirety. The compounds of the invention are advantageously amide derivatives. The invention also encompasses salts, solvates, tautomers, enantiomers and functional derivatives of the compounds of the invention. The compounds are described for use in the treatment of viral infections such as coronavirus and more specifically COVID-19. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art (e.g. in organic, physical or theoretical chemistry; biochemistry and molecular biology). Unless otherwise indicated, the practice of the present invention employs conventional techniques in chemistry and chemical methods, biochemistry, molecular biology, pharmaceutical formulation, and delivery and treatment regimens for patients, which are within the capabilities of a person of ordinary skill in the art. Such techniques are also described in the literature cited herein, each of which is herein incorporated by reference in its entirety. Prior to setting forth the detailed description of the invention, a number of definitions are provided that will assist in the understanding of the invention. In accordance with the invention, the terms 'molecule' or 'molecules’ are used interchangeably with the terms 'compound' or ‘compounds’, and sometimes the term 'chemical structure'. The term 'drug' is typically used in the context of a pharmaceutical, pharmaceutical composition, medicament or the like, which has a known or predicted physiological or in vitro activity of medical significance; but such characteristics and qualities are not excluded in a molecule or compound of the invention. The term 'drug' is therefore used interchangeably with the alternatives terms and phrases 'therapeutic (agent)', 'pharmaceutical (agent)', and 'active (agent)'. Therapeutics of the invention also encompass compositions and pharmaceutical formulations comprising the compounds of the invention. Such a compound or molecule as disclosed herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopically enriched variants of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified. The term “tautomer,” as used herein refers to compounds whose structures differ markedly in arrangement of atoms, but which exist in easy and rapid equilibrium, and it is to be understood that compounds provided herein may be depicted as different tautomers, and when compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the disclosure, and the naming of the compounds does not exclude any tautomer. It will be appreciated that certain compounds provided herein may contain one or more centres of asymmetry and may therefore be prepared and isolated in a mixture of isomers such as a racemic mixture, or in an enantiomerically pure form. Compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. That is, an atom, in particular when mentioned in relation to a compound according to Formula (I) or (II), comprises all isotopes and isotopic mixtures of that atom, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. For example, when hydrogen is mentioned, it is understood to refer to ¹ H, ² H, ³ H or mixtures thereof; when carbon is mentioned, it is understood to refer to ¹¹ C, ¹² C, ¹³ C, ¹⁴ C or mixtures thereof; when nitrogen is mentioned, it is understood to refer to ¹³ N, ¹⁴ N, ¹⁵ N or mixtures thereof; when oxygen is mentioned, it is understood to refer to ¹⁴ O, ¹⁵ O, ¹⁶ O, ¹⁷ O, ¹⁸ O or mixtures thereof; and when fluoro is mentioned, it is understood to refer to ¹⁸ F, ¹⁹ F or mixtures thereof; unless expressly noted otherwise. For example, in deuteroalkyl and deuteroalkoxy groups, where one or more hydrogen atoms are specifically replaced with deuterium ( ² H). As some of the aforementioned isotopes are radioactive, the compounds provided herein therefore also comprise compounds with one or more isotopes of one or more atoms, and mixtures thereof, including radioactive compounds, wherein one or more non- radioactive atoms has been replaced by one of its radioactive enriched isotopes. Radiolabelled compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure. In particular, the term ‘deuterium’ as used herein refers to an isotope of hydrogen that has one proton and one neutron in its nucleus and that has twice the mass of ordinary hydrogen. Deuterium herein is represented by the symbol ‘D’. The term ‘deuterated’ by itself or used to modify a compound or group as used herein refers to the presence of at least one deuterium atom attached to carbon. For example, the term ‘deuterated compound’ refers to a compound which contains one or more carbon-bound deuterium(s). In a deuterated compound of the present disclosure, when a particular position is designated as having deuterium, it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.015%. The term ‘undeuterated’ or ‘non-deuterated’ as used herein refers to the ratio of deuterium atoms of which is not more than the natural isotopic deuterium content, which is about 0.015%; in other words, all hydrogen are present at their natural isotopic percentages. Unless otherwise stated, when a position is designated specifically as ‘H’ or ‘hydrogen’, the position is understood to have hydrogen at its natural abundance isotopic composition. Prodrugs and solvates of the compounds of the invention are also encompassed within the scope of the invention. The term 'prodrug' means a compound (e.g. a drug precursor) that is transformed in vivo to yield a compound of the invention or a pharmaceutically acceptable salt, solvate or ester of the compound. The transformation may occur by various mechanisms (e.g. by metabolic or chemical processes), such as by hydrolysis of a hydrolysable bond, e.g. in blood (see Higuchi & Stella (1987), "Pro-drugs as Novel Delivery Systems", vol. 14 of the A.C.S. Symposium Series; (1987), "Bioreversible Carriers in Drug Design", Roche, ed., American Pharmaceutical Association and Pergamon Press). The compositions and medicaments of the invention therefore may comprise prodrugs of the compounds of the invention. In some aspects and embodiments, the compounds of the disclosure are themselves prodrugs which may be metabolised in vivo to give the therapeutically effective compound. For example, a sulfoxide prodrug may be metabolized in vivo to the therapeutically active sulfone (see Basarab G.S. et al., (2008), Bioorg Med Chem Lett, 18(16),4716-4722; Gibhard L. et al., (2008), Antimicrobial Agents and Chemotherapy, 62(12),00261-18). In the context of the present disclosure, the terms 'individual', 'subject', or 'patient' are used interchangeably to indicate an animal that may be suffering from a medical (pathological) condition and may be responsive to a molecule, pharmaceutical drug, medical treatment or therapeutic treatment regimen of the disclosure. The animal is suitably a mammal, such as a human, cow, sheep, pig, dog, cat, bat, mouse or rat. In particular, the subject may be a human. As used herein, terms ‘treat’ or ‘treatment’ refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. ‘Treatment’ can also mean prolonging survival as compared to expected survival if not receiving treatment The term ‘preventing’ as used herein means the prevention of the onset, recurrence or spread, in whole or in part, of the disease or condition as described herein, or a symptom thereof. The term ‘alkyl’ refers to a monovalent, optionally substituted, saturated aliphatic hydrocarbon radical. Any number of carbon atoms may be present, but typically the number of carbon atoms in the alkyl group may be from 1 to about 20, from 1 to about 12, from 1 to about 6 or from 1 to about 4. Usefully, the number of carbon atoms is indicated, for example, a C1-12 alkyl (or C _1-12 alkyl) refers to any alkyl group containing 1 to 12 carbon atoms in the chain. An alkyl group may be a straight chain (i.e. linear), branched chain, or cyclic. ‘Lower alkyl’ refers to an alkyl of 1 to 6 carbon atoms in the chain, and may have from 1 to 4 carbon atoms, or 1 to 2 carbon atoms. Thus, representative examples of lower alkyl radicals include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, isopentyl, amyl (C5H11), sec-butyl, tert-butyl, sec-amyl, tert-pentyl, 2-ethylbutyl, 2,3-dimethylbutyl, and the like. ‘Higher alkyl’ refers to alkyls of 7 carbons and above, including n-heptyl, n-octyl, n-nonyl, n-decyl, n-dodecyl, n- tetradecyl, n-hexadecyl, n-octadecyl, n-eicosyl, and the like, along with branched variations thereof. A linear carbon chain of say 4 to 6 carbons would refer to the chain length not including any carbons residing on a branch, whereas in a branched chain it would refer to the total number. Optional substituents for alkyl and other groups are described below. The term ‘substituted’ means that one or more hydrogen atoms (attached to a carbon or heteroatom) is replaced with a selection from the indicated group of substituents, provided that the designated atom's normal valency under the existing circumstances is not exceeded. The group may be optionally substituted with particular substituents at positions that do not significantly interfere with the preparation of compounds falling within the scope of this invention and on the understanding that the substitution(s) does not significantly adversely affect the biological activity or structural stability of the compound. Combinations of substituents are permissible only if such combinations result in stable compounds. By ‘stable compound’ or ‘stable structure’, it is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and/or formulation into an efficacious therapeutic agent. By ‘optionally substituted’ it is meant that the group concerned is either unsubstituted, or at least one hydrogen atom is replaced with one of the specified substituent groups, radicals or moieties. Any radical / group / moiety described herein that may be substituted (or optionally substituted) may be substituted with one or more (e.g. one, two, three, four or five) substituents, which are independently selected from the designated group of substituents. Thus, substituents may be selected from the group: halogen (or ‘halo’, e.g. F, Cl and Br), hydroxyl (-OH), amino (-NH ₂ ), thiol (-SH), cyano (-CN), (lower) alkyl, (lower) alkoxy, (lower) alkenyl, (lower) alkynyl, aryl, heteroaryl, (lower) alkylthio, oxo, haloalkyl, hydroxyalkyl, nitro (-NO ₂ ), phosphate, azido (-N ₃ ), alkoxycarbonyl, carboxy, alkylcarboxy, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, thioalkyl, alkylsulfonyl, arylsulfinyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino, arylcarbonylamino, cycloalkyl, heterocycloalkyl, unless otherwise indicated. Alternatively, where the substituents are on an aryl or other cyclic ring system, two adjacent atoms may be substituted with a methylenedioxy or ethylenedioxy group. More suitably, the substituents are selected from: halogen, hydroxy, amino, thiol, cyano, (C ₁ - C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )alkenyl, (C ₁ -C ₆ )alkynyl, aryl, aryl(C ₁ -C ₆ )alkyl, aryl(C ₁ -C ₆ )alkoxy, heteroaryl, (C ₁ -C ₆ )alkylthio, oxo, halo(C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkyl, nitro, phosphate, azido, (C ₁ - C ₆ )alkoxycarbonyl, carboxy, (C ₁ -C ₆ )alkylcarboxy, (C ₁ -C ₆ )alkylamino, di(C ₁ -C ₆ )alkylamino, amino(C ₁ - C ₆ )alkyl, (C ₁ -C ₆ )alkylamino(C ₁ -C ₆ )alkyl, di(C ₁ -C ₆ )alkylamino(C ₁ -C ₆ )alkyl, thio(C ₁ -C ₆ )alkyl, (C ₁ - C ₆ )alkylsulfonyl, arylsulfinyl, (C ₁ -C ₆ )alkylaminosulfonyl, arylaminosulfonyl, (C ₁ -C ₆ )alkylsulfonylamino, arylsulfonylamino, carbamoyl, (C ₁ -C ₆ )alkylcarbamoyl, di(C ₁ -C ₆ )alkylcarbamoyl, arylcarbamoyl, (C ₁ - C ₆ )alkylcarbonylamino, arylcarbonylamino, (C ₁ -C ₆ )cycloalkyl, and heterocycloalkyl. Still more suitably, the substituents are selected from one or more of: fluoro, chloro, bromo, hydroxy, (C ₁ -C ₆ )alkyl, (C ₁ - C ₆ )haloalkyl, (C ₁ -C ₆ )alkoxy, (C ₅ -C ₆ )aryl, a 5- or 6-membered heteroaryl, (C ₄ -C ₆ )cycloalkyl, a 4- to 6- membered heterocycloalkyl, cyano, (C ₁ -C ₆ )alkylthio, amino, -NH(alkyl), -NH((C ₁ -C ₆ )cycloalkyl), -N((C ₁ - C ₆ )alkyl)2, -OC(O)-(C ₁ -C ₆ )alkyl, -OC(O)-(C ₅ -C ₆ )aryl, -OC(O)-(C ₁ -C ₆ )cycloalkyl, carboxy and -C(O)O- (C ₁ -C ₆ )alkyl. Most suitably, the substituents are selected from one or more of: fluoro, chloro, bromo, hydroxy, amino, (C ₁ -C ₆ )alkyl and (C ₁ -C ₆ )alkoxy, wherein alkyl and alkoxy are optionally substituted by one or more chloro. Particularly preferred substituents are: chloro, methyl, ethyl, methoxy and ethoxy. As used herein, the term “cyano” refers to a –CN radical. As used herein, the term “hydroxyl” refers to an –OH radical. As used herein, the term “amino” refers to an –NH ₂ group. As used herein, the term “oxo” refers to an “=O” group attached to a carbon atom. The term ‘halo’ refers to a monovalent halogen radical chosen from chloro, bromo, iodo, and fluoro. A ‘halogenated’ compound is one substituted with one or more halo substituent. Particular halo groups are F, Cl and Br; and most particularly are F or Cl. In some preferred embodiments the halo group is F. The term ‘C ₁ -C ₆ haloalkyl’ refers to a hydrocarbon chain substituted with at least one halogen atom independently chosen at each occurrence, for example fluorine, chlorine, bromine and iodine. The halogen atom may be present at any position on the hydrocarbon chain. Similarly, a C1-C3 haloalkyl group is linear or branched hydrocarbon chain containing 1, 2, or 3 carbon atoms substituted with at least one halogen atom. For example, C ₁ -C ₃ haloalkyl may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl e.g. 1-chloroethyl and 2-chloroethyl, trichloroethyl e.g.1,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl e.g.1-fluoromethyl and 2- fluoroethyl, trifluoroethyl e.g. 1,2,2- trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl. As used herein, the term ‘geminal’ refers to substituent atoms or groups attached to the same atom in a molecule. As used herein, the term ‘vicinal’ refers to substituent atoms or groups attached to adjacent atoms in a molecule. The stereochemical relationship between the substituent atoms or groups can be cis, trans, undefined, or unresolved. When used herein, the term ‘independently’, in reference to the substitution of a parent moiety with one or more substituents, means that the parent moiety may be substituted with any of the listed substituents, either individually or in combination, and any number of chemically possible substituents may be used. In any of the embodiments, where a group is substituted, it may contain up to 5, up to 4, up to 3, or 1 and 2 substituents. As a non-limiting example, useful substituents include: phenyl or pyridine, independently substituted with one or more lower alkyl, lower alkoxy or halo substituents, such as: chlorophenyl, dichlorophenyl, trichlorophenyl, tolyl, xylyl, 2-chloro-3-methylphenyl, 2,3-dichloro- 4- methylphenyl, etc. "Alkylene" or "alkylenyl" means a difunctional group obtained by removal of a hydrogen atom from an alkyl group as defined above. Non-limiting examples of alkylene include methylene, ethylene and propylene. ‘Lower alkylene’ means an alkylene having from 1 to 6 carbon atoms in the chain, and may be straight or branched. Alkylene groups are optionally substituted. Preferred alkylene groups are - (CR ₂ ) _n - where n is from 1 to 6, and R is independent selected from H, F, Cl, NH ₂ or wherein R ₂ is =O. More preferably, n is 1, 2 or 3 and R is H. Most preferable alkylene groups are -(CH ₂ ) ₂ - and -CH ₂ -CO- . The term ‘alkenyl’ refers to a monovalent, optionally substituted, unsaturated aliphatic hydrocarbon radical. Therefore, an alkenyl has at least one carbon-carbon double bond (C=C). The number of carbon atoms in the alkenyl group may be indicated, such as from 2 to about 20. For example, a C2- 12 alkenyl (or C _2-12 alkenyl) refers to an alkenyl group containing 2 to 12 carbon atoms in the structure. Alkenyl groups may be straight (i.e. linear), branched chain, or cyclic. ‘Lower alkenyl’ refers to an alkenyl of 1 to 6 carbon atoms, and may have from 1 to 4 carbon atoms, or 1 to 2 carbon atoms. Representative examples of lower alkenyl radicals include ethenyl, 1-propenyl, 1-butenyl, 1-pentenyl, 1-hexenyl, isopropenyl, isobutenyl, and the like. Higher alkenyl refers to alkenyls of seven carbons and above, such as 1-heptenyl, 1-octenyl, 1-nonenyl, 1-decenyl, 1-dodecenyl, 1-tetradecenyl, 1- hexadecenyl, 1-octadecenyl, 1-eicosenyl, and the like, along with branched variations thereof. Optional substituents include are described elsewhere. ‘Alkenylene’ means a difunctional group obtained by removal of a hydrogen from an alkenyl group that is defined above. Non-limiting examples of alkenylene include -CH=CH-, -C(CH ₃ )=CH-, and - CH=CHCH ₂ -. ‘Alkynyl’ and ‘lower alkynyl’ is defined similarly to the term ‘alkenyl’, except that it includes at least one carbon-carbon triple bond. The term ‘alkoxy’ refers to a monovalent radical of the formula RO-, where R is any alkyl, alkenyl or alkynyl as defined herein. Alkoxy groups may be optionally substituted by any of the optional substituents described herein. ‘Lower alkoxy’ has the formula RO-, where the R group is a lower alkyl, alkenyl or alkynyl. Representative alkoxy radicals include methoxy, ethoxy, n-propoxy, n-butoxy, n- pentyloxy, n-hexyloxy, isopropoxy, isobutoxy, isopentyloxy, amyloxy, sec-butoxy, tert-butoxy, tert- pentyloxy, and the like. Preferred alkoxy groups are methoxy and ethoxy. The term ‘aryl’ as used herein refers to a substituted or unsubstituted aromatic carbocyclic radical containing from 5 to about 15 carbon atoms; and preferably 5 or 6 carbon atoms. An aryl group may have only one individual carbon ring, or may comprise one or more fused rings in which at least one ring is aromatic in nature. A ‘phenyl’ is a radical formed by removal of a hydrogen atom from a benzene ring, and may be substituted or unsubstituted. A ‘phenoxy’ group, therefore, is a radical of the formula RO-, wherein R is a phenyl radical. ‘Benzyl’ is a radical of the formula R-CH ₂ -, wherein R is phenyl, and ‘benzyloxy’ is a radical of the formula RO-, wherein R is benzyl. Non-limiting examples of aryl radicals include, phenyl, naphthyl, benzyl, biphenyl, furanyl, pyridinyl, indanyl, anthraquinolyl, tetrahydronaphthyl, a benzoic acid radical, a furan-2-carboxylic acid radical, and the like. A ‘heteroaryl’ group is herein defined as a substituted or unsubstituted ‘aryl’ group in which one or more carbon atoms in the ring structure has been replaced with a heteroatom, such as nitrogen, oxygen or sulphur. Generally, the heteroaryl group contains one or two heteroatoms selected from N, O and S. Particularly suitable heteroatoms are N and O; and a preferred heteroatom is N. A heteroaryl group may have only one ring, or may comprise one or more fused rings in which at least one ring contains at least one heteroatom. Exemplary heteroaryl groups include: furan, benzofuran, isobenzofuran, pyrrole, indole, isoindole, thiophene, benzothiophene, benzo[c]thiophene, imidazole, benzimidazole, purine, pyrazole, indazole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, pyridine, quinoline, isoquinoline, pyrazine, quinoxaline, acridine, pyrimidine, quinazoline, pyridazine and cinnoline. Heteroaryl groups include as described herein comprise but are not limited to thienyl (thiophenyl), benzo[b]thienyl, naphtho[2,3- b]thienyl, thianthrenyl, furyl (furanyl), isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, including without limitation 2H-pyrrolyl, imidazolyl, pyrazolyl, pyridyl (pyridinyl), including without limitation 2-pyridyl, 3-pyridyl, and 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalzinyl, naphthyridinyl, quinozalinyl, cinnolinyl, pteridinyl, carbazolyl, b-carbolinyl, phenanthridinyl, acrindinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, thaizolyl, isothiazolyl, phenothiazinyl, oxazolyl, isoxazolyl, furazanyl, phenoxazinyl, 1,4- dihydroquinoxaline-2,3-dione, 7- aminoisocoumarin, pyrido[1,2-a]pyrimidin-4-one, pyrazolo[1,5- a]pyrimidinyl, including without limitation pyrazolo[1,5-a]pyrimidin-3-yl, 1,2-benzoisoxazol-3- yl, benzimidazolyl, 2-oxindolyl and 2- oxobenzimidazoly, oxadiazolyl, and thiadiazolyl. Where the heteroaryl group contains a nitrogen atom in a ring, such nitrogen atom may be in the form of an N-oxide, e.g., a pyridyl N-oxide, pyrazinyl N-oxide and pyrimidinyl N-oxide. The terms ‘heterocycle’ or ‘heterocyclic’ group as used herein refer to a monovalent radical of from about 4- to about 15- ring atoms, and preferably 4-, 5- or 6- ring members. Generally, the heterocyclic group contains one, two or three heteroatoms, selected independently from nitrogen, oxygen and sulphur. Particularly suitable heteroatoms are N and O; and a preferred heteroatom is N. A heterocyclic group may have only one individual ring, or may comprise one or more fused rings in which at least one ring contains a heteroatom. It may be fully saturated or partially saturated, and may be substituted or unsubstituted as in the case or aryl and heteroaryl groups. Representative examples of unsaturated 5- membered heterocycles with only one heteroatom include 2- or 3-pyrrolyl, 2- or 3-furanyl, and 2- or 3- thiophenyl. Corresponding partially saturated or fully saturated radicals include 3-pyrrolin-2-yl, 2- or 3- pyrrolindinyl, 2- or 3-tetrahydrofuranyl, and 2- or 3-tetrahydrothiophenyl. Representative unsaturated 5-membered heterocyclic radicals having two heteroatoms include imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and the like. The corresponding fully saturated and partially saturated radicals are also included. Representative examples of unsaturated 6-membered heterocycles with only one heteroatom include 2-, 3-, or 4-pyridinyl, 2H-pyranyl, and 4H-pryanyl. Corresponding partially saturated or fully saturated radicals include 2-, 3-, or 4-piperidinyl, 2-, 3-, or 4-tetrahydropyranyl and the like. Representative unsaturated 6-membered heterocyclic radicals having two heteroatoms include 3- or 4- pyridazinyl, 2-, 4-, or 5-pyrimidinyl, 2-pyrazinyl, morpholino, and the like. The corresponding fully saturated and partially saturated radicals are also included, e.g.2-piperazine. The heterocyclic radical is bonded through an available carbon atom or heteroatom in the heterocyclic ring directly to the entity or through a linker such as an alkylene such as methylene or ethylene. The disclosure encompasses fused ring systems, for example, ‘bicyclic’ or ‘tricyclic’ ring systems. In the context of the present disclosure, it is specifically intended that a fused ring system may include more than one fused aromatic ring, more than one fused non-aromatic / aliphatic ring, or one or more aromatic ring fused to one or more non-aromatic / aliphatic ring, such as a fusion of an aryl group with a cycloalkyl (or cycloalkenyl) group. Furthermore, it is intended that a fused ring system termed a bicyclic (or tricyclic) aryl is attached to the associated molecule via an aryl group, whereas a bicyclic (or tricyclic) cycloalkyl / cycloalkoxyl is attached to the associated molecule via the cycloalkyl / cycloalkoxyl group. Similarly, in the context of fused ring systems, it is specifically intended that a bicyclic (or tricyclic) heteroaryl or heterocycloalkyl / heterocycloalkenyl need not contain heteroatoms in each of the fused ring systems. Rather, a bicyclic of tricyclic heteroaryl group may have one or more heteroatoms in any ring of the fused ring system, and not necessarily in the aryl ring that is the point of attachment to the associated molecule. Likewise, a bicyclic of tricyclic heterocycloalkyl or heterocycloalkenyl group may have one or more heteroatoms in any ring of the fused ring system, and not necessarily in the heterocycloalkyl or heterocycloalkenyl ring that is the point of attachment to the associated molecule. The term ‘pharmaceutically acceptable’ indicates that the compound, or salt or composition thereof is compatible chemically and/or toxicologically with the other ingredients comprising a formulation and/or the subject being treated therewith. Unless defined otherwise, ‘room temperature’ is intended to mean a temperature of from about 18 to 28°C, typically between about 18 and 25°C, and more typically between about 18 and 22°C. As used herein, the phrase ‘room temperature’ may be shortened to ‘rt’ or ‘RT’. Coronavirus as a drug target Figure 1 is a schematic drawing showing viral entry and replication in a host mammalian cell, providing an overview of potential therapeutic targets for novel drug discovery. Figure 1 shows the spike protein of a coronavirus in complex with Angiotensin-converting enzyme 2 (ACE2), which is believed to be a vital interaction for viral entry into the host cell. Without wishing to be bound by theory, similarly to that which has been observed with respect to the SARS coronavirus, COVID-19 viral infection likely begins when the virus-surface spike protein mediates the entry of coronavirus into host cells. The spike protein contains a receptor binding domain that specifically recognises the ACE2 receptor on the surface of, for example, human cells (Shang, J., Ye, G., Shi, K. et al. (2020), Nature, ‘Structural basis of receptor recognition by SARS-CoV-2). Once the viral genomic material has been endocytosed into the cytoplasm of the host cell through the SPIKE-ACE2 receptor interaction, the host ribosome translates the viral genome and forms a long polyprotein which contains its own proteases, such as M ^pro (C ₃ L ^Pro ) and Papain-like protease (PL ^pro ), which each exhibit different substrate specificity. These proteases cleave the polyprotein into multiple non-structural protein molecules including RNA- dependent RNA polymerase (RdRp, RNA Pol) which is directly involved in the replication and transcription of viral RNA and, therefore, the correct synthesis of this protein is crucial for viral replication. The spike protein, as well as viral proteases and RNA polymerase as shown in Figure 1, all represent potential targets for drug discovery. Molecules and Compounds Disclosed herein is an antiviral compound according to the invention having the structural Formula (I) including any diastereomers and enantiomers, or a pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof: The compound of the Formula (I) is described for use in the treatment of infections caused by viruses. The virus is suitably coronavirus such as SARS, MERS, 229E, OC43, HKU1, NL63 and SARS-CoV-2 (COVID-19) or combinations or two, three, four or more thereof. Beneficially, the compounds and compositions of the disclosure are suitable for treatment of a viral infection caused by COVID-19, and are particularly useful due to their broad spectrum activity (e.g. as ). In embodiments, the compound of Formula (I) is not a compound selected from: CPD0077063, CPD0084200, CPD0084205, CPD0084207, CPD0084208, CPD0084209, CPD0084210, CPD0084211, CPD0084212, CPD0084215, CPD0084216, CPD0084217, CPD0084221, CPD0084228, CPD0084231, CPD0084235, CPD0084242, CPD0084248, CPD0084249, CPD0084250, CPD0084252, CPD0084253, CPD0084254, CPD0084301, CPD0084531, CPD0084769, CPD0186407, CPD0186408, CPD0186409, CPD0186410, CPD0186412, CPD0186526, CPD0186529, CPD0186530, CPD0187053, CPD0187106, CPD0187107, CPD0187510, CPD0188058, CPD188059 and CPD0188163. R ¹ may be monocyclic or bicyclic cycloalkyl, heterocycloalkyl, aryl, heteroaryl or combinations thereof, any of which may have one more or substituents, wherein any such monocyclic or bicyclic cycloalkyl, aryl, heteroaryl or combination thereof may be directly connected to the remaining compound (I) or connected via a C ₁ -C ₃ alkylene linker, wherein the alkylene linker may optionally be substituted with one to three R ⁹ . Suitably, R ¹ may be selected from the following monocyclic or bicyclic cycloalkyl, aryl, heteroaryl structures: pyridine, cyclohexyl, cyclopentyl, δ-lactone, cyclobutyl optionally fused to phenyl, pyrazole, thiazole, triazole, pyridine, cyclopentandiene; and wherein R ¹ is optionally substituted with C ₁ -C ₃ alkyl which optionally carries one to four heteroatoms independently selected from N, O and S. R ¹ may be selected from a five or six membered cycloalkyl or heteroaryl group, which is optionally substituted with one or two R ⁹ . In various aspects and embodiments, R ¹ is not a monocyclic lactam, wherein the lactam is directly connected to the remaining compound (I) or connected to the remaining compound via a C ₁ -C ₃ alkylene linker. In various embodiments, R ¹ is not . In embodiments, R ¹ may be a bicyclic group selected from bicyclic cycloalkyl, bicyclic heterocycloalkyl, bicyclic aryl or bicyclic heteroaryl, and combinations thereof, any of which bicyclic group is optionally substituted with one or two R ⁹ . For example, R ¹ may be a bicyclic group selected from bicyclic cycloalkyl, bicyclic heterocycloalkyl, bicyclic aryl or bicyclic heteroaryl, and combinations thereof. In particular embodiments, R ¹ may be selected from any one of the following structures:

. Particularly, R ¹ may be selected from any one of the following structures:

Suitably, R ¹ may be selected from any one of the following structures:

Beneficially, R ¹ may be selected from any one of the following structures: In some embodiments, R ¹ may be selected from pyrrolidin-2-one, isoquinoline, quinoline, CH ₂ -pyridine, CH ₂ -benzo[b][1,4]oxazin-3(4H)-one, phthalazine, 4H-pyrido[1,2-a]pyrimidin-4-one and naphthyridine (e.g.1,6; 2,6; and 3,6-naphthyridine), which may be optionally substituted with one or two R ⁹ . In some embodiments, R ¹ may be selected from quinoline, CH2-pyridine, CH2-benzo[b][1,4]oxazin-3(4H)-one, phthalazine, 4H-pyrido[1,2-a]pyrimidin-4-one and naphthyridine (e.g.1,6; 2,6; and 3,6-naphthyridine), which may be optionally substituted with one or two R ⁹ . In some embodiments, R ¹ may be selected from CH ₂ -pyridine, CH ₂ -benzo[b][1,4]oxazin-3(4H)-one, phthalazine, 4H-pyrido[1,2-a]pyrimidin-4-one and naphthyridine (e.g.1,6; 2,6; and 3,6-naphthyridine), which may be optionally substituted with one or two R ⁹ . R ⁹ may be selected from the group consisting of deuterium, oxo, F, Cl, hydroxy, cyano, amino, C ₁ -C ₂ alkyl, and C ₁ -C ₂ alkyoxy. In embodiments, R ⁹ may be selected from the group consisting of deuterium, oxo, F, Cl, hydroxy, cyano, amino, methyl, and methoxy. Beneficially, R ⁹ may be selected from the group consisting of F, oxo, methyl, and methoxy. For example, R ⁹ may be fluoro; R ⁹ may be oxo; R ⁹ may be methyl; or R ⁹ may be methoxy. R ^1a may be hydrogen, deuterium or methyl. In embodiments R ^1a may particularly be hydrogen. R ² may be selected from the group consisting of hydrogen; straight or branched C ₁ -C ₆ alkyl; straight or branched C ₁ -C ₆ alkoxy; (C ₁ -C ₆ alkoxy)-C ₁ -C ₆ alkyl or (C ₁ -C ₆ alkyl)-C ₁ -C ₆ alkoxy, where each alkyl or alkoxy group may be optionally substituted with one to three fluoro, hydroxy, oxo or C ₁ -C ₃ alkoxy. In embodiments, R ² may be selected from the group consisting of hydrogen; straight or branched C ₁ - C ₃ alkyl; straight or branched C ₁ -C ₃ alkoxy; (C ₁ -C ₃ alkoxy)-C ₁ -C ₃ alkyl or (C ₁ -C ₃ alkyl)-C ₁ -C ₃ alkoxy, wherein each alkyl or alkoxy group may be optionally substituted with one to three fluoro, hydroxy or oxo. Suitably, R ² may be selected from the group consisting of hydrogen; C ₁ -C ₂ alkyl; or C ₁ -C ₂ alkoxy; wherein each alkyl or alkoxy group may be optionally substituted with one to three fluoro, hydroxy or oxo. Beneficially, R ² may be selected from the group consisting of hydrogen; methyl, ethyl, methoxy or ethoxy. In various embodiments, R ² may be hydrogen. R ⁶ may be selected from the group consisting of straight or brached C ₂ -C ₅ alkyl which is optionally substituted with a cyano or with one to three fluoro, or (C ₃ -C ₆ cycloalkyl)-C ₁ -C ₃ alkyl which is optionally substituted with one or two substituents selected from trifluoromethyl and C ₁ -C ₃ alkyl, wherein the C ₁ - C ₃ alkyl is optionally substituted with one to five fluoro. In embodiments, R ⁶ is C ₃ -C ₅ alkyl or (C ₃ -C ₅ cycloalkyl)-C ₁ -C ₂ alkyl, optionally substituted with one to three fluoro; particularly, wherein R ⁶ is selected from n-butyl, sec-butyl, iso-butyl, tert-butyl alkyl or cyclopropyl-CH2-, optionally substituted with one to three fluoro. R ² and R ⁶ taken together with the nitrogen and carbon atoms to which they are attached may form a pyrrolidine or piperidine ring, which is optionally substituted with one to three R ^2a . In embodiments, R ² and R ⁶ taken together with the nitrogen and carbon atoms to which they are attached may form a pyrrolidine or piperidine ring, which is optionally substituted with one or two R ^2a . In embodiments, R ^2a at each occurrence may be independently selected from the group consisting of fluoro, hydroxy, C ₁ -C ₆ alkyl optionally substituted with one to three fluoro, and C ₁ -C ₆ alkoxy optionally substituted with one to three fluoro. Suitably, R ^2a at each occurrence may be independently selected from the group consisting of fluoro, hydroxy, C ₁ -C ₂ alkyl optionally substituted with one to three fluoro, and C ₁ -C ₂ alkoxy optionally substituted with one to three fluoro. In various embodiments, R ^2a at each occurrence is independently selected from fluoro and methyl which is optionally substituted with one to three fluoro; preferably, R ^2a is methyl. According to various embodiments, two R ^2a groups when attached to adjacent carbon atoms and taken together with the carbon atoms to which they are attached may form a C ₃ -C ₆ cycloalkyl which is optionally substituted with one to four R ^2b , such that R ² and R ⁶ form a fused bicyclic ring. Beneficially, two R ^2a groups when attached to adjacent carbon atoms and taken together with the carbon atoms to which they are attached may form a C ₃ -C ₄ cycloalkyl which is optionally substituted with one to three R ^2b , such that R ² and R ⁶ form a fused bicyclic ring. Advantageously, two R ^2a groups when attached to adjacent carbon atoms and taken together with the carbon atoms to which they are attached form a C ₅ -C ₆ cycloalkyl which is optionally substituted with one to three R ^2b , such that R ² and R ⁶ form a fused bicyclic ring. In embodiments, two R ^2a groups when attached to the same carbon atom and taken together with the carbon atom to which they are attached may form a C ₃ -C ₆ cycloalkyl which is optionally substituted with one to four R ^2b , such that R ² and R ⁶ form a spiro bicyclic ring. Suitably, two R ^2a groups when attached to the same carbon atom and taken together with the carbon atom to which they are attached may form a C ₃ -C ₄ cycloalkyl which is optionally substituted with one to three R ^2b , such that R ² and R ⁶ form a spiro bicyclic ring. Beneficially, two R ^2a groups when attached to the same carbon atom and taken together with the carbon atom to which they are attached may form a C ₅ -C ₆ cycloalkyl which is optionally substituted with one to three R ^2b , such that R ² and R ⁶ form a spiro bicyclic ring. R ^2b at each occurrence may be optionally independently selected from fluoro, hydroxy, C ₁ -C ₂ alkyl optionally independently substituted with one to three fluoro or hydroxy, and C ₁ -C ₂ alkoxy optionally independently substituted with one to three fluoro or hydroxy. In embodiments, R ^2b at each occurrence may be optionally independently selected from fluoro and methyl which is optionally substituted with one to three fluoro or hydroxy. Suitably, R ^2b at each occurrence is methyl. In various beneficial embodiments there are two R ^2b . In embodiments, wherein there are two R ^2b , both R ^2b may be attached to the same carbon atom. In a particularly beneficial embodiment, two R ^2a may be attached to adjacent carbon atoms of a pyrrolidine or piperidine ring and are joined together to form a cyclopropyl ring; and wherein two R ^2b substituents may be attached to the same carbon atom of the cyclopropyl ring, and wherein both R ^2b substituents may be methyl. Advantageously, R ² and R ⁶ taken together form the following structure: . In embodiments, two R ^2b groups when attached to the same carbon and taken together with the carbon to which they are attached may form a C ₃ -C ₆ cycloalkyl which is optionally substituted with one to three R ⁹ . In some embodiments, two R ^2b groups when attached to the same carbon and taken together with the carbon to which they are attached may form a C ₃ -C ₄ cycloalkyl which is optionally substituted with one or two R ⁹ . R ⁹ may be selected from the group consisting of fluoro, hydroxy, C ₁ -C ₃ alkyl optionally independently substituted with one to three fluoro or hydroxy, and C ₁ -C ₃ alkoxy optionally independently substituted with one to three fluoro or hydroxy. In embodiments, R ⁹ may be selected from the group consisting of fluoro, hydroxy, C ₁ -C ₂ alkyl optionally independently substituted with one to three fluoro, and C ₁ -C ₂ alkoxy optionally independently substituted with one to three fluoro. In embodiments, R ⁹ may be fluoro. In embodiments, R ⁹ may be hydroxy. In embodiments, R ⁹ may be methyl. In embodiments, R ⁹ may be ethyl. In particular embodiments, R ⁶ and R ² together with the nitrogen and carbon respectively to which they attach may form one of the following structures: Suitably, R ⁶ and R ² together with the nitrogen and carbon respectively to which they attach may form one of the following structures:

Beneficially, R ⁶ and R ² together with the nitrogen and carbon respectively to which they attach may form one of the following structures: R ³ may be selected from the group consisting of straight or branched C ₁ -C ₈ alkyl, straight or branched C ₁ -C ₈ alkoxy, and straight or branched (C ₁ -C ₆ alkoxy)-C ₁ -C ₆ alkyl, wherein R ³ is optionally substituted with one to five R ⁴ . In embodiments, R ³ may be selected from the group consisting of straight or branched C ₁ -C ₆ alkyl, straight or branched C ₁ -C ₆ alkoxy, and straight or branched (C ₁ -C ₄ alkoxy)-C ₁ -C ₄ alkyl, wherein R ³ is optionally substituted with one to four R ⁴ . Suitably, R ³ may be selected from the group consisting of straight or branched C ₁ -C ₅ alkyl, straight or branched C ₁ -C ₅ alkoxy, and straight or branched (C ₁ -C ₃ alkoxy)-C ₁ -C ₃ alkyl, wherein R ³ is optionally substituted with one to three R ⁴ . Beneficially, R ³ may be selected from the group consisting of ethyl, straight or branched propyl (propyl, isopropyl), straight or branched butyl (n-butyl, sec-butyl, iso-butyl, tert-butyl), and straight or branched chain pentyl (n-pentyl, isopentyl, sec-isopentyl, tert-pentyl, neopentyl), wherein R ³ is optionally substituted with one to three R ⁴ . Advantageously, R ³ may be selected from the group consisting of propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, sec-isopentyl, tert-pentyl and neopentyl, wherein R ³ is optionally substituted with one to three R ⁴ . In some particular embodiments, R ³ may be selected from the group consisting of isopropyl, sec-butyl, iso-butyl, tert-butyl, isopentyl, sec-isopentyl, tert-pentyl and neopentyl optionally substituted with one to three R ⁴ . For example, R ³ may be selected from isobutyl and neopentyl optionally substituted with one to three fluoro, hydroxyl or methoxyl. In other embodiments, R ³ may be selected from the group consisting of C ₃ -C ₁₂ cycloalkyl, aryl, heteroaryl optionally fused with a 5- or 6-membered heteroaryl or phenyl, (C ₃ -C ₁₂ cycloalkyl)-C ₁ - C ₆ alkyl, C ₃ -C ₁₂ cycloalkoxy, (C ₃ -C ₁₂ cycloalkoxy)-C ₁ -C ₆ alkyl, 4- to 12-membered heterocycloalkyl which is optionally fused with a 5- to 6-membered heteroaryl or phenyl and wherein said heterocycloalkyl comprises one to four heteroatoms independently selected from N, O and S(O)n; (4- to 12-membered heterocycloalkyl)-C ₁ -C ₆ alkyl wherein said heterocycloalkyl moiety comprises one to four heteroatoms independently selected from N, O and S(O)n; C ₆ -C ₁₀ aryl optionally fused with a C4- C ₆ cycloalkyl or a 4- to 7-membered heterocycloalkyl; (C ₆ -C ₁₀ aryl)-C ₁ -C ₆ alkyl; 5- to 10-membered heteroaryl comprising one to five heteroatoms independently selected from N, O and S, which is optionally fused with a C ₅ -C ₆ cycloalkyl; (5- to 10-membered heteroaryl)-C ₁ -C ₆ alkyl wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S; (C ₆ - C ₁₀ aryl)-(5- to 10-membered heteroaryl)- wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S, (5- to 10-membered heteroaryloxy)-C ₁ -C ₆ alkyl wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S; (5- to 6-membered heteroaryl)-(5- to 6-membered heteroaryl)- wherein each heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; (4- to 7-membered heterocycloalkyl)-(5- to 6-membered heteroaryl)- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n and the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; (5- to 6-membered heteroaryl)-(4- to 7-membered heterocycloalkyl)- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n and the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; wherein each R ³ group is optionally substituted with one to five R ⁴ ; and n at each occurrence is independently selected from 0, 1 and 2. Suitably, R ³ may be selected from the group consisting of C ₃ -C ₁₀ cycloalkyl, C5-C ₁₀ aryl, 5- to 10- membered heteroaryl optionally fused with a 5- or 6-membered heteroaryl or phenyl, (C ₃ - C ₁₀ cycloalkyl)-C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkoxy, (C ₃ -C ₁₀ cycloalkoxy)-C ₁ -C ₆ alkyl, 4- to 10-membered heterocycloalkyl which is optionally fused with a 5- to 6-membered heteroaryl or phenyl and wherein said heterocycloalkyl comprises one to three heteroatoms independently selected from N, O and S(O)n; (4- to 10-membered heterocycloalkyl)-C ₁ -C ₆ alkyl wherein said heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n; C ₆ -C ₁₀ aryl optionally fused with a C ₄ -C ₆ cycloalkyl or a 4- to 7-membered heterocycloalkyl; (C ₆ -C ₁₀ aryl)-C ₁ -C ₆ alkyl; 5- to 10-membered heteroaryl comprising one to five heteroatoms independently selected from N, O and S, which is optionally fused with a C ₅ -C ₆ cycloalkyl; (5- to 10-membered heteroaryl)-C ₁ -C ₆ alkyl wherein the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; (C ₆ - C ₁₀ aryl)-(5- to 10-membered heteroaryl)- wherein the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S, (5- to 10-membered heteroaryloxy)-C ₁ -C ₆ alkyl wherein the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; (5- to 6-membered heteroaryl)-(5- to 6-membered heteroaryl)- wherein each heteroaryl moiety comprises one to three heteroatoms independently selected from N, O and S; (4- to 7-membered heterocycloalkyl)-(5- to 6-membered heteroaryl)- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n and the heteroaryl moiety comprises one to three heteroatoms independently selected from N, O and S; (5- to 6-membered heteroaryl)-(4- to 7-membered heterocycloalkyl)- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n and the heteroaryl moiety comprises one to three heteroatoms independently selected from N, O and S; wherein each R ³ group is optionally substituted with one to four R ⁴ ; and n at each occurrence is independently selected from 0 and 2. Beneficially, in such embodiments, R ³ may be selected from the group consisting of C ₃ -C ₁₀ cycloalkyl, C ₅ -C ₁₀ aryl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, any of which is optionally fused with a 5- or 6-membered heteroaryl or phenyl, wherein the heteroaryl or heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S, and wherein each R ³ group is optionally substituted with one to three R ⁴ . Advantageously, R ³ may be selected from the group consisting of (C ₃ -C ₁₀ cycloalkyl)-C ₁ -C ₆ alkyl, (4- to 10-membered heterocycloalkyl)-C ₁ -C ₄ alkyl wherein said heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S; C ₆ -C ₁₀ aryl optionally fused with a C4- C ₆ cycloalkyl or a 4- to 7-membered heterocycloalkyl; (C ₆ -C ₁₀ aryl)-C ₁ -C ₆ alkyl; 5- to 10-membered heteroaryl comprising one to four heteroatoms independently selected from N, O and S, which is optionally fused with a C ₅ -C ₆ cycloalkyl; (5- to 10-membered heteroaryl)-C ₁ -C ₆ alkyl wherein the heteroaryl moiety comprises one to three heteroatoms independently selected from N, O and S; (C ₆ - C ₁₀ aryl)-(5- to 10-membered heteroaryl)- wherein the heteroaryl moiety comprises one to three heteroatoms independently selected from N, O and S; (5- to 6-membered heteroaryl)-(5- to 6- membered heteroaryl)- wherein each heteroaryl moiety comprises one to three heteroatoms independently selected from N, O and S; (4- to 7-membered heterocycloalkyl)-(5- to 6-membered heteroaryl)- wherein the heterocycloalkyl and heteroaryl moieties each comprises one to three heteroatoms independently selected from N, O and S; (5- to 6-membered heteroaryl)-(4- to 7- membered heterocycloalkyl)- wherein the heteroaryl and heterocycloalkyl moieties each comprises one to three heteroatoms independently selected from N, O and S; and wherein each R ³ group is optionally substituted with one to three R ⁴ . In particular embodiments, R ³ may be selected from the group consisting of (C ₅ -C ₆ cycloalkyl)-C ₂ - C ₅ alkyl, 5- to 6-membered heterocycloalkyl which is optionally fused with a 5- to 6-membered heteroaryl or phenyl and wherein said heterocycloalkyl comprises one to three heteroatoms independently selected from N, O and S; (5- to 6-membered heterocycloalkyl)-C ₂ -C ₅ alkyl wherein said heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S; C ₆ -C ₁₀ aryl optionally fused with a C ₅ -C ₆ cycloalkyl or a 5- to 6-membered heterocycloalkyl; (C ₆ - C ₁₀ aryl)-C ₂ -C ₅ alkyl; 5- to 6-membered heteroaryl comprising one to three heteroatoms independently selected from N, O and S, which is optionally fused with a C ₅ -C ₆ cycloalkyl; (5- to 6-membered heteroaryl)-C ₂ -C ₅ alkyl wherein the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; (C ₆ -C ₁₀ aryl)-(5- to 6-membered heteroaryl)- wherein the heteroaryl moiety comprises one to three heteroatoms independently selected from N, O and S; (5- to 6-membered heteroaryl)-(5- to 6-membered heteroaryl)- wherein each heteroaryl moiety comprises one to three heteroatoms independently selected from N, O and S; (5- to 6-membered heterocycloalkyl)-(5- to 6- membered heteroaryl)- wherein the heterocycloalkyl and heteroaryl moieties each comprises one to three heteroatoms independently selected from N, O and S; (5- to 6-membered heteroaryl)-(5- to 6- membered heterocycloalkyl)- wherein the heteroaryl and heterocycloalkyl moieties each comprises one to three heteroatoms independently selected from N, O and S; and wherein each R ³ group is optionally substituted with one or two R ⁴ . For example, in such embodiments, R ³ may be selected from (C ₃ -C ₁₀ cycloalkyl)-C ₁ -C ₆ alkyl, and wherein each R ³ group is optionally substituted with one to three R ⁴ . In embodiments, R ³ may be selected from (C ₃ -C ₆ cycloalkyl)-C ₁ -C ₄ alkyl, and wherein each R ³ group is optionally substituted with one to three R ⁴ . In some embodiments, R ³ may be selected from (C ₃ -C ₅ cycloalkyl)-C ₁ -C ₃ alkyl, and wherein each R ³ group is optionally substituted with one to three R ⁴ . In some embodiments, R ³ is selected from (C ₃ -C ₄ cycloalkyl)-C ₁ -C ₃ alkyl, and wherein each R ³ group is optionally substituted with one to three R ⁴ . In some particular embodiments, R ³ may be selected from the group consisting of straight or branched C ₁ -C ₅ alkyl (e.g. ethyl, isopropyl, sec-butyl, iso-butyl, tert-butyl, isopentyl, sec-isopentyl, tert-pentyl, neopentyl), (C ₃ -C ₆ cycloalkyl)-C ₂ -C ₅ alkyl; (4- to 6-membered heterocycloalkyl)- C ₁ -C ₅ alkyl wherein said heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S; (C5-C ₁₀ aryl)-C ₁ -C ₅ alkyl; 4- to 6-membered heteroaryl)-C ₁ -C ₅ alkyl wherein the heteroaryl moiety comprises one to three heteroatoms independently selected from N, O and S; and wherein each R ³ group is optionally substituted with one or two R ⁴ . Suitably, R ³ may be selected from the group consisting of straight or branched C ₁ -C ₅ alkyl and (C ₃ - C ₆ cycloalkyl)-C ₂ -C ₅ alkyl; and wherein each R ³ group is optionally substituted with one or two R ⁴ . R ⁴ at each occurrence may be independently selected from the group consisting of oxo, halo, hydroxy, cyano, phenyl, benzyl or amino. In embodiments, R ⁴ at each occurrence may be independently selected from the group consisting of (C ₁ -C ₆ alkyl)amino optionally substituted with one to five fluoro or with one to three R ⁹ , di(C ₁ - C ₆ alkyl)amino optionally substituted with one to ten fluoro or with one to three R ⁹ , C ₁ -C ₆ alkyl optionally substituted with one to five fluoro or with one to three R ⁹ , (5- to 6-membered heteroaryl)amino- wherein the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S and wherein the heteroaryl is optionally substituted with one to three R ⁹ ; (4- to 7-membered heterocycloalkyl)amino- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n and wherein the heterocycloalkyl is optionally substituted with one to three R ⁹ ; C ₁ -C ₆ alkoxy optionally substituted with one to five fluoro or with one to three R ⁹ ; C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl optionally substituted with one to five fluoro or with one to three R ⁹ ; or C ₁ - C ₆ alkyl-C(O)NH- optionally substituted with one to five fluoro or R ⁹ . Suitably, R ⁴ at each occurrence may be independently selected from the group consisting of (C ₁ - C ₄ alkyl)amino optionally substituted with one to three fluoro or with one to three R ⁹ , di(C ₁ - C ₄ alkyl)amino optionally substituted with one to five fluoro or with one to three R ⁹ , C ₁ -C ₄ alkyl optionally substituted with one to three fluoro or with one to three R ⁹ , (5- to 6-membered heteroaryl)amino- wherein the heteroaryl moiety comprises one to three heteroatoms independently selected from N, O and S and wherein the heteroaryl is optionally substituted with one to three R ⁹ ; (5- to 6-membered heterocycloalkyl)amino- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S and wherein the heterocycloalkyl is optionally substituted with one to three R ⁹ ; C ₁ -C ₄ alkoxy optionally substituted with one to three fluoro or with one to three R ⁹ ; C ₁ - C ₃ alkoxy-C ₁ -C ₃ alkyl optionally substituted with one to three fluoro or with one to three R ⁹ ; or C ₁ - C4 alkyl-C(O)NH- optionally substituted with one to three fluoro or one to three R ⁹ . Particularly, R ⁴ at each occurrence may be independently selected from C ₁ -C ₄ alkyl-C(O)NH- optionally substituted with one to three fluoro or one to three R ⁹ . More particularly, R ⁴ at each occurrence may be independently selected from C ₁ -C ₃ alkyl-C(O)NH- optionally substituted with one to three fluoro or one to three R ⁹ . Each R ³ may have 0, 1, 2 or 3 R ⁴ ; for example, there may be 0, 1 or 2 R ⁴ groups. R ⁴ may be selected from CH ₃ -C(O)NH-, CH ₂ F-C(O)NH-, CHF ₂ -C(O)NH- and CF ₃ -C(O)NH-. In embodiments, R ⁴ at each occurrence may be independently selected from the group consisting of C ₃ -C ₆ cycloalkyl optionally substituted with one to three fluoro or C ₁ -C ₃ alkyl or R ⁵ ; C ₃ -C ₆ cycloalkyl- C(O)NH- optionally substituted with one to five fluoro or R ⁵ ; 4- to 7-membered heterocycloalkyl-C(O)NH- optionally substituted with one to five fluoro or R ⁵ and wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n; 5- to 6-membered heteroaryl)- C(O)NH- optionally substituted with one to five fluoro or R ⁵ and wherein the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; C ₁ -C ₆ alkyl-OC(O)NH- optionally substituted with one to five fluoro or R ⁵ ; C ₁ -C ₆ alkyl-NHC(O)NH- optionally substituted with one to five fluoro or R ⁵ ; C ₁ -C ₆ alkyl-S(O)2NH- optionally substituted with one to five fluoro or R ⁵ ; C ₁ -C ₆ alkyl-C(O)- optionally substituted with one to five fluoro or R ⁵ ; C ₁ -C ₆ alkyl-S(O)n- optionally substituted with one to five fluoro or R ⁵ ; and n at each occurrence is independently selected from 0, 1 and 2. Suitably, R ⁴ may be a 4- to 7-membered heterocycloalkyl-C(O)NH- optionally substituted with one to five fluoro or R ⁵ and wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n. In particularly, R ⁴ may be a 4- to 6-membered heterocycloalkyl-C(O)NH- optionally substituted with one to five fluoro or one to three R ⁵ and wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S. Beneficially, R ⁴ may be a 4- to 5-membered heterocycloalkyl-C(O)NH- optionally substituted with one to five fluoro or one or two R ⁵ and wherein the heterocycloalkyl moiety comprises one or two heteroatoms independently selected from N and O. Advantageously, R ⁴ may be a 4- to 5-membered heterocycloalkyl-C(O)NH- optionally substituted with one to three fluoro or one or two R ⁵ and wherein the heterocycloalkyl moiety comprises one or two heteroatoms independently selected from N and O. For example, R ⁴ may be a 5-membered heterocycloalkyl-C(O)NH- optionally substituted with one to three fluoro or one R ⁵ and wherein the heterocycloalkyl moiety comprises one or two heteroatoms independently selected from N and O. In certain beneficial embodiments, R ⁴ is tetrahydrofuran, which is optionally substituted with one to three fluoro or one R ⁵ . R ⁵ may be selected from C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, phenyl, phenoxy, C ₃ -C ₆ cycloalkyl, C ₃ - C ₆ cycloalkoxy, 4- to 6- membered heterocycloalkyl wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n, or a 5- or 6-membered heteroaryl wherein the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; wherein each R ⁵ is optionally independently substituted with one to three R ⁹ ; and n at each occurrence is independently selected from 0, 1 and 2. In embodiments, R ⁵ may be selected from C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, phenyl, phenoxy, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkoxy, 4- to 6- membered heterocycloalkyl wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N and O, or a 5- or 6-membered heteroaryl wherein the heteroaryl moiety comprises one to three heteroatoms independently selected from N and O; wherein each R ⁵ is optionally independently substituted with one to three R ⁹ . R ³ may in various embodiments be selected from any one of the following structures:

In some embodiments, R ³ may be selected from any one of the following structures:

Suitably, R ³ may be selected from any one of the following structures:

Beneficially, R ³ may be selected from any one of the following structures: In some particular embodiments, R ³ may have the following structure: wherein R ⁷ is aryl or heteroaryl; and R ⁸ is independently from R ⁷ selected from the group consisting of: C _1-6 alkyl or C _3-6 cycloalkyl optionally comprising one or more heteroatoms, such as N, O and S; particularly N or O; more particularly N. In some particular embodiments, R ³ may be selected from any one of the following structures: wherein R ⁷ may be selected from the group consisting of: methyl, trifluoromethyl, CH ₃ (CF ₂ H)-, tertiary- butyl; and R ⁸ may be independently from R ⁷ selected from the group consisting of: H, tertiary butyl and isopropyl. In such embodiments, R ³ may be selected from one of the following structures: For example, in embodiments, compounds of the disclosure may have one of the following structures of Formula (II) or (III): wherein R ¹ may be as defined according to any of the aspects and embodiments disclosed herein. For example, R ¹ may be selected from the group consisting of monocyclic or bicyclic cycloalkyl, aryl, heteroaryl or combinations thereof, as described herein. In particular aspects and embodiments, the compounds of the present disclosure may be selected from any one of the compounds shown in Tables 1A, 1B and 1C. In other aspects and embodiments, the compound of the present disclosure may be selected from a compound listed in Table 2. In other aspects and embodiments, the compound of the present disclosure may be selected from a compound listed in Table 3.

CPD0084250 H NMR (400 MH DMSOd6) δ 896

CPD0084302 H NMR (400 MH DMSOd) δ 934

Table 1A: Exemplary compounds of the present disclosure Table 1B: Exemplary compounds of the present disclosure

Table 1C: Exemplary compounds of the present disclosure Dosage Forms, Medicaments and Pharmaceuticals The compounds, molecules or agents of the invention may be used to treat (e.g. cure, alleviate or prevent) one or more diseases, infections or disorders. Thus, in accordance with the invention, the compounds and molecules may be manufactured into medicaments or may be incorporated or formulated into pharmaceutical compositions. The molecules, compounds and compositions of the invention may be administered by any convenient route, for example, methods of administration include intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intravaginal, transdermal, rectally, by inhalation, or topically to the skin. Delivery systems are also known to include, for example, encapsulation in liposomes, microgels, microparticles, microcapsules, capsules, etc. Any other suitable delivery system known in the art is also envisioned in use of the present invention. Administration can be systemic or local. The mode of administration may be left to the discretion of the practitioner. The dosage administered will, of course, vary depending upon known factors, such as the pharmacodynamic properties of the particular active agent; the chosen mode and route of administration; the age, health and weight of the recipient; the nature of the disease or disorder to be treated; the extent of the symptoms; any simultaneous or concurrent treatments; the frequency of treatment; and the effect desired. In general, a daily dosage of active agent of between about 0.001 and about 1,000 mg/kg of body weight can be expected. For some applications, the dosage may suitably be within the range of about 0.01 to about 100 mg/kg, between about 0.1 to about 25 mg/kg, or between about 0.1 and 10 mg/kg. Depending on known factors, such as those noted above, the required dosage of the active agent of the invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily. Dosage forms of the pharmaceutical compositions of the invention suitable for administration may contain from about 1 mg to about 2,000 mg of the active ingredient per unit. Typically, the daily dosage of compounds may be at least about 10 mg and at most about 1,500 mg per human dose; such as between about 25 and 1,250 mg or suitably between about 50 and 1,000 mg. In such compositions the compound of the invention will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition. Each of the compounds of the general Formula (I) may be present in vivo in a concentration of at least about 10 nM. For example, the compound of the disclosure may be present in vivo in a concentration of at least 10 nm and at most about 10 μM, for example, between about 10 nM and about 10 μM, between about 25 nM and about 500 nM or between about 10 nm and about 100 nM. Such a concentration may be measured in blood or other bodily fluid (e.g. whole blood or serum) as an unbound compound. The 'effective amount' or 'therapeutically effective amount' is meant to describe an amount of compound or a composition of the invention that is effective in curing, inhibiting, alleviating, reducing or preventing the adverse effects of the viral infection to be treated (especially COVID-19 infection), or the amount necessary to achieve a physiological or biochemically-detectable effect. Thus, at the effective amount, the compound or agent is able to produce the desired therapeutic, ameliorative, inhibitory or preventative effect. Beneficially, an effective amount of the compound or composition of the invention may have the effect of reducing, inhibiting or preventing viral replication, especially COVID-19 viral replication in a cell, such as a human cell. Particularly preferred cells are those that express the ACE2 receptor; including cells of the nasal passages, respiratory tract, lungs and/or intestine. When administered to a subject, a compound of the invention is suitably administered as a component of a composition that comprises a pharmaceutically acceptable carrier or vehicle. One or more additional pharmaceutical acceptable carrier (such as diluents, adjuvants, excipients or vehicles) may be combined with the compound of the invention in a pharmaceutical composition. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E. W. Martin. Pharmaceutical formulations and compositions of the invention are formulated to conform to regulatory standards and according to the chosen route of administration. Acceptable pharmaceutical vehicles can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical vehicles can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilising, thickening, lubricating and colouring agents may be used. When administered to a subject, the pharmaceutically acceptable vehicles are generally sterile. Water is a suitable vehicle when the compound of the invention is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid vehicles, particularly for injectable solutions. Suitable pharmaceutical vehicles also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The present compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or buffering agents. The medicaments and pharmaceutical compositions of the invention can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, powders, gels, capsules (for example, capsules containing liquids or powders), modified-release formulations (such as slow or sustained-release formulations), suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. Other examples of suitable pharmaceutical vehicles are described in Remington's Pharmaceutical Sciences, Alfonso R. Gennaro ed., Mack Publishing Co. Easton, Pa., 19th ed., 1995, see for example pages 1447- 1676. Suitably, the therapeutic compositions or medicaments of the invention are formulated in accordance with routine procedures as a pharmaceutical composition adapted for oral administration (more suitably for humans). Compositions for oral delivery may be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example. Thus, in one embodiment, the pharmaceutically acceptable vehicle is a capsule, tablet or pill. Orally administered compositions may contain one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavouring agents such as peppermint, oil of wintergreen, or cherry; colouring agents; and preserving agents, to provide a pharmaceutically palatable preparation. When the composition is in the form of a tablet or pill, the compositions may be coated to delay disintegration and absorption in the gastrointestinal tract, so as to provide a sustained release of active agent over an extended period of time. Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered compositions. In these dosage forms, fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture. These dosage forms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations. A time delay material such as glycerol monostearate or glycerol stearate may also be used. Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Such vehicles are preferably of pharmaceutical grade. For oral formulations, the location of release may be the stomach, the small intestine (the duodenum, the jejunem, or the ileum), or the large intestine. One skilled in the art is able to prepare formulations that will not dissolve in the stomach, yet will release the material in the duodenum or elsewhere in the intestine. Suitably, the release will avoid the deleterious effects of the stomach environment, either by protection of the peptide (or derivative) or by release of the peptide (or derivative) beyond the stomach environment, such as in the intestine. To ensure full gastric resistance a coating impermeable to at least pH 5.0 would be essential. Examples of the more common inert ingredients that are used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and Shellac, which may be used as mixed films. To aid dissolution of the therapeutic agent into the aqueous environment a surfactant might be added as a wetting agent. Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic detergents might be used and could include benzalkonium chloride or benzethomium chloride. Potential nonionic detergents that could be included in the formulation as surfactants include: lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 20, 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants, when used, could be present in the formulation of the compound or derivative either alone or as a mixture in different ratios. Typically, compositions for intravenous administration comprise sterile isotonic aqueous buffer. Where necessary, the compositions may also include a solubilising agent. Another suitable route of administration for the therapeutic compositions of the invention is via pulmonary or nasal delivery. Additives may be included to enhance cellular uptake of the therapeutic agent of the invention, such as the fatty acids oleic acid, linoleic acid and linolenic acid. The therapeutic agents of the invention may also be formulated into compositions for topical application to the skin of a subject. Where the invention provides more than one active agent for use in combination, generally, the agents may be formulated separately or in a single dosage form, depending on the prescribed most suitable administration regime for each of the agents concerned. When the therapeutic agents are formulated separately, the pharmaceutical compositions of the invention may be used in a treatment regime involving simultaneous, separate or sequential administration with the other one or more therapeutic agent. The other therapeutic agent(s) may comprise a compound of the invention or a therapeutic agent known in the art). The molecules and pharmaceutical compositions of the invention may be formulated and suitable for administration to the central nervous system (CNS) and/or for crossing the blood-brain barrier (BBB). The invention will now be described by way of the following non-limiting examples. EXAMPLES EXPERIMENTAL SECTION General Methods. Solvent: Tetrahydrofuran (TP) was purchased from Nan Ya Plastics Corporation. Dichloromethane (TP) was purchased from Jiangsu Lee & Man Chemical. N,N-Dimethylformamide (SG) was purchased from Xilong Scientific. Methanol (AR) was purchased from Chron Chemicals. Ethanol (AR) was purchased from Sinopharm Chemical Reagent.1,4-Dioxane (TP) was purchased from Infinity Scientific. Moisture content of tetrahydrofuran, dichloromethane and N,N-dimethylformamide were lower than 100 ppm, and were used without further treatment. Methanol, ethanol and 1,4-dioxane were pre-dried over 4 Å molecular sieves before use. N,N-dimethylformamide (purity>99.9%, ACS/HPLC certified) purchased from Anhui Zesheng Technology was used as reagent. Solvent extra dry over molecular sieves including N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide and dimethylacetamide were purchased from Acros Organics. NMR: A, B, D, E, F instruments used Bruker AVANCEIII 400; G, H, I, J, instruments used Bruker AVANCE NEO 400. LC-MS included Agilent and Shimadzu Below: Agilent LC-MS: Agilent 1200 Series LC-MSD system with DAD and Agilent LC-MS G6110A, mass-spectrometer. Agilent (Degasser: 1200; Pump: 1260; Hip-ALS: 1200; TCC: 1200; DAD: 1100) Series LC-MS system with DAD-ELSD and Agilent LC-MS G6110A, mass-spectrometer. Agilent (Degasser: 1200; Pump: 1260; Hip-ALS: 1100; TCC: 1260; DAD: 1100) Series LC-MS system with DAD and Agilent LC-MS G1956A, mass-spectrometer. Agilent (Degasser: 1200; Pump: 1200; Hip-ALS: 1100; TCC: 1200; DAD: 1200) Series LC-MS system with DAD and Agilent LC-MS G1956A, mass-spectrometer. Shimadzu LC-MS: Shimadzu LC-20AD Series LC-MS system with SPD-M20A and Shimadzu LC-MS LCMS-2020, mass- spectrometer. Shimadzu LC-20AD Series LC-MS system with SPD-M20A-ELSD and Shimadzu LC-MS LCMS-2020, mass-spectrometer. Shimadzu LC-20AD Series LC-MS system with SPD-M40 and Shimadzu LC-MS LC-MS-2020, mass- spectrometer. Shimadzu LC-40AD Series LC-MS system with SPD-M40 and Shimadzu LC-MS LC-MS-2020, mass- spectrometer. Shimadzu LC-20AB Series LC-MS system with SPD-M20A and Shimadzu LC-MS LC-MS-2020, mass- spectrometer. Shimadzu LC-20AB Series LC-MS system with SPD-M20A-ELSD and Shimadzu LC-MS LC-MS-2020, mass-spectrometer. HPLC instruments were from Shimadzu. Shimadzu LC-20AD Series LC system with SPD-M20A. Shimadzu LC-20AB Series LC system with SPD-M40. Shimadzu LC-20AB Series LC system with SPD-M20A. SFC Instrument :CAS-WH-ANA-SFC-A Agilent-1260. Column: Chiralpak OJ-350×4.6mm I.D., 3 μm. Mobile phase: Phase A for CO2, and Phase B for MeOH (0.05% DEA). Gradient elution: MeOH (0.05% DEA) in CO2 from 5% to 40%. Flow rate: 3mL/min; Detector: DAD. Column Temp: 35 °C; Back Pressure: 100 Bar. Instrument : CAS-WH-ANA-SFC-C Shimadzu LC-30ADsf. Column: Column: OD 50×4.6mm I.D., 3 μm. Mobile phase: Phase A for CO ₂ , and Phase B for MeOH (0.05% DEA). Gradient elution: MeOH (0.05% DEA) in CO ₂ from 5% to 40%. Flow rate: 3mL/min; Detector: PDA. Column Temp: 35 °C; Back Pressure: 100 Bar. Instrument :CAS-WH-ANA-SFC-E Shimadzu LC-30ADsf. Column: Chiralpak AD-350×4.6mm I.D., 3 μm. Mobile phase: Phase A for CO2, and Phase B for MeOH (0.05%DEA). Gradient elution: MeOH (0.05% DEA) in CO ₂ from 5% to 40%. Flow rate: 3mL/min; Detector: PDA. Column Temp: 35 °C; Back Pressure: 100 Bar. Microwave irradiator Instrument: Biotage Initiator+. Microwave power : 0-400 W. pressure range :0-30 bar. Example 1 – Chemical synthesis protocols HPLC Methods Method A:0-60AB, Shimadzu Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Chromolith@Flash RP-18E 25-2 MM; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0-0.8 min 0-60% B, 0.8-1.2 min 60% B; flow 1.5 ml/min; temperature: 50°C; PDA: 220 nm & 254 nm. Method B:0-60AB, Agilent Instrument: Agilent 1100\G1956A SingleQuad; Column: Kinetex@ 5um EVO C1830*2.1 mm; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0-0.8 min 0-60% B, 0.8-1.2 min 60% B; flow 1.5 ml/min; temperature: 50°C; PDA: 220 nm & 254 nm. Method C:5-95AB, Shimadzu Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Chromolith@Flash RP-18E 25-2 MM; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0-0.8 min, 5-95% B, 0.8-1.2 min 95% B; flow 1.5 ml/min; temperature: 50°C; PDA: 220 nm & 254 nm. Method D:5-95AB, Agilent Instrument: Agilent 1100\G1956A SingleQuad; Column: Kinetex@ 5 μm EVO C1830*2.1 mm; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0-0.8 min 5-95% B, 0.8-1.2 min 95% B; flow 1.5 ml/min; temperature: 50°C; PDA: 220 nm & 254 nm. Method E:10-80CD, Agilent Instrument: Agilent 1200\G6110A SingleQuad; Column: XBridge C182.1*50 mm, 5 μm; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0-1.2 min 10-80% B, 1.2-1.6 min 80% B; flow 1.2 ml/min; temperature: 40°C; DAD: 220 nm & 254 nm. Method F:0-60CD, Agilent Instrument: Agilent 1200\G6110A SingleQuad; Column: XBridge C182.1*50 mm, 5 μm; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0-1.2 min 0-60% B, 1.2-1.6 min 60% B; flow 1.0 ml/min; temperature: 40°C; DAD: 220 nm & 254 nm. Method G:5-95CD, Shimadzu Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex EVO C182.1*30 mm, 5 μm; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0-0.8 min, 5-95% B, 0.8- 1.2 min 95% B; flow 1.5 ml/min; temperature: 40°C; PDA: 220 nm & 254 nm. Method H:0-60CD, Shimadzu Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex EVO C182.1*30 mm, 5 μm; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0-1.2 min, 0-60% B, 1.2- 1.6 min, 60% B; flow 1.0 ml/min; temperature: 40°C; PDA: 220 nm & 254 nm. Method I:5-95CD, Shimadzu Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex EVO C182.1*30 mm, 5um; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0-0.8 min, 5-95% B, 0.8- 1.2 min, 95% B; flow 1.5 ml/min; temperature: 40°C; PDA: 220 nm & 254 nm. Method J:0-60CD, Shimadzu Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex EVO C182.1*30 mm, 5 μm; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0-0.8 min, 0-60% B, 0.8- 1.2 min, 60% B; flow 1.5 ml/min; temperature: 40°C; PDA: 220 nm & 254 nm. Method K:5-95CD, Agilent Instrument: Agilent LCMS-2020 SingleQuad; Column: XBridge C182.1*50mm, 5 μm; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0-0.7 min, 5-95% B, 0.7-1.0 min, 95% B; flow 1.5 ml/min; temperature: 40°C; PDA: 220 nm & 254 nm. Method L: 5-95AB, SHIMADZU Instrument: SHIMADZU LCMS-2020; SingleQuad; Column: Kinetex EVO C182.1*30 mm, 5 μm; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0-3.6 min, 5-95% B, 3.6-4.0 min, 95% B; flow 1.5 ml/min; temperature: 40°C; PDA: 220 nm & 254 nm. Method M: 0-60CD, SHIMADZU Instrument: SHIMADZU LCMS-2020; SingleQuad; Column: XBridge C182.1*30mm, 3.5μm; eluent A: 0.025% NH3•H2O in water ^v/v ^, eluent B: acetonitrile; gradient: 0-0.8 min, 0-60% B; flow 1.5 ml/min; temperature: 40°C; PDA: 220 nm & 254 nm. Method N: 0-60AB, SHIMADZU Instrument: SHIMADZU LCMS-2020; SingleQuad; Column: XBridge C182.1*30mm, 3.5μm; eluent A: 0.0375% TFA in water (v/v), eluent B: 0.01875% TFA in Acetonitrile (v/v); gradient: 0-0.8 min, 0-60% B; flow 1.5 ml/min; temperature: 40°C; PDA: 220 nm & 254 nm. Method O: 5-95AB, SHIMADZU Instrument: SHIMADZU LCMS-2020; SingleQuad; Column: XBridge C182.1*30mm, 3.5μm; eluent A: 0.0375% TFA in water (v/v), eluent B: 0.01875% TFA in Acetonitrile (v/v); gradient: 0-0.8 min, 5-95% B; flow 1.5 ml/min; temperature: 40°C; PDA: 220 nm & 254 nm. Method P: 5-95CD, SHIMADZU Instrument: SHIMADZU LCMS-2020; SingleQuad; Column: XBridge C182.1*30mm, 3.5μm; eluent A: 0.025% NH3•H2O in water (v/v), eluent B: Acetonitrile; gradient: 0-0.8 min, 5-95% B; flow 1.5 ml/min; temperature: 40°C; PDA: 220 nm & 254 nm. Method Q: 5-95CD, SHIMADZU Instrument: SHIMADZU LCMS-2020; SingleQuad; Column: XBridge C182.1*30mm, 5μm; eluent A: 0.025% NH3•H2O in water˄v/v˅, eluent B: Acetonitrile; gradient: 0-3.0 min, 5-95% B, 3.0-3.5 min, 95% B 3.50-3.51 min, 95-5% B 3.51-4.00 min, 5% B; flow 1.5 ml/min; temperature: 40°C; PDA: 220 nm & 254 nm. Synthesis Procedures Preparation of CPD0077144 Procedure for preparation of O3-tert-butyl O2-methyl (1R,2S,5S)-6,6- dimethyl-3- azabicyclo[3.1.0]hexane-2,3-dicarboxylate To a solution of methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (5.00 g, 29.5 mmol, 1.00 eq) and NaHCO ₃ (6.21 g, 73.9 mmol, 2.87 mL, 2.50 eq) in THF (50.0 mL) and water (50.0 mL) was added Boc ₂ O (7.09 g, 32.5 mmol, 7.47 mL, 1.10 eq) dropwise at 25°C. After stirring at 25°C for 1 h, the reaction mixture was diluted with water (100 ml), and then extracted with ethyl acetate (120 mL × 3). The combined organic layers were washed with brine (50.0 mL × 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give O3-tert-butyl O2-methyl (1R,2S,5S)- 6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (8.60 g, crude) as light yellow oil, which was used into the next step without further purification. LC-MS (Method C): R _t = 0.722 min; MS (ESIpos): m/z = 169.9 [M-99] ⁺ . Procedure for preparation of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6- dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid To a solution of O3-tert-butyl O2-methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,3- dicarboxylate (8.60 g, 31.9 mmol, 1.00 eq) in THF (60.0 mL) was added another solution of LiOH.H ₂ O (2.68 g, 63.8 mmol, 2.00 eq) in H ₂ O (30 mL) dropwise at 25°C. After stirring at 25°C for 20 hr, the reaction mixture was diluted with water (100 ml), and then extracted with ethyl acetate (80.0 mL × 1). The aqueous phase was adjust to pH = 2-3 with HCl (2M), then it was extracted with ethyl acetate: MeOH = 10: 1 (100 mL×3). The combined organic layers were washed with brine (50.0 mL × 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give (1R,2S,5S)-3-tert- butoxycarbonyl-6,6- dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxylic acid (2.50 g, 8.81 mmol, 27% yield, 90% purity) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 4.23-4.19 (m, 0.5H), 4.16-4.08 (m, 0.5H), 3.71-3.62 (m, 0.5H), 3.61- 3.50 (m, 0.5H), 3.49-3.41 (m, 1H), 1.50-1.37 (m, 11H), 1.12-1.02 (m, 3H), 0.98-0.89 (m, 3H) Procedure for preparation of 2-(benzhydrylideneamino)-2-(4- isoquinolyl)acetonitrile To a mixture of 2-(benzhydrylideneamino)acetonitrile (10 g, 45.4 mmol, 1.00 eq), 4-bromoisoquinoline (9.92 g, 47.6 mmol, 1.05 eq) and K ₃ PO ₄ (28.9 g, 136 mmol, 3.00 eq) in DMF (250 mL) was added [2- (2-aminophenyl)phenyl]-chloro-palladium;tritert-butylphospha ne (930 mg, 1.82 mmol, 0.040 eq) at 25°C in one portion. After stirring stirred at 90°C for 20 hr under N ₂ atmosphere, the reaction mixture was diluted with water (500 ml), and then extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (150 mL × 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=10/1 to 0/1) to give 2-(benzhydrylideneamino)-2-(4- isoquinolyl)acetonitrile (5.10 g, 10.3 mmol, 22% yield, 70% purity) as black oil. LC-MS (Method A): R _t = 0.631 min; MS (ESIpos): m/z = 348.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.25 (s, 1H), 8.26 (s, 1H), 7.72-7.64 (m, 4H), 7.59-7.56 (m, 3H), 7.36- 7.32 (m, 5H), 5.83 (s, 1H) Procedure for preparation of 2-amino-2-(4-isoquinolyl)acetonitrile To a solution of 2-(benzhydrylideneamino)-2-(4-isoquinolyl)acetonitrile (5.10 g, 10.3 mmol, 70% purity, 1.00 eq) in MeCN (50.0 mL) was added HCl (6.00 M, 5.00 mL) at 0°C in one portion. After stirring at 0°C for 1 hr, the reaction mixture was diluted with water (150 ml), extracted with ethyl acetate (100 mL). The aqueous phase was adjust to pH = 8 by NaHCO3 (solid) at 0°C, extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous Na ₂ SO ₄ , filtered and filtrate was concentrated under reduced pressure to give 2-amino-2-(4- isoquinolyl)acetonitrile (1.30 g, 4.83 mmol, 47% yield, 68% purity) as red oil. LC-MS (Method G): R _t = 0.635 min; MS (ESIpos): m/z = 184.1 [M+H] ⁺ . Procedure for preparation of tert-butyl (1R,2S,5S)-2-[[cyano(4- isoquinolyl)methyl]carbamoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate To a solution of 2-amino-2-(4-isoquinolyl)acetonitrile (1.45 g, 3.27 mmol, 67% purity, 1.00 eq), (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3 .1.0]hexane-2-carboxylic acid (834 mg, 2.94 mmol, 90% purity, 0.900 eq) and DIPEA (1.27 g, 9.81 mmol, 1.71 mL, 3.00 eq) in DCM (20.0 mL) was added HATU (1.49 g, 3.92 mmol, 1.20 eq) at 0°C in one portion. After stirring at 25°C for 2 hr, the reaction mixture was diluted with water (20 ml), and then extracted with DCM (30 mL × 3). The combined organic layers were washed with water (20 mL × 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed- phase HPLC (H2O, neutral) to give tert-butyl (1R,2S,5S)-2-[[cyano(4-isoquinolyl)methyl]carbamoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.00 g, 2.21 mmol, 68% yield, 93% purity) as red solid. LC-MS (Method C): R _t = 0.654 min; MS (ESIpos): m/z = 421.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.38-9.25 (m, 1H), 8.83-8.77 (m, 1H), 8.24-8.01 (m, 2H), 8.00-7.79 (m, 2H), 7.77-7.68 (m, 1H), 6.89-6.81 (m, 0.4H), 6.73-6.62 (m, 0.6H), 4.15-4.10 (m, 1H), 3.64-3.30 (m, 2H), 1.48-1.32 (m, 5H), 1.11-0.95 (m, 7H), 0.91-0.82 (m, 3H) SFC: de%: 41:59 Procedure for preparation of (1R,2S,5S)-N-[cyano(4-isoquinolyl)methyl]- 6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of tert-butyl (1R,2S,5S)-2-[[cyano(4-isoquinolyl)methyl]carbamoyl]-6,6- dimethyl-3- azabicyclo[3.1.0]hexane-3-carboxylate (100 mg, 0.221 mmol, 93% purity, 1.00 eq) in dioxane (1.60 mL) was added H ₂ SO ₄ (1.47 g, 1.50 mmol, 0.800 mL, 10% purity) at 25°C dropwise. After stirring at 50°C for 12 hr, the reaction mixture was diluted with water (5 ml), extracted with ethyl acetate (5 mL×1). Then the aqueous was adjust to pH = 7-8 with NaHCO ₃ (solid), and extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (5 mL × 1), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give (1R,2S,5S)-N-[cyano(4-isoquinolyl)methyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (70.0 mg, 0.152 mmol, 69% yield, 70.0% purity) as light yellow oil LC-MS (Method G): R _t = 0.877 min; MS (ESIpos): m/z = 321.1 [M+H] ⁺ . Procedure for preparation of CPD0077144 - (1R,2S,5S)-N-[cyano(4-isoquinolyl)methyl]- 6,6- dimethyl-3-[2-(1-piperidyl)acetyl]-3-azabicyclo[3.1.0]hexane -2-carboxamide To a solution of (1R,2S,5S)-N-[cyano(4-isoquinolyl)methyl]-6,6-dimethyl-3-aza bicyclo [3.1.0]hexane- 2- carboxamide (70.0 mg, 0.152 mmol, 70% purity, 1.00 eq), 2-(1-piperidyl)acetic acid (32.8 mg, 0.229 mmol, 1.50 eq) and DIPEA (59.3 mg, 0.458 mmol, 3.00 eq) in DCM (2.00 mL) was added HATU (87.2 mg, 0.229 mmol, 1.50 eq) at 0°C. After stirring at 25°C for 1 hr, the mixture was concentrated at 25°C to give a residue. The residue was purified by prep-HPLC (FA condition) to give (1R,2S,5S)-N- [cyano(4-isoquinolyl)methyl]-6,6-dimethyl-3-[2-(1-piperidyl) acetyl]-3-azabicyclo[3.1.0]hexane-2- carboxamide (20.0 mg, 0.040 mmol, 26% yield, 99% purity, FA) as a light yellow solid. Preparation of CPD0077145 Procedure for preparation of (1R,2S,5S)-N-(cyano(isoquinolin-4-yl)methyl)- 6,6-dimethyl-3-(2- morpholinoacetyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-[cyano(4-isoquinolyl)methyl]-6,6-dimethyl-3-aza bicyclo [3.1.0]hexane- 2-carboxamide (80.0 mg, 0.249 mmol, 1.00 eq), 2-morpholinoacetic acid (54.4 mg, 0.374 mmol, 1.50 eq) and DIPEA (96.8 mg, 0.749 mmol, 0.130 mL, 3.00 eq) in DCM (3.00 mL) was added HATU (142 mg, 0.374 mmol, 1.50 eq) in portions at 0°C. After stirring at 25°C for 2 h, the mixture was concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (TFA condition; column: Phenomenex Synergi C18150 × 25mm × 10 μm; mobile phase: [water (TFA)- ACN]; B%: 1%-27%, 10 min) to afford (1R,2S,5S)-N-(cyano(isoquinolin-4-yl)methyl)-6,6-dimethyl-3- (2- morpholinoacetyl)-3-azabicyclo [3.1.0]hexane-2-carboxamide (24.0 mg, 53.2 μmol, 21% yield, 96% purity) as a white solid. Preparation of CPD0077147 Procedure for preparation of CPD0077147 - methyl 2-(4,4-difluoro-1-piperidyl)acetate A suspension of 4,4-difluoropiperidine (2.00 g, 12.7 mmol, 1.00 eq, HCl salt), methyl 2-bromoacetate (2.14 g, 13.9 mmol, 1.32 mL, 1.10 eq) and K2CO3 (5.26 g, 38.1 mmol, 3.00 eq) in MeCN (20.0 mL) was stirred at 25°C. After warming to 50°C and stirring at the same temperature for 16 h, the reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (100 mL × 5). The combined organic layers were washed with saturated sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~40% Ethylacetate/Petroleum ethergradient @ 40 mL/min) to give methyl 2-(4,4-difluoro-1-piperidyl)acetate (2.00 g, 10.4 mmol, 81% yield) as colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 3.63 (s, 3H), 3.32 (s, 2H), 2.68-2.50 (m, 4H), 1.99-1.91 (m, 4H). Procedure for preparation of CPD0077147 - 2-(4,4-difluoro-1-piperidyl)acetic acid A solution of methyl 2-(4,4-difluoro-1-piperidyl)acetate (1.00 g, 5.18 mmol, 1.00 eq) in HCl (6 M, 10 mL) was stirred at 90°C for 16 h. The reaction mixture was lyophilized to give 2-(4,4-difluoro-1- piperidyl)acetic acid (1.00 g, 4.17 mmol, 80% yield, 90% purity, HCl salt) as a white solid. ¹ H NMR (400 MHz, D ₂ O) δ = 4.05 (s, 2H), 3.60-3.36 (m, 4H), 2.45-2.36 (m, 4H). Procedure for preparation of CPD0077147 - (1R, 2S, 5S)-N-[cyano(4- isoquinolyl)methyl]-3-[2-(4, 4-difluoro-1-piperidyl)acetyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]- hexane-2-carboxamide To a solution of (1R,2S,5S)-N-[cyano(4-isoquinolyl)methyl]-6,6-dimethyl-3-aza bicyclo [3.1.0]hexane- 2- carboxamide (80.0 mg, 0.249 mmol, 1.00 eq), 2-(4, 4-difluoro-1-piperidyl)acetic acid (80.7 mg, 0.374 mmol, 1.50 eq, HCl salt) and DIPEA (96.8 mg, 0.749 mmol, 0.130 mL, 3 eq) in DCM (3.00 mL) was added HATU (142 mg, 0.374 mmol, 1.50 eq) in portions at 0°C. After stirring at 25°C for 2 h, the mixture was concentrated under vacuum to give a residue. The residue was purified by prep-HPLC [TFA condition; column: 3 Phenomenex Luna C1875 × 30mm × 3 μm; mobile phase: [water(TFA)-ACN]; B%: 15%-35%, 7min to afford (1R,2S,5S)-N-[cyano(4-isoquinolyl)methyl]-3-[2-(4,4-difluoro -1- piperidyl)acetyl]-6, 6-dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxamide (47.9 mg, 0.0964 mmol, 38% yield, 96% purity) as yellow solid. Preparation of CPD0084200 Procedure for preparation of tert-butyl ((S)-1-amino-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2- yl)carbamate NH3 was bubbled into MeOH (50.0 mL) at -70°C for 0.5 h (~20 mmol/L). Methyl (2S)-2-(tert- butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (4.70 g, 16.4 mmol, 1.00 eq) was added to above solution (50.0 mL) at 25°C. After stirring at 25°C for 40 h in a sealed tube, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 3/1 to 0/1, then ethyl acetate/methanol = 30/1 to 15/1) to give tert-butyl N-[(1S)-2- amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carba mate (3.40 g, 12.2 mmol, 74% yield, 97% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.21-7.17 (m, 1H), 6.97-6.93 (m, 1H), 6.29-6.25 (m, 1H), 6.10-6.06 (m, 1H), 4.35-4.31 (m, 1H), 3.42-3.27 (m, 2H), 2.53-2.49 (m, 1H), 2.39-2.33 (m, 1H), 2.13-2.03 (m, 1H), 1.91-1.75 (m, 2H), 1.42 (s, 9H). LC-MS (Method A): R _t = 0.567 min; MS (ESIpos): m/z = 171.9 [M-99] ⁺ . SFC: ee% : 100%. Procedure for preparation of (S)-2-amino-3-((S)-2-oxopyrrolidin- 3-yl)propanamide hydrochloride To a solution of tert-butyl N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]e thyl] carbamate (2.00 g, 7.37 mmol, 1.00 eq) in MeCN (20.0 mL) was added HCl/EtOAc (4 M, 8.00 mL, 4.34 eq) at 0°C dropwise. After stirring at 25°C for 2 h, the mixture was concentrated to give (2S)-2-amino-3-[(3S)- 2- oxopyrrolidin-3-yl]propanamide (1.50 g, 6.50 mmol, 88% yield, 90% purity, HCl salt) as a white solid. ¹ H NMR (400 MHz, D ₂ O) δ = 4.12 (dd, J = 8.8, 5.2 Hz, 1H), 3.41-3.31 (m, 2H), 2.78-2.68 (m, 1H), 2.43- 2.35 (m, 1H), 2.18-2.08 (m, 1H), 2.06-2.02 (m, 1H), 1.89-1.80 (m, 1H). Procedure for preparation of tert-butyl (1R,2S,5S)-2-(((S)-1-amino-1- oxo-3-((S)-2-oxopyrrolidin- 3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-3-carboxylate To a solution of (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (1.00 g, 4.82 mmol, 1.00 eq, HCl salt), (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3 .1.0]hexane-2-carboxylic acid (1.23 g, 4.82 mmol, 1.00 eq) and DIPEA (2.49 g, 19.3 mmol, 3.36 mL, 4.00 eq) in DCM (20.0 mL) was added HATU (2.20 g, 5.78 mmol, 1.20 eq) at 0°C in portions. After stirring at 25°C for 2 h, the reaction mixture was diluted with water (20.0 mL), and then extracted with DCM (20.0 mL × 3). The combined organic layers were washed with water (10.0 mL × 2), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography [Instrument: Agela Technologies OCTOPUS HS-1200; Column: 330g Flash Column Welch Ultimate XB_C1820-40μm; 120 A, Mobile phase: [water: acetonitrile]; Gradient B%: 0%-40%, 10min; 40%, 10min ; flow 150 ml/min; temperature: room temperature] to give tert-butyl (1R,2S,5S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3 -yl]methyl]ethyl]carbamoyl]-6,6-dimethyl- 3-azabicyclo [3.1.0]hexane-3-carboxylate (1.20 g, 2.79 mmol, 58.0% yield, 95.0% purity) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.36-8.32 (m, 0.7H), 7.85-7.73 (m, 0.3H), 7.44-7.40 (m, 0.7H), 7.21-7.18 (m, 0.3H), 6.03-5.98 (m, 0.3H), 5.83-5.79 (m, 0.7H), 5.58-5.49 (m, 0.3H), 5.47-5.32 (m, 0.7H), 4.68- 4.58 (m, 0.3H), 4.44-4.40 (m, 0.7H), 4.11-4.06 (m, 0.7H), 4.07-4.03 (m, 0.3H), 3.85-3.81 (m, 0.7H), 3.69-3.65 (m, 0.3H), 3.59-3.30 (m, 3H), 2.57-2.38 (m, 2H), 2.26-2.12 (m, 1H), 2.05-1.82 (m, 4H), 1.57- 1.42 (m, 9H), 1.03 (s, 3H), 0.97-0.89 (m, 3H). LC-MS (Method C): R _t = 0.608 min; MS (ESIpos): m/z = 409.1 [M+H] ⁺ . SFC: de%: 100%. Procedure for preparation of (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2- oxopyrrolidin-3- yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-car boxamide hydrochloride To a solution of tert-butyl (1R,2S,5S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3 -yl]methyl] ethyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-ca rboxylate (1.20 g, 2.94 mmol, 1.00 eq) in MeCN (10.0 mL) was added HCl/EtOAc (4 M, 0.734 mL, 1.00 eq) at 0°C. After stirring at 25°C for 2 h, the mixture was concentrated to give (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-ca rboxamide (1.20 g, crude, HCl salt) as a white solid. ¹ H NMR (400 MHz, D2O) δ = 4.35 (dd, J = 10.4, 4.8 Hz, 1H), 3.67 (dd, J = 12.4, 5.2 Hz, 1H), 3.37-3.19 (m, 3H), 2.60-2.47 (m, 1H), 2.35-2.21 (m, 1H), 2.13-2.04 (m, 1H), 2.02-1.96 (m, 1H), 1.87-1.74 (m, 4H), 1.06-0.98 (m, 6H). Procedure for preparation of (1R,2S,5S)-N-((S)-1-amino-1-oxo- 3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-6,6-dimethyl-3-(2-(piperidin-1-yl)acetyl)-3- azabicyclo[3.1.0]hexane-2- carboxamide To a solution of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]- 6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (150 mg, 0.435 mmol, 1.00 eq, HCl salt), 2-(1- piperidyl)acetic acid (93.4 mg, 0.652 mmol, 1.50 eq) and DIPEA (225 mg, 1.74 mmol, 0.303 mL, 4.00 eq) in DCM (4.00 mL) was added HATU (281 mg, 0.739 mmol, 1.70 eq) in portions at 0°C. After stirring at 25°C for 18 h, the reaction mixture was concentrated under reduced pressure to give (1R,2S,5S)-N- [(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]eth yl]-6,6-dimethyl-3-[2-(1-piperidyl)acetyl]-3- azabicyclo[3.1.0]hexane-2-carboxamide (0.80 g, 0.369 mmol, 85% yield, 20% purity) as yellow oil. LC-MS (Method H): R _t = 0.973 min; MS (ESIpos): m/z = 434.2 [M+H] ⁺ . Procedure for preparation of CPD0084200 - (1R,2S,5S)-N-((S)-1-cyano-2-((S)- 2-oxopyrrolidin-3- yl)ethyl)-6,6-dimethyl-3-(2-(piperidin-1-yl)acetyl)-3-azabic yclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]- 6,6- dimethyl-3-[2-(1-piperidyl)acetyl]-3-azabicyclo[3.1.0]hexane -2-carboxamide (0.80 g, 0.369 mmol, 20% purity, 1.00 eq) in DCM (8.00 mL) was added methoxycarbonyl-(triethylammonio)sulfonyl-azanide (264 mg, 1.11 mmol, 3.00 eq) at 0°C in portions. After stirring at 25°C for 4 h, the reaction mixture was quenched with saturated sodium bicarbonate solution (6.00 mL), extracted with ethyl acetate (5.00 mL × 2). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C1875*30mm*3 μm;mobile phase: [water(FA)-ACN];B%: 0%-30%,7min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethy l]-6,6-dimethyl-3-[2-(1-piperidyl) acetyl]-3- azabicyclo [3.1.0]hexane-2-carboxamide (45.0 mg, 0.105 mmol, 29% yield, 97% purity) as a white solid. Preparation of CPD0084205 Procedure for preparation of tert-butyl 3-vinyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxylate A mixture of tert-butyl 3-bromo-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (1.00 g, 3.31 mmol, 1.00 eq), potassium;trifluoro (vinyl) boranuide (1.33 g, 9.93 mmol, 3.00 eq) and potassium carbonate (1.37 g, 9.93 mmol, 3.00 eq) in dimethylsulfoxide (10.0 mL), follow by cyclopenta-2,4-dien- 1-yl(diphenyl)phosphane;dichloropalladium;iron(II) (121 mg, 0.165 mmol, 0.05 eq) at 25°C. After stirring at 100°C for 12 h under nitrogen atmosphere, the reaction mixture was diluted with water (30.0 mL) and extracted with dichloromethane (30.0 mL × 3). The combined organic layers were washed with brine (60.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , Petroleum ether: Ethyl acetate = 3:1) to afford tert-butyl 3-vinyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (578 mg, 2.32 mmol, 70% yield) as colorless oil. LCMS (Method C): R _t = 0.854 min; MS (ESIpos): m/z = 250.2 [M+H] ⁺ . Procedure for preparation of tert-butyl 3-ethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5- carboxylate To a solution of tert-butyl 3-vinyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (1.29 g, 5.17 mmol, 1.00 eq) in ethyl acetate (15.0 mL) was added palladium on carbon (120 mg, 5.17 mmol, 10% purity, 1.00 eq) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen 3 times. After stirring at 25°C for 3 h under hydrogen (15.0 psi), the reaction mixture was filtered and concentrated under reduced pressure to afford tert-butyl 3-ethyl-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazine-5-carboxylate (1.18 g, crude) as yellow oil. LC-MS (Method C): R _t = 0.862 min; MS (ESIpos): m/z = 252.2 [M+H] ⁺ . Procedure for preparation of 3-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine To a solution of tert-butyl 3-ethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (1.18 g, 4.70 mmol, 1.00 eq) in dioxane (5.00 mL) was added hydrochloric acid (4.00 M in dioxane, 5.00 mL, 4.26 eq) at 25°C. After stirring at 25°C for 4 h, the reaction mixture was filtered and concentrated under reduced pressure to afford 3-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (1.24 g, crude, hydrochloric acid salt) as a white solid, which was used into the next step without further purification. LC-MS (Method H): R _t = 0.721 min; MS (ESIpos): m/z = 152.1 [M+H] ⁺ . Procedure for preparation of benzyl 2-(3-ethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5- yl)acetate To a solution of 3-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (1.09 g, 5.81 mmol, 1.00 eq, hydrochloric acid salt) and benzyl 2-bromoacetate (1.46 g, 6.39 mmol, 1.00 mL, 1.10 eq) in acetonitrile (20.0 mL) was added potassium carbonate (4.01 g, 29.0 mmol, 5.00 eq) at 25°C. After stirring at 25°C for 12 h, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition; column: Waters Xbridge C18150*50 mm* 10 μm; mobile phase: [water (NH ₄ HCO ₃ ) -ACN];B%: 31%-61%, 10 min) to afford benzyl 2-(3-ethyl-6,7- dihydro-4H-pyrazolo [1,5-a]pyrazin-5-yl) acetate (320 mg, 1.07 mmol, 18% yield) as yellow oil. LC-MS (Method G): R _t = 0.914 min; MS (ESIpos): m/z = 300.1 [M+H] ⁺ . Procedure for preparation of 2-(3-ethyl-6,7-dihydro-4H-pyrazolo[1, 5-a]pyrazin-5-yl) acetic acid To a solution of benzyl 2-(3-ethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl) acetate (280 mg, 0.935 mmol, 1.00 eq) in ethyl acetate (5.00 mL) was added palladium on carbon (30.0 mg, 0.935 mmol, 10% purity, 1.00 eq) at 25°C under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen 3 times, after stirring at 25°C for 3 h under hydrogen (15 psi), the reaction mixture was filtered and concentrated under reduced pressure to give 2-(3-ethyl-6,7-dihydro-4H-pyrazolo[1,5- a]pyrazin-5-yl) acetic acid (150 mg, crude) as colorless oil. LC-MS (Method H): R _t = 0.215 min; MS (ESIpos): m/z = 208.2 [M-H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[(1S) -2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-3-[2-(3-ethyl-6,7-dihydro-4H- pyrazolo[1,5-a]pyrazin-5-yl)acetyl]-6,6-dimethyl-3-azabicycl o[3.1.0]hexane-2-carboxamide To a solution of 2-(3-ethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)acetic acid (140 mg, 0.669 mmol, 1.00 eq) and (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl] -6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (254 mg, 0.736 mmol, 1.10 eq, hydrochloric acid salt) in dichloromethane (5.00 mL) were added diisopropylethylamine (259 mg, 2.01 mmol, 350 μL, 3.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (381 mg, 1.00 mmol, 1.50 eq). After stirring at 25°C for 3 h, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi C18150*25 mm* 10 μm; mobile phase: [water (FA) -ACN];B%: 7%-37%, 10 min) to afford (1R, 2S, 5S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]meth yl]ethyl]-3-[2-(3-ethyl- 6,7-dihydro-4H-pyrazolo [1,5-a]pyrazin-5-yl)acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2- carboxamide (115 mg, 230 μmol, 34% yield) as a white solid. LC-MS (Method C): R _t = 0.703 min; MS (ESIpos): m/z = 500.4 [M+H] ⁺ . Procedure for preparation of CPD0084205 - (1R,2S,5S) -N-[(1S)-1-cyano-2-[(3S) -2-oxopyrrolidin- 3-yl]ethyl]-3-[2-(3-ethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyra zin-5-yl)acetyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl] ethyl]-3-[2-(3- ethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)acetyl]-6,6 -dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (100 mg, 0.200 mmol, 1.00 eq) in dichloromethane (3.00 mL), follow by methoxycarbonyl- (triethylammonio)sulfonyl-azanide (95.4 mg, 0.400 mmol, 2.00 eq) at 0°C. After stirring at 25°C for 2 h, the reaction mixture was diluted with water (30.0 mL) at 25°C. The solution was extracted with dichloromethane (10.0 mL × 3), ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi C18150*25 mm*10 μm; mobile phase: [water (FA) -ACN];B%: 17%-37%, 10 min) to afford (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethy l]-3-[2-(3-ethyl-6,7-dihydro-4H-pyrazolo [1,5-a]pyrazin-5-yl)acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxamide (23.0 mg, 47.8 μmol, 24% yield, 100% purity) as yellow oil. Preparation of CPD0084207 Procedure for preparation of tert-butyl N-[(1S)-2-[(1R,2S,5S)-2-[[(1S) -1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]carbamoyl]-6,6-dimethyl-3-azabicycl o[3.1.0] hexan-3-yl]-1-methyl-2- oxo-ethyl]-N-ethyl-carbamate To a solution of (2S)-2-[tert-butoxycarbonyl (ethyl) amino]propanoic acid (399 mg, 1.84 mmol, 1.20 eq) in dichloromethane (10.0 mL) were added diisopropylethylamine (593 mg, 4.59 mmol, 799 μL, 3.00 eq), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (872 mg, 2.29 mmol, 1.50 eq) and (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethy l]-6,6-dimethyl-3- azabicyclo[3.1.0] hexane-2-carboxamide (500 mg, 1.53 mmol, 1.00 eq, hydrochloric acid salt) at 0°C. After stirring at 25°C for 4 h, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex luna C18150*40 mm* 15μm; mobile phase: [water(FA)-ACN]; B%:35%-65%,10 min) to afford tert-butyl N- [(1S)-2-[(1R,2S,5S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin -3-yl]ethyl]carbamoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexan-3-yl]-1-methyl-2-oxo-ethyl]-N-ethyl-c arbamate (240 mg, 0.490 mmol, 32% yield) as a white solid. LCMS (Method C): R _t = 0.800 min; MS (ESIpos): m/z = 490.3 [M+H] ⁺ . Procedure for preparation of CPD0084207 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S) -2-oxopyrrolidin- 3-yl]ethyl]-3-[(2S)-2-(ethylamino)propanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2- carboxamide To a solution of tert-butyl N-[(1S)-2-[(1R,2S,5S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolid in-3-yl] ethyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl] -1-methyl-2-oxo-ethyl]-N-ethyl-carbamate (100 mg, 0.204 mmol, 1.00 eq) in acetonitrile (1.00 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol, 0.500 mL, 33.1 eq) at 0°C. After stirring at 25°C for 1 h, the reaction mixture was filtered to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi C18 150*25 mm* 10 μm; mobile phase: [water(FA)-ACN];B%:2%-26%, 10 min) to afford (1R,2S,5S)-N-[(1S)- 1-cyano-2- [(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-[(2S)-2-(ethylamino)prop anoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (59.0 mg, 144 μmol, 70% yield, 95% purity) as yellow oil. Preparation of CPD0084208 Procedure for preparation of CPD0084208 - (1R,2S,5S)-3-(acetyl-L-prolyl)-N-((S)-1-cyano-2-((S)- 2-oxopyrrolidin-3-yl)ethyl)-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxamide To a solution of (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethy l]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (200 mg, 688 μmol, 1.00 eq), (2S)-1-acetylpyrrolidine-2- carboxylic acid (162 mg, 1.03 mmol, 1.50 eq), diisopropylethylamine (267 mg, 2.07 mmol, 359 μL, 3.00 eq) in dichloromethane (4.00 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (392 mg, 1.03 mmol, 1.50 eq) at 0°C. After stirring at 25°C for 6 h, the reaction mixture was concentrated at 25°C to give a residue. The residue was purified by prep-HPLC (formic acid, column: Phenomenex Synergi C18 150*25mm* 10 μm; mobile phase: [water(formic acid)- acetonitrile];B%: 10%-40%,10min) to afford (1R,2S,5S)-3-[(2S)-1-acetylpyrrolidine-2-carbonyl]-N-[(1S)- 1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-6,6-dimethyl-3-a zabicyclo[3.1.0]hexane-2-carboxamide (34.0 mg, 78.3 μmol, 11% yield, 99% purity) as a white solid. Preparation of CPD0084209 Procedure for preparation of tert-butyl N-[(1S)-2-amino-2-oxo-1-[[(3S) -2-oxopyrrolidin-3- yl]methyl]ethyl]carbamate Ammonia gas (20.0 M, 873 μL, 1.00 eq) was bubbled into methanol (250 mL) at -70°C for 0.5 h. Methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3- yl]propanoate (5.00 g, 17.5 mmol, 1.00 eq) was added to the above solution (50.0 mL, 20.0 mmol/L) at 25°C. After stirring at 25°C for 40 h in a sealed tube, the mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 3/1 to 0/1, then ethyl acetate/methanol = 30/1 to 15/1) to give tert-butyl N-[(1S)-2-amino-2-oxo-1-[[(3S) -2-oxopyrrolidin-3-yl]methyl]ethyl]carbamate (20.0 g, 73.7 mmol, 84% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.37-7.27 (m, 1H), 7.19 (br. s, 1H), 6.64 (br. s, 1H), 6.17 (d, J = 6.2 Hz, 1H), 4.31-4.17 (m, 1H), 3.33-3.20 (m, 2H), 2.51-2.38 (m, 1H), 2.36-2.22 (m, 1H), 2.06-1.98 (m, 1H), 1.84-1.69 (m, 2H). Procedure for preparation of tert-butyl N-[(1S) -2-amino-2-oxo-1-[[(3S) -2-oxopyrrolidin-3- yl]methyl]ethyl]carbamate To a solution of tert-butyl N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]e thyl]carbamate (15.0 g, 55.3 mmol, 1.00 eq) in acetonitrile (120 mL) was added hydrochloric acid (4.00 M in ethyl acetate, 60.0 mL, 4.34 eq) at 0°C dropwise. After stirring at 25°C for 2 h, the mixture was concentrated to give (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (15.4 g, crude, 2 hydrochloric acid salt) as a white solid. ¹ H NMR (400 MHz, D ₂ O) δ = 4.12 (dd, J = 8.8, 5.6 Hz, 1H), 3.43-3.28 (m, 2H), 2.73 (q, J = 8.4 Hz, 1H), 2.39-2.37 (m, 1H), 2.18-2.08 (m, 1H), 2.06-2.02 (m, 1H), 1.90-1.78 (m, 1H). Procedure for preparation of tert-butyl (1R,2S,5S)-2-(((S)-1-amino-1-oxo-3-((R)-2-oxopyrrolidin- 3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-3-carboxylate To a mixture of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3 .1.0]hexane-2-carboxylic acid (7.13 g, 27.9 mmol, 1.00 eq), (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (5.80 g, 27.9 mmol, 1.00 eq, hydrochloric acid salt) and diisopropylethylamine (10.8 g, 83.8 mmol, 14.6 mL, 3.00 eq) in dichloromethane (100 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (15.9 g, 41.9 mmol, 1.5 eq) 0°C. After stirring at 25°C for 16 h, the mixture was concentrated at 40°C to give a residue. The residue was purified by flash silica gel chromatography [Instrument: Agela Technologies OCTOPUS HS-1200; Column: 330g Flash Column Welch Ultimate XB_C1820-40 μm; 120 A, Mobile phash: [water: acetonitrile]; Gradient B%: 0%-50%, 10 min; 50%, 10 min; flow 150 ml/min; temperature] to give tert-butyl (1R,2S,5S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2- oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-6,6-dimethyl-3-az abicyclo[3.1.0]hexane-3-carboxylate (6.00 g, 14.7 mmol, 53% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.24-8.14 (m, 1H), 7.61 (d, J = 16.0 Hz, 1H), 7.39-7.20 (m, 1H), 7.04 (d, J = 5.6 Hz, 1H), 4.28-4.24 (m, 1H), 4.01 (d, J = 18.0 Hz, 1H), 3.62-3.45 (m, 1H), 3.29-3.24 (m, 1H), 3.21-3.03 (m, 2H), 2.34-2.09 (m, 2H), 2.05-1.89 (m, 1H), 1.78-1.47 (m, 2H), 1.40-1.24 (m, 11H), 1.00 (s, 3H), 0.89 (s, 3H). LC-MS (Method D): Rt = 0.816 min; MS (ESIpos): m/z = 254.0 [M+H] ⁺ . SFC: de% = 100%. Procedure for preparation of (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((R)-2-oxopyrrolidin-3- yl)propan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-car boxamide To a solution of tert-butyl (1R,2S,5S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3 - yl]methyl]ethyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]h exane-3-carboxylate (6.00 g, 14.7 mmol, 1.00 eq) in acetonitrile (70.0 mL) was added hydrochloric acid (4.00 M in ethyl acetate, 21.2 mL, 5.77 eq) at 0°C. After stirring at 25°C for 2 h, the mixture was filtered and the filter cake was dried under reduced pressure to give (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (5.00 g, 14.5 mmol, 99% yield, hydrochloric acid salt) as a yellow solid. ¹ H NMR (400 MHz, D ₂ O) δ = 4.42 (dd, J = 10.4, 4.8 Hz, 1H), 3.74 (dd, J = 12.8, 5.2 Hz, 1H), 3.44-3.25 (m, 3H), 2.68-2.68 (m, 1H), 2.38-2.36 (m, 1H), 2.22 (m, 1H), 2.05 (d, J = 5.2 Hz, 1H), 1.96-1.78 (m, 4H), 1.08 (d, J = 4.4 Hz, 6H). LC-MS (Method H): Rt = 1.222 min; MS (ESIpos): m/z = 309.3 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-tert-butyl 2-methyl 6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2,3-dicarboxylate To a solution of methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (10.0 g, 48.6 mmol, 1.00 eq, hydrochloric acid salt) and sodium bicarbonate (16.3 g, 194 mmol, 7.56 mL, 4.00 eq) in tetrahydrofuran (80.0 mL) and water (80.0 mL) were added tert-butyl (2-methylpropan-2-yl)oxycarbonyl carbonate (12.7 g, 58.3 mmol, 13.4 mL, 1.20 eq) dropwise at 25°C. After stirring at 25°C for 16 h, the reaction mixture was diluted with water (200 mL) at 25°C, and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue to give (1R,2S,5S)-3-tert-butyl 2-methyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (15.0 g, crude) as light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 4.21 (s, 1H), 4.09 (s, 1H), 3.79-3.71 (m, 3H), 3.70-3.60 (m, 1H), 3.49- 3.36 (m, 1H), 1.45-1.36 (m, 11H), 1.03 (s, 3H), 0.98 (d, J = 4.8 Hz, 3H). LC-MS (Method H): Rt = 1.643 min; MS (ESIpos): m/z = 214.2 [M+H-56] ⁺ . m/z = 170.2 [M+H-100] ⁺ . Procedure for preparation of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid To a solution of (1R,2S,5S)-3-tert-butyl 2-methyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,3- dicarboxylate (15.0 g, 55.7 mmol, 1.00 eq) in tetrahydrofuran (100 mL) was added lithium hydroxide hydrate (9.35 g, 223 mmol, 4.00 eq) in water (100 mL) at 25°C dropwise. After stirring at 25°C for 16 h, the reaction mixture was diluted with water (100 mL) and adjust pH to 3-4 with hydrogen chloride (2.00 M in water), and extracted with ethyl acetate (80.0 mL), ethyl acetate/methanol (v/v = 10/1, 100 mL × 3). The combined organic layers were washed with brine (50.0 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-3-tert-butoxycarbonyl-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (13.0 g, 50.9 mmol, 91% yield) as light yellow oil. 1H NMR (400 MHz, CDCl ₃ ) δ = 4.22-4.11 (m, 1H), 3.70-3.55 (m, 1H), 3.44 (dd, J = 19.2, 11.2 Hz, 1H), 1.49-1.39 (m, 11H), 1.06 (s, 3H), 0.98 (s, 3H). LC-MS (Method G): Rt = 0.177 min; MS (ESIpos): m/z = 254.0 [M-H]-. Procedure for preparation of methyl ethyl-L-prolinate To a solution of methyl (2S)-pyrrolidine-2-carboxylate (5.00 g, 30.2 mmol, 1.00 eq, hydrogen chloride) in N,N-dimethylformamide (40.0 mL) were added triethylamine (6.11 g, 60.3 mmol, 8.40 mL, 2.00 eq) and dimethylaminopyridine (36.8 mg, 301 μmol, 0.01 eq). After stirring at 25°C for 30 min, a solution of iodoethane (5.18 g, 33.2 mmol, 2.66 mL, 1.10 eq) in N,N-dimethylformamide (10.0 mL) was added dropwise. After stirring at 60°C for 3.5 h, the reaction mixture was cooled to room temperature. The solution was diluted with ethyl acetate (20.0 mL) and water (20.0 mL). The solution was washed with water (20.0 mL × 2). The organic phase was washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give methyl (2S)-1-ethylpyrrolidine-2-carboxylate (2.19 g, 13.9 mmol, 46% yield) as yellow oil. Procedure for preparation of (S)-1-ethylpyrrolidine-2-carboxylic acid A solution of methyl (2S)-1-ethylpyrrolidine-2-carboxylate (1.00 g, 6.36 mmol, 1.00 eq) in water (5.00 mL) and hydrochloric acid (12.0 M in water, 5.00 mL, 9.43 eq) was stirred at 80°C for 12 h. The mixture was lyophilized to give (2S)-1-ethylpyrrolidine-2-carboxylic acid (1.28 g, crude, hydrochloride acid salt) as yellow oil. ¹ H NMR (400 MHz, CD ₃ OD) δ = 4.44-4.35 (m, 1H), 3.85-3.77 (m, 1H), 3.53-3.40 (m, 1H), 3.36-3.18 (m, 3H), 2.67-2.51 (m, 1H), 2.28-2.14 (m, 2H), 2.12-1.95 (m, 1H), 1.38 (t, J = 7.2 Hz, 3H). Procedure for preparation of (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((R)-2-oxopyrrolidin-3- yl)propan-2-yl)-3-(ethyl-L-prolyl)-6,6-dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (300 mg, 870 μmol, 1.00 eq, hydrochloride acid salt), (2S)-1-ethylpyrrolidine-2-carboxylic acid (234 mg, 1.30 mmol, 1.50 eq, hydrochloric acid salt), diisopropylethylamine (337 mg, 2.61 mmol, 454 μL, 3.00 eq) in N,N-dimethylformamide (4.00 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (496 mg, 1.30 mmol, 1.50 eq) at 0°C. After stirring at 25°C for 6 h, the reaction mixture was concentrated at 25°C to give a residue. The residue was purified by preparative HPLC (formic acid condition, column: Waters Xbridge 150*25mm* 5 μm; mobile phase: [water(ammonium hydrogen carbonate)- acetonitrile];B%: 2%-32%,10min) to give (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]- 3-[(2S)-1-ethylpyrrolidine-2-carbonyl]-6,6-dimethyl-3-azabic yclo[3.1.0]hexane-2-carboxamide (102 mg, 235 μmol, 27% yield) as a white solid. LC-MS (Method C): Rt = 0.127 min; MS (ESIpos): m/z = 434.3 [M+H] ⁺ . Procedure for preparation of CPD0084209 - (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3- yl)ethyl)-3-(ethyl-L-prolyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxamide A mixture of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-3-[(2S)-1- ethylpyrrolidine-2-carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxamide (100 mg, 231 μmol, 1.00 eq) and Burgess reagent (219 mg, 922 μmol, 4.00 eq) in dichloromethane (2.00 mL) was degassed and purged with nitrogen for 3 times. After stirring at 25°C for 6 h under nitrogen atmosphere, the mixture was concentrated at 25°C to give a residue. The residue was purified by prep-HPLC (nitrogen, column: Phenomenex Synergi Polar-RP 100*25 mm*4 μm; mobile phase: [water(trifluoroacetic acid)- acetonitrile]; B%: 15%-35%,7min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2- [(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-[(2S)-1-ethylpyrrolidine -2-carbonyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (25.0 mg, 59.5 μmol, 26% yield, 99% purity) as a white solid. Preparation of CPD0084210 Procedure for preparation of tert-butylN-[(1S)-2-[(1R,2S,5S)-2-[[(1S)-2-amino-2-oxo-1-[[( 3S)-2- oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-6,6-dimethyl-3-az abicyclo[3.1.0]hexan-3-yl]-1- methyl-2-oxo-ethyl]carbamate To a solution of (2S)-2-(tert-butoxycarbonylamino) propanoic acid (180 mg, 0.951 mmol, 1.50 eq) and (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-6,6-dimethyl-3- azabicyclo [3.1.0]hexane-2-carboxamide (219 mg, 0.634 mmol, 1.00 eq, hydrochloric acid salt) in dichloromethane (6.00 mL) were added dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]- dimethyl-ammonium; hexafluorophosphate (361 mg, 0.951 mmol, 1.50 eq) and N,N- diisopropylethylamine (246 mg, 1.90 mmol, 0.331 mL, 3.00 eq) at 0°C. After stirring at 20°C for 2 h, the reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi C18150*25 mm* 10 μm; mobile phase: [water (FA) -ACN]; B%: 17%-47%, 10 min) and lyophilized to afford tert-butyl N-[(1S)-2-[(1R,2S,5S)-2-[[(1S)-2-amino-2- oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]- 1-methyl-2-oxo-ethyl]carbamate (145 mg, 0.302 mmol, 48% yield) as a white solid. Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-aminopropanoyl]-N-[(1S)-1-cyano-2-[(3S) -2- oxopyrrolidin-3-yl]ethyl]-6,6-dimethyl-3-azabicyclo[3.1.0]he xane-2-carboxamide To a solution of tert-butyl N-[(1S)-2-[(1R,2S,5S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxop yrrolidin-3- yl]methyl]ethyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]h exan-3-yl]-1-methyl-2-oxo- ethyl]carbamate (130 mg, 0.271 mmol, 1.00 eq) in dichloromethane (10.0 mL) was added Burgess reagent (194 mg, 0.813 mmol, 3.00 eq) at 0°C. After stirring at 20°C for 5 h under nitrogen atmosphere, the reaction mixture was quenched with hydrogen chloride aqueous solution (1.00 M, 10.0 mL) at 25°C. The solution was extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi C18150*25 mm* 10 μm; mobile phase: [water (FA) -ACN];B%: 27%-57%, 10 min) and lyophilized to afford (1R,2S,5S)-3-[(2S)-2-aminopropanoyl]-N-[(1S)-1-cyano-2-[(3S) -2- oxopyrrolidin-3-yl]ethyl]-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxamide (25.0 mg, 0.692 mmol, 25% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.85 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H), 7.06 (d, J = 7.2 Hz, 1H), 5.00- 4.83 (m, 1H), 4.13 (s, 1H), 3.85-3.67 (m, 2H), 3.19-3.05 (m, 2H), 2.43-2.34 (m, 1H), 2.17-2.02 (m, 2H), 1.78-1.71 (m, 1H), 1.71-1.62 (m, 1H), 1.56-1.50 (m, 1H), 1.34 (s, 10H), 1.27 (d, J = 7.6 Hz, 1H), 1.08 (d, J = 7.2 Hz, 3H), 1.03 (s, 3H), 0.92 (s, 3H). Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-acetamidopropanoyl]-N-[(1S)-1-cyano-2-[ (3S)- 2-oxopyrrolidin-3-yl]ethyl]-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-2-aminopropanoyl]-N-[(1S)-1-cyano-2-[(3S) -2-oxopyrrolidin-3- yl]ethyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxami de (25.0 mg, 0.692 mmol, 1.00 eq) in dichloromethane (4.00 mL) were added triethylamine (35.0 mg, 0.346 mmol, 0.481 mL, 5.00 eq) and acetic anhydride (14.1 mg, 0.138 mmol, 0.130 mL, 2.00 eq) at 20°C. After stirring at 20°C for 15 h, the reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi C18150*25 mm* 10 μm; mobile phase: [water (FA) -ACN]; B%: 9%-39%, 10 min) and lyophilized to afford (1R,2S,5S)-3-[(2S)-2-acetamidopropanoyl]-N-[(1S)-1- cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (17.5 mg, 0.434 mmol, 63% yield, 100% purity) as a white solid. Preparation of CPD0084211 Procedure for preparation of (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-6,6-dimethyl-3-(3-(trifluoromethoxy)propanoy l)-3-azabicyclo[3.1.0]hexane-2- carboxamide To a solution of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (200 mg, 580 μmol, 1.00 eq, hydrochloric acid salt), 3-(trifluoromethoxy)propanoic acid (137 mg, 869 μmol, 1.50 eq), diisopropylethylamine (224 mg, 1.74 mmol, 303 μL, 3.00 eq) in dichloromethane (4.00 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N’,N’- tetramethyluronium hexafluorophosphate (330 mg, 870 μmol, 1.50 eq) at 0°C. After stirring at 25°C for 6 h, the mixture was concentrated at 25°C to give a residue. The residue was purified by prep-HPLC (formic acid, column: Phenomenex luna C18150*25mm*10 μm; mobile phase: [water(formic acid)- acetonitrile]; B%: 18%-48%,10min) to give (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin- 3-yl]methyl]ethyl]-6,6-dimethyl-3-[3-(trifluoromethoxy)propa noyl]-3-azabicyclo[3.1.0]hexane-2- carboxamide (126 mg, 281 μmol, 48% yield) as a white solid. LC-MS (Method D): Rt = 0.808 min; MS (ESIpos): m/z = 449.2 [M+H] ⁺ . Procedure for preparation of CPD0084211 - (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3- yl)ethyl)-6,6-dimethyl-3-(3-(trifluoromethoxy)propanoyl)-3-a zabicyclo[3.1.0]hexane-2- carboxamide A mixture of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-6,6- dimethyl-3-[3-(trifluoromethoxy)propanoyl]-3-azabicyclo[3.1. 0]hexane-2-carboxamide (126 mg, 280 μmol, 1.00 eq), Burgess reagent (267 mg, 1.12 mmol, 4.00 eq) in dichloromethane (2.00 mL) was degassed and purged with nitrogen for 3 times. The mixture was stirred at 25°C for 6 h under nitrogen atmosphere. The mixture was concentrated at 25°C to give a residue. The residue was purified by prep- HPLC (Neutral, column: Waters Xbridge 150*25mm*5 μm; mobile phase: [water(ammonium hydrogen carbonate)-acetonitrile]; B%: 24%-54%, 8 min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]-6,6-dimethyl-3-[3-(trifluoromethox y)propanoyl]-3-azabicyclo[3.1.0]hexane-2- carboxamide (12.0 mg, 27.3 μmol, 10% yield, 98% purity) as a white solid. Preparation of CPD0084212 Procedure for preparation of (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S) -2-oxopyrrolidin-3- yl)propan-2-yl)-3-(2-(diisopropylamino)acetyl)-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2- carboxamide To a solution of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-6, 6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (100 mg, 290 μmol, 1.00 eq, hydrochloric acid salt), 2-(diisopropylamino) acetic acid (69.3 mg, 435 μmol, 1.50 eq) and N,N-diisopropylethylamine (150 mg, 1.16 mmol, 202 μL, 4.00 eq) in dichloromethane (5.00 mL) were added N-[(dimethylamino)-3-oxo-1H- 1,2, 3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanamini um hexafluorophosphate (165 mg, 436 μmol, 1.50 eq) at 0°C in portions. After warming to 25°C and stirring at this temperature for 6 h, the reaction mixture was concentrated under reduced pressure to afford (1R,2S,5S)-N-[(1S) -2-amino-2- oxo-1-[[(3S)-2-oxopyrrolidin-3-yl] methyl]ethyl]-3-[2-(diisopropylamino) acetyl]-6, 6-dimethyl- 3- azabicyclo [3.1.0]hexane-2-carboxamide (300 mg, crude) as yellow oil. Procedure for preparation of CPD0084212 - (1R,2S,5S) -N-((S)-1-cyano-2- ((S)-2 -oxopyrrolidin-3- yl)ethyl)-3-(2-(diisopropylamino)acetyl)-6,6-dimethyl-3-azab icyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl] ethyl]-3-[2- (diisopropylamino) acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (300 mg, 267 μmol, 40% purity, 1.00 eq) in dichloromethane (5.00 mL) was added Burgess reagent (318 mg, 1.33 mmol, 5.00 eq) in portions at 0°C. After stirring at 25°C for 5 h, the resulting mixture was quenched with saturated sodium bicarbonate aqueous solution (6.00 mL) at 25°C, extracted with ethyl acetate (5.00 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Shim-pack C18150*25*10 μm; mobile phase: [water (TFA) -ACN]; B%: 18%-48%, 10 min) to afford (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethy l]-3-[2-(diisopropylamino)acetyl]- 6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxamide (40.0 mg, 24.2 μmol, 65% yield, 88% purity, trifluoroacetic acid salt) as colorless oil. Procedure for preparation of CPD0084212 - (1R,2S,5S)-N-((S)-1-cyano-2- ((S)-2-oxopyrrolidin-3- yl)ethyl)-3-(2-(diisopropylamino)acetyl)-6,6-dimethyl-3-azab icyclo[3.1.0]hexane-2-carboxamide The crude product was purified by reversed-phase HPLC (column: Phenomenex Synergi Polar-RP 100*25 mm*4 μm; mobile phase: [water (TFA)-ACN];B%:18%-38%, 7 min) to afford (1R,2S,5S) -N- [(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-[2-(diis opropylamino)acetyl]-6,6-dimethyl-3- azabicyclo[3.1.0] hexane-2-carboxamide (30.0 mg, 69.5 μmol, 75% yield) as colorless oil. Preparation of CPD0084215 Procedure for preparation of Dibenzyl (E)-but-2-enedioate To a solution of fumaric acid (5.00 g, 43.1 mmol, 1.00 eq) in N,N-dimethylformamide (100 mL) was added triethylamine (8.72 g, 86.2 mmol, 12.0 mL, 2.00 eq) dropwise at 20°C, follow by bromomethylbenzene (14.7 g, 86.2 mmol, 10.2 mL, 2.00 eq) at 25°C. After stirring at 100°C for 15 h, the reaction mixture was quenched by water (400 mL) at 25°C. The resulting suspension was stirred at 25°C for 0.5 h, filtered to afford dibenzyl (E)-but-2-enedioate (7.29 g, 24.6 mmol, 57% yield) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.43-7.33 (m, 10H), 6.85 (s, 2H), 5.23 (s, 4H). Procedure for preparation of benzyl 2-oxoacetate Dibenzyl (E) -but-2-enedioate (1.00 g, 3.37 mmol, 1.00 eq) was dissolved in dichloromethane (20.0 mL), then cooled to -78°C. Ozone was bubbled into the stirred solution for 10 min, follow by adding dimethylsulfane (252 mg, 4.05 mmol, 0.297 mL, 1.20 eq) dropwise. After stirring at -78°C for 5 h, the mixture was warmed to 20°C and stirred at this temperature for 15 h. The reaction mixture was concentrated to give a residue. The residue was quenched with water (30.0 mL) at 25°C, and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 1/0 then 1/1) to afford benzyl 2-oxoacetate (800 mg, crude) as light yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.44-7.30 (m, 5H), 5.20-5.05 (m, 2H). Procedure for preparation of benzyl 2-[[3-(trifluoromethyl) oxetan-3-yl] amino] acetate A solution of 3-(trifluoromethyl) oxetan-3-amine (400 mg, 2.25 mmol, 1.00 eq, hydrochloric acid salt) and benzyl 2-oxoacetate (555 mg, 3.38 mmol, 0.235 mL, 1.50 eq) in N,N-dimethylformamide (6.00 mL) was stirred at 0°C for 0.5 h. Trimethylsilyl trifluoromethanesulfonate (1.25 g, 5.63 mmol, 1.02 mL, 2.50 eq) was then added to the solution above at 0°C. After stirring at 0°C for 1 h, borane (1.00 M in tetrahydrofuran, 2.25 mL, 1.00 eq) was added and stirred at 0°C for another 1 h. The mixture was purified by reversed phase (Instrument: 80g Flash; Column: Welch Ultimate XB_C1820-40μm; eluent A: water (0.01% FA), eluent B: acetonitrile; gradient: 0-15 min 0-62% B; flow 50 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give benzyl 2-[[3-(trifluoromethyl) oxetan-3- yl]amino]acetate (200 mg, 0.691 mmol, 31% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.41-7.30 (m, 5H), 5.14 (s, 2H), 4.62-4.47 (m, 4H), 3.55 (d, J = 6.0 Hz, 2H), 3.44 (t, J = 6.4 Hz, 1H). LC-MS (Method C): R _t = 0.858 min; MS (ESIpos): m/z = 289.9 [M+H] ⁺ . Procedure for preparation of 2-[[3-(trifluoromethyl)oxetan-3-yl]amino]acetic acid To a solution of benzyl 2-[[3-(trifluoromethyl)oxetan-3-yl]amino]acetate (150 mg, 0.519 mmol, 1.00 eq) in methanol (6.00 mL) was added palladium on carbon (10 mg, 10% purity) at 20°C under nitrogen atmosphere. The suspension was degassed and purged with hydrogen for 3 times. After stirring at 20°C for 15 h under hydrogen (15.0 psi), the mixture was filtered through a pad of celite, the filter cake was washed with petroleum ether (150 mL). The filtrate was concentrated under reduced pressure to give 2-[[3-(trifluoromethyl)oxetan-3-yl]amino]acetic acid (90.0 mg, 0.452 mmol, 87% yield) as colorless oil. Procedure for preparation of CPD0084215 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin- 3-yl]ethyl]-6,6-dimethyl-3-[2-[[3-(trifluoromethyl)oxetan-3- yl]amino]acetyl]-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of 2-[[3-(trifluoromethyl)oxetan-3-yl]amino]acetic acid (60.0 mg, 0.301 mmol, 1.00 eq) and (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethy l]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (118 mg, 0.362 mmol, 1.20 eq, hydrochloric acid salt) in dichloromethane (5.00 mL) were added N,N-diisopropylethylamine (156 mg, 1.21 mmol, 0.210 mL, 4.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (172 mg, 0.452 mmol, 1.50 eq) at 20°C. After stirring at 20°C for 2 h, the reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi C18 150*25 mm*10 μm;mobile phase: [water (FA) -ACN];B%: 22%-42%, 10 min) and lyophilized to obtain (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethy l]-6,6-dimethyl-3-[2-[[3-(trifluoromethyl) oxetan-3-yl]amino]acetyl]-3-azabicyclo [3.1.0]hexane-2-carboxamide (30.0 mg, 0.629 mmol, 21% yield, 99% purity) as yellow oil. Preparation of CPD0084216 Procedure for preparation of CPD0084216 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin- 3-yl]ethyl]-3-[2-(cyclohexanecarbonylamino)acetyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxamide To a solution of (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethy l] -6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (100 mg, 0.344 mmol, 1.00 eq) were added 2- (cyclohexanecarbonylamino)acetic acid (95.7 mg, 0.516 mmol, 1.50 eq) in dichloromethane (1.50 mL) and diisopropylethylamine (134 mg, 1.03 mmol, 180 μL, 3.00 eq) N-[(dimethylamino)-3-oxo-1H-1,2,3- triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate (196 mg, 0.517 mmol, 1.50 eq) at 0°C. After stirring at this temperature for 10 min, the mixture was warmed to 20°C and stirred for another 2 h. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: [water(FA)-ACN]; B%: 18%-48%,5min) to afford (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]-3-[2-(cyclohexanecarbonylamino)ace tyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (20.0 mg, 43.7 μmol, 12% yield, 100% purity) as yellow gum. Preparation of CPD0084217 Procedure for preparation of (4-nitrophenyl)N-phenylcarbamate To a mixture of aniline (3.00 g, 32.2 mmol, 2.94 mL, 1.00 eq) and (4-nitrophenyl) carbonochloridate (7.79 g, 38.7 mmol, 1.20 eq) in tetrahydrofuran (50.0 mL) were added N-ethyl-N-propan-2-ylpropan-2- amine (5.00 g, 38.7 mmol, 6.73 mL, 1.20 eq) dropwise at 20°C. After stirring at 20°C for 16 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with ethyl acetate (100 mL), washed with brine (80.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (4-nitrophenyl) N-phenylcarbamate (12 g, crude) as a white solid which was used into the next step without further purification. Procedure for preparation of methyl 2-(phenylcarbamoylamino)acetate To a mixture of (4-nitrophenyl) N-phenylcarbamate (8.00 g, 31.0 mmol, 1.00 eq) and methyl 2- aminoacetate (3.31 g, 37.2 mmol, 1.20 eq, hydrochloric acid salt) in tetrahydrofuran (15.0 mL) were added N-ethyl-N-propan-2-ylpropan-2-amine (8.01 g, 62.0 mmol, 10.8 mL, 2.00 eq) in one portion at 20°C. After stirring at this temperature for 16 h, the reaction mixture was concentrated to give a residue. The residue was diluted with ethyl acetate (100 mL), washed with brine (80.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 80.0 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ethergradient @ 100 mL/min) and concentrated to afford methyl 2- (phenylcarbamoylamino)acetate (3.00 g, 14.4 mmol, 46% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.77 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.29- 7.18 (m, 2H), 6.44 (t, J = 5.6 Hz, 1H), 3.88 (d, J = 6.0 Hz, 2H), 3.64 (s, 3H). LC-MS (Method C): Rt = 0.257 min; MS (ESIpos): m/z = 209.9 [M+H] ⁺ . Procedure for preparation of 2-(phenylcarbamoylamino)acetic acid To a mixture of methyl 2-(phenylcarbamoylamino)acetate (3.00 g, 14.4 mmol, 1.00 eq) in tetrahydrofuran (8.00 mL) and water (8.00 mL) was added lithium hydroxide monohydrate (907 mg, 21.6 mmol, 1.50 eq). After stirring at 20°C for 5 h, the reaction mixture was filtered and diluted with water (10.0 mL) at 20°C, extracted with ethyl acetate (20.0 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered. Hydrogen chloride aqueous solution (1M) was added to the filtrate to adjust pH to 4-5. The resulting suspension was filtered and the filter cake was dried under reduced pressure to afford 2-(phenylcarbamoylamino)acetic acid (2.00 g, 10.3 mmol, 71% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.77 (s, 1H), 7.39 (dd, J = 1.0, 8.4 Hz, 2H), 7.28-7.15 (m, 2H), 7.00- 6.83 (m, 1H), 6.37 (t, J = 5.6 Hz, 1H), 3.80 (s, 2H). Procedure for preparation of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-6,6-dimethyl-3-[2-(phenylcarbamoylamino)ace tyl]-3-azabicyclo[3.1.0]hexane-2- carboxamide To a solution of 2-(phenylcarbamoylamino)acetic acid (113 mg, 0.584 mmol, 1.20 eq), (1R,2S,5S)-N- [(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]eth yl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (150 mg, 0.486 mmol, 1.00 eq), and diisopropylethylamine (189 mg, 1.46 mmol, 254 uL, 3.00 eq) in dichloromethane (5.00 mL) was added O-(7-azabenzotriazol- 1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (277 mg, 0.730 mmol, 1.50 eq) at 0°C. After stirring at 0°C for 10 min, the mixture was warmed to 20°C and stirred for 2 h. The resulting reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Phenomenex luna C18150*25mm*10 μm; mobile phase:[water(FA)-ACN];B%:15%- 45%,10min) to afford (1R,2S,5S)-N- [(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]eth yl]- 6,6-dimethyl-3-[2-(phenylcarbamoylamino)acetyl]-3-azabicyclo [3.1.0]hexane-2-carboxamide (60.0 mg, 0.128 mmol, 25% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.67-8.98 (m, 1H), 8.51 (d, J = 8.4 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 7.60 (s, 1H), 7.43 (br. s, 1H), 7.40-7.28 (m, 2H), 7.23-7.15 (m, 1H), 7.24-7.14 (m, 1H), 7.11 (br. s, 1H), 7.02 (br. s, 1H), 7.24-6.95 (m, 1H), 7.24-6.95 (m, 1H), 6.86 (t, J = 7.2 Hz, 1H), 6.32-6.21 (m, 1H), 4.37- 4.10 (m, 2H), 4.00-3.67 (m, 3H), 3.56-3.41 (m, 2H), 3.17-2.99 (m, 3H), 2.20-1.82 (m, 3H), 1.74-1.26 (m, 5H), 1.01 (s, 3 H), 0.93-0.81 (m, 3 H). LC-MS (Method C): R _t = 0.675 min; MS (ESIpos): m/z = 485.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethy l]-6,6- dimethyl-3-[2-(phenylcarbamoylamino)acetyl]-3-azabicyclo[3.1 .0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]- 6,6- dimethyl-3-[2-(phenylcarbamoylamino)acetyl]-3-azabicyclo[3.1 .0]hexane-2-carboxamide (50.0 mg, 0.103 mmol, 1.00 eq) in dichloromethane (4.00 mL) was added Burgess reagent (73.8 mg, 0.310 mmol, 3.00 eq) at 0°C. After stirring at 20°C for 7 h under nitrogen atmosphere, the mixture was quenched by water (8.00 mL), and extracted with dichloromethane (8.00 mL × 3). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase:[water(FA)-ACN];B%:18%-48%,10min) to afford (1R,2S,5S)-N- [(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-6,6-dimeth yl-3-[2-(phenylcarbamoylamino)acetyl]-3- azabicyclo[3.1.0]hexane-2-carboxamide (30.0 mg, 62.6 μmol, 60% yield, 97% purity) as a yellow solid. Preparation of CPD0084221 Procedure for preparation of tert-butyl N-[(1S)-2-[(1R,2S,5S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2- oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-6,6-dimethyl-3-az abicyclo[3.1.0]hexan-3-yl]-1- methyl-2-oxo-ethyl]-N-methyl-carbamate To a solution of (2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoic acid (265 mg, 1.30 mmol, 1.50 eq) and (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-6,6-dimethyl-3- azabicyclo [3.1.0]hexane-2-carboxamide (300 mg, 0.870 mmol, 1.00 eq, hydrochloric acid salt) in dichloromethane (6.00 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (496 mg, 1.30 mmol, 1.50 eq) and N,N-diisopropylethylamine (337 mg, 2.61 mmol, 0.455 mL, 3.00 eq) at 0°C. After stirring at 25°C for 2 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Unisil 3- 100 C18 Ultra 150*50mm*3 μm; mobile phase:[water(FA)-ACN];B%: 20%-50%,10min) to afford tert- butyl N-[(1S)-2-[(1R,2S,5S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxop yrrolidin-3- yl]methyl]ethyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]h exan-3-yl]-1-methyl-2-oxo-ethyl]-N- methyl-carbamate (310 mg, 0.628 mmol, 72% yield, 100% purity) as a white solid. LC-MS (Method A): R _t = 0.828 min; MS (ESIpos): m/z = 494.1 [M+H] ⁺ . Procedure for preparation of tert-butyl N-[(1S)-2-[(1R,2S,5S)-2-[[(1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]carbamoyl]-6,6-d methyl-3-azabicyclo [3.1.0]hexan-3-yl]-1-methyl-2- oxo-ethyl]-N-methyl-carbamate To a solution of tert-butyl N-[(1S)-2-[(1R,2S,5S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxop yrrolidin-3- yl]methyl]ethyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]h exan-3-yl]-1-methyl-2-oxo-ethyl]-N- methyl-carbamate (310 mg, 628 mmol, 1.00 eq) in dichloromethane (5.00 mL) was added Burgess reagent (449 mg, 1.88 mmol, 3.00 eq) at 0°C. After stirring at 25°C for 2 h, the reaction mixture was quenched with water (20.0 mL) at 25°C. The solution was extracted with ethyl acetate (20.0 mL × 2). The combined organic layers were washed with brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by reversed phase (Instrument: 120g Flash; Column: Welch Ultimate XB_C1820-40μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-10 min 0-60% B; flow 85 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to afford tert-butyl N-[(1S)-2-[(1R,2S,5S)-2-[[(1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]carbamoyl]-6,6-dimethyl-3-azabicycl o[3.1.0]hexan-3-yl]-1-methyl-2-oxo-ethyl]- N-methyl-carbamate (200 mg, 0.416 mmol, 66% yield, 99% purity) as a white solid. LC-MS (Method A): R _t = 0.876 min; MS (ESIpos): m/z = 473.6 [M+H] ⁺ . Procedure for preparation of tert-butyl (2R,4S)-4-(3-chloro-5-(2-(isoquinolin-4-ylamino)-2- oxoethyl)phenoxy)-2-(methylcarbamoyl)pyrrolidine-1-carboxyla te To a solution of tert-butyl N-[(1S)-2-[(1R,2S,5S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolid in-3-yl] ethyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl] -1-methyl-2-oxo-ethyl]-N-methyl- carbamate (200 mg, 0.420 mmol, 1.00 eq) in acetonitrile (3.00 mL) was added hydrochloric acid in ethyl acetate (4.00 M, 1.00 mL). After stirring at 25°C for 2 h, the reaction mixture was directly concentrated under reduced pressure to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethy l]-6,6- dimethyl-3-[(2S)-2-(methylamino)propanoyl]-3-azabicyclo [3.1.0]hexane-2-carboxamide (120 mg, 0.320 mmol, 76% yield, 100% purity) as colorless oil. LC-MS (Method A): R _t = 0.468 min; MS (ESIpos): m/z = 375.9 [M+H] ⁺ . Procedure for preparation of CPD0084221 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin- 3-yl]ethyl]-3-[(2S)-2-[(2-methoxyacetyl)-methyl-amino]propan oyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethy l]-6,6-dimethyl-3-[(2S)-2- (methylamino)propanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxam ide (100 mg, 0.266 mmol, 1.00 eq) and 2-methoxyacetic acid (36.0 mg, 0.400 mmol, 0.0305 mL, 1.50 eq) in dichloromethane (5.00 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (152 mg, 0.400 mmol, 1.50 eq) and N,N-diisopropylethylamine (103 mg, 0.799 mmol, 0.139 mL, 3.00 eq) at 0°C. After stirred at 25°C for 2 h, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Shim-pack C18150*25*10 μm; mobile phase: [water(FA)-ACN];B%: 12%-42%,10min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]-3-[(2S)-2-[(2-methoxyacetyl)-methy l-amino]propanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (29.6 mg, 0.0648 mmol, 24% yield, 98% purity) as colorless oil. Preparation of CPD0084228 Procedure for preparation of tert-butyl N-[(1S)-2-[(1R,2S,5S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2- oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-6,6-dimethyl-3-az abicyclo[3.1.0]hexan-3-yl]-1- (methoxymethyl)-2-oxo-ethyl]carbamate To a solution of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl] methyl]ethyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (150 mg, 0.486 mmol, 1.00 eq), (2S)-2-(tert- butoxycarbonylamino)-3-methoxy-propanoic acid (160 mg, 0.730 mmol, 1.50 eq) and N,N- diisopropylethylamine (189 mg, 1.46 mmol, 254μL, 3.00 eq) in dichloromethane (1.50 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (277 mg, 0.730 mmol, 1.50 eq) at 0°C. After stirring at this temperature for 10 min, the reaction mixture was warmed to 20°C and stirred for 16 h. The reaction mixture was concentrated to give a residue. The residue was purified by reversed phase reversed phase (Instrument: 120g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.05%FA), eluent B: acetonitrile; gradient: 0-15 min 50%-55% B; flow 85 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to afford tert-butyl N-[(1S)-2- [(1R,2S,5S)- 2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl] ethyl]carbamoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexan-3-yl]-1-(methoxymethyl)-2-oxo-ethyl]c arbamate (200 mg, 392 μmol, 80% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.62-7.97 (m, 1H), 7.71-7.55 (m, 1H), 7.27-6.82 (m, 3H), 4.40-4.27 (m, 1H), 4.39-4.02 (m, 3H), 3.86-3.82 (m, 1H), 3.92-3.78 (m, 1H), 3.80-3.76 (m, 1H), 3.86-3.76 (m, 1H), 3.60-3.45 (m, 1H), 3.62-3.40 (m, 3H), 3.23 (s, 7H), 3.18-3.03 (m, 2H), 2.38-2.24 (m, 2H), 2.17-2.03 (m, 1H), 1.96-1.85 (m, 1H), 1.68-1.45 (m, 4H), 1.42-1.30 (m, 22H), 1.06-0.98 (m, 3H), 0.96-0.8 (m, 3H). LC-MS (Method C): R _t = 0.813 min; MS (ESIpos): m/z = 488.2 [M+H] ⁺ . Procedure for preparation of tert-butyl N-[(1S)-2-[(1R,2S,5S)-2-[[(1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]carbamoyl]-6,6-dimethyl-3-azabicycl o[3.1.0]hexan-3-yl]-1- (methoxymethyl)-2-oxo-ethyl]carbamate To a solution of tert-butyl N-[(1S)-2-[(1R,2S,5S)-2-[[(1S)-2-amino-2-oxo-1- [[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]h exan-3-yl]-1-(methoxymethyl)-2-oxo- ethyl]carbamate (200 mg, 0.392 mmol, 1.00 eq) in dichloromethane (4.00 mL) was added Burgess reagent (234 mg, 0.981 mmol, 2.50 eq) at 0°C. After stirring at 20°C for 6 h under nitrogen atmosphere, the mixture was quenched by water (5.00 mL) at 20°C, and extracted with dichloromethane (4.00 mL × 3). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed phase reversed phase (Instrument: 80 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.05% FA), eluent B: acetonitrile; gradient: 0-15 min 50%-55% B; flow 85 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to afford tert-butyl N-[(1S)-2- [(1R,2S,5S)- 2-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoy l]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan- 3-yl]-1-(methoxymethyl)-2-oxo-ethyl]carbamate (100 mg, 203 mmol, 51% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.89-8.59 (m, 1H), 7.67 (s, 1H), 7.16 (d, J = 8.0 Hz, 1H), 5.03-4.81 (m, 1H), 4.34-4.23 (m, 1H), 4.09 (s, 1H), 3.81 (d, J = 2.0 Hz, 2H), 3.39-3.47 (m, 2H), 3.20 (s, 2H), 3.17- 3.02 (m, 2H), 2.39-2.28 (m, 2H), 2.17-1.98 (m, 2H), 1.80-1.60 (m, 2H), 1.56-1.45 (m, 1H), 1.35 (br. s, 1H), 1.28-1.23 (m, 1H), 1.28-1.22 (m, 1H), 1.44-1.20 (m, 6H), 1.05-0.95 (m, 3H), 0.94-0.76 (m, 3H). LC-MS (Method C): R _t = 0.764 min; MS (ESIpos): m/z = 392.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-amino-3-methoxy-propanoyl]-N-[(1S)-1-cy ano- 2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-6,6-dimethyl-3-azabicycl o[3.1.0]hexane-2-carboxamide To a mixture of tert-butyl N-[(1S)-2-[(1R,2S,5S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolid in-3-yl] ethyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl] -1-(methoxymethyl)-2-oxo- ethyl]carbamate (100 mg, 0.203 mmol, 1.00 eq) in acetonitrile (5.00 mL) was added hydrogen chloride in ethyl acetate (4.00 M, 500 μL, 9.83 eq) at 0°C. After stirred at 20 °C for 1 h, the reaction mixture was quenched by N,N-diisopropylethylamine (1.00 mL) at 20°C, and concentrated under reduced pressure to give (1R,2S,5S)-3-[(2S)-2-amino-3-methoxy-propanoyl]-N-[(1S)-1-cy ano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]-6,6-dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxamide (79.0 mg, crude) as colorless oil. LC-MS (Method C): R _t = 0.821 min; MS (ESIpos): m/z =392.3[M+H] ⁺ . Procedure for preparation of CPD084228 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]-3-[(2S)-3-methoxy-2-[(2,2,2-trifluoroacetyl)amino] propanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-2-amino-3-methoxy-propanoyl]-N-[(1S)-1-cy ano-2-[(3S) -2- oxopyrrolidin-3-yl]ethyl]-6,6-dimethyl-3-azabicyclo[3.1.0]he xane-2-carboxamide (70.0 mg, 0.179 mmol, 1.00 eq) and N,N-diisopropylethylamine (139 mg, 1.07 mmol, 187 μL, 6.00 eq) in methanol (2.00 mL) were added methyl 2,2,2-trifluoroacetate (68.7 mg, 0.536 mmol, 54.1 μL, 3.00 eq) at 25°C. After stirring at 20°C for 4 h, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 μm; mobile phase: [water(FA)- ACN]; B%: 20%-50%,5min) to afford (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin -3-yl]ethyl]-3- [(2S)-3-methoxy-2-[(2,2,2-trifluoroacetyl) amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (30.0 mg, 61.5 μmol, 34% yield) as a white solid. Procedure for preparation of CPD0084531 - (1R, 2S, 5S)-N-((1S)-1-cyano-2-(2- oxopyrrolidin-3- yl)ethyl)-6,6-dimethyl-3-(2-morpholinoacetyl)-3-azabicyclo[3 .1.0]hexane-2-carboxamide To a solution of (1R, 2S, 5S)-N-[(1S)-1-cyano-2-(2-oxopyrrolidin-3-yl)ethyl]-6, 6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (120 mg, 0.367 mmol, 1.00 eq, HCl salt), 2-morpholinoacetic acid (64.0 mg, 0.441 mmol, 1.20 eq) and DIPEA (142 mg, 1.10 mmol, 0.191 mL, 3.00 eq) in DCM (3.00 mL) was added HATU (167 mg, 0.440 mmol, 1.20 eq) in portions at 0°C. After stirring at 25°C for 2 h, the reaction mixture was added DCM (20.0 mL). The organic layer was washed with water (10.0 mL × 3), dried over anhydrous Na2SO4, filtered and filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C1875 × 30mm × 3 μm; mobile phase: [water(FA)-ACN]; B%: 0%-30%,7min) to afford (1R, 2S, 5S)-N-[(1S)-1-cyano-2-(2- oxopyrrolidin-3-yl) ethyl]-6, 6-dimethyl-3-(2-morpholinoacetyl)-3-azabicyclo[3.1.0]hexane- 2- carboxamide (14.0 mg, 0.033 mmol, 9% yield, 98% purity) as yellow gum. Preparation of CPD0084528 Procedure for preparation of tert-butyl (1-amino-1-oxo-3-(4,5,6,7-tetrahydrobenzo[d]thiazol-4- yl)propan-2-yl)carbamate A mixture of methyl 2-((tert-butoxycarbonyl)amino)-3-(4,5,6,7-tetrahydrobenzo[d] thiazol-4- yl)propanoate (0.300 g, 0.881 mmol, 1.00 eq) in NH3/MeOH (20 M, 20 mL) was stirred at 25 °C for 64 h. The mixture was concentrated to give tert-butyl (1-amino-1-oxo-3-(4,5,6,7-tetrahydrobenzo[d]thiazol- 4-yl)propan-2-yl)carbamate (300 mg, crude) as yellow oil. The crude product was used for next step directly without purification. LC-MS (Method C): R _t = 0.707 min; MS (ESIpos): m/z = 326.3 [M+H] ⁺ . Procedure for preparation of 2-amino-3-(4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)propanamid e hydrochloride To a solution of tert-butyl (1-amino-1-oxo-3-(4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)pro pan-2- yl)carbamate (300 mg, 0.922 mmol, crude, 1.00 eq) in dioxane (10 mL) was added HCl (4 M in dioxane, 20 mL) at 0 °C. The mixture was warmed to 25 °C and stirred at this temperature for 2 h. The mixture was concentrated to give 2-amino-3-(4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)propanamid e hydrochloride as a white solid. The residue was used for next step directly without purification. Procedure for preparation of (1R,2S,5S)-N-(1-amino-1-oxo-3-(4,5,6,7-tetrahydrobenzo[d]thi azol- 4-yl)propan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacet amido) butanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of (1R,2S,5S)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)b utanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (278 mg, 0.764 mmol, 1.00 eq) in N,N-dimethylformamide (5 mL) were added O-(7-Aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (436 mg, 1.15 mmol, 1.50 eq) and N,N-diisopropylethylamine (395 mg, 3.06 mmol, 0.532 mL, 4.00 eq) at 0 °C. After stirring for 0.5 h, a solution of 2-amino-3-(4,5,6,7-tetrahydrobenzo[d]thiazol-4- yl)propanamide hydrochloride (200 mg, 0.764 mmol, crude, 1.00 eq) in N,N-dimethylformamide (2 mL) was added dropwise. After addition, the mixture was allowed to warm to 25 °C and stirred for 16 h. The mixture was poured into water (30.0 mL) and extracted with ethyl acetate (30.0 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~90% ethyl acetate/petroleum ether gradient @ 15 mL/min) to give (1R,2S,5S)-N- (1-amino-1-oxo-3-(4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)pro pan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxamide (220 mg, 385 μmol, 50% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.40-9.31 (m, 1H), 8.90-8.84 (m, 1H), 8.62-8.50 (m, 0.7H), 8.38-8.30 (m, 0.3H), 7.31-7.00 (m, 2H), 4.53-4.25 (m, 3H), 3.92-3.85 (m, 1H), 3.72-3.67 (m, 1H), 2.76-2.73 (m, 2H), 1.96-1.54 (m, 7H), 1.40-1.30 (m, 2H), 1.02-0.87 (m, 15H). Procedure for preparation of CPD0084528 - (1R,2S,5S)-N-(1-cyano-2-(4,5,6,7- tetrahydrobenzo[d]thiazol-4-yl)ethyl)-3-((S)-3,3-dimethyl-2- (2,2,2-trifluoroacetamido) butanoyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-(1-amino-1-oxo-3-(4,5,6,7-tetrahydrobenzo[d]thi azol-4-yl)propan-2-yl)-3- ((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (200 mg, 0.350 mmol, 1.00 eq) in dichloromethane (10.0 mL) was added Burgess reagent (250 mg, 1.05 mmol, 3.00 eq) at 0 °C. After stirring at 25 °C for 3 h, the mixture was poured into saturated sodium bicarbonate solution (10.0 mL) and extracted with dichloromethane (20.0 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~20% ethyl acetate/petroleum ether gradient @ 15 mL/min) to give crude product. The crude product was further purified by preparative HPLC(column: Unisil 3-100 C18 Ultra 150*50mm*3 μm; mobile phase: [water (FA)-ACN];B%: 45%-65%,10min) to give (1R,2S,5S)-N-(1-cyano-2-(4,5,6,7- tetrahydrobenzo[d]thiazol-4-yl)ethyl)-3-((S)-3,3-dimethyl-2- (2,2,2-trifluoroacetamido)butanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxamide (105.5 mg, 190 μmol, 54 % yield, 99% purity) as a white solid. Preparation of CPD0084529 Procedure for preparation of methyl (1R,2S,5S)-6,6-dimethyl-3-(pyrrolo[1,2-a]pyrazine-3- carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylate A mixture of pyrrolo[1,2-a]pyrazine-3-carboxylic acid (150 mg, 0.925 mmol, 1.00 eq), methyl (1R, 2S, 5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (190 mg, 0.925 mmol, 1.00 eq, HCl), O-(7- Aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (528 mg, 1.39 mmol, 1.50 eq) and N,N-diisopropylethylamine (359 mg, 2.78 mmol, 3.00 eq) in N,N-dimethylformamide (2.00 mL) was stirred at 25°C for 12 h. The combined reaction mixture (EW30036-104 and EW30036-106) was diluted with water (60.0 mL) and extracted with ethyl acetate (60.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, Eluent of 0~50% ethyl acetate/petroleum ether gradient @ 45 mL/min) to give methyl (1R,2S,5S)-6,6-dimethyl-3-(pyrrolo[1,2-a]pyrazine-3-carbonyl )-3-azabicyclo[3.1.0]hexane-2- carboxylate (260 mg, 0.830 mmol, 90% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.90-8.71 (m, 2H), 7.93-7.89 (m, 1H), 7.02-7.01 (m, 1H), 6.94-6.91 (m, 1H), 5.10-4.47 (m, 1H), 4.08-4.07 (m, 1H), 3.81-3.74 (m, 1H), 3.74-3.63 (m, 3H), 1.58-1.56 (m, 1H), 1.46-1.43 (m, 1H), 1.03-1.02 (m, 3H), 0.94-0.93 (m, 3H). SFC: ee: 99% Procedure for preparation of (1R,2S,5S)-6,6-dimethyl-3-(pyrrolo[1,2-a]pyrazine-3-carbonyl )-3- azabicyclo[3.1.0]hexane-2-carboxylic acid To a mixture of methyl (1R,2S,5S)-6,6-dimethyl-3-(pyrrolo[1,2-a]pyrazine-3-carbonyl )-3- azabicyclo[3.1.0] hexane-2-carboxylate (210 mg, 0.670 mmol, 1.00 eq) in a mixed solvent of tetrahydrofuran (4.00 mL) and methanol (4.00 mL) was added a solution of lithium hydroxide hydrate (42.2 mg, 1.01 mmol, 1.50 eq) in water (4.00 mL) at 0°C. After stirring at 25°C for 2 h, the mixture was diluted with water (50.0 mL) and washed with ethyl acetate (40.0 mL). Hydrochloric acid (1M) was added to the aqueous phase to adjust pH = 6. The aqueous layer was lyophilized to give (1R, 2S, 5S)-6,6- dimethyl-3-(pyrrolo[1,2-a] pyrazine-3-carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (370 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.03-8.97 (m, 1H), 8.84-8.77 (m, 1H), 8.09-7.94 (m, 1H), 7.17-7.13 (m, 1H), 7.03-6.95 (m, 1H), 5.19-4.43 (m, 1H), 4.01-3.98 (m, 1H), 3.72-3.71 (m, 1H), 1.59-1.42 (m, 2H), 1.05-1.03 (m, 3H), 0.99-0.93 (m, 3H). Procedure for preparation of (1R,2S,5S)-N-[(1S)-1-cyano-2-(2-oxopyrrolidin-3-yl)ethyl]-6, 6- dimethyl-3-(pyrrolo[1,2-a]pyrazine-3-carbonyl)-3-azabicyclo[ 3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-6,6-dimethyl-3-(pyrrolo[1,2-a]pyrazine-3-carbonyl )-3-azabicyclo[3.1.0] hexane-2-carboxylic acid (70.0 mg, 0.234 mmol, 1.00 eq), N,N-diisopropylethylamine (121 mg, 0.935 mmol, 0.163 mL, 4.00 eq) and 1-propanephosphonic anhydride (298 mg, 0.468 mmol, 50% purity in ethyl acetate, 2.00 eq) in N,N-dimethylformamide (1.00 mL) was added (S)-2-amino-3-(2-oxopyrrolidin- 3-yl) propanenitrile (53.2 mg, 0.281 mmol, 1.20 eq, HCl salt). After stirring at 25°C for 12 h, the reaction mixture was concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (column: Waters X-bridge 150*25mm*5 μm; mobile phase: [water (ammonia hydroxide v/v)- ACN]; B%: 17%-47%, 9min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2-(2-oxopyrrolidin-3-yl)ethyl]-6, 6- dimethyl-3-(pyrrolo [1,2-a]pyrazine-3-carbonyl)-3-azabicyclo[3.1.0]hexane-2-carb oxamide (6.23 mg, 13.3 μmol, 93% purity) as a white solid. Synthetic Scheme of CPD0077325, CPD0077326, CPD0077327 and CPD0077328. Procedure for preparation of methyl (2S)-2-amino-3-cyclopropyl-propanoate To a mixture of (2S)-2-amino-3-cyclopropyl-propanoic acid (30.0 g, 232 mmol, 1.00 eq) in methanol (150 mL) was added thionyl chloride (82.9 g, 697 mmol, 50.6 mL, 3.00 eq) at 0°C. After stirring at 25°C for 12 h, the mixture was concentrated under vacuum to give a crude product. The crude product was triturated with tert-butyl methyl ether (50.0 mL). After filtration, the filter cake was dried under vacuum to give methyl (2S)-2-amino-3-cyclopropyl-propanoate (42.0 g, 192 mmol, 83% yield, 99% purity, 2 HCl salt) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.89 (s, 2H), 4.22 (d, J = 4.0 Hz, 1H), 3.83 (s, 3H), 2.08-1.93 (m, 2H), 1.01-0.89 (m, 1H), 0.65-0.53 (m, 2H), 0.29-0.15 (m, 2H). Procedure for preparation of methyl (2S)-3-cyclopropyl-2-(1H-indole-2- carbonylamino)propanoate To a stirred solution of 1H-indole-2-carboxylic acid (22.4 g, 139 mmol, 1.00 eq) in dimethylformamide (200 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexaflu orophosphate (63.3 g, 167 mmol, 1.20 eq) and N,N-diisopropylethylamine (53.8 g, 416 mmol, 72.5 mL, 3.00 eq) at 0°C. After stirring at 0°C for 0.1 hour, methyl (2S)-2-amino-3-cyclopropyl-propanoate (30.0 g, 139 mmol, 1 eq, 2 HCl salt) was added. After stirring at 25°C for 1 h, the reaction mixture was poured into ice- water (500 mL) to give a solid product. After filtration, the filter cake was washed with water (50.0 mL × 2) and dried under vacuum to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1 to 1: 1) to give methyl (2S)-3-cyclopropyl-2- (1H-indole-2-carbonylamino) propanoate (33.0 g, 109 mmol, 79% yield, 95% purity) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.57 (s, 1H), 8.72 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.42 (dd, J = 8.0, 0.6 Hz, 1H), 7.26 (d, J = 1.6 Hz, 1H), 7.21-7.15 (m, 1H), 7.06-7.00 (m, 1H), 4.58-7.50 (m, 1H), 3.65 (s, 3H), 1.88-1.79 (m, 1H), 1.67-1.56 (m, 1H), 0.90-0.77 (m, 1H), 0.48-0.36 (m, 2H), 0.23-0.16 (m, 1H), 0.10-0.02 (m, 1H). LC-MS (Method C): R _t = 0.892 min; MS (ESIpos): m/z = 287.0 [M+H] ⁺ _. SFC: ee%: 100%. Procedure for preparation of (2S)-3-cyclopropyl-2-(1H-indole-2-carbonylamino)propanoic acid Hydroxy(trimethyl)stannane (250 g, 138 mmol, 2.50 eq) was added to a solution of methyl (2S)-3- cyclopropyl-2-(1H-indole-2-carbonylamino)propanoate (15.8 g, 55.3 mmol, 1.00 eq) in 1,2- dichloroethane (500 mL) at 25°C. After stirring at 80°C for 16 h, the mixture was poured into water (300 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (column: I.D.150mm*H400mm; Phenomenex Luna C1815μm; 100 A; mobile phase: [water (FA)-ACN]; B%: 5-55% 35min; 500 mL/min; 60 min). After removing most of the organic solvent, the solution was extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give (2S)-3-cyclopropyl-2-(1H-indole-2-carbonylamino)propanoic acid (14.2 g, 51.6 mmol, 93% yield, 99% purity) as a light yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 10.22 (s, 1H), 8.13-7.72 (m, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.31-7.23 (m, 1H), 7.18-7.09 (m, 2H), 7.00 (d, J = 1.6 Hz, 1H), 5.03-4.87 (m, 1H), 1.90 (t, J = 6.4 Hz, 2H), 0.88-0.75 (m, 1H), 0.58-0.44 (m, 2H), 0.22-0.11 (m, 2H). LC-MS (Method C): R _t = 0.719 min; MS (ESIpos): m/z = 273.2 [M+H] ⁺ . Procedure for preparation of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5- a]pyridine A mixture of 6-bromopyrazolo[1,5-a]pyridine (3.00 g, 15.2 mmol, 1.00 eq), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxabor olane (4.06 g, 16.0 mmol, 1.05 eq), [1,1- bis(diphenylphosphino)ferrocene]dichloropalladium (II) (557 mg, 0.761 mmol, 0.05 eq) and potassium acetate (4.48 g, 45.7 mmol, 3.00 eq) in 1,4-dioxane (30.0 mL) was degassed under vacuum, and purged with nitrogen for three times. The mixture was stirred at 100°C for 12 h. After filtration, the filtrate was concentrated under vacuum to give 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo [1,5- a]pyridine (7 g, crude) as brown oil. The crude product was used for the next step reaction directly without further purification. Procedure for preparation of pyrazolo[1,5-a]pyridin-6-ol To a mixture of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5- a]pyridine (6.80 g, 27.9 mmol, 1.00 eq) in tetrahydrofuran (50.0 mL) and water (20.0 mL) was added sodium perborate monohydrate (8.34 g, 83.6 mmol, 3.00 eq). After stirring at 25°C for 5 minutes, the reaction mixture was filtered. The filtrate was poured into water (50.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether, then petroleum ether/ethyl acetate = 2/1) to afford pyrazolo[1,5-a]pyridin-6-ol (1.8 g, 12.1 mmol, 43% yield, 90% purity) as yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.57 (s, 1H), 8.14-8.06 (m, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 6.95 (dd, J = 8.4, 2.0 Hz, 1H), 6.49 (d, J = 1.6 Hz, 1H). Procedure for preparation of 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-6-ol To a solution of pyrazolo[1,5-a]pyridin-6-ol (2.50 g, 15.8 mmol, 1.00 eq) in acetic acid (30.0 mL) was added platinum dioxide (180 mg, 0.792 mmol, 0.05 eq) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen for three times. The mixture was stirred under hydrogen atmosphere (3 MPa in autoclave) at 70°C for 36 h. After filtration, the filtrate was concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (petroleum ether then petroleum ether/ethyl acetate = 1/1) to afford 4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-6-ol (1.40 g, 9.12 mmol, 58% yield, 90% purity) as brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.45 (d, J = 1.2 Hz, 1H), 6.01 (s, 1H), 4.44-4.35 (m, 1H), 4.30-4.22 (m, 1H), 4.13-4.03 (m, 1H), 3.10-2.97 (m, 1H), 2.91-2.78 (m, 2H), 2.10-1.93 (m, 2H). Procedure for preparation of 4,5-dihydropyrazolo[1,5-a]pyridin-6(7H)-one To a solution of 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-6-ol (1.00 g, 6.51 mmol, 1.00 eq) in dichloromethane (10.0 mL) was added Dess-Martin periodinane (3.32 g, 7.82 mmol, 1.20 eq) at 0°C. After stirring at 25°C for 3 h, the mixture was poured into saturated sodium bicarbonate/sodium thiosulfate solution (50.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed by brine (20.0 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4,5-dihydropyrazolo[1,5-a]pyridin-6(7H)-one (0.9 g, crude) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.51 (d, J = 1.2 Hz, 1H), 6.12 (s, J = 1.2 Hz, 1H), 4.77 (m, 2H), 3.10 (d, J = 6.4 Hz, 2H), 2.13 (d, J = 6.4 Hz, 2H). Procedure for preparation of 6-amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-6-carbonit rile To a solution of saturated ammonium chloride aqueous solution (982 mg, 18.4 mmol, 5.00 eq) in ammonium hydroxide (6.00 mL) was added sodium cyanide (839 mg, 17.1 mmol, 4.66 eq) at 25°C. A solution of 5,7-dihydro-4H-pyrazolo[1,5-a]pyridin-6-one (0.50 g, 3.67 mmol, 1.00 eq) in isopropanol (2.00 mL) was added dropwise to the reaction mixture above at 25°C. After stirring at 50°C for 12 h in sealed tube, the reaction mixture was diluted with water (50.0 mL), adjusted pH to 11~14 with sodium hydroxide and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 6-amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-6-carbonit rile (0.430 g, 2.25 mmol, 61% yield, 85% purity) as brown gum. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.50 (d, J = 1.6 Hz, 1H), 6.11-6.04 (m, 1H), 4.55 (dd, J = 12.8, 0.8 Hz, 1H), 4.13-4.08 (m, 1H), 3.19-2.96 (m, 2H), 2.35-2.25 (m, 1H), 2.17-2.08 (m, 1H). Procedure for preparation of CPD0077325, CPD0077326, CPD0077327 and CPD0077328 - N-((R or S)-1-(((R or S)-6-cyano-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-6-yl)ami no) -3-cyclopropyl-1- oxopropan-2-yl)-1H-indole-2-carboxamide To a solution of 6-amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-6-carbonit rile (300 mg, 1.85 mmol, 1.00 eq) in N,N-dimethylformamide (3.00 mL) were added (S)-3-cyclopropyl-2-(1H-indole-2- carboxamido)propanoic acid (529 mg, 1.94 mmol, 1.05 eq), O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (844 mg, 2.22 mmol, 1.20 eq) and N,N-diisopropylethylamine (359 mg, 2.77 mmol, 0.483 mL, 1.50 eq). After stirring at 25°C for 12 h, the mixture was poured into water (50.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative-HPLC (FA condition; column: Phenomenex Synergi C18150*25mm*10 μm; mobile phase: [water (FA)-ACN]; B%: 35%-57%, 11 min) to give 350 mg of Compound 11. The obtained compound was purified by SFC (condition: column: DAICEL CHIRALPAK AD (250mm*30 mm, 10um); mobile phase: [IPA-ACN]; B%: 65%-65%, 6.6 min; 65min) to give Peak1 and Peak2. Peak1 was further separated by SFC (column: DAICEL CHIRALPAK IC (250mm*30mm,10um); mobile phase: [IPA-ACN]; B%: 45%-45%, 2.5 min; 50 min) and Peak2 was further separated by SFC (column: Phenomenex-Cellulose-2 (250mm*30mm,10 μm); mobile phase: [0.1% NH _3· H ₂ O Metanol]; B%: 45%-45%, 4min; 50min) to give four isomers. The obtained four isomers were purified by preparative-HPLC (FA condition: column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 40%-60%, 9min) to give CPD0077325 (43.7 mg), CPD0077326 (50.0 mg), CPD0077327 (39.8 mg) and CPD0077328 (53.7 mg) as white solids. Preparation of CPD0082406, CPD0082407, CPD0082408 and CPD0082409. Procedure for preparation of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(p- tolylsulfonyloxy)propanoate To a mixture of methyl (2S)-2-(tert-butoxycarbonylamino)-3-hydroxy-propanoate (50.0 g, 228 mmol, 46.3 mL, 1.00 eq) and pyridine (36.1 g, 456 mmol, 36.8 mL, 2.00 eq) in dichloromethane (250 mL) was added 4-methylbenzenesulfonyl chloride (52.2 g, 274 mmol, 1.20 eq) at 0°C in portions. After stirring at 0°C for 4 h, the reaction mixture was warmed to 20°C, and stirred at 20°C for 12 h. The mixture was poured into water (300 mL), adjusted pH to 5~6 with hydrochloric acid (1.00 mol/L) and extracted with ethyl acetate (300 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1 to 5/1) to give methyl (2S)-2-(tert- butoxycarbonylamino)-3-(p-tolylsulfonyloxy)propanoate (68.0 g, 173 mmol, 76% yield, 95% purity) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.77 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.4 Hz, 1H), 4.39-4.33 (m, 1H), 4.23- 4.14 (m, 2H), 3.58 (s, 3H), 2.42 (s, 3H), 1.40-1.32 (m, 9H). SFC: ee%: 100%. Procedure for preparation of methyl 3- (2S)-2-(tert-butoxycarbonylamino)-3-(1- piperidyl)propanoate To a mixture of methyl methyl (2S)-2-(tert-butoxycarbonylamino)-3-(p-tolylsulfonyloxy)prop anoate (25.0 g, 66.9 mmol, 1.00 eq) in tetrahydrofuran (250 mL) was added piperidine (14.3 g, 167 mmol, 16.5 mL, 2.50 eq) at 0°C. After addition, the mixture was warmed to 25°C and stirred at this temperature for 12 h. After filtration, the filtrate was concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1 to 3/1).to give methyl (2S)- 2-(tert-butoxycarbonylamino)-3-(1-piperidyl)propanoate (16.4 g, 54.41 mmol, 81% yield, 95% purity) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.41 (s, 1H), 4.28 (d, J = 5.2 Hz, 1H), 3.75 (s, 3H), 2.64 (s, 2H), 2.46- 2.31 (m, 4H), 1.56-1.53 (m, 3H), 1.46 (s, 9H), 1.43-1.39 (m, 2H). Procedure for preparation of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(2-oxo-1- piperidyl)propanoate To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(1-piperidyl)propanoate (16.4 g, 57.3 mmol, 1.00 eq) in 1,4-dioxane (135 mL) and water (15.0 mL) was added 1-bromopyrrolidine-2,5-dione (25.5 g, 143 mmol, 2.50 eq) at 25°C. After stirring at 25°C for 12 h, the mixture was poured into water (200 mL) and extracted with ethyl acetate (200 mL× 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1 to 1/3) to give a crude product. The crude product was triturated with 2-methoxy-2-methylpropane (20.0 mL). After filtration, the filtrate was concentrated under vacuum to give methyl (2S)-2-(tert-butoxycarbonylamino)- 3-(2-oxo-1-piperidyl)propanoate (2.00 g, 4.66 mmol, 8% yield, 70% purity) as light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.69-5.59 (m, 1H), 4.45-4.41 (m, 1H), 3.94-3.86 (m, 1H), 3.69 (s, 3H), 3.40-3.35 (m, 2H), 3.24-3.18 (m, 1H), 2.31 (t, J = 6.0 Hz, 2H), 1.75-1.70 (m, 4H), 1.36 (s, 9H). Procedure for preparation of methyl (2S)-2-amino-3-(2-oxo-1-piperidyl)propanoate A mixture of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(2-oxo-1-piperidyl)propa noate (2.00 g, 4.66 mmol, 70% purity, 1.00 eq) in ethyl acetate (2.00 mL) and hydrochloric acid /ethyl acetate (4.00 M, 5.88 mL, 5.05 eq) was stirred at 25°C for 12 h. The mixture was concentrated under vacuum to give methyl (2S)-2-amino-3-(2-oxo-1-piperidyl)propanoate (660 mg, 2.05 mmol, 44% yield, 85% purity, 2HCl) as light yellow solid ¹ H NMR (400 MHz, CDCl ₃ ) δ = 3.83-3.78 (m, 1H), 3.76-3.74 (m, 3H), 3.62-3.58 (m, 2H), 3.41-3.31 (m, 2H), 2.45-2.34 (m, 2H), 1.87-1.76 (m, 4H). Procedure for preparation of methyl (2S)-2-[[(2S)-3-cyclopropyl-2-(1H-indole-2- carbonylamino)propanoyl]amino]-3-(2-oxo-1-piperidyl)propanoa te To a mixture of (2S)-3-cyclopropyl-2-(1H-indole-2-carbonylamino)propanoic acid (559 mg, 2.05 mmol, 1.10 eq) in N,N-dimethylformamide (10.0 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (852 mg, 2.24 mmol, 1.20 eq) at 0°C. After stirring at 0°C for 0.1 h, methyl (2S)-2-amino-3-(2-oxo-1-piperidyl)propanoate (600 mg, 1.87 mmol, 85% purity, 1.00 eq, 2HCl) and N,N-diisopropylethylamine (965 mg, 7.47 mmol, 1.30 mL, 4.00 eq) were added. The resulting mixture was stirred at 25°C for 12 h. The mixture was poured into water (30.0 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1 to 1/1) to give methyl (2S)-2-[[(2S)-3-cyclopropyl-2-(1H-indole-2-carbonylamino)pro panoyl]amino]-3-(2-oxo-1- piperidyl)propanoate (1.00 g, 1.65 mmol, 88% yield, 75% purity) as light yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 10.18 (s, 1H), 8.20-8.07 (m, 1H), 7.66 (dd, J = 4.4, 7.8 Hz, 1H), 7.49- 7.43 (m, 1H), 7.32-7.22 (m, 1H), 7.17-7.07 (m, 2H), 7.05-6.97 (m, 1H), 5.20-5.00 (m, 1H), 4.93-4.74 (m, 1H), 4.17-4.08 (m, 1H), 3.91-3.63 (m, 3H), 3.51-3.37 (m, 2H), 3.30-3.23 (m, 1H), 2.41-2.20 (m, 2H), 1.81-1.68 (m, 4H), 0.86-0.75 (m, 1H), 0.58-0.35 (m, 2H), 0.20-0.04 (m, 2H). LC-MS (Method C): R _t = 0.838&0.893 min; MS (ESIpos): m/z = 454.9 [M+H] ⁺ . Procedure for preparation of N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[(2-oxo-1- piperidyl)methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-1H-indole-2-carboxamide A mixture of methyl (2S)-2-[[(2S)-3-cyclopropyl-2-(1H-indole-2-carbonylamino)pro panoyl]amino]-3-(2- oxo-1-piperidyl)propanoate (1.00 g, 2.20 mmol, crude purity, 1.00 eq) and 3,4,6,7,8,9-hexahydro-2H- pyrimido[1,2-a] pyrimidine (123 mg, 880 umol, 0.40 eq) in NH3/ methanol (7.00 M, 3.14 mL) and methanol (20.0 mL) was stirred at 25°C for 12 h. The mixture was concentrated under vacuum to give a residue. The residue was partitioned between with ethyl acetate (50.0 mL) and water (20.0 mL), adjusted to pH = 6 with hydrochloric acid (1M) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[(2-oxo- 1-piperidyl)methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo- ethyl]-1H-indole-2-carboxamide (800 mg, 1.73 mmol, 79% yield, 95% purity) as light yellow solid which was used for next step reaction directly. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 10.56-10.21 (m, 1H), 8.65-8.38 (m, 1H), 7.66-7.56 (m, 1H), 7.55-7.48(m, 1H), 7.48-7.38 (m, 1H), 7.26-7.20 (m, 2H), 7.15-6.98 (m, 2H), 6.68-6.39 (m, 1H), 4.70-4.58 (m, 1H), 4.04-3.87 (m, 1H), 3.75-3.52 (m, 2H), 3.33 (br s, 2H), 2.41-2.24 (m, 1H), 2.20-2.09 (m, 1H), 1.84-1.52 (m, 6H), 0.87-0.70 (m, 1H), 0.58-0.42 (m, 2H), 0.24-0.06 (m, 2H). LC-MS (Method C): R _t = 0.829 min; MS (ESIpos): m/z = 440.3 [M+H] ⁺ . Procedure for preparation of N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[(2-oxo-1- piperidyl)methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-1H-indole-2-carboxamide A mixture of N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[(2-oxo-1-piperidyl)methyl] ethyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-1H-indole-2-carboxamide (630 mg, 1.43 mmol, 1.00 eq) and methoxycarbonyl-(triethylammonio)sulfonyl-azanide (1.02 g, 4.30 mmol, 3.00 eq) in dichloromethane (20.0 mL) was stirred at 25°C for 2 h. The mixture was poured into water (20.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18150*40mm* 15um; mobile phase: [water (FA)-ACN]; B%: 30%-60%,10min) and lyophilized. N-[(1S)-2-[[(1S)-1-cyano-2-(2-oxo-1-piperidyl)ethyl]amino]-1 - (cyclopropylmethyl)-2-oxo-ethyl]-1H-indole-2-carboxamide (210 mg, 450 umol, 31% yield, 90% purity) was obtained as light yellow solid. LC-MS (Method C): R _t = 0.841 min; MS (ESIpos): m/z = 422.0 [M+H] ⁺ . SFC: dr: 9:44:37:10. Procedure for preparation of CPD0082406, CPD0082407, CPD0082408 and CPD0082409- N-[(1(R or S))-2-[[(1(R or S))-2-amino-2-oxo-1-[(2-oxo-1-piperidyl)methyl]ethyl]amino]- 1- (cyclopropylmethyl)-2-oxo-ethyl]-1H-indole-2-carboxamide N-[2-[[1-cyano-2-(2-oxo-1-piperidyl)ethyl]amino]-1-(cyclopro pylmethyl)-2-oxo-ethyl]-1H-indole-2- carboxamide (four diastereomers) (210 mg, 498 μmol, 1.00 eq) was purified by SFC (column: DAICEL CHIRALCEL OD(250mm*30mm,10 μm); mobile phase: [0.1%NH3·H2O in IPA];B%: 40%- 40%,3.2;40min) to give peak 2 and a mixture of three unseparated diastereomers. The mixture of the three unseparated diastereomers was further purified by SFC (column: REGIS(S,S)WHELK- O1(250mm*25mm,10 μm);mobile phase: [0.1% NH ₃ ·H ₂ O in ethanol]; B%: 40%-40%,3.7;60min) to give peak 1 and a mixture of two unseparated diastereomers. The mixture of two unseparated diastereomers was further purified by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10 μm); mobile phase: [0.1%N NH3·H2O in methanol]; B%: 70%-70%, 9;50min) to give CPD0082408 (41.26 mg, 96.7 μmol, 19% yield, 99% purity) and CPD0082409 (11.14 mg, 26.2 μmol, 5% yield, 99% purity) as an off-white solids. Peak 1 was purified by prep-HPLC (column: Phenomenex C1875*30mm*3 μm; mobile phase: [water (FA)-ACN]; B%: 30%-60%, 7min) and lyophilized to give CPD0082406 (8.91 mg, 20.7 μmol, 4% yield, 98% purity) as an off-white solid. Peak 2 was purified by prep-HPLC (column: Phenomenex C18 75*30mm*3 μm; mobile phase: [water (FA)-ACN]; B%: 30%-60%, 7min) and lyophilized to give CPD0082407 (53.86 mg, 126 μmol, 25% yield, 99% purity) as an off-white solid. Preparation of CPD0082453 Procedure for preparation of methyl 2-(benzhydrylideneamino)-2-(1-methyl-2-oxo-4- quinolyl)acetate A mixture of 4-bromo-1-methyl-quinolin-2-one (900 mg, 3.78 mmol, 1.00 eq), methyl 2- (benzhydrylideneamino)acetate (958 mg, 3.78 mmol, 1.00 eq), tBu3P-Pd-G2 (77.5 mg, 151 μmol, 0.04 eq) and potassium phosphate (2.41 g, 11.34 mmol, 3.00 eq) in N,N-dimethylformamide (8.00 mL) was degassed under vacuum and purged with nitrogen for 3 times. After stirring at 90°C for 12 h under nitrogen atmosphere, the reaction mixture was diluted with water (120 mL) and extracted with ethyl acetate (120 mL × 2). The combined organic layers were washed with brine (80.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ ethyl acetate = 40/1 to 10/1) to give methyl 2-(benzhydrylideneamino)-2-(1-methyl-2-oxo-4-quinolyl)acetat e (450 mg, 877 μmol, 5% yield, 80% purity) as a light yellow solid ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.79-7.69 (m, 1H), 7.66-7.61 (m, 2H), 7.61-7.58 (m, 2H), 7.56-7.50 (m, 4H), 7.45-7.41 (m, 2H), 7.32-7.28 (m, 1H), 7.27-7.21 (m, 1H), 7.19-7.17 (m, 1H), 6.66-6.52 (m, 1H), 5.42 (s, 1H), 4.74 (s, 1H), 3.61 (d, J = 1.6 Hz, 6H). LC-MS (Method C): R _t = 0.995 min; MS (ESIpos): m/z = 411.1 [M+H] ⁺ Procedure for preparation of 2-(benzhydrylideneamino)-2-(1-methyl-2-oxo-4- quinolyl)acetamide A mixture of methyl 2-(benzhydrylideneamino)-2-(1-methyl-2-oxo-4-quinolyl)acetat e (450 mg, 877 μmol, 80% purity, 1.00 eq) in ammonia (15 M in methanol, 8.00 mL) was stirred at 25°C for 12 h. After concentration, the crude product was triturated with methyl tert-butyl ether (20.0 mL) at 25°C for 30 min and filtered. The filter cake was dried under vacuum to give 2-(benzhydrylideneamino)-2-(1-methyl-2- oxo-4-quinolyl)acetamide (300 mg, 607 μmol, 69% yield, 80% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.72-7.68 (m, 2H), 7.64-7.44 (m, 10H), 7.33-7.17 (m, 2H), 6.61 (s, 1H), 5.16 (s, 1 H), 3.60 (s, 3 H). LC-MS (Method C): R _t = 0.913 min; MS (ESIpos): m/z = 396.1 [M+H] ⁺ . Procedure for preparation of 2-amino-2-(1-methyl-2-oxo-4-quinolyl)acetamide 2-(Benzhydrylideneamino)-2-(1-methyl-2-oxo-4-quinolyl)acetam ide (285 mg, 577 μmol, 80% purity, 1.00 eq) in a mixed solvent of hydrochloric acid (1 M in water, 4.00 mL, 6.94 eq), dichloromethane (2.00 mL) and methanol (2.00 mL) was stirred at 25°C for 0.5 h. After filtration, the filter cake was dried under vacuum to give 2-amino-2-(1-methyl-2-oxo-4-quinolyl)acetamide (118 mg, 459 μmol, 80% yield, 90% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.97 (d, J = 2.4 Hz, 2H), 8.15 (s, 1 H), 8.13-8.10 (m, 1H), 7.85-7.81 (m, 1H), 7.74-7.86 (m, 1H), 7.65-7.61 (m, 1H), 7.36 (t, J = 7.6 Hz, 1H), 6.85 (s, 1H), 5.47 (d, J = 4.2 Hz, 1H), 3.65 (s, 3H). LC-MS (Method C): R _t = 0.368 min; MS (ESIpos): m/z = 232.1 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[2-amino-1-(1-methyl-2-oxo-4-quinolyl)-2-oxo-et hyl]- 3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoy l]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide A mixture of 2-amino-2-(1-methyl-2-oxo-4-quinolyl)acetamide (118 mg, 441 μmol, 1.00 eq, HCl salt), (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxylic acid (161 mg, 441 μmol, 1.00 eq), O-(7-Aza-1H-benzotriazol-1-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (335 mg, 881 μmol, 2.00 eq) and N,N- diisopropylethylamine (228 mg, 1.76 mmol, 4.00 eq) in N,N-dimethylformamide (4.00 mL) was stirred at 25°C for 16 h. The reaction mixture was diluted with water (60.0 mL) and extracted with ethyl acetate (60.0 mL × 2). The combined organic layers were washed with brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 0/1) to give (1R,2S,5S)-N-[2-amino-1-(1-methyl-2-oxo-4-quinolyl)-2-oxo-et hyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (90 mg, 140 μmol, 32% yield, 90% purity) as a yellow solid. LC-MS (Method C): R _t = 0.882 min; MS (ESIpos): m/z = 578.2 [M+H] ⁺ . Procedure for preparation of Compound CPD0082453 - (1R,2S,5S)-N-[cyano-(1-methyl-2-oxo-4- quinolyl)methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroace tyl)amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide A mixture of (1R,2S,5S)-N-[2-amino-1-(1-methyl-2-oxo-4-quinolyl)-2-oxo-et hyl]-3-[(2S)-3,3-dimethyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabi cyclo[3.1.0]hexane-2-carboxamide (70 mg, 121 μmol, 1.00 eq) and Burgess reagent (144 mg, 606 μmol, 5.00 eq) in dichloromethane (2.50 mL) was stirred at 25°C for 10 h. The reaction mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1 to 5/1) to give (1R,2S,5S)-N-[cyano-(1-methyl-2-oxo-4-quinolyl)methyl]-3-[(2 S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (53.67 mg, 95.0 μmol, 78% yield, 99% purity) as a white solid Preparation of CPD0082454 Procedure for preparation of 4-bromo-1-[(4-methoxyphenyl)methyl]quinolin-2-one To a mixture of 4-bromo-1H-quinolin-2-one (900 mg, 4.02 mmol, 1.00 eq) and potassium carbonate (1.39 g, 10.0 mmol, 2.50 eq) in N,N-dimethylformamide (20.0 mL) was added 1-(chloromethyl)-4- methoxy-benzene (692 mg, 4.42 mmol, 1.10 eq) at 25°C. After stirring at 25°C for 16 h, the mixture was poured into water (50.0 mL) and extracted with ethyl acetate (80.0 mL × 2). The combined organic layers were washed with brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~30% ethyl acetate/petroleum ether gradient @40 mL/min) to afford 4-bromo-1-[(4-methoxyphenyl)methyl]quinolin- 2-one (1.50 g, 3.49 mmol, 87% yield, 80% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.94 (dd, J = 8.0, 0.8 Hz, 1H), 7.66-7.57 (m, 1H), 7.53-7.47 (m, 1H), 7.39-7.32 (m, 1H), 7.28 (s, 1H), 7.19-7.14 (m, 2H), 6.88-6.85 (m, 2H), 5.45 (s, 2H), 3.69 (s, 3H). LC-MS (Method C): R _t = 0.840 min; MS (ESIpos): m/z = 368.1 [M+H] ⁺ . Procedure for preparation of methyl 2-(benzhydrylideneamino)-2-[1-[(4-methoxyphenyl)methyl]- 2-oxo-4-quinolyl]acetate A mixture of 4-bromo-1-[(4-methoxyphenyl)methyl]quinolin-2-one (200 mg, 465 μmol, 80% purity, 1.00 eq), methyl 2-(benzhydrylideneamino)acetate (143 mg, 604 μmol, 1.30 eq), chloro[(tri-tert- butylphosphine)-2-(2-aminobiphenyl)]palladium (II) (9.52 mg, 18.6 μmol, 0.04 eq) and potassium phosphate (296 mg, 1.39 mmol, 3.00 eq) in N,N-dimethylformamide (2.00 mL) was degassed under vacuum and purged with nitrogen for 3 times, and the mixture was stirred at 90°C for 12 h under nitrogen atmosphere. The reaction mixture (combined 3 batches) was poured into ammonium chloride aqueous solution (30.0 mL) and extracted with ethyl acetate (50.0 mL × 2). The combined organic layers were washed with brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~100% ethyl acetate/petroleum ether gradient @40 mL/min) to give methyl 2-(benzhydrylideneamino)-2-[1-[(4-methoxyphenyl)methyl]-2-ox o-4- quinolyl]acetate (400 mg, 619 umol, 44% yield, 80% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.71-7.39 (m, 11H), 7.35-7.26 (m, 2H), 7.22-7.09 (m, 3H), 6.88-6.83 (m, 2H), 6.76 (s, 1H), 5.45 (s, 1H), 4.77 (s, 2H), 3.68 (s, 3H), 3.44-3.37 (m, 3H). Procedure for preparation of 2-(benzhydrylideneamino)-2-[1-[(4-methoxyphenyl)methyl]-2-ox o- 4-quinolyl]acetamide A solution of methyl 2-(benzhydrylideneamino)-2-[1-[(4-methoxyphenyl)methyl]-2-ox o-4- quinolyl]acetate (400 mg, 619 μmol, 80% purity, 1.00 eq) in ammonia (19.0 M in methanol, 10.0 mL) was stirred at 25°C for 12 h. The reaction mixture was concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~50% ethyl acetate/petroleum ether gradient @30 mL/min) to give 2- (benzhydrylideneamino)-2-[1-[(4-methoxyphenyl) methyl]-2-oxo-4-quinolyl]acetamide (200 mg, 359 μmol, 58% yield, 90% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.87 (d, J = 8.0 Hz, 1H), 7.75-7.63 (m, 3H), 7.54-7.36 (m, 9H), 7.19- 7.08 (m, 5H), 6.90-6.83 (m, 2H), 6.70 (s, 1H), 5.43 (s, 2H), 5.21 (s, 1H), 3.69 (s, 3H). LC-MS (Method C): R _t = 0.870 min; MS (ESIpos): m/z = 502.2 [M+H] ⁺ . Procedure for preparation of 2-amino-2-(2-oxo-1H-quinolin-4-yl)acetamide A mixture of 2-(benzhydrylideneamino)-2-[1-[(4-methoxyphenyl)methyl]-2-ox o-4-quinolyl]acetamide (200 mg, 399 μmol, 1.00 eq) in trifluoroacetic acid (5.00 mL) was stirred at 100°C for 12 h in sealed tube. The reaction mixture was concentrated under vacuum to give a residue. The residue was triturated with tert-butyl methyl ether (10.0 mL) and filtered. The filter cake was washed with tert-butyl methyl ether (10.0 mL × 2) and dried to give 2-amino-2-(2-oxo-1H-quinolin-4-yl)acetamide (80.0 mg, 368 μmol, 92% yield, crude purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.05-11.85 (m, 1H), 8.58-8.19 (m, 1H), 8.02-7.87 (m, 2H), 7.82- 7.51 (m, 3H), 7.42-7.33 (m, 1H), 7.30-7.21 (m, 1H), 6.75-6.43 (m, 1H), 5.91-5.31 (m, 1H). Procedure for preparation of (1R,2S,5S)-N-[2-amino-2-oxo-1-(2-oxo-1H-quinolin-4-yl)ethyl] -3- [(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl] -6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl - 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (134 mg, 368 μmol, 1.00 eq) in N,N-dimethylformamide (2.00 mL) were added N,N-diisopropylethylamine (476 mg, 3.68 mmol, 10.0 eq) and O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (210 mg, 552 μmol, 1.50 eq) at 25°C. After stirring at 25°C for 0.25 h, 2-amino-2-(2-oxo-1H-quinolin-4-yl)acetamide (80.0 mg, 368 μmol, 1.00 eq) was added. The resulting mixture was stirred at 25°C for 16 h. The mixture was poured into ammonium chloride aqueous solution (15.0 mL) and extracted with ethyl acetate (30.0 mL × 2). The combined organic layers were washed with brine (10.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®;40 g SepaFlash® Silica Flash Column, Eluent of 0~100% ethyl acetate/petroleum ether gradient @ 30 mL/min) to give (1R,2S,5S)-N-[2-amino-2-oxo-1-(2-oxo-1H- quinolin-4-yl)ethyl] -3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butano yl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (80.0 mg, 129 μmol, 35% yield, 91% purity) as a yellow solid. LC-MS (Method C): R _t = 0.594 min; MS (ESIpos): m/z = 564.1 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[cyano-(2-oxo-1H-quinolin-4-yl)methyl]-3-[(2S)- 3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxamide To a mixture of (1R,2S,5S)-N-[2-amino-2-oxo-1-(2-oxo-1H-quinolin-4-yl)ethyl] -3-[(2S)-3,3-dimethyl -2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabi cyclo[3.1.0]hexane-2-carboxamide (70.0 mg, 124 μmol, 1.00 eq) in dichloromethane (2.00 mL) was added Burgess reagent (88.8 mg, 373 μmol, 3.00 eq) at 20°C. After stirring at 20°C for 16 h, a saturated solution of sodium bicarbonate was added to the reaction mixture to adjust pH = 9 and extracted with ethyl acetate (20.0 mL × 2). The combined organic layers were washed with brine (15.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C18 75*30mm*3um;mobile phase: [water(FA)-ACN]; B%: 38%-68%,7 min) to afford (1R,2S,5S)-N-[cyano-(2-oxo-1H-quinolin-4-yl)methyl]-3-[(2S)- 3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino] butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxami de (22.1 mg, 36.4 μmol, 29% yield, 97% purity, formic acid) as a white solid. Preparation of CPD0084107; CPD0084108; CPD0084109; CPD0084110 Experimental procedures for the largest scale run: Procedure for preparation of 1-(2-pyridyl)ethanol To a solution of 1-(2-pyridyl)ethanone (20.0 g, 165 mmol, 1.00 eq) in methanol (400 mL) was added sodium borohydride (12.5 g, 330 mmol, 2.00 eq) at 0°C under nitrogen atmosphere. After stirring at 0°C for 1 h, the reaction mixture was poured into ammonium chloride (300 mL) aqueous solution and extracted with ethyl acetate (200 mL × 5). The combined organic layers were washed with brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~20% ethyl acetate/petroleum ether gradient @100 mL/min) to afford 1-(2- pyridyl)ethanol (20.0 g, 154 mmol, 93% yield, 95% purity) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.52 (d, J = 4.8 Hz, 1H), 7.67 (td, J = 8.0, 1.2 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.23-7.13 (m, 1H), 4.93-4.84 (m, 1H), 4.36 (s, 1H), 1.49 (d, J = 6.8 Hz, 3H). Procedure for preparation of 2-(1-chloroethyl)pyridine To a solution of 1-(2-pyridyl)ethanol (15.0 g, 122 mmol, 1.00 eq) in tetrahydrofuran (300 mL) was added thionyl chloride (72.5 g, 609 mmol, 44.2 mL, 5.00 eq) at 0°C. After stirring at 25°C for 4 h, saturated sodium bicarbonate aqueous solution (1.00 L) was added to the mixture to adjust pH~9 at 0°C. The solution was extracted with dichloromethane (300 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~20% ethyl acetate/petroleum ether gradient @80 mL/min) to afford 2-(1-chloroethyl)pyridine (6.00 g, 40.2 mmol, 33% yield, 95% purity) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.62-8.52 (m, 1H), 7.71 (td, J = 7.6, 2.0 Hz, 1H), 7.53-7.45 (m, 1H), 7.25-7.17 (m, 1H), 5.19-5.10 (m, 1H), 1.89 (d, J = 6.8 Hz, 3H). Procedure for preparation of methyl 2-(benzhydrylideneamino)-3-(2-pyridyl)butanoate To a solution of methyl 2-(benzhydrylideneamino)acetate (11.8 g, 46.6 mmol, 1.20 eq) and 2-(1- chloroethyl)pyridine (5.50 g, 38.8 mmol, 1.00 eq) in N,N-dimethylformamide (100 mL) were added cesium carbonate (31.6 g, 97.1 mmol, 2.50 eq) and iodide sodium (5.82 g, 38.8 mmol, 1.00 eq). After stirring at 80°C for 16 h, the reaction mixture was poured into ammonium chloride aqueous solution (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~30% ethyl acetate/petroleum ether gradient@ 80 mL/min) to give methyl 2-(benzhydrylideneamino)-3-(2-pyridyl)butanoate (12.0 g, 30.1 mmol, 78% yield, 90% purity) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.45-8.40 (m, 1H), 7.65-7.59 (m, 1H), 7.58-7.52 (m, 1H), 7.46-7.29 (m, 6H), 7.26-7.15 (m, 2H), 7.10-7.04 (m, 1H), 6.82 (dd, J = 16.4, 6.0 Hz, 2H), 4.57-4.40 (m, 1H), 3.82-3.62 (m, 4H), 1.49-1.27 (m, 3H). Procedure for preparation of methyl 2-amino-3-(2-pyridyl)butanoate A solution of methyl 2-(benzhydrylideneamino)-3-(2-pyridyl)butanoate (11.0 g, 27.6 mmol, 90% purity, 1.00 eq) in tetrahydrofuran (100 mL) and hydrochloric acid aqueous solution (1.00 M, 99.0 mL) was stirred at 25°C for 12 h. The mixture was diluted with cold water (100 mL) and washed with ethyl acetate (100 mL × 2). The aqueous phase was concentrated under vacuum to afford methyl 2-amino-3-(2- pyridyl)butanoate (6.00 g, 26.0 mmol, 94% yield, crude purity, HCl) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.70 (s, 2H), 8.65 - 8.57 (m, 1H), 8.10-7.97 (m, 1H), 7.62-7.55 (m, 1H), 7.55-7.48 (m, 1H), 4.55-4.42 (m, 1H), 3.71-3.70 (m, 1H), 3.65-3.64 (m, 1H), 1.46-1.30 (m, 3H). Procedure for preparation of (S)-2-((tert-butoxycarbonyl)amino)-3-cyclopropylpropanoic acid To a solution of (2S)-2-amino-3-cyclopropyl-propanoic acid (10.0 g, 77.4 mmol, 1.00 eq) in tetrahydrofuran (100 mL) and water (100 mL) were added triethylamine (11.8 g, 116 mmol, 1.50 eq) and di-tert-butyl dicarbonate (20.3 g, 92.9 mmol, 1.20 eq) at 0°C. After stirring at 25°C for 12 h, the mixture was washed with tert-butyl methyl ether (50 mL × 3). The pH of the aqueous phase was adjusted to 4.0 with hydrochloric acid (1 M) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (50.0 ml), dried over anhydrous sodium sulfate, filtered and concentrated to give (S)-2-((tert-butoxycarbonyl)amino)-3-cyclopropylpropanoic acid (9.50 g, 41.4 mmol, 54% yield) as colorless oil. The crude product was used for the next step directly without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.43 (s, 1H), 7.14-7.02 (d, J = 8.0 Hz, 1H), 3.96-3.87 (m, 1H), 1.66- 1.28 (m, 11H), 0.86-0.69 (m, 1H), 0.46-0.29 (m, 2H), 0.21-0.06 (m, 2H). Procedure for preparation of methyl 2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl- propanoyl]amino]-3-(2-pyridyl)butanoate To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propanoic acid (2.98 g, 13.0 mmol, 1.00 eq) in N,N-dimethylformamide (50.0 mL) were added N,N-diisopropylethylamine (5.04 g, 39.0 mmol, 6.80 mL, 3.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (5.93 g, 15.6 mmol, 1.20 eq) at 25°C. After stirring at 25°C for 0.25 h, methyl 2-amino-3-(2-pyridyl)butanoate (3.00 g, 13.0 mmol, crude, 1.00 eq, HCl) was added at 25°C. After addition, the mixture was stirred at 25°C for 12 h. The reaction mixture was poured into ammonium chloride aqueous solution (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a reside. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~50% ethyl acetate/petroleum ether gradient @ 50 mL/min) to give methyl 2-[[(2S)-2-(tert-butoxycarbonylamino)-3- cyclopropyl-propanoyl]amino]-3-(2-pyridyl)butanoate (3.00 g, 7.40 mmol, 57% yield) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.57-8.43 (m, 1H), 7.69-7.53 (m, 1H), 7.23-7.09 (m, 2H), 5.35-5.09 (m, 1H), 4.94-4.77 (m, 1H), 4.38-4.12 (m, 1H), 3.67-3.53 (m, 4H), 1.67-1.53 (m, 2H), 1.49-1.43 (m, 9H), 1.43-1.37 (m, 3H), 0.92-0.58 (m, 1H), 0.55-0.39 (m, 2H), 0.23-0.00 (m, 2H). LC-MS (Method C): R _t = 0.480 min; MS (ESIpos): m/z = 406.2 [M+H] ⁺ . Procedure for preparation of methyl 2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-(2- pyridyl)butanoate To a solution of methyl 2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propanoy l] amino]-3-(2- pyridyl)butanoate (3.00 g, 7.40 mmol, crude purity, 1.00 eq) in ethyl acetate (30.0 mL) was added hydrogen chloride (4.00 M in ethyl acetate, 31.6 mL) at 25°C. After stirring at 25°C for 2 h, the reaction mixture was concentrated to give methyl 2-[[(2S)-2-amino-3-cyclopropyl-propanoyl] amino]-3-(2- pyridyl)butanoate (2.50 g, 7.31 mmol, 99% yield, HCl) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.15-8.84 (m, 1H), 8.70-8.55 (m, 1H), 8.28-8.06 (m, 3H), 7.75-7.40 (m, 2H), 4.96-4.79 (m, 1H), 3.96-3.89 (m, 1H), 3.73-3.68 (m, 3H), 1.72-1.44 (m, 2H), 1.39-1.24 (m, 3H), 0.88-0.61 (m, 1H), 0.56-0.32 (m, 2H), 0.22-0.06 (m, 3H). LC-MS (Method A): R _t = 0.448 min; MS (ESIpos): m/z = 306.1 [M+H] ⁺ . Procedure for preparation of methyl 2-[[(2S)-3-cyclopropyl-2-(1H-indole-2- carbonylamino)propanoyl]amino]-3-(2-pyridyl)butanoate To a solution of 1H-indole-2-carboxylic acid (1.30 g, 8.04 mmol, 1.10 eq) in N,N-dimethylformamide (50.0 mL) were added N,N-diisopropylethylamine (2.84 g, 21.9 mmol, 3.82 mL, 3.00 eq) and O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (3.34 g, 8.78 mmol, 1.20 eq) at 25°C. After stirring at 25°C for 0.25 h, methyl 2-[[(2S)-2-amino-3-cyclopropyl-propanoyl] amino]-3-(2- pyridyl)butanoate (2.50 g, 7.31 mmol, 1.00 eq, HCl) was added. After addition, the resulting mixture was stirred at 25°C for 1 h. The reaction mixture was poured into ammonium chloride aqueous solution (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®;40 g SepaFlash® Silica Flash Column, Eluent of 0~50% ethyl acetate/petroleum ether gradient @ 50 mL/min) to give methyl 2-[[(2S)-3-cyclopropyl-2-(1H-indole-2-carbonylamino)propanoy l]amino]-3-(2-pyridyl)butanoate (3.00 g, 6.69 mmol, 92% yield) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 10.00-9.42 (m, 1H), 8.60-8.24 (m, 1H), 7.93-7.28 (m, 5H), 7.25-6.92 (m, 5H), 4.95-4.86 (m, 1H), 3.73-3.45 (m, 4H), 1.91-1.69 (m, 2H), 1.49-1.34 (m, 3H), 0.97-0.71 (m, 1H), 0.55-0.33 (m, 2H), 0.25-0.00 (m, 2H). LC-MS (Method C): R _t = 0.535 min; MS (ESIpos): m/z = 449.1 [M+H] ⁺ . Procedure for preparation of N-[(1S)-2-[[(2R)-1-carbamoyl-2-(2-pyridyl)propyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-1H-indole-2-carboxamide (11_peak1 and 11_peak2) A solution of methyl 2-[[(2S)-3-cyclopropyl-2-(1H-indole-2-carbonylamino)propanoy l] amino]-3-(2- pyridyl) butanoate (750 mg, 1.67 mmol, 1 eq) in ammonia (19 M in methanol, 15.0 mL) was stirred at 25°C for 48 h. The reaction mixture was concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®;20 g SepaFlash® Silica Flash Column, eluent of 0~100% ethyl acetate/petroleum ether gradient @40 mL/min) to give 11_peak1 (300 mg, 657 μmol, 39% yield, 95% purity) and 11_peak2 (280 mg, 613 umol, 37% yield, 95% purity) as colorless oil. LC-MS (Method C): R _t = 0.673 min; MS (ESIpos): m/z = 434.2 [M+H] ⁺ . LC-MS (Method C): R _t = 0.669 min; MS (ESIpos): m/z = 434.2 [M+H] ⁺ . Procedure for preparation of N-[(1S)-2-[[(1S,2R)-1-cyano-2-(2-pyridyl)propyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-1H-indole-2-carboxamide To a solution of N-[(1S)-2-[[(1S,2R)-1-carbamoyl-2-(2-pyridyl)propyl]amino]-1 -(cyclopropylmethyl) -2- oxo-ethyl]-1H-indole-2-carboxamide 11_peak1 (250 mg, 548 umol, 95% purity, 1.00 eq) in dichloromethane (5.00 mL) was added Burgess reagent (392 mg, 1.64 mmol, 3.00 eq) at 0°C. After stirring at 25°C for 4 h, saturated sodium bicarbonate aquesou solution (20.0 mL) was added to the reaction mixture to adjust pH ~ 9 and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~60% ethyl acetate/petroleum ether gradient @ 40 mL/min) to give N-[(1S)-2-[[(1S,2R)-1-cyano-2-(2- pyridyl)propyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-1H- indole-2-carboxamide 12_peak1 (150 mg, 343 μmol, 63% yield, 95% purity) as yellow oil. LC-MS (Method C): R _t = 0.828 min; MS (ESIpos): m/z = 416.0 [M+H] ⁺ . Procedure for preparation of N-[(1S)-2-[[(1S,2R)-1-cyano-2-(2-pyridyl)propyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-1H-indole-2-carboxamide To a solution of N-[(1S)-2-[[(1S,2R)-1-carbamoyl-2-(2-pyridyl)propyl]amino]-1 -(cyclopropylmethyl) -2- oxo-ethyl]-1H-indole-2-carboxamide 11_peak2 (280.00 mg, 614 μmol, 95% purity, 1.00 eq) in dichloromethane (6.00 mL) was added burgess reagent (439 mg, 1.84 mmol, 3.00 eq) at 0°C. After stirring at 25°C for 4 h, saturated sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture to adjust pH ~ 9. The aqueous phase was extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®;12 g SepaFlash® Silica Flash Column, Eluent of 0~60% ethyl acetate/petroleum ether gradient @ 40 mL/min) to give N-[(1S)-2-[[(1S,2R)-1-cyano-2-(2- pyridyl)propyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-1H -indole-2-carboxamide 12_peak2 (120 mg, 274 μmol, 45% yield, 95% purity) as yellow oil. LC-MS (Method C): R _t = 0.824 min; MS (ESIpos): m/z = 416.0 [M+H] ⁺ . Procedure for preparation of N-[(1S)-2-[[(1S,2R)-1-cyano-2-(2-pyridyl)propyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-1H-indole-2-carboxamide N-[(1S)-2-[[(1S,2R)-1-cyano-2-(2-pyridyl)propyl]amino]-1-(cy clopropylmethyl)-2-oxo-ethyl]-1H-indole- 2-carboxamide 12_peak1 (150 mg, 343 μmol, 95% purity) was purified by SFC (column: Daicel ChiralPak IG (250*30mm, 10 μm); mobile phase: [0.1% NH3·H2O methanol]; B%: 70%-70%,4.1;30 min), and N-[(1S)-2-[[(1S,2R)-1-cyano-2-(2-pyridyl)propyl]amino]-1-(cy clopropylmethyl)-2-oxo-ethyl]-1H- indole-2-carboxamide 12_peak2 (120 mg, 274 μmol, 95% purity) was purified by SFC (column: DAICEL CHIRALPAK AD (250mm*30 mm,10 μm); mobile phase: [IPA-ACN]; B%: 70%-70%,5.5;40 min) to give CPD0084107 (46.38 mg, 110.85 μmol, 32% yield, 99% purity) as a white solid; CPD0084108 (25.2 mg, 59.9 μmol, 17% yield, 99% purity) as a yellow solid. CPD0084109 (20.9 mg, 49.4 μmol, 14% yield, 98% purity) as a white solid; CPD0084110 (24.14 mg, 55.20 μmol, 16% yield, 95% purity) as a yellow solid. Preparation of CPD0084193, CPD0084194, CPD0084195 and CPD0084196 Procedure for preparation of 6,7-dihydrobenzo[d]thiazol-4(5H)-one To a solution of 2-amino-6,7-dihydro-5H-1,3-benzothiazol-4-one (4.50 g, 26.8 mmol, 1.00 eq) and hypophosphorous acid (27.0 g, 205 mmol, 27.0 mL, 50% purity, 7.65 eq) in acetonitrile (30 mL) was added a solution of sodium nitrite (9.23 g, 134 mmol, 5.00 eq) in water (30.0 mL) dropwise at 0°C. After stirring at 0°C for 1 h, the mixture was allowed to warm to 25°C and stirred at this temperature for 16 h. The reaction mixture was poured into water (40.0 mL) and extracted with ethyl acetate (30 mL × 5). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , (ethyl acetate: methanol = 10/1)/petroleum ether = 1/50 to 2/3) to give 6,7-dihydrobenzo[d]thiazol-4(5H)-one (4.00 g, 26.1 mmol, 98% yield) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.99 (s, 1H), 3.14 (t, J = 6.4 Hz 2H), 3.57 (t, J = 6.4 Hz, 2H), 2.17- 2.10 (m, 2H). LC-MS (Method C): R _t = 0.219 min; MS (ESIpos): m/z = 154.1 [M+H] ⁺ . Procedure for preparation of 4-(methoxymethylene)-4,5,6,7-tetrahydrobenzo[d]thiazole To a solution of methoxymethyl(triphenyl)phosphonium;chloride (10.1 g, 29.4 mmol, 1.50 eq) in tetrahydrofuran (50.0 mL) was added dropwise n-butyl lithium (2.5 M in tetrahydrofuran, 11.8 mL, 1.50 eq) at -70°C. After addition, the mixture was stirred at this temperature for 30 min, and then a solution of 6,7-dihydrobenzo[d]thiazol-4(5H)-one (3.00 g, 19.6 mmol, 1.00 eq) in tetrahydrofuran (30.0 mL) was added dropwise at -70°C. After addition, the resulting mixture was allowed to warm to 25°C and stirred for at this temperature 16 h. The reaction mixture was quenched by addition saturated ammonium chloride aqueous solution (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~30% ethyl acetate/petroleum ether gradient @ 45 mL/min) to give 4-(methoxymethylene)-4,5,6,7- tetrahydrobenzo[d]thiazole (1.80 g, 9.93 mmol, 51% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.84 (s, 1H), 6.11 (s, 1H), 3.62 (s, 3H), 2.85 (t, J = 6.4 Hz, 2H), 2.28 (t, J = 6.4 Hz, 2H), 1.85-1.79 (m, 2H). LC-MS (Method C): R _t = 0.606 min; MS (ESIpos): m/z = 182.1 [M+H] ⁺ . Procedure for preparation of 4,5,6,7-tetrahydrobenzo[d]thiazole-4-carbaldehyde A mixture of 4-(methoxymethylene)-4,5,6,7-tetrahydrobenzo[d]thiazole (1.50 g, 8.28 mmol, 1.00 eq) and hydrochloric acid (6 M in water, 20.0 mL, 14.5 eq) was stirred at 25°C for 6 h. The mixture was adjusted pH = 7 ~ 8 with sodium bicarbonate solid and extracted with ethyl acetate (50.0 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give 4,5,6,7-tetrahydrobenzo[d]thiazole-4-carbaldehyde (1.10 g, 6.58 mmol, crude) as yellow oil. The crude product was used for the next step reaction directly. Procedure for preparation of methyl 2-((tert-butoxycarbonyl)amino)-3-(4,5,6,7- tetrahydrobenzo[d]thiazol-4-yl)acrylate To a mixture of 4,5,6,7-tetrahydrobenzo[d]thiazole-4-carbaldehyde (1.10 g, 6.58 mmol, 1.00 eq) and methyl 2-(tert-butoxycarbonylamino)-2-dimethoxyphosphoryl-acetate (2.35 g, 7.89 mmol, 1.20 eq) in dichloromethane (50.0 mL) was added 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (1.20 g, 7.89 mmol, 1.19 mL, 1.20 eq) at 0°C. After addition, the mixture was allowed to warm to 25°C and stirred at this temperature for 16 h. After concentration, the residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~30% ethyl acetate/petroleum ether gradient @ 30 mL/min) to give methyl 2-((tert-butoxycarbonyl)amino)-3- (4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)acrylate (1.50 g, 4.43 mmol, 67% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.89 (s, 1H), 7.61 (d, J = 7.6 Hz, 1H), 6.29 (d, J = 8.4 Hz, 1H), 4.93 (t, J = 8.4 Hz, 1H), 3.62 (s, 3H), 2.93-2.88 (m, 2H), 2.60 (m, 1H), 1.90-1.82 (m, 3H), 1.38 (s, 9H). LC-MS (Method C): R _t = 0.827 min; MS (ESIpos): m/z = 339.1 [M+H] ⁺ . Procedure for preparation of methyl 2-((tert-butoxycarbonyl)amino)-3-(4,5,6,7- tetrahydrobenzo[d]thiazol-4-yl)propanoate To a solution of methyl 2-((tert-butoxycarbonyl)amino)-3-(4,5,6,7-tetrahydrobenzo[d] thiazol-4- yl)acrylate (1.50 g, 4.43 mmol, 1.00 eq) in methanol (20 mL) was added Pd/C (150 mg, 10% purity, contained 50% water) at 25°C. After stirring at 25°C under hydrogen atmosphere (15 psi) for 76 h, the mixture was filtered through a pad of Celite. The filtrate was concentrated to give methyl 2-((tert- butoxycarbonyl)amino)-3-(4,5,6,7-tetrahydrobenzo[d]thiazol-4 -yl)propanoate (1.50 g, 4.41 mmol, 99% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.88-8.84 (m, 1H), 7.47-7.32 (m, 1H), 4.55-4.22 (m, 1H)), 3.61 (s, 3H), 2.87-2.75 (m, 3H), 2.16-2.07 (m, 1H), 1.99-1.84 (m, 2H), 1.71-1.63 (m, 2H), 1.54-1.47 (m, 1H),1.38 (s, 9H). LC-MS (Method C): R _t = 0.866 min; MS (ESIpos): m/z = 341.1 [M+H] ⁺ . Procedure for preparation of methyl 2-amino-3-(4,5,6,7-tetrahydrobenzo[d]thiazol-4- yl)propanoate hydrochloride To a mixture of methyl 2-((tert-butoxycarbonyl)amino)-3-(4,5,6,7-tetrahydrobenzo[d] thiazol-4- yl)propanoate (1.50 g, 4.41 mmol, 1.00 eq) in ethyl acetate (50 mL) was added HCl/EtOAc (4 M, 50.0 mL) at 0°C. After stirring at 25°C for 1 h, the mixture was concentrated to give methyl 2-amino-3- (4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)propanoate hydrochloride (1.20 g, crude) as a yellow solid. The crude product was used for the next step reaction directly. LC-MS (Method C): R _t = 0.140 min; MS (ESIpos): m/z = 241.2 [M+H] ⁺ . Procedure for preparation of methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-3- cyclopropylpropanamido)-3-(4,5,6,7-tetrahydrobenzo[d]thiazol -4-yl)propanoate To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propanoic acid (994 mg, 4.34 mmol, 1.00 eq) in N,N-dimethylformamide (5.00 mL) was added O-(7-Aza-1H-benzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (2.47 g, 6.50 mmol, 1.50 eq) at 0°C. After stirring the mixture at 25°C for 0.5 h, methyl 2-amino-3-(4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)propanoate hydrochloride (1.20 g, 4.34 mmol, crude, 1.00 eq) and N,N-diisopropylethylamine (2.24 g, 17.34 mmol, 3.02 mL, 4.00 eq) were added. After stirring at 25°C for 16 h, the mixture was poured into water (100 mL) and extracted with ethyl acetate (50.0 mL × 2). The combined organic phases was dried with anhydrous sodium sulfate, filtered and concentrated to a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~30% ethyl acetate/petroleum ether gradient @ 30 mL/min) to give methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-3- cyclopropylpropanamido)-3-(4,5,6,7-tetrahydrobenzo[d]thiazol -4-yl)propanoate (1.40 g, 3.10 mmol, 71.5% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.86-8.85 (m, 1H), 8.48-8.35 (m, 1H), 6.87-6.75 (m, 1H), 4.74-4.46 (m 1H), 4.00-3.88 (m, 1H), 3.61-3.59 (m, 3H), 2.80-2.75 (m, 2H), 2.57-2.51 (m, 2H), 2.43-2.19 (m, 1H), 1.97-1.87 (m, 2H), 1.74-1.44 (m, 4H), 1.37-1.33 (m, 9H), 0.82-0.72 (m, 1H), 0.36-0.27 (m, 2H), 0.15- 0.06 (m, 2H). LC-MS (Method C): R _t = 0.846 min; MS (ESIpos): m/z = 452.2 [M+H] ⁺ . Procedure for preparation of methyl 2-((S)-2-amino-3-cyclopropylpropanamido)-3-(4,5,6,7- tetrahydrobenzo[d]thiazol-4-yl)propanoate hydrochloride To a solution of methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-3-cyclopropylpropanami do)-3-(4,5,6,7- tetrahydrobenzo[d]thiazol-4-yl)propanoate (1.40 g, 3.10 mmol, 1.00 eq) in ethyl acetate (10.0 mL) was added HCl/EtOAc (4 M, 20.0 mL) at 0°C. After stirring at 25°C for 1 h, the mixture was concentrated to give methyl 2-((S)-2-amino-3-cyclopropylpropanamido)-3-(4,5,6,7-tetrahyd robenzo[d]thiazol-4- yl)propanoate hydrochloride (1.20 g, crude) as yellow oil. The crude product was used for the next step reaction directly. LC-MS (Method C): R _t = 0.768 min, 0.793 min; MS (ESIpos): m/z = 352.1 [M+H] ⁺ . Procedure for preparation of methyl 2-((S)-3-cyclopropyl-2-(1H-indole-2- carboxamido)propanamido)-3-(4,5,6,7-tetrahydrobenzo[d]thiazo l-4-yl)propanoate To a mixture of 1H-indole-2-carboxylic acid (499 mg, 3.09 mmol, 1.00 eq) in N,N-dimethylformamide (15 mL) was added O-(7-Aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.53 g, 4.02 mmol, 1.30 eq) and N,N-diisopropylethylamine (1.60 g, 12.4 mmol, 2.16 mL, 4.00 eq) at 0°C. After stirring at 25°C for 0.2 h, methyl 2-((S)-2-amino-3-cyclopropylpropanamido)-3-(4,5,6,7- tetrahydrobenzo[d]thiazol-4-yl)propanoate hydrochloride (1.20 g, 3.09 mmol, crude, 1.00 eq) was added. After stirring the mixture at 25°C for 0.5 h, the mixture was poured into water (50.0 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic phases was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~80% ethyl acetate/petroleum ether gradient @ 30 mL/min) to give methyl 2-((S)-3-cyclopropyl-2-(1H-indole-2- carboxamido)propanamido)-3-(4,5,6,7-tetrahydrobenzo[d]thiazo l-4-yl)propanoate (900 mg, 1.82 mmol, 59% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.60-11.55 (m, 1H), 8.84-8.80 (m, 1H), 8.70-8.52 (m, 1H), 8.45- 8.40 (m, 1H), 7.64-7.58 (m, 1H), 7.44-7.40 (m, 1H), 7.26-7.25 (m, 1H), 7.21-7.16 (m, 1H), 7.07-7.01 (m, 1H), 4.81-4.53 (m, 2H), 3.61-3.60 (m, 3H), 2.84-2.80 (m, 1H), 2.78-2.75 (m, 1H), 2.45-2.36 (m, 1H), 2.29-2.24 (m, 1H), 1.97-1.42 (m, 7H), 0.85-0.77 (m, 1H), 0.41-0.35 (m, 2H), 0.20-0.07 (m, 2H). LC-MS (Method C): R _t = 0.941 min; MS (ESIpos): m/z = 495.0 [M+H] ⁺ . Procedure for preparation of N-((2S)-1-((1-amino-1-oxo-3-(4,5,6,7-tetrahydrobenzo[d]thiaz ol-4- yl)propan-2-yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-1H-ind ole-2-carboxamide To a solution of methyl 2-((S)-3-cyclopropyl-2-(1H-indole-2-carboxamido)propanamido) -3-(4,5,6,7- tetrahydrobenzo[d]thiazol-4-yl)propanoate (800 mg, 1.62 mmol, 1.00 eq) in methanol (5.00 mL) was added ammonia/methanol (20 M, 20.0 mL) at 25°C. After stirring at 25°C for 60 h, the mixture was concentrated to give N-((2S)-1-((1-amino-1-oxo-3-(4,5,6,7-tetrahydrobenzo[d]thiaz ol-4-yl)propan-2- yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-1H-indole-2-carbox amide (750 mg, 1.56 mmol, 97% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.59 (s, 1H), 8.87-8.78 (m, 1H), 8.55-8.19 (m, 2H), 7.64-7.62 (m, 1H), 7.45-7.42 (m, 1H), 7.357.24 (m, 2H), 7.21-7.17 (m, 1H), 7.11-7.02 (m, 2H), 4.60-4.43 (m, 2H), 2.85-2.78 (m, 2H), 2.44-2.35 (m, 2H), 2.02-1.85 (m, 3H), 1.72-1.47 (m, 4H), 0.89-0.76 (m, 1H), 0.42- 0.36 (m, 2H), 0.21-0.07 (m, 2H). LC-MS (Method C): R _t = 0.793 min; MS (ESIpos): m/z = 480.3 [M+H] ⁺ . Procedure for preparation of N-((2S)-1-((1-cyano-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-4- yl)ethyl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-1H-indole-2- carboxamide To a solution of N-((2S)-1-((1-amino-1-oxo-3-(4,5,6,7-tetrahydrobenzo[d]thiaz ol-4-yl)propan-2- yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-1H-indole-2-carbox amide (700 mg, 1.46 mmol, 1.00 eq) in dichloromethane (20.0 mL) was added Burgess reagent (1.04 g, 4.38 mmol, 3.00 eq) at 0°C. After addition, the mixture was allowed to warm to 25°C and stirred at this temperature for 3 h. The mixture was poured into saturated sodium bicarbonate solution (10.0 mL) and extracted with dichloromethane (20.0 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 15mL/min) to give N-((2S)-1-((1-cyano-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-4-y l)ethyl)amino)-3- cyclopropyl-1-oxopropan-2-yl)-1H-indole-2-carboxamide (360 mg, 772 μmol, 53% yield, 99% purity) as yellow solid. LC-MS (Method C): R _t = 0.900 min; MS (ESIpos): m/z = 462.1 [M+H] ⁺ . Procedure for preparation of CPD0084193, CPD0084194, CPD0084195 and CPD0084196- N-[(1S)- 2-[[(1R)-1-cyano-2-[(4R)-4,5,6,7-tetrahydro-1,3-benzothiazol -4-yl]ethyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-1H-indole-2-carboxamide N-((2S)-1-((1-cyano-2-(4,5,6,7-tetrahydrobenzo[d]thiazol-4-y l)ethyl)amino)-3-cyclopropyl-1- oxopropan-2-yl)-1H-indole-2-carboxamide (360 mg, 0.780 mmol) was purified by SFC (column: REGIS (S,S) WHELK-O1 (250mm*50mm,10um); mobile phase: [IPA-ACN]; B%: 50%-50%, 2.7min; 75min) to afford CPD0084196: (peak 4, 53.68 mg, 0.107 mmol, 13.73% yield, 92.1% purity) as an off-white solid. A mixture of peak 1, peak 2 and peak 3 was further purified by SFC for twice (column: DAICEL CHIRALPAK AS (250mm*30mm,10um); mobile phase: [0.1%NH3·H2O IPA]; B%: 35%-35%, 8min;140min) and SFC (column: REGIS(S,S)WHELK-O1 (250mm*25mm,10um); mobile phase: [0.1% NH _3· H ₂ O IPA]; B%: 55%-55%, 2.6; 60min) to give CPD0084193: (peak 1, 33.85 mg, 73.26 μmol, 9.39% yield, 99.9% purity), CPD0084194: (peak 2, 53.09 mg, 114.90 μmol, 14.73% yield, 99.9% purity), CPD0084195: (peak 3, 20.34 mg, 44.02 μmol, 5.64% yield, 99.9% purity) as a white solid. Preparation of CPD0084231 Procedure for preparation of (2S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butan oyl]- 3,3-dimethyl-azetidine-2-carboxylic acid A mixture of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid (358 mg, 1.55 mmol, 1.00 eq) and di(imidazol-1-yl)methanone (377 mg, 2.32 mmol, 1.50 eq) in N,N-dimethylformamide (5.00 mL) was stirred at 25°C for 1 h. A solution of (2S)-3,3-dimethylazetidine-2-carboxylic acid (200 mg, 1.55 mmol, 1.00 eq) and N,N-diisopropylethylamine (742 mg, 5.74 mmol, 3.71 eq) in N,N-dimethylformamide (5.00 mL) was added drop-wise. After stirring at 25°C for 12 h, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The aqueous phase was adjusted pH = 6 with hydrochloric acid (1M) and extracted with ethyl acetate (100 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, Eluent of 0~50% ethyl acetate/petroleum ether gradient @ 45 mL/min) to give (2S)-1-[(2S)-2-(tert- butoxycarbonylamino)-3,3-dimethyl-butanoyl]-3,3-dimethyl-aze tidine-2-carboxylic acid (280 mg, 818 μmol, 53% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.71 (s, 1H), 6.62 (d, J = 8.4 Hz, 1 H), 4.15 (s, 1H), 3.93-3.91 (m, 1H), 3.80-3.77 (m, 2H), 1.38 (s, 9H), 1.30 (s, 3H), 1.11 (s, 3H), 0.94 (s, 9H). Procedure for preparation of (2S)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3,3-dimethyl- azetidine-2-carboxylic acid To a solution of (2S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butan oyl]-3,3-dimethyl- azetidine-2-carboxylic acid (280 mg, 0.818 mmol,1.00 eq) in dichloromethane (5.00 mL) was added trifluoroacetic acid (1.00 mL) at 0°C. After stirring at 25°C for 1 h, the pH of the reaction mixture was adjusted to 9 with trimethylamine and then concentrated under vacuum to give (2S)-1-[(2S)-2-amino- 3,3-dimethyl-butanoyl]-3,3-dimethyl-azetidine-2-carboxylic acid (200 mg, crude) as yellow oil. Procedure for preparation of (2S)-1-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]bu tanoyl]- 3,3-dimethyl-azetidine-2-carboxylic acid A mixture of (2S)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3,3-dimethyl-aze tidine-2-carboxylic acid (200 mg, 0.825 mmol, 1.00 eq), methyl 2,2,2-trifluoroacetate (211 mg, 1.65 mmol, 2.00 eq) and triethylamine (251 mg, 2.48 mmol, 3.00 eq) in methanol (2.00 mL) was stirred at 25°C for 12 h. After concentration, the residue was purified by reversed phase column (column: C1845-60um 60A, 30 g; mobile phase: [water (0.1% FA)-ACN]; B%: 0%-30%, 30 min) to give (2S)-1-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-3,3-dimethyl-azetidine-2-car boxylic acid (160 mg, 468 μmol, 57% yield, 99% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.80 (s, 1 H), 9.31 (d, J = 8 Hz, 1 H), 4.22-4.20 (m, 2 H), 3.89-3.83 (m, 2H), 1.31 (s, 3 H), 1.12 (s, 3 H), 1.01 (s, 9 H). LC-MS (Method C): R _t = 0.732 min, MS (ESIpos): m/z = 339.2 [M+H] ⁺ . Procedure for preparation of (2S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-1-[ (2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-3,3-dimet hyl-azetidine-2-carboxamide To a mixture of (2S)-1-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]bu tanoyl]-3,3-dimethyl- azetidine-2-carboxylic acid (160 mg, 0.468 mmol, 99% purity, 1.00 eq), N,N-diisopropylethylamine (242 mg, 1.87 mmol, 4.00 eq) and O-(7-Aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (267 mg, 0.702 mmol, 1.50 eq) in N,N-dimethylformamide (4.00 mL) was added (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanamide (171 mg, 0.702 mmol, 1.50 eq, 2HCl). After stirring at 25°C for 2 h, the mixture was concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 18%-48%, 10 min) to give (2S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]-1-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl) amino]butanoyl]-3,3-dimethyl-azetidine-2- carboxamide (150 mg, 0.317 mmol, 68% yield) as a white solid. LC-MS (Method C): R _t = 0.813 min, MS (ESIpos): m/z = 492.3 [M+H] ⁺ . Procedure for preparation of (2S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-1-[ (2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-3,3-dimet hyl-azetidine-2-carboxamide A mixture of (2S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-1-[ (2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-3,3-dimethyl-azetidine-2-car boxamide (150 mg, 0.305 mmol, 1.00 eq) and methoxycarbonyl-(triethylammonio)sulfonyl-azanide (218 mg, 0.916 mmol, 3.00 eq) in dichloromethane (10.0 mL) was stirred at 25°C for 1 h. Saturated sodium bicarbonate aqueous solution was added to the mixture to adjust pH = 7 and concentrated under vacuum. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm* 5 μm; mobile phase: [water( NH ₄ ·HCO ₃ )- ACN]; B%: 32%-62%, 9 min) to give (2S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-1-[ (2S)- 3,3-dimethyl-2-[(2,2,2-trifluoroacetyl) amino]butanoyl]-3,3-dimethyl-azetidine-2-carboxamide (113 mg, 0.236 mmol, 77% yield, 99% purity) as a white solid. Preparation of CPD0084235 Procedure for preparation of (2S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl- butanoyl]pyrrolidine-2-carboxylate A mixture of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid (698 mg, 3.02 mmol, 1.00 eq), methyl (2S)-pyrrolidine-2-carboxylate (500 mg, 3.02 mmol, 1.00 eq, HCl), O-(7-Aza-1H- benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.72 g, 4.53 mmol, 1.50 eq) and N,N-diisopropylethylamine (1.17 g, 9.06 mmol, 1.58 mL, 3.00 eq) in N,N-dimethylformamide (10.0 mL) was stirred at 25°C for 12 h. The mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (50.0 mL). The organic phase was washed with water (50.0 mL × 2), brine (50.0 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, Eluent of 0~30% ethyl acetate/petroleum ether gradient @ 45 mL/min) to give methyl (2S)-1-[(2S)-2-(tert- butoxycarbonylamino)-3,3-dimethyl-butanoyl]pyrrolidine-2-car boxylate (0.7 g, 1.47 mmol, 49% yield, 72% purity) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.28-5.25 (m, 1H), 4.55-4.51 (m, 1H), 4.30 (m, J = 10 Hz, 1H), 3.86- 3.80 (m, 1H), 3.74-3.66 (m, 4H), 2.26-2.21 (m, 1H), 2.04-1.96 (m, 3H), 1.73 (s, 2H), 1.42 (s, 9H) , 1.03 (s, 9H) , 0.97-0.96 (m, 1H). LC-MS (Method C): R _t = 0.885 min, MS (ESIpos): m/z = 343.1 [M+H] ⁺ . Procedure for preparation of (2S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl- butanoyl]pyrrolidine-2-carboxylic acid A mixture of methyl (2S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butan oyl]pyrrolidine-2- carboxylate (700 mg, 2.04 mmol, 1.00 eq) and lithium hydroxide hydrate (129 mg, 3.07 mmol, 1.50 eq) in a mixed solvent of tetrahydrofuran (10.0 mL), methanol (10.0 mL) and water (10.0 mL) was stirred at 25°C for 2 h. The mixture was diluted with water (50.0 mL) and washed with ethyl acetate (50.0 mL). Hydrochloric acid (1M) was added to the aqueous phase to adjust pH~6 and extracted with ethyl acetate (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (2S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl- butanoyl]pyrrolidine-2-carboxylic acid (640 mg, 1.93 mmol, 99% purity) as a white solid. LC-MS (Method C): R _t = 0.739 min, MS (ESIpos): m/z = 273.2 [M+H-t-Bu] ⁺ . SFC: de: 100%. Procedure for preparation of (2S)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]pyrrolidine-2- carboxylic acid A mixture of (2S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butan oyl]pyrrolidine-2-carboxylic acid (640 mg, 1.95 mmol, 1.00 eq) in hydrochloric acid (4 M in dioxane, 20 mL) was stirred at 25°C for 12 h. The mixture was concentrated by evaporation under vacuum to give (2S)-1-[(2S)-2-amino-3,3- dimethyl-butanoyl]pyrrolidine-2-carboxylic acid (520 mg, crude, HCl) as a white solid. Procedure for preparation of (2S)-1-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]pyrrolidine-2-carboxylic acid To a mixture of (2S)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]pyrrolidine-2-car boxylic acid (520 mg, 1.96 mmol, 1.00 eq, HCl) and triethylamine (595 mg, 5.88 mmol, 3.00 eq) in methanol (10.0 mL) was added drop-wise methyl 2,2,2-trifluoroacetate (502 mg, 3.92 mmol, 2.00 eq) at 0°C. After stirring at 25°C for 12 h, the mixture was concentrated under vacuum to give a residue. The residue was diluted with water (50.0 mL) and washed with petroleum ether (50.0 mL). Hydrochloric acid (1 M) was added to the aqueous phase to adjust pH~6 and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (2S)-1-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]bu tanoyl]pyrrolidine-2-carboxylic acid (500 mg, 1.50 mmol, 97% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.52 (br. s, 1H), 9.29 (d, J = 8.8 Hz, 1H), 4.60 (d, J = 8.4 Hz, 1H), 4.29-4.26 (m, 1H), 3.72-3.60 (m, 2H), 2.22-2.14 (m, 1H), 1.93-1.80 (m, 3H), 1.01 (s, 9H). LC-MS (Method A): R _t = 0.948 min, MS (ESIpos): m/z = 324.8 [M+H] ⁺ . Procedure for preparation of (2S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-1-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroace tyl)amino] butanoyl]pyrrolidine-2- carboxamide To a solution of (2S)-1-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]bu tanoyl]pyrrolidine-2- carboxylic acid (350 mg, 1.08 mmol, 1.00 eq), O-(7-Aza-1H-benzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (821 mg, 2.16 mmol, 2.00 eq) and N,N-diisopropylethylamine (558 mg, 4.32 mmol, 0.752 mL, 4.00 eq) in N,N-dimethylformamide (5.00 mL) was added (2S)-2-amino- 3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (336 mg, 1.62 mmol, 1.50 eq, HCl). After stirring at 25°C for 12 h, the mixture was concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18150*40 mm* 15 μm; mobile phase: [water(FA)- ACN]; B%: 13%-43%,10min) to give (2S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-1-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroace tyl)amino]butanoyl]pyrrolidine-2-carboxamide (370 mg, 775 μmol, 72% yield) as a yellow solid. LC-MS (Method C): R _t = 0.755 min, MS (ESIpos): m/z = 478.2 [M+H] ⁺ . Procedure for preparation of (2S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-1-[ (2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl] pyrrolidine-2-carboxamide A mixture of (2S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]met hyl]ethyl]-1-[(2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]pyrrolidin e-2-carboxamide (370 mg, 0.775 mmol, 1.00 eq) and methoxycarbonyl-(triethylammonio)sulfonyl-azanide (554 mg, 2.32 mmol, 3.00 eq) in dichloromethane (10.0 mL) was stirred at 25°C for 2 h. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture to adjust pH~7 and concentrated by evaporation under vacuum. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18150*25 mm* 10 μm; mobile phase: [water (FA)-ACN]; B%: 25%-52%, 9 min) to give (2S)-N-[(1S)-1-cyano-2- [(3S)-2-oxopyrrolidin-3-yl]ethyl]-1-[(2S)-3,3-dimethyl-2-[(2 ,2,2- trifluoroacetyl)amino]butanoyl]pyrrolidine-2-carboxamide (67.5 mg, 0.145 mmol, 99% purity) as a white solid. Preparation of CPD0084242 Procedure for preparation of Compound ethyl (3S,3aS,6aR)-2-[(2S)-2-(tert- butoxycarbonylamino)-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-he xahydro-1H- cyclopenta[c]pyrrole-3-carboxylate To a solution of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid (500 mg, 2.16 mmol, 1.00 eq) in N,N-dimethylformamide (5.00 mL) were added N,N-diisopropylethylamine (1.12 g, 8.65 mmol, 4.00 eq), ethyl (3S,3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole -3-carboxylate (522 mg, 2.38 mmol, 1.1 eq, HCl salt) and O-(7-Aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.23 g, 3.24 mmol, 1.50 eq). After stirring at 25°C for 2 h, the reaction mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (15.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 1/0 to 10/1) to give ethyl (3S,3aS,6aR)-2-[(2S)-2-(tert- butoxycarbonylamino)-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-he xahydro-1H-cyclopenta [c]pyrrole-3- carboxylate (750 mg, 1.89 mmol, 87% yield) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.35-5.12 (m, 1H), 4.36 (d, J = 4.0 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.21-4.15 (m, 2H), 3.88-3.81 (m, 1H), 3.78-3.71 (m, 1H), 2.00-1.81 (m, 2H), 1.80-1.71 (m, 1H), 1.70- 1.57 (m, 3H), 1.55-1.45 (m, 1H)1.42 (s, 9H), 1.29-1.25 (m, 3H), 1.03 (s, 9H). Procedure for preparation of (3S,3aS,6aR)-2-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimeth yl- butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3- carboxylic acid A mixture of ethyl (3S,3aS,6aR)-2-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimeth yl-butanoyl]- 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylat e (600 mg, 1.51 mmol, 1 eq) and lithium hydroxide monohydrate (95.25 mg, 2.27 mmol, 1.5 eq) in a mixed solvent of tetrahydrofuran (10.0 mL), methanol (10.0 mL) and water (10.0 mL) was stirred at 25°C for 2 h. Hydrochloric acid (1M) was added to the reaction mixture to adjust pH = 5~6 and extracted with ethyl acetate (15 mL × 6). The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuum to give (3S,3aS,6aR)-2-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimeth yl-butanoyl]- 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c] pyrrole-3-carboxylic acid (370 mg, 0.994 mmol, 66% yield, 99% purity) as a white solid. The crude product was used for next step directly without further purification. LC-MS (Method C): R _t = 0.906 min; MS (ESIpos): m/z = 369.3 [M+H] ⁺ . Procedure for preparation of (3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3,3a,4,5 ,6,6a- hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid A mixture of (3S,3aS,6aR)-2-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimeth yl-butanoyl]-3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (370 mg, 1.00 mmol, 1 eq) in HCl (4 M in dioxane, 10 mL, 40.00 mmol) was stirred at 25°C for 1 h. The reaction mixture was concentrated under vacuum to give (3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3,3a,4,5 ,6,6a-hexahydro-1H- cyclopenta[c]pyrrole-3-carboxylic acid (300 mg, crude, HCl salt) as a white solid. LC-MS (Method C): R _t = 0.341 min; MS (ESIpos): m/z = 269.3 [M+H] ⁺ . Procedure for preparation of (3S,3aS,6aR)-2-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-c yclopenta[c]pyrrole-3-carboxylic acid To a mixture of (3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3,3a,4,5 ,6,6a-hexahydro-1H- cyclopenta[c]pyrrole-3-carboxylic acid (150 mg, 0.49 mmol, 1.00 eq, HCl salt) and triethylamine (199 mg, 1.97 mmol, 4.00 eq) in methanol (5 mL) was added dropwise methyl 2,2,2-trifluoroacetate (126 mg, 0.984 mmol, 99.23 μL, 2 eq) at 0°C. After stirring at 25°C for 16 h, the mixture was concentrated under vacuum to give a residue. The residue was diluted with water (20.0 mL) and washed with petroleum ether (20.0 mL). Hydrochloric acid (1 M) was added to the aqueous phase to adjust pH to 4~5, and extracted with ethyl acetate (20 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give (3S,3aS,6aR)-2-[(2S)-3,3-dimethyl-2- [(2,2,2-trifluoroacetyl)amino] butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3- carboxylic acid (100 mg, 0.272 mmol, 55% yield, 99% purity) as a white solid. LC-MS (Method C): R _t = 0.865 min; MS (ESIpos): m/z = 365.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.59 (s, 1H), 9.33 (d, J = 8 Hz, 1H), 4.56-4.51 (m, 1H), 4.09 (d, J = 4.4 Hz, 1H), 3.79-3.72 (m, 1H), 3.65 (dd, J = 10.4, 3.2 Hz, 1H), 1.93-1.73 (m, 3H), 1.71-1.47 (m, 4H), 1.41-1.32 (m, 1H), 1.01 (s, 9H). Procedure for preparation of (3S,3aS,6aR)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin- 3- yl]methyl]ethyl]-2-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroace tyl)amino] butanoyl]-3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]pyrrole-3-carboxamide To a solution of (3S,3aS,6aR)-2-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl) amino]butanoyl]- 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (50.0 mg, 0.137 mmol, 1.00 eq) in N,N-dimethylformamide (2.00 mL) were added N,N-diisopropylethylamine (70.9 mg, 0.549 mmol, 4.00 eq) , (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (31.4 mg, 0.151 mmol, 1.10 eq, HCl) and O-(7-Aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (104 mg, 0.274 mmol, 2.00 eq). After stirring at 25°C for 16 h, the reaction mixture was concentrated under vacuum to give (3S,3aS,6aR)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin- 3-yl]methyl]ethyl]-2-[(2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl) amino]butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrr ole-3- carboxamide (70 mg, 86.6 μmol, 63% yield, 64% purity) as yellow oil. LC-MS (Method C): Rt = 0.817 min; MS (ESIpos): m/z = 518.3 [M+H] ⁺ . Procedure for preparation of (3S,3aS,6aR)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]et hyl]-2- [(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl] -3,3a,4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrole-3-carboxamide A mixture of (3S,3aS,6aR)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin- 3-yl]methyl]ethyl]-2-[(2S)- 3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-3,3a, 4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrole-3-carboxamide (70 mg, 86.6 μmol, 64% purity, 1.00 eq) and methoxycarbonyl- (triethylammonio)sulfonyl-azanide (61.9 mg, 0.260 mmol, 3.00 eq) in dichloromethane (2.00 mL) was stirred at 25°C for 3 h. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10.0 mL) and extracted with dichloromethane (10 mL × 3). The combined organic layers were washed by brine (15.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 32%-62%,10 min) to give (3S,3aS,6aR)- N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-2-[(2S)- 3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino] butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c] pyrrole-3-carboxamide (19.6 mg, 38.9 μmol, 44% yield, 99% purity) as a white solid. Preparation of CPD0084248, CPD0186410 Procedure for preparation of 1-(tert-butyl) 2-methyl (S)-4-(((trifluoromethyl)sulfonyl)oxy)-2,5- dihydro-1H-pyrrole-1,2-dicarboxylate To a solution of O1-tert-butyl O2-methyl (2S)-4-oxopyrrolidine-1,2-dicarboxylate (20.0 g, 82.2 mmol, 1.00 eq) in dichloromethane (100 mL) at 0°C were added 4-dimethylaminopyridine (30.1 g, 247 mmol, 3.00 eq) and trifluoromethanesulfonic anhydride (34.8 g, 123 mmol, 20.4 mL, 1.50 eq) under nitrogen atmosphere. After stirring at 25°C for 12 h, the reaction mixture was partitioned between dichloromethane (200 mL) and water (100 mL). After separation, the aqueous phase was extracted with dichloromethane (100 mL × 2). The combined extracts were washed with brine (60.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was purified by flash column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 10/1) to afford 1- (tert-butyl) 2-methyl (S)-4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrol e-1,2-dicarboxylate (16.0 g, 42.6 mmol, 52% yield) as colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 6.21-6.18 (m, 1H), 5.07-5.05 (m, 1H), 4.32-4.02 (m, 2H), 3.71-3.68 (m, 3H), 1.41-1.35 (m, 9H). Procedure for preparation of 1-(tert-butyl) 2-methyl (S)-4-(prop-1-en-2-yl)-2,5-dihydro-1H- pyrrole-1,2-dicarboxylate To a solution of 1-(tert-butyl) 2-methyl (S)-4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro -1H-pyrrole-1,2- dicarboxylate (16.0 g, 42.6 mmol, 1.00 eq) and potassium isopropenyltrifluoroborate (6.31 g, 42.6 mmol, 1.00 eq) in dioxane (200 mL) at 25°C were added potassium phosphate (2 M in water, 21.3 mL, 1.00 eq) and methanesulfonato(2-dicyclohexylphosphino-2,4,6-tri-i-propyl- 1,1-biphenyl) (2-amino-1,1- biphenyl-2-yl)palladium(II) (3.61 g, 4.26 mmol, 0.10 eq) under nitrogen atmosphere. After stirring at 60°C for 12 h, the reaction mixture was cooled to room temperature and partitioned between ethyl acetate (40.0 mL) and water (40.0 mL). The separated aqueous phase was extracted with ethyl acetate (80.0 mL × 2). The combined extracts were washed with brine (60.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was purified by flash column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 1: 0 to 10: 1) to afford 1-(tert-butyl) 2- methyl (S)-4-(prop-1-en-2-yl)-2,5-dihydro-1H-pyrrole-1,2-dicarboxyl ate (6.00 g, 22.5 mmol, 53% yield) as colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 5.83-5.80 (m, 1H), 5.11-5.09 (m, 1H), 5.00-4.96 (m, 2H), 4.26-4.23 (m, 2H), 3.68-3.57 (m, 3H), 1.88 (s, 2H), 1.43 (s, 3H), 1.41 (s, 1H), 1.35-1.34 (m, 6H). Procedure for preparation of 1-(tert-butyl) 2-methyl (2S,4R)-4-isopropylpyrrolidine-1,2- dicarboxylate To a solution of 1-(tert-butyl) 2-methyl (S)-4-(prop-1-en-2-yl)-2,5-dihydro-1H-pyrrole-1,2-dicarboxyl ate (6.00 g, 22.5 mmol, 1.00 eq) in methanol (100 mL) was added palladium on carbon (0.60 g, 10% purity) at 25°C. After stirring at 25°C for 4 h under hydrogen (15 psi) atmosphere, the reaction mixture was diluted with methanol (100 mL) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to afford 1-(tert-butyl) 2-methyl (2S,4R)-4-isopropylpyrrolidine-1,2-dicarboxylate (6.00 g, crude) as yellow oil. Procedure for preparation of methyl (2S,4R)-4-isopropylpyrrolidine-2-carboxylate A solution of 1-(tert-butyl) 2-methyl (2S,4R)-4-isopropylpyrrolidine-1,2-dicarboxylate (6.00 g, 22.1 mmol, 1.00 eq) in hydrogen chloride (4 M in ethyl acetate, 100 mL, 18.1 eq) was stirred at 25°C for 0.5 h. The mixture was concentrated under reduced pressure to afford methyl (2S,4R)-4-isopropylpyrrolidine-2- carboxylate (5 g, crude) as colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 4.50-4.25 (m, 1H), 3.75 (s, 3H), 2.90-2.75 (m, 1H), 2.42-2.37 (m, 1H), 2.00-1.80 (m, 1H), 1.61-1.52 (m, 2H), 1.35-1.20 (m, 2H), 0.88-0.84 (m, 6H). Procedure for preparation of methyl (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3- dimethylbutanoyl)-4-isopropylpyrrolidine-2-carboxylate To a solution of methyl (2S,4R)-4-isopropylpyrrolidine-2-carboxylate (5.00 g, 29.2 mmol, 1.00 eq) and (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid (8.10 g, 35.0 mmol, 1.20 eq) in N,N- dimethylformamide (60.0 mL) were added N,N-diisopropylethylamine (11.3 g, 87.6 mmol, 15.3 mL, 3.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (16.7 g, 43.8 mmol, 1.50 eq) at 0°C. After stirring at 25°C for 12 h, the reaction mixture was cooled to room temperature and partitioned between ethyl acetate (200 mL) and water (200 mL). The separated aqueous phase was extracted with ethyl acetate (100 mL × 2). The combined extracts were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was purified by flash column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 1: 0 to 5: 1) to afford methyl (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3- dimethylbutanoyl)-4-isopropylpyrrolidine-2- carboxylate (8 g, 20.81 mmol, 71% yield)) as colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 6.55 (d, J = 8.0 Hz, 1H), 4.26-4.25 (m, 1H), 4.18-4.16 (m, 1H), 3.62 (s, 3H), 3.12-3.07 (m, 1H), 2.39-2.37 (m, 1H), 1.99-1.80 (m, 1H), 1.48-1.47 (m, 1H), 1.46-1.41 (m, 1H), 1.39-1.20 (m, 10H), 0.96-0.94 (m, 9H), 0.93-0.89 (m, 6H). Procedure for preparation of (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3- dimethylbutanoyl)-4-isopropylpyrrolidine-2-carboxylic acid To a solution of methyl (2S,4R)-1-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-bu tanoyl]-4- isopropyl -pyrrolidine-2-carboxylate (4.00 g, 10.4 mmol, 1.00 eq) in tetrahydrofuran (40.0 mL) were added lithium hydroxide hydrate (873 mg, 20.8 mmol, 2.00 eq) and water (40.0 mL) at 25°C. After stirring at 25°C for 12 h, hydrogen chloride (1M in water) was added to the mixture to adjust pH~7. The solution was extracted with ethyl acetate (100 mL × 3). The combined organic layers were concentrated to afford (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbu tanoyl)-4-isopropylpyrrolidine-2- carboxylic acid (3.00 g, crude) as colorless oil. Procedure for preparation of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4- isopropylpyrrolidine-2-carboxylic acid A solution of (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbu tanoyl)-4- isopropylpyrrolidine- 2-carboxylic acid (3.50 g, 9.45 mmol, 1.00 eq) in hydrogen chloride (4 M in ethyl acetate, 40 mL) was stirred at 25°C for 4 h. The reaction mixture was concentrated to afford (2S,4R)- 1-((S)-2-amino-3,3- dimethylbutanoyl)-4-isopropylpyrrolidine-2-carboxylic acid (2.00 g, crude) as colorless oil ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.25 (s, 2H), 4.24-4.20 (m, 1H), 4.13-4.10 (m, 1H), 3.98-3.94 (m, 1H), 3.15-2.95 (m, 1H), 2.41-2.38 (m, 1H), 1.87-1.74 (m, 1H), 1.55-1.45(m, 1H), 1.38-1.32 (m, 1H), 0.99 (s, 10H), 0.91-0.85 (m, 6H). Procedure for preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)buta noyl)-4- isopropylpyrrolidine-2-carboxylic acid To a solution of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-isopropylpyrr olidine-2-carboxylic acid (1.00 g, 3.70 mmol, 1.00 eq) in methanol (10.0 mL) were added triethylamine (1.50 g, 14.8 mmol, 2.06 mL, 4.00 eq) and methyl 2,2,2-trifluoroacetate (948 mg, 7.40 mmol, 2.00 eq) at 25°C. After stirring at 50°C for 2 h, the reaction mixture was concentrated in vacuo at 50°C to give a residue. The residue was diluted with water (10.0 mL), adjusted to pH~4 with hydrogen chloride (1M in water). The solution was extracted with ethyl acetate (30.0 ml × 3). The combined organic layers were washed with brine (50.0 ml), dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated to afford (2S,4R)- 1-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-4- isopropylpyrrolidine-2-carboxylic acid (0.700 g, 1.91 mmol) as a white solid. LC-MS (Method C): R _t = 1.115 min; MS (ESIpos): m/z = 366.9 [M+H] ⁺ . Procedure for preparation of (2S,4R)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)pro pan-2- yl)-1-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl )-4-isopropylpyrrolidine-2- carboxamide To a solution of (2S,4R)-1-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino ] butanoyl]-4-isopropyl- pyrrolidine-2-carboxylic acid (0.200 g, 546 μmol, 1.00 eq) in dichloromethane (5.00 mL) were added(2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (113 mg, 546 μmol, 1.00 eq, HCl), N,N- diisopropylethylamine (282 mg, 2.18 mmol, 4.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N’,N’- tetramethyluronium hexafluorophosphate (415 mg, 1.09 mmol, 2.00 eq) under nitrogen atmosphere. After stirring at 25°C for 12 h, the reaction mixture was used for the next step without further purification. LC-MS (Method C): R _t = 0.940 min; MS (ESIpos): m/z = 520.3 [M+H] ⁺ . Procedure for preparation of CPD0084248, CPD0186410 (2S,4R)-N-((S)-1-cyano-2-((S)-2- oxopyrrolidin-3-yl)ethyl)-1-((S)-3,3-dimethyl-2-(2,2,2-trifl uoroacetamido)butanoyl)-4- isopropylpyrrolidine-2-carboxamide, (2S,4S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]- 1-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoy l]-4-propyl-pyrrolidine-2- carboxamide To a mixture of (2S,4R)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl) propan-2-yl)-1-((S)-3,3- dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-4-isopropylpy rrolidine-2-carboxamide (200 mg, 385 μmol, 1.00 eq) in dichloromethane (2.00 mL) was added Burgess reagent (184 mg, 770 μmol, 2.00 eq) at 25°C. After stirring at 25°C for 30 min, the reaction mixture was cooled to room temperature and partitioned between dichloromethane (40.0 mL) and water (40.0 mL). The aqueous phase was extracted with dichloromethane (30.0 mL × 2). The combined organic layers were washed with brine (60.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was purified by prep-HPLC [Instrument:Gilson-281; Column: Phenomenex Synergi C18 150*30mm*4 μm; eluent A: water (0.225% formic acid in water), eluent B: acetonitrile; gradient: 0-10.5 min 5-35% B; flow 25 ml/min; temperature: RT; Detector: UV 220/254 nm] and SFC (column: Daicel ChiralPak AD-H (250*30 mm, 5 μm); mobile phase: [0.1% NH ₃ ·H ₂ O IPA]; B%: 15%-15%; 3.2 min) to afford (2S,4R)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]- 1-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-4-isopropyl-pyrrolidine-2-ca rboxamide (CPD0084248, 50.0 mg, 99.7 μmol, 26% yield) as a white solid and (2S,4S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl] ethyl]-1- [(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl] -4-propyl-pyrrolidine-2-carboxamide (CPD0186410, 8.00 mg, 15.3 μmol, 77% yield, 96% purity) as a white solid. Preparation of CPD0084249 Procedure for preparation of ditert-butyl (2S,3Z)-3-(dimethylaminomethylene)-4-oxo-pyrrolidine- 1,2-dicarboxylate A mixture of di-tert-butyl (2S)-4-oxopyrrolidine-1,2-dicarboxylate (6.22 g, 21.8 mmol, 1 eq) and 1-tert- butoxy-N,N,N',N'-tetramethyl-methanediamine (7.60 g, 43.6 mmol, 9.00 mL, 2 eq) in 1,2- dimethoxyethane (40.0 mL) was stirred at 70°C for 16 h. After cooling to ambient temperature, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 0/1) to afford di-tert-butyl (2S,3Z)-3- (dimethylaminomethylene)-4-oxo-pyrrolidine-1,2-dicarboxylate (3.00 g, 8.28 mmol, 38% yield, 94% purity) as yellow oil. LC-MS (Method C): R _t = 0.792 min; MS (ESIpos): m/z = 341.3 [M+H] ⁺ . Procedure for preparation of ditert-butyl (2S,3E)-3-ethylidene-4-oxo-pyrrolidine-1,2- dicarboxylate Methyl magnesium bromide (3.00 M in diethyl ether, 7.05 mL, 3.00 eq) was added into a solution of di- tert-butyl (2S,3Z)-3-(dimethylaminomethylene)-4-oxo-pyrrolidine-1,2-dic arboxylate (2.40 g, 7.05 mmol, 1.00 eq) in tetrahydrofuran (40.0 mL) at -70°C. After addition, the mixture was stirred at 20°C for 16 h. The reaction mixture was poured into saturated ammonium chloride aqueous solution (50.0 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic phase was washed with brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~35% ethyl acetate/petroleum ether gradient @60 mL/min) to afford di-tert-butyl (2S,3E)-3-ethylidene-4-oxo-pyrrolidine-1,2-dicarboxylate (1.3 g, 3.97 mmol, 56% yield, 95% purity) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.92 (dd, J = 7.6, 2.0 Hz, 1H), 5.19-5.07 (m, 1H), 4.02-3.93 (m, 2H), 2.06-2.02 (m, 3H), 1.50 (s, 9H), 1.45 (d, J = 4.4 Hz, 9H). Procedure for preparation of ditert-butyl (2S,3E)-3-ethylidene-4-hydroxy-pyrrolidine-1,2- dicarboxylate To a solution of di-tert-butyl (2S,3E)-3-ethylidene-4-oxo-pyrrolidine-1,2-dicarboxylate (1.30 g, 3.97 mmol, 95% purity, 1.00 eq) in tetrahydrofuran (20.0 mL) was added lithium triethylborohydride (1.00 M in tetrahydrofuran, 5.95 mL, 1.50 eq) at -70°C. After stirring at -70°C for 1 h, the reaction mixture was poured into saturated ammonium chloride aqueous solution (50.0 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~30% ethyl acetate/petroleum ether gradient@ 40 mL/min) to give ditert-butyl (2S,3E)-3-ethylidene-4-hydroxy- pyrrolidine -1,2-dicarboxylate (1.24 g, 3.56 mmol, 90% yield, 90% purity) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.97-5.85 (m, 1H), 4.80-4.65 (m, 1H), 4.42-4.33 (m, 1H), 3.78-3.69 (m, 2H), 3.54-3.44 (m, 1H), 1.80 (d, J = 7.2 Hz, 3H), 1.48 (s, 18H). Procedure for preparation of ditert-butyl (2S)-3-ethylpyrrolidine-1,2-dicarboxylate To a solution of di-tert-butyl (2S,3E)-3-ethylidene-4-hydroxy-pyrrolidine-1,2-dicarboxylate (1.24 g, 3.56 mmol, 90% purity, 1.00 eq) in ethanol (20.0 mL) were added palladium in carbon (500 mg, 3.56 mmol, 10% purity, 1.00 eq, contained 50% water) and concentrated hydrochloric acid (12.0 M, 594 μL, 2.00 eq) at 25°C under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen for three times and stirred at 25°C under hydrogen atmosphere (15 psi) for 16 h. After filtration, the filtrate was concentrated to afford di-tert-butyl (2S)-3-ethylpyrrolidine-1,2-dicarboxylate (1.05 g, 2.10 mmol, 59% yield, 60% purity) as yellow oil. Procedure for preparation of tert-butyl (2S,3R)-3-ethylpyrrolidine-2-carboxylate A mixture of di-tert-butyl (2S,3R)-3-ethylpyrrolidine-1,2-dicarboxylate (1.05 g, 2.10 mmol, 60% purity) in hydrochloric acid (4.00 M in dioxane, 20.0 mL, 20.0 eq) was stirred at 25°C for 2 h. The mixture was concentrated under vacuum to give tert-butyl (2S,3R)-3-ethylpyrrolidine-2-carboxylate (800 mg, 3.21 mmol, 80% yield) as a gray solid. The crude product was used for the next step directly without further purification. Procedure for preparation of tert-butyl (2S,3R)-1-[(2S)-2-(tert-butoxycarbonylamino)-3,3- dimethyl-butanoyl]-3-ethyl-pyrrolidine-2-carboxylate To a solution of tert-butyl (2S,3R)-3-ethylpyrrolidine-2-carboxylate (800 mg, 4.01 mmol, crude, 1.00 eq) and (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid (928 mg, 4.01 mmol, 1.00 eq) in N,N- dimethylformamide (50.0 mL) were added N,N-diisopropylethylamine (5.04 g, 39.0 mmol, 6.80 mL, 3.00 eq) and 1-propylphosphonicanhydride (3.83 g, 6.02 mmol, 50% purity in ethyl acetate, 1.50 eq) at 25°C. After stirring at 25°C for 16 h, the reaction mixture was poured into saturated ammonium chloride aqueous solution (30.0 mL) and extracted with ethyl acetate (50.0 mL × 2). The combined organic layers were washed with brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a reside. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~20% ethyl acetate/petroleum ether gradient @ 30 mL/min) to give tert-butyl (2S,3R)-1-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-bu tanoyl] -3-ethyl- pyrrolidine-2-carboxylate (180 mg, 393 μmol, 10% yield, 90% purity) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.29-7.12 (m, 1H), 6.58 (d, J = 8.8 Hz, 1H), 4.26-4.10 (m, 2H), 3.85- 3.72 (m, 1H), 3.56-3.49 (m, 1H), 2.26-2.13 (m, 1H), 2.11-2.00 (m, 1H), 1.74-1.61 (m, 1H), 1.40-1.33 (m, 18H), 1.24 (s, 2H), 0.99-0.89 (m, 12H). LC-MS (Method C): R _t = 0.950 min; MS (ESIpos): m/z = 413.3 [M+H] ⁺ . Procedure for preparation of (2S,3R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3-ethyl-pyrro lidine- 2-carboxylic acid To a solution of tert-butyl (2S,3R)-1-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-bu tanoyl] -3-ethyl- pyrrolidine-2-carboxylate (180 mg, 436 μmol, 1.00 eq) in dichloromethane (3.00 mL) was added trifluoroacetic acid (4.62 g, 40.5 mmol, 3.00 mL, 92.9 eq) at 25°C. After stirring at 25°C for 16 h, the reaction mixture was concentrated to give (2S,3R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl] -3-ethyl- pyrrolidine-2-carboxylic acid (100 mg, 390 μmol, 89% yield) as a gray solid. LC-MS (Method C): R _t = 0.294 min; MS (ESIpos): m/z = 257.0 [M+H] ⁺ . Procedure for preparation of (2S,3R)-1-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-3-ethyl-pyrrolidine-2-carbox ylic acid To a mixture of (2S,3R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3-ethyl-pyrro lidine-2-carboxylic acid (100 mg, 390 μmol, 1 eq) and triethylamine (395 mg, 3.90 mmol, 10.0 eq) in methanol (2.00 mL) was added methyl 2,2,2-trifluoroacetate (400 mg, 3.12 mmol, 8.00 eq) at 25°C. After stirring at 25°C for 16 h, the reaction mixture was poured into saturated ammonium chloride aqueous solution (20.0 mL) and extracted with ethyl acetate (30.0 mL × 2). The combined organic layers were washed with brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by reversed phase HPLC (C18, 40 g; condition: water (volume ratio: 0.1% formic acid) / acetonitrile = 95/5 to 40/60) to give (2S,3R)-1-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino] butanoyl]-3-ethyl-pyrrolidine-2-carboxylic acid (70 mg, 193 μmol, 49% yield, 97% purity) as a gray solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.53 (s, 1H), 9.34 (d, J = 8.0 Hz, 1H), 4.61 (d, J = 8.4 Hz, 1H), 4.33 (d, J = 8.4 Hz, 1H), 3.84 (t, J = 8.4 Hz, 1H), 3.61-3.48 (m, 1H), 2.29-2.15 (m, 1H), 2.12-2.01 (m, 1H), 1.74-1.59 (m, 1H), 1.54-1.41 (m, 1H), 1.26-1.11 (m, 1H), 1.04-0.96 (m, 9H), 0.95-0.90 (m, 3H). LC-MS (Method C): R _t = 0.867 min; MS (ESIpos): m/z = 353.2 [M+H] ⁺ . Procedure for preparation of CPD0084249 - (2S,3R)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]-1-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)ami no]butanoyl]-3-ethyl-pyrrolidine-2- carboxamide To a mixture of (2S,3R)-1-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino ]butanoyl] -3-ethyl- pyrrolidine-2-carboxylic acid (70.0 mg, 199 μmol, 1.00 eq) and (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3- yl]propanenitrile (56.5 mg, 298 μmol, 1.50 eq, HCl) in N,N-dimethylformamide (2.00 mL) were added [chloro(dimethylamino)methylene]-dimethyl-ammonium; hexafluorophosphate (167 mg, 596 μmol, 3.00 eq) and 1-methylimidazole (97.9 mg, 1.19 mmol, 6.00 eq) at 25°C. After stirring at 25°C for 16 h, the reaction mixture was poured into saturated ammonium chloride aqueous solution (10.0 mL) and extracted with ethyl acetate (20.0 mL × 2). The combined organic layers were washed with brine (10.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (column: Unisil 3-100 C18 ultra 150*50mm*3 um; mobile phase: [water(FA)-ACN]; B%: 28%-58%, 5 min) to afford (2S,3R)-N-[(1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]-1-[(2S)-3,3-dimethyl-2-[(2,2,2-tri fluoroacetyl)amino]butanoyl]-3-ethyl- pyrrolidine-2-carboxamide (45.01 mg, 92.2 μmol, 46% yield, 99% purity) as a white solid. Preparation of CPD0084250 and CPD0186407 Procedure for preparation of O1-tert-butyl O2-methyl (2S,3R)-3-methoxypyrrolidine-1,2- dicarboxylate A mixture of O1-tert-butyl O2-methyl (2S,3R)-3-hydroxypyrrolidine-1,2-dicarboxylate (800 mg, 3.26 mmol, 1.00 eq), silver oxide (2.57 g, 11.1 mmol, 3.40 eq) and methyl iodide (3.70 g, 26.1 mmol, 8.00 eq) in acetonitrile (10.0 mL) was stirred at 25°C for 80 h. After filtration (combined with EW30035-95), the filter cake was washed with acetonitrile (30 mL × 3). The filtrate was concentrated and purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~30% ethyl acetate/petroleum ether gradient @ 15 mL/min) to give O1-tert-butyl O2-methyl (2S,3R)-3- methoxypyrrolidine-1,2-dicarboxylate as colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 4.42-4.38 (m, 1H), 4.19-4.11 (m, 1H), 3.64-3.60 (m, 3H), 3.44-3.37(m, 1H), 3.30-3.22 (m, 4H), 2.08-1.96 (m, 1H), 1.92-1.81 (m, 1H), 1.39-1.31 (m, 9H). Procedure for preparation of methyl (2S,3R)-3-methoxypyrrolidine-2-carboxylate To a solution of O1-tert-butyl O2-methyl (2S,3R)-3-methoxypyrrolidine-1,2-dicarboxylate (800 mg, 3.09 mmol, 1.00 eq) in ethyl acetate (5.00 mL) was added hydrochloric acid (4.00 M in ethyl acetate, 10.0 mL, 13.0 eq) at 0°C. After stirring at 25°C for 1 h, the mixture was concentrated under reduced pressure to give methyl (2S,3R)-3-methoxypyrrolidine-2-carboxylate hydrochloric acid (600 mg, 2.91 mmol, 94% yield, 95% purity) as a white solid which was used for next step reaction directly without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 11.47 (s, 1H), 8.49 (s, 1H), 4.65-4.59 (m, 1H), 4.32-4.28 (m, 1H), 3.84 (s, 3H), 3.74-3.65 (m, 1H), 3.64-3.57 (m, 1H), 3.33 (s, 3H), 2.33-2.25 (m, 1H), 2.19-2.10 (m, 1H). Procedure for preparation of methyl (2S,3R)-1-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl- butanoyl]-3-methoxy-pyrrolidine-2-carboxylate To a solution of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid (709 mg, 3.07 mmol, 1.00 eq) in dimethylformamide (4.00 mL) were added N,N-diisopropylethylamine (1.19 g, 9.20 mmol, 1.60 mL, 3.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (1.17 g, 3.07 mmol, 1.00 eq). After stirring at 25°C for 0.5 h, methyl (2S,3R)-3-methoxypyrrolidine-2- carboxylate (600 mg, 3.07 mmol, 1.00 eq, hydrochloric acid) was added. After stirring at 25°C for 2 h, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed phase flash column (water (0.1% formic acid)/acetonitrile = 10/1 to 40/1) to give methyl (2S,3R)-1-[(2S)- 2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]-3-methox y-pyrrolidine-2-carboxylate (1.10 g, 2.81 mmol, 92% yield, 95% purity) as yellow oil ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.31 (d, J = 12.0 Hz, 1H), 4.75 (d, J = 12.0 Hz, 1H), 4.31 (d, J = 9.6 Hz, 1H), 3.91-3.85 (m, 1H), 3.80-3.77 (m, 1H), 3.74-3.71 (m, 3H), 3.38 (s, 3H), 2.20-2.14 (m, 1H), 2.04-1.98 (m, 1H), 1.43 (s, 9H), 1.04 (s, 9H). LC-MS (Method A): R _t = 0.783 min; MS (ESIpos): m/z = 373.2 [M+H] ⁺ . Procedure for preparation of (2S,3R)-1-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl- butanoyl]-3-methoxy-pyrrolidine-2-carboxylic acid A mixture of methyl (2S,3R)-1-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-bu tanoyl]-3-methoxy - pyrrolidine-2-carboxylate (1.10 g, 2.95 mmol, 1.00 eq), lithium hydroxide monohydrate (620 mg, 14.8 mmol, 5.00 eq) in methanol (10.0 mL) and water (2.00 mL) was stirred at 25°C for 12 h. After concentration, the residue was dissolved into water (100 mL), adjusted to pH = 5~6 with (1.00 M) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give (2S,3R)-1-[(2S)-2-(tert-butoxycarbonylamino)-3,3- dimethyl-butanoyl]-3-methoxy -pyrrolidine-2-carboxylic acid (1.10 g, 2.76 mmol, 94% yield, 904% purity) as a yellow solid. The crude product was used for the next step reaction directly. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.42-5.22 (m, 1H), 4.34-4.29 (d, J = 8.0 Hz, 1H), 4.20-4.17 (m, 1H), 4.03–3.89 (m, 1H), 3.79-3.70 (m, 1H), 3.41-3.37 (m, 3H), 2.19-2.12 (m, 2H), 2.05 (s, 1H), 1.44-1.42 (m, 9H), 1.03-1.01(m, 9H). LC-MS (Method A): R _t = 0.758 min; MS (ESIpos): m/z = 359.2 [M+H] ⁺ Procedure for preparation of (2S,3R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3-methoxy- pyrrolidine-2-carboxylic acid A mixture of (2S,3R)-1-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-bu tanoyl] -3-methoxy- pyrrolidine-2-carboxylic acid (1.10 g, 2.76 mmol, 90% purity, 1.00 eq) in a mixed solvent of dioxane (5.00 mL) and hydrochloric acid (4.00 M in dioxane, 10 mL, 14.5 eq) was stirred at 25°C for 1 h. The reaction mixture was concentrated under reduced pressure to give (2S,3R)-1-[(2S)-2-amino-3,3- dimethyl-butanoyl]-3-methoxy-pyrrolidine-2-carboxylic acid hydrochloric acid (900 mg, 2.75 mmol, 99% yield, 90% purity) as a yellow solid which was used for the next step reaction directly. LC-MS (Method C): R _t = 0.587 min; MS (ESIpos): m/z = 259.2 [M+H] ⁺ Procedure for preparation of (2S,3R)-1-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-3-methoxy-pyrrolidine-2-carb oxylic acid To a mixture of (2S,3R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3-methoxy-pyr rolidine-2-carboxylic acid (900 mg, 2.75 mmol, 90% purity, 1.00 eq, hydrochloric acid) and trifluoroacetic acid (1.39 g, 13.7 mmol, 1.91 mL, 5.00 eq) in methanol (10.0 mL) was added methyl 2,2,2-trifluoroacetate (703 mg, 5.50 mmol, 554 μL, 2.00 eq) at 25°C. After stirring at 25°C for 16 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase flash column (water (0.1% FA)/acetonitrile = 1/3) to give (2S,3R)-1-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino ] butanoyl]-3-methoxy-pyrrolidine-2-carboxylic acid (700 mg, 1.88 mmol, 68% yield, 95% purity) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.48-9.27 (m, 1H), 4.71-4.57 (m, 1H), 4.51-4.48 (d, J = 4.0 Hz, 0.5H), 4.27 (s, 0.5H), 4.21-4.00 (m, 1H), 3.77-3.64 (m, 2H), 3.67-3.58 (m, 1H), 3.28 (s, 3H), 2.10-1.95 (m, 2H), 1.03-0.94 (m, 9H). LC-MS (Method C): R _t = 0.533 min; MS (ESIpos): m/z = 355.1 [M+H] ⁺ . Procedure for preparation of (2S,3R)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-1-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroace tyl)amino] butanoyl]-3-methoxy- pyrrolidine-2-carboxamide A mixture of (2S,3R)-1-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino ] butanoyl]-3-methoxy- pyrrolidine-2-carboxylic acid (700 mg, 1.98 mmol, 1.00 eq), (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3- yl]propanamide (617 mg, 2.97 mmol, 1.50 eq, hydrochloric acid), O-(7-azabenzotriazol-1-yl)-N,N,N’,N’- tetramethyluronium hexafluorophosphate (1.13 g, 2.97 mmol, 1.50 eq), N,N-diisopropylethylamine (768 mg, 5.94 mmol, 1.03 mL, 3.00 eq) in N,N-dimethylformamide (8.00 mL) was stirred at 25°C for 12 h. The reaction mixture was concentrated under reduced pressure to give (2S,3R)-N-[(1S)-2-amino-2-oxo- 1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]-1-[(2S)-3,3-dime thyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-3-methoxy-pyrrolidine-2-carb oxamide (660 mg, 1.04 mmol, 53% yield, 80% purity) as a yellow solid. LC-MS (Method A): Rt = 0.483 min; MS (ESIpos): m/z = 508.3 [M+H] ⁺ Procedure for preparation of CPD0084250 - (2S,3R)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]-1-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)ami no]butanoyl]-3-methoxy-pyrrolidine-2- carboxamide and CPD0186407 - (2R,3R)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]- 1- [(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl] -3-methoxy-pyrrolidine-2- carboxamide To a solution of (2S,3R)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl] methyl] ethyl]-1-[(2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-3-methoxy -pyrrolidine-2-carboxamide (660 mg, 1.30 mmol, 1.00 eq) in dichloromethane (15.0 mL) was added Burgess reagent (1.55 g, 6.50 mmol, 5.00 eq). After stirring at 25°C for 16 h, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi C18150*25mm* 10 μm; mobile phase: [water (FA)-ACN]; B%: 21%-51%, 10 min). to give (2S,3R)-N-[(1S)-1-cyano-2- [(3S)-2-oxopyrrolidin-3-yl]ethyl]-1-[(2S)-3,3-dimethyl-2-[(2 ,2,2-trifluoroacetyl)amino]butanoyl]-3- methoxy-pyrrolidine-2-carboxamide (35.0 mg, 68.1 μmol, 95.30% yield, 95.3% purity) as off-white gum and (2R,3R)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl] ethyl]-1-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl) amino]butanoyl]-3-methoxy-pyrrolidine-2-carboxamide (27.8 mg, 54.1 μmol, 76% yield, 95% purity) as off-white gum. Preparation of CPD0084252 Procedure for preparation of 1,3-benzothiazole-2-carbonyl chloride To a mixture of 1,3-benzothiazole-2-carboxylic acid (200 mg, 1.12 mmol, 1.00 eq) and N,N- dimethylformamide (8.16 mg, 111 μmol, 0.100 eq) in dichloromethane (10.0 mL) was added oxalyl dichloride (424 mg, 3.35 mmol, 3.00 eq). After stirring at 25°C for 1 h, the reaction mixture was concentrated under vacuum to give 1,3-benzothiazole-2-carbonyl chloride (200 mg, crude) as a yellow solid. The crude product was used for the next step reaction directly. Procedure for preparation of methyl (1R,2S,5S)-3-(1,3-benzothiazole-2-carbonyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate To a mixture of methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (208 mg, 1.01 mmol, 1.00 eq, hydrochloride) and N,N-diisopropylethylamine (392 mg, 3.04 mmol, 3.00 eq) in dichloromethane (10.0 mL) was added 1,3-benzothiazole-2-carbonyl chloride (200 mg, 1.01 mmol, 1.00 eq crude) at 0°C. After stirring at 25°C for 1 h, the reaction mixture was poured into saturated ammonium chloride (30.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 8/1 to 4/1) to give methyl (1R,2S,5S)-3-(1,3-benzothiazole-2-carbonyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (300 mg, 817 μmol, 80% yield, 90% purity) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.19-7.91 (m, 2H), 7.61-7.42 (m, 2H), 5.44 (s, 1H), 4.73-4.33 (m, 1H), 3.97 (d, J = 3.2 Hz, 1H), 3.84-3.72 (m, 3H), 1.74-1.66 (m, 1H), 1.55-1.46 (m, 1H), 1.11 (s, 3H), 1.04- 1.00 (m, 3H). Procedure for preparation of (1R,2S,5S)-3-(1,3-benzothiazole-2-carbonyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid To a mixture of methyl (1R,2S,5S)-3-(1,3-benzothiazole-2-carbonyl)-6,6-dimethyl-3-a zabicyclo[3.1.0] hexane-2-carboxylate (250 mg, 680 μmol, 90% purity, 1.00 eq) in methanol (5.00 mL) and tetrahydrofuran (5.00 mL) was added a aqueous solution (5.00 mL) of lithium hydroxide monohydrate (85.7 mg, 2.04 mmol, 3.00 eq) at 0°C. After stirring at 25°C for 16 h, the reaction mixture was poured into water (20.0 ml), adjusted pH to 5~6 with hydrochloric acid (1 M in water) and extracted with ethyl acetate (10.0 mL × 3). The separated organic phase was concentrated under vacuum to give (1R, 2S, 5S)-3-(1,3-benzothiazole-2-carbonyl)-6,6-dimethyl-3-azabicyc lo[3.1.0]hexane-2-carboxylic acid (230 mg, crude) as a colorless oil. LC-MS (Method G): R _t = 0.243 min; MS (ESIpos): m/z = 317.0 [M+1] ⁺ . Procedure for preparation of tert-butyl N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]carbamate Triethylamine (5.59 g, 55.3 mmol, 3.00 eq) and trifluoroacetic anhydride (7.74 g, 36.9 mmol, 5.13 mL, 2.00 eq) were added dropwise into a solution of tert-butyl N-[(1S)-2-amino-2-oxo-1-[[(3S)-2- oxopyrrolidin-3-yl]methyl]ethyl]carbamate (5.00 g, 18.4 mmol, 1.00 eq) in tetrahydrofuran (50.0 mL) at 0°C. After stirring at 0°C for 2 h, the reaction mixture was quenched with saturation ammonium chloride solution (10.0 mL) at 0°C, and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether: ethyl acetate (v/v: 1/1) to give tert-butyl N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl] ethyl]carbamate (3.50 g, 13.8 mmol, 75% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.37-6.11 (m, 1 H), 5.88 (s, 1H), 4.79-4.60 (m, 1H), 3.49-3.30 (m, 2H), 2.58-2.40 (m, 2H), 2.35-2.24 (m, 1H), 1.99-1.83 (m, 2H), 1.47 (s, 9H). Procedure for preparation of (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanenitrile To a solution of tert-butyl N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamate (3.50 g, 13.8 mmol, 1.00 eq) in acetonitrile (30.0 mL) was added hydrochloride acid dropwise (4.00 M in ethyl acetate, 15.9 mL, 4.61 eq) at 0°C. After stirring at 25°C for 1 h, the mixture was concentrated under vacuum to give (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanenitrile (2.60 g, 12.3 mmol, 89% yield, 90% purity, HCl salt) as a white solid. ¹ H NMR (400 MHz, D ₂ O) δ = 3.43-3.22 (m, 2H), 2.83-2.66 (m, 1H), 2.43-2.33 (m, 1H), 2.32-2.14 (m, 2H), 1.95-1.79 (m, 1H). Procedure for preparation of CPD0084252 - (1R,2S,5S)-3-(1,3-benzothiazole-2-carbonyl)-N-[(1S)- 1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-6,6-dimethyl-3-a zabicyclo[3.1.0]hexane-2- carboxamide To a mixture of (1R,2S,5S)-3-(1,3-benzothiazole-2-carbonyl)-6,6-dimethyl-3-a zabicyclo [3.1.0]hexane- 2-carboxylic acid (200 mg, 632 μmol, 1.00 eq) in N,N-dimethylformamide (5.00 mL) were added [chloro(dimethylamino)methylene]-dimethyl-ammonium;hexafluor ophosphate (266 mg, 948 μmol, 1.50 eq) and 1-methylimidazole (155 mg, 1.90 mmol, 3.00 eq) at 0°C. After stirring for 0.2 h, (2S)-2-amino- 3-[(3S)-2-oxopyrrolidin-3-yl]propanenitrile (146 mg, 695 μmol, 90% purity, 1.10 eq, HCl salt) was added. The mixture was stirred at 25°C for 12 h, and purified by preparative HPLC (column: Waters Xbridge 150*25mm*5 μm; mobile phase: [water(NH ₄ HCO ₃ )-ACN]; B%:30%-60%, 8 min) to give (1R,2S,5S)-3- (1,3-benzothiazole-2-carbonyl)-N-[(1S)-1-cyano-2-[(3S)-2-oxo pyrrolidin-3-yl]ethyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (73.02 mg, 161 μmol, 26% yield, 99% purity) as a white solid. Preparation of CPD0084253 Procedure for preparation of methyl (1R,2S,5S)-3-(imidazo[1,2-a]pyridine-6-carbonyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate A mixture of imidazo[1,2-a]pyridine-6-carboxylic acid (200 mg, 1.23 mmol, 1.00 eq), methyl (1R,2S,5S)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (208 mg, 1.23 mmol, 1.00 eq), O-(7-Aza-1H- benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (938 mg, 2.47 mmol, 2.00 eq), N,N-diisopropylethylamine (478 mg, 3.70 mmol, 3.00 eq) in N,N-dimethylformamide (1.00 mL) was stirred at 25°C for 12 h. The reaction mixture was poured into water (60.0 mL) and extracted with ethyl acetate (60.0 mL × 2). The combined organic layers were washed with brine (60.0 mL × 2), dried over anhydrous sodium sulfate filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 30/1 to 1/1) to give methyl (1R,2S,5S)-3-(imidazo[1,2-a]pyridine-6-carbonyl)-6,6-dimethy l-3-azabicyclo[3.1.0]hexane- 2-carboxylate (350 mg, 1.06 mmol, 86% yield, 95% purity) as yellow oil. LC-MS (Method A): Rt = 0.483 min; MS (ESIpos): m/z = 314.1 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-(imidazo[1,2-a]pyridine-6-carbonyl)-6,6-dimethy l-3- azabicyclo[3.1.0]hexane-2-carboxylic acid A mixture of methyl (1R,2S,5S)-3-(imidazo[1,2-a]pyridine-6-carbonyl)-6,6-dimethy l-3-azabicyclo [3.1.0]hexane-2-carboxylate (300 mg, 957 μmol, 1.00 eq), lithium hydroxide monohydrate (200 mg, 4.79 mmol, 5.00 eq) in a mixed solvent of tetrahydrofuran (10.0 mL) and water (2.00 mL) was stirred at 25°C for 10 h. Hydrochloric acid solution (1 M) was added to the reaction mixture to adjust pH to 5~7. The solution was lyophilized to give a crude product. The crude product was wash with ethyl acetate (20.0 ml) and filtered. The filtrate was concentrated under reduced pressure to give (1R,2S,5S)-3- (imidazo[1,2-a]pyridine-6-carbonyl)-6,6-dimethyl-3-azabicycl o [3.1.0]hexane-2-carboxylic acid (280 mg, 889 μmol, 93% yield, 95% purity) as yellow oil. LC-MS (Method A): R _t = 0.712 min; MS (ESIpos): m/z = 300 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-3-(imidazo[1,2-a]pyridine-6-carbonyl)-6,6-d imethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide A mixture of (1R,2S,5S)-3-(imidazo[1,2-a]pyridine-6-carbonyl)-6,6-dimethy l-3-azabicyclo[3.1.0] hexane-2-carboxylic acid (230 mg, 768 μmol, 1.00 eq), (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl] propanamide (132 mg, 768 μmol, 1.00 eq), O-(7-Aza-1H-benzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (584 mg, 1.54 mmol, 2.00 eq), N,N-diisopropylethylamine (397 mg, 3.07 mmol, 535 μL, 4.00 eq) in N,N-dimethylformamide (1 mL) was stirred at 25°C for 12 h. The reaction mixture was concentrated under reduced pressure to give (1R,2S,5S)-N-[(1S)-2-amino-2- oxo-1- [[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]-3-(imidazo[1,2-a]p yridine-6-carbonyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (300 mg, crude) as yellow oil. The crude product was used for the next step reaction directly. LC-MS (Method A): R _t = 0.619 min; MS (ESIpos): m/z = 453.2 [M+H] ⁺ . Procedure for preparation of CPD0084253 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin- 3-yl]ethyl]-3-(imidazo[1,2-a]pyridine-6-carbonyl)-6,6-dimeth yl-3-azabicyclo[3.1.0]hexane-2- carboxamide To a solution of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl] -3- (imidazo[1,2-a]pyridine-6-carbonyl)-6,6-dimethyl-3-azabicycl o[3.1.0]hexane-2-carboxamide (300 mg, 663 μmol, 1.00 eq) in dichloromethane (6.00 mL) was added Burgess reagent (790 mg, 3.31 mmol, 5.00 eq). After stirring at 25°C for 16 h, the mixture was filtered. The filtrate was concentrated and purified by preparative HPLC for twice (column: Phenomenex C1875*30mm*3 μm; mobile phase: [water(FA)-ACN]; B%: 42%-72%, 7min) and preparative-HPLC (column: Phenomenex C1875*30mm*3 μm; mobile phase: [water(FA)-ACN];B%: 0%-30%, 7 min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2- [(3S)- 2-oxopyrrolidin-3-yl]ethyl]-3-(imidazo[1,2-a]pyridine-6-carb onyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (17.6 mg, 40.6 μmol, 24 % yield) as black oil. Preparation of CPD0084254 Procedure for preparation of Compound 2 - 4-(trifluoromethyl)thiazole-2-carbonyl chloride To a solution of 4-(trifluoromethyl)thiazole-2-carboxylic acid (150 mg, 761 μmol, 1.00 eq) in dichloromethane (3.00 mL) were added oxalyl dichloride (290 mg, 2.28 mmol, 3.00 eq) and N,N- dimethylformamide (5.56 mg) at 25°C. After stirring at 25°C for 0.5 h, the mixture was concentrated under vacuum to give 4-(trifluoromethyl)thiazole-2-carbonyl chloride (164 mg, 761 μmol, 100% yield, crude purity) as a gray solid. The crude product was used for the next step reaction directly. Procedure for preparation of methyl (1R,2S,5S)-6,6-dimethyl-3-[4-(trifluoromethyl)thiazole-2- carbonyl]-3-azabicyclo[3.1.0]hexane-2-carboxylate To a mixture of methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (143 mg, 696 μmol, 1.00 eq, HCl) and triethylamine (282 mg, 2.78 mmol, 4.00 eq) in dichloromethane (3.00 mL) was added a solution 4-(trifluoromethyl)thiazole-2-carbonyl chloride (150 mg, 0.696 mmol, crude, 1.00 eq) in dichloromethane (3.00 mL) at 25°C. After stirring at 25°C for 2 h, the reaction mixture was poured into saturated ammonium chloride aqueous solution (20.0 mL) and extracted with ethyl acetate (30.0 mL × 2). The combined organic layers were washed with brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®;12 g SepaFlash® Silica Flash Column, Eluent of 0~30% ethyl acetate/petroleum ether gradient @30 mL/min) to afford methyl (1R,2S,5S)-6,6-dimethyl-3-[4- (trifluoromethyl) thiazole-2-carbonyl]-3-azabicyclo[3.1.0]hexane-2-carboxylate (240 mg, 654 μmol, 94% yield, 95% purity) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.96-7.88 (m, 1H), 5.23-4.61 (m, 1H), 4.49-4.28 (m, 1H), 3.96-3.92 (m, 1H), 3.83-3.71 (m, 3H), 1.71-1.62 (m, 1H), 1.51-1.45 (m, 1H), 1.11 (s, 3H), 1.00 (s, 3H). LC-MS (Method C): R _t = 0.845 min; MS (ESIpos): m/z = 349.1 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-6,6-dimethyl-3-[4-(trifluoromethyl)thiazole-2-car bonyl]- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid To a solution of methyl (1R,2S,5S)-6,6-dimethyl-3-[4-(trifluoromethyl)thiazole-2-car bonyl]-3-azabicyclo [3.1.0]hexane-2-carboxylate (140 mg, 402 μmol, 1.00 eq) in a mixed solvent of tetrahydrofuran (2.00 mL) and water (2.00 mL) was added lithium hydroxide (84.3 mg, 2.01 mmol, 5.00 eq) at 25°C. After stirring at 25°C for 16 h, hydrochloric acid (1 M in water) was added to the reaction mixture to adjust pH 3~4, and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford (1R,2S,5S)-6,6-dimethyl-3-[4-(trifluoromethyl)thiazole-2-car bonyl]-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (134 mg, 381 μmol, 95% yield, 95% purity) as a white solid. LC-MS (Method C): R _t = 0.858, 0.892 min; MS (ESIpos): m/z = 334.9 [M+H] ⁺ . Procedure for preparation of CPD0084254 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin- 3-yl]ethyl]-6,6-dimethyl-3-[4-(trifluoromethyl)thiazole-2-ca rbonyl]-3-azabicyclo[3.1.0]hexane-2- carboxamide To a mixture of (1R,2S,5S)-6,6-dimethyl-3-[4-(trifluoromethyl)thiazole-2-car bonyl]-3-azabicyclo[3.1.0] hexane-2-carboxylic acid (120 mg, 359 μmol, 1.00 eq) and (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3- yl]propanenitrile (136 mg, 718 μmol, 2.00 eq, HCl) in N,N-dimethylformamide (2.00 mL) were added 1- methylimidazole (177 mg, 2.15 mmol, 6.00 eq) and [chloro(dimethylamino)methylene]-dimethyl- ammonium;hexafluorophosphate (302 mg, 1.08 mmol, 3.00 eq) at 25°C. After stirring at 25°C for 16 h, the reaction mixture was poured into saturated ammonium chloride aqueous solution (10.0 mL) and extracted with ethyl acetate (30.0 mL × 2). The combined organic layers were washed with brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm* 5 μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 30%-60%, 8 min) to afford (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin- 3-yl]ethyl]-6,6-dimethyl-3-[4-(trifluoromethyl)thiazole-2-ca rbonyl]-3-azabicyclo[3.1.0]hexane-2- carboxamide (23.1 mg, 48.6 μmol, 14% yield, 99% purity) as a white solid. Preparation of CPD0084258 Procedure for preparation of methyl (1R,2S,5S)-3-((S)-2-amino-3,3-dimethylbutanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate A solution of methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethy lbutanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (3.00 g, 7.84 mmol, 1.00 eq) in trifluoroacetic acid (10.0 mL) and dichloromethane (50.0 mL) was stirred at 25°C for 1 h. Saturated sodium bicarbonate solution was added to the mixture to adjust pH~7 and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (40.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give methyl (1R,2S,5S)-3-((S)-2-amino-3,3-dimethylbutanoyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (2.1 g, 5.65 mmol, 72% yield, 76% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 6.38-5.35 (m, 2H), 4.24 (s, 1H), 3.81-3.74 (m, 1H), 3.71-3.67 (m, 1H), 3.66 (s, 3H), 3.56 (s, 1H), 1.02 (s, 3H), 0.97 (s, 9H), 0.92 (s, 3H). Procedure for preparation of methyl (1R,2S,5S)-3-((S)-3,3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxylate To a mixture of methyl (1R,2S,5S)-3-((S)-2-amino-3,3-dimethylbutanoyl)-6,6-dimethyl -3- azabicyclo[3.1.0]hexane-2-carboxylate (2.10 g, 7.44 mmol, 1.00 eq), N,N-diisopropylethylamine (2.88 g, 22.3 mmol, 3.00 eq) in dichloromethane (50.0 mL) was added trifluoroacetic anhydride (1.72 g, 8.18 mmol, 1.1 eq) at 0°C. After stirring at 25°C for 1 h under nitrogen atmosphere, the reaction mixture was poured into saturated ammonium chloride (20.0 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (50.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 3/1) to afford methyl (1R,2S,5S)-3-((S)- 3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxylate (2.95 g, 4.76 mmol, 64% yield, 61% purity) as colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.45 (d, J = 8.4 Hz, 1H), 4.42 (d, J = 8.4 Hz, 1H), 4.22 (s, 1H), 3.89- 3.83 (m, 1H), 3.77-3.73 (m, 1H), 3.66 (s, 3H), 1.47-1.43 (m, 1H), 1.25-1.20 (m, 1H), 1.01-0.99 (m, 12H), 0.83 (s, 3H). Procedure for preparation of (1R,2S,5S)-3-((S)-3,3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxylic acid To a mixture of methyl (1R,2S,5S)-3-((S)-2-amino-3,3-dimethylbutanoyl)-6,6-dimethyl -3- azabicyclo[3.1.0] hexane-2-carboxylate (2.95 g, 7.80 mmol, 1.00 eq) in a mixed solvent of methanol (10.0 mL) and tetrahydrofuran (10.0 mL) was added a solution of lithium hydroxide monohydrate (654 mg, 15.6 mmol, 2.00 eq) in water (10.0 mL) at 0°C. After stirring at 20°C for 2 h, hydrochloric acid solution (1M) was added to the mixture to adjust pH~7 and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (30.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 3/1 to 1/1) to afford (1R,2S,5S)-3-((S)-3,3- dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.0 g, 2.72 mmol, 35% yield, 99% purity) as white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.71 (s, 1H), 9.56-9.37 (m, 1H), 4.49-4.39 (m, 1H), 4.15 (d, J = 2.8 Hz, 1H), 3.87-3.82 (m, 1H), 3.74-3.70 (m, 1H), 1.56-1.50 (m, 1H), 1.45-1.40 (m, 1H), 1.03-0.99 (m, 12H), 0.83-0.81 (m, 3H). Procedure for preparation of CPD0084258- (1R,2S,5S)-N-((S)-6-cyano-4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-6-yl)-3-((S and R)-3,3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)b utanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (378 mg, 987 μmol, 95% purity, 1.00 eq) in N,N- dimethylformamide (5.00 mL) were added N,N-diisopropylethylamine (255 mg, 1.97 mmol, 344 uL, 2.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (563 mg, 1.48 mmol, 1.50 eq) at 0°C. After stirring for 10 min, 6-amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-6- carbonitrile (200 mg, 0.987 mmol, 80% purity, 1.00 eq) in N,N-dimethylformamide (1.00 mL) was added dropwise at 0°C. After stirring at 25°C for 12 h, the mixture was poured into water (20.0 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed by brine (20.0 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (FA condition; column: Phenomenex Synergi C18150*25mm*10μm; mobile phase: [water(FA)-ACN]; B%: 38%-68%,10min) to give (1R,2S,5S)-N- ((S)-6-cyano-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-6-yl)- 3-((S and R)-3,3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxamide (76.61 mg, 0.149 mmol, 15% yield, 99% purity) as yellow solid. Preparation of CPD0084259 Procedure for preparation of ethyl 4-bromo-3-oxo-cyclohexanecarboxylate To a solution of ethyl 3-oxocyclohexanecarboxylate (10.0 g, 58.8 mmol, 1.00 eq) in methyl tertiary butyl ether (80.0 mL) was added bromine dropwise (9.39 g, 58.8 mmol, 3.03 mL, 1.00 eq) at 0°C under nitrogen atmosphere. After addition, the mixture was stirred at 0°C for 1.5 h. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (150 mL). The separated organic layer was washed with brine (60.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give ethyl 4-bromo-3-oxo-cyclohexanecarboxylate (13.0 g, 52.2 mmol, 89% yield) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 4.16-4.02 (m, 2H), 3.21-2.76(m, 2H), 2.72-2.59 (m, 1H), 2.45-2.28 (m, 1H), 2.14-1.99 (m, 2H), 1.95-1.70 (m, 2H), 1.23-1.14 (m, 3H). Procedure for preparation of ethyl 4,5,6,7-tetrahydro-1,3-benzothiazole-5-carboxylate A solution of ethyl 4-bromo-3-oxo-cyclohexanecarboxylate (13.0 g, 52.2 mmol, 1.00 eq) and thioformamide (981 mg, 8.03 mmol, 80.3 μL, 50% purity in tetrahydrofuran, 2.00 eq) in N,N- dimethylformamide (120 mL) was stirred at 25°C for 12 h. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL × 2). The combined organic layers were washed with brine (80.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed phase column (0.1% FA condition, Column 330 g Flash Column Welch Ultimate XB_C1820-40 μm; 120 A; Flow rate: 100mL/min; Mobile phase MeCN / H2O; Gradient B%: 5-40% 30min; 40% 20min; Instrument TELEDYNE ISCO CombiFlashRf150) to give ethyl 4,5,6,7-tetrahydro-1,3-benzothiazole-5-carboxylate (2.5 g, 11.24 mmol, 22% yield, 95% purity) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.66 (s, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.10-3.01 (m, 1H), 2.96-2.78 (m, 2H), 2.76-2.65 (m, 2H), 2.18-2.11 (m, 1H), 1.90-1.77 (m, 1H), 1.12 (t, J = 7.2 Hz, 3H). LC-MS (Method C): R _t = 0.479 min; MS (ESIpos): m/z = 212.0 [M+H] ⁺ . Procedure for preparation of 4,5,6,7-tetrahydro-1,3-benzothiazol-5-ylmethanol A solution of lithium aluminum hydride (1.00 M, 18.9 mL, 1.00 eq) in tetrahydrofuran (35.0 mL) was degassed under vacuum and purged with nitrogen for 3 times at 0°C. After that, ethyl 4,5,6,7-tetrahydro- 1,3-benzothiazole-5-carboxylate (4.00 g, 18.9 mmol, 1.00 eq) in tetrahydrofuran (8.00 mL) was added to the reaction mixture dropwise. After addition, the mixture was stirred at this temperature for 1 h under nitrogen atmosphere. The reaction mixture was added dropwise into saturated ammonium chloride aqueous solution (200 mL), diluted with water (200 mL) and extracted with ethyl acetate (200 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4,5,6,7-tetrahydro-1,3-benzothiazol-5- ylmethanol (3.00 g, 16.0 mmol, 84% yield, 90% purity) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.60 (s, 1H), 3.74-3.62 (m, 2H), 3.02 (dd, J=16.6, 4.8 Hz, 1H), 2.96-2.88 (m, 1H), 2.84-2.74 (m, 1H), 2.57-2.48 (m, 1H), 2.16-2.06 (m, 2H), 1.64-1.51 (m, 1H). LC-MS (Method A): R _t = 0.334 min; MS (ESIpos): m/z = 170.1 [M+H] ⁺ . Procedure for preparation of 4,5,6,7-tetrahydro-1,3-benzothiazole-5-carbaldehyde To a solution of 4,5,6,7-tetrahydro-1,3-benzothiazol-5-ylmethanol (3.00 g, 17.7 mmol, 1.00 eq) in dichloromethane (40.0 mL) was added Dess-Martin periodinane (11.3 g, 26.6 mmol, 8.23 mL, 1.50 eq) at 0°C under nitrogen atmosphere. After stirring at 0°C for 2 h, the reaction was warmed to 25°C and kept stirring for 2 h. The reaction mixture was quenched with sodium bicarbonate aqueous solution and sodium thiosulfate (150 mL) respectively at 25°C. After filtration, the filtrate was diluted with water (200 mL) and extracted with ethyl acetate (200 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4,5,6,7-tetrahydro-1,3-benzothiazole-5-carbaldehyde (2.60 g, 13.2 mmol, 75% yield, 85% purity) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.80 (s, 1H), 8.66 (s, 1H), 3.19-3.01 (m, 2H), 2.98-2.90 (m, 1H), 2.90- 2.79 (m, 2H), 2.30-2.21 (m, 1H), 2.01-1.91 (m, 1H). LC-MS (Method A): R _t = 0.182 min; MS (ESIpos): m/z = 168.0 [M+H] ⁺ . Procedure for preparation of 2-methyl-N-(4,5,6,7-tetrahydro-1,3-benzothiazol-5- ylmethylene)propane-2-sulfinamide To a solution of 4,5,6,7-tetrahydro-1,3-benzothiazole-5-carbaldehyde (2.60 g, 15.6 mmol, 1.00 eq) and 2-methylpropane-2-sulfinamide (1.88 g, 1.56 mmol, 1.00 eq) in tetrahydrofuran (20.0 mL) was added titanium (IV) isopropoxide (8.84 g, 31.1 mmol, 2.00 eq). After addition, the resulting mixture was stirred at 50°C for 10 h. The mixture was suspended into water (300 mL) and filtered. After filtration, the filtrate was extracted with ethyl acetate (300 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 50/1 to 10/1) to give 2-methyl-N-(4,5,6,7-tetrahydro-1,3-benzothiazol-5-ylmethylen e)propane- 2-sulfinamide (2.00 g, 6.66 mmol, 42% yield, 90% purity) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.63 (s, 1H), 8.15 (dd, J = 11.4, 3.2 Hz, 1H), 3.20-3.12 (m, 1H), 3.10 (m, 2H), 2.98-2.84 (m, 2H), 2.33-2.21 (m, 1H), 2.02-1.89 (m, 1H), 1.23-1.10 (m, 9H). LC-MS (Method C): Rt = 0.727 min; MS (ESIpos): m/z = 271.1 [M+H] ⁺ . Procedure for preparation of N-[cyano(4,5,6,7-tetrahydro-1,3-benzothiazol-5-yl)methyl]-2- methyl-propane-2-sulfinamide To a solution of 2-methyl-N-(4,5,6,7-tetrahydro-1,3-benzothiazol-5-ylmethylen e)propane-2-sulfinamide (2.00 g, 7.40 mmol, 1.00 eq) in N,N-dimethylformamide (18.0 mL) was degassed under vacuum and purged with nitrogen for 3 times and then cesium fluoride (1.35 g, 8.88 mmol, 1.20 eq) was added. After stirring at 25°C for 5 minutes, timethylsilyl cyanide (880 mg, 8.88 mmol, 1.11 mL, 1.2 eq) was added and the resulting mixture was stirred for 1 h. The reaction mixture was added dropwise into saturated ammonium chloride aqueous solution (100 mL), diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to ethyl acetate) to give N-[cyano(4,5,6,7-tetrahydro-1,3-benzothiazol-5-yl)methyl]-2- methyl-propane-2-sulfinamide (1.98 g, 6.32 mmol, 86% yield, 95% purity) as a yellow solid. LC-MS (Method C): R _t = 0.710 min; MS (ESIpos): m/z = 298.0 [M+H] ⁺ . Procedure for preparation of 2-amino-2-(4,5,6,7-tetrahydro-1,3-benzothiazol-5-yl)acetonit rile A mixture of N-[cyano(4,5,6,7-tetrahydro-1,3-benzothiazol-5-yl)methyl]-2- methyl-propane-2- sulfinamide (1.00 g, 3.36 mmol, 1.00 eq) in hydrochloric acid/methanol (4.00 M, 10.0 mL) was stirred at 25°C for 10 h. The pH was adjusted to 7~8 with saturated sodium bicarbonate solution and concentrated under vacuum to give 2-amino-2-(4,5,6,7-tetrahydro-1,3-benzothiazol-5-yl)acetonit rile (460 mg, 2.02 mmol, 60% yield, 85% purity) as colorless oil. LC-MS (Method A): Rt = 0.158 min; MS (ESIpos): m/z = 194.0 [M+H] ⁺ . Procedure for preparation of CPD0084259 - (1R,2S,5S)-N-[cyano(4,5,6,7-tetrahydro-1,3- benzothiazol-5-yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-tri fluoroacetyl)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a solution of 2-amino-2-(4,5,6,7-tetrahydro-1,3-benzothiazol-5-yl)acetonit rile (460 mg, 1.67 mmol, 70% purity, 1.00 eq) and (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino] butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (607 mg, 1.67 mmol, 1.00 eq) in N,N- dimethylformamide (8.00 mL) were added N,N-diisopropylethylamine (431 mg, 3.33 mmol, 580 μL, 2.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (950 mg, 2.50 mmol, 1.5 eq) at 25°C. After addition, the mixture was stirred at 25°C for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (80.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1 to 10/1) followed by preparative HPLC (FA condition, column: Phenomenex Synergi C18150*25mm*10μm; mobile phase: [water(FA)-ACN]; B%: 42%-72%, 10 min to give (1R,2S,5S)-N-[cyano(4,5,6,7-tetrahydro-1,3-benzothiazol-5-yl )methyl]-3-[(2S)-3,3-dimethyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabi cyclo[3.1.0]hexane-2-carboxamide (294 mg, 545 μmol, 33% yield, 99% purity) as a white solid CPD0084259: Preparation of CPD0084776, CPD0084777, CPD0084778, CPD0084779 Procedure for preparation of (1R,2S,5S)-N-[(S)-cyano-[(5R)-4,5,6,7-tetrahydro-1,3-benzoth iazol- 5-yl]methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl) amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide CPD0084776, CPD0084777, CPD0084778, CPD0084779 Compound CPD0084259 was purified by SFC column: Daicel ChiralPak IG (250*30 mm, 10 um); mobile phase: [0.1% NH3·H2O ethanol]; B%: 35%-35%, 6.6 min to give two impure isomers Peak1 and Peak2. Peak1 was further purified by SFC column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: [Neu-IPA]; B%: 15%-15%, 6.0 min) twice to give CPD0084776 (6.66 mg, 12.3 μmol, 2% yield, 99.99% purity) as a white solid and impure CPD0084777. CPD0084777 was purified by SFC column: REGIS(S,S) WHELK-O1(250mm*25mm,10um); mobile phase: [Neu-IPA]; B%: 30%-30%, 2.1 min twice to give CPD0084777 (17.7 mg, 32.9 μmol, 6.34% yield, 99.99% purity) as a white solid. Peak2 was purified by SFC column: DAICEL CHIRALCEL OD (250mm*30mm, 10 um); mobile phase: [Neu- IPA]; B%: 20%-20%, 2.7 min for four times to give CPD0084778 (12 mg, 22.3 μmol, 4% yield, 99% purity) as a white solid and impure CPD0084779. CPD0084779 was purified by SFC twice column: DAICEL CHIRALCEL OJ(250mm*30 mm,10 μm);mobile phase: [Neu-IPA]; B%: 0%-0%,6.0 min to give CPD0084779 (34.6 mg, 64.0 μmol, 12% yield, 99% purity) as a white solid. CPD0084776: Preparation of CPD0084260, CPD0084780, CPD0084781, CPD0084906, and CPD0084907 Procedure for preparation of 5-oxo-7-trimethylsilyl-hept-6-ynoic acid To a solution of tetrahydropyran-2,6-dione (30.0 g, 263 mmol, 1.00 eq) in dichloromethane (500 mL) were added trimethyl(2-trimethylsilylethynyl)silane (49.3 g, 289 mmol, 65.5 mL, 1.10 eq) and aluminum chloride (35.1 g, 263 mmol, 1.00 eq) at 0°C. After stirring at 0°C for 2 h, the reaction mixture was allowed to warm to 25°C and stirred at this temperature for 2 h. The reaction mixture was quenched slowly with hydrochloric acid (1.00 M in water, 300 mL), kept the internal temperature below 10°C. The layers were separated. And the aqueous phase was extracted with dichloromethane (300 mL × 2). The combined organic layers were washed with hydrochloric acid (1.00 M in water, 100 mL), water (200 mL), brine (200 mL). The organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to give a residue. The residue was purified by flash column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 2/1) to afford 5-oxo-7-trimethylsilyl-hept-6-ynoic acid (29.5 g, 139 mmol, 53% yield) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 2.68 (t, J = 7.2 Hz, 2H), 2.44 (t, J = 7.2 Hz, 2H), 2.04-1.93 (m, 2H), 0.25 (s, 9H). Procedure for preparation of 5-(tert-butoxycarbonylhydrazono)-7-trimethylsilyl-hept-6-yno ic acid To a solution of 5-oxo-7-trimethylsilyl-hept-6-ynoic acid (29.5 g, 139 mmol, 1.00 eq) in ethanol (300 mL) was added tert-butyl N-aminocarbamate (20.2 g, 153 mmol, 1.10 eq) at 25°C. After stirring at 25°C for 2 h, the reaction mixture was concentrated to give 5-(tert-butoxycarbonylhydrazono)-7-trimethylsilyl- hept-6-ynoic acid (45.0 g, crude) as light yellow oil. The crude product was used for the next step reaction without further purification. LC-MS (Method C): R _t = 0.908 min; MS (ESIpos): m/z = 327.1 [M+H] ⁺ . Procedure for preparation of 4-(1-tert-butoxycarbonylpyrazol-3-yl)butanoic acid To a solution of 5-(tert-butoxycarbonylhydrazono)-7-trimethylsilyl-hept-6-yno ic acid (45.0 g, 138 mmol, 1.00 eq) in tetrahydrofuran (450 mL) was added tetrabutylammonium fluoride (1.00 M in tetrahydrofuran, 179 mL, 1.30 eq) at 25°C. After stirring at 25°C for 48 h, the reaction mixture was poured into acetic acid (5% in water, 1000 mL) and extracted with ethyl acetate (500 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated to give 4-(1-tert-butoxycarbonylpyrazol-3-yl)butanoic acid (35.0 g, crude) as yellow oil. Procedure for preparation of tert-butyl 3-(4-benzyloxy-4-oxo-butyl)pyrazole-1-carboxylate To a solution of 4-(1-tert-butoxycarbonylpyrazol-3-yl)butanoic acid (35.0 g, 137 mmol, 1.00 eq) in N,N- dimethylformamide (500 mL) were added potassium carbonate (28.5 g, 206 mmol, 1.5 eq) and benzyl bromide (47.1 g, 275 mmol, 2.00 eq). After stirring at 25°C for 16 h, the reaction mixture was diluted with water (1000 mL) and extracted with ethyl acetate (500 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 3/1) to give tert-butyl 3-(4- benzyloxy-4-oxo-butyl)pyrazole-1-carboxylate (39.5 g, 115 mmol, 83% yield) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.88 (d, J = 2.8 Hz, 1H), 7.31-7.21 (m, 5H), 6.12 (d, J = 2.8 Hz, 1H), 5.04 (s, 2H), 2.65 (t, J = 7.6 Hz, 2H), 2.35 (t, J = 7.6 Hz, 2H), 2.00-1.92 (m, 2H), 1.56 (s, 9H). Procedure for preparation of tert-butyl 3-(4-benzyloxy-3-bromo-4-oxo-butyl)pyrazole-1- carboxylate To a solution of tert-butyl 3-(4-benzyloxy-4-oxo-butyl)pyrazole-1-carboxylate (28.0 g, 81.3 mmol, 1.00 eq) in tetrahydrofuran (500 mL) was added lithium bis(trimethylsilyl)amide (1 M, 122 mL, 1.50 eq) at - 70°C. After stirring at -70°C for 0.5 h, trimethylchlorosilane (13.3 g, 122 mmol, 15.5 mL, 1.50 eq) was added at -70°C. The resulting mixture was stirred -70°C for 0.5 h, and then 1-bromopyrrolidine-2,5- dione (28.9 g, 163 mmol, 2.00 eq) was added at the same temperature. After addition, the reaction mixture was stirred at -70°C for 4 h. The reaction mixture was poured into saturated ammonium chloride (500 mL) and extracted with ethyl acetate (600 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl 3-(4-benzyloxy-3-bromo-4-oxo- butyl)pyrazole-1-carboxylate (22.1 g, crude) as yellow oil. The crude product was used for the next step reaction directly without further purification. Procedure for preparation of benzyl 2-bromo-4-(1H-pyrazol-3-yl)butanoate To a solution of tert-butyl 3-(4-benzyloxy-3-bromo-4-oxo-butyl)pyrazole-1-carboxylate (22.1 g, 52.2 mmol, 1.00 eq) in dichloromethane (160 mL) was added trifluoroacetic acid (85.1 g, 746 mmol, 55.3 mL, 14.3 eq) at 25°C. After stirring at 25°C for 0.5 h, the reaction mixture was concentrated to give benzyl 2-bromo-4-(1H-pyrazol-3-yl)butanoate (16.0, crude) as yellow oil. Procedure for preparation of benzyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-6-carboxylate To a solution of benzyl 2-bromo-4-(1H-pyrazol-3-yl)butanoate (16.0 g, crude, 49.5 mmol, 1.00 eq) in acetonitrile (120 mL) were added potassium carbonate (10.3 g, 74.3 mmol, 1.50 eq) and sodium iodide (11.1 g, 74.3 mmol, 1.50 eq) at 25°C. After stirring at 80°C for 16 h, the reaction mixture was diluted with ethyl acetate (100 mL) and filtered. The filtrate was concentrated, purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 3/1) to give benzyl 5,6-dihydro-4H- pyrrolo[1,2-b] pyrazole-6-carboxylate (3.90 g, 16.1 mmol, 33% yield) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.59 (d, J = 1.6 Hz, 1H), 7.43-7.29 (m, 5H), 6.00 (d, J = 1.6 Hz, 1H), 5.22 (s, 2H), 5.08-4.89 (m, 2H), 3.08-2.82 (m, 3H), 2.79-2.50 (m, 1H). LC-MS (Method A): R _t = 0.908 min; MS (ESIpos): m/z = 243.0 [M+H] ⁺ . Procedure for preparation of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-6-ylmethanol To a solution of benzyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-6-carboxylate (1.00 g, 4.13 mmol, 1.00 eq) in tetrahydrofuran (30.0 mL) was added lithium aluminum hydride (1.00 M in tetrahydrofuran, 4.95 mL, 1.20 eq) at 25°C under nitrogen atmosphere. After stirring at 25°C for 4 h, the reaction mixture was poured into hydrochloric acid (0.5 M in water, 10 mL), adjusted pH ~11 with sodium hydroxide (2 M in water) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated to give 5,6-dihydro-4H-pyrrolo[1,2- b]pyrazol-6-ylmethanol (0.48 g, crude) as yellow oil. The crude product was used for next step without purification. LC-MS (Method A): R _t = 0.165 min; MS (ESIpos): m/z = 139.1 [M+H] ⁺ . Procedure for preparation of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-6-carbaldehyde To a solution of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-6-ylmethanol (480 mg, 3.47 mmol, 1.00 eq) in dichloromethane (20.0 mL) was added Dess-Martin periodinane (1.77 g, 4.17 mmol, 1.20 eq) at 25°C. After stirring at 25°C for 2 h, the reaction mixture was quenched with saturated sodium thiosulfate (35.0 mL) and saturated sodium bicarbonate aqueous solution (35.0 mL). After stirring at 25°C for 0.5 h, the mixture was extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated to give 5,6-dihydro-4H-pyrrolo[1,2- b]pyrazole-6-carbaldehyde (0.6 g, crude) as yellow oil. The crude product was used for next step without further purification. Procedure for preparation of methyl 2-(tert-butoxycarbonylamino)-3-(5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-6-yl)prop-2-enoate To a solution of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-6-carbaldehyde (600 mg, 4.41 mmol, 1.00 eq) and methyl 2-(tert-butoxycarbonylamino)-2-diethoxyphosphoryl-acetate (2.15 g, 6.61 mmol, 1.50 eq) in dichloromethane (15.0 mL) was added 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (1.34 g, 8.81 mmol, 2.00 eq) at 25°C. After stirring at 25°C for 16 h, the reaction mixture was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 2/1) to give methyl 2-(tert- butoxycarbonylamino)-3-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol -6-yl)prop-2-enoate (280 mg, 893 μmol, 20 % yield, 98% purity) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.69-7.41 (m, 1H), 6.04-5.96 (m, 2H), 5.18 (d, J = 6.4 Hz, 1H), 3.79- 3.76 (m, 3H), 3.55-3.30 (m, 1H), 3.03-2.90 (m, 2H), 1.53-1.40 (m, 9H), 1.28-1.25 (m, 2H). LC-MS (Method C): R _t = 0.831 min; MS (ESIpos): m/z = 307.9 [M+H] ⁺ . Procedure for preparation of methyl 2-[[(1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3- dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carbonyl]amino]-3-(5,6-dihydro- 4H-pyrrolo[1,2-b]pyrazol-6-yl)propanoate To a solution of methyl 2-(tert-butoxycarbonylamino)-3-(5,6-dihydro-4H-pyrrolo[1,2-b ]pyrazol-6-yl) prop-2-enoate (280 mg, 911 μmol, 1.00 eq) in methanol (20.0 mL) was added palladium on carbon (28.0 mg, 10% purity) at 25°C. After stirring at 50°C for 16 h, the reaction mixture was filtered. The filtrate was concentrated to give methyl 2-(tert-butoxycarbonylamino)-3-(5,6-dihydro-4H-pyrrolo[1,2- b]pyrazol-6-yl) propanoate (230 mg, 743 μmol, 82% yield) as a white solid. LC-MS (Method C): R _t = 0.838 min; MS (ESIpos): m/z = 310.1 [M+H] ⁺ . Procedure for preparation of methyl 2-amino-3-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-6- yl)propanoate To a solution of methyl 2-(tert-butoxycarbonylamino)-3-(5,6-dihydro-4H-pyrrolo[1,2-b ]pyrazol-6-yl) propanoate (230 mg, 743 μmol, 1.00 eq) in dioxane (5.00 mL) was added hydrochloric acid (4 M in dioxane, 5.00 mL, 26.9 eq) at 25°C. After stirring at 25°C for 0.5 h, the reaction mixture was concentrated to give methyl 2-amino-3-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-6-yl)propano ate (190 mg, crude, HCl salt) as yellow oil. LC-MS (Method I): R _t = 0.705 min; MS (ESIpos): m/z = 210.2 [M+H] ⁺ . Procedure for preparation of methyl 2-[[(1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3- dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carbonyl]amino]-3-(5,6-dihydro- 4H-pyrrolo[1,2-b]pyrazol-6-yl)propanoate To a solution of methyl 2-amino-3-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-6-yl)propano ate (190 mg, 773 μmol, 1.00 eq, HCl) and (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl -butanoyl]- 6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (427 mg, 1.16 mmol, 1.50 eq) in acetonitrile (10.0 mL) were added N,N,N,N-tetramethylchloroformamidinium hexafluorophosphate (651 mg, 2.32 mmol, 3.00 eq) and 4-methylmorpholine (469 mg, 4.64 mmol, 6.00 eq) at 25°C. After stirring at 25°C for 16 h, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated sodium bicarbonate (30.0 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 1/1) to give methyl 2-[[(1R,2S,5S)-3-[(2S)-2-(tert- butoxycarbonylamino)-3,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carbonyl]amino]-3-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-6-yl )propanoate (400 mg, 627 μmol, 81% yield, 88% purity) as colorless oil. LC-MS (Method C): R _t = 0.942 min; MS (ESIpos): m/z = 560.3 [M+H] ⁺ . Procedure for preparation of tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-[[2-amino-1-(5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-6-ylmethyl)-2-oxo-ethyl]carbamoyl]-6,6 -dimethyl-3- azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]carb amate A solution of methyl 2-[[(1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dime thyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-3-(5,6- dihydro-4H-pyrrolo[1,2-b]pyrazol-6- yl)propanoate (600 mg, 1.07 mmol, crude purity, 1.00 eq) in ammonium (20 M in methanol, 10.0 mL) was stirred at 25°C for 16 h. The reaction mixture was concentrated to give tert-butyl N-[(1S)-1- [(1R,2S,5S)-2-[[2-amino-1-(5,6-dihydro-4H-pyrrolo [1,2-b]pyrazol-6-ylmethyl)-2-oxo-ethyl]carbamoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimet hyl-propyl]carbamate (550 mg, crude) as red oil. LC-MS (Method C): R _t = 0.824 min; MS (ESIpos): m/z = 545.5 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[2-amino-1-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazo l-6- ylmethyl)-2-oxo-ethyl]-3-[(2S)-2-amino-3,3-dimethyl-butanoyl ]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-[[2-amino-1-(5,6-dihydro-4H-pyrrolo[ 1,2-b] pyrazol- 6-ylmethyl)-2-oxo-ethyl]carbamoyl]-6,6-dimethyl-3-azabicyclo [3.1.0]hexane-3-carbonyl]-2,2-dimethyl- propyl]carbamate (300 mg, 551 μmol, 1.00 eq) in dichloromethane (10.0 mL) was added trifluoroacetic acid (2.64 g, 1.71 mL, 23.2 mmol, 42.0 eq) at 25°C. After stirring at 25°C for 0.5 h, the reaction mixture was concentrated to give (1R,2S,5S)-N-[2-amino-1-(5,6-dihydro-4H-pyrrolo[1,2-b] pyrazol-6-ylmethyl)- 2-oxo-ethyl]-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dime thyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (250 mg, crude) as yellow oil. The crude product was used for the next step reaction directly without further purification. LC-MS (Method C): R _t = 0.747 min; MS (ESIpos): m/z = 445.3 [M+H] ⁺ . Procedure for preparation of CPD0084260 - (1R,2S,5S)-N-[1-cyano-2-(5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-6-yl)ethyl]-3-[(2S)-3,3-dimethyl-2-[(2 ,2,2-trifluoroacetyl)amino] butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-[2-amino-1-(5,6-dihydro-4H-pyrrolo[1,2-b] pyrazol-6-ylmethyl)-2-oxo- ethyl]-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3 -azabicyclo[3.1.0]hexane-2-carboxamide (250 mg, 562 μmol, 1.00 eq) in dichloromethane (10.0 mL) were added N,N-diisopropylethylamine (218 mg, 1.69 mmol, 294 μL, 3.00 eq) and trifluoroacetic anhydride (236 mg, 1.12 mmol, 2.00 eq) at 0°C. After stirring at 0°C for 4 h, the reaction mixture was quenched with methanol (5.00 mL). The reaction mixture (combined with EW30038-95) was diluted with ethyl acetate (200 mL) and washed with brine (50.0 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-HPLC (FA condition: column: Unisil 3-100 C18 ΜLtra 150*50 mm*3 μm; mobile phase: [water (FA)-ACN]; B%: 40%-70%, 10 min) to give (1R,2S,5S)- N-[1-cyano-2-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-6-yl)ethy l]-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino] butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxami de (110 mg, 199 μmol, 35% yield, 95% purity) as an off-white solid. Procedure for preparation of CPD0084780 - (1R,2S,5S)-N-[(1R or S)-1-cyano-2-[(6R or S)-5,6- dihydro-4H-pyrrolo[1,2-b]pyrazol-6-yl]ethyl]-3-[(2S)-3,3-dim ethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide ; CPD0084781 - (1R,2S,5S)-N-[(1R or S)-1-cyano-2-[(6R or S)-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazol-6-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluo roacetyl)amino]butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxamide ; CPD0084906 - (1R,2S,5S)-N-[(1R or S)-1-cyano-2- [(6R or S)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-6-yl]ethyl]-3-[(2S)- 3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide ; CPD0084907 - (1R,2S,5S)-N-[(1R or S)-1-cyano-2-[(6R or S)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- 6-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)a mino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (1R,2S,5S)-N-[1-cyano-2-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazo l-6-yl)ethyl]-3-[(2S)-3,3-dimethyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabi cyclo[3.1.0]hexane-2-carboxamide (CPD0084260, 90 mg) was separated by SFC (column: Daicel ChiralPak IG (250*30 mm, 10 μm); mobile phase: [0.1% NH3H2O/EtOH]; B%: 15%-15%, 7min) to give (1R,2S,5S)-N-[(1R or S)-1-cyano- 2-[(6R or S)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-6-yl]ethyl]-3-[(2S)- 3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino] butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxami de (CPD0084780, 11 mg, 20.8 μmol, 11% yield, 99% purity) as a white solid, (1R,2S,5S)-N-[(1R or S)-1-cyano-2-[(6R or S)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-6-yl]ethyl]-3-[(2S)- 3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino] butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxami de (CPD0084781, 10.6 mg, 20.1 μmol, 11% yield, 99% purity) as a white solid and an impure compound. The impure compound was further purified by SFC separation (column: DAICEL CHIRALPAK IC (250 mm*30 mm,10 μm); mobile phase: [Neu-IPA]; B%: 25%-25%, 2.8 min) to give (1R,2S,5S)-N-[(1R or S)-1-cyano-2-[(6R or S)-5,6-dihydro- 4H-pyrrolo[1,2-b]pyrazol-6-yl]ethyl]-3-[(2S)-3,3-dimethyl-2- [(2,2,2-trifluoroacetyl)amino] butanoyl]-6,6- dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxamide (CPD0084906, 7.30 mg, 13.8 μmol, 7% yield, 99% purity) as a white solid and (1R,2S,5S)-N-[(1R or S)-1-cyano-2-[(6R or S)-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazol-6-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluo roacetyl)amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (CPD0084907, 7.50 mg, 14.2 μmol, 8% yield, 99% purity) as a white solid. Preparation of CPD0084300 Procedure for preparation of methyl 2-[[(1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3- dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carbonyl]amino]-3-(2-oxo-1- piperidyl)propanoate A mixture of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl -butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (641 mg, 1.74 mmol, 0.95 eq), O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (1.04 g, 2.75 mmol, 1.50 eq) and N,N- diisopropylethylamine (946 mg, 7.32 mmol, 1.28 mL, 4.00 eq) in N,N-dimethylformamide (10.0 mL) was stirred at 0°C for 0.1 h. Methyl 2-amino-3-(2-oxo-1-piperidyl)propanoate (500 mg, 1.83 mmol, 1.00 eq, 2 hydrochloric acid) was then added to the mixture above. After stirring at 25°C for 16 h, the mixture was poured into water (40.0 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18150*40mm* 15 μm; mobile phase: [water(FA)-ACN]; B%: 45%-75%,10 min) and lyophilized to give methyl 2-[[(1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dime thyl-butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-3-( 2-oxo-1-piperidyl)propanoate (350 mg, 0.604 mmol, 33% yield, 95% purity) as light yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.37 (d, J = 7.2 Hz, 0.5H), 7.13 (d, J = 7.2 Hz, 0.5H), 5.15-5.03 (m, 1H), 4.72-4.57 (m, 1H), 4.20-4.13 (m, 1H), 4.09-3.82 (m, 2H), 3.80-3.55 (m, 5H), 3.36-3.27 (m, 1H), 3.26- 3.14 (m, 1H), 2.34-2.26 (m, 1H), 1.76-1.68 (m, 4H), 1.56-1.48 (m, 1H), 1.43-1.37 (m, 2H), 1.33 (s, 9H), 1.02-0.89 (m, 12H), 0.82-0.76 (m, 3H). LC-MS (Method C): R _t = 0.908 min; MS (ESIpos): m/z = 551.2 [M+H] ⁺ . SFC: dr: 45:55. Procedure for preparation of tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-[[2-amino-2-oxo-1-[(2-oxo-1- piperidyl)methyl]ethyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[ 3.1.0] hexane-3-carbonyl]-2,2- dimethyl-propyl]carbamate A mixture of methyl 2-[[(1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dime thyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-3-(2-ox o-1-piperidyl)propanoate (350 mg, 636 μmol, 1.00 eq) in ammonia (15 M in methanol, 20.0 mL) was stirred at 25°C for 16 h. The mixture was concentrated under vacuum to give tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-[[2-amino-2-oxo-1-[(2-oxo-1- piperidyl)methyl]ethyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[ 3.1.0]hexane-3-carbonyl]-2,2-dimethyl- propyl]carbamate (340 mg, 603 μmol, 95% yield, 95% purity) as a light yellow solid. The crude product was used for the next step reaction directly. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.48 (d, J = 6.8 Hz, 0.5H), 7.77 (d, J = 5.6 Hz, 0.5H), 7.52 (s, 1H), 7.16 (s, 1H), 5.46-5.27 (m, 1H), 5.13-5.01 (m, 1H), 4.68-4.53 (m, 1H), 4.34-3.69 (m, 7H), 3.59-3.27 (m, 3H), 2.53-2.21 (m, 2H), 1.84-1.77 (m, 4H), 1.42 (s, 9H), 1.06 (s, 6H), 1.01-0.90 (m, 6H). Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-N-[2-amino -2- oxo-1-[(2-oxo-1-piperidyl)methyl] ethyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide A mixture of tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-[[2-amino-2-oxo-1-[(2-oxo-1-piperidy l) methyl]ethyl] carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl ]-2,2-dimethyl-propyl]carbamate (340 mg, 0.635 mmol,) in a mixed solvent of hydrochloric acid (4 M in ethyl acetate, 1.00 mL) and ethyl acetate (5.00 mL) was stirred at 25°C for 12 h. The mixture was concentrated under vacuum to give (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-N-[2-amino -2-oxo-1-[(2-oxo-1- piperidyl)methyl]ethyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexa ne-2-carboxamide (320 mg, 599 μmol, 95% yield, 95% purity, 2 hydrochloric acid salt) as a light yellow solid. The crude product was used for the next step reaction directly. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.25-8.04 (m, 3H), 7.40-7.29 (m, 1H), 7.23-7.06 (m, 1H), 4.72-4.44 (m, 1H), 4.12-3.85 (m, 3H), 3.82-3.79 (m, 2H), 3.47-3.18 (m, 4H), 2.22-2.09 (m, 2H), 1.70-1.52 (m, 6H), 1.40-1.13 (m, 2H), 1.09-0.92 (m, 12H). Procedure for preparation of (1R,2S,5S)-N-[2-amino-2-oxo-1-[(2-oxo-1-piperidyl)methyl]eth yl]-3- [(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl] -6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-N-[2-amino -2-oxo-1-[(2-oxo-1- piperidyl)methyl]ethyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexa ne-2-carboxamide (270 mg, 531 μmol, 1.00 eq, 2 hydrochloric acid) and triethylamine (269 mg, 2.65 mmol, 5.00 eq) in dichloromethane (5.00 mL) was added trifluoroacetic anhydride (223 mg, 1.06 mmol, 2.00 eq) at -20°C. After stirring at -20°C for 1 h, the mixture was poured into water (20.0 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give (1R,2S,5S)-N-[2-amino-2-oxo-1-[(2-oxo-1- piperidyl)methyl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifl uoroacetyl)amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (100 mg, 117 μmol, 22% yield, 62% purity) as light yellow solid. LC-MS (Method C): R _t = 0.767 min; MS (ESIpos): m/z = 532.3 [M+H] ⁺ . Procedure for preparation of CPD0084300 - (1R,2S,5S)-N-[1-cyano-2-(2-oxo-1-piperidyl)ethyl]-3- [(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl] -6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of (1R,2S,5S)-N-[2-amino-2-oxo-1-[(2-oxo-1-piperidyl)methyl]eth yl]-3-[(2S)-3,3-dimethyl- 2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-aza bicyclo[3.1.0]hexane-2-carboxamide (90.0 mg, 103 μmol, 62% purity, 1.00 eq) in dichloromethane (5.00 mL) was added methoxycarbonyl- (triethylammonio)sulfonyl-azanide (73.8 mg, 310 μmol, 3.00 eq) at 25°C. After stirring at 25°C for 13 h, the mixture was poured into water (10.0 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (10.0 mL), dried over sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi Polar-RP 100*25mm*4 μm; mobile phase: [water(TFA)-ACN];B%: 48%-68%,7min) and Prep- HPLC (column: Waters Xbridge 150*25mm* 5 μm; mobile phase: [water (ammonia hydroxide v/v)- ACN]; B%: 35%-65%,9min) to give (1R,2S,5S)-N-[1-cyano-2-(2-oxo-1-piperidyl)ethyl]-3-[(2S)-3, 3- dimethyl-2-[(2,2,2-trifluoroacetyl) amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (9.7 mg, 18.3 μmol, 18% yield, 97% purity) as an off-white solid. Preparation of CPD0084301 Procedure for preparation of methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3- dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-c arboxylate To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (10.0 g, 43.2 mmol, 1.00 eq) 4-methylmorpholine (10.9 g, 108 mmol, 594 μL, 2.50 eq) and benzotriazol-1-yloxy(tripyrrolidin-1-yl) phosphanium; hexafluorophosphate (24.8 g, 47.6 mmol, 1.10 eq) in dichloromethane (100 mL) was added methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (9.34 g, 45.4 mmol, 1.05 eq, hydrochloric acid salt). After stirring at 25°C for 12 h, the reaction mixture was poured into ammonium chloride aqueous solution (200 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 5/1) to afford methyl (1R,2S,5S)-3-((S)- 2-((tert-butoxycarbonyl) amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ] hexane-2- carboxylate (14.5 g, 37.9 mmol, 88% yield) as colorless oil. ¹ H NMR (400 MHz, CD ₃ OD) δ = 6.44 (d, J = 8.0 Hz, 1H), 4.37 (s, 1H), 4.22 (d, J = 9.6 Hz, 1H), 4.06- 4.01 (m, 1H), 3.97-3.89 (m, 1H), 3.75 (s, 3H), 1.61-1.57 (m, 1H), 1.51-1.49 (m, 1H), 1.43 (s, 9H), 1.09 (s, 3H), 1.03 (s, 9H), 0.95 (s, 3H). Procedure for preparation of (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3- dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-c arboxylic acid To a mixture of methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethy lbutanoyl)-6,6 - dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (10.0 g, 26.1 mmol, 1.00 eq) in tetrahydrofuran (30.0 mL) and methanol (30.0 mL) was added a solution of lithium hydroxide monohydrate (2.19 g, 52.3 mmol, 2.00 eq) in water (30.0 mL) at 0°C. After stirring at 0°C for 6 h, hydrochloric acid (0.5 M) was added to the reaction mixture to adjust pH = 5~6 and extracted with ethyl acetate (100 mL × 4). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with methyl tert-butyl ether (40.0 mL). After filtration, the filter cake was collected and dried under vacuum to give (1R,2S,5S)-3-((S) -2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-di methyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (5.30 g, 14.1 mmol, 54% yield, 98% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.62 (s, 1H), 6.68 (d, J = 9.6 Hz, 1H), 4.13 (s, 1H), 4.06 (d, J = 9.6 Hz, 1H), 3.95-3.88 (m, 1H), 3.82-3.73 (m, 1H), 1.56-1.46 (m, 1H), 1.44-1.31 (m, 10H), 1.01 (s, 3H), 0.94 (s, 9H), 0.85 (s, 3H). Procedure for preparation of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4- chlorobutanamido)propanoate To a solution of methyl (S)-3-amino-2-((tert-butoxycarbonyl)amino)propanoate (3.00 g, 11.8 mmol, 1.00 eq, hydrochloric acid salt) in dichloromethane (30.0 mL) were added triethylamine (2.74 g, 27.1 mmol, 2.30 eq) and 4-chlorobutanoyl chloride (1.79 g, 12.7 mmol, 1.42 mL, 1.08 eq). After stirring at 25°C for 12 h, the mixture was poured into water (50.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give methyl (S)-2-((tert-butoxycarbonyl)amino)-3 - (4-chlorobutanamido)propanoate (4.1 g, crude) as light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.02 (s, 1H), 5.43 (s, 1H), 4.39-4.24 (m, 1H), 3.70 (s, 3H), 3.60-3.50 (m, 4H), 2.30 (t, J = 8.0Hz, 2H), 2.08-2.00 (m, 2H), 1.38 (s, 9H). Procedure for preparation of methyl 2-((tert-butoxycarbonyl)amino)-3-(4- chlorobutanamido)propanoate To a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-chlorobutanamido)pro panoate (5.10 g, 15.8 mmol, 1.00 eq) in N,N-dimethylformamide (50.0 mL) was added sodium hydride (758 mg, 19.0 mmol, 60% purity, 1.20 eq). After stirring at 0°C for 1 h, the mixture was poured into saturated ammonium chloride (50.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give methyl 2-((tert-butoxycarbonyl)amino)-3-(4- chlorobutanamido)propanoate (2.20 g, crude) as light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.49 (d, J = 7.6 Hz, 1H), 4.56-4.40 (m, 1H), 3.77 (s, 4H), 3.62-3.45 (m, 2H), 3.43-3.31 (m, 1H), 2.41-2.33 (m, 2H), 2.07-2.00 (m, 2H), 1.44 (s, 9H). LC-MS (Method A): R _t = 0.579 min; MS (ESIpos): m/z = 187.1 [M+H] ⁺ _. Procedure for preparation of methyl 2-amino-3-(2-oxopyrrolidin-1-yl)propanoate To a solution of methyl 2-((tert-butoxycarbonyl)amino)-3-(4-chlorobutanamido)propano ate (2.20 g, 6.92 mmol, 1.00 eq) in ethyl acetate (4.00 mL) was added hydrochloric acid (4 M in ethyl acetate, 17.3 mL, 10.0 eq). After stirring at 25°C for 12 h, the mixture was concentrated under reduced pressure to give methyl 2-amino-3-(2-oxopyrrolidin-1-yl)propanoate (2.20 g, crude) as off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.72 (s, 3H), 4.22-4.18 (m, 1H), 3.71 (s, 3H), 3.69-3.57 (m, 2H), 3.40- 3.31 (m, 2H), 2.24-2.16 (m, 2H), 1.99-1.92 (m, 2H). Procedure for preparation of methyl 2-((1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3- dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-c arboxamido)-3-(2-oxopyrrolidin- 1-yl)propanoate To a solution of (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethy lbutanoyl) -6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.60 g, 4.14 mmol, 1.10 eq) in N,N-dimethylformamide (10.0 mL) were added N,N-diisopropylethylamine (2.14 g, 5.64 mmol, 1.50 eq) and N,N- diisopropylethylamine (1.94 g, 15.0 mmol, 2.62 mL, 4.00 eq) at 0°C. After stirring at this temperature for 10 min, methyl 2-amino-3-(2-oxopyrrolidin-1-yl)propanoate (0.70 g, 3.76 mmol, 1.00 eq) in N,N- dimethylformamide (3.00 mL) was added dropwise at 0°C. The resulting mixture was stirred at 25°C for 12 h, and poured into water (20.0 mL). The solution was extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 2/1) to afford methyl 2-((1R,2S,5S)- 3-((S) -2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-di methyl-3-azabicyclo[3.1.0]hexane- 2-carboxamido)-3-(2-oxopyrrolidin-1-yl)propanoate (1.3 g, 2.18 mmol, 58% yield, 90% purity) as light yellow oil. LC-MS (Method A): R _t = 0.861 min; MS (ESIpos): m/z = 537.2 [M+H] ⁺ _. Procedure for preparation of tert-butyl ((2S)-1-((1R,2S,5S)-2-((1-amino-1-oxo-3-(2-oxopyrrolidin- 1-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0] hexan-3-yl)-3,3-dimethyl-1- oxobutan-2-yl)carbamate A mixture of methyl 2-((1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dime thylbutanoyl) -6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-(2-oxopy rrolidin-1-yl)propanoate (1.00 g, 1.86 mmol, 1.00 eq) in a solution of ammonia (15 M in methanol, 20.0 mL, 161 eq) in methanol (5.00 mL) was stirred at 25°C for 12 h. The mixture was concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to ethyl acetate, and then ethyl acetate/methanol = 10:1) to afford tert-butyl ((2S)-1-((1R,2S,5S)-2-((1-amino-1-oxo-3 - (2-oxopyrrolidin-1-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexan-3-yl)-3,3-dimethyl- 1-oxobutan-2-yl)carbamate (700 mg, 1.27 mmol, 68% yield, 95% purity) as light yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.43-7.98 (m, 1H), 7.37-7.13 (m, 2H), 6.71-6.58 (m, 1H), 4.50-4.39 (m, 1H), 4.27-4.17 (m, 1H), 4.07-3.99 (m, 1H), 3.91-3.85 (m, 1H), 3.83-3.75 (m, 1H), 3.47-3.43 (m, 2H), 3.18-3.15 (m, 2H), 2.29-2.09 (m, 2H), 1.90-1.81 (m, 2H), 1.50-1.32 (m, 11H), 1.03-0.82 (m, 15H) LC-MS (Method C): R _t = 0.799 min; MS (ESIpos): m/z = 522.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-(1-amino-1-oxo-3-(2-oxopyrrolidin-1-yl)propan-2 -yl)- 3-((S)-2-amino-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyc lo[3.1.0]hexane-2-carboxamide To a solution of tert-butyl ((2S)-1-((1R,2S,5S)-2-((1-amino-1-oxo-3-(2-oxopyrrolidin-1-y l)propan-2-yl) carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3,3-d imethyl-1-oxobutan-2-yl) carbamate (100 mg, 192 μmol, 1.00 eq) in dichloromethane (1.00 mL) was added trifluoroacetic acid (0.20 mL) at 0°C. After stirring at 25°C for 1 h, a saturated sodium bicarbonate solution was added to the mixture to adjust pH to 7 and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated to give (1R,2S,5S)- N-(1-amino-1-oxo-3-(2-oxopyrrolidin-1-yl)propan-2-yl)-3-((S) -2-amino-3,3-dimethylbutanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (50 mg, 83.0 μmol, 43% yield, 70% purity) as light yellow oil. LC-MS (Method C): R _t = 0.408 min; MS (ESIpos): m/z = 422.1 [M+H] ⁺ _. Procedure for preparation of CPD0084301 - (1R,2S,5S)-N-(1-cyano-2-(2-oxopyrrolidin-1-yl)ethyl)- 3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6, 6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-(1-amino-1-oxo-3-(2-oxopyrrolidin-1-yl)propan-2 -yl)-3-((S) -2-amino-3,3- dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-c arboxamide (50.0 mg, 119 μmol, 1.00 eq) and triethylamine (60.0 mg, 593 μmol, 5.00 eq) in dichloromethane (3.00 mL) was added trifluoroacetic anhydride (49.8 mg, 237 μmol, 2.00 eq) dropwise at -20°C. After stirring at -20°C for 10 min, the mixture was poured into saturated sodium bicarbonate aqueous solution (20.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were washed by brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 μm; mobile phase: [water(FA)-ACN];B%: 30%-60%,10min) to afford (1R,2S,5S)-N-(1-cyano-2-(2- oxopyrrolidin-1-yl) ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butan oyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (9.51 mg, 18.8 μmol, 16% yield, 99% purity) as white solid. Preparation of CPD0084302 Procedure for preparation of pyrazolo[1,5-a]pyridine-7-carbaldehyde To a solution of pyrazolo[1,5-a]pyridine (24.0 g, 203 mmol, 1.00 eq) in tetrahydrofuran (200 mL) was added dropwise n- butyl lithium (2.50 M in hexane, 85.3 mL, 1.05 eq) at -78 °C. After stirring at -78 °C for 1 h, ethyl formate (16.5 g, 223 mmol, 18.0 mL, 1.10 eq) was added to the solution above. After stirring at -78 °C for 1 h, the reaction mixture was adjusted to pH~7 with hydrochloric acid (2 M in water) and extracted with ethyl acetate (200.0 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford pyrazolo[1,5-a]pyridine-7-carbaldehyde (15.0 g, 82.1 mmol, 40% yield, 80% purity) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 10.88 (s, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.83 (d, J = 8.8, 1.6 Hz, 1H), 7.49 (d, J = 7.2, 1.6 Hz, 1H), 7.26-7.20 (m, 1H), 6.73 (d, J = 2.4 Hz, 1H). Procedure for preparation of 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-7-ylmethanol To a solution of pyrazolo[1,5-a]pyridine-7-carbaldehyde (5.00 g, 34.2 mmol, 1.00 eq) in methanol (200 mL) was added palladium on carbon (2.00 g, 10% purity, wet) at 25 °C under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen for 3 times. After stirring at 80 °C for 32 h under hydrogen (50 psi) atmosphere, the reaction mixture was filtered. The filtrate was concentrated and then purified by flash silica gel chromatography (ISCO®;80 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @60 mL/min) to afford 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-7-ylmethanol (5.00 g, 31.2 mmol, 91% yield, 95% purity) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ =7.44 (d, J = 1.6 Hz, 1H), 6.00 (s, 1H), 4.31-4.19 (m, 1H), 3.91 -3.76 (m, 2H), 2.97 – 2.83 (m, 1H), 2.76 -2.64 (m, 1H), 2.15 -1.95 (m, 2H), 1.79 - 1.73 (m, 1H), 1.70 - 1.63 (m, 1H). Procedure for preparation of 7-(iodomethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine To a mixture of 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-7-ylmethanol (2.00 g, 13.1 mmol, 1.00 eq) and triphenyl phosphine (8.62 g, 32.8 mmol, 2.50 eq) and imidazole (4.47 g, 65.7 mmol, 5.00 eq) in tetrahydrofuran (40.0 mL) was added iodide (8.34 g, 32.8 mmol, 2.50 eq) at 0 °C. After stirring at 25 °C for 16 h, the reaction mixture was poured into saturated ammonium chloride (50.0 mL) and extracted with ethyl acetate (50.0 mL × 2). The combined organic layers were washed with brine (15.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®;40 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ether gradient @50 mL/min) to give 7- (iodomethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (3.00 g, 10.9 mmol, 83% yield, 95% purity) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.48 (d, J = 1.6 Hz, 1H), 6.01-5.97 (m, 1H), 4.21-4.12 (m, 1H), 3.87- 3.81 (m, 1H), 3.71-3.64 (m, 1H), 2.89-2.70 (m, 2H), 2.32-2.21 (m, 1H), 2.08-1.92 (m, 2H), 1.85-1.73 (m, 1H). Procedure for preparation of methyl 2-(benzhydrylideneamino)-3-(4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-7-yl)propanoate To a mixture of 7-(iodomethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (2.00 g, 7.63 mmol, 1.00 eq) and methyl 2-(benzhydrylideneamino)acetate (2.13 g, 8.39 mmol, 1.10 eq) in acetonitrile (40.0 mL) was added potassium carbonate (3.16 g, 22.9 mmol, 3.00 eq) at 0 °C. After stirring at 0 °C for 2 h, the reaction mixture was poured into saturated ammonium chloride (50.0 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®;40 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ether gradient @50 mL/min) to afford methyl 2- (benzhydrylideneamino)-3-(4,5,6,7-tetrahydropyrazolo[1,5-a]p yridin-7-yl)propanoate (2.00 g, 5.16 mmol, 68% yield, crude purity) as yellow oil. LC-MS (Method C): R _t = 0.627 min; MS (ESIpos): m/z = 388.2 [M+H] ⁺ . Procedure for preparation of 2-(benzhydrylideneamino)-3-(4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-7-yl)propanamide A solution of methyl 2-(benzhydrylideneamino)-3-(4,5,6,7-tetrahydropyrazolo[1,5-a ]pyridin-7- yl)propanoate (100 mg, 0.258 mmol, 1.00 eq) in methanol (0.50 mL) and ammonia (14.0 M in methanol, 5.00 mL) was stirred at 25 °C for 24 h. The mixture was concentrated under vacuum to give 2- (benzhydrylideneamino)-3-(4,5,6,7-tetrahydropyrazolo[1,5-a]p yridin-7-yl)propanamide (100 mg, 0.255 mmol, 99% yield) as yellow oil. Procedure for preparation of 2-amino-3-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-7- yl)propanamide A mixture of 2-(benzhydrylideneamino)-3-(4,5,6,7-tetrahydropyrazolo[1,5-a ]pyridin-7-yl)propanamide (100 mg, 0.268 mmol, 1.00 eq) in hydrochloride acid (4 M in in dioxane, 5.00 mL) was stirred at 25 °C for 1 h. The mixture was concentrated under vacuum to give 2-amino-3-(4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-7-yl)propanamide (65.0 mg, 0.265 mmol, 99% yield, crude purity, HCl salt) as a yellow solid. Procedure for preparation of (1R,2S,5S)-N-[2-amino-2-oxo-1-(4,5,6,7-tetrahydropyrazolo[1, 5- a]pyridin-7-ylmethyl)ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-t rifluoroacetyl)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl - 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (118 mg, 0.292 mmol, 90.0% purity, 1.10 eq) and N,N- diisopropylethylamine (103 mg, 0.797 mmol, 0.139 mL, 3.00 eq) in N,N-dimethylformamide (3.00 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexaflu orophosphate (121 mg, 0.318 mmol, 1.20 eq). After stirring at 25 °C for 0.25 h, 2-amino-3-(4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-7-yl)propanamide (65.0 mg, 0.265 mmol, crude purity, 1.00 eq, HCl salt) was added. After addition, the mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into saturated ammonium chloride (20.0 mL) and extracted with ethyl acetate (50.0 mL × 2). The combined organic layers were washed with brine (15.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®;12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @35 mL/min) to afford (1R,2S,5S)-N-[2-amino-2-oxo-1-(4,5,6,7- tetrahydropyrazolo[1,5-a] pyridin-7-ylmethyl)ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (120 mg, 0.179 mmol, 68% yield, 83% purity) as yellow oil. LC-MS (Method C): R _t = 0.929 min; MS (ESIpos): m/z = 555.3 [M+H] ⁺ . Procedure for preparation of CPD0084302 - (1R,2S,5S)-N-[1-cyano-2-(4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-7-yl)ethyl]-3-[(2S)-3,3-dim ethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-[2-amino-2-oxo-1-(4,5,6,7-tetrahydropyrazolo[1, 5-a] pyridin-7- ylmethyl)ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacet yl)amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (120 mg, 0.179 mmol, 68% yield, 83% purity) in dichloromethane (2.00 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (107 mg, 0.449 mmol, 3.00 eq) at 0 °C. After stirring at 25 °C for 3 h, the mixture was adjusted to pH~9 with saturated sodium hydrogen carbonate (20.0 mL) and extracted with ethyl acetate (30.0 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 250*50mm*15 μm; mobile phase: [water(FA)-ACN]; B%: 53%-83%, 10 min) to give (1R,2S,5S)-N-[1- cyano-2-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-7-yl)ethyl ]-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (21.8 mg, 40.0 μmol, 27% yield, 99% purity) as a white solid. Preparation of CPD0084303 Procedure for preparation of 2-chloro-3-(1,3-dioxolan-2-yl)pyridine To a mixture of 2-chloropyridine-3-carbaldehyde (100 g, 706 mmol, 1.00 eq) in toluene (500 mL) were added ethylene glycol (87.7 g, 1.41 mol, 2.00 eq) and 4-methylbenzenesulfonic acid; hydrate (6.72 g, 35.3 mmol, 0.05 eq). The mixture was refluxed for 1 h to remove water by a Dean Stark trap. The reaction mixture was concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10/1 to 3/1) to give 2-chloro-3-(1,3-dioxolan-2- yl)pyridine (110 g, 563 mmol, 80% yield, 95% purity) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.40 (dd, J = 4.8, 2.0 Hz, 1H), 7.95 (dd, J = 7.2, 2.0 Hz, 1H), 7.30-7.27 (m, 1H), 6.10 (s, 1H), 4.20-4.13 (m, 2H), 4.13-4.06 (m, 2H). LC-MS (Method C): R _t = 0.436 min; MS (ESIpos): m/z = 186.2 [M+H] ⁺ . Procedure for preparation of [3-(1,3-dioxolan-2-yl)-2-pyridyl]hydrazine A mixture of 2-chloro-3-(1,3-dioxolan-2-yl)pyridine (110 g, 563 mmol, 95% purity, 1.00 eq) and hydrazine; hydrate (87.7 g, 1.75 mol, 3.11 eq) in n-butanol (1.00 L) was stirred at 130°C for 16 h. The mixture was poured into water (1.50 L) and extracted with ethyl acetate (400 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (ethyl acetate/methanol = 20/1 to 10/1) to give [3-(1,3-dioxolan-2-yl)-2-pyridyl]hydrazine (30.0 g, 149 mmol, 26% yield, 90% purity) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.10 (dd, J = 5.2, 1.6 Hz, 1H), 7.50 (dd, J = 7.2, 1.6 Hz, 1H), 6.95 (s, 1H), 6.63 (d, J = 7.2, 4.8 Hz, 1H), 5.70 (s, 1H), 4.18 (s, 2H), 4.07-4.01 (m, 2H), 3.95-3.90 (m, 2H). LC-MS (Method A): R _t = 0.160 min; MS (ESIpos): m/z = 182.1 [M+H] ⁺ . Procedure for preparation of 8-(1,3-dioxolan-2-yl)-[1,2,4]triazolo[4,3-a]pyridine A mixture of [3-(1,3-dioxolan-2-yl)-2-pyridyl]hydrazine (30.0 g, 149 mmol, 90% purity, 1.00 eq), trimethoxymethane (31.6 g, 298 mmol, 32.6 mL, 2.00 eq) and acetic acid (894 mg, 14.9 mmol, 0.100 eq) in toluene (300 mL) was stirred at 100°C for 12 h. The reaction mixture was cooled to 0°C and filtered. The filter cake was triturated with methyl tert-butyl ether and filtered. The solid cake was dried under vacuum to give 8-(1,3-dioxolan-2-yl)-[1,2,4]triazolo[4,3-a]pyridine (19.0 g, 94.4 mmol, 63% yield, 95% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 9.30 (s, 1H), 8.58 (d, J = 6.8 Hz, 1H), 7.44 (d, J = 6.8 Hz, 1H), 6.99 (t, J = 6.8 Hz, 1H), 6.28 (s, 1H), 4.21-4.11 (m, 2H), 4.08-3.99 (m, 2H). Procedure for preparation of [1,2,4]triazolo[4,3-a]pyridine-8-carbaldehyde A mixture of 8-(1,3-dioxolan-2-yl)-[1,2,4]triazolo[4,3-a]pyridine (8.50 g, 42.2 mmol, 95% purity, 1.00 eq) in hydrochloric acid (100 mL) was stirred at 0°C for 1 h. After concentration, the residue was triturated with acetonitrile (20.0 mL) to give [1,2,4]triazolo[4,3-a]pyridine-8-carbaldehyde (6.00 g, 36.7 mmol, 86% yield, 90% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.37 (s, 1H), 9.72 (s, 1H), 9.10 (dd, J = 6.8, 0.88 Hz, 1H), 8.50 (dd, J = 6.8, 0.88 Hz, 1H), 7.55 (t, J = 6.8 Hz, 1H). Procedure for preparation of methyl 2-(tert-butoxycarbonylamino)-3-([1,2,4]triazolo[4,3- a]pyridin-8-yl)prop-2-enoate A mixture of methyl 2-(tert-butoxycarbonylamino)-2-dimethoxyphosphoryl-acetate (9.55 g, 32.1 mmol, 1.05 eq) and 1,8-diazabicyclo[5.4.0]undec-7-ene (5.59 g, 36.7 mmol, 1.20 eq) in dichloromethane (50.0 mL) was stirred at 0°C for 10 min under nitrogen atmosphere. The resulting mixture was added into a solution of [1,2,4]triazolo[4,3-a]pyridine-8-carbaldehyde (5.00 g, 30.5 mmol, 90% purity, 1.00 eq) in dichloromethane (50.0 mL) at 0°C. After stirring at 0°C for 2 h, the reaction mixture was poured into saturated ammonium chloride aqueous (200 mL) and extracted with ethyl acetate (100 mL × 5). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 1/1 to 1/2) to give methyl 2-(tert- butoxycarbonylamino)-3-([1,2,4] triazolo[4,3-a]pyridin-8-yl)prop-2-enoate (2.00 g, 5.65 mmol, 18% yield, 90% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.25 (s, 1H), 9.35 (s, 1H), 8.60 (d, J = 6.7 Hz, 1H), 7.67 (d, J = 7.0 Hz, 1H), 7.15-7.04 (m, 2H), 3.78 (s, 3H), 1.38 (s, 9H). Procedure for preparation of methyl 2-(tert-butoxycarbonylamino)-3-(5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyridin-8-yl)propanoate To a mixture of methyl 2-(tert-butoxycarbonylamino)-3-([1,2,4]triazolo[4,3-a]pyridi n-8-yl)prop-2-enoate (2.00 g, 5.65 mmol, 90% purity, 1.00 eq) in methanol (50.0 mL) was added palladium on carbon (1.00 g, 10% purity) under nitrogen atmosphere. The mixture was degassed under vacuum and purged with hydrogen for three times. After stirring at 80°C under hydrogen atmosphere (50 psi) for 16 h, the reaction mixture was filtered, the filter cake was washed with methanol (50 mL × 3). The filtrate was concentrated under vacuum to give methyl 2-(tert-butoxycarbonylamino)-3-(5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyridin-8-yl) propanoate (2 g, crude) as a colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.35 (d, J = 4.6 Hz, 1H), 7.58-7.42 (m, 1H), 4.72-4.23 (m, 1H), 4.10- 4.01 (m, 1H), 3.92-3.80 (m, 1H), 3.61-3.60 (m, 3H), 2.96-2.83 (m, 1H), 2.38-2.11 (m, 1H), 2.06-1.93 (m, 2H), 1.85-1.70 (m, 2H), 1.56-1.44 (m, 1H), 1.38 (s, 9H). Procedure for preparation of methyl 2-amino-3-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin- 8- yl)propanoate A mixture of methyl 2-(tert-butoxycarbonylamino)-3-(5,6,7,8-tetrahydro-[1,2,4]tr iazolo[4,3-a]pyridin-8- yl) propanoate (2.00 g, 6.17 mmol, 1.00 eq) in hydrochloric acid/1,4-dioxane (30.0 mL) was stirred at 25°C for 1 h. The reaction mixture was concentrated under vacuum to give methyl 2-amino-3-(5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)propanoate (2.10 g, crude ^HCl salt) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.51-9.36 (m, 1H), 8.92 (s, 2H), 4.09-4.03 (m, 2H), 3.77-3.75 (m, 3H), 3.47-3.42 (m, 1H), 2.48-2.44 (m, 1H), 2.30-2.03 (m, 4H), 1.97-1.63 (m, 2H). Procedure for preparation of methyl 2-[[(1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3- dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carbonyl]amino]-3-(5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)propanoate To a mixture of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl -butanoyl]-6,6-dimethyl - 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (2.47 g, 6.04 mmol, 90% purity, 1.05 eq) and O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (3.28 g, 8.63 mmol, 1.50 eq) in N,N-dimethylformamide (20.0 mL) was added N,N-diisopropylethylamine (2.97 g, 23.0 mmol, 4.00 eq) at 0°C. After stirring for 0.2 h, methyl 2-amino-3-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin- 8-yl) propanoate·HCl (1.50 g, 6.69 mmol, 1.00 eq) in N,N-dimethylformamide (10.0 ml) was added dropwise at 0°C. After addition, the mixture was stirred at 25°C for 12 h. The reaction mixture was poured into saturated ammonium chloride aqueous solution (200 mL) and extracted with a mixed solvent of dichloromethane and methanol (dichloromethane: methanol = 10: 1, 100 mL × 5). The organic phase was concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (ethyl acetate/methanol = 50/1 to 10/1) to give methyl 2-[[(1R,2S,5S)-3-[(2S)-2-(tert- butoxycarbonylamino) -3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexa ne-2- carbonyl]amino]-3-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a] pyridin-8-yl)propanoate (1.50 g, 2.19 mmol, 38% yield, 84% purity) as yellow oil. LC-MS (Method C): R _t = 0.849 min; MS (ESIpos): m/z = 575.2 [M+H] ⁺ . Procedure for preparation of tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-[[2-amino-2-oxo-1-(5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-8-ylmethyl)ethyl]ca rbamoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]carb amate A mixture of methyl 2-[[(1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dime thyl-butanoyl] -6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-3-(5,6, 7,8-tetrahydro-[1,2,4]triazolo [4,3- a]pyridin-8-yl)propanoate (1.00 g, 1.46 mmol, 84% purity, 1.00 eq) in ammonia/methanol (15 M, 20.0 mL) was stirred at 25°C for 12 h. The reaction mixture was concentrated and purified by reversed phase flash column (0.1% NH ₃ ·H ₂ O, 50% - 60% ACN) to give tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-[[2-amino-2- oxo-1- (5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-8-ylmethyl ) ethyl]carbamoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl] carbamate (510 mg, 0.865 mmol, 59% yield, 95% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.76-8.46 (m, 1H), 8.39-8.30 (m, 1H), 7.36-6.96 (m, 2H), 6.71-6.49 (m, 1H), 4.64-4.32 (m, 1H), 4.29-4.16 (m, 1H), 4.11-3.99 (m, 2H), 3.88-3.82 (m, 2H), 2.99-2.86 (m, 1H), 2.36-2.29 (m, 1H), 2.09-1.94 (m, 2H), 1.85-1.66 (m, 2H), 1.53-1.47 (m, 1H), 1.41-1.31 (m, 10H), 1.30- 1.22 (m, 1H), 1.01-1.00 (m, 3H), 0.88-0.87 (m, 1H), 0.96-0.79 (m, 12H). LC-MS (Method C): R _t = 0.818 min; MS (ESIpos): m/z = 560.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-N-[2-amino -2- oxo-1-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-8-yl methyl) ethyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide A mixture of tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-[[2-amino-2-oxo-1-(5,6,7,8-tetrahydr o-[1,2,4] triazolo[4,3-a]pyridin-8-ylmethyl)ethyl]carbamoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]- 2,2-dimethyl-propyl]carbamate (510 mg, 0.865 mmol, 95% purity, 1.00 eq) in hydrochloric acid/1,4- dioxane (4 M, 10 mL) was stirred at 0°C for 0.5 h. The reaction mixture was concentrated under vacuum to give (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-N-[2-amino -2-oxo-1-(5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyridin-8-ylmethyl)ethyl]-6,6-dimethyl -3-azabicyclo[3.1.0]hexane-2-carboxamide (400 mg, crude, HCl salt) as a gray solid . LC-MS (Method A): R _t = 0.633 min; MS (ESIpos): m/z = 460.4 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[2-amino-2-oxo-1-(5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyridin-8-ylmethyl)ethyl]-3-[(2S)-3,3- dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide To a mixture of (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-N-[2-amino -2-oxo-1 -(5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-8-ylmethyl)ethyl]-6 ,6-dimethyl-3-azabicyclo [3.1.0]hexane-2- carboxamide (400 mg, 0.870 mmol, 1.00 eq) and triethylamine (440 mg, 4.35 mmol, 5.00 eq) in dichloromethane (20.0 mL) was added trifluoroacetic anhydride (365 mg, 1.74 mmol, 2.00 eq) at 0°C. After stirring for 0.5 h, the reaction was quenched with water (0.500 mL). After concentration, the residue was purified by reversed phase flash column chromatography (0.1% FA, 45% - 55% ACN) to give (1R,2S,5S)-N-[2-amino-2-oxo-1-(5,6,7,8-tetrahydro-[1,2,4]tri azolo[4,3-a]pyridin-8-ylmethyl)ethyl]-3- [(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl] -6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (40.0 mg, 57.6 μmol, 7% yield, 80% purity) as a colorless solid. LC-MS (Method C): R _t = 0.701 min; MS (ESIpos): m/z = 556.2 [M+H] ⁺ . Procedure for preparation of CPD0084303 - (1R,2S,5S)-N-[(1S)-1-cyano-2-(5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyridin-8-yl)ethyl]-3-[(2S)-3,3-dimeth yl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide

216 To a mixture of (1R,2S,5S)-N-[2-amino-2-oxo-1-(5,6,7,8-tetrahydro-[1,2,4]tri azolo[4,3-a]pyridin-8- ylmethyl) ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino] butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (40.0 mg, 57.6 μmol, 80% purity, 1.00 eq) in dichloromethane (2.00 mL) was added Burgess reagent (41.1 mg, 0.172 mmol, 3.00 eq). After stirring at 25°C for 2 h, the reaction was quenched with water (0.300 mL). The mixture was concentrated under vacuum and purified by preparative HPLC (column: Phenomenex Synergi C18150*25mm*10μm; mobile phase: [water(FA)-ACN]; B%: 33%-53%,10min) to give (1R,2S,5S)-N-[1-cyano-2-(5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyridin-8-yl) ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino] butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (7.54 mg, 13.8 μmol, 24% yield, 98% purity) as a white solid. Preparation of CPD0084397 Procedure for preparation of tert-butyl 8-oxo-6,7-dihydro-5H-isoquinoline-7-carboxylate To a solution of methyl 4-methylpyridine-3-carboxylate (25.0 g, 165 mmol, 1.00 eq) in tetrahydrofuran (400 mL) was added dropwise lithium diisopropylamide (2.00 M in tetrahydrofuran, 91.0 mL, 1.10 eq) at -78°C. After stirring at this temperature for 30 min, a solution of tert-butyl prop-2-enoate (23.3 g, 182 mmol, 26.4 mL, 1.10 eq) in tetrahydrofuran (100 mL) was added dropwise at -78°C. After stirring at - 78°C for 1.5 h, the reaction mixture was poured into saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1 to 0/1) to afford tert-butyl 8-oxo-6,7-dihydro-5H-isoquinoline-7-carboxylate (28.7 g, 111 mmol, 67% yield, 96% purity) as brown oil. LC-MS (Method C): R _t = 0.798 min; MS (ESIpos): m/z = 247.8 [M+H] ⁺ . Procedure for preparation of 6,7-dihydro-5H-isoquinolin-8-one A solution of tert-butyl 8-oxo-6,7-dihydro-5H-isoquinoline-7-carboxylate (28.7 g, 111 mmol, 96% purity, 1.00 eq) in hydrochloric acid (12 M in water, 200 mL) was stirred at 100°C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (100 mL), adjusted to pH = 7-8 with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (60.0 mL × 3). The combined organic layers were washed with brine (30.0 mL × 3), dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure to afford 6,7- dihydro-5H-isoquinolin-8-one (3.70 g, 24.9 mmol, 22% yield, 99% purity) as brown oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.92 (s, 1H), 8.61 (d, J = 5.2 Hz, 1H), 7.39 (d, J = 5.2 Hz, 1H), 2.95 (t, J = 6.4 Hz, 2H), 2.64 (t, J = 6.4 Hz, 2H), 2.14-2.00 (m, 2H). LC-MS (Method C): R _t = 0.174 min; MS (ESIpos): m/z = 147.7 [M+H] ⁺ . Procedure for preparation of 5,6,7,8-tetrahydroisoquinolin-8-ol To a solution of 6,7-dihydro-5H-isoquinolin-8-one (3.70 g, 24.9 mmol, 99% purity, 1.00 eq) in methanol (60.0 mL) was added sodium borohydride (753 mg, 19.9 mmol, 0.800 eq) at 0°C. After stirring at 0°C for 1 h, the mixture was allowed to warm to 25°C and stirred at this temperature for 1 h. The reaction mixture was quenched with saturated ammonium chloride solution (50.0 mL) at 0°C, diluted with water (50.0 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine (20.0 mL × 3), dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure to afford 5,6,7,8-tetrahydroisoquinolin-8-ol (3.6 g, 23.9 mmol, 96% yield, 99% purity) as brown oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.52 (s, 1H), 8.27 (d, J = 4.8 Hz, 1H), 7.08 (d, J = 5.2 Hz, 1H), 5.30 (s, 1H), 4.65-4.63 (m, 1H), 2.81-2.58 (m, 2H), 1.96-1.81 (m, 2H), 1.79-1.60 (m, 2H). LC-MS (Method C): R _t = 0.128 min; MS (ESIpos): m/z = 149.8 [M+H] ⁺ . Procedure for preparation of 8-chloro-5,6,7,8-tetrahydroisoquinoline - A solution of 5,6,7,8-tetrahydroisoquinolin-8-ol (3.60 g, 23.9 mmol, 99% purity, 1.00 eq) in thionyl chloride (56.8 g, 478 mmol, 34.7 mL, 20.0 eq) was stirred at 80°C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (30.0 mL) and ethyl acetate (30.0 mL), adjusted to pH = 7-8 with sodium bicarbonate (solid) and extracted with ethyl acetate (20.0 mL × 2). The combined organic layers were washed with brine (10.0 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give afford 8- chloro-5,6,7,8-tetrahydroisoquinoline (3.80 g, 20.4 mmol, 85% yield, 90% purity) as black oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.52 (s, 1H), 8.34 (d, J = 5.2 Hz, 1H), 7.16 (d, J = 5.2 Hz, 1H), 5.61 (t, J = 3.6 Hz, 1H), 2.90-2.68 (m, 2H), 2.24-2.14 (m, 2H), 2.06-1.77 (m, 2H). LC-MS (Method C): R _t = 0.301 min; MS (ESIpos): m/z = 168.1 [M+H] ⁺ . Procedure for preparation of methyl 2-(benzhydrylideneamino)-2-(5,6,7,8-tetrahydroisoquinolin- 8-yl)acetate To a solution of 8-chloro-5,6,7,8-tetrahydroisoquinoline (3.80 g, 20.4 mmol, 90% purity, 1.00 eq) and methyl 2-(benzhydrylideneamino)acetate (5.17 g, 20.4 mmol, 1.00 eq) in N,N-dimethylformamide (100 mL) was added cesium carbonate (13.3 g, 40.8 mmol, 2.00 eq) at 25°C. After stirring at 25°C for 16 h, the reaction mixture was diluted with saturated ammonium chloride solution (50.0 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine (30.0 mL× 5), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1 to 1/1) to afford methyl 2-(benzhydrylideneamino)-2-(5,6,7,8-tetrahydroisoquinolin-8- yl)acetate (5.70 g, 12.5 mmol, 61% yield, 84% purity) as black oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.22-7.93 (m, 2H), 7.52-7.32 (m, 8H), 7.03 (d, J = 4.8 Hz, 1H), 6.93- 6.83 (m, 1H), 6.37 (s, 1H), 4.40-4.11 (m, 1H), 3.65 (d, J = 22.4 Hz, 3H), 3.59-3.48 (m, 1H), 2.88 (s, 1H), 2.73 (s, 1H), 2.70-2.61 (m, 1H), 1.88-1.52 (m, 3H). LC-MS (Method C): R _t = 0.820 min; MS (ESIpos): m/z = 384.9 [M+H] ⁺ . Procedure for preparation of methyl 2-amino-2-(5,6,7,8-tetrahydroisoquinolin-8-yl)acetate To a solution of methyl 2-(benzhydrylideneamino)-2-(5,6,7,8-tetrahydroisoquinolin-8- yl)acetate (5.70 g, 12.4 mmol, 84% purity, 1.00 eq) in dioxane (36.0 mL) was added hydrochloric acid (4 M in dioxane, 12.5 mL, 4.00 eq) at 25°C. After stirring at 25°C for 16 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with ethyl acetate (50.0 mL) and extracted with water (20.0 mL × 3). The combined aqueous phase was washed with ethyl acetate (10.0 mL × 3), lyophilized to afford methyl 2-amino-2-(5,6,7,8-tetrahydroisoquinolin-8-yl)acetate (3.20 g, 12.2 mmol, 98% yield, 98% purity, hydrochloric acid salt) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.16-9.02 (m, 2H), 8.76 (s, 1H), 8.68 (t, J = 6.0 Hz, 1H), 7.89-7.79 (m, 1H), 5.18-4.71 (m, 1H), 3.78 (s, 3H), 3.58 (s, 2H), 3.03-2.93 (m, 2H), 2.10-1.56 (m, 4H). LC-MS (Method C): R _t = 0.121 min; MS (ESIpos): m/z = 220.8 [M+H] ⁺ . Procedure for preparation of methyl 2-[[(1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3- dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carbonyl]amino]-2-(5,6,7,8- tetrahydroisoquinolin-8-yl)acetate To a solution of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl -butanoyl]- 6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (0.800 g, 2.17 mmol, 1.00 eq) in N,N-dimethylformamide (40.0 mL) were added N,N-diisopropylethylamine (1.40 g, 10.8 mmol, 1.90 mL, 5.00 eq) and O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (1.65 g, 4.34 mmol, 2.00 eq) at 0°C. After stirring at 0°C for 12 min, methyl 2-amino-2-(5,6,7,8-tetrahydroisoquinolin-8-yl)acetate (853 mg, 3.26 mmol, 98% purity, 1.50 eq, hydrochloric acid salt) was added at 0°C. After stirring at 25°C for 16 h, the reaction mixture was diluted with water (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (20.0 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1 to 0/1) to afford methyl 2-[[(1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dime thyl-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carbonyl]amino]-2-(5,6,7,8-tetrahy droisoquinolin-8-yl)acetate (1.20 g, 2.04 mmol, 94% yield, 97% purity) as brown oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.77-8.33 (m, 1.5H), 8.27-8.07 (m, 1.5H), 7.11-7.01 (m, 1H), 6.62- 6.49 (m, 1H), 5.08-4.58 (m, 1H), 4.37-4.24 (m, 1H), 3.90-3.73 (m, 1.5H), 3.64-3.59 (m, 2H), 3.50 (s, 0.5H), 3.26-3.10 (m, 1.5H), 2.81-2.62 (m, 2.5H), 1.86-1.40 (m, 5H), 1.37-1.31 (m, 9H), 1.02-0.75 (m, 17H). LC-MS (Method C): R _t = 0.861 min; MS (ESIpos): m/z = 571.4 [M+H] ⁺ . Procedure for preparation of tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-[[2-amino-2-oxo-1-(5,6,7,8- tetrahydroisoquinolin-8-yl)ethyl]carbamoyl]-6,6-dimethyl-3-a zabicyclo[3.1.0]hexane-3- carbonyl]-2,2-dimethyl-propyl]carbamate A solution of methyl 2-[[(1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dime thyl-butanoyl]- 6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-2-(5,6, 7,8-tetrahydroisoquinolin-8-yl)acetate (1.20 g, 2.04 mmol, 97% purity, 1.00 eq) was added to ammonia (7 M in methanol, 25 mL, 85.8 eq) at 25°C. After stirring at 25°C for 36 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (Instrument: 120g Flash; Column: Welch Ultimate XB_C1820-40μm; eluent A: water (0.1% NH ₃ ^H ₂ O), eluent B: acetonitrile; gradient: 0-10 min 0-60% B; flow 85 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to afford tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-[[2-amino-2-oxo-1-(5,6,7,8-tetrahydr oisoquinolin-8-yl)ethyl]carbamoyl]-6,6- dimethyl-3-azabicyclo[3.1.0] hexane-3-carbonyl]-2,2-dimethyl-propyl]carbamate (0.500 g, 0.890 mmol, 44% yield, 99% purity) as a white solid. LC-MS (Method D): R _t = 0.736 min; MS (ESIpos): m/z = 556.3 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-N-[2-amino -2- oxo-1-(5,6,7,8-tetrahydroisoquinolin-8-yl)ethyl]-6,6-dimethy l-3-azabicyclo[3.1.0]hexane-2- carboxamide A solution of tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-[[2-amino-2-oxo-1-(5,6,7,8-tetrahydr oisoquinolin-8-yl) ethyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-ca rbonyl]-2,2-dimethyl-propyl] carbamate (0.400 g, 0.712 mmol, 99% purity, 1.00 eq) was added to hydrochloric acid (4 M in dioxane, 8.00 mL, 44.9 eq) at 25°C. After stirring at 25°C for 2 h, the reaction mixture was concentrated under reduced pressure to afford (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-N-[2-amino -2-oxo-1-(5,6,7,8- tetrahydroisoquinolin-8-yl)ethyl]-6,6-dimethyl-3-azabicyclo[ 3.1.0]hexane-2-carboxamide (0.370 g, 0.677 mmol, 95% yield, 90% purity, hydrochloric acid salt) as a white solid. LC-MS (Method C): R _t = 0.732 min; MS (ESIpos): m/z = 456.0 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[2-amino-2-oxo-1-(5,6,7,8-tetrahydroisoquinolin -8- yl)ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)ami no] butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-N-[2-amino -2-oxo-1-(5,6,7,8- tetrahydroisoquinolin-8-yl)ethyl]-6,6-dimethyl-3-azabicyclo[ 3.1.0]hexane-2-carboxamide (0.370 g, 0.677 mmol, 90% purity, 1.00 eq, hydrochloric acid salt) in dichloromethane (10.0 mL) were added trifluoroacetic anhydride (284 mg, 1.35 mmol, 0.190 mL, 2.00 eq) and triethylamine (342 mg, 3.38 mmol, 0.470 mL, 5.00 eq) at 0°C. After stirring at 25°C for 16 h, the reaction mixture was concentrated under reduced pressure to afford (1R,2S,5S)-N-[2-amino-2-oxo-1-(5,6,7,8-tetrahydroisoquinolin -8-yl)ethyl]-3- [(2S)-3,3-dimethyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabi cyclo[3.1.0]hexane-2- carboxamide (0.500 g, 0.353 mmol, 52% yield, 39% purity) as a yellow solid. LC-MS (Method C): R _t = 0.960 min; MS (ESIpos): m/z = 552.3 [M+H] ⁺ . Procedure for preparation of CPD0084397 - (1R,2S,5S)-N-[cyano(5,6,7,8-tetrahydroisoquinolin- 8-yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl) amino] butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-[2-amino-2-oxo-1-(5,6,7,8-tetrahydroisoquinolin -8-yl) ethyl]-3-[(2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (383 mg, 0.271 mmol, 39% purity, 1.00 eq) in dichloromethane (10.0 mL) were added triethylamine (137 mg, 1.35 mmol, 0.190 mL, 5.00 eq) and trifluoroacetic anhydride (114 mg, 0.542 mmol, 0.0750 mL, 2.00 eq) at 0°C. After stirring at 25°C for 16 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , ethyl acetate) to give the crude product as a yellow oil. The crude product was purified by prep-HPLC (column: Phenomenex Synergi C18150*25mm* 10 μm; mobile phase: [water (FA)-ACN]; B%: 21%-41%, 10 min) to afford (1R,2S,5S)-N-[cyano(5,6,7,8-tetrahydroisoquinolin-8-yl)methy l]-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (28.40 mg, 0.0527 mmol, 19% yield, 99% purity) as a white solid. Preparation of CPD0084444 Procedure for preparation of 6-(benzhydrylideneamino)-5,7-dihydrocyclopenta[b]pyridine-6- carbonitrile A solution of sodium tert-butoxide (15.8 g, 164 mmol, 3.50 eq) and 2- (benzhydrylideneamino)acetonitrile (11.4 g, 51.8 mmol, 1.10 eq) in anhydrous tetrahydrofuran (400 mL) was stirred at 0°C. After stirring for 0.1 h, 2,3-bis(chloromethyl)pyridine (10.0 g, 47.1 mmol, 1.00 eq, hydrochloric acid salt) was added to the mixture above. After stirring at 0°C for 0.5 h under nitrogen atmosphere, the reaction mixture was poured into saturated ammonium chloride aqueous solution (200 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 3/1 to 2/1) to give 6-(benzhydrylidene amino)-5,7-dihydrocyclopenta[b] pyridine-6-carbonitrile (2.60 g, 5.63 mmol, 12% yield, 70% purity) as light yellow oil. LC-MS (Method C): R _t = 0.869 min; MS (ESIpos): m/z = 324.1 [M+H] ⁺ . Procedure for preparation of 6-amino-5,7-dihydrocyclopenta[b]pyridine -6-carboxamide A mixture of tert-butyl N-[3-chloro-5-[2-(4-isoquinolylamino)-2-oxo-ethyl]phenyl]car bamate (200 mg, 486 μmol, 1.00 eq) in hydrochloric acid (4M in dioxane, 5.00 mL, 20.0 mmol) was stirred at 25°C for 12 h. The reaction mixture was diluted with water (10.0 mL) and washed with ethyl acetate (20.0 mL). Ammonium hydroxide (10% in water) was added to the aqueous layer to adjust pH~8. The solution was lyophilized to give 2-(3-amino-5-chloro -phenyl)-N-(4-isoquinolyl)acetamide (145 mg, 372 μmol, 77% yield, 80% purity) as a brown solid. LC-MS (Method J): Rt = 0.267 min; MS (ESIpos): m/z = 178.1 [M+H] ⁺ . Procedure for preparation of 6-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl- 2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carbonyl]amino]-5,7- dihydrocyclopenta[b]pyridine-6-carboxamide A solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl] -6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (120 mg, 329 μmol, 1.00 eq), O-(7-azabenzotriazol-1-yl) - N,N,N,N-tetramethyluroniumhexafluorophosphate (187 mg, 494 μmol, 1.50 eq) and N,N- diisopropylethylamine (127 mg, 988 μmol, 3.00 eq) in N,N-dimethylformamide (2.00 mL) was stirred at 25°C. After stirring for 0.1 h, 6-amino-5,7-dihydrocyclopenta[b]pyridine-6-carboxamide (110 mg, 362 μmol, 70% purity, 1.10 eq, hydrochloric acid) was added. After stirring at 25°C for 12 h, the reaction mixture was diluted with saturated ammonium chloride aqueous solution (20.0 mL) and extracted with ethyl acetate (20.0 mL × 2). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , dichloromethane: methanol = 10: 1) to give 6-[[(1R,2S,5S)-3- [(2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carbonyl] amino]-5,7-dihydrocyclopenta[b]pyridine-6-carboxamide (60.0 mg, 97.4 μmol, 30% yield, 85% purity) as a white solid. LC-MS (Method M): R _t = 0.84 min; MS (ESIpos): m/z = 426.3 [M+H] ⁺ . Procedure for preparation of CPD0084444 - (1R,2S,5S)- N-(6-cyano-5,7–dihydro cyclopenta[b]pyridin-6-yl)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-tr ifluoroacetyl)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of 6-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacety l)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-5,7-dih ydrocyclopenta[b]pyridine-6- carboxamide (50.0 mg, 95.5 μmol, 1.00 eq) in dichloromethane (2.00 mL) was added Burgess reagent (68.3 mg, 286 μmol, 3.00 eq) at 0°C. After stirring stirred at 25°C for 0.5 h, the mixture was poured into saturated ammonium chloride (5.00 ml) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm*10 μm; mobile phase: [water(FA)-acetonitrile]; B%:32%-62%,10 min) to give (1R,2S,5S)-N-(6-cyano-5,7- dihydrocyclopenta[b]pyridin-6-yl)-3-[(2S)-3,3-dimethyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabi cyclo[3.1.0]hexane-2-carboxamide (11.5 mg, 20.5 μmol, 22% yield, 91% purity) as a white solid. Preparation of CPD0084445 Procedure for preparation of methyl 2-[[(1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3- dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carbonyl]amino]-3-(2- pyridyl)butanoate To a solution of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl -butanoyl] -6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.60 g, 4.33 mmol, 1.00 eq) in N,N-dimethylformamide (20.0 mL) were added N,N-diisopropylethylamine (1.68 g, 13.0 mmol, 3.00 eq) and O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (1.98 g, 5.20 mmol, 1.20 eq) at 25°C. After stirring at 25°C for 0.25 h, the mixture was cooled to 0°C, methyl 2-amino-3-(2- pyridyl)butanoate (1.00 g, 4.33 mmol, 1.00 eq, HCl) was added. After stirring at 25°C for 16 h, the mixture was poured into saturated ammonium chloride aqueous solution (50 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~50% ethyl acetate/petroleum ether gradient @40 mL/min) to afford methyl 2-[[(1R,2S,5S)-3-[(2S)-2- (tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimeth yl-3-azabicyclo[3.1.0]hexane-2- carbonyl]amino]-3-(2-pyridyl)butanoate (1.70 g, 2.97 mmol, 68% yield, 95% purity) as gray oil. LC-MS (Method C): R _t = 1.057,1.067 min; MS (ESIpos): m/z = 545.1 [M+H] ⁺ . Procedure for preparation of tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-[[1-carbamoyl-2-(2- pyridyl)propyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]he xane-3-carbonyl]-2,2-dimethyl- propyl]carbamate A solution of methyl 2-[[(1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dime thyl-butanoyl] -6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-3-(2-py ridyl)butanoate (1.70 g, 3.12 mmol, 1.00 eq) in ammonia/methanol (19 M, 20.0 mL) was stirred at 25°C for 16 h. The reaction mixture was concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®;20 g SepaFlash® Silica Flash Column, Eluent of 0~100% ethyl acetate/petroleum ether gradient @40 mL/min) to give tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-[[1- carbamoyl-2-(2-pyridyl)propyl] carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-3-carbonyl]-2,2-dimethyl-propyl]carbamate (800 mg, 1.43 mmol, 46% yield, 95% purity) as yellow oil. LC-MS (Method C): R _t = 0.562 min; MS (ESIpos): m/z = 530.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-N-[1-carba moyl- 2-(2-pyridyl)propyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide A solution of tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-[[1-carbamoyl-2-(2-pyridyl)propyl]ca rbamoyl] -6,6- dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl- propyl]carbamate (750 mg, 1.42 mmol, 1.00 eq) in hydrogen chloride (4.00 M in 1,4-dioxane, 20.0 mL) was stirred at 25°C for 2 h. The reaction mixture was concentrated to give (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-N-[1-carba moyl - 2-(2-pyridyl)propyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide (600 mg, 1.40 mmol, 98% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.87-8.62 (m, 1H), 8.58-8.32 (m, 1H), 8.28-8.01 (m, 3H), 7.98-7.55 (m, 2H), 7.51-7.19 (m, 1H), 4.88-4.61 (m, 1H), 4.41-4.20 (m, 1H), 3.95-3.87 (m, 1H), 3.83-3.75 (m, 3H), 1.60-1.41 (m, 1H), 1.38-1.25 ( m, 3H), 1.24-1.12 m, 1H), 1.11-0.50 (m, 15H). Procedure for preparation of CPD0084445 - (1R,2S,5S)-N-[1-cyano-2-(2-pyridyl)propyl]-3-[(2S)- 3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-d imethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide To a mixture of (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-N-[1-carba moyl-2-(2-pyridyl)propyl] -6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (300 mg, 698 μmol, crude purity, 1.00 eq) and triethylamine (353 mg, 3.49 mmol, 486 μL, 5.00 eq) in dichloromethane (6.00 mL) was added trifluoroacetic anhydride (293 mg, 1.40 mmol, 2.00 eq) dropwise at 0°C. The mixture was stirred at 25°C for 1 h. Saturated sodium bicarbonate (20.0 mL) was added to the reaction mixture to adjust pH = 9. The aqueous phase was extracted with ethyl acetate (50.0 mL × 2). The combined organic layers were washed with brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®;12 g SepaFlash® Silica Flash Column, Eluent of 0~60% ethyl acetate/petroleum ether gradient @ 40 mL/min) to afford (1R,2S,5S)-N-[1-cyano-2-(2-pyridyl)propyl]-3-[(2S)-3,3-dimet hyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (13.22 mg, 25.9 μmol, 4% yield, 99% purity) as a white solid. Preparation of CPD0084675 Procedure for preparation of methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3- dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-c arboxylate To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (10.0 g, 43.2 mmol, 1.00 eq) 4-methylmorpholine (10.9 g, 108 mmol, 594 μL, 2.50 eq) and benzotriazol-1-yloxy(tripyrrolidin-1-yl) phosphanium; hexafluorophosphate (24.8 g, 47.6 mmol, 1.10 eq) in dichloromethane (100 mL) was added methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (9.34 g, 45.4 mmol, 1.05 eq, hydrochloric acid salt). After stirring at 25°C for 12 h, the reaction mixture was poured into ammonium chloride aqueous solution (200 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 5/1) to afford methyl (1R,2S,5S)-3-((S)- 2-((tert-butoxycarbonyl) amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ] hexane-2- carboxylate (14.5 g, 37.9 mmol, 88% yield) as colorless oil. ¹ H NMR (400 MHz, CD ₃ OD) δ = 6.44 (d, J = 8.0 Hz, 1H), 4.37 (s, 1H), 4.22 (d, J = 9.6 Hz, 1H), 4.06- 4.01 (m, 1H), 3.97-3.89 (m, 1H), 3.75 (s, 3H), 1.61-1.57 (m, 1H), 1.51-1.49 (m, 1H), 1.43 (s, 9H), 1.09 (s, 3H), 1.03 (s, 9H), 0.95 (s, 3H). Procedure for preparation of (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3- dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-c arboxylic acid To a mixture of methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethy lbutanoyl)-6,6 - dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (10.0 g, 26.1 mmol, 1.00 eq) in tetrahydrofuran (30.0 mL) and methanol (30.0 mL) was added a solution of lithium hydroxide monohydrate (2.19 g, 52.3 mmol, 2.00 eq) in water (30.0 mL) at 0°C. After stirring at 0°C for 6 h, hydrochloric acid (0.5 M) was added to the reaction mixture to adjust pH = 5~6 and extracted with ethyl acetate (100 mL × 4). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with methyl tert-butyl ether (40.0 mL). After filtration, the filter cake was collected and dried under vacuum to give (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethy lbutanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (5.30 g, 14.1 mmol, 54% yield, 98% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.62 (s, 1H), 6.68 (d, J = 9.6 Hz, 1H), 4.13 (s, 1H), 4.06 (d, J = 9.6 Hz, 1H), 3.95-3.88 (m, 1H), 3.82-3.73 (m, 1H), 1.56-1.46 (m, 1H), 1.44-1.31 (m, 10H), 1.01 (s, 3H), 0.94 (s, 9H), 0.85 (s, 3H). Procedure for preparation of methyl (1R,2S,5S)-3-((S)-2-amino-3,3-dimethylbutanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate A solution of methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethy lbutanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (3.00 g, 7.84 mmol, 1.00 eq) in trifluoroacetic acid (10.0 mL) and dichloromethane (50.0 mL) was stirred at 25°C for 1 h. Saturated sodium bicarbonate solution was added to the mixture to adjust pH~7 and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (40.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give methyl (1R,2S,5S)-3-((S)-2-amino-3,3-dimethylbutanoyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (2.1 g, 5.65 mmol, 72% yield, 76% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 6.38-5.35 (m, 2H), 4.24 (s, 1H), 3.81-3.74 (m, 1H), 3.71-3.67 (m, 1H), 3.66 (s, 3H), 3.56 (s, 1H), 1.02 (s, 3H), 0.97 (s, 9H), 0.92 (s, 3H). Procedure for preparation of methyl (1R,2S,5S)-3-((S)-3,3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxylate To a mixture of methyl (1R,2S,5S)-3-((S)-2-amino-3,3-dimethylbutanoyl)-6,6-dimethyl -3- azabicyclo[3.1.0]hexane-2-carboxylate (2.10 g, 7.44 mmol, 1.00 eq), N,N-diisopropylethylamine (2.88 g, 22.3 mmol, 3.00 eq) in dichloromethane (50.0 mL) was added trifluoroacetic anhydride (1.72 g, 8.18 mmol, 1.1 eq) at 0°C. After stirring at 25°C for 1 h under nitrogen atmosphere, the reaction mixture was poured into saturated ammonium chloride (20.0 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (50.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 3/1) to afford methyl (1R,2S,5S)-3-((S)- 3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxylate (2.95 g, 4.76 mmol, 64% yield, 61% purity) as colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.45 (d, J = 8.4 Hz, 1H), 4.42 (d, J = 8.4 Hz, 1H), 4.22 (s, 1H), 3.89- 3.83 (m, 1H), 3.77-3.73 (m, 1H), 3.66 (s, 3H), 1.47-1.43 (m, 1H), 1.25-1.20 (m, 1H), 1.01-0.99 (m, 12H), 0.83 (s, 3H). Procedure for preparation of (1R,2S,5S)-3-((S)-3,3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxylic acid To a mixture of methyl (1R,2S,5S)-3-((S)-2-amino-3,3-dimethylbutanoyl)-6,6-dimethyl -3- azabicyclo[3.1.0] hexane-2-carboxylate (2.95 g, 7.80 mmol, 1.00 eq) in a mixed solvent of methanol (10.0 mL) and tetrahydrofuran (10.0 mL) was added a solution of lithium hydroxide monohydrate (654 mg, 15.6 mmol, 2.00 eq) in water (10.0 mL) at 0°C. After stirring at 20°C for 2 h, hydrochloric acid solution (1M) was added to the mixture to adjust pH~7 and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (30.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 3/1 to 1/1) to afford (1R,2S,5S)-3-((S)-3,3- dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.0 g, 2.72 mmol, 35% yield, 99% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.71 (s, 1H), 9.56-9.37 (m, 1H), 4.49-4.39 (m, 1H), 4.15 (d, J = 2.8 Hz, 1H), 3.87-3.82 (m, 1H), 3.74-3.70 (m, 1H), 1.56-1.50 (m, 1H), 1.45-1.40 (m, 1H), 1.03-0.99 (m, 12H), 0.83-0.81 (m, 3H). Procedure for preparation of 2-amino-2-(1,3-benzothiazol-5-yl)acetonitrile To a solution of 1,3-benzothiazole-5-carbaldehyde (100 mg, 0.613 mmol, 1.00 eq) in methanol (2.00 mL) and ammonia (7.00 M in methanol, 0.438 mL, 5.00 eq) was added dropwise titanium (IV) isopropoxide (209 mg, 0.735 mmol, 1.20 eq) at 20 ^. After stirring at 20°C for 2 h, trimethylsilyl cyanide (73.0 mg, 0.735 mmol, 1.20 eq) was added dropwise at 20 ^ to the reaction mixture above. After addition, the mixture was stirred at 20°C for 14 h. The reaction mixture was quenched with saturated sodium bicarbonate solution (20.0 mL) and extracted with ethyl acetate (15.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (100~200 mesh, petroleum ether then petroleum ether/ethyl acetate = 2/1) to afford 2- amino-2-(1,3-benzothiazol-5-yl)acetonitrile (75.0 mg, 396 μmol, 65% yield) as yellow oil. LC-MS (Method K): R _t = 0.640 min; MS (ESIpos): m/z = 190.1 [M+H] ⁺ . Procedure for preparation of CPD0084675 - (1R,2S,5S)-N-[1,3-benzothiazol-5-yl(cyano)methyl]- 3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoy l]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide A mixture of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (144 mg, 0.396 mmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (226 mg, 0.594 mmol, 1.50 eq) and N,N-diisopropyl ethylamine (154 mg, 1.19 mmol, 3.00 eq) in N,N-dimethylformamide (2.00 mL) was stirred at 25°C for 0.1 h, followed by 2-amino-2-(1,3-benzothiazol-5-yl)acetonitrile (75.0 mg, 0.396 mmol, 1.00 eq). After stirring at 25°C for 16 h, the reaction mixture was poured into water (20.0 mL) and extracted with ethyl acetate (15.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (FA condition; column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 41%-71%,10 min) to give (1R,2S,5S)-N-[1,3-benzothiazol- 5-yl(cyano)methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroa cetyl)amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (61.9 mg, 115 μmol, 29% yield, 99% purity) as a white solid. Preparation of CPD0084676 Procedure for preparation of amino-2-pyrazolo[1,5-a]pyridin-3-yl-acetonitrile To a mixed solvent solution of pyrazolo[1,5-a]pyridine-3-carbaldehyde (400 mg, 2.74 mmol, 1.00 eq) in methanol (10.0 mL) and ammonia (7.00 M in methanol, 1.95 mL, 5.00 eq) was added dropwise titanium(IV) isopropoxide (934 mg, 3.28 mmol, 1.20 eq). After stirring at 20°C for 1 h, trimethylsilyl cyanide (326 mg, 3.28 mmol, 0.41 mL, 1.20 eq) was added dropwise. After addition, the mixture was stirred at 20°C for 2 h. The reaction mixture was quenched with saturated sodium bicarbonate solution (30.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (100~200 mesh, dichloromethane) to afford 2-amino-2-pyrazolo[1,5-a]pyridin-3-yl-acetonitrile (200 mg, 1.16 mmol, 42% yield) as a black brown solid. LC-MS (Method P): R _t = 0.382 min; MS (ESIpos): m/z = 173.2 [M+H] ⁺ . Procedure for preparation of CPD0084676 - (1R,2S,5S)-N-[cyano(pyrazolo[1,5-a]pyridin-3- yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide A mixture of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (423 mg, 1.16 mmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (663 mg, 1.74 mmol, 1.50 eq), N,N- diisopropylethylamine (451 mg, 3.48 mmol, 3.00 eq) in N,N-dimethylformamide (6.00 mL) was stirred at 25°C for 0.1 h, and then 2-amino-2-pyrazolo[1,5-a]pyridin-3-yl-acetonitrile (200 mg, 1.16 mmol, 1.00 eq) was added. After stirring at 25°C for 16 h, the reaction mixture was poured into water (40.0 mL) and extracted with ethyl acetate (25.0 mL × 3). The combined organic layers were washed with brine (40.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Luna C18 200*40mm*10um;mobile phase: [water(FA)-ACN]; B%: 40%-70%,10 min) to give (1R,2S,5S)-N- [cyano(pyrazolo[1,5-a]pyridin-3-yl)methyl]-3-[(2S)-3,3-dimet hyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (284 mg, 0.51 mmol, 44% yield, 93% purity) as a yellow solid. Preparation of CPD0084677 Procedure for preparation of bromo-4-isopropoxypyridine A mixture of 3-bromopyridin-4-ol (5.00 g, 28.74 mmol, 1.00 eq), 2-iodopropane (15.0 g, 88.2 mmol, 3.07 eq) and potassium carbonate (10.0 g, 72.4 mmol, 2.52 eq) in N,N-dimethylformamide (70.0 mL) was stirred at 80°C for 16 h. The mixture was filtered and concentrated under reduced pressure to afford a residue. The residue was triturated with ethyl acetate/dichloromethane (v/v = 1/1, 50.0 mL). The filtrate was concentrated under reduced pressure to afford a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to ethyl acetate, then ethyl acetate/ methanol = 50/1 to 8/1) to give 3-bromo-4-isopropoxypyridine (1.6 g, 7.40 mmol, 26% yield) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.58 (s, 1H), 8.35 (d, J = 5.6 Hz, 1H), 6.80 (d, J = 5.6 Hz, 1H), 4.74-4.65 (m, 1H), 1.43 (d, J = 6.0 Hz, 6H) Procedure for preparation of isopropoxynicotinaldehyde Isopropylmagnesium chloride-lithium chloride complex (1.30 M, 1.50 mL, 2.11 eq) was added dropwise to a solution of 3-bromo-4-isopropoxy-pyridine (0.200 g, 925 μmol, 1.00 eq) in tetrahydrofuran (4.00 mL) under nitrogen at 5°C. After addition, a solution of anhydrous N,N-dimethylformamide (190 mg, 2.60 mmol, 2.81 eq) in tetrahydrofuran (1.00 mL) was added. After stirring at 20°C for 1 h., the reaction was quenched with saturated aqueous ammonium chloride (10.0 mL), extracted with ethyl acetate (10.0 mL × 2). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-isopropoxypyridine-3-carbaldehyde (190 mg, crude) as yellow oil and used directly without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 10.48 (s, 1H), 8.89 (s, 1H), 8.59 (d, J = 5.6 Hz, 1H), 6.89 (d, J = 5.6 Hz, 1H), 4.83-4.73 (m, 1H), 1.46 (d, J = 6.0 Hz, 6H). LC-MS (Method A): R _t = 0.193 min; MS (ESIpos): m/z = 184.1 [M+H ₂ O+H] ⁺ Procedure for preparation of amino-2-(4-isopropoxypyridin-3-yl)acetonitrile To a solution of 4-isopropoxypyridine-3-carbaldehyde (190 mg, 1.15 mmol, 1 eq) in a mixed solution of anhydrous methanol (4 mL) and ammonia (7 M, 0.900 mL, 5.48 eq) was added dropwise titanium(IV) isopropoxide (400 mg, 1.41 mmol, 1.22 eq) at 5°C. After stirring at 25°C for 2 h, trimethylsilyl cyanide (140 mg, 1.41 mmol, 1.23 eq) was added dropwise to the reaction mixture above at 5°C. After addition, the mixture was stirred at 25°C for 1 h. The reaction mixture was quenched with saturated sodium bicarbonate solution (5.00 mL), and extracted with ethyl acetate (5.00 mL × 3). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Biotage, SiO ₂ , petroleum ether/ethyl acetate = 1/1 to 1/2) to give 2-amino-2-(4- isopropoxypyridin-3-yl)acetonitrile (0.150 g, 784 μmol, 68% yield) as a white solid. LC-MS (Method A): R _t = 0.417 min; MS (ESIpos): m/z = 192.2 [M+H] ⁺ Procedure for preparation of CPD0084677 - (1R,2S,5S)-N-(cyano(4-isopropoxypyridin-3- yl)methyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)b utanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (229 mg, 627 μmol, 1 eq) in N,N-dimethylformamide (3 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyl uroniumhexafluorophosphate (330 mg, 868 μmol, 1.38 eq) and N,N-diisopropyl ethylamine (267 mg, 2.07 mmol, 3.29 eq). After stirring at 25°C for 0.5 h, 2-amino-2-(4-isopropoxy-3-pyridyl)acetonitrile (0.15 g, 628 μmol, 80% purity, 1.00 eq) was added to the mixture above. After stirring at 25°C for 16 h, the mixture was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 22%-52%, 10min) to give (1R,2S,5S)-N-[cyano-(4-isopropoxy-3-pyridyl)methyl]-3-[(2S)- 3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (118 mg, 220 μmol, 35% yield) as a white solid. Preparation of CPD0084678 Procedure for preparation of amino-2-imidazo[1,5-a]pyridin-1-yl-acetonitrile To a solution of 1,3-benzothiazole-5-carbaldehyde (500 mg, 3.42 mmol, 1.00 eq) in methanol (10.0 mL) and ammonia (7.00 M in methanol, 2.44 mL, 5.00 eq) was added dropwise titanium (IV) isopropoxide (1.17 g, 4.11 mmol, 1.20 eq) 20 ^. After stirring at 20°C for 1 h, trimethylsilyl cyanide (407 mg, 4.11 mmol, 1.20 eq) was added dropwise at 20°C. After addition, the mixture was stirred at 20°C for 14 h. The reaction mixture was quenched with saturated sodium bicarbonate solution (20.0 mL) and extracted with ethyl acetate (15.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (100~200 mesh, dichloromethane) to afford 2-amino-2-imidazo[1,5-a]pyridin-1-yl-acetonitrile (300 mg, 1.74 mmol, 51% yield) as black brown oil. LC-MS (Method P): R _t = 0.350 min; MS (ESIpos): m/z = 173.2 [M+H] ⁺ . Procedure for preparation of CPD0084678 - (1R,2S,5S)-N-[cyano(imidazo[1,5-a]pyridin-1- yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide A mixture of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (635 mg, 1.74 mmol, 1.00 eq) , O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (994 mg, 2.61 mmol, 1.50 eq) and N, N- diisopropylethylamine (676 mg, 5.23 mmol, 3.00 eq) in N,N-dimethylformamide (6.00 mL) was stirred at 25°C for 0.1 h, and then 2-amino-2-imidazo[1,5-a]pyridin-1-yl-acetonitrile (300 mg, 1.74 mmol, 1.00 eq) was added. After stirring at 25°C for 16 h, the reaction mixture was poured into water (40.0 mL) and then extracted with ethyl acetate (25.0 × 3 mL). The combined organic layers were washed with brine (40.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (FA condition; column: Phenomenex Luna C18 200*40mm*10 μm; mobile phase: [water(FA)-ACN];B%: 40%-70%,10min) to give (1R,2S,5S)-N-[cyano(imidazo[1,5-a]pyridin-1-yl)methyl]-3-[(2 S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (253 mg, 0.47 mmol, 28% yield, 99% purity) as a yellow solid. Preparation of CPD0084679 Procedure for preparation of 2-amino-2-(benzo[d]thiazol-4-yl)acetonitrile To a solution of 1,3-benzothiazole-4-carbaldehyde (500 mg, 3.06 mmol, 1.00 eq) in methanol (10 mL) were added tetraisopropoxytitanium (1.04 g, 3.68 mmol, 1.20 eq) and ammonia (7 M in methanol, 5.00 mL, 11.4 eq). After stirring at 25°C for 2 h, trimethylcyanosilane (365 mg, 3.68 mmol, 1.20 eq) was added dropwise to the reaction mixture. After addition, the mixture was stirred at 25°C for 5 h. The reaction mixture was poured into water and filtered. The filtrate was concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~80% ethyl acetate/petroleum ether gradient @ 45 mL/min) to give 2-amino- 2-(1,3-benzothiazol-4-yl)acetonitrile (121 mg, 0.639 mmol) as a yellow solid. ¹ H NMR (400 MHZ, DMSO-d ₆ ) δ = 9.51 (s, 1H), 8.23-8.18 (m, 1H), 7.73-7.70 (m, 1H), 7.58-7.56 (m, 1H), 5.62 (s, 1H), 3.03 (s, 2H). Procedure for preparation of (1R,2S,5S)-N-(benzo[d]thiazol-4-yl(cyano)methyl)-3-((S)-3,3- dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2- carboxamide CPD0084679 To a solution of 2-amino-2-(1,3-benzothiazol-4-yl)acetonitrile (100 mg, 0.528 mmol, 1.00 eq) in N,N- dimethylformamide (2.00 mL) were added (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxylic acid (193 mg, 0.528 mmol, 1.00 eq), N,N-dimethylformamide (205 mg, 1.59 mmol, 3.00 eq) and O-(7-azabenzotriazol- 1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (301 mg, 0.793 mmol, 1.50 eq). After stirring at 25°C for 1 h, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20.0 mL × 2). The combined organic layers were washed with saturated ammonium chloride aqueous solution (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (petroleum ether: ethyl acetate = 1: 1) and preparative HPLC (column: Waters Xbridge 150×25mm ×5um;mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 50%-80%, 8min) to give (1R,2S,5S)-N-[1,3-benzothiazol-4-yl(cyano)methyl]-3- [(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino] butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (6.47 mg, 12.0 μmol, 2% yield, 99% purity) as a white solid. Preparation of CPD0084680 Procedure for preparation of 2-amino-2-(3-pyridyl)acetonitrile To a solution of pyridine-3-carbaldehyde (5.00 g, 46.7 mmol, 1.00 eq) in methanol (20.0 mL) and ammonia (7.00 M in methanol, 134 mL) was added titanium (IV) isopropoxide (15.9 g, 56.0 mmol, 16.5 mL, 1.2 eq) at 20°C. After stirring at 25°C for 1 h, trimethylsilylformonitrile (5.56 g, 56.0mmol, 7.01 mL, 1.20 eq) was added dropwise at 20°C. After addition, the resulting mixture was stirred at 20°C for 12 h. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (50.0 mL) and extracted with ethyl acetate (150 mL × 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=2/1 to ethyl acetate) to give 2-amino-2-(3-pyridyl)acetonitrile (1.00 g, 7.13 mmol, 15% yield, 95% purity) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.81 (d, J = 1.6 Hz, 1H), 8.65 (dd, J = 4.0, 1.6 Hz, 1H 1H), 7.97-7.86 (m, 1H), 7.43-7.31 (m, 1H), 4.98 (s, 1H), 1.98 (s, 2H). LC-MS (Method C): R _t = 0.140 min; MS (ESIpos): m/z = 134.0 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[cyano(3-pyridyl)methyl]-3-[(2S)-3,3-dimethyl-2 - [(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabi cyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (149 mg, 410 μmol, 1.00 eq) and N,N- diisopropylethylamine (159 mg, 1.23 mmol, 3.00 eq) in N,N-dimethylformamide (1.00 mL) was added O-(7-azabenzotriazol-1-yl) -N,N,N,N-tetramethyluroniumhexafluorophosphate (234 mg, 614 μmol, 1.50 eq). After addition, the mixture was stirred at 25°C for 0.1 h, and 2-amino-2-(3-pyridyl) acetonitrile (60.0 mg, 451 μmol, 1.10 eq) was added. After stirring at 25°C for 12 h, the reaction mixture was diluted with saturated ammonium chloride aqueous solution (20.0 mL) and extracted with ethyl acetate (20.0 mL × 2). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column : PhenomenexlunaC18150*25mm10 μm; mobile phase:[water(FA)-ACN]; B%: 42%-72%,10 min) to give (1R,2S,5S)-N-[cyano(3-pyridyl)methyl]-3-[(2S)-3,3-dimethyl-2 -[(2,2,2- trifluoroacetyl) amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-car boxamide (30.0 mg, 59.4 μmol, 15% yield, 95% purity) as a white solid. Preparation of CPD0084769 Procedure for preparation of methyl (2S,4S)-4-methoxypyrrolidine-2-carboxylate To a solution of O1-tert-butyl O2-methyl (2S,4S)-4-methoxypyrrolidine-1,2-dicarboxylate (2.00 g, 7.71 mmol, 1.00 eq) in dichloromethane (5.00 mL) was added hydrochloric acid (4 M in ethyl acetate, 5.00 mL, 2.59 eq) at 25°C. After stirring at 25°C for 1 h, the reaction mixture was filtered. The filter cake was dried under reduced pressure to afford methyl (2S,4S)-4-methoxypyrrolidine-2-carboxylate (1.10 g, 5.62 mmol, 73% yield, hydrochloric acid salt) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 4.52 (dd, J = 8.4, 4.8 Hz, 1H), 4.15-4.03 (m, 1H), 3.75 (s, 3H), 3.35 (s, 3H), 3.31 (s, 1H), 3.28-3.21 (m, 1H), 2.37-2.25 (m, 2H). Procedure for preparation of methyl (2R,4S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl- butanoyl]-4-methoxy-pyrrolidine-2-carboxylate To a solution of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid (1.56 g, 6.75 mmol, 1.20 eq) in N,N-dimethylformamide (20.0 mL) were added N,N-diisopropylethylamine (2.91 g, 22.5 mmol, 3.90 mL, 4.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (3.21 g, 8.43 mmol, 1.50 eq) at 0°C. After stirring at this temperature for 12 min, methyl (2S,4S)-4- methoxypyrrolidine-2-carboxylate (1.10 g, 5.62 mmol, 1.00 eq, hydrochloric acid) was added at 0°C. The resulting mixture was stirred at 25°C for 16 h. The reaction mixture was diluted with water (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (20.0 mL × 3), dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1 to 1/1) to afford methyl (2R,4S)-1-[(2S)-2-(tert- butoxycarbonylamino)-3,3-dimethyl-butanoyl]-4-methoxy-pyrrol idine-2-carboxylate (2.10 g, 5.36 mmol, 95% yield, 95% purity) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 6.59 (d, J = 8.8 Hz, 1H), 4.49 (dd, J = 8.8, 4.0 Hz, 1H), 4.13 (d, J = 8.8 Hz, 1H), 4.09-3.96 (m, 2H), 3.90 (dd, J = 10.4, 5.2 Hz, 1H), 3.58 (s, 3H), 3.19 (s, 3H), 2.35-2.25 (m, 1H), 2.05-1.99 (m, 1H), 1.37 (s, 9H), 0.98 (s, 9H). LC-MS (Method C): R _t = 0.871 min; MS (ESIpos): m/z = 373.0 [M+H] ⁺ . Procedure for preparation of (2R,4S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl- butanoyl]-4-methoxy-pyrrolidine-2-carboxylic acid To a solution of methyl (2R,4S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-bu tanoyl]-4- methoxy-pyrrolidine-2-carboxylate (2.10 g, 5.36 mmol, 95% purity, 1.00 eq) in tetrahydrofuran (10.0 mL) and water (10.0 mL) was added lithium hydroxide monohydrate (449 mg, 10.7 mmol, 2.00 eq) at 25°C. After stirring at 25°C for 16 h, the reaction mixture was concentrated under reduced pressure to remove the organic solvent. Formic acid was added to adjust pH = 1~2 and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (20.0 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (2R,4S)-1-[(2S)-2-(tert- butoxycarbonylamino)-3,3-dimethyl-butanoyl]-4-methoxy-pyrrol idine-2-carboxylic acid (2.00 g, 5.30 mmol, 99% yield, 95% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 6.35 (d, J = 8.8 Hz, 1H), 4.18 (dd, J = 9.2, 4.8 Hz, 1H), 4.02-3.68 (m, 4H), 3.35-3.28 (m, 1H), 3.02 (s, 3H), 2.17-2.08 (m, 1H), 1.80-1.74 (m, 1H), 1.18 (s, 9H), 0.78 (s, 9H). LC-MS (Method C): R _t = 0.833 min; MS (ESIpos): m/z = 358.9 [M+H] ⁺ . Procedure for preparation of (2S,4S)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-methoxy- pyrrolidine-2-carboxylic acid To a solution of (2R,4S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-bu tanoyl]-4-methoxy- pyrrolidine-2-carboxylic acid (2.00 g, 5.30 mmol, 95% purity, 1.00 eq) in dichloromethane (10.0 mL) was added hydrochloric acid (4 M in ethyl acetate, 9.50 mL, 7.20 eq) at 25°C. After stirring at 25°C for 1 h, the reaction mixture was concentrated under reduced pressure to give a residue. The crude product was triturated with ethyl acetate (10.0 mL) and filtered. The filter cake was dried under reduced pressure to afford (2S,4S)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-methoxy-pyr rolidine-2-carboxylic acid (1.60 g, 5.16 mmol, 97% yield, 95% purity, hydrochloric acid salt) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.28 (d, J = 3.2 Hz, 3H), 4.43 (dd, J = 9.2, 4.8 Hz, 1H), 4.08-3.98 (m, 2H), 3.88-3.82 (m, 1H), 3.50-3.44 (m, 1H), 3.21 (s, 3H), 2.38-2.23 (m, 1H), 2.07-1.97 (m, 1H), 1.05 (s, 9H). Procedure for preparation of (2S,4S)-1-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-4-methoxy-pyrrolidine-2-carb oxylic acid To a solution of (2S,4S)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-methoxy-pyr rolidine-2-carboxylic acid (1.60 g, 5.88 mmol, 95% purity, 1.00 eq) in methanol (20.0 mL) were added triethylamine (2.38 g, 23.5 mmol, 3.30 mL, 4.00 eq) and methyl 2,2,2-trifluoroacetate (1.13 g, 8.83 mmol, 0.890 mL, 1.50 eq) at 25°C. After stirring at 25°C for 16 h, the reaction mixture was concentrated under reduced pressure to afford (2S,4S)-1-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino ]butanoyl]-4-methoxy-pyrrolidine- 2-carboxylic acid (2.30 g, 5.58 mmol, 95% yield, 86% purity) as an off-white solid. LC-MS (Method C): R _t = 0.786 min; MS (ESIpos): m/z = 354.8 [M+H] ⁺ . Procedure for preparation of (2S,4S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-1-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroace tyl)amino] butanoyl]-4-methoxy- pyrrolidine-2-carboxamide To a solution of (2S,4S)-1-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino ]butanoyl]-4-methoxy- pyrrolidine-2-carboxylic acid (0.500 g, 1.21 mmol, 86% purity, 1.00 eq) in dichloromethane (10.0 mL) were added N,N-diisopropylethylamine (627 mg, 4.85 mmol, 0.845 mL, 4.00 eq) and O-(7- azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (692 mg, 1.82 mmol, 1.50 eq) at 0°C. After stirring at this temperature for 12 min, (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3- yl]propanamide (302 mg, 1.46 mmol, 1.20 eq, hydrochloric acid salt) was added at 0°C. After stirring at 25°C for 16 h, the reaction mixture was used for the next step reaction without further purification. LC-MS (Method C): R _t = 0.770 min; MS (ESIpos): m/z = 508.0 [M+H] ⁺ . Procedure for preparation of CPD0084769 - (2S,4S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]-1-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)ami no]butanoyl]-4-methoxy-pyrrolidine-2- carboxamide To a solution of (2S,4S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl] methyl]ethyl]-1-[(2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-4-methoxy -pyrrolidine-2-carboxamide (0.400 g, 788 μmol, 1.00 eq) in dichloromethane (3.00 mL) was added Burgess reagent (563 mg, 2.36 mmol, 3.00 eq) at 25°C. After stirring at 25°C for 16 h, the reaction mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (10.0 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 22%-52%,10 min) to afford (2S,4S)-N-[(1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]-1-[(2S)-3,3-dimethyl-2-[(2,2,2-tri fluoroacetyl)amino]butanoyl]-4-methoxy- pyrrolidine-2-carboxamide (175 mg, 353 μmol, 45% yield, 99% purity) as an off-white solid. Preparation of CPD0085272 Procedure for preparation of 7-(2,2-diethoxyethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine To a mixture of 6,7-dihydro-5H-cyclopenta[b]pyridine (3.00 g, 25.2 mmol, 1.00 eq) in tetrahydrofuran (45 mL) was added lithium diisopropylamide (2.00 M in tetrahydrofuran, 12.6 mL, 1.00 eq) dropwise at -78°C under nitrogen atmosphere. After stirring at -78°C for 30 min, 2-bromo-1,1-diethoxyethane (9.92 g, 50.4 mmol, 7.57 mL, 2.00 eq) was added. After continue stirring at -78°C for 30 min, the mixture was warmed to 20°C, and stirred for 16 h. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (30.0 mL), extracted with ethyl acetate (40.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ethergradient @ 50 mL/min) and concentrated to afford 7- (2,2-diethoxyethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (2.00 g, 8.50 mmol, 34% yield) as brown oil. Procedure for preparation of 2-(6,7-dihydro-5H-cyclopenta [b]pyridin-7-yl)acetaldehyde To a mixture of 7-(2,2-diethoxyethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (200 mg, 0.850 mmol, 1.00 eq) in water (4.00 mL) was added hydrochloric acid (12.0 M in water, 0.350 mL, 4.94 eq). After stirring at 20°C for 2 h, saturated sodium bicarbonate solution (5.00 mL) was added to the reaction mixture to adjust pH to 7-8. The solution was extracted with dichloromethane (30.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford 2-(6,7-dihydro-5H- cyclopenta[b] pyridin-7-yl)acetaldehyde (120 mg, 0.744 mmol, 88% yield) as brown oil without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.95 (s, 1H), 8.37 (d, J = 4.8 Hz, 1H), 7.52 (dd, J = 7.6, 0.8 Hz, 1H), 7.07 (dd, J = 7.6, 5.2 Hz, 1H), 3.67 (dd, J = 8.4, 4.8 Hz, 1H), 3.28-3.22 (m, 1H), 3.00-2.85 (m, 2H), 2.65 (dt, J = 8.8, 1.6 Hz, 1H), 2.56-2.46 (m, 1H), 1.78-1.72 (m, 1H). Procedure for preparation of 2-(6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)-1- isocyanoethanamine To a mixture of 2-(6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)acetaldehyde (110 mg, 0.682 mmol, 1.00 eq) in methanol (3.00 mL) were added ammonia (7.00 M in methanol, 0.682 mL, 7.00 eq) and titanium(IV) isopropylate (291 mg, 1.02 mmol, 0.302 mL, 1.50 eq) at 20°C. After stirring at 20°C for 0.5 h, trimethylsilyl cyanide (102 mg, 1.02 mmol, 0.128 mL, 1.50 eq) was added. After stirring at 20°C for 5 h, the reaction mixture was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~100% ethyl acetate / petroleum ether gradient @ 50 mL/min) to afford 2-amino-3- (6,7-dihydro-5H-cyclopenta[b]pyridin-7- yl)propanenitrile (20.0 mg, 0.107 mmol, 16% yield) as colorless oil. LC-MS (Method B): R _t = 0.156 min; MS (ESIpos): m/z = 187.8 [M+H] ⁺ . Procedure for preparation of CPD0085272 - (1R,2S,5S)-N-(1-cyano-2-(6,7-dihydro-5H- cyclopenta[b]pyridin-7-yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2, 2-trifluoroacetamido)butanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of 2-(6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)-1-isocyano-etha namine (20.0 mg, 0.107 mmol, 1.00 eq) and (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl) amino]butanoyl] -6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (38.9 mg, 0.107 mmol, 1.00 eq) in dichloromethane (2.00 mL) were added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene] - dimethylazanium ; hexafluorophosphate (48.7 mg, 0.128 mmol, 1.20 eq) and N,N-diisopropylethylamine (41.4 mg, 0.320 mmol, 0.0558 mL, 3.00 eq) at 20°C. After stirring at 20°C for 2 h, the reaction mixture was concentrated to give a residue. The residue was purified by reversed phase (Instrument: 10g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.5% FA), eluent B: acetonitrile; gradient: 0-10 min 0-60% B; flow 85 ml/min; temperature: room temperature; Detector: UV 220/254 nm) and lyophilized to afford(1R,2S,5S)-N-[1-cyano-2-(6,7-dihydro-5H-cyclopenta[b]p yridin-7-yl)ethyl]-3-[(2S)- 3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-d imethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (25.0 mg, 0.469 mmol, 44% yield) as a white solid. Preparation of CPD0085275 Procedure for preparation of methyl 8-oxo-6,7-dihydro-5H-quinoline-7-carboxylate To a solution of 6,7-dihydro-5H-quinolin-8-one (20.0 g, 136 mmol, 1.00 eq) in tetrahydrofuran (100 mL) was added sodium hydride (10.8 g, 272 mmol, 60 % purity, 2 eq) in portions at 0 °C. After stirring at 0 °C for 0.5 h, dimethyl carbonate (12.2 g, 136 mmol, 1.00 eq) was added. After addition, the mixture was stirred at 80 °C for 11.5 h. After cooling to ambient temperature, the reaction mixture was poured into saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate= 3/1 then ethyl acetate) to give methyl 8-oxo- 6,7-dihydro-5H-quinoline-7-carboxylate (15.2 g, 74.1 mmol, 55% yield) as a yellow solid. LC-MS (Method O): Rt = 0.177 min; MS (ESIpos): m/z = 206.2[M+H] ⁺ . Procedure for preparation of methyl 8-hydroxy-5,6,7,8-tetrahydroquinoline-7-carboxylate To a solution of methyl 8-oxo-6,7-dihydro-5H-quinoline-7-carboxylate (14.0 g, 68.2 mmol, 1.00 eq) in anhydrous methanol (100 mL) was added sodium borohydride (2.84 g, 75.1 mmol, 1.10 eq) at -50 °C. After stirring at -50 °C for 0.5 h, the mixture was quenched with hydrochloric acid (0.5 M in water, 100 mL). The resulting mixture was diluted with ethyl acetate (100 mL × 3), washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , dichloromethane/ methanol = 20/1 to 5/1) to give methyl 8-hydroxy-5,6,7,8-tetrahydroquinoline-7-carboxylate (7.80 g, 30.1 mmol, 44% yield, 80% purity) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.47-8.44 (m, 1H), 7.51-7.45 (m, 1H), 7.21-7.16 (m, 1H), 5.15-4.90 (m, 1H), 3.69-3.53 (m, 3H), 3.01-2.88 (m, 2H), 2.85-2.80 (m, 1H), 2.02-1.70 (m, 2H). LC-MS (Method M): R _t = 0.497 min; MS (ESIpos): m/z = 208.2 [M+H] ⁺ . Procedure for preparation of methyl 8-chloro-5,6,7,8-tetrahydroquinoline-7-carboxylate A solution of methyl 8-hydroxy-5,6,7,8-tetrahydroquinoline-7-carboxylate (5.53 g, 26.7 mmol, 1.00 eq) in thionyl chloride (20.0 mL) was stirred at 60 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (20.0 mL). Saturated sodium bicarbonate solution (100 mL) was added to adjust pH to 8~9 and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (80.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give methyl 8-chloro-5,6,7,8- tetrahydroquinoline-7-carboxylate (6.50 g, crude) as brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.55-8.50 (m, 1H), 7.49-7.41 (m, 1H), 7.21-7.15 (m, 1H), 5.62-5.55 (m, 1H), 3.86-3.69 (m, 3H), 3.39-3.08 (m, 1H), 2.96-2.81 (m, 2H), 2.30-2.14 (m, 2H). LC-MS (Method O): R _t = 0.297 & 0.307 min; MS (ESIpos): m/z = 226.1[M+H] ⁺ . Procedure for preparation of methyl 5,6,7,8-tetrahydroquinoline-7-carboxylate A mixture of methyl 8-chloro-5,6,7,8-tetrahydroquinoline-7-carboxylate (6.50 g, 21.6 mmol, 75% purity, 1.00 eq) and palladium on carbon (100 mg, 10% purity) in tetrahydrofuran (20.0 mL) was degassed and purged with hydrogen for 3 times. After stirring at 25 °C for 48 h under hydrogen (15.0 psi) atmosphere, the reaction mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to ethyl acetate) to give methyl 5,6,7,8-tetrahydroquinoline-7-carboxylate (5.00 g, crude) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.32 (d, J = 2.2 Hz, 1H), 7.34 (d, J = 3.6 Hz, 1H), 7.05-6.95 (m, 1H), 3.67 (s, 3H), 3.25-3.02 (m, 2H), 2.86-2.78 (m, 2H), 2.20-2.08 (m, 1H), 1.93-1.76 (m, 2H). Procedure for preparation of 5,6,7,8-tetrahydroquinolin-7-ylmethanol To a suspension of lithium aluminium hydride (992.39 mg, 26.15 mmol, 1.25 eq) in anhydrous tetrahydrofuran (50.0 mL) was added a solution of methyl 5,6,7,8-tetrahydroquinoline-7-carboxylate (4.00 g, 20.9 mmol, 1.00 eq) in anhydrous tetrahydrofuran (20.0 mL) at 0 °C. After stirring at 25 °C for 0.5 h. The mixture was quenched with sodium sulfate decahydrate (20.0 g). After stirring at 25 °C for 10 min, the mixture was diluted with ethyl acetate (200 mL) and filtered. The filtrate was concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , dichloromethane/methanol = 20/1 to 6/1) to give 5,6,7,8-tetrahydroquinolin-7-ylmethanol (2.10 g, 10.9 mmol, 52% yield, 85% purity) as colorless oil. ¹ H NMR (400 MHz, CDCl3) δ = 8.35-8.25 (m, 1H), 7.35-7.31 (m, 1H), 7.09-6.98 (m, 1H), 3.69-3.53 (m, 2H), 3.09-2.94 (m, 1H), 2.83-2.52 (m, 4H), 2.06-1.96 (m, 2H), 1.47-1.35 (m, 1H). LC-MS (Method M): R _t = 0.506 min; MS (ESIpos): m/z = 164.3 [M+H] ⁺ . Procedure for preparation of 5,6,7,8-tetrahydroquinoline-7-carbaldehyde To a stirred mixture of 5,6,7,8-tetrahydroquinolin-7-ylmethanol (2.50 g, 15.3 mmol, 1.00 eq) in dichloromethane (50.0 mL) was added Dess-Martin periodinane (7.80 g, 18.4 mmol, 1.20 eq) at 0°C. After stirring at 25°C for 1.5 h, the mixture was filtered. The filtrate was washed with saturated sodium bicarbonate aqueous solution (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , dichloromethane/methanol = 20/1 to 6/1) to give 5,6,7,8-tetrahydroquinoline-7-carbaldehyde (1.10 g, 5.60 mmol, 37% yield, 82% purity) as white oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.74 (s, 1H), 8.37-8.32 (m, 1H), 7.35-7.31 (m, 1H), 7.09-6.98 (m, 1H), 3.15-3.06 (m, 2H), 2.83-2.72 (m, 4H), 1.86-1.77 (m, 1H). LC-MS (Method M): R _t = 0.485 min; MS (ESIpos): m/z = 180.2[M+H+H ₂ O] ⁺ . Procedure for preparation of methyl 2-(tert-butoxycarbonylamino)-3-(5,6,7,8-tetrahydroquinolin- 7-yl)prop-2-enoate To a solution of methyl 2-(tert-butoxycarbonylamino)-2-dimethoxyphosphoryl-acetate (1.99 g, 6.70 mmol, 1.20 eq) in dichloromethane (20.0 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.70 g, 11.2 mmol, 1.68 mL, 2.00 eq). After stirring at 25 °C for 0.1 h, 5,6,7,8-tetrahydroquinoline-7- carbaldehyde (0.900 g, 5.58 mmol, 1.00 eq) was added. After stirring at 25 °C for 1 h, the reaction mixture was poured into saturated ammonium chloride aqueous (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5/1 to 1/1) to give methyl 2-(tert- butoxycarbonylamino)-3-(5,6,7,8-tetrahydroquinolin-7-yl)prop -2-enoate (1.00 g, 2.86 mmol, 51% yield, 95% purity) as a white solid. LC-MS (Method M): R _t = 0.735 min; MS (ESIpos): m/z = 333.3 [M+H] ⁺ . Procedure for preparation of methyl 2-(tert-butoxycarbonylamino)-3-(5,6,7,8-tetrahydroquinolin- 7-yl)propanoate A mixture of methyl 2-(tert-butoxycarbonylamino)-3-(5,6,7,8-tetrahydroquinolin-7 -yl)prop-2-enoate (1.00 g, 3.01 mmol, 1.00 eq) and palladium on carbon (0.100 g, 10% purity) in methanol (20.0 mL) was degassed under vacuum and purged with hydrogen for 3 times. After stirring at 25 °C for 10 h under hydrogen atmosphere (15 psi), the mixture was filtered. The filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , dichloromethane/methanol = 20/1 to 6/1) to give methyl 2-(tert-butoxycarbonylamino)-3-(5,6,7,8-tetrahydroquinolin-7 -yl)propanoate (900 mg, 2.64 mmol, 88% yield, 98% purity) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.36-8.25 (m, 1H), 7.40-7.30 (m, 1H), 7.04-6.95 (m, 1H), 4.93-4.92(m, 1H), 4.49-4.30 (m, 1H), 3.69 (s, 3H), 3.10-2.97 (m, 1H), 2.80-2.69 (m, 2H), 2.59-2.44 (m, 1H), 1.99-1.59 (m, 4H), 1.38 (s, 9H),1.37-1.35(m,1H). LC-MS (Method O): R _t = 0.330 min; MS (ESIpos): m/z = 335.1 [M+H] ⁺ . Procedure for preparation of tert-butyl N-[2-amino-2-oxo-1-(5,6,7,8-tetrahydroquinolin-7- ylmethyl)ethyl]carbamate A mixture of methyl 2-(tert-butoxycarbonylamino)-3-(5,6,7,8-tetrahydroquinolin-7 -yl)propanoate (900 mg, 2.69 mmol, 1.00 eq) in ammonia (7.00 M in methanol, 20 mL) was stirred at 25 °C for 12 h. After concentration, the residue was triturated with acetonitrile (5.00 mL). After filtration, the filter cake was collected and dried under vacuum to give tert-butyl N-[2-amino-2-oxo-1-(5,6,7,8-tetrahydroquinolin-7- ylmethyl)ethyl]carbamate (700 mg, 2.19 mmol, 81% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.32-8.30 (m, 1H), 7.48-7.43 (m, 1H), 7.29 (s, 1H), 7.10 (dd, J = 7.6, 4.8 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.96 (s, 1H), 4.18-3.95 (m, 1H), 2.98-2.76 (m, 2H), 2.55-2.52 (m, 2H), 1.99-1.73 (m, 2H), 1.66-1.52 (m, 2H), 1.38 (s, 9H),1.36-1.34 (m,1H). LC-MS (Method N): R _t = 0.439 min; MS (ESIpos): m/z = 320.2 [M+H] ⁺ . Procedure for preparation of 2-amino-3-(5,6,7,8-tetrahydroquinolin-7-yl)propanamide A mixture of tert-butyl N-[2-amino-2-oxo-1-(5,6,7,8-tetrahydroquinolin-7-ylmethyl)et hyl]carbamate (0.300 g, 939 μmol, 1.00 eq) in hydrochloric acid (4 M in dioxane, 10 mL) was stirred at 25 °C for 1 h. After filtration, the filter cake was collected to give 2-amino-3-(5,6,7,8-tetrahydroquinolin-7- yl)propanamide (280 mg, 852 μmol, 91% yield, 3 hydrochloric acid) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.56-8.55 (m, 1H),8.40-8.15 (m, 4H), 8.06-7.96 (m, 1H), 7.79-7.66 (m, 1H), 7.62-7.55 (m, 1H), 3.91-3.75 (m, 1H), 3.04-2.63 (m, 4H), 2.09-1.97 (m, 2H), 1.80 (t, J = 6.8 Hz, 2H), 1.50-1.38 (m, 1H). LC-MS (Method N): R _t = 0.174 min; MS (ESIpos): m/z = 220.1 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S) -N-[2-amino-2-oxo-1- (5,6,7,8-tetrahydroquinolin-7- ylmethyl) ethyl]-3-[ (2S) -3,3-dimethyl-2-[ (2,2,2-trifluoroacetyl) amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide A mixture of 2-amino-3- (5,6,7,8-tetrahydroquinolin-7-yl) propanamide (200 mg, 609 μmol, 1.00 eq, 3 hydrochloric acid), (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-di methyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (222 mg, 609 μmol, 1.00 eq), O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (301 mg, 791 μmol, 1.30 eq), N,N-diisopropyl ethylamine (315 mg, 2.43 mmol, 4.00 eq) in N,N-dimethylformamide (2.00 mL) was stirred at 25 °C for 12 h. The mixture was poured into saturated aqueous ammonium chloride solution (10.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic phases were washed with brine (10.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give a residue. The residue was purified by column chromatography on silica gel (200 mesh, dichloromethane/methanol = 20/1 to 6/1) to give (1R,2S,5S)-N-[2-amino-2-oxo-1-(5,6,7,8- tetrahydroquinolin-7-ylmethyl)ethyl]-3-[(2S)-3,3-dimethyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (210 mg, 342 μmol, 56 % yield, 92% purity) as a white solid. LC-MS (Method N): R _t = 0.560 & 0.573 min; MS (ESIpos): m/z = 566.1 [M+H] ⁺ . Procedure for preparation of CPD0085275 (1R,2S,5S)-N-[2-amino-2-oxo-1-(5,6,7,8- tetrahydroquinolin-7-ylmethyl)ethyl]-3-[(2S)-3,3-dimethyl-2- [(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide A mixture of (1R,2S,5S)-N-(1-amino-1-oxo-3-(5,6,7,8-tetrahydroquinolin-7- yl)propan-2-yl)-3-((S)-3,3- dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxamide (190 mg, 0.335 mmol, 1.00 eq) in dichloromethane (3.00 mL) was added Burgess reagent (240 mg, 1.01 mmol, 3.00 eq) at 0 °C. After stirring at 25 °C for 0.5 h, the reaction mixture was quenched with saturated sodium bicarbonate solution (10.0 mL) and extracted with ethyl acetate (5.00 mL × 3). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (1000 mesh, petroleum ether then petroleum ether/ethyl acetate = 1/1) followed by prep-HPLC (FA condition; column: Phenomenex luna C18 150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 22%-52%,10min) to give (1R,2S,5S)-N-(1-cyano-2-(5,6,7,8- tetrahydroquinolin-7-yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (113 mg, 0.207 mmol, 61% yield, purity:99%) as a white solid. Preparation of CPD0186408 Procedure for preparation of O1-benzyl O5-methyl 2,3-dihydropyrrole-1,5-dicarboxylate To a mixture of methyl (2S)-pyrrolidine-2-carboxylate (10.0 g, 60.4 mmol, 1.00 eq, HCl) in dichloromethane (100 mL) were added triethylamine (13.4 g, 133 mmol, 18.5 mL, 2.20 eq) and 1- chloropyrrolidine-2,5-dione (8.87 g, 66.4 mmol, 1.10 eq) at 0°C. After stirring at 25°C for 2.5 h, pyridine (11.2 mL, 139 mmol, 2.30 eq) was added dropwise during a period of 0.5 h. After cooling to -20°C, benzyl carbonochloridate (22.7 g, 133 mmol, 18.9 mL, 2.2 eq) was added into the above mixture at - 20°C. After addition, the mixture was stirred at 25°C for 12 h. The mixture was washed with saturated citric acid aqueous solution (100 mL × 2), saturated sodium bicarbonate aqueous solution (100 mL) and brine (100 mL). The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~100% ethyl acetate/petroleum ether gradient @ 100 mL/min) to give O1-benzyl O5-methyl 2,3-dihydropyrrole-1,5- dicarboxylate (7.8 g, 29.8 mmol, 49% yield) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.38-7.33 (m, 5H), 5.85 (t, J = 2.8 Hz, 1H), 5.15 (s, 2H), 4.00 (t, J = 8.8 Hz, 2H), 3.66 (s, 3H), 2.70-2.64 (td, J = 8.8 Hz, 2.8 Hz, 2H). Procedure for preparation of O1-benzyl O2-methyl 3-isopropylpyrrolidine-1,2-dicarboxylate To a mixture of lithium chloride chloro(isopropyl)magnesium complex (1.30 M in tetrahydrofuran, 22.1 mL, 1.50 eq) in tetrahydrofuran (50.0 mL) was added copper (I) bromide dimethylsulfane complex (0.787 g, 3.83 mmol, 0.20 eq) at -35°C. After stirring at -35°C for 1 h, a solution of O1-benzyl O5-methyl 2,3-dihydropyrrole-1,5-dicarboxylate (5.00 g, 19.1 mmol, 1.00 eq) in tetrahydrofuran (30.0 mL) was added dropwise. After stirring at -35°C for 2 h, the reaction mixture was quenched with saturated ammonium chloride aqueous solution (100 mL), ammonium hydroxide (10.0 mL), and extracted with ethyl acetate (100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~10% ethyl acetate/petroleum ether gradient @ 45 mL/min) to give O1-benzyl O2-methyl 3-isopropylpyrrolidine- 1,2-dicarboxylate (2.7 g, 8.84 mmol, 46% yield) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.36-7.29 (m, 5H), 5.17 (d, J = 12.4 Hz, 0.5H), 5.11-5.10 (m, 1H), 4.98 (d, J = 12.4 Hz, 0.5H), 4.13-4.07 (m, 1H), 3.73-3.71 (m, 1H), 3.65-3.62 (m, 1H), 3.54 (s, 1H), 3.49-3.42 (m, 1H), 2.17-1.95 (m, 3H), 1.85-1.68 (m, 2H), 1.04-0.89 (m, 6H). LC-MS (Method C): R _t = 0.953 min, MS (ESIpos): m/z = 305.8 [M+H] ⁺ . Procedure for preparation of methyl 3-isopropylpyrrolidine-2-carboxylate A mixture of O1-benzyl O2-methyl 3-isopropylpyrrolidine-1,2-dicarboxylate (500 mg, 1.64 mmol, 1.00 eq) and palladium on activated carbon (50.0 mg, 0.164 mmol, 10% purity, 0.10 eq) in methanol (10.0 mL) was stirred under hydrogen atmosphere (15 psi) at 25°C for 1 h. After filtration, the filtrate was concentrated under vacuum to give methyl 3-isopropylpyrrolidine-2-carboxylate (260 mg, 1.52 mmol, 93% yield) as yellow oil. ¹ H NMR (400 MHz, CD3OD-d4) δ = 3.72 (s, 3H), 3.47 (d, J = 6.4 Hz, 1H), 3.33-3.29 (m, 1H), 2.97-2.89 (m, 2H), 2.05-1.98 (m, 1H), 1.94-1.87 (m, 1H), 1.74-1.64 (m, 1H), 1.58-1.49 (m, 1H), 0.98-0.93 (dd, J = 14.0 Hz, 6.4 Hz, 1H). Procedure for preparation of methyl 1-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl- butanoyl]-3-isopropyl-pyrrolidine-2-carboxylate acid To a mixture of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid (257 mg, 1.11 mmol, 1.00 eq), N,N-diisopropylethylamine (287 mg, 2.22 mmol, 0.386 mL, 2.00 eq) and 1-propanephosphonic anhydride (847 mg, 50% purity in ethylene acetate,1.33 mmol, 1.20 eq) in N,N-dimethylformamide (4.00 mL) was added methyl 3-isopropylpyrrolidine-2-carboxylate (190 mg, 1.11 mmol, 1.00 eq). After stirring at 25°C for 2 h, the reaction mixture (combined with: EW30036-153 and EW30036-155) was diluted with water (30.0 mL) and extracted with ethyl acetate (40.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, Eluent of 0~10% ethyl acetate/petroleum ether gradient @ 45 mL/min) to give methyl 1- [(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]-3- isopropyl-pyrrolidine-2-carboxylate (200 mg, 0.520 mmol, 47% yield) as colorless oil. ¹ H NMR (400 MHz, CD ₃ OD-d ₄ ) δ = 4.33-4.16 (m, 2H), 3.85-3.76 (m, 2H), 3.70-3.69 (m, 3H), 2.14-2.01 (m, 2H), 1.89-1.66 (m, 2H), 1.45-1.43 (m, 9H), 1.02-0.94 (m, 15H). Procedure for preparation of 1-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]- 3- isopropyl-pyrrolidine-2-carboxylic acid A mixture of methyl 1-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]- 3-isopropyl- pyrrolidine-2-carboxylate (200 mg, 0.520 mmol, 1.00 eq) and lithium hydroxide hydrate (32.7 mg, 0.780 mmol, 1.50 eq) in a mixed solvent of tetrahydrofuran (2.00 mL), methanol (2.00 mL) and water (2.00 mL) was stirred at 25°C for 1 h. The mixture was concentrated under vacuum to remove most of the organic solvent, diluted with water (40.0 mL) and washed with petroleum ether (50.0 mL). Hydrochloric acid (1.00 M in water) was added to the separated aqueous phase to adjust pH~5 and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-[(2S)-2-(tert-butoxycarbonylamino)-3,3- dimethyl-butanoyl]-3-isopropyl-pyrrolidine-2-carboxylic acid (190 mg, 0.480 mmol, 92% yield, 94% purity) as yellow oil. LC-MS (Method C): R _t = 0.914 min, MS (ESIpos): m/z = 370.0 [M+H] ⁺ . Procedure for preparation of 1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3-isopropyl-pyrrolidi ne-2- carboxylic acid A mixture of 1-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]- 3-isopropyl-pyrrolidine-2- carboxylic acid (190 mg, 0.513 mmol, 1.00 eq) in hydrochloric acid (4 M in dioxane, 5.00 mL) was stirred at 25°C for 2 h. The mixture was concentrated under vacuum, and the residue was basified with ammonia (7.00 M in methanol, 1 mL). The mixture was concentrated under vacuum to give 1-[(2S)-2- amino-3,3-dimethyl-butanoyl]-3-isopropyl-pyrrolidine-2-carbo xylic acid (200 mg, crude) as yellow oil. Procedure for preparation of 1-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoy l]-3- isopropyl-pyrrolidine-2-carboxylic acid A mixture of 1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3-isopropyl-pyrrolidi ne-2-carboxylic acid (200 mg, 0.740 mmol, 1.00 eq), methyl 2,2,2-trifluoroacetate (189 mg, 1.48 mmol, 0.150 mL, 2.00 eq) and triethylamine (225 mg, 2.22 mmol, 0.309 mL, 3.00 eq) in methanol (5.00 mL) was stirred at 25°C for 12 h. After concentration, the residue was diluted with water (50.0 ml) and washed with petroleum ether (50.0 mL). Hydrochloric acid (1.00 M in water) was added to aqueous phase to adjust pH~6 and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-3-isopropyl-pyrrolidine-2-ca rboxylic acid (170 mg, 0.410 mmol, 88% purity) as brown oil. LC-MS (Method C): R _t = 0.885 min, MS (ESIpos): m/z =367.1 [M+H] ⁺ . Procedure for preparation of N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]e thyl]- 1-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino] butanoyl]-3-isopropyl-pyrrolidine-2- carboxamide To a solution of 1-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoy l]-3-isopropyl-pyrrolidine-2- carboxylic acid (85.0 mg, 0.204 mmol, 88% purity, 1.00 eq) and (2S)-2-amino-3-[(3S)-2-oxopyrrolidin- 3-yl]propanamide (63.7 mg, 0.306 mmol, 1.50 eq, HCl salt) in N,N-dimethylformamide (2.00 mL) were added [chloro(dimethylamino)methylene]-dimethyl-ammonium;hexafluor ophosphate (172 mg, 0.612 mmol, 3 eq) and 1-methylimidazole (101 mg, 1.22 mmol, 6.00 eq). After stirring at 25°C for 2 h, the mixture was concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 μm; mobile phase: [water(FA)-ACN]; B%: 23%- 53%,10 min) to give N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]e thyl]-1-[(2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl) amino]butanoyl]-3-isopropyl-pyrrolidine-2-carboxamide (26 mg, 50.0 μmol, 25% yield) as a white solid. LC-MS (Method C): R _t = 0.830 min, MS (ESIpos): m/z = 520.0 [M+H] ⁺ . Procedure for preparation of CPD0186408 - N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]- 1-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoy l]-3-isopropyl-pyrrolidine-2- carboxamide A mixture of N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]e thyl]-1-[(2S)-3,3-dimethyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-3-isopropyl-pyrrolid ine-2-carboxamide (57.0 mg, 0.110 mmol, 1.00 eq) and methoxycarbonyl-(triethylammonio)sulfonyl-azanide (78.4 mg, 0.329 mmol, 3.00 eq) in dichloromethane (5.00 mL) was stirred at 25°C for 12 h. Saturated sodium bicarbonate aqueous solution was added to the mixture to adjust pH~7 and concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm* 5 μm; mobile phase: [water(NH ₄ HCO ₃ )-ACN];B%: 37%-67%,8min) to give N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]-1-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)ami no]butanoyl]-3-isopropyl-pyrrolidine-2- carboxamide (33.8 mg, 66.3 μmol, 60% yield, 99% purity) as a white solid. Preparation of CPD0186412, CPD0186409 Procedure for preparation of methyl (1S,2S,5R)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3- dimethyl-butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylate To a solution of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid (1.00 g, 4.32 mmol, 1.00 eq) in N,N-dimethylformamide (5.00 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluronium hexafluorophosphate (1.97 g, 5.19 mmol, 1.20 eq) at 0°C. After stirring at 0°C for 0.5 h, N,N-diisopropylethylamine (2.79 g, 21.6 mmol, 3.77 mL, 5.00 eq) and methyl (1S,2S,5R)-3- azabicyclo[3.1.0]hexane-2-carboxylate (768 mg, 4.32 mmol, 1.00 eq, hydrochloric acid) were added at 0°C. After stirring at 25°C for 12 h, the mixture was diluted with ethyl acetate (20.0 mL) and washed with brine (10.0 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 3/1) to afford methyl (1S,2S,5R)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3- dimethyl-butanoyl]-3-azabicyclo [3.1.0]hexane-2-carboxylate (1.30 g, 3.67 mmol, 85% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 6.77-6.45 (m, 1H), 4.59-4.31 (m, 1H), 4.02-3.96 (m, 1H), 3.87-3.77 (m, 1H), 3.73-3.56 (m, 4H), 1.77-1.55 (m, 2H), 1.40-1.35 (m, 9H), 0.96-0.85 (m, 9H), 0.83-0.71 (m, 1H), 0.25-0.04 (m, 1H). LC-MS (Method C): R _t = 0.893 min; MS (ESIpos): m/z = 355.0 [M+H] ⁺ . Procedure for preparation of (1S,2S,5R)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl - butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid To a solution of methyl (1S,2S,5R)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl -butanoyl] -3- azabicyclo[3.1.0]hexane-2-carboxylate (1.30 g, 3.67 mmol, 1.00 eq) in a mixed solvent of tetrahydrofuran (5 mL), methanol (5.00 mL) and water (5.00 mL) was added lithium hydroxide monohydrate (462 mg, 11.0 mmol, 3.00 eq) at 25°C. After stirring at 25°C for 1 h, the mixture was concentrated to give a residue. The residue was diluted with water (10.0 mL), adjusted pH~4 with saturated citric acid and extracted with ethyl acetate (20.0 mL). The separated organic phase washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford (1S,2S,5R)-3-[(2S)-2-(tert-butoxycarbonylamino) -3,3-dimethyl-butanoyl]-3-azabicyclo [3.1.0]hexane- 2-carboxylic acid (1.3 g, crude) as a yellow solid. LC-MS (Method C): R _t = 0.862 min; MS (ESIpos): m/z = 362.9 [M+Na] ⁺ . Procedure for preparation of (1S,2S,5R)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxylic acid A solution of (1S,2S,5R)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl -butanoyl]-3-azabicyclo [3.1.0]hexane-2-carboxylic acid (1.30 g, 3.82 mmol, 1.00 eq) in hydrochloric acid (4 M in dioxane, 20.0 mL, 80 mmol) was stirred at 25°C for 1 h. The mixture was concentrated to afford (1S,2S,5R)-3-[(2S)- 2-amino-3,3-dimethyl-butanoyl]-3-azabicyclo[3.1.0]hexane-2-c arboxylic acid (920 mg, crude, hydrochloric acid) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 14.10-12.03 (m, 1H), 8.34 (s, 3H), 4.60-4.23 (m, 1H), 3.99-3.87 (m, 1H), 3.85-3.75 (m, 1H), 3.60-3.52 (m, 1H), 1.77-1.52 (m, 2H), 1.05-0.89 (m, 9H), 0.82-0.64 (m, 1H), 0.56-0.11 (m, 1H). Procedure for preparation of (1S,2S,5R)-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2- carboxylic acid To a solution of (1S,2S,5R)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3-azabicyc lo[3.1.0] hexane-2- carboxylic acid (920 mg, 3.32 mmol, 1.00 eq, hydrochloric acid) in methanol (20.0 mL) were added triethylamine (1.68 g, 16.62 mmol, 2.31 mL, 5.00 eq) and methyl 2,2,2-trifluoroacetate (851 mg, 6.65 mmol, 2.00 eq) at 25°C. After stirring at 50°C for 12 h, the mixture was concentrated to give a residue. The residue was diluted with hydrochloric acid (1M in water, 20.0 mL) and extracted with ethyl acetate (20.0 mL). The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to afford (1S,2S,5R)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-3- azabicyclo[3.1.0] hexane-2-carboxylic acid (1.10 g, crude) as yellow oil. LC-MS (Method C): R _t = 0.909 min; MS (ESIpos): m/z = 337.2 [M+H] ⁺ . Procedure for preparation of (1S,2S,5R)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroace tyl)amino] butanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of (1S,2S,5R)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-3-azabicyclo [3.1.0]hexane-2-carboxylic acid (300 mg, 892 μmol, 1.00 eq) in dichloromethane (5.00 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (509 mg, 1.34 mmol, 1.50 eq) at 0°C. After stirring at 0°C for 0.5 h, N,N-diisopropylethylamine (576 mg, 4.46 mmol, 777 μL, 5.00 eq) and (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (204 mg, 981 μmol, 1.10 eq, hydrochloric acid) were added at 0°C. After stirring at 25°C for 12 h, the reaction mixture was used for the next step reaction directly. LC-MS (Method C): R _t = 0.828 min; MS (ESIpos): m/z = 490.3 [M+H] ⁺ . Procedure for preparation of N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-[(2S)- 3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-3-azabicy clo[3.1.0]hexane-2-carboxamide & N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-[(2S)- 3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2- carboxamide To a solution of (1S,2S,5R)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl] ethyl]-3-[(2S)- 3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-3-aza bicyclo[3.1.0]hexane-2-carboxamide (349 mg, 713 μmol, 1.00 eq) in dichloromethane (4.00 mL) was added Burgess reagent (510 mg, 2.14 mmol, 3.00 eq) at 0°C. After stirring at 25°C for 12 h, the mixture was diluted with dichloromethane (10.0 mL) and washed with brine (10.0 mL). The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 μm; mobile phase: [water (FA)-ACN]; B%: 20%-50%, 10 min) to afford (1S,2S,5R)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethy l]-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino] butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide (10 mg, 20.8 μmol, 3% yield, 98% purity, CPD0186412) and (1S,2S,5R)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethy l]-3-[(2S)- 3,3-dimethyl -2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-3-azabicyclo[3.1. 0]hexane-2-carboxamide (60 mg, 122 μmol, 17% yield, 96% purity, CPD0186409) as a white solid. Preparation of CPD0186411 Procedure for preparation of ethyl isoquinoline-8-carboxylate To a mixture of isoquinoline-8-carboxylic acid (5.00 g, 28.9 mmol, 1.00 eq) in ethanol (30.0 mL) was added thionyl chloride (13.7 g, 115 mmol, 4.00 eq) at 25°C. After stirring at 70°C for 4 h, the mixture was concentrated under vacuum to give a residue. The residue was triturated with 2-methoxy-2- methylpropane (30.0 mL) at 25°C and then filtered. The filter cake was dried over vacuum to give ethyl isoquinoline-8-carboxylate (6.40 g, 26.9 mmol, 93% yield, HCl salt) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.44 (s, 1H), 8.87-8.78 (m, 2H), 8.57-8.55 (m, 2H), 8.30-8.21 (m, 2H), 4.49 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H). Procedure for preparation of ethyl 5,6,7,8-tetrahydroisoquinoline-8-carboxylate To a solution of ethyl isoquinoline-8-carboxylate (6.40 g, 26.9 mmol, 1.00 eq, HCl salt) in trifluoroacetic acid (120 mL) was added platinum dioxide (602 mg, 265 μmol, 10% purity, 0.01 eq) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen for 3 times and stirred under hydrogen (45 psi) at 60°C for 12 h. After filtration, the filtrate was concentrated under vacuum to give a residue. The residue was diluted with ethyl acetate, adjusted to pH~8 with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (50.0 mL × 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1 to 4/1) to give ethyl 5,6,7,8- tetrahydroisoquinoline-8-carboxylate (1.60 g, 7.41 mmol, 27% yield, 95% purity) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.36 (s, 1H), 8.25 (d, J = 5.2 Hz, 1H), 6.95 (d, J = 5.2 Hz, 1H), 4.11 (q, J = 7.2 Hz, 2H), 3.74 (t, J = 7.2 Hz, 1H), 2.81-2.59 (m, 2H), 2.20-2.10 (m, 1H), 1.96-1.84 (m, 2H), 1.78- 1.66 (m, 1H), 1.20 (t, J = 7.2 Hz, 3H). Procedure for preparation of ethyl 8-azido-6,7-dihydro-5H-isoquinoline-8-carboxylate To a mixture of ethyl 5,6,7,8-tetrahydroisoquinoline-8-carboxylate (1.40 g, 6.82 mmol, 1.00 eq) in tetrahydrofuran (40.0 mL) was added lithium bis(trimethylsilyl)amide (1.00 M in tetrahydrofuran, 13.6 mL, 2.00 eq) dropwise at -70°C. After stirring at -70°C for 0.5 h, a solution of N-diazo-2,4,6-triisopropyl- benzenesulfonamide (3.17 g, 10.2 mmol, 1.50 eq) in tetrahydrofuran (10.0 mL) was added. After addition, the mixture was stirred at -70°C for 0.5 h and acetic acid (1.23 g, 20.4 mmol, 1.17 mL, 3.00 eq) was added. After stirring at 25°C for 12 h, the mixture was poured into water (30.0 mL) and extracted with ethyl acetate (30.0 mL × 2). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1 to 6/1) to give ethyl 8-azido-6,7-dihydro-5H-isoquinoline-8-carboxylate (1 g, 3.65 mmol, 54% yield, 90% purity) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.33 (s, 1H), 8.31 (d, J = 5.2 Hz, 1H), 6.98 (d, J = 5.2 Hz, 1H), 4.22-4.09 (m, 2H), 2.77-2.69 (m, 2H), 2.28-2.20 (m, 1H), 2.04-1.97 (m, 1H), 1.90-1.76 (m, 2H), 1.18-1.14 (m, 3H), 1.14-1.14 (m, 1H). LC-MS (Method C): R _t = 0.387 min; MS (ESIpos): m/z = 246.8 [M+H] ⁺ . Procedure for preparation of ethyl 8-amino-6,7-dihydro-5H-isoquinoline-8-carboxylate To a mixture of ethyl 8-azido-6,7-dihydro-5H-isoquinoline-8-carboxylate (1.00 g, 3.65 mmol, 90% purity, 1.00 eq) in ethanol (20.0 mL) was added palladium on carbon (100 mg, 10% purity, 1.00 eq) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen for 3 times. After stirring at 25°C under hydrogen (15 psi) for 12 h, the mixture was filtered. The filtrate was concentrated under vacuum to give ethyl 8-amino-6,7-dihydro-5H-isoquinoline-8-carboxylate (840 mg, 3.62 mmol, 99% yield, 95% purity) as colorless oil. The crude was used for the next step reaction directly. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.44 (s, 1H), 8.35 (d, J = 5.2 Hz, 1H), 7.04 (dd, J = 5.2, 0.6 Hz, 1H), 4.26-4.16 (m, 2H), 2.84-2.79 (m, 2H), 2.31-224 (m, 1H), 2.06-1.86 (m, 3H), 1.23 (t, J = 7.2 Hz, 3H). LC-MS (Method C): Rt = 0.310 min; MS (ESIpos): m/z = 221.2 [M+H] ⁺ . SFC: dr: 48: 5 Procedure for preparation of 8-amino-6,7-dihydro-5H-isoquinoline-8-carboxamide A solution of ethyl 8-amino-6,7-dihydro-5H-isoquinoline-8-carboxylate (200 mg, 908 μmol, 1.00 eq) and 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine (63.2 mg, 454 μmol, 0.50 eq) in ammonia (10 M in methanol, 6.00 mL, 66.1 eq) in a sealed tube was stirred at 100°C for 12 h. After concentration, the residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm* 5 μm; mobile phase: [water (ammonia hydroxide)-ACN]; B%: 0%-25%,9 min) to give 8-amino-6,7-dihydro-5H-isoquinoline- 8-carboxamide (130 mg, 673 μmol, 74% yield, 99% purity) as a light yellow gum. LC-MS (Method C): R _t = 0.118 min; MS (ESIpos): m/z = 191.8 [M+H] ⁺ . Procedure for preparation of 8-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carbonyl] amino]-6,7- dihydro-5H-isoquinoline-8-carboxamide A mixture of 8-amino-6,7-dihydro-5H-isoquinoline-8-carboxamide (110 mg, 575 μmol, 1.00 eq), (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (210 mg, 575 μmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (328 mg, 863 μmol, 1.50 eq) and N,N- diisopropylethylamine (297 mg, 2.30 mmol, 401 μL, 4.00 eq) in N,N-dimethylformamide (2.00 mL) was stirred at 25°C for 12 h. The mixture was poured into water (6.00 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (5.00 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi Polar-RP 100*25mm*4 μm; mobile phase: [water(TFA)-ACN]; B%: 29%-49%,7 min) to give 8-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carbonyl]amino]-6,7-dihydro- 5H-isoquinoline-8-carboxamide (40 mg, 70.69 μmol, 12% yield, 95% purity) as light yellow gum. LC-MS (Method C): Rt = 0.667 min; MS (ESIpos): m/z = 538.2 [M+H] ⁺ . Procedure for preparation of CPD0186411 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin- 3-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)a mino]butanoyl]-6,6-dimethyl-3- azabicyclo [3.1.0]hexane-2-carboxamide To a mixture of 8-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacety l)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-6,7-dih ydro-5H-isoquinoline-8-carboxamide (40.0 mg, 74.4 μmol, 1.00 eq) in dichloromethane (1.00 mL) was added Burgess reagent (53.2 mg, 223 μmol, 3.00 eq) at 0°C. After stirring at 25°C for 12 h, the mixture was poured into water (5.00 mL) and extracted with dichloromethane (5.00 mL × 3). The combined organic layers were washed with brine (5.00 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (column: Phenomenex C1875*30mm*3 μm; mobile phase: [water(FA)-ACN]; B%: 30%-60%, 7 min) to give (1R,2S,5S)-N-[(8S)-8-cyano-6,7- dihydro-5H-isoquinolin-8-yl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (7.57 mg, 14.0 μmol, 18.8% yield, 96% purity) as an off-white solid. Preparation of CPD0186526 Procedure for preparation of O3-tert-butyl O2-methyl (1R,2S,5S)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2,3-dicarboxylate To a solution of methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (3.00 g, 14.6 mmol, 1 eq, HCl) in tetrahydrofuran (30.0 mL) and water (30.0 mL) were added sodium bicarbonate (4.90 g, 58.3 mmol, 2.27 mL, 4.00 eq) and di-tert-butyldicarbonate (3.82 g, 17.5 mmol, 4.02 mL, 1.20 eq). After stirring at 20°C for 16 h, the reaction mixture was poured into saturated ammonium chloride aqueous solution (50.0 mL) and extracted with ethyl acetate (60.0 mL × 2). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford O3-tert-butyl O2-methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0] hexane- 2,3-dicarboxylate (4.80 g, 14.26 mmol, 98% yield, 80% purity) as colorless oil. LC-MS (Method C): R _t = 0.942 min; MS (ESIpos): m/z = 292.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid To a solution of O3-tert-butyl O2-methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2,3- dicarboxylate (4.8 g, 14.26 mmol, 80% purity, 1.00 eq) in tetrahydrofuran (50.0 mL) and water (50.0 mL) was added lithium hydroxide (2.99 g, 71.3 mmol, 5 eq) at 20°C. After stirring at 20°C for 16 h, the reaction mixture was adjusted to pH~4 with hydrochloric acid (1 M in water) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®;40 g SepaFlash® Silica Flash Column, Eluent of 0~50% ethyl acetate/petroleum ether gradient @40 mL/min) to give (1R,2S,5S)-3-tert-butoxycarbonyl- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (3.50 g, 13.0 mmol, 91% yield, 95% purity) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 4.23-4.15 (m, 1H), 3.71-3.54 (m, 1H), 3.50-3.39 (m, 1H), 1.75-1.38 (m, 11H), 1.10-1.04 (m, 3H), 1.02-0.93 (m, 3H). LC-MS (Method C): R _t = 0.851 min; MS (ESIpos): m/z = 200.1 [M+H] ⁺ . Procedure for preparation of Compound CPD0186648 - tert-butyl (1R,2S,5S)-2-[[(1S)-1-cyano-2- [(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl]-6,6-dimethyl-3-a zabicyclo[3.1.0] hexane-3- carboxylate To a solution of (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanenitrile (2.03 g, 10.7 mmol, 1.00 eq, HCl), (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3 .1.0]hexane-2-carboxylic acid (3.00 g, 11.7 mmol, 1.10 eq) and N,N-diisopropylethylamine (5.52 g, 42.3 mmol, 7.44 mL, 4.00 eq) in dichloromethane (30.0 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (4.26 g, 11.2 mmol, 1.05 eq) at 0°C in portions. After stirring at 20°C for 16 h, the reaction mixture was poured into ammonium chloride (50.0 mL) aqueous solution and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~100% ethyl acetate/petroleum ether gradient @ 60 mL/min) to afford tert- butyl (1R,2S,5S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl] ethyl]carbamoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-3-carboxylate (4.40 g, 10.14 mmol, 95% yield, 90% purity) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.94-8.81 (m, 1H), 7.79-7.64 (m, 1H), 5.02-4.90 (m, 1H), 3.95-3.88 (m, 1H), 3.63-3.55 (m, 1H), 3.31-3.25 (m, 1H), 3.21-3.03 (m, 2H), 2.42-2.06 (m, 3H), 1.88-1.64 (m, 2H), 1.44-1.39 (m, 1H), 1.38-1.30 (m, 9H), 1.29-1.24 (m, 1H), 1.00 (s, 3H), 0.92-0.85 (m, 3H). LC-MS (Method C): R _t = 0.835 min; MS (ESIpos): m/z = 391.2 [M+H] ⁺ . SFC: de% = 99%. Procedure for preparation of CPD0187056 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin- 3-yl]ethyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxa mide To a solution of tert-butyl (1R,2S,5S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]eth yl] carbamoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (4.00 g, 9.73 mmol, 95% purity, 1.00 eq) in acetonitrile (80.0 mL) was added hydrochloric acid (4 M in ethyl acetate, 14.29 mL, 5.87 eq) at 0°C drop-wises. After stirring at 20°C for 2 h, the mixture was concentrated under vacuum to give a residue. The residue was triturated with methyl tert-butyl ether (50.0 mL) and filtered. The filter cake was collected and dried under vacuum to afford (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl] ethyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (3.10 g, 9.01 mmol, 93% yield, 95% purity, HCl) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.26-10.02 (m, 1H), 9.89-9.69 (m, 1H), 9.11-8.90 (m, 1H), 7.84- 7.69 (m, 1H), 5.09-4.97 (m, 1H), 4.11-4.05 (m, 1H), 3.67-3.56 (m, 1H), 3.24-3.04 (m, 3H), 2.45-2.34 (m, 1H), 2.27-2.12 (m, 2H), 1.93-1.84 (m, 1H), 1.82-1.65 (m, 3H), 1.13-1.09 (m, 3H), 1.08-1.03 (m, 3H). LC-MS (Method F): R _t = 1.200 min; MS (ESIpos): m/z = 291.1 [M+H] ⁺ . Procedure for preparation of methyl (S)-3,3-dimethyl-2-(thiazol-5-ylamino)butanoate A mixture of 5-bromothiazole (6.00 g, 36.6 mmol, 1.00 eq), methyl (2S)-2-amino-3,3-dimethyl-butanoate (16.6 g, 91.5 mmol, 2.50 eq, HCl salt), cesium carbonate (47.7 g, 146 mmol, 4.00 eq) and [2-(2- aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[2-(2,6-di isopropoxyphenyl) phenyl]phosphane (284 mg, 366 μmol, 0.01 eq) in dioxane (50.0 mL) was degassed under vacuum and purged with nitrogen for 3 times. The mixture was stirred at 110°C for 12 h under nitrogen atmosphere. After filtration, the filtrate was concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 4/1), reversed phase column (Basic condition: 330g Flash Column Welch Ultimate XB_C18 20-40μm; 120 A; mobile phase: [water(0.225% NH ₃ H ₂ O)-ACN]; B%: 10%-50%, 100 ml/min, 35 min) to give methyl (S)-3,3-dimethyl-2- (thiazol-5-ylamino)butanoate (0.40 g, 1.58 mmol, 4% yield, 90% purity) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.12 (d, J = 0.8 Hz, 1H), 6.79 (s, 1H), 6.56 (d, J = 10.0 Hz, 1H), 3.63 (s, 3H), 3.59 (d, J = 10.0 Hz, 1H), 1.00 (s, 9H). LC-MS (Method C): R _t = 0.410 min; MS (ESIpos): m/z = 229.1 [M+H] ⁺ . Procedure for preparation of (S)-3,3-dimethyl-2-(thiazol-5-ylamino)butanoic acid To a mixture of methyl (S)-3,3-dimethyl-2-(thiazol-5-ylamino)butanoate (0.300 g, 1.31 mmol, 1.00 eq) in methanol (2.00 mL) was added a solution of lithium hydroxide (551 mg, 13.1 mmol, 10.0 eq) in water (2.00 mL). After stirring at 50°C for 12 h, the mixture was poured into water (20.0 mL) and washed with ethyl acetate (30.0 mL × 2). Hydrochloric acid (1M in water) was added to the aqueous phase to adjust pH to ~5 and extracted with ethyl acetate (30.0 mL× 3). The combined organic layers were concentrated under reduced pressure to give a residue. The crude product was triturated with methanol at 20°C for 10 min and filtered. The filter cake was dried under vacuum to afford (S)-3,3-dimethyl-2-(thiazol-5- ylamino)butanoic acid (150 mg, 630 μmol, 48% yield, 90% purity) as light yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 12.62 (s, 1H), 8.11 (s, 1H), 6.82 (s, 1H), 6.43 (d, J = 10.0 Hz, 1H), 3.45 (d, J = 10.0 Hz, 1H), 1.02 (s, 9H). SFC: de% = 100%. Preparation of CPD0186529 Procedure for preparation of methyl (2S)-3,3-dimethyl-2-(2,2,2-trifluoroethylamino)butanoate To a mixture of methyl (2S)-2-amino-3,3-dimethyl-butanoate (25.0 g, 137 mmol, 1.00 eq, HCl) and potassium carbonate (57.1 g, 412 mmol, 3.00 eq) in acetonitrile (300 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (47.9 g, 206 mmol, 1.50 eq). After stirring at 80°C for 12 h, the reaction mixture was filtered and the filter cake was washed with ethyl acetate (200 mL × 3). The filtrate was concentrated under vacuum to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 50/1 to 20/1) to give methyl (2S)-3,3-dimethyl-2-(2,2,2- trifluoroethylamino) butanoate (21.0 g, 83.2 mmol, 60% yield, 90% purity) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 3.73 (s, 3H), 3.32-3.12 (m, 1H), 3.04-2.83 (m, 2H), 1.95-1.81 (m, 1H), 0.96 (s, 9H). Procedure for preparation of (2S)-3,3-dimethyl-2-(2,2,2-trifluoroethylamino)butanoic acid To a mixture of methyl (2S)-3,3-dimethyl-2-(2,2,2-trifluoroethylamino)butanoate (5.00 g, 19.8 mmol, 90% purity, 1.00 eq) in methanol (20.0 mL) and tetrahydrofuran (20.0 mL) was added a solution of lithium hydroxide monohydrate (2.49 g, 59.4 mmol, 3.00 eq) in water (20.0 mL). After stirring at 20°C for 48 h, the reaction mixture was concentrated in vacuum to give a residue. The residue was diluted with water (50.0 mL) and washed with ethyl acetate (20.0 mL × 3). Hydrochloric acid (1.00 M) was added to the aqueous phase to adjust pH to 5~6 and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were concentrated under vacuum to give (2S)-3,3-dimethyl-2-(2,2,2- trifluoroethylamino)butanoic acid (4.50 g, crude) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 3.32-3.22 (m, 1H), 3.11 - 2.97 (m, 2H), 1.03 (s, 9H). Procedure for preparation of CPD0186529 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin- 3-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroethylamin o) butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of (2S)-3,3-dimethyl-2-(2,2,2-trifluoroethylamino)butanoic acid (50.0 mg, 0.234 mmol, 1.00 eq) in N,N-dimethylformamide (1.00 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (178 mg, 0.469 mmol, 2.00 eq) and N,N- diisopropylethylamine (121 mg, 0.938 mmol, 4.00 eq) at 0°C. After stirring at 0°C for 0.2 h, (1R,2S,5S)- N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-6,6-dime thyl-3-azabicyclo[3.1.0] hexane-2- carboxamide (84.3 mg, 0.258 mmol, 1.10 eq, HCl) was added. The resulting mixture was stirred at 20°C for 4 h, and purified by prep-HPLC (column: Phenomenex Synergi C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 44%-64%, 10min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-(2,2,2-trif luoroethylamino)butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (19.9 mg, 39.8 μmol, 17% yield, 97% purity) as a white solid. Preparation of CPD0186530 and CPD0188059 Procedure for preparation of CPD0186530&CPD0188059 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(1S)-2- oxocyclopentyl]ethyl]-3-[(2S)-2-(2,2-difluoropropanoylamino) -3,3-dimethyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (1R,2S,5S)-N-[(1R)-1-cyano-2-[(1S)-2- oxocyclopentyl]ethyl]-3-[(2S)-2-(2,2-difluoropropanoylamino) -3,3-dimethyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-N-[(1S)-1- cyano-2- [(3S)-2- oxopyrrolidin-3-yl]ethyl]-6,6-dimethyl-3-azabicyclo[3.1.0]he xane-2-carboxamide (80.0 mg, 198 μmol, 1.00 eq) and 2,2-difluoropropanoic acid (24.0 mg, 218 μmol, 1.10 eq) in N,N-dimethylformamide (2.00 mL) were added N,N-diisopropylethylamine (76.9 mg, 595 μmol, 3.00 eq) and bis(2-oxo-3- oxazolidinyl)phosphinicchloride (75.7 mg, 297 μmol, 1.50 eq) at 20°C. After stirring at 20°C for 16 h, the reaction mixture was poured into ammonium chloride (20.0 mL) aqueous solution and extracted with ethyl acetate (30.0 mL × 2). The combined organic layers were washed with brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C1875*30mm*3 μm; mobile phase: [water (FA)-ACN]; B%: 30%-60%, 7 min) and SFC (column: DAICEL CHIRALPAK IC (250mm*30mm,10 μm); mobile phase: [0.1% NH3^H2O MeOH]; B%: 20%-20%, 3.3 min) to give CPD0186530 (1R,2S,5S)-N- [(1S)-1-cyano-2-[(1S)-2-oxocyclopentyl]ethyl]-3-[(2S)-2-(2,2 -difluoropropanoylamino)-3,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxami de (10.6 mg, 20.7 μmol, 10% yield, 97% purity) and CPD0188059 (1R,2S,5S)-N-[(1R)-1-cyano-2-[(1S)-2-oxocyclopentyl] ethyl]-3-[(2S)-2-(2,2- difluoropropanoylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2- carboxamide (4.8 mg, 9.16 μmol, 5% yield, 94% purity) as a white solid. Preparation of CPD0186848 Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl - butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyli c acid To a solution of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl -butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (30.0 g, 78.4 mmol, 1.00 eq) in tetrahydrofuran (100 mL) and water (100 mL) was added lithium hydroxide (9.87 g, 235 mmol, 3.00 eq) at 20°C. After stirring at 20°C for 16 h, the reaction mixture was adjusted to pH~3-4 with hydrochloric acid (1 M in water) and extracted with ethyl acetate (300 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated at vacuum to afford (1R,2S,5S)- 3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxylic acid (26.0 g, 67.0 mmol, 85% yield, 95% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.61 (s, 1H), 6.67 (d, J = 9.2 Hz, 1H), 4.12 (s, 1H), 4.05 (d, J = 9.2 Hz, 1H), 3.96-3.87 (m, 1H), 3.82-3.71 (m, 1H), 1.55-1.45 (m, 1H), 1.41-1.38 (m, 1H), 1.34 (s, 9H), 1.00 (s, 3H), 0.93 (s, 9H), 0.84 (s, 3H). LC-MS (Method C): R _t = 0.912 min; MS (ESIpos): m/z = 369.3 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimeth yl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid A mixture of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl -butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (26.0 g, 70.6 mmol, 1.00 eq) in hydrochloric acid (4 M in dioxane, 250 mL) was stirred at 25°C for 1 h. The mixture was concentrated under vacuum to afford (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimeth yl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (21.0 g, 68.9 mmol, 98% yield, HCl) as a white solid. The crude product was used for the next step reaction directly. Procedure for preparation of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxylic acid To a solution of (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimeth yl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (21.0 g, 68.9 mmol, 1.00, HCl salt) and triethylamine (69.7 g, 689 mmol, 95.9 mL, 10.0 eq) in methanol (200 mL) was added methyl 2,2,2-trifluoroacetate (70.6 g, 551 mmol, 55.6 mL, 8.00 eq) at 0°C. After stirring at 20°C for 16 h, the reaction mixture was poured into saturated ammonium chloride aqueous solution (100 mL) and extracted with ethyl acetate (300 mL × 2). The combined organic layers were washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®;220 g SepaFlash® Silica Flash Column, Eluent of 0~60% ethyl acetate/petroleum ether gradient @100 mL/min) to afford (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxylic acid (25.5 g, 66.5 mmol, 97% yield, 95% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.75 (s, 1H), 9.46 (d, J = 9.6 Hz, 1H), 4.43 (d, J = 8.8 Hz, 1H), 4.14 (s, 1H), 3.90-3.79 (m, 1H), 3.76-3.66 (m, 1H), 1.58-1.47 (m, 1H), 1.45-1.38 (m, 1H), 1.04-0.95 (m, 12H), 0.82 (s, 3H). LC-MS (Method C): R _t = 0.590 min; MS (ESIpos): m/z = 365.1 [M+H] ⁺ . Procedure for preparation of imidazo[1,2-a]pyrazine-3-carbaldehyde To a solution of 3-bromoimidazo[1,2-a]pyrazine (200 mg, 1.01 mmol, 1.00 eq) in tetrahydrofuran (4.00 mL) was added lithium magnesium dichloride propan-2-ide (1.30 M, 1.55 mL, 2.00 eq) dropwise at 0°C. After stirring at 0°C for 0.5 h, a solution of N,N-dimethylformamide (0.200 mL, 2.60 mmol, 2.57 eq) in anhydrous tetrahydrofuran (1.00 mL) was added dropwise at 20 ^. After stirring at 20°C for 1 h, the reaction mixture was quenched with saturated ammonium chloride solution (20.0 mL) and extracted with ethyl acetate (15.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether/ethyl acetate = 1/1) to afford imidazo[1,2-a]pyrazine-3-carbaldehyde (110 mg, 729 μmol, 72% yield, 97% purity) as a light yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 10.11 (s, 1H), 9.36-9.30 (m, 2H), 8.45 (s, 1H), 8.27 (d, J = 4.4 Hz, 1H). LC-MS (Method O): R _t = 0.140 min; MS (ESIpos): m/z = 148.1 [M+H] ⁺ . Procedure for preparation of 2-amino-2-(imidazo[1,2-a]pyrazin-3-yl)acetonitrile To a mixture of imidazo[1,2-a]pyrazine-3-carbaldehyde (110 mg, 748 μmol, 1.00 eq) and ammonium hydroxide (15.0 M in methanol, 0.500 mL, 10.0 eq) in methanol (1.00 mL) was added titanium(IV) isopropoxide (255 mg, 897 μmol, 1.20 eq). After stirring at 20°C for 2 h, trimethylsilylformonitrile (89.0 mg, 897 μmol, 1.20 eq) was added. After stirring at 20°C for 12 h, the reaction mixture was poured into water (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 2-amino-2-(imidazo[1,2-a]pyrazin-3-yl)acetonitrile (120 mg, crude) as a yellow oil. The crude product was used for the next step reaction without further purification. LC-MS (Method N): R _t = 0.100 min; MS (ESIpos): m/z = 174.1 [M+H] ⁺ . Procedure for preparation of CPD0186848 (1R,2S,5S)-N-(cyano(imidazo[1,2-a]pyrazin-3- yl)methyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)b utanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (189 mg, 520 μmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (296 mg, 780 μmol, 1.50 eq) and N-ethyl-N- isopropyl-propan-2-amine (134 mg, 1.04 mmol, 2.00 eq) in N,N-dimethylformamide (1.00 mL) was added 2-amino-2-imidazo[1,2-a]pyrazin-3-yl-acetonitrile (90.0 mg, 520 μmol, 1.00 eq) at 0°C. After stirring at 20°C for 12 h, the reaction mixture was quenched with saturated ammonium chloride aqueous solution (20.0 mL) and extracted with ethyl acetate (15.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (300-400 mesh, petroleum ether, then petroleum ether/ethyl acetate = 1/1) followed by prep-HPLC (TFA condition; column: Welch Ultimate C18150*25mm*5 μm; mobile phase: [water(TFA)-ACN]; B%: 30%- 60%,10 min) to give (1R,2S,5S)-N-(cyano(imidazo[1,2-a]pyrazin-3-yl)methyl)-3-((S )-3,3-dimethyl-2- (2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicycl o[3.1.0]hexane-2-carboxamide (16.6 mg, 31.8 μmol, 6% yield, 99% purity) as a yellow solid. Preparation of CPD0186849 Procedure for preparation of 2-amino-2-(imidazo[1,2-a]pyridin-3-yl)acetonitrile To a mixed solution of imidazo[1,2-a]pyridine-3-carbaldehyde (0.300 g, 2.05 mmol, 1.00 eq) in methanol (4.00 mL) and ammonia (7.00 M in methanol, 1.47 mL) was added dropwise titanium(iv) isopropoxide (700 mg, 2.46 mmol, 1.20 eq). After stirring for 0.5 h, trimethylsilyl cyanide (244 mg, 2.46 mmol, 0.308 mL, 1.20 eq) was added dropwise. After addition, the mixture was stirred at 20°C for 16 h. The reaction mixture was poured into saturated sodium bicarbonate solution (5.00 mL), extracted with ethyl acetate (10.0 mL × 3). The combined layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give a residue, which was purified by column chromatography (Biotage, SiO ₂ , petroleum ether/ethyl acetate =1/1 then dichloromethane / methanol =10/1) to give 2-amino-2-imidazo[1,2-a]pyridin-3-yl-acetonitrile (0.183 g, 1.06 mmol, 52% yield) as a yellow oil. LC-MS (Method O): R _t = 0.209 min; MS (ESIpos): m/z = 173.1 [M+H] ⁺ . Procedure for preparation of CPD0186849 – (1R,2S,5S)-N-[cyano(imidazo[1,2-a]pyridin-3- yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide A solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0] hexane-2-carboxylic acid (387 mg, 1.06 mmol, 1.00 eq), N,N-diisopropylethylamine (452 mg, 3.50 mmol, 0.610 mL, 3.29 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (558 mg, 1.47 mmol, 1.38 eq).in N,N-dimethylformamide (3.00 mL) was stirred at 25°C for 0.5 h.2-Amino-2-imidazo[1,2-a]pyridin-3-yl-acetonitrile (183 mg, 1.06 mmol, 1.00 eq) was added. After stirring at 25°C for 15.5 h, the mixture was poured into water (10.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Ultimate C18150*25mm*5 μm; mobile phase: [water(TFA)-ACN]; B%: 25%-55%,10 min) to give (1R,2S,5S)-N-[cyano(imidazo[1,2- a]pyridin-3-yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-triflu oroacetyl)amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (24.0 mg, 35.2 μmol, 3% yield, TFA) as a light yellow solid. Preparation of CPD0186850 Procedure for preparation of 2-amino-2-imidazo[1,2-a]pyrimidin-3-yl-acetonitrile To a solution of imidazo[1,2-a]pyrimidine-3-carbaldehyde (0.600 g, 4.08 mmol, 1.00 eq) in methanol (10.0 mL) and ammonia (7 M in methanol, 2.91 mL, 5.00 eq) was added titanium (IV) isopropoxide (1.39 g, 4.90 mmol, 1.45 mL, 1.20 eq) at 20 °C. After stirring at 20 °C for 2 h, trimethylsilylcyanide (486 mg, 4.90 mmol, 613 μL, 1.20 eq) was added dropwise. After addition, the resulting mixture was stirred at 20 °C for 14 h. The reaction mixture was concentrated under vacuum to give a residue. The residue was triturated with ethyl acetate (40.0 mL). After filtration, the filtrate was concentrated to give 2-amino- 2-imidazo[1,2-a]pyrimidin-3-yl-acetonitrile (200 mg, crude purity) as a yellow solid. Procedure for preparation of CPD0186850 - (1R,2S,5S)-N-[cyano(imidazo[1,2-a]pyrimidin-3- yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (460 mg, 1.26 mmol, 1.09 eq) in N,N-dimethylformamide (10 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (660 mg, 1.74 mmol, 1.50 eq) and N,N-diisopropylethylamine (450 mg, 3.48 mmol, 606 μL, 3.01 eq) at 0 °C. After stirring at 0 °C for 10 min, a solution of 2-amino-2-imidazo[1,2-a]pyrimidin-3-yl-acetonitrile (200 mg, crude) in N,N-dimethylformamide (1.00 mL) was added into the above mixture. After addition, the resulting mixture was stirred at 20 °C for 16 h. The reaction mixture was poured into saturated sodium bicarbonate aqueous solution (20.0 mL) and extracted with ethyl acetate (90.0 mL × 3). The combined organic layers were washed with brine (40.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 0/1) to give an impure product. The impure compound was combined with EW33018-4 and purified by prep-HPLC twice (column: Phenomenex luna C18 150*25mm* 10 μm; mobile phase: [water (FA)-ACN]; B%: 32%-62%, 2 min), (column: Phenomenex Synergi Polar-RP 100*25mm*4 μm; mobile phase: [water(TFA)-ACN];B%: 38%-58%,7min) to give (1R,2S,5S)-N-[cyano(imidazo[1,2-a]pyrimidin-3-yl)methyl]-3-[ (2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (190 mg, 359 μmol, 31% yield, 98% purity) as a white solid. Preparation of CPD0186927 Procedure for preparation of 7-amino-5,6-dihydrocyclopenta[c]pyridine-7-carboxamide To a solution of ammonium chloride (402 mg, 7.51 mmol, 10 eq) in ammonium hydroxide (13.0 mmol, 2.00 mL, 25.0% purity) was added sodium cyanide (0.22 g, 4.47 mmol, 5.95 eq) at 25°C. After addition, a mixture of 5,6-dihydrocyclopenta[c]pyridin-7-one (100 mg, 751 umol, 1.00 eq) in isopropanol (2.00 mL) was added into dropwise at 25°C. After stirring at 50°C for 16 h in a sealed tube, the reaction was diluted with water (10.0 mL), adjusted to pH 11~14 with potassium carbonate and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (10.0 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reversed phase HPLC (C18, 40 g; condition: H ₂ O (0.1% ammonium hydroxide)/CH ₃ CN = 100/0 to 50/50,) to give 7-amino-5,6-dihydrocyclopenta[c]pyridine-7-carboxamide (130 mg, 587 μmol, 78% yield, 80% purity) as a black brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.87-8.82 (m, 1H), 8.73 (d, J = 4.0 Hz, 1H), 8.58-8.54 (m, 1H), 8.51- 8.44 (m, 1H), 7.97 (dd, J = 13.6 , 1.6 Hz, 1H), 7.67 (dd, J = 5.2, 1.2 Hz, 1H), 7.62 (s, 1H), 3.19-3.13 (m, 2H), 2.68-2.64 (m, 2H). LC-MS (Method A): R _t = 0.126 min; MS (ESIpos): m/z = 178.2 [M+H] ⁺ . Procedure for preparation of 7-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carbonyl] amino]-5,6- dihydrocyclopenta[c]pyridine-7-carboxamide To a mixture of 7-amino-5,6-dihydrocyclopenta[c]pyridine-7-carboxamide (100 mg, 564 μmol, 1.00 eq) and (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (206 mg, 564 μmol, 1.00 eq) in N,N-dimethylformamide (3.00 mL) were added N,N-diisopropylethylamine (219 mg, 1.69 mmol, 3.00 eq) and O-(7-azabenzotriazol-1- yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (279 mg, 734 μmol, 1.30 eq) After stirring at 25°C for 16 h, the reaction mixture was poured into saturated ammonium chloride (10.0 mL) aqueous solution and extracted with ethyl acetate (20.0 mL × 2). The combined organic layers were washed with brine (10.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative HPLC (column: Shim-pack C18150*25*10 μm; mobile phase: [water(FA)-ACN]; B%: 15%-45%,10 min) to afford 7-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl) amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-car bonyl]amino]-5,6- dihydrocyclopenta[c]pyridine-7-carboxamide (20.0 mg, 38.2 μmol, 7% yield) as a gray solid. LC-MS (Method C): R _t = 0.812 min; MS (ESIpos): m/z = 524.3 [M+H] ⁺ . Procedure for preparation of CPD0186927 - (1R,2S,5S)-N-(7-cyano-5,6- dihydrocyclopenta[c]pyridin-7-yl)-3-[(2S)-3,3-dimethyl-2-[(2 ,2,2-trifluoroacetyl)amino] butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxami de To a solution of 7-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacety l)amino] butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-5,6-dih ydrocyclopenta[c]pyridine-7- carboxamide (20.0 mg, 38.2 μmol, 1.00 eq) in dichloromethane (2.00 mL) was added Burgess reagent (36.4 mg, 153 μmol, 4.00 eq) at 0°C. After stirring at 25°C for 4 h, saturated sodium bicarbonate aquesou solutionwas added to the mixture to adjust pH~7 and extracted with ethyl acetate (20.0 mL × 2). The combined organic layers were washed with brine (10.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (column: Shim-pack C18150*25*10 μm; mobile phase: [water(FA)-ACN]; B%: 25%- 55%, 10 min) to afford (1R,2S,5S)-N-(7-cyano-5,6-dihydrocyclopenta[c]pyridin-7-yl)- 3-[(2S)-3,3- dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2- carboxamide (4.88 mg, 9.56 μmol, 25% yield, 99% purity) as a black gum. CPD0186927: Preparation of CPD0187053 Procedure for preparation of tert-butyl 3-[1-(benzyloxycarbonylamino) -2-methoxy-2-oxo- ethylidene]pyrrolidine-1-carboxylate To a solution of methyl 2-(benzyloxycarbonylamino)-2-dimethoxyphosphoryl-acetate (21.4 g, 64.7 mmol, 1.20 eq) in dichloromethane (150 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (8.42 g, 55.3 mmol, 8.34 mL, 1.02 eq) at 0°C under nitrogen. After stirring at 0°C for 0.5 h, tert-butyl 3- oxopyrrolidine-1-carboxylate (10.0 g, 53.9 mmol, 1.00 eq) was added dropwise. After stirring at 25°C for 12 h, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 1/0 to 3/1) to afford tert-butyl 3-[1-(benzyloxycarbonylamino)-2-methoxy-2-oxo-ethylidene]pyr rolidine-1- carboxylate (16.3 g, 41.8 mmol, 77% yield) as yellow oil. LCMS (Method G): R _t = 0.987 min; MS (ESIpos): m/z = 389.0 [M-H] ⁺ . Procedure for preparation of tert-butyl 3-(1-amino-2-methoxy-2-oxo-ethyl) pyrrolidine-1- carboxylate To a solution of tert-butyl 3-[1-(benzyloxycarbonylamino)-2-methoxy-2-oxo-ethylidene] pyrrolidine-1- carboxylate (8.00 g, 20.4 mmol, 1.00 eq) in methanol (100 mL) was added palladium on carbon (800 mg, 20.4 mmol, 10% purity, 1.00 eq) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen 3 times. After stirring at 25°C for 3 h under hydrogen (15.0 psi) atmosphere, the reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl 3-(1-amino-2- methoxy-2-oxo-ethyl) pyrrolidine-1-carboxylate (4.66 g, crude) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 3.63 (d, J = 0.8 Hz, 3H), 3.31-3.24 (m, 2H), 3.22-3.08 (m, 2H), 3.07- 2.94 (m, 1H), 2.28 (dt, J = 16.4, 7.8 Hz, 1H), 1.86 (br. s, 2H), 1.79-1.52 (m, 2H), 1.38 (s, 9H). Procedure for preparation of 2-amino-2-(1-tert-butoxycarbonylpyrrolidin-3-yl) acetic acid To a solution of tert-butyl 3-(1-amino-2-methoxy-2-oxo-ethyl) pyrrolidine-1-carboxylate (4.66 g, 18.0 mmol, 1.00 eq) in water (50.0 mL) was added sodium hydroxide (1.44 g, 36.0 mmol, 2.00 eq). After stirring at 25°C for 12 h, the reaction mixture was filtered and concentrated under reduced pressure to give 2-amino-2-(1-tert-butoxycarbonylpyrrolidin-3-yl) acetic acid (4.3 g, crude) as an orange solid. LC-MS (Method H): R _t = 0.186 min; MS (ESIpos): m/z = 243.0 [M-H] ⁺ . Procedure for preparation of 2-(1-tert-butoxycarbonylpyrrolidin-3-yl) -2-[ (2, 2, 2-trifluoroacetyl) amino]acetic acid To a solution of 2-amino-2-(1-tert-butoxycarbonylpyrrolidin-3-yl) acetic acid (4.30 g, 17.6 mmol, 1.00 eq) in methanol (50.0 mL) was added triethylamine (7.12 g, 70.4 mmol, 9.80 mL, 4.00 eq), ethyl 2,2,2- trifluoroacetate (7.50 g, 52.8 mmol, 7.28 mL, 3.00 eq). After stirring at 25°C for 12 h, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed phase (Instrument: 120g Flash; Column: Welch Ultimate XB_C1820-40μm; eluent A: water (0.1% NH3^H2O), eluent B: acetonitrile; gradient: 0-10 min 0-60% B; flow 85 ml/min; temperature: room temperature; Detector: UV 220/254 nm)) to afford 2-(1-tert-butoxycarbonylpyrrolidin-3-yl)-2-[(2,2,2- trifluoroacetyl)amino]acetic acid (4.68 g, 13.7 mmol, 78% yield) as a colorless solid. LC-MS (Method G): R _t = 0.320 min; MS (ESIpos): m/z = 363.0 [M+Na] ⁺ . Procedure for preparation of tert-butyl (3S)-3-[(1S)-2-[ (1R,2S,5S) -2-[[(1S)-2-amino-2-oxo-1- [[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-6,6-dime thyl-3-azabicyclo[3.1.0]hexan-3-yl]- 2-oxo-1-[(2,2,2-trifluoroacetyl)amino]ethyl]pyrrolidine-1-ca rboxylate To a solution of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-6, 6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (500 mg, 1.45 mmol, 1.00 eq, hydrochloric acid salt), 2-(1-tert-butoxycarbonylpyrrolidin-3-yl)-2-[ (2,2,2-trifluoroacetyl)amino]acetic acid (592 mg, 1.74 mmol, 1.20 eq) in dichloromethane (20.0 mL) were added diisopropylethylamine (562 mg, 4.35 mmol, 757 μL, 3.00 eq), O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (826 mg, 2.17 mmol, 1.50 eq) at 0°C. After stirring at 25°C for 12 h, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex luna C18150*40 mm* 15 μm; mobile phase: [water (FA) -ACN];B%: 27%-57%, 10 min) to afford tert-butyl (3S)-3-[(1S)-2-[(1R,2S,5S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2 - oxopyrrolidin-3-yl]methyl] ethyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl] -2-oxo-1- [(2,2,2-trifluoroacetyl)amino]ethyl]pyrrolidine-1-carboxylat e (310 mg, 491 μmol, 34% yield) as a yellow solid. LC-MS (Method C): R _t = 0.770 min; MS (ESIpos): m/z = 631.3 [M+H] ⁺ . Procedure for preparation of tert-butyl (3S)-3-[(1S)-2-[ (1R,2S,5S) -2-[[(1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]carbamoyl]-6,6-dimethyl-3-azabicycl o [3.1.0]hexan-3-yl]-2-oxo-1-[(2,2,2- trifluoroacetyl)amino]ethyl]pyrrolidine-1-carboxylate To a solution of tert-butyl (3S)-3-[(1S)-2-[(1R,2S,5S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S) -2-oxopyrrolidin- 3-yl]methyl]ethyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexan-3-yl]-2-oxo-1-[(2,2,2- trifluoroacetyl)amino]ethyl]pyrrolidine-1-carboxylate (310 mg, 491 μmol, 1.00 eq) in dichloromethane (2.00 mL) was added Burgess reagent (234 mg, 983 μmol, 2.00 eq) at 0°C. After stirring at 25°C for 2 h under nitrogen atmosphere, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi C18150*25mm*10 μm; mobile phase: [water (FA) -ACN];B%: 35%-65%, 10 min) to afford tert- butyl (3S)-3-[(1S)-2-[(1R,2S,5S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxopyr rolidin-3-yl]ethyl]carbamoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-1-[ (2, 2, 2-trifluoroacetyl) amino]ethyl]pyrrolidine-1- carboxylate (130 mg, 212 μmol, 43% yield) as a white solid. LC-MS (Method C): R _t = 0.816 min; MS (ESIpos): m/z = 513.2 [M+H] ⁺ . Procedure for preparation of CPD0187053 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S) -2-oxopyrrolidin- 3-yl]ethyl]-6,6-dimethyl-3-[(2S)-2-[(3S)-pyrrolidin-3-yl]-2- [(2,2,2-trifluoroacetyl)amino]acetyl]-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of tert-butyl (3S)-3-[(1S)-2-[(1R,2S,5S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxopyr rolidin-3- yl]ethyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3- yl]-2-oxo-1-[(2,2,2-trifluoroacetyl) amino]ethyl]pyrrolidine-1-carboxylate (70.0 mg, 114 μmol, 1.00 eq) in acetonitrile (2.00 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol, 1.00 mL, 118 eq) at 0°C. After stirring at 25°C for 1 h, the reaction mixture was quenched by triethylamine (0.50 mL) at 0°C, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Synergi Polar-RP 100*25 mm*4 μm; mobile phase: [water(TFA)-ACN];B%:21%-41%, 7 min) to afford (1R,2S,5S)-N-[(1S)-1-cyano-2- [(3S)-2-oxopyrrolidin-3-yl]ethyl]-6,6-dimethyl-3-[(2S)-2- [(3S)-pyrrolidin-3-yl]-2-[(2,2,2-trifluoroacetyl) amino]acetyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide (43.3 mg, 83.5 μmol, 73% yield, 98% purity) as yellow oil. Preparation of CPD0187106 and CPD0187107. Procedure for preparation of methyl (2S)-3,3-dimethyl-2-[(6-methyl-3-pyridyl)amino]butanoate Toluene (200 mL) was added to a mixture of 5-bromo-2-methyl-pyridine (4.00 g, 23.2 mmol, 1.00 eq), methyl (2S)-2-amino-3,3-dimethyl-butanoate (5.07 g, 27.9 mmol, 1.20 eq, HCl), bis(dibenzylideneacetone)palladium (0) (2.13 g, 2.33 mmol, 0.10 eq), (bis (diphenylphosphino)-1,1'- binaphthyl (2.90 g, 4.65 mmol, 0.20 eq) and sodium tert-butoxide (6.70 g, 69.8 mmol, 3.00 eq) under nitrogen atmosphere at room temperature. After stirring at 100°C for 12 h, the reaction mixture was poured into saturated ammonium chloride (200 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 2/1) to give methyl (2S)-3,3-dimethyl-2- [(6-methyl-3-pyridyl)amino]butanoate (3.2 g, 10.0 mmol, 43% yield, 74% purity) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.99 (d, J = 2.9 Hz, 1H), 6.93-6.98 (m, 1H), 6.84-6.91 (m, 1H), 3.74 (d, J = 10.8 Hz, 1H), 3.65-3.71 (m, 3H), 2.43 (s, 3H), 1.06 ppm (s, 9H). LC-MS (Method A): R _t = 0.676 min, MS (ESIpos): m/z = 223.2 [M+H] ⁺ . SFC: er: 1/1. Procedure for preparation of 3,3-dimethyl-2-[(6-methyl-3-pyridyl)amino]butanoic acid A mixture of methyl 3,3-dimethyl-2-[(6-methyl-3-pyridyl)amino]butanoate (1.00 g, 4.23 mmol, 1.00 eq) and lithium hydroxide hydrate (355 mg, 8.46 mmol, 2.00 eq) in mixed solvent of methanol (10.0 mL) and water (10.0 mL) was stirred at 20°C for 14 h. The mixture was concentrated, and diluted with water (50.0 mL). Formic acid was added to adjust pH = 5. The solution was extracted with ethyl acetate (50.0 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 3,3-dimethyl-2-[(6-methyl-3-pyridyl)amino]butanoic acid (540 mg, 2.43 mmol, 57% yield) as yellow oil. LC-MS (Method C): R _t = 0.353 min, MS (ESIpos): m/z = 223.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethy l]-3- [(2S)-3,3-dimethyl-2-[(6-methyl-3-pyridyl)amino]butanoyl]-6, 6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide A mixture of (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethy l]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (261 mg, 0.799 mmol, 0.90 eq, HCl), 3,3-dimethyl-2-[(6- methyl-3-pyridyl)amino]butanoic acid (200 mg, 0.90 mmol, 1.00 eq), N,N-diisopropylethylamine (233 mg, 1.80 mmol, 2.00 eq) and 1-propanephosphonic anhydride (513 mg, 1.35 mmol, 1.50 eq) in N,N- dimethylformamide (4.00 mL) was stirred at 20°C for 14 h. The combined mixture (EW30036-216, EW30036-214) was diluted with water (50.0 mL) and extracted with ethyl acetate (50.0 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under vacuum to give a residue. The residue was purified by prep-TLC (ethyl acetate / methanol = 10/1) to give two fractions of diastereomers. One diastereomer was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10 μm; mobile phase: [water(FA)-ACN];B%: 10%- 30%,2min) to give CPD0187106 (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethy l]-3- [(2S)-3,3-dimethyl-2-[(6-methyl-3-pyridyl)amino]butanoyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (8.16 mg, 16.2 μmol, 1.80% yield, 98% purity) as white solid. The other diastereomer was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water (FA)- ACN]; B%: 10%-30%,2min), SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um); mobile phase: [Neu-IPA];B%: 50%-50%,5min) and pre-HPLC(column: Waters Xbridge 150*25mm* 5 μm;mobile phase: [water( NH4HCO3)-ACN]; B%: 32%-62%, 8 min) to give CPD0187607 (1R,2S,5S)-N- [(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-[(2S)-3, 3-dimethyl-2-[(6-methyl-3- pyridyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexa ne-2-carboxamide (4.49 mg, 8.44 μmol, 0.09% yield, 93% purity) as a white solid. Preparation of CPD0187510 Procedure for preparation of O1-tert-butyl O2-methyl (2S)-5-oxopyrrolidine-1,2-dicarboxylate To a mixture of methyl (2S)-5-oxopyrrolidine-2-carboxylate (20.0 g, 140 mmol, 1.00 eq) and N,N- dimethylpyridin-4-amine (1.71 g, 14.0 mmol, 0.100 eq) in acetonitrile (200 mL) was drop-wise added di- tert-butyldicarbonate (33.5 g, 154 mmol, 1.10 eq) at 0°C. After stirring at 25°C for 1 h, the mixture was concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120g SepaFlash® Silica Flash Column, Eluent of 0~50% ethyl acetate/ petroleum ether gradient @ 100 mL/min) to give O1-tert-butyl O2-methyl (2S)-5-oxopyrrolidine-1,2- dicarboxylate (29.7 g, 122 mmol, 87% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 4.61 (dd, J = 10.0, 3.6 Hz, 1H), 3.71 (s, 3H), 2.47-2.42 (m, 2H), 2.35- 2.27 (m, 1H), 1.93-1.87 (m, 1H), 1.40 (s, 9H). Procedure for preparation of O1-tert-butyl O2-methyl (2S)-4-(1-hydroxycyclobutyl)-5-oxo- pyrrolidine-1,2-dicarboxylate To a solution of O1-tert-butyl O2-methyl (2S)-5-oxopyrrolidine-1,2-dicarboxylate (23.0 g, 94.6 mmol, 1.00 eq) in tetrahydrofuran (230 mL) was added lithium bis(trimethylsilyl)amide (1.00 M in tetrahydrofuran, 100 mL, 1.06 eq) at -78°C. After stirring at -78°C for 1 h, a solution of cyclobutanone (6.96 g, 99.3 mmol, 1.05 eq) and boron trifluoride diethyl ether (14.1 g, 99.3 mmol, 1.05 eq) in tetrahydrofuran (100 mL) was added at -78°C. After addition, the mixture was stirred at -78°C for 2.5 h. The mixture was quenched with saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate (150 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~35% Ethyl acetate / Petroleum ether gradient @ 80 mL/min) to give O1-tert-butyl O2-methyl (2S)-4-(1-hydroxycyclobutyl)-5-oxo-pyrrolidine- 1,2-dicarboxylate (25.8 g, 82.3 mmol, 87% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 5.37 (s, 1H), 4.51 (dd, J = 9.6, 4.0 Hz, 1H), 3.71 (s, 3H), 2.88-2.80 (m, 1H), 2.47-2.17 (m, 2H), 2.045-1.89 (m, 3H), 1.63-1.46 (m, 2H), 1.39 (s, 9H). Procedure for preparation of O1-tert-butyl O2-methyl (2S)-4-cyclobutylidene-5-oxo-pyrrolidine- 1,2-dicarboxylate To a mixture of O1-tert-butyl O2-methyl (2S)-4-(1-hydroxycyclobutyl)-5-oxo-pyrrolidine-1,2- dicarboxylate (25.8 g, 82.3 mmol, 1.00 eq) and triethylamine (33.3 g, 329 mmol, 4.00 eq) in dichloromethane (200 mL) was added methane sulfonyl chloride (19.0 g, 166 mmol, 2.01 eq) dropwise at 0°C. The reaction mixture was warmed to 25°C and stirred for 64 h. The mixture was poured into water (200 mL) and extracted with dichloromethane (100 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~22% ethyl acetate / petroleum ether gradient @ 80 mL/min) to give O1-tert-butyl O2-methyl (2S)-4- cyclobutylidene-5-oxo-pyrrolidine-1,2-dicarboxylate (11.8 g, 40.0 mmol, 49% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 4.62 (dd, J = 10.8, 3.2 Hz, 1H), 3.69 (s, 3H), 3.09-2.97 (m, 2H), 2.92- 2.83 (m, 1H), 2.79-2.72 (m, 2H), 2.45-2.40 (m, 1H), 2.11-2.03 (m, 2H), 1.40 (s, 9H). Procedure for preparation of O7-tert-butyl O8-methyl (8S)-6-oxo-7-azadispiro[3.0.45.14]decane- 7,8-dicarboxylate To a solution of trimethylsulfoxide iodide (8.79 g, 40.0 mmol, 1.00 eq) in dimethylsulfoxide (80.0 mL) was added sodium hydride (1.60 g, 40.0 mmol, 60% purity, 1.00 eq) at 0°C. After stirring at 0°C for 0.5 h, O1-tert-butyl O2-methyl (2S)-4-cyclobutylidene-5-oxo-pyrrolidine-1,2-dicarboxylate (11.8 g, 40.0 mmol, 1.00 eq) in dimethylsulfoxide (100 mL) was added dropwise at 0°C. The reaction mixture was allowed to warm to 25°C and stirred for 0.5 h. The mixture was poured into saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate (150 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~20% ethyl acetate/petroleum ether gradient @ 80 mL/min) to give O7-tert-butyl O8-methyl (8S)-6- oxo-7-azadispiro[3.0.45.14]decane-7,8-dicarboxylate (3.90 g, 12.6 mmol, 32% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 4.73-4.68 (m, 1H), 3.76-3.71 (m, 3H), 2.46-2.36 (m, 1H), 2.25-2.14 (m, 1H), 2.06-1.80 (m, 5H), 1.71-1.63 (m, 1H), 1.41-1.40 (m, 9H), 1.21-1.15 (m, 1H), 0.96-0.90 (m, 1H). Procedure for preparation of tert-butyl (8S)-8-(hydroxymethyl)-7-azadispiro[3.0.45.14]decane-7- carboxylate A mixture of O7-tert-butyl O8-methyl (8S)-6-oxo-7-azadispiro[3.0.45.14]decane-7,8-dicarboxylate (2.9 g, 9.37 mmol, 1.00 eq) in tetrahydrofuran (30 mL) was added borane dimethyl sulfide complex (10 M, 5 mL, 5.33 eq) at 25°C. The mixture was heated to 50°C and stirred at this temperature for 16 h. The mixture was quenched with methanol (20 mL) dropwise at 15°C, followed by glycerinum (10 mL). The mixture was stirred at 15°C for 16 h, and purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~17% Ethyl acetate/Petroleum ether gradient @ 50 mL/min) to give tert-butyl (8S)-8-(hydroxymethyl)-7-azadispiro[3.0.45.14]decane-7-carbo xylate (2.00 g, 7.48 mmol, 90% yield) as a colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 4.76-4.68 (m, 1H), 3.86-3.80 (m, 1H), 3.62-3.50 (m, 1H), 3.36-3.08 (m, 2H), 2.89-2.82 (m, 1H), 2.17-2.01 (m, 3H), 1.90-1.74 (m, 4H), 1.63-1.50 (m, 1H), 1.39 (s, 9H), 0.57- 0.47 (m, 2H). Procedure for preparation of [(8S)-7-azadispiro[3.0.45.14]decan-8-yl]methanol To a mixture of tert-butyl (8S)-8-(hydroxymethyl)-7-azadispiro[3.0.45.14]decane-7-carbo xylate (2.00 g, 7.48 mmol, 1.00 eq) in acetonitrile (20.0 mL) was added hydrochloric acid (4 M in dioxane, 15 mL, 8.02 eq) dropwise at 0°C. After stirring at 25°C for 1 h, the mixture was concentrated to give [(8S)-7- azadispiro[3.0.45.14]decan-8-yl]methanol (1.50 g, crude, HCl salt) as yellow gum. The residue was used for next step directly. Procedure for preparation of tert-butyl N-[(1S)-1-[(8S)-8-(hydroxymethyl)-7- azadispiro[3.0.45.14]decane-7-carbonyl]-2,2-dimethyl-propyl] carbamate To a mixture of [(8S)-7-azadispiro[3.0.45.14]decan-8-yl]methanol (1.50 g, 7.36 mmol, crude, 1.00 eq, HCl salt) and (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid (1.36 g, 5.89 mmol, 0.80 eq) in N,N-dimethylformamide (15 mL) were added 1-propanephosphonic anhydride (7.03 g, 11.1 mmol, 50% purity in ethyl acetate, 1.50 eq) and N,N-diisopropylethylamine (3.81 g, 29.5 mmol,, 4.00 eq) at 15°C. After stirring at 15°C for 16 h, the mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~20% ethyl acetate/petroleum ether gradient @ 30 mL/min). The crude product was further purified by prep-HPLC (column: Phenomenex luna C18 150*40mm* 15 μm; mobile phase: [water (FA)-ACN]; B%: 52%-82%,10 min) to give tert-butyl N-[(1S)- 1-[(8S)-8-(hydroxymethyl)-7-azadispiro[3.0.45.14]decane-7-ca rbonyl]-2,2-dimethyl-propyl]carbamate (400 mg, 1.05 mmol, 14% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 6.56-6.49 (m, 1H), 5.03-4.51 (m, 1H), 4.31-3.98 (m, 2H), 3.66-3.47 (m, 2H), 3.25-2.92 (m, 2H), 2.20-1.61 (m, 8H), 1.39-1.37 (m, 9H), 0.93-0.91 (m, 9H), 0.61-0.53 (m, 2H). Procedure for preparation of (8S)-7-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butan oyl]- 7-azadispiro[3.0.45.14]decane-8-carboxylic acid To a mixture of tert-butyl N-[(1S)-1-[(8S)-8-(hydroxymethyl)-7-azadispiro[3.0.45.14]dec ane-7-carbonyl]- 2,2-dimethyl-propyl]carbamate (100 mg, 0.263 mmol, 1.00 eq), disodium hydrogen phosphate (0.67 M in water, 0.5 mL), sodium dihydrogen phosphate (0.67 M in water, 0.5 mL) in acetonitrile (1.00 mL) and water (1.00 mL) were added 2,2,6,6-tetramethylpiperidinooxy (4.13 mg, 26.3 μmol, 0.100 eq) and sodium chlorite (47.5 mg, 0.526 mmol, 2.00 eq) at 0°C. After stirring at 0°C for 0.5 h, sodium hypochlorite (19.6 mg, 26.3 μmol, 10% purity in water, 0.100 eq) was added. The mixture was allowed to warm to 15°C and stirred at 15°C for 1 h. The mixture was concentrated, purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 μm; mobile phase: [water(FA)-ACN]; B%: 41%-71%,7 min) to give (8S)-7-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butan oyl]-7- azadispiro[3.0.45.14]decane-8-carboxylic acid (85.0 mg, 75% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.77-12.49 (m, 1H), 6.66-6.59 (m, 1H), 4.46-4.26 (m, 1H), 4.17- 4.06 (m, 1H), 3.61-3.46 (m, 2 H), 2.23-1.58 (m, 8H), 1.37 (s, 9H), 0.97-0.89 (m, 9H), 0.63-0.54 (m, 2H). Procedure for preparation of (8S)-7-[(2S)-2-amino-3,3-dimethyl-butanoyl]-7- azadispiro[3.0.45.14]decane-8-carboxylic acid To a mixture of (8S)-7-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butan oyl]-7- azadispiro[3.0.45.14]decane-8-carboxylic acid (85.0 mg, 215 μmol, 1.00 eq) in acetonitrile (3.00 mL) was added hydrochloric acid (4 M in dioxane, 3.00 mL, 55.7 eq) at 0°C. After stirring at 15°C for 1 h, the mixture was concentrated to give (8S)-7-[(2S)-2-amino-3,3-dimethyl-butanoyl]-7- azadispiro[3.0.45.14]decane-8-carboxylic acid (70 mg, crude, HCl salt) as a white solid. Procedure for preparation of (8S)-7-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]bu tanoyl]- 7-azadispiro[3.0.45.14]decane-8-carboxylic acid To a mixture of (8S)-7-[(2S)-2-amino-3,3-dimethyl-butanoyl]-7-azadispiro[3.0 .45.14]decane-8- carboxylic acid (70.0 mg, 0.212 mmol, crude, 1.00 eq, HCl salt) and triethylamine (85.6 mg, 0.846 mmol, 4.00 eq) in methanol (3.00 mL) was added methyl 2,2,2-trifluoroacetate (54.2 mg, 0.423 mmol, 2.00 eq) at 15°C. After stirring at 15°C for 16 h, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 μm; mobile phase: [water(FA)- ACN]; B%: 38%-68%, 7 min) to give (8S)-7-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]bu tanoyl]- 7-azadispiro[3.0.45.14] decane-8-carboxylic acid (70.0 mg, 179 μmol, 85% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.50-8.48 (m, 1H), 7.37-7.35 (m, 1H), 4.57-4.53 (m, 1H), 4.49-4.34 (m, 1H), 3.59-3.57 (m, 1H), 3.50-3.49 (m, 1H), 2.25-1.58 (m, 8H), 1.04-0.94 (m, 9H), 0.64-0.55 (m, 2H). Procedure for preparation of CPD0187510 - 8S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]-7-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)ami no]butanoyl]-7- azadispiro[3.0.45.14]decane-8-carboxamide To a mixture of (8S)-7-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]bu tanoyl]-7- azadispiro[3.0.45.14]decane-8-carboxylic acid (50 mg, 0.128mol, 1.00 eq) and (2S)-2-amino-3-[(3S)-2- oxopyrrolidin-3-yl]propanenitrile (36.4 mg, 0.192 mmol, 1.50 eq, HCl salt) in dimethyl formamide (2 mL) were added 2,4,6-tripropyl-1,3,5-trioxatriphosphinane 2,4,6-trioxide (122 mg, 0.192 mmol, 50% purity in ethyl acetate, 1.50 eq) and N,N-diisopropylethylamine (66.2 mg, 0.512 mmol, 4.00 eq) at 0°C. The mixture was warmed to 15°C and stirred for 16 h. The mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 μm; mobile phase: [water(FA)-ACN]; B%: 37%-67%,7 min) to give (8S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]- 7-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoy l]-7-azadispiro[3.0.45.14]decane-8- carboxamide (19.5 mg, 35.3 μmol, 28% yield, 95% purity) as a white solid. Preparation of CPD0187553 and CPD0187554 Procedure for preparation of ethyl 3-bromo-2-oxo-cyclopentanecarboxylate To a mixture of ethyl 2-oxocyclopentanecarboxylate (40.0 g, 256 mmol, 1.00 eq) in trichloromethane (280 mL) was added a mixture of bromine (45.0 g, 282 mmol, 14.5 mL, 1.10 eq) in trichloromethane (80.0 mL) dropwise at 0°C over 0.25 h. After stirring at 0°C for 1 h, the mixture was poured into water (200 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with saturated sodium bicarbonate (200 mL), brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (Petroleum ether: Ethyl acetate= 1: 0 to 30: 1) to give ethyl 3-bromo-2-oxo- cyclopentanecarboxylate (50.0 g, 202 mmol, 79% yield, 95% purity) as yellow gum. The crude product was used for the next step reaction directly. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 4.92-4.87 (m, 1H), 4.30-4.25 (m, 2H), 2.71-2.64 (m, 1H), 2.54-2.43 (m, 2H), 2.41-2.32 (m, 1H), 2.31-2.23 (m, 1H), 1.36-1.32 (m, 3H). LC-MS (Method C): Rt = 0.792 min; MS (ESIpos): m/z = 234.9 [M+H] ⁺ . Procedure for preparation of ethyl 2-amino-5,6-dihydro-4H-cyclopenta[d]thiazole-4-carboxylate A mixture of ethyl 3-bromo-2-oxo-cyclopentanecarboxylate (50.0 g, 213 mmol, 1.00 eq) and thiourea (16.2 g, 213 mmol, 1.00 eq) in 1,4-dioxane (300 mL) was stirred at 100°C for 12 h. The mixture was poured into water (300 mL) and adjusted to pH = 8 with saturated sodium bicarbonate to give a suspension. After filtration, the filter cake was dried under vacuum to give a crude product. The crude product was triturated with petroleum ether/ethyl acetate (v/v = 3/1, 200 mL) and dried under vacuum to give ethyl 2-amino-5,6-dihydro-4H-cyclopenta[d]thiazole-4-carboxylate (29.0 g, 130 mmol, 61% yield, 95% purity) as a brown solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ = 6.90 (s, 2H), 4.15-4.00 (m, 2H), 3.70-3.63 (m, 1H), 2.82-2.73 (m, 1H), 2.71-2.62 (m, 1H), 2.61-2.53 (m, 1H), 2.49-2.40 (m, 1H), 1.19 (t, J = 7.2 Hz, 3H). Procedure for preparation of ethyl 5,6-dihydro-4H-cyclopenta[d]thiazole-4-carboxylate To a mixture of tert-butyl nitrite (9.72 g, 94.2 mmol, 2.00 eq) in tetrahydrofuran (100 mL) was added a solution of ethyl 2-amino-5,6-dihydro-4H-cyclopenta[d]thiazole-4-carboxylate (10.0 g, 47.1 mmol, 1.00 eq) in tetrahydrofuran (400 mL) dropwise at 60°C under nitrogen over 3 h. After stirring at 60°C for 0.5 h, the mixture was poured into water (100 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20/1 to 3/1) to give ethyl 5,6-dihydro-4H- cyclopenta[d]thiazole-4-carboxylate (4.50 g, 21.9 mmol, 46% yield, 96% purity) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.94 (s, 1H), 4.11 (q, J = 7.2 Hz, 2H), 4.02-3.95 (m, 1H), 3.04-2.94 (m, 1H), 2.93-2.85 (m, 1H), 2.84-2.74 (m, 1H), 2.70-2.59 (m, 1H), 1.20 (t, J = 7.2 Hz, 3H). LC-MS (Method C): Rt = 0.736 min; MS (ESIpos): m/z = 198.0 [M+H] ⁺ Procedure for preparation of 5,6-dihydro-4H-cyclopenta[d]thiazol-4-ylmethanol A suspension of lithium aluminum hydride (1.00 M in tetrahydrofuran, 27.4 mL, 1.20 eq) in tetrahydrofuran (50.0 mL) was degassed under vacuum and purged with nitrogen for 3 times. After cooling the suspension to 0°C, a solution of ethyl 5,6-dihydro-4H-cyclopenta[d]thiazole-4-carboxylate (4.50 g, 22.8 mmol, 1.00 eq) in tetrahydrofuran (50.0 mL) was added dropwise. After stirred at this temperature for 1 h under nitrogen atmosphere, the reaction mixture was quenched with saturated sodium sulfate solution (3.00 mL) at 0°C. After stirring at 0°C for 10 min, the suspension was diluted with ethyl acetate (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 5,6-dihydro-4H-cyclopenta[d]thiazol-4-ylmethanol (2.80 g, 17.5 mmol, 77% yield, 97% purity) as black brown gum. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.89 (s, 1H), 4.70-4.60 (m, 1H), 3.77-3.70 (m, 1H), 3.46-3.38 (m, 1H), 3.20-3.09 (m, 1H), 2.93-2.77 (m, 2H), 2.65-2.55 (m, 1H), 2.41-2.32 (m, 1H). LC-MS (Method C): Rt = 0.361 min; MS (ESIpos): m/z = 156.1 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[(1S)-2-(1,3-benzothiazol-2-yl)-2-hydroxy-1-(2- pyridylmethyl)ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluor oacetyl) amino]butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of oxalyl chloride (2.82 g, 22.2 mmol, 1.50 eq) in dichloromethane (40.0 mL) was added a mixture of dimethylsulfoxide (2.32 g, 29.6 mmol, 2.00 eq) in dichloromethane (20.0 mL) dropwise at - 70°C. After stirring at -70°C for 0.1 h, a mixture of 5,6-dihydro-4H-cyclopenta[d]thiazol-4-ylmethanol (2.30 g, 14.8 mmol, 1.00 eq) in dichloromethane (20.0 mL) was added. After stirring at -70°C for 0.5 h, triethylamine (6.00 g, 59.3 mmol, 4.00 eq) was added at this temperature. The reaction mixture was stirred at -70°C for 0.5 h. The mixture was poured into water (50.0 mL) and extracted with dichloromethane (30.0 mL × 3). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 5,6-dihydro-4H- cyclopenta[d]thiazole-4-carbaldehyde (1.70 g, crude) as an black brown gum which was used for next step directly. LC-MS (Method C): Rt = 0.282 min; MS (ESIpos): m/z = 154.0 [M+H] ⁺ . Procedure for preparation of methyl 2-(tert-butoxycarbonylamino)-3-(5,6-dihydro-4H- cyclopenta[d]thiazol-4-yl)prop-2-enoate To a mixture of methyl 2-(tert-butoxycarbonylamino)-2-dimethoxyphosphoryl-acetate (3.30 g, 11.1 mmol, 1.00 eq) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (2.03 g, 13.3 mmol,, 1.20 eq) in dichloromethane (50.0 mL) was added 5,6-dihydro-4H-cyclopenta[d]thiazole-4-carbaldehyde (1.70 g, 11.1 mmol, crude purity, 1.00 eq) at 25°C. After stirring at 25°C for 12 h, the mixture was poured into water (50.0 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1 to 3/1) to give methyl 2-(tert-butoxycarbonylamino)-3-(5,6-dihydro-4H- cyclopenta[d]thiazol-4-yl)prop-2-enoate (850 mg, 2.59 mmol, 23% yield, 99% purity) and impure methyl 2-(tert-butoxycarbonylamino)-3-(5,6-dihydro-4H-cyclopenta[d] thiazol-4-yl)prop-2-enoate (380 mg, 937 μmol, 8% yield, 80% purity) as a light yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.73 (s, 1H), 5.85-5.76 (m, 1H), 5.30 (d, J = 6.4 Hz, 1H), 5.09-4.94 (m, 1H), 3.76 (s, 3H), 3.45-3.37 (m, 2H), 3.09 (t, J = 6.0 Hz, 2H), 1.46 (s, 9H). LC-MS (Method C): Rt = 0.894 min; MS (ESIpos): m/z = 324.8 [M+H] ⁺ . Procedure for preparation of methyl 2-(tert-butoxycarbonylamino)-3-(5,6-dihydro-4H- cyclopenta[d]thiazol-4-yl)propanoate To a solution of methyl 2-(tert-butoxycarbonylamino)-3-(5,6-dihydro-4H-cyclopenta[d] thiazol-4-yl)prop- 2-enoate (850 mg, 2.62 mmol, 1.00 eq) in methanol (10.0 mL) was added palladium on carbon (30.0 mg, 10% purity) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen for 3 times. After stirring at 25°C for 12 h under hydrogen (15.0 psi) atmosphere, LCMS showed most of the starting material remained, the mixture was heated to 65°C and stirred for 72 h. After filtration, palladium on carbon (0.50 g, 10% purity) was added. The suspension was degassed under vacuum and purged with hydrogen for 3 times. After stirring at 65°C for 192 h under hydrogen (15 psi), the suspension was filtered. The filtrate was concentrated under vacuum to give methyl 2-(tert- butoxycarbonylamino)-3-(5,6-dihydro-4H-cyclopenta[d]thiazol- 4-yl)propanoate (660 mg, crude) as an light yellow gum which was used for next step directly. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.59-8.58 (m, 1H), 6.24-6.15 (m, 1H), 4.56-4.46 (m, 1H), 3.68 (s, 3H), 2.84-2.77 (m, 3H), 2.14-2.11 (m, 2H), 1.97 (br. s, 1H), 1.88-1.83 (m, 1H), 1.38 (s, 9H). Procedure for preparation of tert-butyl N-[2-amino-1-(5,6-dihydro-4H-cyclopenta[d]thiazol-4- ylmethyl)-2-oxo-ethyl]carbamate A mixture of methyl 2-(tert-butoxycarbonylamino)-3-(5,6-dihydro-4H-cyclopenta[d] thiazol-4- yl)propanoate (660 mg, 2.02 mmol, 1.00 eq) in ammonia (7 M in methanol, 10 mL, 34.6 eq) was stirred at 40°C for 60 h. After concentration, the residue was partitioned between ethyl acetate (30.0 mL) and saturated ammonium chloride solution (30.0 mL). The separated aqueous phase was extracted with ethyl acetate (30.0 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate and filtered and concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate/methanol = 1/0/0 to 60/36/4) to give tert-butyl N-[2-amino-1-(5,6-dihydro-4H-cyclopenta[d]thiazol-4-ylmethyl )-2-oxo- ethyl]carbamate (300 mg, 962 μmol, 48% yield, 99% purity) as light yellow gum. LC-MS (Method C): Rt = 0.713 min; MS (ESIpos): m/z = 312.2 [M+H] ⁺ . Procedure for preparation of 2-amino-3-(5,6-dihydro-4H-cyclopenta[d]thiazol-4-yl)propanam ide A mixture of tert-butyl N-[2-amino-1-(5,6-dihydro-4H-cyclopenta[d]thiazol-4-ylmethyl )-2-oxo- ethyl]carbamate (300 mg, 963 μmol, 1.00 eq) in hydrochloric acid (4 M in ethyl acetate, 2.00 mL, 8.30 eq) and ethyl acetate (4.00 mL) was stirred at 25°C for 12 h. The mixture was concentrated under vacuum to give 2-amino-3-(5,6-dihydro-4H-cyclopenta[d]thiazol-4-yl)propanam ide (270 mg, 949 μmol, 99% yield, 99% purity, 2 HCl salt) as a light yellow solid which was used for next step directly. LC-MS (Method C): Rt = 0.164&0.242 min; MS (ESIpos): m/z = 212.2 [M+H] ⁺ . Procedure for preparation of P1- (1R,2S,5S)-N-[2-amino-1-(5,6-dihydro-4H-cyclopenta[d]thiazol - 4-ylmethyl)-2-oxo-ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trif luoroacetyl)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide and Compound 11_P2- (1R,2S,5S)-N-[2- amino-1-(5,6-dihydro-4H-cyclopenta[d]thiazol-4-ylmethyl)-2-o xo-ethyl]-3-[(2S)-3,3-dimethyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabi cyclo[3.1.0]hexane-2-carboxamide A mixture of 2-amino-3-(5,6-dihydro-4H-cyclopenta[d]thiazol-4-yl)propanam ide (220 mg, 774 μmol, 1.00 eq, 2HCl), (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (296 mg, 813 μmol, 1.05 eq), O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (442 mg, 1.16 mmol, 1.50 eq) and N,N- diisopropylethylamine (400 mg, 3.10 mmol, 4.00 eq) in N,N-dimethylformamide (3.00 mL) was stirred at 25°C for 12 h. The mixture was poured into water (10.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate/methanol = 1/0/0 to 60/36/4) to give diastereomers Compound 11_P1 (1R,2S,5S)-N-[2-amino-1-(5,6-dihydro-4H-cyclopenta[d]thiazol -4- ylmethyl)-2-oxo-ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-triflu oroacetyl)amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (180 mg, 323 μmol, 42% yield, 99% purity) and Compound 11_P2 (1R,2S,5S)-N-[2-amino-1-(5,6-dihydro-4H-cyclopenta[d]thiazol -4-ylmethyl)-2-oxo-ethyl]-3-[(2S)- 3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-d imethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (180 mg, 323 μmol, 42% yield, 99% purity) as light yellow gum. Compound 11_P1: LC-MS (Method C): Rt = 0.923 min; MS (ESIpos): m/z = 558.2 [M+H] ⁺ . Compound 11_P2: LC-MS (Method C): Rt = 0.907 min; MS (ESIpos): m/z = 558.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[1-cyano-2-(5,6-dihydro-4H-cyclopenta[d]thiazol -4- yl)ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)ami no] butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide A mixture of (1R,2S,5S)-N-[2-amino-1-(5,6-dihydro-4H-cyclopenta[d]thiazol -4-ylmethyl)-2-oxo-ethyl]-3- [(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl] -6,6-dimethyl-3-azabicyclo [3.1.0]hexane-2- carboxamide (160 mg, 287 μmol, 1.00 eq), Burgess reagent (342 mg, 1.43 mmol, 5.00 eq) in dichloromethane (1.50 mL) was stirred at 25°C for 12 h. The reaction mixture was diluted with water (15.0 mL) and extracted with ethyl acetate (15.0 mL × 2). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25mm* 10 μm; mobile phase: [water(FA)-ACN];B%: 50%-80%, 10 min) to give (1R,2S,5S)-N-[1- cyano-2-(5,6-dihydro-4H-cyclopenta[d]thiazol-4-yl)ethyl]-3-[ (2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (93.5 mg, 165 μmol, 57% yield, 95% purity) as a pink solid. Procedure for preparation of (1R,2S,5S)-N-[1-cyano-2-(5,6-dihydro-4H-cyclopenta[d]thiazol -4- yl)ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)ami no] butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide A mixture of (1R,2S,5S)-N-[2-amino-1-(5,6-dihydro-4H-cyclopenta[d]thiazol -4-ylmethyl)-2-oxo-ethyl]-3- [(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl] -6,6-dimethyl-3-azabicyclo [3.1.0]hexane-2- carboxamide (160 mg, 287 μmol, 1.00 eq), Burgess (342 mg, 1.43 mmol, 5.00 eq) in dichloromethane (1.50 mL) was stirred at 25°C for 12 h. The reaction mixture was diluted with water (15.0 mL) and extracted with ethyl acetate (15 mL × 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN];B%: 50%-80%,10min) to give (1R,2S,5S)-N-[1-cyano-2-(5,6- dihydro-4H-cyclopenta[d]thiazol-4-yl)ethyl]-3-[(2S)-3,3-dime thyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (80.3 mg, 141 μmol, 49% yield, 95% purity) as an off-white solid. Preparation of CPD0187911 Procedure for preparation of 2-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one A mixture of pyridin-2-amine (2.00 g, 21.3 mmol, 1.00 eq) and diethyl propanedioate (4.08 g, 25.5 mmol, 1.20 eq) was stirred at 135°C for 6 h. The resulting precipitate was triturated with mixed solvent of ethyl acetate and petroleum ether (v/v = 1/1, 20 mL) and stirred for 0.5 h. After filtration, the filter cake was washed with ethyl acetate (3.00 mL). The filter cake was dried to give 2-hydroxy-4H-pyrido[1,2- a]pyrimidin-4-one (2.20 g, 13.6 mmol, 64% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.03 (s, 1H), 8.93 (d, J = 6.8 Hz, 1H), 8.09 (t, J = 7.2 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.33 (t, J = 7.2 Hz, 1H), 4.97 (s, 1H). Procedure for preparation of 2-chloro-4H-pyrido[1,2-a]pyrimidin-4-one A mixture of 2-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (1.00 g, 6.17 mmol, 1.00 eq) in phosphorus oxychloride (4.95 g, 32.3 mmol, 5.23 eq) was stirred at 110°C for 1 h. The reaction mixture was concentrate to give a residue. The residue was triturated with ethyl acetate (30 mL) and stirred at 15°C for 15 min. After filtration, the filter cake was washed with ethyl acetate (5 mL). The solid cake was dried to give 2-chloro-4H-pyrido[1,2-a]pyrimidin-4-one (480 mg, 2.66 mmol, 43% yield) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.98 (d, J = 6.4 Hz, 1H), 8.14-8.09 (m, 1H), 7.73 (dt, J = 9.2, 1.2 Hz, 1H), 7.48 (td, J = 6.8, 1.2 Hz, 1H), 6.50 (s, 1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ = 157.54, 157.17, 150.76, 140.24, 128.25, 125.79, 117.97, 101.54. Procedure for preparation of methyl 2-((diphenylmethylene)amino)-2-(4-oxo-4H-pyrido[1,2- a]pyrimidin-2-yl)acetate To a mixture of 2-chloro-4H-pyrido[1,2-a]pyrimidin-4-one (480 mg, 2.66 mmol, 1.00 eq) and methyl 2- (benzhydrylideneamino)acetate (673 mg, 2.66 mmol, 1.00 eq) in dimethylacetamide (20 mL) was added cesium carbonate (1.30 g, 3.99 mmol, 1.50 eq) at 15°C. After stirring at 90°C for 16 h, the reaction mixture was cooled to ambient temperature, and poured into water (50 mL). The solution was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~50% ethyl acetate/petroleum ether gradient @ 30 mL/min) to give methyl 2-((diphenylmethylene)amino)-2-(4-oxo-4H-pyrido[1,2-a]pyrimi din-2- yl)acetate (480 mg, 1.21 mmol, 45% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.96 (d, J = 6.8 Hz, 1H), 7.99-7.95 (m, 1H), 7.65-7.63 (m, 3H), 7.55- 7.50 (m, 4H), 7.47-7.43 (m, 2H), 7.37 (td, J = 7.2, 1.2 Hz, 1H), 7.21-7.19 (m, 2H), 6.57 (s, 1H), 5.08 (s, 1H), 3.64 (s, 3H). Procedure for preparation of 2-((diphenylmethylene)amino)-2-(4-oxo-4H-pyrido[1,2-a]pyrimi din- 2-yl)acetamide A mixture of methyl 2-(benzhydrylideneamino)-2-(4-oxopyrido[1,2-a]pyrimidin-2-yl )acetate (500 mg, 1.26 mmol, 1.00 eq) in ammonia (20 M in methanol, 20 mL) was stirred at 20°C for 16 h. The mixture was concentrated to give 2-((diphenylmethylene)amino)-2-(4-oxo-4H-pyrido[1,2-a]pyrimi din-2- yl)acetamide (500 mg, crude) as red oil. Procedure for preparation of 2-amino-2-(4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)acetamide A mixture of 2-((diphenylmethylene)amino)-2-(4-oxo-4H-pyrido[1,2-a]pyrimi din-2-yl)acetamide (500 mg, crude) in a mixed solvent of hydrochloric acid (1 M in water, 1.70 mL), dichloromethane (5 mL) and methanol (5 mL) was stirred at 15°C for 2 h. The mixture was concentrated to give a residue. The residue was triturated with a mixed solvent of methyl tert-butyl ether/ethyl acetate (v/v=1/1, 20.0 mL). After stirring for 15 min, the suspension was filtered. The filter cake was washed with methyl tert-butyl ether (2.00 mL), collected and dried to give 2-amino-2-(4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)acetamide (350 mg, crude, HCl salt) as a red solid. Procedure for preparation of (1R,2S,5S)-N-(2-amino-2-oxo-1-(4-oxo-4H-pyrido[1,2-a]pyrimid in-2- yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido) butanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of 2-amino-2-(4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)acetamide (300 mg, crude) and (1R,2S,5S)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)b utanoyl)-6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid (451 mg, 1.24 mmol) in N,N-dimethylformamide (5 mL) were added O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (627 mg, 1.65 mmol) and N,N- diisopropylethylamine (711 mg, 5.50 mmol) at 15°C. After stirring at 15°C for 16 h, the mixture was poured into water (20.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~65% (ethyl acetate : methanol = 10:1)/petroleum ether gradient @ 30 mL/min) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-(4-oxo-4H-pyrido[1,2-a]pyrimid in-2-yl)ethyl)-3-((S)-3,3-dimethyl-2- (2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicycl o[3.1.0]hexane-2-carboxamide (200 mg, 0.351 mmol, 99% purity) as a yellow solid. LC-MS (Method C): R _t = 0.788 min; MS (ESIpos): m/z = 565.3 [M+H] ⁺ . Procedure for preparation of CPD0187911 - (1R,2S,5S)-N-(cyano(4-oxo-4H-pyrido[1,2- a]pyrimidin-2-yl)methyl)-3-((S)-3,3-dimethyl-2-(2,2,2-triflu oroacetamido)butanoyl)-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of (1R,2S,5S)-N-(2-amino-2-oxo-1-(4-oxo-4H-pyrido[1,2-a]pyrimid in-2-yl)ethyl)-3-((S)-3,3- dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxamide (180 mg, 0.319 mmol, 1.00 eq) in dichloromethane (20.0 mL) was added Burgess reagent (228 mg, 0.956 mmol, 3.00 eq) at 15°C. After stirring at 15°C for 18 h, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 μm; mobile phase: [water(FA)-ACN]; B%: 33%-63%, 7 min) to give (1R,2S,5S)-N-(cyano(4-oxo-4H- pyrido[1,2-a]pyrimidin-2-yl)methyl)-3-((S)-3,3-dimethyl-2-(2 ,2,2-trifluoroacetamido)butanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxamide (95.95 mg, 0.174 mmol, 55% yield, 99% purity) as an off-white solid. Preparation of CPD0188058 and CPD0188163 Procedure for preparation of methyl 3,3-dimethyl-2-((1-methyl-1H-pyrazol-4-yl)amino)butanoate A mixture of 4-bromo-1-methyl-1H-pyrazole (1.00 g, 6.21 mmol, 1.00 eq), methyl (S)-2-amino-3,3- dimethylbutanoate hydrochloride (0.902 g, 6.21 mmol, 1.00 eq), sodium tert-butoxide (1.19 g, 12.4 mmol, 2.00 eq) and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium;ditert -butyl-[2-(2,4,6- triisopropylphenyl)phenyl]phosphane (0.247 g, 0.311 mmol, 0.05 eq) in toluene (10.0 mL) was stirred at 100°C under nitrogen atmosphere for 16 h. After concentration, the residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~80% ethyl acetate/petroleum ether gradient @ 60 mL/min) to give methyl 3,3-dimethyl-2-((1-methyl-1H-pyrazol-4- yl)amino)butanoate (500 mg, 1.93 mmol, 31% yield, 87% purity) as yellow oil. LC-MS (Method C): R _t = 0.492 min; MS (ESIpos): m/z = 226.1 [M+H] ⁺ . Procedure for preparation of 3,3-dimethyl-2-((1-methyl-1H-pyrazol-4-yl)amino)butanoic acid To a mixture of methyl 3,3-dimethyl-2-((1-methyl-1H-pyrazol-4-yl)amino)butanoate (590 mg, 2.28 mmol, 87% purity, 1.00 eq) in mixed solvent of methanol (5.00 mL) and water (5.00 mL) was added lithium hydroxide monohydrate (478 mg, 11.4 mmol, 5.00 eq) at 15°C. After stirring at 50°C for 16 h, the mixture was concentrated to remove the organic solvent. The resulting solution was diluted with water (20.0 mL) and washed with ethyl acetate (20.0 mL). Hydrochloric acid (12 M in water) was added to the aqueous phase to adjust pH = 5 and extracted with ethyl acetate (30 mL × 9). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated by evaporation under vacuum to give 3,3-dimethyl-2-((1-methyl-1H-pyrazol-4-yl)amino)butanoic acid (600 mg, crude, hydrochloric acid salt) as yellow oil. The crude product was used for next step directly without purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.16 (s, 1H), 6.95 (s, 1H), 3.80 (s, 3H), 3.32 (s, 1H), 1.09 (s, 9H). Procedure for preparation of CPD0188058 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin- 3-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(1-methylpyrazol-4-yl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide – and CPD0188163 -(1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)- 2-oxopyrrolidin-3-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(1-methy lpyrazol-4-yl)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of 3,3-dimethyl-2-((1-methyl-1H-pyrazol-4-yl)amino)butanoic acid (300 mg, 1.21 mmol, crude, hydrochloric acid salt) and (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethy l]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (594 mg, 1.82 mmol, 1.50 eq, hydrochloric acid salt) in N,N-dimethyl formamide (5.00 mL) were added N,N-diisopropylethylamine (626 mg, 4.84 mmol, 4.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexaflu orophosphate (691 mg, 1.82 mmol, 1.50 eq) at 0°C. After stirring at 40°C for 16 h, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 μm; mobile phase: [water (FA)-ACN]; B%: 21%-51%, 7 min) to give two diastereomers. One isomer was further purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 μm; mobile phase: [water(FA)-ACN]; B%: 21%-51%, 7 min) to give CPD0188058 (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(1-methylp yrazol-4-yl)amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (50.0 mg, 99.3 μmol, 8% yield, 96% purity) as a yellow solid. Another isomer was further purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 μm; mobile phase: [water(FA)-ACN];B%: 26%-56%,7min) and SFC (column: REGIS(S,S)WHELK- O1(250mm*25mm,10um);mobile phase: [0.1%NH3H2O MEOH]; B%: 30%-30%, 4.4 min; column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [Neu-IPA]; B%: 35%-35%,1.6min) twice to give CPD0188163 (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethy l]-3-[(2S)-3,3- dimethyl-2-[(1-methylpyrazol-4-yl)amino]butanoyl]-6,6-dimeth yl-3-azabicyclo[3.1.0]hexane-2- carboxamide (27.1 mg, 55.5 μmol, 5% yield, 99% purity) as a yellow solid.. Procedure for preparation of amino-2-(1,3-benzothiazol-5-yl)acetonitrile To a solution of 1,3-benzothiazole-5-carbaldehyde (1.0 g, 6.13 mmol, 1.00 eq) in mixed solvent of methanol (5.00 mL) and ammonia (20.0 M in methanol, 3.00 mL, 9.79 eq) was added dropwise titanium (IV) isopropoxide (2.09g, 7.35 mmol, 1.20 eq) at 20 ^. After stirring at 20°C for 2 h, trimethylsilyl cyanide (730 mg, 7.35 mmol, 1.20 eq) was added dropwise at 20 ^ to the reaction mixture above. After addition, the mixture was stirred at 20°C for 14 h. The reaction mixture was quenched with saturated sodium bicarbonate solution (20.0 mL) and extracted with ethyl acetate (30.0 mL × 6). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (100~200 mesh, petroleum ether then petroleum ether/ethyl acetate = 2/1) to afford 2- amino-2-(1,3-benzothiazol-5-yl)acetonitrile (800 mg, 4.02 mmol, 66% yield) as yellow oil. LC-MS (Method A): R _t = 0.252 min; MS (ESIpos): m/z = 190.1 [M+H] ⁺ . Procedure for preparation of CPD0084675 - (1R,2S,5S)-N-[1,3-benzothiazol-5-yl(cyano)methyl]- 3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoy l]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide A mixture of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (578 mg, 1.59 mmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (904 mg, 2.38 mmol, 1.50 eq) and N,N-diisopropyl ethylamine (615 mg, 4.76 mmol, 3.00 eq) in dichloromethane (10.0 mL) was stirred at 20°C for 15 min, followed by 2-amino-2-(1,3-benzothiazol-5-yl)acetonitrile (300 mg, 1.59 mmol, 1.00 eq). After stirring at 20°C for 16 h, the reaction mixture was poured into water (20.0 mL) and extracted with ethyl acetate (15.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 3/1) to give single diastereomer CPD0188164 (~90 mg), diastereomer CPD0188165 (~100 mg) and mixture of two diasteromers CPD0084675_003 (1R,2S,5S)-N-[1,3-benzothiazol-5-yl(cyano)methyl]-3-[(2S)-3, 3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (276 mg, 514 μmol, 32% yield, 99% purity) as a white solid. Preparation of CPD0188166 Procedure for preparation of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2- thioxopyrrolidin-3-yl)propanoate A mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin-3- yl)propanoate (8.50 g, 29.7 mmol, 1.00 eq) and Lawesson reagent (7.20 g, 17.8 mmol, 0.600 eq) in toluene. (90.0 mL) was stirred at 80°C for 1 h. The mixture was concentrated under vacuum and purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~25% ethyl acetate/petroleum ether gradient @ 80 mL/min) to give methyl (S)-2-((tert-butoxycarbonyl)amino)-3- ((S)-2-thioxopyrrolidin-3-yl)propanoate (7.70 g, 25.5 mmol, 86% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.20 (s, 1H), 7.40 (d, J = 8.4 Hz, 1H), 4.08-4.04 (m, 1H), 3.63 (s, 3H), 3.43-3.41 (m, 2H), 2.63-2.56 (m, 1H), 2.41-2.34 (m, 1H), 2.24-2.18 (m, 1H), 1.70-1.53 (m, 2H), 1.38 (s, 9H). Procedure for preparation of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-5-(methylthio)-3,4 - dihydro-2H-pyrrol-4-yl)propanoate To a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-thioxopyrrolidin -3-yl)propanoate (7.70 g, 25.5 mmol, 1.00 eq) and potassium carbonate (10.6 g, 76.4 mmol, 3.00 eq) in tetrahydrofuran (100 mL) was added methyl iodide (10.8 g, 76.4 mmol, 3.00 eq) at 15°C. After stirring at 15°C for 4 h, the mixture was filtered and the cake was washed with ethyl acetate (30 mL × 3). The combined filtrate was concentrated to give methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-5-(methylthio)-3,4 -dihydro- 2H-pyrrol-4-yl)propanoate (8 g, crude) as yellow oil. Procedure for preparation of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-5-(2- formylhydrazineyl)-3,4-dihydro-2H-pyrrol-4-yl)propanoate A mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-5-(methylthio)-3,4 -dihydro-2H-pyrrol-4- yl)propanoate (8.00 g, crude) and formohydrazide (1.67 g, 27.8 mmol) in methanol (100 mL) was heated to 75°C for 16 h. The mixture was concentrated to give a residue. The residue was purified by reversed phase chromatography (C18, 300 g; condition: H2O (additive: 0.1% formic acid)/CH3CN = 100/0 to 93/7) to give methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-5-(2-formylhydrazi neyl)-3,4-dihydro-2H-pyrrol- 4-yl)propanoate (3.50 g, 10.7 mmol, 42% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.69 (s, 0.5H), 8.27 (s, 0.5H), 8.14 (s, 1H), 7.79 (s, 0.5H), 7.49-7.45 (m, 0.5H), 7.16-6.46 (m, 1H), 4.20-4.02 (m, 1H), 3.63-3.62 (m, 3H), 3.31-3.17 (m, 2H), 2.59-2.56 (m, 1H), 2.11-2.02 (m, 2H), 1.65-1.54 (m, 2H), 1.38 (s, 9H). Procedure for preparation of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-6,7-dihydro-5H- pyrrolo[2,1-c][1,2,4]triazol-7-yl)propanoate A mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-5-(2-formylhydrazi neyl)-3,4-dihydro-2H- pyrrol-4-yl)propanoate (3.00 g, 9.14 mmol, 1.00 eq) in trimethyl orthoformate (15 mL) was stirred at 100°C for 16 h. The mixture was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~100% ethyl acetate/petroleum ether gradient @ 65 mL/min) to give methyl (S)-2-((tert-butoxycarbonyl)amino)-3- ((S)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl)propan oate (2.00 g, 6.44 mmol, 71% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.37-8.36 (m 1H), 7.51-7.47 (m, 1H), 4.47-4.20 (m, 1H), 4.09-4.02 (m, 1H), 3.96-3.92 (m, 1H), 3.64 (s, 3H), 3.22-3.179m, 1H), 2.79-2.71 (m, 1H), 2.38-2.29 (m, 1H), 2.14- 2.05 (m, 1H), 1.92-1.85 (m, 1H), 1.40 (s, 9H). Procedure for preparation of tert-butyl ((S)-1-amino-3-((S)-6,7-dihydro-5H-pyrrolo[2,1- c][1,2,4]triazol-7-yl)-1-oxopropan-2-yl)carbamate A mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-6,7-dihydro-5H-pyr rolo[2,1- c][1,2,4]triazol-7-yl)propanoate (1.00 g, 3.22 mmol, 1.00 eq) and ammonium (20 M in methanol, 33.33 mL, 206 eq) was stirred at 15°C for 16 h. The mixture was concentrated to give tert-butyl ((S)-1-amino- 3-((S)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl)-1-o xopropan-2-yl) carbamate (950 mg, 2.96 mmol, 92% yield, 92% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.36 (s, 1H), 7.31 (s, 1H), 7.12-7.04 (m, 2H), 4.10-4.00 (m, 2H), 3.18- 3.11 (m, 2H), 2.80-2.72 (m, 1H), 2.43-2.34 (m, 1H), 2.08-1.99 (m, 1H), 1.83-1.75 (m, 1H), 1.40 (s, 9H). Procedure for preparation of (S)-2-amino-3-((S)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triaz ol-7- yl)propanamide To a mixture of tert-butyl ((S)-1-amino-3-((S)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]tria zol-7-yl)-1- oxopropan-2-yl)carbamate (50.0 mg, 0.169 mmol, 1.00 eq) and triethylamine (85.6 mg, 0.846 mmol, 5.00 eq) in dichloromethane (2.00 mL) was added trimethylsilyl trifluoromethanesulfonate (188 mg, 0.846 mmol, 5.00 eq) dropwise at 0°C. The mixture was allowed to warm to 15°C and stirred for 1 h. The reaction mixture was quenched with methanol (1 mL) and concentrated to give (S)-2-amino-3-((S)- 6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-7-yl)propanamide (33.0 mg, crude) as yellow oil. Procedure for preparation of (1R,2S,5S)-N-((S)-1-amino-3-((S)-6,7-dihydro-5H-pyrrolo[2,1- c][1,2,4]triazol-7-yl)-1-oxopropan-2-yl)-3-((S)-3,3-dimethyl -2-(2,2,2-trifluoroacetamido)butanoyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of (S)-2-amino-3-((S)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triaz ol-7-yl)propanamide (33.0 mg, crude) and (1R,2S,5S)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)b utanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (61.6 mg, 0.169 mmol, 1.00 eq) in N,N-dimethylformamide (1.00 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexaflu orophosphate (96.4 mg, 0.253 mmol, 1.50 eq) and N,N-diisopropylethylamine (87.4 mg, 0.676 mmol, 4.00 eq) at 0°C. After stirring at 15°C for 16 h, the reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 18%-48%,10 min) to give (1R,2S,5S)-N-((S)-1-amino-3-((S)-6,7-dihydro-5H- pyrrolo[2,1-c][1,2,4]triazol-7-yl)-1-oxopropan-2-yl)-3-((S)- 3,3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ] hexane-2-carboxamide (28.0 mg, 51.7 μmol, 31% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.42-9.36 (m, 1H), 8.49-8.40 (m, 2H), 7.39 (s, 1H), 7.11 (s, 1H), 4.48- 4.40 (m, 2H0, 4.30-4.25 (m, 1H), 4.11-4.05 (m, 1H), 3.93-3.89 (m, 1H), 3.82-3.77 (m, 1H), 3.70-3.67 (m, 1H), 2.77-2.69 (m, 1H), 2.42-2.35 (m, 2H), 2.18-2.05 (m, 1H), 1.87-1.79 (m, 1H), 1.53-1.50 (m, 1H), 1.44-1.40 (m, 1H), 1.03 (s, 3H), 0.97 (s, 9H), 0.85 (s, 3H). Procedure for preparation of CPD0188166- (1R,2S,5S)-N-((S)-1-cyano-2-((S)-6,7-dihydro-5H- pyrrolo[2,1-c][1,2,4]triazol-7-yl)ethyl)-3-((S)-3,3-dimethyl -2-(2,2,2-trifluoroacetamido)butanoyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of (1R,2S,5S)-N-((S)-1-amino-3-((S)-6,7-dihydro-5H-pyrrolo[2,1- c][1,2,4]triazol-7-yl)-1- oxopropan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetam ido)butanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0] hexane-2-carboxamide (28.0 mg, 51.7 μmol, 1.00 eq) in dichloromethane (2.00 mL) was added Burgess reagent (14.8 mg, 62.0 μmol, 1.20 eq) at 0°C. After stirring at 15°C for 3 h, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN];B%: 27%-57%,10 min) to give (1R,2S,5S)-N-((S)-1-cyano-2-((S)-6,7-dihydro-5H-pyrrolo[2,1- c][1,2,4]triazol-7-yl)ethyl)-3-((S)- 3,3-dimethyl-2-(2,2,2-trifluoroacetamido) butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (12.8 mg, 23.7 μmol, 46% yield, 97% purity) as a white solid. Preparation of CPD0188250 Procedure for preparation of (E)-4-(2-hydroxyanilino)-4-oxo-but-2-enoic acid To a solution of furan-2,5-dione (4.49 g, 45.8 mmol, 1.00 eq) in toluene (50.0 mL) was added 2- aminophenol (5.00 g, 45.8 mmol, 1.00 eq) at 30°C. After stirring at 30°C for 16 h, the mixture was concentrated under vacuum to give (E)-4-(2-hydroxyanilino)-4-oxo-but-2-enoic acid (9.00 g, 43.4 mmol, 95% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 13.30 (s, 1H), 10.00-9.77 (m, 2H), 7.83-7.71 (m, 1H), 7.04-6.95 (m, 1H), 6.93-6.86 (m, 1H), 6.83-6.75 (m, 1H), 6.66 (d, J = 12.0 Hz, 1H), 6.34 (d, J = 12.0 Hz, 1H). LC-MS (Method A): R _t = 0.487 min; MS (ESIpos): m/z = 208.1 [M+H] ⁺ . Procedure for preparation of 2-(3-oxo-4H-1,4-benzoxazin-2-yl)acetic acid To a solution of (E)-4-(2-hydroxyanilino)-4-oxo-but-2-enoic acid (7.00 g, 33.8 mmol, 1.00 eq) in dioxane (100 mL) was added triethylamine (10.3 g, 101 mmol, 14.1 mL, 3.00 eq) at 20°C. After stirring at 100°C for 16 h, the reaction mixture was adjusted to pH~4 with hydrochloric acid (1 M in water) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 2-(3-oxo-4H-1,4- benzoxazin-2-yl)acetic acid (7.00 g, 30.4 mmol, 90% yield, 90% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.43 (s, 1H), 10.71 (s, 1H), 6.94-6.84 (m, 4H), 4.89-4.82 (m, 1H), 2.94-2.87 (m, 1H), 2.82-2.74 (m, 1H). Procedure for preparation of methyl 2-(3-oxo-4H-1,4-benzoxazin-2-yl)acetate To a solution of 2-(3-oxo-4H-1,4-benzoxazin-2-yl)acetic acid (6.30 g, 30.4 mmol, 1.00 eq) in a mixed solvent of dichloromethane (30.0 mL) and methanol (30.0 mL) was added trimethylsilyl diazomethane (1 M, 60.8 mL, 2.00 eq) at 0°C. After stirring at 25°C for 16 h, the reaction mixture was adjusted to pH~4 with hydrochloric acid (1.0 M in water) and extracted with ethyl acetate (200 mL × 2). The combined organic phase was washed with brine(50.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~100% ethyl acetate/petroleum ether gradient @60 mL/min) to give methyl 2-(3-oxo-4H-1,4-benzoxazin-2-yl)acetate (4.50 g, 18.3 mmol, 60% yield, 90% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.75 (s, 1H), 6.99-6.82 (m, 4H), 4.95-4.88 (m, 1H), 3.63 (s, 3H), 3.05-2.97 (m, 1H), 2.95-2.87 (m, 1H). Procedure for preparation of 2-(2-hydroxyethyl)-4H-1,4-benzoxazin-3-one To a solution of methyl 2-(3-oxo-4H-1,4-benzoxazin-2-yl)acetate (3.00 g, 13.6 mmol, 1.00 eq) in tetrahydrofuran (30.0 mL) was added lithium aluminum hydride (1.00 M in tetrahydrofuran, 27.1 mL, 2.00 eq) dropwise at -70°C. After stirring at -70°C for 1 h. the reaction was quenched with saturated sodium sulfate aqueous solution (20.0 ml), triturated with isopropanol (100 ml) and filtered. The filtrate was concentrated and purified by flash silica gel chromatography (ISCO®;40 g SepaFlash® Silica Flash Column, Eluent of 0~100% ethyl acetate/petroleum ether gradient @60 mL/min) to give 2-(2- hydroxyethyl)-4H-1,4-benzoxazin-3-one (2.00 g, 9.63 mmol, 71% yield, 93% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.65 (s, 1H), 7.18-6.74 (m, 4H), 4.66-4.61 (m, 1H), 3.65-3.51 (m, 2H), 2.00-1.89 (m, 1H), 1.88-1.73 (m, 1H). LC-MS (Method A): R _t = 0.778 min; MS (ESIpos): m/z = 194.2 [M+H] ⁺ . Procedure for preparation of 2-(3-oxo-4H-1,4-benzoxazin-2-yl)acetaldehyde To a solution of 2-(2-hydroxyethyl)-4H-1,4-benzoxazin-3-one (2.00 g, 10.4 mmol, 1.00 eq) in dichloromethane (30.0 mL) was added Dess-Martin periodinane (5.71 g, 13.5 mmol, 4.17 mL, 1.30 eq) at 0°C. After stirring at 25°C for 2 h, the mixture was poured into a mixed saturated aqueous sodium thiosulfate (20.0 mL) and saturated sodium bicarbonate aqueous solution (20.0 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-(3-oxo-4H- 1,4-benzoxazin-2-yl)acetaldehyde (1.00 g, 4.71 mmol, 45% yield, 90% purity) as a gray solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.80 (s, 1H), 9.71 (s, 1H), 6.98-6.91 (m, 4H), 5.12-5.06 (m, 1H), 3.12-3.04 (m, 1H), 3.01-2.93 (m, 1H). Procedure for preparation of 2-amino-3-(3-oxo-4H-1,4-benzoxazin-2-yl)propanenitrile To a solution of 2-(3-oxo-4H-1,4-benzoxazin-2-yl)acetaldehyde (1.00 g, 5.23 mmol, 1.00 eq) in methanol (20.0 mL) and ammonia (7.00 M in methanol, 10.0 mL, 13.4 eq) was added dropwise titanium (IV) isopropoxide (1.78 g, 6.28 mmol, 1.85 mL, 1.20 eq) at 20 ^. After stirring at 20°C for 2 h, trimethylsilyl nitrile (623 mg, 6.28 mmol, 785 μL, 1.2 eq) was added dropwise at 20 ^. After stirring at 20°C for 14 h, the mixture was adjusted pH = 9 with saturated solution of sodium bicarbonate aqueous solution and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~100% ethyl acetate/petroleum ether gradient @40 mL/min) to give 2- amino-3-(3-oxo-4H-1,4-benzoxazin-2-yl)propanenitrile (500 mg, 2.19 mmol, 42% yield, 95% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.77 (s, 1H), 7.02-6.84 (m, 4H), 4.78-4.65 (m, 1H), 3.98-3.89 (m, 1H), 2.29-2.18 (m, 1H), 2.12-2.03 (m, 1H). LC-MS (Method C): R _t = 0.311 min; MS (ESIpos): m/z = 190.9 [M+H] ⁺ . Procedure for preparation of CPD0188250 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-3-oxo-4H-1,4- benzoxazin-2-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-triflu oroacetyl)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of 2-amino-3-(3-oxo-4H-1,4-benzoxazin-2-yl)propanenitrile (150 mg, 690 μmol, 1.00 eq) and (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (252 mg, 690 μmol, 1.00 eq) in N,N-dimethylformamide (2.00 mL) were added N,N-diisopropylethylamine (268 mg, 2.07 mmol, 360 μL, 3.00 eq) and O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (394 mg, 1.04 mmol, 1.50 eq). After stirring at 25°C for 16 h, formic acid (5 drops) was added to the mixture to adjust pH~5.0 and purified by prep-HPLC (column: Phenomenex Synergi C18 150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 44%-74%, 10 min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-3-oxo-4H-1,4- benzoxazin-2-yl] ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino] butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (92.4 mg, 162 μmol, 24% yield, 99% purity) as a yellow solid. Preparation of CPD0188251. Procedure for preparation of benzyl 3-[1-(tert-butoxycarbonylamino)-2-methoxy-2-oxo- ethylidene]azetidine-1-carboxylate To a mixture of benzyl 3-oxoazetidine-1-carboxylate (5.00 g, 24.4 mmol, 1.00 eq) and methyl 2-(tert- butoxycarbonylamino)-2-dimethoxyphosphoryl-acetate (7.24 g, 24.4 mmol, 1.00 eq) in dichloromethane (50.0 mL) was added dropwise 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (4.45 g, 29.2 mmol, 4.41 mL, 1.20 eq) at 0°C. After stirring at 20°C for 14 h, the mixture was washed with water (50.0 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~20% ethyl acetate/petroleum ether gradient @ 80 mL/min) to give benzyl 3-[1-(tert-butoxycarbonylamino)-2-methoxy-2-oxo-ethylidene]a zetidine-1- carboxylate (6.78 g, 18.0 mmol, 74% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.38-7.33 (m, 5H), 6.47 (s, 1H), 5.13 (s, 2H), 4.84-4.82 (m, 4H), 3.81 (s, 3H), 1.46 (s, 9H). Procedure for preparation of methyl 2-(azetidin-3-yl)-2-(tert-butoxycarbonylamino) acetate A mixture of benzyl 3-[1-(tert-butoxycarbonylamino)-2-methoxy-2-oxo-ethylidene]a zetidine-1- carboxylate (5.78 g, 15.4 mmol, 1.00 eq) and palladium on carbon (500 mg, 10% purity, 0.10 eq) in methanol (60.0 mL) was stirred at 20°C for 14 h under hydrogen (15 psi) atmosphere. After filtration, the filtrate was concentrated under vacuum to give methyl 2-(azetidin-3-yl)-2-(tert- butoxycarbonylamino)acetate (3.60 g, 14.7 mmol, 96% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.49 (s, 1H), 4.44 (s, 1H), 3.76-3.72 (m, 3H), 3.70-3.62 (m, 4H), 3.07- 3.06 (m, 1H), 1.45 (s, 9H). Procedure for preparation of methyl 2-(1-acetylazetidin-3-yl)-2-(tert-butoxycarbonylamino) acetate A mixture of methyl 2-(azetidin-3-yl)-2-(tert-butoxycarbonylamino)acetate (3.6 g, 14.7 mmol, 1.00 eq), acetic anhydride (1.81 g, 17.7 mmol, 1.66 mL, 1.20 eq) and triethylamine (4.47 g, 44.2 mmol, 6.15 mL, 3.00 eq) in dichloromethane (40.0 mL) was stirred at 20°C for 14 h. The combined mixture (EW30036- 264, EW30036-269) was concentrated under vacuum and purified by reversed phase column (column: Phenomenex Synergi C18120 g; mobile phase: [water (additive: 0.5% formic acid)-ACN]; B%: 0%- 100%, 50 min) to give methyl 2-(1-acetylazetidin-3-yl)-2-(tert-butoxycarbonylamino)acetat e (1.70 g, 5.94 mmol, 40% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.47-7.44 (m, 1H), 4.28-4.20 (m, 1H), 4.15-4.04 (m, 1H), 3.92-3.75 (m, 2H), 3.64-3.53 (m, 4H), 2.90-2.83 (m, 1H), 1.71 (s, 3H), 1.37-1.34 (m, 9H). Procedure for preparation of tert-butyl N-[1-(1-acetylazetidin-3-yl)-2-amino-2-oxo-ethyl] carbamate A mixture of methyl 2-(1-acetylazetidin-3-yl)-2-(tert-butoxycarbonylamino)acetat e (1.60 g, 5.59 mmol, 1.00 eq) in ammonium (10.0 M in methanol, 40.0 mL) was stirred at 20°C for 14 h. The mixture was concentrated under vacuum to give tert-butyl N-[1-(1-acetylazetidin-3-yl)-2-amino-2-oxo- ethyl]carbamate (1.50 g, 5.53 mmol, 99% yield) as a white solid. Procedure for preparation of 2-(1-acetylazetidin-3-yl)-2-amino-acetamide A mixture of tert-butyl N-[1-(1-acetylazetidin-3-yl)-2-amino-2-oxo-ethyl]carbamate (1.50 g, 5.53 mmol, 1.00 eq) in hydrochloric acid (4.00 M in dioxane, 30.0 mL) was stirred at 20°C for 1 h. The mixture was concentrated under vacuum to give 2-(1-acetylazetidin-3-yl)-2-amino-acetamide (1.90 g, crude, 4 HCl salt) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.54-8.50 (m, 2H), 8.14-8.08 (m, 1H), 7.67-7.65 (m, 1H), 4.18-4.13 (m, 2H), 3.90-3.83 (m, 3H), 2.95-2.92 (m, 1H), 1.72 (s, 3H). Procedure for preparation of (1R,2S,5S)-N-[1-(1-acetylazetidin-3-yl)-2-amino-2-oxo-ethyl] -3- [(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl] -6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide A mixture of 2-(1-acetylazetidin-3-yl)-2-amino-acetamide (300 mg, 0.946 mmol, 1.00eq, 4HCl salt), (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0] hexane-2-carboxylic acid (310 mg, 0.852 mmol, 0.90 eq), O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (432 mg, 1.14 mmol, 1.20 eq) and N,N- diisopropylethylamine (734 mg, 5.68 mmol, 0.989 mL, 6.00 eq) in N,N-dimethylformamide (5.00 mL) was stirred at 20°C for 14 h. The reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*40mm* 15 μm; mobile phase: [water (FA)- ACN]; B%: 22%-52%,10 min) to give (1R,2S,5S)-N-[1-(1-acetylazetidin-3-yl)-2-amino-2-oxo-ethyl] -3- [(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl) amino] butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (380 mg, 734 μmol, 78% yield) as a brown solid. LC-MS (Method C): R _t = 0.724 min, MS (ESIpos): m/z = 518.3 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[(1-acetylazetidin-3-yl)-cyano-methyl]-3-[(2S)- 3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxamide A mixture of (1R,2S,5S)-N-[1-(1-acetylazetidin-3-yl)-2-amino-2-oxo-ethyl] -3-[(2S)-3,3-dimethyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabi cyclo[3.1.0]hexane-2-carboxamide (230 mg, 0.444 μmol, 1.00 eq) and Burgess reagent (106 mg, 0.444 mmol, 1.00 eq) in DCM (10.0 mL) was stirred at 20°C for 14 h. Saturated sodium bicarbonate aqueous solution was added to the mixture to adjust pH~7 and concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 μm; mobile phase: [water(FA)-ACN]; B%: 28%-58%,7 min) to give (1R,2S,5S)-N-[(1-acetylazetidin-3-yl)-cyano-methyl]-3-[(2S)- 3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (55.2 mg, 111 μmol, 25% yield) as a white solid. Preparation of CPD0188255 Procedure for preparation of ethyl (3S,3aS,6aR)-2-[(2S)-2-(tert-butoxycarbonylamino)-3,3- dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta [c]pyrrole-3-carboxylate To a solution of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid (10.0 g, 43.2 mmol, 1.00 eq) and N-ethyl-N-isopropylpropan-2-amine (16.3 g, 126 mmol, 22.0 mL, 3.92 eq) in anhydrous N,N- dimethylformamide (150 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene] – dimethyl-ammonium; hexafluorophosphate (20.0 g, 52.6 mmol, 1.22 eq) in portions at 5°C. After stirring for 0.5 h, ethyl (3S,3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole -3- carboxylate;hydrochloride (9.50 g, 43.2 mmol, 1.00 eq) was added. The resulting mixture was stirred at 20°C for 15.5 h. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with brine (150 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 50/1 to 5/1) to afford ethyl (3S,3aS,6aR)-2-[(2S)-2-(tert- butoxycarbonylamino)-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]pyrrole-3- carboxylate (15.0 g, 37.8 mmol, 87% yield) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.23 (d, J = 9.6 Hz, 1H), 4.41-4.27 (m, 2H), 4.25-4.14 (m, 2H), 3.89- 3.80 (m, 1H), 3.79-3.69 (m, 1H), 2.85-2.61 (m, 2H), 2.01-1.81 (m, 2H), 1.80-1.70 (m, 1H), 1.70-1.56 (m, 2H), 1.55-1.46 (m, 1H), 1.46-1.38 (m, 9H), 1.29-1.24 (m, 3H), 1.08-0.95 (m, 9H). LC-MS (Method C): Rt = 0.998 min; MS (ESIpos): m/z = 341.1 [M-C ₄ H ₈ +H] ⁺ . SFC: de% = 93%. Procedure for preparation of (3S,3aS,6aR)-2-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimeth yl- butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta [c]pyrrole-3-carboxylic acid A mixture of ethyl (3S,3aS,6aR)-2-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimeth yl-butanoyl]- 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylat e (5.00 g, 12.6 mmol, 1.00 eq), lithium hydroxide hydrate (0.90 g, 21.4 mmol, 1.70 eq) in tetrahydrofuran (30.0 mL) and water (10.0 mL) was stirred at 20°C for 16 h. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran. Hydrogen chloride (1M) was added to the solution to adjust pH ~ 4. The resulting suspension was filtered and the filter cake was dried under reduced pressure to afford (3S,3aS,6aR)- 2-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]- 3,3a,4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrole-3-carboxylic acid (5.00 g, crude) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.63 (s, 1H), 5.35 (d, J = 9.6 Hz, 1H), 4.42-4.26 (m, 1H), 3.82-3.78 (m, 1H), 2.97-2.63 (m, 1H), 2.02-1.81 (m, 2H), 1.80-1.69 (m, 1H), 1.68-1.56 (m, 2H), 1.55-1.48 (m, 1H), 1.47-1.37 (m, 9H), 1.04-0.96 (m, 9H). LC-MS (Method C): R _t = 0.894 min; MS (ESIpos): m/z = 313.1 [M-C ₄ H ₈ +H] ⁺ . Procedure for preparation of (3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3,3a,4,5 ,6,6a- hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid A mixture of (3S,3aS,6aR)-2-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimeth yl-butanoyl]-3,3a,4,5,6,6a - hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (5.00 g, 13.6 mmol, 1.00 eq) in hydrogen chloride/dioxane (4M, 80.0 mL, 23.6 eq) was stirred at 20°C for 2 h. The reaction mixture was concentrated under reduced pressure to afford (3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-butanoyl]- 3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (4.20 g, crude, hydrogen chloride salt) as a white solid LC-MS (Method C): R _t = 0.798 min; MS (ESIpos): m/z = 269.1 [M+H] ⁺ . Procedure for preparation of (3S,3aS,6aR)-2-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-c yclopenta[c]pyrrole-3-carboxylic acid Triethylamine (2.91 g, 28.7 mmol, 4.00 mL, 2.43 eq) was added to a mixture of (3S,3aS,6aR)-2-[(2S)- 2-amino-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cy clopenta[c]pyrrole-3-carboxylic acid (3.60 g, 11.8 mmol, 1.00 eq, hydrogen chloride salt) in anhydrous dichloromethane (60.0 mL) at 5°C. Methyl 2,2,2-trifluoroacetate (1.91 g, 14.9 mmol, 1.50 mL, 1.26 eq) was added to the mixture. After stirring at 30°C for 16 h, the reaction mixture was concentrated under reduced pressure to afford (3S,3aS,6aR)-2-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl) amino]butanoyl]-3,3a,4,5,6,6a-hexahydro- 1H-cyclopenta[c]pyrrole-3-carboxylic acid (4.50 g, crude) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.23 (t, J = 8.0 Hz, 1H), 4.72-4.46 (m, 1H), 4.36-4.25 (m, 1H), 3.94-3.69 (m, 1H), 3.65-3.36 (m, 1H), 3.04-2.58 (m, 1H), 2.01-1.96 (m, 0.5H), 1.94-1.80 (m, 1H), 1.79-1.69 (m, 1H), 1.69-1.52 (m, 2H), 1.50-1.39 (m, 1H), 1.39-1.32 (m, 0.5H), 1.09-0.95 (m, 9H). LC-MS (Method C): R _t = 0.798 min; MS (ESIpos): m/z = 365.2 [M+H] ⁺ . Procedure for preparation of amino-2-(1,3-benzothiazol-5-yl)acetonitrile Trimethylsilanecarbonitrile (396 mg, 4.00 mmol, 0.50 mL, 1.30 eq) was added to a mixture of 1,3- benzothiazole-5-carbaldehyde (0.50 g, 3.06 mmol, 1.00 eq), ammonia/methanol (7 M, 1.5 mL, 3.43 eq) and titanium tetraisopropanolate (1.06 g, 3.73 mmol, 1.10 mL, 1.22 eq) in methanol (5.00 mL). After stirring at 20°C for 2 h, the mixture was quenched with saturated aqueous of sodium hydrogen carbonate (15.0 mL) at 5°C. The resulting mixture was extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 2-amino-2-(1,3-benzothiazol-5- yl)acetonitrile (0.51 g, crude) as yellow oil. LC-MS (Method A): R _t = 0.307 min; MS (ESIpos): m/z = 190.1 [M+H] ⁺ . Procedure for preparation of CPD0188255 (3S,3aS,6aR)-N-[1,3-benzothiazol-5-yl(cyano)methyl]- 2-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoy l]-3,3a,4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrole-3-carboxamide [Dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]–d imethyl-ammonium; hexafluorophosphate (1.23 g, 3.23 mmol, 1.20 eq) was added to a mixture of (3S,3aS,6aR)-2-[(2S)-3,3-dimethyl-2- [(2,2,2- trifluoroacetyl)amino]butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-c yclopenta[c]pyrrole-3-carboxylic acid (1.10 g, 3.02 mmol, 1.12 eq) and N-ethyl-N-isopropylpropan-2-amine (1.11 g, 8.61 mmol, 1.50 mL, 3.20 eq) in anhydrous N,N-dimethylformamide (10.0 mL) at 5°C. After stirring for 30 min, 2-amino-2-(1,3- benzothiazol-5-yl)acetonitrile (0.51 g, 2.70 mmol, 1.00 eq) was added to the mixture. The mixture was stirred at 20°C for 15.5 h. The resulting solution was diluted with ethyl acetate (20.0 mL), and washed with brine (20.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Phenomenex luna C18150*40mm* 15 μm; mobile phase: [water(FA)-ACN]; B%: 43%- 73%, 10 min) to afford (3S,3aS,6aR)-N-[1,3-benzothiazol-5-yl(cyano)methyl]-2-[(2S)- 3,3-dimethyl-2- [(2,2,2- trifluoroacetyl)amino]butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-c yclopenta [c]pyrrole-3- carboxamide (461 mg, 861 μmol, 32% yield, 100% purity) as a white solid. Preparation of CPD0189159 Procedure for preparation of methyl 3-oxo-3-pyrrolidin-1-yl-propanoate To a solution of methyl 3-chloro-3-oxo-propanoate (15.0 g, 110 mmol, 1.00 eq) in dichloromethane (50.0 mL) were added triethylamine (11.1 g, 110 mmol, 1.00 eq) and pyrrolidine (8.20 g, 115 mmol, 1.05 eq) at 0°C. After stirring at 25°C for 12 h, the reaction mixture was poured into water (50.0 mL) and extracted with dichloromethane (50.0 mL × 2). The combined organic layers were washed with hydrochloric acid (1.50 M in water, 50.0 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated to give methyl 3-oxo-3-pyrrolidin-1-yl-propanoate (15.0 g, 87.6 mmol, 80% yield) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 3.68 (s, 3H), 3.47-3.36 (m, 4H), 3.35 (s, 2H), 1.99-1.75 (m, 4H). LC-MS (Method A): R _t = 0.388 min; MS (ESIpos): m/z = 172.3 [M+H] ⁺ . Procedure for preparation of methyl (2Z)-2-hydroxyimino-3-oxo-3-pyrrolidin-1-yl-propanoate To a solution of methyl 3-oxo-3-pyrrolidin-1-yl-propanoate (0.500 g, 2.92 mmol, 1.00 eq) in dichloromethane (10.0 mL) were added tert-butyl nitrite (331 mg, 3.21 mmol, 1.10 eq) and hydrochloric acid (2 M in ethyl acetate, 2.04 mL, 1.40 eq) at 0°C. After stirring at 25°C for 2 h, the mixture was concentrated under vacuum to give methyl (2Z)-2-hydroxyimino-3-oxo-3-pyrrolidin-1-yl-propanoate (500 mg, 2.25 mmol, 77% yield, 90% purity) as a yellow solid. LC-MS (Method A): R _t = 0.621 min; MS (ESIpos): m/z = 201.2 [M+H] ⁺ . Procedure for preparation of methyl 2-(3-oxo-4H-1,4-benzoxazin-2-yl)acetate To a solution of methyl (2Z)-2-hydroxyimino-3-oxo-3-pyrrolidin-1-yl-propanoate (500 mg, 2.50 mmol, 1.00 eq) in hydrochloric acid (4 M in methanol, 10.0 mL) was added palladium on carbon (300 mg, 10% purity) at 20°C under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen for 3 times. After stirring at 20°C for 16 h under hydrogen (50 psi) atmosphere, the reaction mixture was filtered. The filtrate was concentrated under vacuum to give methyl 2-amino-3- oxo-3-pyrrolidin-1-yl-propanoate (500 mg, 2.13 mmol, 85% yield, 95% purity, HCl) as a yellow solid. LC-MS (Method A): R _t = 0.133 min; MS (ESIpos): m/z = 187.2 [M+H] ⁺ . Procedure for preparation of 2-amino-3-oxo-3-pyrrolidin-1-yl-propanamide A solution of methyl 2-amino-3-oxo-3-pyrrolidin-1-yl-propanoate (0.500 g, 2.69 mmol, 1.00 eq) in ammonia (7 M in methanol, 10.0 mL, 26.0 eq) was stirred at 25°C for 16 h. The mixture was concentrated under vacuum to give 2-amino-3-oxo-3-pyrrolidin-1-yl-propanamide (440 mg, 2.06 mmol, 77% yield, 80% purity) as a gray solid. LC-MS (Method A): R _t = 0.120 min; MS (ESIpos): m/z = 172.1 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-(1-carbamoyl-2-oxo-2-pyrrolidin-1-yl-ethyl)-3-[ (2S)- 3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-d imethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide To a mixture of 2-amino-3-oxo-3-pyrrolidin-1-yl-propanamide (200 mg, 1.17 mmol, 1.00 eq) and (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (340 mg, 934 μmol, 0.80 eq) in N,N-dimethylformamide (6.00 mL) were added N,N-diisopropylethylamine (453 mg, 3.50 mmol, 3.00 eq) and O-(7-azabenzotriazol-1- yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (533 mg, 1.40 mmol, 1.20 eq) at 25°C. After stirring at 25°C for 16 h, the mixture was poured into saturated ammonia chloride (30.0 mL) and extracted with ethyl acetate (50.0 mL × 2). The combined organic layers were washed with brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-N-(1-carbamoyl-2-oxo-2-pyrrolidin-1-yl-ethyl)-3-[ (2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (0.400 g, 773 μmol, 66% yield) as yellow oil. LC-MS (Method C): R _t = 0.867 min; MS (ESIpos): m/z = 518.3 [M+H] ⁺ . Procedure for preparation of CPD0189159 - (1R,2S,5S)-N-[(1R)-1-cyano-2-oxo-2-pyrrolidin-1-yl- ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino] butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-(1-carbamoyl-2-oxo-2-pyrrolidin-1-yl-ethyl)-3-[ (2S)-3,3-dimethyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabi cyclo[3.1.0]hexane-2-carboxamide (0.400 g, 773 μmol, 1.00 eq) in dichloromethane (8.00 mL) was added Burgess reagent (553 mg, 2.32 mmol, 3.00 eq) at 25°C. After stirring at 25°C for 4 h, saturated sodium bicarbonate aqueous solution was added to adjust pH~9 and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (15.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by prep-HPLC(column: Waters Xbridge C18 150*50mm* 10 μm; mobile phase: [water(NH ₄ HCO ₃ )-ACN]; B%: 4%-34%, 10 min) to give (1R,2S,5S)- N-[(1R)-1-cyano-2-oxo-2-pyrrolidin-1-yl-ethyl]-3-[(2S)-3,3-d imethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (123 mg, 242 μmol, 31% yield, 98% purity) as a white solid. Preparation of CPD0186843 Procedure for preparation of 4-[(E)-2-(dimethylamino)vinyl]pyridine-3-carbonitrile A mixture of 4-methylpyridine-3-carbonitrile (14.0 g, 118 mmol, 1.00 eq) in 1,1-dimethoxy-N,N- dimethylmethanamine (40.0 mL) was stirred at 130 °C for 12 h. After concentration, the residue was purified by silica gel chromatography (petroleum ether/[ethyl acetate: methanol=10:1] = 3/1 to 1/1) to give 4-[(E)-2-(dimethylamino)vinyl]pyridine-3-carbonitrile (13.0 g, 71.3 mmol, 60% yield, 95% purity) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.51 (s, 1H), 8.26 (d, J = 6.0 Hz, 1H), 7.31 (d, J = 13.2 Hz, 1H), 7.11 (d, J = 6.0 Hz, 1H), 5.26 (d, J = 13.4 Hz, 1H), 3.01 (s, 6H). Procedure for preparation of 2,7-naphthyridin-1-amine A mixture of 4-[(E)-2-(dimethylamino)vinyl]pyridine-3-carbonitrile (9.00 g, 49.3 mmol, 95% purity, 1.00 eq) and ammonia formic acid (15.5 g, 246 mmol, 5.00 eq) in acetic acid (50.0 mL) was stirred at 115°C for 12 h. The reaction mixture was poured into water (500 mL) and washed with ethyl acetate (100 mL × 3). The aqueous phase was adjusted pH to 8-9 with sodium hydroxide (solid) and extracted with ethyl acetate (100 mL × 8). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 2,7-naphthyridin-1-amine (5.50 g, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.51 (s, 1H), 8.55 (d, J = 5.6 Hz, 1H), 7.99 (d, J = 5.6 Hz, 1H), 7.56 (d, J = 5.6 Hz, 1H), 7.26 (s, 2H), 6.86 (d, J = 5.6 Hz, 1H). Procedure for preparation of 4-bromo-2,7-naphthyridin-1-amine A mixture of 2,7-naphthyridin-1-amine (5.20 g, 35.8 mmol, 1.00 eq) and N-bromosuccinimide (6.69 g, 37.6 mmol, 1.05 eq) in dichloromethane (200 mL) was stirred at 20°C for 12 h. The reaction mixture was poured into saturated sodium bicarbonate aqueous solution (500 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were concentrated under vacuum to give a residue. The residue was triturated with acetonitrile (30.0 mL) at 20°C for 30 minutes. After filtration, the filter cake was dried under vacuum to give 4-bromo-2,7-naphthyridin-1-amine (6.10 g, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.54 (s, 1H), 8.73 (d, J = 5.6 Hz, 1H), 8.19 (s, 1H), 7.69-7.56 (m, 3H). Procedure for preparation of 4-bromo-2,7-naphthyridine To a mixture of 4-bromo-2,7-naphthyridin-1-amine (6.10 g, 27.2 mmol, 1.00 eq) in tetrahydrofuran (100 mL) was added isopentyl nitrite (9.57 g, 81.6 mmol, 11.0 mL, 3.00 eq) at 20 °C. After stirring at 70 °C for 12 h, the reaction mixture was concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (petroleum ether/[ethyl acetate: methanol = 10: 1] = 10: 1 to 1: 1) to give 4-bromo-2,7-naphthyridine (2.10 g, 8.04 mmol, 29% yield, 80% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.60 (s, 1H), 9.56 (s, 1H), 9.02 (s, 1H), 8.92 (d, J = 5.6 Hz, 1H), 7.93 (d, J = 5.6 Hz, 1H). Procedure for preparation of methyl 2-(benzhydrylideneamino)-2-(2,7-naphthyridin-4-yl)acetate To a mixture of 4-bromo-2,7-naphthyridine (300 mg, 1.15 mmol, 80% purity, 1.00 eq), methyl 2- (benzhydrylideneamino)acetate (348 mg, 1.38 mmol, 1.20 eq) and [2-(2-aminophenyl)phenyl]-chloro- palladium;tritert-butylphosphane (117 mg, 0.229 mmol, 0.200 eq) in N,N-dimethylformamide (5.00 mL) was added potassium phosphate (731 mg, 3.44 mmol, 3.00 eq). The mixture was purged with nitrogen for 3 times and stirred at 90 °C for 12 h. The reaction mixture (5 batches carried out in parallel) was poured into saturated sodium bicarbonate aqueous solution (200 mL) and extracted with ethyl acetate (80.0 mL × 3). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1: 1 to 0: 1) to give methyl 2-(benzhydrylideneamino)-2-(2,7-naphthyridin-4-yl)acetate (1.40 g, 2.57 mmol, 44% yield, 70% purity) as brown oil. LC-MS (Method C): R _t = 0.863 min; MS (ESIpos): m/z = 382.1 [M+H] ⁺ . Procedure for preparation of 2-(benzhydrylideneamino)-2-(2,7-naphthyridin-4-yl)acetamide A mixture of methyl 2-(benzhydrylideneamino)-2-(2,7-naphthyridin-4-yl)acetate (1.40 g, 2.57 mmol, 70% purity, 1.00 eq) in ammonia (7 M in methanol, 20.0 mL) was stirred at 20 °C for 12 h. After concentration, the residue was purified by silica gel chromatography (petroleum ether/[ethyl acetate: methanol = 10: 1] = 3: 1 to 0: 1) to give 2-(benzhydrylideneamino)-2-(2,7-naphthyridin-4-yl)acetamide (900 mg, 2.24 mmol, 87% yield, 91% purity) as brown syrup. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.51 (s, 1H), 9.42 (s, 1H), 8.71 (d, J = 6.0 Hz, 1H), 8.44 (s, 1H), 8.01 (d, J = 6.0 Hz, 1H), 7.74 (s, 1H), 7.70 (s, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.55 (s, 1H), 7.50-7.37 (m, 6H), 7.00 (d, J = 6.4 Hz, 2H), 5.31 (s, 1H). LC-MS (Method C): R _t = 0.802 min; MS (ESIpos): m/z = 367.1 [M+H] ⁺ . Procedure for preparation of 2-amino-2-(2,7-naphthyridin-4-yl)acetamide A mixture of 2-(benzhydrylideneamino)-2-(2,7-naphthyridin-4-yl)acetamide (900 mg, 2.24 mmol, 91% purity, 1.00 eq) in a mixed solvent of methanol (10.0 mL) and hydrochloric acid (10.0 mL, 1 M in water) was stirred at 20 °C for 1 h. The reaction mixture was poured into water (100 mL) and washed with methyl tertiary butyl ether (30.0 mL × 2). The aqueous layer was concentrated under vacuum to give 2- amino-2-(2,7-naphthyridin-4-yl)acetamide (450 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.65 (s, 1H), 9.63 (s, 1H), 8.94 (s, 2H), 8.89-8.88 (m, 2H), 8.28 (d, J = 6.4 Hz, 1H), 8.00 (s, 1H), 7.77 (s, 1H), 5.66 (s, 1H). LC-MS (Method I): R _t = 0.257 min; MS (ESIpos): m/z = 203.1 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[2-amino-1-(2,7-naphthyridin-4-yl)-2-oxo-ethyl] -3- [(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl] -6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide A mixture of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6- dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (297 mg, 0.815 mmol, 1.10 eq), O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (423 mg, 1.11 mmol, 1.50 eq) and N,N- diisopropylethylamine (287 mg, 2.23 mmol, 3.00 eq) in N,N-dimethylformamide (2.00 mL) was stirred at 20 °C for 0.5 h. 2-Amino-2-(2,7-naphthyridin-4-yl)acetamide (150 mg, 0.741 mmol, 1.00 eq) was added to the solution above. After stirring at 20 °C for 11.5 h, the reaction mixture was poured into water (50.0 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by reversed phase column (formic acid condition, MeCN/water (additive: 0.1% formic acid) = 50% - 60%) to give (1R,2S,5S)-N-[2-amino-1- (2,7-naphthyridin-4-yl)-2-oxo-ethyl]-3-[(2S)-3,3-dimethyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (250 mg, 432 mmol, 58% yield, 95% purity) as a brown solid. LC-MS (Method L): R _t = 0.494 min; MS (ESIpos): m/z = 549.4 [M+H] ⁺ . Procedure for preparation of CPD0186843 - (1R,2S,5S)-N-[cyano(2,7-naphthyridin-4-yl)methyl]- 3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoy l]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide A mixture of (1R,2S,5S)-N-[2-amino-1-(2,7-naphthyridin-4-yl)-2-oxo-ethyl] -3-[(2S)-3,3-dimethyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabi cyclo[3.1.0]hexane-2-carboxamide (250 mg, 0.432 mmol, 95% purity, 1.00 eq) and (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (154 mg, 0.649 mmol, 1.50 eq) in dichloromethane (10.0 mL) was stirred at 20°C for 4 h. The reaction mixture was poured into water (50.0 mL) and extracted with ethyl acetate (20.0 mL ×3). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Boston Prime C18150*30mm*5 μm; mobile phase: [water(AA)-ACN]; B%: 37%-67%, 10min) to give (1R,2S,5S)-N-[cyano(2,7-naphthyridin-4-yl)methyl]-3-[(2S)-3, 3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (225 mg, 0.425 mmol, 98% yield, 99% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.73-9.24 (m, 4H), 8.93 (d, J = 6.0 Hz, 1H), 8.90-8.74 (m, 1H), 7.89- 7.84 (m, 1H), 7.04-6.80 (m, 1H), 4.39-4.34 (m, 1H), 4.26-4.12 (m, 1H), 4.01-3.86 (m, 1H), 3.71-3.64 (m, 1H), 1.64-1.52 (m, 1H), 1.39-1.13 (m, 1H), 1.08-0.77 (m, 15H). LC-MS (Method K): R _t = 2.054 min; MS (ESIpos): m/z = 531.3 [M+H] ⁺ . SFC: dr: 51: 49. Preparation of CPD0186846 Procedure for preparation of 4-chlorocinnoline To a solution of cinnolin-4-ol (25.0 g, 171 mmol, 1.00 eq) in toluene (300 mL) were added phosphorus oxychloride (39.3 g, 257 mmol, 23.8 mL, 1.50 eq) and pyridine (4.04 g, 51.1 mmol, 4.13 mL,0.3 eq) at 20 °C. After stirring at 135 °C for 1 h, the reaction mixture was concentrated in vacuum to give a residue. The residue was added slowly into water (300 mL). The mixture was neutralized with solid sodium bicarbonate. The mixture was extracted with ethyl acetate (200 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give 4-chlorocinnoline (14.0 g, 85.1 mmol, 50% yield) as a black solid. Procedure for preparation of methyl 2-(benzhydrylideneamino)-2-cinnolin-4-yl-acetate To a solution of methyl 2-(benzhydrylideneamino)acetate (32.3 g, 128 mmol, 1.50 eq) in N,N-dimethyl formamide (150 mL) were added cesium carbonate (41.6 g, 128 mmol, 1.50 eq) and 4-chlorocinnoline (14.0 g, 85.1 mmol, 1.00 eq) at 20 °C. After stirring at 50 °C for 14 h, the reaction mixture was filtered. The filtrate was concentrated in vacuum to give methyl 2-(benzhydrylideneamino)-2-cinnolin-4-yl- acetate (32.4 g, 85.1 mmol, 100% yield) as black oil. Procedure for preparation of methyl 2-(tert-butoxycarbonylamino)-2-cinnolin-4-yl-acetate To a solution of methyl 2-(benzhydrylideneamino)-2-cinnolin-4-yl-acetate (32.0 g, 83.90 mmol, 1.00 eq) in mixed solvent of dichloromethane (150 mL) and methanol (150 mL) was added hydrogen chloride (in water) (1 M, 207 mL, 2.47 eq) at 20 °C. After stirring at 20 °C for 0.5 h, sodium bicarbonate (42.3 g, 503 mmol, 19.6 mL, 6.00 eq) was added into the reaction mixture in portions at 20 °C. Di-tert- butyldicarbonate (54.9 g, 252 mmol, 57.8 mL, 3.00 eq) was added into the reaction mixture at 20 °C. The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated to remove organic solvent. The mixture was filtered, and the filtrate was diluted with water (300 mL) and extracted with ethyl acetate (150 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 10: 1 to 1: 1) and triturated with mixed solvent of petroleum ether and methyl tertiary butyl ether (v/v = 10/1, 300 mL × 3). The suspension was filtered under reduced pressure and filter cake was dried to give methyl 2-(tert-butoxycarbonylamino)-2- cinnolin-4-yl-acetate (16.0 g, 50.4 mmol, 60% yield) as brown solid. LC-MS (Method C): R _t = 0.734 min; MS (ESIpos): m/z = 318.0 [M+H] ⁺ . Procedure for preparation of tert-butyl N-(2-amino-1-cinnolin-4-yl-2-oxo-ethyl)carbamate A solution of methyl 2-(tert-butoxycarbonylamino)-2-cinnolin-4-yl-acetate (16.0 g, 50.4 mmol, 1.00 eq) in ammonia (7.00 M in methanol, 246 mL, 34.2 eq) was stirred at 20 °C for 16 h. The reaction mixture was concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 20: 1 to give 0: 1) to give tert-butyl N-(2-amino-1-cinnolin-4-yl-2-oxo- ethyl)carbamate (8.50 g, 28.1 mmol, 56% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.24 (s, 1H), 8.56 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.91-7.82 (m, 2H), 6.25-6.09 (m, 2H), 5.83-5.30 (m, 2H), 1.40 (s, 9 H). Procedure for preparation of 2-amino-2-cinnolin-4-yl-acetamide A suspension of tert-butyl N-(2-amino-1-cinnolin-4-yl-2-oxo-ethyl)carbamate (1.00 g, 3.31 mmol, 1.00 eq) in hydrogen chloride (4.00 M in ethyl acetate, 10.0 mL, 12.09 eq) was stirred at 20 °C for 3 h. The reaction mixture was concentrated in vacuum to give 2-amino-2-cinnolin-4-yl-acetamide (0.789 g, 3.31 mmol, 99% yield, hydrochloride) as a light green solid. Procedure for preparation of (1R,2S,5S)-N-(2-amino-1-cinnolin-4-yl-2-oxo-ethyl)-3-[(2S)-3 ,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxamide To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (0.50 g, 1.37 mmol, 1.00 eq) in N,N-dimethyl formamide (5.00 mL) were added N,N-diisopropylethylamine (621 mg, 4.80 mmol, 0.836 mL, 3.50 eq) and O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (783 mg, 2.06 mmol, 1.50 eq) at 0 °C. After stirring at 0 °C for 10 min, 2-amino-2-cinnolin-4-yl-acetamide (491 mg, 2.06 mmol, 1.50 eq, hydrochloride) was added to the mixture at 0 °C. After stirring at 20 °C for 15 h, the mixture was added dropwise into water (50.0 mL) at 0 °C. The mixture was extracted with ethyl acetate (50.0 mL × 3), washed with saturated sodium bicarbonate aqueous solution (100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 1: 0 to 1: 4) to give (1R,2S,5S)-N-(2-amino-1-cinnolin-4-yl-2-oxo-ethyl)-3-[(2S)-3 ,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (0.20 g, 0.365 mmol, 27% yield) as yellow oil. LC-MS (Method C): R _t = 0.773 min; MS (ESIpos): m/z = 549.3 [M+H] ⁺ . Procedure for preparation of CPD0186846 - (1R,2S,5S)ǦNǦ[(cinnolinǦ4Ǧyl)(cyano)methyl]Ǧ3Ǧ[(2S)Ǧ 3,3ǦdimethylǦ2Ǧ(2,2,2Ǧtrifluoroacetamido)butanoyl]Ǧ6,6� �dimethylǦ3-azabicyclo[3.1.0]hexaneǦ2Ǧ carboxamide To a solution of (1R,2S,5S)-N-(2-amino-1-cinnolin-4-yl-2-oxo-ethyl)-3-[(2S)-3 ,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (0.19 g, 0.346 mmol, 1.00 eq) in dichloromethane (10.0 mL) was added Burgess reagent (248 mg, 1.04 mmol, 3.00 eq) at 20 °C. After stirring at 20 °C for 3 h, the mixture was added dropwise into water (30.0 mL). The mixture was extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with saturated sodium bicarbonate aqueous solution (30.0 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN];B%: 45%-75%,10 min) to give (1R,2S,5S)-N-[cinnolin-4-yl(cyano)methyl]-3-[(2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (65 mg, 0.122 mmol, 35% yield, 99% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.54 (br. s, 1H), 9.90 (s, 0.3H), 9.68 (s, 0.7H), 9.42 (br s, 1H), 8.51 (d, J = 8.0 Hz, 0.7H), 8.31 (d, J = 9.2 Hz, 0.3H), 7.71 (s, 0.3H),7.69 (s, 0.6H), 7.61-7.56 (m, 0.6H), 7.54- 7.50 (m, 0.2H), 7.30-7.23 (m, 1.3H), 7.17-7.10 (m, 0.7H), 4.43-4.40 (m, 1.3H), 4.33 (s, 0.7H), 3.96-3.90 (m, 1H), 3.74-3.69 (m, 1H).1.63-1.60 (m, 1H), 1.41 (d, J = 7.6 Hz, 0.7H), 1.33 (d, J = 8.0 Hz, 0.3H), 1.05-0.88 (m, 15H). LCMS (Method J): R _t = 0.651 min; MS (ESIpos): m/z = 531.3 [M+H] ⁺ . HPLC (Method K): R _t = 2.665 min. Preparation of CPD0186847 Procedure for preparation of 1-chlorophthalazine To a mixture of phthalazin-1-ol (30.0 g, 205 mmol, 1.00 eq) in toluene (200 mL) was added phosphorus oxychloride (94.4 g, 614 mmol, 57.2 mL, 3.00 eq). After stirring at 100 °C for 12 h, the mixture was concentrated under vacuum to give a residue. The residue was triturated with methanol/ethyl acetate (v/v = 1/3, 200 mL) and filtered. The filter cake was dried under vacuum to give.1-chlorophthalazine (38.0 g, 184 mmol, 90% yield, 90% purity) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.79 (s, 1H), 8.37-8.29 (m, 2H), 8.24-8.16 (m, 2H). LC-MS (Method S): R _t = 0.325min; MS (ESIpos): m/z = 164.9 [M+H] ⁺ . Procedure for preparation of 1-(tert-butyl) 3-methyl 2-(phthalazin-1-yl)malonate A mixture of 1-chlorophthalazine (28.0 g, 135 mmol, 90% purity, 1.00 eq), tert-butyl methyl malonate (27.1 g, 156 mmol, 1.15 eq) and cesium carbonate (132 g, 406 mmol, 3.00 eq) in N,N- dimethylacetamide (300 mL) was stirred at 80 °C for 12 h. The mixture was poured into water (500 mL) and extracted with ethyl acetate (300 mL × 3). The combined organic layers were washed with saturated calcium chloride (100 mL × 2), brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 1/1) to give 1-(tert-butyl) 3-methyl 2-(phthalazin-1- yl)malonate (16.0 g, 42.3 mmol, 31% yield, 80% purity) as yellow gum. LC-MS (Method S): R _t = 0.433 min; MS (ESIpos): m/z = 302.9 [M+H] ⁺ . Procedure for preparation of methyl 2-(phthalazin-1-yl)acetate To a mixture of 1-(tert-butyl) 3-methyl 2-(phthalazin-1-yl)malonate (16.0 g, 42.3 mmol, 80% purity, 1.00 eq) in dichloromethane (30.0 mL) was added trifluoroacetic acid (20.0 mL). After stirring at 20 °C for 12 h, the mixture was quenched with saturated sodium carbonate (300 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate/methanol = 1/0/0 to 50/45/5) to give methyl 2-(phthalazin-1-yl)acetate (7.40 g, 34.0 mmol, 80% yield, 93% purity) as yellow gum. LC-MS (Method S): R _t = 0.237 min; MS (ESIpos): m/z = 202.9 [M+H] ⁺ . Procedure for preparation of methyl 2-(hydroxyimino)-2-(phthalazin-1-yl)acetate To a mixture of methyl 2-(phthalazin-1-yl)acetate (7.40 g, 34.0 mmol, 93% purity, 1.00 eq) in dichloromethane (50.0 mL) was added tert-butyl nitrite (3.86 g, 37.4 mmol, 1.10 eq) at 0 °C. After stirring at 0 °C for 12 h, hydrochloric acid (4 mol/L in ethyl acetate, 11.9 mL, 1.40 eq) was added. The resulting mixture was stirred at 25 °C for 1 h. The mixture was concentrated under vacuum to give methyl 2- (hydroxyimino)-2-(phthalazin-1-yl)acetate (8.00 g, 33.9 mmol, 99% yield, 98% purity) as a yellow solid which was used for next reaction directly. LC-MS (Method O): R _t = 0.256 min; MS (ESIpos): m/z =231.9 [M+H-56] ⁺ . Procedure for preparation of methyl 2-amino-2-(phthalazin-1-yl)acetate To a mixture of methyl 2-(hydroxyimino)-2-(phthalazin-1-yl)acetate (8.00 g, 34.6 mmol, 1.00 eq) in a mixed solvent of methanol (200 mL) and water (100 mL) was added sodium hydrosulfite (60.2 g, 346 mmol, 10.0 eq). After stirring at 80 °C for 4 h, the mixture was filtered. The filtrate was used for next step directly without further purification due to the stability issue. LC-MS (Method S): R _t = 0.169 min; MS (ESIpos): m/z = 217.9 [M+H] ⁺ . Procedure for preparation of methyl 2-(tert-butoxycarbonylamino)-2-phthalazin-1-yl-acetate A mixture of methyl 2-amino-2-phthalazin-1-yl-acetate (7.5 g crude in a mixed solvent of methanol (200 mL) and water (100 mL) and di-tert-butyldicarbonate (11.3 g, 51.8 mmol, 1.50 eq) was stirred at 20 °C for 12 h. The mixture was poured into water (200 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 4/1 to 1/1) to give methyl 2-(tert- butoxycarbonylamino)-2-phthalazin-1-yl-acetate (3.80 g, 11.9 mmol, 34 % yield, 99% purity) as light yellow gum. LC-MS (Method S): R _t = 0.408 min; MS (ESIpos): m/z = 261.8 [M+H-56] ⁺ . Procedure for preparation of tert-butyl N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl) carbamate A mixture of methyl 2-(tert-butoxycarbonylamino)-2-phthalazin-1-yl-acetate (3.80 g, 12.0 mmol, 1.00 eq) in ammonia (7 mol/L in methanol, 100 mL, 58.5 eq) was stirred at 20 °C for 12 h. The mixture was concentrated under vacuum to give tert-butyl N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl) carbamate (3.60 g, 10.8 mmol, 90% yield, 91% purity) as a light yellow solid. LC-MS (Method S): R _t = 0.354 min; MS (ESIpos): m/z = 246.8 [M+H-56] ⁺ . Procedure for preparation of 2-amino-2-phthalazin-1-yl-acetamide To a mixture of tert-butyl N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl) carbamate (400 mg, 1.20 mmol, 91% purity, 1.00 eq) in ethyl acetate (5.00 mL) was added hydrochloric acid (4 M in ethyl acetate, 5.00 mL, 16.6 eq) at 20 °C. After stirring at 20 °C for 12 h, the mixture was concentrated under vacuum to give 2-amino-2-phthalazin-1-yl-acetamide (290 mg, crude, hydrochloric acid) as an off-white solid which was used for next step directly. LC-MS (Method T): R _t = 0.131 min; MS (ESIpos): m/z = 202.9 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-(2-amino-1-cinnolin-4-yl-2-oxo-ethyl)-3-[(2S)-3 ,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxamide To a mixture of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (487 mg, 1.34 mmol, 1.10 eq), 2-amino-2-phthalazin-1-yl- acetamide (290 mg, 1.22 mmol, crude purity, 100 eq, hydrochloric acid) and N,N-diisopropylethylamine (471 mg, 3.65 mmol, 3.00 eq) in N,N-dimethylformamide (5.00 mL) was added O-(7-azabenzotriazol- 1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (693mg, 1.82 mmol, 1.50 eq) at 0 °C. After stirring at 20 °C for 12 h, the mixture was poured into water (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 2/1 to ethyl acetate) to give (1R,2S,5S)- N-(2-amino-1-cinnolin-4-yl-2-oxo-ethyl)-3-[(2S)-3,3-dimethyl -2-[(2,2,2-trifluoroacetyl)amino]butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxamide (600 mg, 1.04 mmol, 86% yield, 95% purity) as light yellow gum. LC-MS (Method O): R _t = 0.407 min; MS (ESIpos): m/z = 549.2 [M+H] ⁺ . Procedure for preparation of CPD0186847 -(1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]-3-[(2S)- 3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-d imethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide To a mixture of (1R,2S,5S)-N-(2-amino-1-cinnolin-4-yl-2-oxo-ethyl)-3-[(2S)-3 ,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (600 mg, 1.09 mmol, 1.00 eq) in dichloromethane (10.0 mL) was added methoxycarbonyl-(triethylammonio)sulfonyl- azanide (782 mg, 3.28 mmol, 3.00 eq) at 20 °C. After stirring at 20 °C for 12 h, the mixture was poured into water (20.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10 μm; mobile phase: [water (FA)-ACN]; B%: 41%-71%, 10 min) to give (1R, 2S, 5S)-N- [cyano(phthalazin-1-yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2, 2-trifluoroacetyl)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (153 mg, 280 μmol, 26% yield, 97% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.50-10.44 (m, 0.3H), 9.72 (s, 0.5H), 9.60-8.77 (m, 2H), 8.27-7.71 (m, 4H), 7.25-7.12 (m, 0.5 H), 4.47-4.39 (m, 1H), 4.36-4.23 (m, 1H), 4.00-3.91 (m, 1H), 3.76-3.65 (m, 1H), 1.65-1.51 (m, 1H), 1.38-1.15 (m, 1H), 1.10-0.79 (m, 15H). LC-MS (Method L): R _t = 2.134 min; MS (ESIpos): m/z = 531.5 [M+H] ⁺ . SFC: dr = 57: 43. Preparation of CPD018790 Procedure for preparation of ethyl 2-oxo-2-(pyrazin-2-ylmethylamino)acetate To a solution of pyrazin-2-ylmethanamine (25.0 g, 229 mmol, 1.00 eq) and saturated sodium bicarbonate (38.5 g, 458 mmol, 17.8 mL, 2.00 eq) in tetrahydrofuran (300 mL) was added ethyl 2-chloro- 2-oxo-acetate (36.0 g, 263 mmol, 29.5 mL, 1.15 eq) at 0 °C. After stirring at 20 °C for 12 h, the reaction mixture was filtered. The filtrate was quenched with methanol (200 mL) and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 10: 1 to 0: 1) to afford ethyl 2-oxo-2-(pyrazin-2-ylmethylamino)acetate (37.0 g, 168 mmol, 73% yield, 95% purity) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.50 (t, J = 5.6 Hz, 1H), 8.61 (s, 1H), 8.59-8.58 (m, 1H), 8.54-8.53 (m, 1H), 4.5 (d, J = 5.6 Hz, 2H), 4.28-4.20 (m, 4H), 1.29-1.23 (m, 6H). LC-MS (Method A): R _t = 0.380 min; MS (ESIpos): m/z = 210.0 [M+H] ⁺ . Procedure for preparation of ethyl imidazo[1,5-a]pyrazine-3-carboxylate A mixture of ethyl 2-oxo-2-(pyrazin-2-ylmethylamino)acetate (37.0 g, 177 mmol, 1.00 eq) in Eaton’s reagent (337 g, 1.41 mol, 222 mL, 8.00 eq) was stirred at 110 °C for 12 h. The reaction mixture was diluted with water (1000 mL). Sodium bicarbonate was added to the mixture to adjust pH~8 and extracted with a mixed solvent of dichloromethane/isopropanol (v/v = 3/1, 1000 mL × 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give ethyl imidazo[1,5-a]pyrazine-3-carboxylate (27.4 g, 136 mmol, 77% yield, 95% purity) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.33 (d, J = 1.6 Hz, 1H), 8.98 (d, J = 4.4 Hz, 1H), 8.07 (s, 1H), 7.95 (d, J = 4.8 Hz, 1H), 4.43 (d, J = 7.2 Hz, 1H), 1.37 (q, J = 7.2 Hz, 2H). LC-MS (Method A): R _t = 0.664 min; MS (ESIpos): m/z = 192.0 [M+H] ⁺ . Procedure for preparation of ethyl 1-bromoimidazo[1,5-a]pyrazine-3-carboxylate To a solution of ethyl imidazo[1,5-a]pyrazine-3-carboxylate (26.4 g, 138 mmol, 1.00 eq) in acetonitrile (280 mL) was added N-bromosuccinimide (24.6 g, 138 mmol, 1.00 eq). After stirring at 0 °C for 1 h, triethylamine (19.2 g, 190 mmol, 26.4 mL, 1.37 eq) was added and the resulting mixture was stirred at 0 °C for 4 h. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (500 mL × 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 20: 1 to 10: 1) to give ethyl 1- bromoimidazo[1,5-a]pyrazine-3-carboxylate (45.0 g, 133 mmol, 97% yield, 80% purity) as a light yellow solid ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.19 (d, J = 2.0 Hz, 1H), 8.99 (dd, J = 4.0, 1.6 Hz, 1H), 8.04 (d, J = 4.0 Hz, 1H), 4.42 (q, J = 7.2 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H). LC-MS (Method C): R _t = 0.516 min; MS (ESIpos): m/z = 270.2 [M+H] ⁺ . Procedure for preparation of 1-bromoimidazo[1,5-a]pyrazine-3-carboxylic acid To a solution of ethyl 1-bromoimidazo[1,5-a]pyrazine-3-carboxylate (45.0 g, 166 mmol, 1.00 eq) in tetrahydrofuran (400 mL) and water (80.0 mL) was added lithium hydroxide monohydrate (14.0 g, 333 mmol, 2.00 eq). After stirring at 70 °C for 4 h, hydrochloric acid (1 M in water) was added to the reaction mixture. The resulting precipitation was filtered. The filter cake was dried under reduced pressure to give 1-bromoimidazo[1,5-a]pyrazine-3-carboxylic acid (36.0 g, 134 mmol, 80% yield, 90% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.14 (d, J = 1.2 Hz, 1H), 9.01 (d, J = 4.0, 1.2 Hz, 1H), 7.97 (d, J = 4.8 Hz, 1H). Procedure for preparation of 1-bromoimidazo[1,5-a]pyrazine To a solution of 1-bromoimidazo[1,5-a]pyrazine-3-carboxylic acid (36.0 g, 149 mmol, 1.00 eq) in dimethylsulfoxide (300 mL) was added lithium chloride (31.5 g, 744 mmol, 15.2 mL, 5.00 eq). After stirring at 120 °C for 12 h, the reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (500 mL × 4). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1- bromoimidazo[1,5-a]pyrazine (19.8 g, 100 mmol, 67% yield) as a black brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.92 (d, J = 1.2 Hz, 1H), 8.57 (s, 1H), 8.34 (d, J = 4.0, 1.6 Hz, 1H), 7.62 (d, J = 5.2 Hz, 1H). Procedure for preparation of 1-vinylimidazo[1,5-a]pyrazine A mixture of 1-bromoimidazo[1,5-a]pyrazine (5.00 g, 25.3 mmol, 1.00 eq), potassium;trifluoro(vinyl)boranuide (4.06 g, 30.3 mmol, 1.20 eq), potassium carbonate (6.98 g, 50.5 mmol, 2.00 eq), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (2.06 g, 2.52 mmol, 0.100 eq) in dioxane (50.0 mL) and water (10.0 mL) were degassed under vacuum and purged with nitrogen for 3 times. After stirring at 90 °C for 12 h under nitrogen atmosphere, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with brine (60.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 30: 1 to 10: 1) to give 1-vinylimidazo[1,5-a]pyrazine (2.37 g, 15.5 mmol, 61% yield, 95% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.24 (s, 1H), 8.49 (s, 1H), 8.25 (dd, J = 4.8, 1.2 Hz, 1H), 7.52 (d, J = 4.8 Hz, 1H), 7.17-7.10 (m, 1H), 6.03 (dd, J = 20.0, 1.2 Hz, 1H), 5.31 (dd, J = 12.0, 1.2 Hz, 1H). Procedure for preparation of imidazo[1,5-a]pyrazine-1-carbaldehyde Ozone was bubbled through a solution of 1-vinylimidazo[1,5-a]pyrazine (1.50 g, 10.3 mmol, 1.00 eq) in dichloromethane (60.0 mL) at -78 °C for 10 min, until a blue-grey suspension formed. The excess ozone was eliminated using argon, and then dimethyl sulfide (19.0 g, 306 mmol, 22.5 mL, 29.7 eq) was added. After stirring at -78 °C for 0.5 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 20: 1 to 0: 1) to give imidazo[1,5-a]pyrazine-1-carbaldehyde (240 mg, 1.55 mmol, 15% yield, 95% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.1 (s, 1H), 9.52 (d, J = 1.6 Hz, 1H), 8.75 (s, 1H), 8.60 (d, J = 4.8, 1.6 Hz, 1H), 7.98(d, J = 4.8 Hz, 1H). Procedure for preparation of 2-amino-2-imidazo[1,5-a]pyrazin-1-yl-acetonitrile To a solution of imidazo[1,5-a]pyrazine-1-carbaldehyde (100 mg, 680 umol, 1.00 eq) in methanol (0.50 mL) were added ammonia (15.0 M in methanol, 0.833 mL, 18.4 eq) and titanium (IV) isopropoxide (232 mg, 816 umol, 0.24 mL, 1.20 eq) at 25 °C. After stirring at 25 °C for 2 h, trimethylsilyl cyanide (80.9 mg, 816 μmol, 0.102 mL, 1.20 eq) was added dropwise into the reaction mixture at 25 °C. After addition, the reaction mixture was stirred at 25 °C for 2 h. The reaction was concentrated, and then purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 0: 1) to give 2-amino-2-imidazo[1,5- a]pyrazin-1-yl-acetonitrile (48.0 mg, 277 μmol, 40.8% yield) as a yellow solid. LCMS (Method A): R _t = 0.231 min; MS (ESIpos): m/z =174.3 [M+H] ⁺ . Procedure for preparation of CPD0187902 - (1R,2S,5S)-N-[cyano(imidazo[1,5-a]pyrazin-1- yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide A mixture of 2-amino-2-imidazo[1,5-a]pyrazin-1-yl-acetonitrile (25.0 mg, 144 μmol, 1.00 eq), (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (52.6 mg, 144 μmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (82.3 mg, 217 μmol, 1.50 eq) and N,N- diisopropylethylamine (37.3 mg, 289 μmol, 0.05 mL, 2.00 eq) in N,N-dimethylformamide (0.500 mL) was stirred at 20 °C for 12 h. The reaction mixture was diluted with water (15.0 mL) and extracted with ethyl acetate (15.0 mL × 2). The combined organic layers were washed with brine (15.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 36%-56%, 10 min) to give (1R,2S,5S)-N-[cyano(imidazo[1,5- a]pyrazin-1-yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-triflu oroacetyl)amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide. (17.7 mg, 33.7 μmol, 88% yield, 99% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.60-9.48 (m, 1H), 9.41-9.31 (m, 1H), 9.23-9.11 (m, 1H), 8.66-8.56 (m, 1H), 8.37-8.31 (m, 1H), 7.67-7.59 (m, 1H), 6.81-6.66 (m, 1H), 4.41-4.26 (m, 2H), 3.95-3.86 (m, 1H), 3.76-3.64 (m, 1H), 1.62-1.46 (m, 1H), 1.39-1.13 (m, 1H), 1.05-0.95 (m, 12H), 0.86-0.81 (m, 3H). LCMS (Method L): R _t = 1.958 min; MS (ESIpos): m/z =520.2 [M+H] ⁺ . SFC: dr = 49: 44. Preparation of CPD0187903 Procedure for preparation of 1-aminopyridazin-1-ium iodide Hydroxylamine-O-sulfonic acid (26.3 g, 2323 mmol, 1.50 eq) was dissolved in water (25.0 mL) and the reaction mixture was cooled to 10 °C. Then aqueous potassium bicarbonate (2.40 M in water, 96.0 mL, 1.49 eq) was added. Pyridazine (12.4 g, 155 mmol, 11.2 mL, 1.00 eq) was added in one portion and then the reaction mixture was stirred at 70 °C for 1.5 h. Then, potassium bicarbonate (2.4 M, 20.00 mL, 0.310 eq) was added into the reaction mixture at 70 °C. The reaction mixture was cooled to 40 °C and was stirred for 1 h. Potassium iodide (25.70 g, 154.83 mmol, 1.00 eq) in water (25 mL) was added to the reaction mixture and the reaction stirred at 70 °C for a further 1 h. The reaction mixture was concentrated in vacuum to give a residue. No need further purification.1-aminopyridazin-1-ium iodide (34.53 g, 154.83 mmol) as yellow solid was obtained and used directly for next step. Procedure for preparation of Methyl 2-methylpyrazolo[1,5-b]pyridazine-3-carboxylate To a solution of 1-aminopyridazin-1-ium iodide (34.5 g, 155 mmol, 1.00 eq, crdue) in dichloromethane (300 mL) was added a solution of potassium hydroxide (10.4 g, 185 mmol, 1.19 eq) in water (50.0 mL) and methyl but-2-ynoate (16.7 g, 170 mmol, 1.10 eq) at 0 °C. After stirring at 20 °C for 4 h, the reaction mixture was diluted with water (300 mL) and extracted with dichloromethane (200 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10/1 to 3/1) to give methyl 2-methylpyrazolo[1,5-b]pyridazine-3-carboxylate (7.00 g, 36.6 mmol, 24% yield) as purple solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.47-8.44 (m, 1H), 8.36-8.35 (m, 1H), 7.23-7.19 (m, 1H), 3.94 (s, 3H), 2.74 (3, 3H). Procedure for preparation of 2-methylpyrazolo[1,5-b]pyridazine A mixture of methyl 2-methylpyrazolo[1,5-b]pyridazine-3-carboxylate (7.00 g, 36.6 mmol, 1.00 eq) in sulfuric acid (147 g, 600 mmol, 80.0 mL, 40 % purity, 16.4 eq) was stirred at 100 °C for 18 h. After cooling to20 °C, the mixture was added dropwise into saturated potassium carbonate (600 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 1/0 to 3/1) to give 2-methylpyrazolo[1,5- b]pyridazine (3.10 g, 23.3 mmol, 64% yield) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.14-8.13 (m, 1H), 7.80-7.77 (m, 1H), 6.90-6.86 (m, 1H), 6.35 (s, 1H), 2.51 (s, 3H). Procedure for preparation of 3-bromo-2-(bromomethyl)pyrazolo[1,5-b]pyridazine To a solution of 2-methylpyrazolo[1,5-b]pyridazine (3.10 g, 23.3 mmol, 1.00 eq) in chloroform (50.0 mL) was added 2,2-azobis(2-methylpropionitrile) (382 mg, 2.33 mmol, 0.100 eq) and N-bromosuccinimide (10.4 g, 58.2 mmol, 2.50 eq) at 20 °C. After stirring at 70 °C for 16 h, the reaction mixture was concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 20/1-3/1) to give 3-bromo-2-(bromomethyl)pyrazolo[1,5-b]pyridazine (6.50 g, 22.3 mmol, 96% yield) as white solid. Procedure for preparation of 3-bromopyrazolo[1,5-b]pyridazine-2-carbaldehyde To a solution of 3-bromo-2-(bromomethyl)pyrazolo[1,5-b]pyridazine (6.50 g, 22.3 mmol, 1.00 eq) in acetonitrile (70.0 mL) was added 4-methyl-4-oxido-morpholin-4-ium (5.28 g, 45.1 mmol, 4.75 mL, 2.02 eq) at 20 °C. After stirring at 20 °C for 14 h, the reaction mixture was concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 3/1) to give 3-bromopyrazolo[1,5-b]pyridazine-2-carbaldehyde (2.30 g, 10.18 mmol, 45.55% yield) as white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 10.27 (s, 1H), 8.51-8.49 (m, 1H), 8.08-8.06 (m, 1H), 7.20-7.16 (m, 2H). Procedure for preparation of pyrazolo[1,5-b]pyridazine-2-carbaldehyde To a solution of 3-bromopyrazolo[1,5-b]pyridazine-2-carbaldehyde (2.50 g, 11.1 mmol, 1.00 eq) in methanol (30.0 mL) was added triethylamine (1.68 g, 16.6 mmol, 2.31 mL, 1.50 eq) and palladium on activated carbon (250 mg, 10% purity, wet) at 20 °C. After stirring at 20 °C under hydrogen (15 Psi) for 1 h, the reaction mixture was filtered, the filtered cake was washed with methanol (30.0 mL). The combined filtrate was concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10/1 to 5/1) to give pyrazolo[1,5-b]pyridazine-2- carbaldehyde (1.60 g, 10.8 mmol, 98% yield) as white solid was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 10.29 (s, 1H), 8.47 (d, J = 3.2 Hz, 1H), 8.07 (dd, J = 0.8 Hz, J = 8.8 Hz, 1H), 7.16 (s, 1H), 7.12-7.09 (m, 1H). Procedure for preparation of pyrazolo[1,5-b]pyridazine-2-carbaldehyde To a solution of pyrazolo[1,5-b]pyridazine-2-carbaldehyde (600 mg, 4.08 mmol, 1.00 eq) in methanol (6.00 mL) was added ammonia (7 M in methanol, 2.44 mL, 5.00 eq) and titanium (IV) isopropoxide (1.40 g, 4.93 mmol, 1.45 mL, 1.21 eq) at 20 °C. After stirring at 20 °C for 2 h, trimethylsilyl cyanide (500 mg, 5.04 mmol, 1.24 eq) was added dropwise into the reaction mixture at 20 °C. After addition, the mixture was stirred at 20 °C for 4 h. After concentration, the residue was suspended into ethyl acetate (30.0 mL). The suspension was filtered and the filter cake was washed with ethyl acetate (50.0 mL). The combined filtrate was concentrated under vacuum to give 2-amino-2-pyrazolo[1,5-b]pyridazin-2-yl- acetonitrile (0.500 g, crude purity) as yellow solid. Procedure for preparation of CPD0187903 - (1R,2S,5S)-N-[cyano(pyrazolo[1,5-b]pyridazin-2- yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide. To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (600 mg, 1.65 mmol, 1.00 eq) in N,N- dimethylformamide (10.0 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (750 mg, 1.97 mmol, 1.20 eq) and N,N-diisopropylethylamine (645 mg, 4.99 mmol, 869.27 μL, 3.03 eq) at 0 °C. After stirring at 0 °C for 10 min, 2-amino-2-pyrazolo[1,5-b]pyridazin-2-yl-acetonitrile (500 mg, 2.89 mmol, 1.75 eq) was added 0 °C. After stirirng at 20 °C for 14 h, the reaction mixture was poured into ice-water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give residue. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 20/1 to 0/1) to give an impure product. The impure product was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 45%-65%,10 min) to give (1R,2S,5S)-N- [cyano(pyrazolo[1,5-b]pyridazin-2-yl)methyl]-3-[(2S)-3,3-dim ethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (183.71 mg, 349.02 umol, 21.19% yield, 98.7% purity) as white solid was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.59 (d, J = 8.0 Hz, 1H), 9.44-9.39 (m, 1H), 8.53-8.51 (m, 1H), 8.26 (dd, J = 1.2 Hz, J = 9.2 Hz, 1H), 7.30-7.26 (m, 1H), 6.86 (m, 1H), 6.45-6.42 (m, 1H), 4.21-4.40 (m, 1H), 4.34 (d, J = 5.6 Hz, 1H), 3.94-3.88 (m, 1H), 3.73-3.69 (m, 1H), 1.59-1.53 (m, 1H), 1.39-1.32 (m, 1H), 1.04-0.85 (m, 15H). LC-MS (Method C): R _t = 0.800 min; MS (ESIpos): m/z = 520.3 [M+H] ⁺ . HPLC (Method K): R _t = 2.238 min. SFC: dr: 47: 53. Preparation of CPD0187909 Procedure for preparation of methyl 2-(benzyloxycarbonylamino)-2-(1-methyl-2-oxo-4- piperidylidene)acetate To a solution of methyl 2-(benzyloxycarbonylamino)-2-dimethoxyphosphoryl-acetate (5.32 g, 16.1 mmol, 1.20 eq) in dichloromethane (60.0 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (2.14 g, 14.0 mmol, 2.12 mL, 1.05 eq) at 0 °C under nitrogen atmosphere. The mixture was stirred at this temperature for 0.5 h.1-Methylpiperidine-2,4-dione (1.70 g, 13.4 mmol, 1.00 eq) was added dropwise. After stirring at 25 °C for 12 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 500 g SepaFlash® Silica Flash Column, Eluent of 0~90% Ethylacetate/Petroleum ethergradient @ 100 mL/min) to give methyl 2-(benzyloxycarbonylamino)-2-(1-methyl-2-oxo-4-piperidyliden e)acetate (5.10 g, crude) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.40-7.18 (m, 16H), 5.66 (d, J = 8.4 Hz, 2H), 5.12-4.97 (m, 7H), 3.91- 3.59 (m, 25H), 3.41-3.20 (m, 3H), 2.95-2.83 (m, 4H), 2.49-2.26 (m, 2H). Procedure for preparation of benzyl N-[2-amino-1-(1-methyl-2-oxo-4-piperidylidene)-2-oxo- ethyl]carbamate To a solution of methyl 2-(benzyloxycarbonylamino)-2-(1-methyl-2-oxo-4-piperidyliden e)acetate (5.00 g, 15.0 mmol, 1.00 eq) in ammonia/methanol (5.00 M, 50.0 mL, 16.6 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (Instrument: 300 g Flash; Column: Welch Ultimate XB_C1820- 40μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-10 min 0-70% B; flow 100 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give benzyl N-[2-amino-1-(1-methyl-2- oxo-4-piperidylidene)-2-oxo-ethyl]carbamate (2.20 g, 6.93 mmol, 46.1% yield) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.34-7.33 (m, 1H), 7.41-7.29 (m, 10H), 6.87 (s, 2H), 6.30-6.03 (m, 2H), 5.92-5.59 (m, 3H), 5.23-5.04 (m, 4H), 4.98-4.79 (m, 2H), 3.85 (d, J = 11.2 Hz, 3H), 3.78 (d, J = 10.8 Hz, 3H), 3.49-3.31 (m, 2H), 2.99-2.91 (m, 3H), 2.45-2.27 (m, 2H). Procedure for preparation of 2-amino-2-(1-methyl-2-oxo-4-piperidyl)acetamide To a solution of benzyl N-[(1Z)-2-amino-1-(1-methyl-2-oxo-4-piperidylidene)-2-oxo-et hyl]carbamate (2.00 g, 6.30 mmol, 1.00 eq) in methanol (30.0 mL) was added Pd/Carbon (200 mg, 2.39 mmol, 10.0% purity) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred at 25 °C for 5 h under hydrogen (15 psi). The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase column (150g Flash; Column: Welch Ultimate XB_C1820-40μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 5-17min 7-23% B; flow 50 ml/min; temperature: room temperature; Detector: UV 220 nm) to give 2-amino-2-(1-methyl-2-oxo-4-piperidyl)acetamide (330 mg, 1.78 mmol, 28% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 7.38 (s, 1H), 7.18-6.90 (m, 1H), 3.47-3.32 (m, 2H), 3.31-3.18 (m, 2H), 3.12-2.96 (m, 1H), 2.79 (s, 3H), 2.23-2.16 (m, 1H), 2.15-2.07 (m, 1H), 2.06-1.92 (m, 1H), 1.85-1.68 (m, 1H), 1.63-1.36 (m, 1H). Procedure for preparation of (1R,2S,5S)-N-[2-amino-1-(1-methyl-2-oxo-4-piperidyl)-2-oxo-e thyl]- 3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoy l]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of 2-amino-2-(1-methyl-2-oxo-4-piperidyl)acetamide (230 mg, 1.24 mmol, 1.00 eq) and (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0] hexane-2-carboxylic acid (452 mg, 1.24 mmol, 1.00 eq) in dimethyl formamide (6.00 mL) were added N,N-diisopropylethylamine (481 mg, 3.73 mmol, 649 μL, 3.00 eq) and O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (708 mg, 1.86 mmol, 1.50 eq) at 0 °C. After stirring at 20 °C for 12 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase column (80g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 10-21min 36- 60% B; flow 50 ml/min; temperature: room temperature; Detector: UV 220 nm) to give (1R,2S,5S)-N-[2- amino-1-(1-methyl-2-oxo-4-piperidyl)-2-oxo-ethyl]-3-[(2S)-3, 3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (560 mg, 1.05 mmol, 85% yield) as a pink solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.58-9.21 (m, 1H), 8.24-8.17 (m, 1H), 8.43-8.14 (m, 1H), 7.52-6.96 (m, 1H), 4.46-4.16 (m, 2H), 3.94-3.80 (m, 1H), 3.76-3.62 (m, 1H), 3.46-3.10 (m, 5H), 2.81-2.74 (m, 2H), 2.28-1.96 (m, 2H), 1.92-1.66(m, 1H), 1.65-1.41 (m, 2H), 1.37-1.26 (m, 1H), 1.04-0.98 (m, 9H), 0.98- 0.74 (m, 6H). Procedure for preparation of (1R,2S,5S)-N-[cyano-(1-methyl-2-oxo-4-piperidyl)methyl]-3-[( 2S)- 3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-d imethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide To a solution of (1R,2S,5S)-N-[2-amino-1-(1-methyl-2-oxo-4-piperidyl)-2-oxo-e thyl]-3-[(2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (500 mg, 941 μmol, 1.00 eq) in dichloromethane (6.00 mL) was added burgess reagent (672 mg, 2.82 mmol, 3.00 eq). After stirring at 20 °C for 3 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18200*40mm*10 μm; mobile phase: [water(FA)-ACN];B%: 35%-65%,10min) to give (1R,2S,5S)-N-[(S)-cyano-(1-methyl-2-oxo-4-piperidyl)methyl]- 3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxamide (208 mg, 392 μmol, 42% yield, 97% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.51-9.30 (m, 1H), 9.10-8.81 (m, 1H), 4.97-4.62 (m, 1H), 4.48-4.33 (m, 1H), 4.31-4.10 (m, 1H), 3.96-3.83 (m, 1H), 3.75-3.58 (m, 1H), 3.27-3.20 (m, 1H), 2.90-2.70 (m, 3H), 2.35-2.19 (m, 2H), 2.17-1.82(m, 2H), 1.77-1.41 (m, 2H), 1.40-1.21 (m, 1H), 1.09-0.79 (m, 15H). LC-MS (Method C): R _t = 1.908 min; MS (ESIpos): m/z = 514.7 [M+H] ⁺ . SFC: dr = 72:27 Preparation of CPD0187913 Procedure for preparation of 5-benzyloxy-1-methyl-pyrazole To a mixture of 2-methylpyrazol-3-ol (10.0 g, 101 mmol, 1.00 eq) and potassium carbonate (28.1 g, 203 mmol, 2.00 eq) in N,N-dimethylformamide (100 mL) was added benzyl bromide (19.1 g, 112 mmol, 13.3 mL, 1.10 eq) at 25 °C. After stirring at 100 °C for 16 h, the mixture was poured into saturated ammonium chloride (300 mL) and extracted with ethyl acetate (300 mL × 2). The combined organic layers were washed with brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~40% ethyl acetate/petroleum ether gradient @ 100 mL/min) to give 5-benzyloxy-1-methyl-pyrazole (8.00 g, 36.1 mmol, 35% yield, 85% purity) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.41-7.36 (m, 5H), 7.30 (s, 1H), 7.27 (s, 1H), 5.07 (s, 2H), 3.66 (s, 3H). Procedure for preparation of - 5-benzyloxy-4-bromo-1-methyl-pyrazole To a mixture of 5-benzyloxy-1-methyl-pyrazole (7.00 g, 37.1 mmol, 1.00 eq) in acetonitrile (70.0 mL) was added 1-bromopyrrolidine-2,5-dione (7.28 g, 40.9 mmol, 1.10 eq) at 0 °C. After stirring at 0 °C for 0.5 h, saturated sodium bicarbonate aqueous solution (200 mL) was added to the mixture to adjust pH to 9 and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~100% ethyl acetate/petroleum ether gradient @ 60 mL/min) to give 5-benzyloxy- 4-bromo-1-methyl-pyrazole (5.00 g, 17.7 mmol, 47% yield, 95% purity) as yellow oil. LC-MS (Method C): R _t = 0.902 min; MS (ESIpos): m/z = 267.0 [M+H] ⁺ . Procedure for preparation of 5-benzyloxy-1-methyl-pyrazole-4-carbaldehyde To a solution of 5-benzyloxy-4-bromo-1-methyl-pyrazole (4.50 g, 16.8 mmol, 1.00 eq) in tetrahydrofuran (50.0 mL) was added n-butyllithium (2.50 M in hexane, 10.1 mL, 1.50 eq) dropwise at -78 °C. After stirring at -78 °C for 1 h, N,N-dimethylformamide (1.85 g, 25.2 mmol, 1.94 mL, 1.50 eq) was added to the mixture. After stirring at -78 °C for 1 h, the reaction mixture was poured into saturated ammonium chloride (50.0 mL). The solution was extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, eluent of 0~100% ethyl acetate/petroleum ether gradient @ 50 mL/min) to give 5-benzyloxy-1-methyl-pyrazole-4-carbaldehyde (3.00 g, 13.1 mmol, 78% yield, 95% purity) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.71 (s, 1H), 7.79 (s, 1H), 7.39 (s, 5H), 5.59 (s, 2H), 3.57 (s, 3H). Procedure for preparation of 2-amino-2-(5-benzyloxy-1-methyl-pyrazol-4-yl)acetonitrile To a solution of 5-benzyloxy-1-methyl-pyrazole-4-carbaldehyde (2.00 g, 9.25 mmol, 1.00 eq) in methanol (10.0 mL) and ammonia (7 M in methanol, 10.0 mL, 7.57 eq) was added titanium(IV) isopropoxide (3.15 g, 11.1 mmol, 3.28 mL, 1.20 eq) dropwise at 20 °C. After stirring for 2 h, trimethylsilylformonitrile (1.10 g, 11.1 mmol, 1.39 mL, 1.20 eq) was added dropwise. After stirring at 20 °C for 14 h, saturated sodium bicarbonate (20.0 mL) was added to the mixture to adjust pH~9 and extracted with ethyl acetate (50.0 mL × 2). The combined organic layers were washed with brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated to give 2-amino-2-(5-benzyloxy- 1-methyl-pyrazol-4-yl)acetonitrile (1.70 g, crude) as yellow oil. LC-MS (Method C): R _t = 0.414 min; MS (ESIpos): m/z = 216.2 [M-CN] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[(5-benzyloxy-1-methyl-pyrazol-4-yl)-cyano-meth yl]- 3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoy l]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of 2-amino-2-(5-benzyloxy-1-methyl-pyrazol-4-yl)acetonitrile (1.50 g, 6.19 mmol, 1.00 eq) and (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (2.26 g, 6.19 mmol, 1.00 eq) in N,N-dimethylformamide (20.0 mL) were added N,N-diisopropylethylamine (2.40 g, 18.5 mmol, 3.24 mL, 3.00 eq) and O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (2.82 g, 7.43 mmol, 1.20 eq) at 25 °C. After stirirng at 25 °C for 12, the mixture was poured into saturated ammonium chloride (40.0 mL) and extracted with ethyl acetate (60.0 mL × 3). The combined organic layers were washed with brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40.0 g SepaFlash® Silica Flash Column, Eluent of 0~60% ethyl acetate/petroleum ether gradient @ 50 mL/min) to give (1R,2S,5S)-N- [(5-benzyloxy-1-methyl-pyrazol-4-yl)-cyano-methyl]-3-[(2S)-3 ,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (2 g, 1.70 mmol, 27% yield, 50% purity) as yellow oil. LC-MS (Method C): R _t = 0.790 min; MS (ESIpos): m/z = 589.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[2-amino-1-(5-benzyloxy-1-methyl-pyrazol-4-yl)- 2- oxo-ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide A mixture of (1R,2S,5S)-N-[(5-benzyloxy-1-methyl-pyrazol-4-yl)-cyano-meth yl]-3-[(2S)- 3,3-dimethyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabi cyclo[3.1.0]hexane-2-carboxamide (500 mg, 0.424 mmol, 50% purity, 1.00 eq) in trifluoroacetic acid (5.00 mL) and dichloromethane (5.00 mL) was stirred at 20 °C for 1 h. The reaction mixture was poured into saturated sodium bicarbonate (50.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were concentrated under vacuum to give (1R,2S,5S)-N-[2-amino-1-(5-benzyloxy-1-methyl-pyrazol-4-yl)- 2-oxo-ethyl]- 3- [(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl] -6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (300 mg, crude) as a yellow solid. LC-MS (Method C): R _t = 0.870 min; MS (ESIpos): m/z = 607.3 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[2-amino-1-(5-hydroxy-1-methyl-pyrazol-4-yl)-2- oxo- ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino] butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide A mixture of (1R,2S,5S)-N-[2-amino-1-(5-benzyloxy-1-methyl-pyrazol-4-yl)- 2-oxo-ethyl] -3-[(2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (200 mg, 0.253 mmol, 77% purity, 1.00 eq) in methanol (2.00 mL) was added palladium on carbon (20.0 mg, 10% purity) under nitrogen atmosphere. The mixture was degassed under vacuum and purged with hydrogen for 3 times. After stirring at 20°C for 2 h under hydrogen atmosphere (15.0 psi), the reaction mixture was filtered. The filter cake was washed with methanol (20.0 mL), and the combined filtrate was concentrated under vacuum to give (1R,2S,5S)-N-[2-amino-1-(5-hydroxy-1- methyl-pyrazol-4-yl)-2-oxo-ethyl]-3-[(2S)-3,3-dimethyl-2-[(2 ,2,2-trifluoroacetyl)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (200 mg, crude) as a yellow solid. LC-MS (Method C): R _t = 0.798 min; MS (ESIpos): m/z = 517.2 [M+H] ⁺ . Procedure for preparation of CPD0187913 - (1R,2S,5S)-N-[cyano-(5-hydroxy-1-methyl-pyrazol-4- yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of (1R,2S,5S)-N-[2-amino-1-(5-hydroxy-1-methyl-pyrazol-4-yl)-2- oxo-ethyl]- 3-[(2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (200 mg, 0.387 mmol, 1.00 eq) in dichloromethane (5.00 mL) was added burgess reagent (276 mg, 1.16 mmol, 3.00 eq). After stirring at 20 °C for 12 h, the reaction mixture was concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 30%-60%, 10 min) to give (1R,2S,5S)- N-[cyano-(5-hydroxy-1-methyl-pyrazol-4-yl)methyl]-3-[(2S)-3, 3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (41.1 mg, 81.0 μmol, 20% yield, 98% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.37-9.34 (m, 1H), 9.08-8.01 (m, 1H), 7.42-7.37 (m, 1H), 5.87-5.69 (m, 1H), 4.42-4.39 (m, 1H), 4.28-4.27 (m, 1H), 3.90-3.86 (m, 1H), 3.70-3.68 (m, 1H), 3.50-3.47 (m, 3H), 1.58-1.47 (m, 1H), 1.34-1.20 (m, 1H), 1.10-0.74 (m, 15H). LC-MS (Method G): R _t = 1.902 min; MS (ESIpos): m/z = 499.2 [M+H] ⁺ . Preparation of CPD0187916 Procedure for preparation of 3-benzyloxy-1-methyl-pyrazole To a mixture of 1-methylpyrazol-3-ol (13.0 g, 133 mmol, 1.00 eq) and potassium carbonate (22.0 g, 159 mmol, 1.20 eq) in N,N-dimethylformamide (60.0 mL) was added 1-(bromomethyl)-4-methylbenzene (24.9 g, 146 mmol, 1.10 eq) dropwise at 0 °C. After stirring at 50 °C for 2 h, the reaction mixture was filtered. The filtrate was diluted with saturated ammonium chloride (500 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (100 mL), dried over sodium, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate= 6/1 to 3/1) to give 3-benzyloxy-1- methyl-pyrazole (12.0 g, 60.6 mmol, 46% yield, 95% purity) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.51-7.29 (m, 5H), 7.06 (d, J = 2.4 Hz, 1H), 5.58 (d, J = 2.4 Hz, 1H), 5.12 (s, 2H), 3.69 (s, 3H). LC-MS (Method C): R _t = 0.743 min; MS (ESIpos): m/z = 189.6 [M+H] ⁺ . Procedure for preparation of 3-benzyloxy-1-methyl-pyrazole-4-carbaldehyde Phosphorus oxychloride (11.7 g, 76.5 mmol, 1.20 eq) was added dropwise to a mixture of N,N- dimethylformamide (9.32 g, 128 mmol, 2.00 eq) in dichloromethane (60.0 mL) at -10°C. After stirring at -10 °C for 10 min, 3-benzyloxy-1-methyl-pyrazole (12.0 g, 63.8 mmol, 1.00 eq) was added. After stirring at 25 °C for 11 h 50 min, the reaction mixture was poured into saturated sodium bicarbonate (300 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (50.0 mL × 2), dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 1/1) to give 3- benzyloxy-1-methyl-pyrazole-4-carbaldehyde (9.20 g, 42.6 mmol, 67% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.77 (s, 1H), 7.77 (s, 1H), 7.51-7.30(m, 5 H), 5.33 (s, 2H), 3.80 (s, 3H) Procedure for preparation of 2-amino-2-(3-benzyloxy-1-methyl-pyrazol-4-yl)acetonitrile To a solution of 3-benzyloxy-1-methyl-pyrazole-4-carbaldehyde (3.00 g, 13.9 mmol, 1.00 eq) in ammonium (10.0 M in methanol, 20.0 mL) was added dropwise titanium (IV) isopropoxide (4.73 g, 16.65 mmol,, 1.20 eq) at 25 °C. After stirring for 0.5 h, trimethylsilyl cyanide (1.65 g, 16.7 mmol, 1.20 eq) was added dropwise to above mixture. After stirring at 25 °C for 11.5 h, the reaction mixture was poured into saturated ammonium chloride aqueous solution (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (50.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2-amino-2-(3-benzyloxy-1-methyl-pyrazol-4- yl)acetonitrile (2.50 g, 8.26 mmol, 60% yield, 80% purity) as brown oil, which was used for the next step reaction directly. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.33-7.10 (m, 5H), 5.13-5.04 (m, 2H), 4.69-4.58 (m, 1H), 3.62-3.45 (m, 3H). Procedure for preparation of (1R,2S,5S)-N- [(3-benzyloxy -1-methyl-pyrazol-4-yl)-cyano-methyl]- 3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoy l]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl- 3 -azabicyclo[3.1.0]hexane-2-carboxylic acid (1.20 g, 3.30 mmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (1.51 g, 3.96 mmol, 1.20 eq) and N,N- diisopropylethylamine (640 mg, 4.95 mmol, 1.50 eq) in N,N-dimethylformamide (10.0 mL) was added 2-amino-2-(3-benzyloxy-1-methyl-pyrazol-4-yl)acetonitrile (1.00 g, 3.30 mmol, 80% purity, 1.00 eq) at 0 °C. After stirring at 25 °C for 12 h, the reaction mixture was poured into saturated ammonium chloride (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (80 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=2/1 to 1/2) to give (1R,2S,5S)-N-[(3-benzyloxy-1-methyl-pyrazol-4-yl)-cyano-meth yl]-3- [(2S)- 3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-d imethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (1.20 g, 1.65 mmol, 50 % yield, 81% purity) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.58-7.32 (m, 7H), 5.84 (t, J = 7.2 Hz, 1H), 5.34 (s, 1H), 5.30-5.23 (m, 2H), 4.58-4.45 (m, 1H), 4.40-4.33 (m, 1H), 3.84-3.80 (m, 2H), 3.79-3.74 (m, 3H), 1.78-1.69 (m, 1H), 1.31-1.25 (m, 1H), 1.10-1.06 (m, 3H), 1.01-0.85 (m, 9H), 0.84-0.78 (m, 3H). LC-MS (Method C): R _t = 1.000 min; MS (ESIpos): m/z = 589.3 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N- [2-amino-1-(3-benzyloxy-1-methyl-pyrazol-4-yl)-2- oxo-ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide A mixture of (1R,2S,5S)-N-[(3-benzyloxy-1-methyl-pyrazol-4-yl)-cyano-meth yl]-3-[(2S)-3,3-di methyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabi cyclo[3.1.0]hexane-2-carboxamide (1.20 g, 2.04 mmol, 1.00 eq) in a mixed solvent of trifluoroacetic acid (5.00 mL) and dichloromethane (5.00 mL) was stirred at 20 °C for 2 h. The reaction mixture was basified with saturated sodium carbonate (50.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=3/1 to ethyl acetate) to give (1R,2S,5S)-N-[2-amino-1-(3-benzyloxy-1-methyl-pyrazol-4-yl)- 2-oxo-ethyl]-3- [(2S)-3,3-dimethyl -2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-az abicyclo[3.1.0]hexane-2- carboxamide (0.450 g, 705 μmol, 35% yield, 95% purity) was obtained as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.50-7.32 (m, 6H), 6.92-6.85 (m, 1H), 5.49-5.39(m, 1H),5.34-5.23 (m, 2H), 4.60-4.50(m, 1H), 4.17-4.11 (m, 1H), 4.04-3.88 (m, 1H), 3.86-3.78 (m, 1H), 3.76-3.68 (m, 3H), 1.61-1.46 (m, 2H), 1.08-0.98 (m, 12H), 0.93-0.85 (m, 3H). LC-MS (Method C): R _t = 0.583 min; MS (ESIpos): m/z = 607.3 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[2-amino -1-(2-methyl-5-oxo-1H-pyrazol-4-yl)-2-oxo- ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino] butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide A mixture of (1R,2S,5S)-N-[2-amino-1-(3-benzyloxy-1-methyl-pyrazol-4-yl)- 2-oxo-ethyl]-3-[(2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (400 mg, 659 μmol, 1.00 eq) in methanol (5.00 mL) was added Pd/Carbon (40 mg, 10% purity) at nitrogen atmosphere. The mixture was degassed under vacuum and purged with hydrogen for 3 times. After stirring at 20 °C under hydrogen atmosphere (15 psi) for 2 h, the mixture was filtered. The filtrate was concentrated to give (1R,2S,5S)-N-[2-amino-1-(2-methyl-5-oxo-1H-pyrazol-4-yl)-2-o xo- ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (330 mg, 632 μmol, 96 yield, 99% purity) as a white solid. LC-MS (Method C): R _t = 0.807 min; MS (ESIpos): m/z = 517.4 [M+H] ⁺ . Procedure for preparation of CPD0187916 - (1R,2S,5S)-N-[cyano-(2-methyl -5-oxo-1H-pyrazol-4- yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of (1R,2S,5S)-N-[2-amino-1-(2-methyl-5-oxo-1H-pyrazol-4-yl)-2-o xo-ethyl]-3-[(2S)-3,3-di methyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethy l-3-azabicyclo[3.1.0]hexane-2- carboxamide (300 mg, 580 μmol, 1 eq) and triethylamine (176 mg, 1.74 mmol, 3.00 eq) in tetrahydrofuran (10.0 mL) was added trifluoroacetic anhydride (183 mg, 871 μmol, 1.50 eq) at 0 °C . After stirring at 20 °C for 12 h, the mixture was poured into saturated sodium bicarbonate aqueous (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (10.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was purified by Prep-HPLC(column: Phenomenex Luna C18150*25mm*10 μm; mobile phase: [water(FA)-ACN];B%: 33%-63%,10min) and Prep-HPLC(column: Waters Xbridge 150*25mm* 5um;mobile phase: [water (ammonia hydroxide v/v)-ACN];B%: 5%-35%,9min) to give (1R,2S,5S)-N-[cyano-(2-methyl-5-oxo-1H-pyrazol-4-yl)methyl]- 3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (17.52 mg, 35.2 μmol, 6% yield, 96% purity) as white solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 10.41-9.78 (m, 1H), 9.59-9.24 (m, 1H), 9.22-8.75 (m, 1H), 7.60-7.55 (m, 1H), 5.69-5.61 (m, 1H), 4.39 (s, 1H), 4.31-4.23 (m, 1H), 3.95-3.75 (m, 1H), 3.74-3.64 (m, 1H), 3.61 (s, 3H), 1.56-1.46 (m, 1H), 1.31-1.21 (m, 1H), 1.04-0.96 (m, 12H), 0.82 (s, 3 H). LC-MS (Method C): R _t = 0.856 min; MS (ESIpos): m/z = 499.2 [M+H] ⁺ . HPLC (Method S): R _t = 1.941 min; purity: 96%. SFC: dr =39: 52. Preparation of CPD0187919 Procedure for preparation of 6-chloro-2,3-dimethylpyrimidin-4(3H)-one A mixture of 4-chloro-2-methyl-1H-pyrimidin-6-one (14.0 g, 96.8 mmol, 1.00 eq), iodomethane (34.2 g, 241 mmol, 2.50 eq), dicesium carbonate (70.0 g, 214.8 mmol, 2.20 eq) in anhydrous N,N- dimethylformamide (240 mL) was stirred at 40 °C for 16 h under nitrogen atmosphere. The reaction mixture was filtered and the cake was washed with anhydrous N,N-dimethylformamide (30.0 mL). The filtrate was concentrated under reduced pressure to afford crude product. The crude product was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=50/1 to 3/1) to afford 6-chloro- 2,3-dimethyl- pyrimidin-4-one (8.20 g, 51.7 mmol, 54% yield) as a white solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 6.40 (s, 1H), 3.50 (s, 3H), 2.54 (s, 3H) LC-MS (Method A): Rt = 0.415 min; MS (ESIpos): m/z = 158.8 [M+H] ⁺ . Procedure for preparation of methyl 2-(benzhydrylideneamino)-2-(1,2- dimethyl-6-oxo- pyrimidin-4-yl)acetate To a solution of 6-chloro-2,3-dimethyl-pyrimidin-4-one (4.00 g, 25.2 mmol, 1.00 eq) and methyl 2- (benzhydrylideneamino)acetate (5.70 g, 22.5 mmol, 0.90 eq) in anhydrous N,N-dimethylformamide (60.0 mL) were added [2-(2-aminophenyl)phenyl]-chloro-palladium tritert-butylphosphane (1.60 g, 3.10 mmol, 1.20 eq) and anhydrous tripotassium phosphate (16.0 g, 75.4 mmol, 3.00 eq) under nitrogen atmosphere. After stirring at 90 °C for 16 h under nitrogen atmosphere, the reaction mixture was filtered and the cake was washed with ethyl acetate (30.0 mL). The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1 to 1/2) to afford methyl 2-(benzhydrylideneamino)-2- (1,2-dimethyl-6-oxo- pyrimidin-4-yl)acetate (5.50 g, 14.6 mmol, 58% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.12-7.97 (m, 2H), 7.76-7.69 (m, 2H), 7.51-7.30 (m, 8H), 7.17 (dd, J = 6.4, 2.8, Hz, 2H), 6.67-6.63 (m, 1H), 5.06 (s, 1H), 3.74 (s, 3H), 3.51 (s, 3H), 2.71 (s, 1H), 2.50 (s, 3H). Procedure for preparation of 2-(benzhydrylideneamino)-2-(1,2-dimethyl- 6-oxo-pyrimidin-4- yl)acetamide A mixture of methyl 2-(1,2-dimethyl-6-oxo-1,6-dihydropyrimidin-4-yl)-2-((dipheny lmethylene)-amino) acetate (1.00 g, 2.66 mmol, 1.00 eq) in ammonia/methanol (7M, 8.00 mL, 21.0 eq) was stirred at 20 °C for 3 h. The mixture was concentrated under vacuum to afford 2-(benzhydrylideneamino)-2-(1,2- dimethyl- 6-oxo-pyrimidin-4-yl)acetamide (4.00 g, crude) as a yellow solid. LC-MS (Method G): Rt = 0.827 min; MS (ESIpos): m/z = 361.1 [M+H] ⁺ . Procedure for preparation of 2-amino-2-(1,2-dimethyl-6-oxo- pyrimidin-4-yl)acetamide A mixture of 2-(benzhydrylideneamino)-2-(1,2-dimethyl-6-oxo-pyrimidin-4-y l)acetamide (4.00 g, 11.1 mmol, 1.00 eq) in hydrogen chloride/dioxane (4M, 15.0 mL, 2.70 eq) and dioxane (20.0 mL) was stirred at 20 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with 2-methoxy-2-methylpropane (15.0 mL) at 20 °C for 0.5 h. The resulting suspension was filtered and the solid was collected to afford 2-amino-2-(1,2-dimethyl-6- oxo-pyrimidin- 4-yl)acetamide (3.00 g, crude) as a yellow solid. LC-MS (Method A): R _t = 0.127 min; MS (ESIpos): m/z = 197.0 [M-Ph ₂ C+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[2-amino-1-(1,2-dimethyl-6- oxo-pyrimidin-4-yl)-2- oxo-ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino] butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoro- acetyl)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (0.40 g, 1.10 mmol, 1.08 eq) and N-ethyl-N- isopropylpropan-2-amine (594 mg, 4.60 mmol, 4.51 eq) in anhydrous N,N- dimethylformamide (6.00 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dim ethyl- ammonium;hexafluorophosphate (420 mg, 1.10 mmol, 1.08 eq) at 5 °C. After stirring at 5 °C for 30 min, 2-amino-2-(1,2-dimethyl-6-oxo- pyrimidin-4-yl)acetamide (800 mg, 4.08 mmol, 4.00 eq) was added. After stirring at 20 °C for 15.5 h, the reaction mixture was concentrated under vacuum and diluted with ethyl acetate (30.0 mL) and washed with brine (50.0 mL × 3). The organic phase was dried over anhydrous disodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed phase MPLC (column: Welch Ultimate XB_C1820-40 μm; 120 A; mobile phase: [water(0.1%FA)-ACN]; B%: 0%-100%, 45 mL/min, 45 min) to afford (1R,2S,5S)-N-[2- amino-1-(1,2-dimeth yl-6-oxo-pyrimidin-4-yl)-2-oxo-ethyl] -3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (0.90 g, 1.66 mmol, 41% yield) as a yellow solid. LC-MS (Method C): R _t = 0.798 min; MS (ESIpos): m/z = 543.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ = 7.46-7.41 (m, 0.7H), 7.40-7.32 (m, 1.3H), 6.64-6.43 (m, 1H), 5.27 (d, J = 8.8 Hz, 1H), 4.61-4.56 (m, 3H), 4.35 (s, 1H), 4.04-3.95 (m, 3H), 3.91-3.82 (m, 3H), 3.53 (d, J = 6.0 Hz, 3H), 2.61-2.57 (m, 3H), 1.60-1.54 (m, 3H), 1.47-1.41 (m, 2H), 1.10-1.03 (m, 29H), 1.02-0.97 (m, 7H), 0.94 (d, J = 4.0 Hz, 3H), 0.91 (s, 5H). Procedure for preparation of CPD0187919 (1R,2S,5S)-N-(cyano(1,2-dimethyl-6-oxo- 1,6- dihydropyrimidin-4-yl)methyl)-3-((S)-3,3-dimethyl-2-(2,2,2-t rifluoroacetamido)butanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of (1R,2S,5S)-N-[2-amino-1-(1,2-dimethyl-6-oxo-pyrimidin-4-yl)- 2-oxo-ethyl]-3-[(2S) -3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (0.35 g, 0.65 mmol, 1.00 eq) in anhydrous dichloromethane (6.00 mL) was added methoxycarbonyl-(triethylammonio)sulfonyl-azanide (550 mg, 2.31 mmol, 3.60 eq). After stirring at 20 °C for 4 h, the mixture was quenched with water (15.0 mL), extracted with dichloromethane (10.0 mL × 3). The combined organic layers were washed with brine (15.0 mL × 2), dried over anhydrous disodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 μm; mobile phase: [water(FA)-ACN]; B%: 39%-69%, 7 min) to afford (1R,2S,5S)-N-[cyano-(1,2-dimethyl-6-oxo-pyrimidin-4- yl)methyl]-3-[(2S)- 3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2- carboxamide (249 mg, 0.480 mmol, 73% yield, 100% purity). ¹ H NMR (400 MHz, CD ₃ OD) δ = 6.74-6.50 (m, 1H), 5.88 (d, J = 16.0 Hz, 1H), 4.62-4.55 (m, 1H), 4.40 (d, J = 10.4 Hz, 1H), 4.01 (td, J = 10.4, 5.2 Hz, 1H), 3.87 (t, J = 10.4 Hz, 1H), 3.58-3.53 (m, 3H), 2.61 (s, 3H), 1.68-1.57 (m, 1H), 1.53-1.42 (m, 1H), 1.15-0.98 (m, 5H), 0.93 (br. s, 1H). LC-MS (Method C): R _t = 0.864 min; MS (ESIpos): m/z = 536.3 [M+H] ⁺ . SFC: dr = 64:36. Preparation of CPD0187928 Procedure for preparation of 4-bromo-1-(difluoromethyl)quinolin-2-one- To a solution of 4-bromoquinoline (2.00 g, 9.61 mmol, 1.00 eq) in acetonitrile (30 mL) were added ethyl 2-bromo-2,2-difluoro-acetate (7.80 g, 38.4 mmol, 4.94 mL, 4.00 eq), 1,8-diazabicyclo[5.4.0]undec-7- ene (4.39 g, 28.8 mmol, 4.35 mL, 3.00 eq) and 2-hydroperoxy-2-methyl-propane (3.47 g, 38.4 mmol, 3.69 mL, 4.00 eq), The mixture was stirred at 80 °C for 16 h under nitrogen. The mixture was quenched with excess saturated sodium sulfite solution. The resulting mixture was diluted with water (200 mL) and extracted with ethyl acetate (50.0 mL×3). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 0: 1) to give 4-bromo-1-(difluoromethyl)quinolin-2- one (650 mg, 2.37 mmol, 25% yield) as a white solid. LCMS (Method C): R _t = 0.907 min; MS (ESIpos): m/z = 275.9 [M+H] ⁺ . Procedure for preparation of methyl 2-(benzhydrylideneamino)-2-[1-(difluoromethyl) -2-oxo-4- quinolyl]acetate To a solution of 4-bromo-1-(difluoromethyl)quinolin-2-one (2.50 g, 9.12 mmol, 1.00 eq), methyl 2- (benzhydrylideneamino)acetate (3.47 g, 13.6 mmol, 1.50 eq) in N,N-dimethylformamide (3 mL) were added potassiumphosphate (3.87 g, 18.2 mmol, 2.00 eq) and [2-(2-aminophenyl)phenyl]-chloro- palladium;tritert-butylphosphane (467 mg, 0.912 mmol, 0.100 eq). After stirring at 90 °C for 16 h under nitrogen atmosphere, the mixture was concentrated under vacuum to give a residue. The residue was purified by reversed phase column (column: Phenomenex Luna C18150*25mm*10 μm; mobile phase: [water(FA)-ACN];B%: 20%-40%, 6 min) to give methyl 2-(benzhydrylideneamino)-2-[1-(difluoromethyl)- 2-oxo-4-quinolyl]acetate (400 mg, 0.895 mmol, 10% yield) as red oil. LCMS (Method C): R _t = 1.031 min; MS (ESIpos): m/z = 447.1 [M+H] ⁺ . Procedure for preparation of 2-(benzhydrylideneamino)-2-[1-(difluoromethyl) -2-oxo-4- quinolyl]acetamide A solution of methyl 2-(benzhydrylideneamino)-2-[1-(difluoromethyl)-2-oxo-4-quino lyl]acetate (400 mg, 0.895 mmol, 1.00 eq) in ammonia (7M in methanol, 5.00 mL) was stirred at 60 °C for 16 h. The mixture was concentrated under vacuum to give 2-(benzhydrylideneamino)-2-[1-(difluoromethyl)-2-oxo-4- quinolyl]acetamide (350 mg, crude) as red oil. LCMS (Method C): R _t = 0.935 min; MS (ESIpos): m/z = 432.1 [M+H] ⁺ . Procedure for preparation of 2-amino-2-[1-(difluoromethyl)-2-oxo-4-quinolyl]acetamide To a solution of 2-(benzhydrylideneamino)-2-[1-(difluoromethyl)-2-oxo-4-quino lyl]acetamide (300 mg, 0.695 mmol, 1.00 eq) in methyl alcohol (5 mL) was added hydrochloric acid (3 M, 5.00 mL, 21.5 eq). After stirring at 20 °C for 16 h, the mixture was concentrated under vacuum to give 2-amino-2-[1- (difluoromethyl)-2-oxo-4-quinolyl]acetamide (250 mg, crude) as red oil. LCMS (Method C): R _t = 0.297 min; MS (ESIpos): m/z = 268.4 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[2-amino-1-[1-(difluoromethyl)-2-oxo-4-quinolyl ]-2- oxo-ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide - To a solution of 2-amino-2-[1-(difluoromethyl)-2-oxo-4-quinolyl]acetamide (250 mg, 0.935 mmol, 1.00 eq), (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0] hexane-2-carboxylic acid (374 mg, 1.03 mmol, 1.10 eq) in N,N-dimethylformamide (3.00 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N’,N’- tetramethyluronium hexafluorophosphate (427 mg, 1.12 mmol, 1.20 eq), diisopropylethylamine (241 mg, 1.87 mmol, 325 μL, 2.00 eq). After stirring at 20 °C for 16 h, the mixture was concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10 μm; mobile phase: [water(FA)-ACN];B%: 30%-60%,7min) to give (1R,2S,5S)-N-[2-amino-1-[1-(difluoromethyl)-2-oxo-4- quinolyl]-2-oxo-ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-triflu oroacetyl)amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (80.0 mg, 0.130 mmol, 14% yield) as a white solid. LCMS (Method C): R _t = 0.840 min; MS (ESIpos): m/z = 614.2 [M+H] ⁺ . Procedure for preparation of CPD0187928- (1R,2S,5S)-N-[cyano-[1-(difluoromethyl)-2-oxo-4- quinolyl]methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroace tyl)amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-[2-amino-1-[1-(difluoromethyl)-2-oxo-4-quinolyl ]-2-oxo-ethyl]-3-[(2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (80.0 mg, 0.130 mmol, 1.00 eq) in dichloromethane (3.00 mL) was added methoxycarbonyl-(triethylammonio)sulfonyl-azanide (155 mg, 0.651 mmol, 5.00 eq). After stirring at 20 °C for 16 h, the mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (5.00 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuum to give a residue. The residue was purified by the prep-HPLC (column: Phenomenex luna C18 150*25mm* 10 μm; mobile phase: [water(FA)-ACN];B%: 48%-78%,10 min) to give (1R,2S,5S)-N- [cyano-[1-(difluoromethyl)-2-oxo-4-quinolyl]methyl]-3-[(2S)- 3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (43.3 mg, 0.720 mmol, 56% yield, 99% purity) as a white solid. LCMS (Method C): R _t = 1.017 min; MS (ESIpos): m/z = 596.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.74-9.51 (m, 1H), 9.43 (d, J = 8.0 Hz, 1H), 8.27 (t, J = 57.6 Hz, 1H), 7.84-7.70 (m, 3H), 7.49-7.32 (m, 1H), 6.86-6.72 (m, 2H), 4.40-4.36 (m, 1H), 4.22-4.21 (m, 1H), 3.99- 3.88 (m, 1H), 3.78-3.62 (m, 1H), 1.63-1.56 (m, 1H), 1.33 (d, J = 7.6 Hz, 0.6H), 1.16 (d, J = 7.6 Hz, 0.5H), 1.03-0.99 (m, 6H), 0.97-0.91 (m, 6H), 0.84-0.81 (m, 3H). SFC: dr = 41: 59. Preparation of CPD0187929 Procedure for preparation of methyl (1R,2S,5S)-3-[(2S,3R)-3-tert-butoxy-2-(tert- butoxycarbonylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1. 0]hexane-2-carboxylate To a solution of (2S,3R)-3-tert-butoxy-2-(tert-butoxycarbonylamino)butanoic acid (3.00 g, 10.9 mmol, 1.00 eq) in dichloromethane (20.0 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3- yloxy)methylene]-dimethyl-ammonium;hexafluorophosphate (5.39 g, 14.2 mmol, 1.30 eq), methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate hydrochloride (2.24 g, 10.9 mmol, 1.00 eq) and N,N-diisopropylethylamine (2.82 g, 21.8 mmol, 2.00 eq). After stirring at 20 °C for 16 h, the reaction mixture was quenched with saturated ammonium chloride aqueous solution (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 50/1 to 5/1) to give methyl (1R,2S,5S)-3-[(2S,3R)-3-tert-butoxy-2-(tert- butoxycarbonylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1. 0]hexane-2-carboxylate (3.50 g, 7.38 mmol, 68% yield, 90% purity) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.43 (d, J = 7.6 Hz, 1H), 5.13 (d, J = 8.8 Hz, 1H), 4.17-4.12 (m, 1H), 4.07-4.00 (m, 1H), 3.84-3.79 (m, 1H), 3.77 (s, 3H), 3.69-3.59 (m, 1H), 1.54-1.50 (m, 1H), 1.49-1.47(m, 1H), 1.42 (s, 9H), 1.24 (s, 9H), 1.17 (d, J = 6.0 Hz, 3H), 1.05 (s, 6H). LC-MS (Method O): R _t = 0.628 min; MS (ESIpos): m/z = 417.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S,3R)-3-tert-butoxy-2-(tert- butoxycarbonylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1. 0]hexane-2-carboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S,3R)-3-tert-butoxy-2-(tert-butoxycarbonylam ino)butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (3.50 g, 8.21 mmol, 1.00 eq, 90% purity) in tetrahydrofuran (8.00 mL), methanol (8.00 mL) and water (8.00 mL) was added lithium hydrate (590 mg, 24.6 mmol, 3.00 eq) at 0 °C. After stirring at 20 °C for 12 h, hydrochloric acid aqueous (0.500 mol/L) was added to the reaction mixture to acidify pH~7 and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-3-[(2S,3R)-3-tert-butoxy-2-(tert- butoxycarbonylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1. 0]hexane-2-carboxylic acid (3.50 g, crude) as a white solid. 1H NMR (400 MHz, CDCl ₃ ) δ = 5.63 (d, J = 8.8 Hz, 1H), 5.38 (d, J = 8.0 Hz, 1H), 4.72-4.51 (m, 1H), 4.32-4.30 (m, 1H), 4.02-3.96 (m, 1H), 3.58-3.50 (m, 1H), 1.70-1.65 (m, 1H), 1.63-1.59(m, 1H), 1.42 (s, 9H), 1.21 (s, 9H), 1.09 (d, J = 6.4 Hz, 3H), 1.03 (s, 6H). LC-MS (Method R): R _t = 0.513 min; MS (ESIpos): m/z = 411.3 [M-H]-. Procedure for preparation of (1R, 2S, 5S)-3-((2S, 3R)-2-amino-3-(tert-butoxy) butanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid To a solution of (1R, 2S, 5S)-3-((2S, 3R)-3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)butanoyl)- 6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.00 g, 2.42 mmol, 1.00 eq) in dichloromethane (10.0 mL) were added 2,6-dimethylpyridine (1.04 g, 9.70 mmol, 4.00 eq) and trimethylsilyl triflate (1.08 g, 4.85 mmol, 2.00 eq) at 0 °C. After stirring at 25 °C for 12 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC ([water (0.1% ammonium hydroxide)-acetonitrile]; B%: 30%-70%) to afford (1R, 2S, 5S)-3-((2S, 3R)-2-amino- 3-(tert-butoxy) butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxylic acid (660 mg, crude) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.56-6.28 (s, 2H), 4.48 (s, 1H), 4.10-4.01 (m, 1H), 3.82-3.69 (m, 2H), 3.53-3.44 (m, 1H), 1.42-1.35 (m, 1H), 1.34-1.27(m, 1H), 1.23 (s, 9H), 1.18-1.15 (m, 3H), 1.08-0.99 (m, 6H). LC-MS (Method R): R _t = 0.347&0.418 min; MS (ESIpos): m/z = 311.2 [M-H]-. Procedure for preparation of (1R, 2S, 5S)-3-((2S, 3R)-3-(tert-butoxy)-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxylic acid To a solution of (1R, 2S, 5S)-3-((2S, 3R)-2-amino-3-(tert-butoxy) butanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0] hexane-2-carboxylic acid (660 mg, 2.11 mmol, 1.00 eq) in methanol (7.00 mL) were added triethylamine (641 mg, 6.34 mmol, 3.00 eq) and methyl 2,2,2-trifluoroacetate (405 mg, 3.17 mmol, 1.50 eq). After stirring at 25 °C for 12 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether then dichloromethane/methanol = 10/1) to afford (1R, 2S, 5S)-3-((2S, 3R)-3-(tert-butoxy)-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxylic acid (270 mg, crude) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.55-7.33 (m, 1H), 6.41-6.24 (m, 1H), 5.09 (s, 1H), 4.60-4.40 (m, 1H), 4.16-4.06 (m, 1H), 4.01-3.87 (m, 1H), 3.81-3.59 (m, 1H), 2.10-1.98 (m, 3H), 1.71-1.64 (m, 1H), 1.58-1.39 (m, 1H), 1.26-1.21 (m, 9H), 1.11-1.01 (m, 6H). LC-MS (Method R): R _t = 0.475; 0.485 min; MS (ESIpos): m/z = 407.2 [M+H] ⁺ . Procedure for preparation of CPD0187929 - (1R, 2S, 5S)-N-(benzo[d]thiazol-5-yl(cyano)methyl)- 3-((2S,3R)-3-(tert-butoxy)-2-(2,2,2-trifluoroacetamido)butan oyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide A mixture of (1R, 2S, 5S)-3-((2S, 3R)-3-(tert-butoxy)-2-(2,2,2-trifluoroacetamido)butanoyl)-6, 6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (270 mg, 0.53 mmol, 1.00 eq), O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (301 mg, 0.80 mmol, 1.50 eq) and N,N-diisopropylethylamine(136 mg, 1.06 mmol, 2.00 eq) in dimethylformamide (3.00 mL) was stirred at 25 °C for 0.1 h.2-Amino-2-(benzo[d]thiazol-5-yl)acetonitrile (141 mg, 0.634 mmol, 1.20 eq) was added to the above mixture and stirred at 25 °C for another 16 h. The reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (FA condition:column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 47%-77%,15 min) to give (1R, 2S, 5S)-N-(benzo[d]thiazol-5-yl(cyano)methyl)-3-((2S,3R)-3-(tert -butoxy)-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxamide (87.0 mg, 0.162 mmol, 28% yield, 97% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.66-9.59 (m, 1H), 9.50-9.39 (m, 2H), 8.26 (d, J = 8.4 Hz, 1H), 8.20- 8.16 (m, 1H), 7.63-7.54 (m, 1H), 6.40 (t, J = 8.0 Hz, 1H), 4.42-4.36 (m, 1H), 4.27 (d, J = 3.6 Hz, 1H), 4.02-3.95 (m, 1H), 3.94-3.86 (m, 1H), 3.70-3.59 (m, 1H), 1.62-1.53 (m, 1H), 1.42-1.28 (m, 1H), 1.09 (d, J = 8.4 Hz, 9H), 1.07-0.99 (m, 6H), 0.84 (d, J = 7.2 Hz, 3H). LC-MS (Method L): R _t = 2.270 min; MS (ESIpos): m/z = 524.2 [M+H] ⁺ . SFC: four peaks ratio. dr: 38:47:10:5. Preparation of CPD0187930 Procedure for preparation of methyl (1R,2S,5S)-3-[(2S,3R)-2-(benzyloxycarbonylamino)-3-tert- butoxy-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-ca rboxylate To a mixture of (2S,3R)-2-(benzyloxycarbonylamino)-3-tert-butoxy-butanoic acid (4.00 g, 12.9 mmol, 1.00 eq) in dichloromethane (40.0 mL) were added (benzotriazol-1- yloxy)tripyrrolidinophosphonium,hexafluorophosphate (8.75 g, 16.8 mmol, 1.30 eq), 4- methylmorpholine (3.92 g, 38.8 mmol, 3.00 eq) and methyl (1R,2S,5S)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (2.66 g, 12.9 mmol, 1.00 eq, hydrochloric acid) at 0 °C. After stirring at 20 °C for 12 h, the mixture was poured into water (80.0 mL) and extracted with ethyl acetate (80 mL × 3). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1 to 5: 1) to give methyl (1R,2S,5S)-3-[(2S,3R)-2-(benzyloxycarbonylamino)-3-tert-buto xy-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (5.80 g, 12.6 mmol, 97% yield, 99% purity) as colorless gum. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.37-7.32 (m, 4H), 5.81-5.43 (m, 1H), 5.13-5.04 (m, 2H), 4.35-4.18 (m, 1H), 4.12-4.03 (m, 1H), 3.89-3.80 (m, 2H), 3.76-3.73 (m, 3H), 3.72-3.62 (m, 1H), 1.52-1.39 (m, 2H), 1.26 (s, 3H), 1.20 (s, 6H), 1.18 (s, 1H), 1.07-1.04 (m, 4H), 1.02-0.99 (m, 1H), 0.95-0.92 (m, 2H). LC-MS (Method O): R _t = 0.537&0.562 min; MS (ESIpos): m/z = 483.0 [M+23] ⁺ . SFC: dr = 70: 30 (should be mixture of two rotamers, they are separable by column, and will convert to mixture again after column). Procedure for preparation of (1R,2S,5S)-3-[(2S,3R)-2-(benzyloxycarbonylamino)-3-tert-buto xy- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyli c acid To a mixture of methyl (1R,2S,5S)-3-[(2S,3R)-2-(benzyloxycarbonylamino)-3-tert-buto xy-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (3.00 g, 6.51 mmol, 1.00 eq) in methanol (30.0 mL) and water (30.0 mL) was added lithium hydroxide hydrate (547 mg, 13.0 mmol, 2.00 eq) at 0 °C. After stirring at 20 °C for 14 h, the mixture was concentrated under vacuum to remove organic solvent. The resulting aqueous solution was diluted with water (20.0 mL), adjusted to pH = 4 with hydrochloric acid (1 M) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give (1R,2S,5S)-3-[(2S,3R)-2-(benzyloxycarbonylamino)-3-tert-buto xy-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (2.9 g, 6.43 mmol, 99% yield, 99% purity) as colorless gum which was used for next step reaction directly. LC-MS (Method S): R _t = 0.541; 0.573 min; MS (ESIpos): m/z = 391.0 [M+H-56] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S,3R)-2-amino-3-tert-butoxy-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid To a suspension of (1R,2S,5S)-3-[(2S,3R)-2-(benzyloxycarbonylamino)-3-tert-buto xy-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (2.90 g, 6.49 mmol, 1.00 eq) in methanol (30.0 mL) was added palladium-carbon catalyst (300 mg, 10% purity) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen for 3 times. After stirring at 20 °C for 12 h under hydrogen (15 psi), the reaction mixture was filtered. The filtrate was concentrated under vacuum to give (1R,2S,5S)-3-[(2S,3R)-2-amino-3-tert-butoxy-butanoyl]-6,6-di methyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (200 g, crude) as a white solid which was used for next step directly. LC-MS (Method S): R _t = 0.322; 0.385 min; MS (ESIpos): m/z = 256.9 [M+H-56] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S,3R)-2-amino-3-tert-butoxy-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid A mixture of (1R,2S,5S)-3-[(2S,3R)-2-amino-3-tert-butoxy-butanoyl]-6,6-di methyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (2.00 g, 6.40 mmol, crude purity, 1.00 eq), triethylamine (1.94 g, 19.2 mmol, 3.00 eq) and methyl 2,2,2-trifluoroacetate (1.23 g, 9.60 mmol, 1.50 eq) in methanol (20.0 mL) was stirred at 25 °C for 19 h. After concentration, the residue was diluted with water (50.0 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give (1R,2S,5S)-3-[(2S,3R)-3-tert-butoxy-2-[(2,2,2-trifluoroacety l)amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (2.6 g, 6.18 mmol, 96% yield, 97% purity) as an off-white solid which was used for next step directly. LC-MS (Method S): R _t = 0.511; 0.537 min; MS (ESIpos): m/z = 352.9 [M+H-56] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[2-amino-1-(1-methyl-2-oxo-4-quinolyl)-2-oxo-et hyl]- 3-[(2S,3R)-3-tert-butoxy-2-[(2,2,2-trifluoroacetyl)amino]but anoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of (1R,2S,5S)-3-[(2S,3R)-3-tert-butoxy-2-[(2,2,2-trifluoroacety l)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (381 mg, 934 μmol, 1.00 eq), O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (533 mg, 1.40 mmol, 1.50 eq) and N,N-diisopropylethylamine (362 mg, 2.80 mmol, 3.00 eq) in N,N-dimethylformamide (5.00 mL) was added 2-amino-2-(1-methyl-2-oxo-4-quinolyl)acetamide (250 mg, 934 μmol, 1.00 eq, hydrochloric acid) at 0 °C. After stirring at 20 °C for 12 h, the mixture was poured into water (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate/methanol = 30/63/7 to 10/81/9) to give (1R,2S,5S)-N-[2-amino-1-(1-methyl-2-oxo-4-quinolyl)-2-oxo-et hyl]-3-[(2S,3R)-3-tert- butoxy-2-[(2,2,2-trifluoroacetyl)amino] butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (550 mg, 849 μmol, 91% yield, 96% purity) as a light yellow solid. LC-MS (Method S): R _t = 0.524; 0.536 min; MS (ESIpos): m/z = 566.0 [M+H-56] ⁺ . Procedure for preparation of CPD0187930 - (1R,2S,5S)-3-[(2S,3R)-3-tert-butoxy-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-N-[cyano-(1-methyl-2-oxo-4-q uinolyl)methyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of (1R,2S,5S)-N-[2-amino-1-(1-methyl-2-oxo-4-quinolyl)-2-oxo-et hyl]-3-[(2S,3R)-3-tert- butoxy-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethy l-3-azabicyclo[3.1.0]hexane-2- carboxamide (300 mg, 483 umol, 1.00 eq) in dichloromethane (10.0 mL) was added methoxycarbonyl- (triethylammonio)sulfonyl-azanide (345 mg, 1.45 mmol, 3.00 eq) at 0 °C. After stirring at 25 °C for 12 h, the mixture was poured into water (30.0 mL) and extracted with dichloromethane (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18200*40mm*10 μm; mobile phase: [water(FA)-ACN]; B%: 50%-80%, 10 min) to give (1R,2S,5S)-3-[(2S,3R)-3-tert-butoxy-2-[(2,2,2-trifluoroacety l)amino]butanoyl]-N-[cyano- (1-methyl-2-oxo-4-quinolyl) methyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (164 mg, 267 μmol, 55% yield, 98% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.64 (t, J = 9.6 Hz, 1H), 9.55 (d, J = 8.0 Hz, 0.5H), 9.40 (d, J = 8.0 Hz, 0.5H), 7.79-7.68 (m, 2H), 7.66-7.61 (m, 1H), 7.37-7.26 (m, 1H), 6.85 (d, J = 5.2 Hz, 1H), 6.73 (dd, J = 13.2, 8.0 Hz, 1H), 4.44-4.36 (m, 1H), 4.22 (d, J = 4.4 Hz, 1H), 4.04-3.95 (m, 1H), 3.94-3.83 (m, 1H), 3.68-3.64 (m, 4H), 1.61-1.57 (m, 1H), 1.16-1.13 (m, 1H), 1.12 (d, J = 2.4 Hz, 9H), 1.05-1.02 (m, 2H), 1.00-0.94 (m, 4H), 0.82 (d, J = 9.6 Hz, 3H). LC-MS (Method L): R _t = 2.273; 2.287 min; MS (ESIpos): m/z = 548.5 [M+H-56] ⁺ . SFC: dr = 11: 42: 47. Preparation of CPD0191185, CPD0191190, CPD0191191, CPD0191192 Procedure for preparation of CPD0191185, CPD0191190, CPD0191191, CPD0191192 - (1R,2S,5S)- N-[1-cyano-2-(3-oxo-4H-1,4-benzoxazin-2-yl)ethyl]-3-[(2S)-3, 3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2- (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-3-oxo-4H-1,4-benzoxazin-2 -yl]ethyl]-3-[(2S)-3,3-dimethyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabi cyclo[3.1.0]hexane-2-carboxamide CPD0188250 (480 mg, 809 μmol, 95% purity) was purified by SFC (column: DAICEL CHIRALPAK AD(250mm*30 mm,10 μm); mobile phase: [Neu-IPA];B%: 25%-25%,2.7min;) to give peak1 and peak 2. The separated two peaks were further purified by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10 μm); mobile phase: [Neu-IPA]; B%: 30%-30%, 2.4 min; column: DAICEL CHIRALPAK IG (250 mm*30 mm,10 μm); mobile phase: [0.1% NH ₃ H ₂ O MeOH]; B%: 15%-15%, 6.0 min) to give CPD0191185 (1R,2S,5S)-N-[1-cyano-2-(3-oxo-4H-1,4-benzoxazin-2-yl)ethyl] -3-[(2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (59.3 mg, 105 μmol, 13% yield, 99% purity), CPD0191190 (1R,2S,5S)-N-[1-cyano-2-(3- oxo-4H-1,4-benzoxazin-2-yl) ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino] butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (43.2 mg, 76.6 μmol, 9% yield, 99% purity), CPD0191191 (1R,2S,5S)-N-[1-cyano-2-(3-oxo-4H-1,4-benzoxazin-2-yl)ethyl] -3-[(2S)-3,3-dimethyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabi cyclo[3.1.0]hexane-2-carboxamide (74.2 mg, 131 μumol, 16% yield, 99% purity) and CPD0191192 (1R,2S,5S)-N-[1-cyano-2-(3-oxo-4H-1,4- benzoxazin-2-yl)ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-triflu oroacetyl)amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (84.3 mg, 149 μmol, 18% yield, 99% purity) as a white solid. CPD0191185: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.83 (s, 1H), 9.46-9.13 (m, 1H), 9.08 (d, J = 7.6 Hz, 1H), 7.17-6.65 (m, 4H), 5.20-5.01 (m, 1H), 4.69-4.65 (m, 1H), 4.56-4.31 (m, 1H), 4.20 (s, 1H), 3.91-3.87 (m, 1H), 3.67 (d, J = 10.4 Hz, 1H), 2.45-2.35 (m, 1H), 2.23-2.16 (m, 1H), 1.60-1.47 (m, 1H), 1.33 (d, J = 7.8 Hz, 1H), 1.11-0.74 (m, 15H). LC-MS (Method K): R _t = 2.255 min; MS (ESIpos): m/z = 564.3 [M+H] ⁺ . SFC: de%: 87%. CPD0191190: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.77 (s, 1H), 9.34 (d, J = 8.4 Hz, 1H), 9.08 (d, J = 8.4 Hz, 1H), 7.05-6.83 (m, 4H), 5.27-5.04 (m, 1H), 4.58-4.41 (m, 1H), 4.33 (d, J = 7.0 Hz, 1H), 4.13 (s, 1H), 3.89-3.86 (m, 1H), 3.67 (d, J = 10.6 Hz, 1H), 2.47 (d, J = 2.4 Hz, 1H), 2.32-2.23 (m, 1H), 1.57-1.54 (m, 1H), 1.34 (d, J = 7.8 Hz, 1H), 1.14-0.72 (m, 15H). LC-MS (Method K): R _t = 2.261 min; MS (ESIpos): m/z = 564.4 [M+H] ⁺ . SFC: de%: 85%. CPD0191191: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.82 (s, 1H), 9.42 (d, J = 7.8 Hz, 1H), 9.02 (d, J = 7.8 Hz, 1H), 7.03-6.85 (m, 4H), 5.00-4.94 (m, 1H), 4.64-4.61 (m, 1H), 4.39 (d, J = 8.0 Hz, 1H), 4.19 (s, 1H), 3.90-3.87 (m, 1H), 3.66 (d, J = 10.6 Hz, 1H), 2.48-2.42 (m, 1H), 2.31-2.24 (m, 1H), 1.52-1.48 (m, 1H), 1.31 (d, J = 7.6 Hz, 1H), 1.13-0.75 (m, 15H). LC-MS (Method K): R _t = 2.247 min; MS (ESIpos): m/z = 564.4 [M+H] ⁺ . SFC: de%: 100%. CPD0191192: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.85 (s, 1H), 9.54-9.33 (m, 1H), 9.06 (d, J = 8.0 Hz, 1H), 7.05-6.85 (m, 4H), 5.12-4.94 (m, 1H), 4.75-4.62 (m, 1H), 4.45-4.34 (m, 1H), 4.21 (s, 1H), 3.91-3.87 (m, 1H), 3.67 (d, J = 10.4 Hz, 1H), 2.44-2.41 (m, 1H), 2.29-2.19 (m, 1H), 1.56-1.47 (m, 1H), 1.37 (d, J = 7.6 Hz, 1H), 1.17-0.74 (m, 15H). LC-MS (Method K): R _t = 2.263 min; MS (ESIpos): m/z = 564.3 [M+H] ⁺ . SFC: de%: 90%. Preparation of CPD0189159 Procedure for preparation of methyl 3-oxo-3-pyrrolidin-1-yl-propanoate To a solution of methyl 3-chloro-3-oxo-propanoate (15.0 g, 110 mmol, 1.00 eq) in dichloromethane (50.0 mL) were added triehylamine (11.1 g, 110 mmol, 1.00 eq) and pyrrolidine (8.20 g, 115 mmol, 1.05 eq) at 0 °C. After stirring at 25 °C for 12 h, the reaction mixture was poured into water (50.0 mL) and extracted with dichloromethane (50.0 mL × 2). The combined organic layers were washed with hydrochloric acid (1.50 M in water, 50.0 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated to give methyl 3-oxo-3-pyrrolidin-1-yl-propanoate (15.0 g, 87.6 mmol, 80% yield) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 3.68 (s, 3H), 3.47-3.36 (m, 4H), 3.35 (s, 2H), 1.99-1.75 (m, 4H). LC-MS (Method A): R _t = 0.388 min; MS (ESIpos): m/z = 172.3 [M+H] ⁺ . Procedure for preparation of methyl (2Z)-2-hydroxyimino-3-oxo-3-pyrrolidin-1-yl-propanoate To a solution of methyl 3-oxo-3-pyrrolidin-1-yl-propanoate (0.500 g, 2.92 mmol, 1.00 eq) in dichloromethane (10.0 mL) were added tert-butyl nitrite (331 mg, 3.21 mmol, 1.10 eq) and hydrochloric acid (2 M in ethyl acetate, 2.04 mL, 1.40 eq) at 0°C. After stirring at 25 °C for 2 h, the mixture was concentrated under vacuum to give methyl (2Z)-2-hydroxyimino-3-oxo-3-pyrrolidin-1-yl-propanoate (500 mg, 2.25 mmol, 77% yield, 90% purity) as a yellow solid. LC-MS (Method A): R _t = 0.621 min; MS (ESIpos): m/z = 201.2 [M+H] ⁺ . Procedure for preparation of methyl 2-(3-oxo-4H-1,4-benzoxazin-2-yl)acetate To a solution of methyl (2Z)-2-hydroxyimino-3-oxo-3-pyrrolidin-1-yl-propanoate (500 mg, 2.50 mmol, 1.00 eq) in hydrochloric acid (4 M in methanol, 10.0 mL) was added palladium on carbon (300 mg, 10% purity) at 20 °C under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen for 3 times. After stirring at 20°C for 16 h under hydrogen (50 psi) atmosphere, the reaction mixture was filtered. The filtrate was concentrated under vacuum to give methyl 2-amino-3- oxo-3-pyrrolidin-1-yl-propanoate (500 mg, 2.13 mmol, 85% yield, 95% purity, HCl) as a yellow solid. LC-MS (Method A): R _t = 0.133 min; MS (ESIpos): m/z = 187.2 [M+H] ⁺ . Procedure for preparation of 2-amino-3-oxo-3-pyrrolidin-1-yl-propanamide - A solution of methyl 2-amino-3-oxo-3-pyrrolidin-1-yl-propanoate (0.500 g, 2.69 mmol, 1.00 eq) in ammonia (7 M in methanol, 10.0 mL, 26.0 eq) was stirred at 25 °C for 16 h. The mixture was concentrated under vacuum to give 2-amino-3-oxo-3-pyrrolidin-1-yl-propanamide (440 mg, 2.06 mmol, 77% yield, 80% purity) as a gray solid. LC-MS (Method A): R _t = 0.120 min; MS (ESIpos): m/z = 172.1 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-(1-carbamoyl-2-oxo-2-pyrrolidin-1-yl-ethyl)-3-[ (2S)- 3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-d imethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide To a mixture of 2-amino-3-oxo-3-pyrrolidin-1-yl-propanamide (200 mg, 1.17 mmol, 1.00 eq) and (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (340 mg, 934 μmol, 0.80 eq) in N,N-dimethylformamide (6.00 mL) were added N,N-diisopropylethylamine (453 mg, 3.50 mmol, 3.00 eq) and O-(7-azabenzotriazol-1- yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (533 mg, 1.40 mmol, 1.20 eq) at 25 °C. After stirring at 25 °C for 16 h, the mixture was poured into saturated ammonia chloride (30.0 mL) and extracted with ethyl acetate (50.0 mL × 2). The combined organic layers were washed with brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-N-(1-carbamoyl-2-oxo-2-pyrrolidin-1-yl-ethyl)-3-[ (2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (0.400 g, 773 μmol, 66% yield) as yellow oil. LC-MS (Method C): R _t = 0.867 min; MS (ESIpos): m/z = 518.3 [M+H] ⁺ . Procedure for preparation of CPD0189159- (1R,2S,5S)-N-[1-cyano-2-oxo-2-pyrrolidin-1-yl-ethyl]- 3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoy l]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-(1-carbamoyl-2-oxo-2-pyrrolidin-1-yl-ethyl)-3-[ (2S)-3,3-dimethyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabi cyclo[3.1.0]hexane-2-carboxamide (0.400 g, 773 μmol, 1.00 eq) in dichloromethane (8.00 mL) was added Burgess reagent (553 mg, 2.32 mmol, 3.00 eq) at 25 °C. After stirring at 25 °C for 4 h, saturated sodium bicarbonate aqueous solution was added to adjust pH~9 and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (15.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by prep-HPLC(column: Waters Xbridge C18 150*50mm* 10 μm; mobile phase: [water(NH ₄ HCO ₃ )-ACN]; B%: 4%-34%, 10 min) to give (1R,2S,5S)- N-[1-cyano-2-oxo-2-pyrrolidin-1-yl-ethyl]-3-[(2S)-3,3-dimeth yl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (123 mg, 242 μmol, 31% yield, 98% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.51-9.29 (m, 2H), 5.99-5.83 (m, 1H), 4.41 (s, 1H), 4.32 (d, J = 8.8 Hz, 1H), 3.95-3.87 (m, 1H), 3.76-3.65 (m, 1H), 3.58-3.34 (m, 3H), 3.31-3.24 (m, 2H), 1.95-1.69 (m, 4H), 1.60-1.49 (m, 1H), 1.40-1.25 (m, 1H), 1.05-1.02 (m, 3H), 0.99 (s, 9H), 0.84(s, 3H). LC-MS (Method K): R _t = 2.056 min; MS (ESIpos): m/z = 500.3 [M+H] ⁺ . Preparation of CPD0278001, CPD0278002 Procedure for preparation of tert-butyl 4-(1-((tert-butoxycarbonyl)amino)-2-methoxy-2- oxoethylidene)piperidine-1-carboxylate To a mixture of methyl 2-((tert-butoxycarbonyl)amino)-2-(dimethoxyphosphoryl)acetat e (37.3 g, 0.125 mol, 1.00 eq) in dichloromethane (300 mL) was added 2,3,4,6,7,8,9,10-octahydropyrimido[1,2- a]azepine (28.6 g, 0.188 mol, 1.50 eq) at 0 °C. Tert-butyl 4-oxopiperidine-1-carboxylate (25.0 g, 0.125 mol, 1.00 eq) was added to the solution above. After stirring at 15 °C for 16 h, the mixture was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0~40% Ethyl acetate/Petroleum ether gradient @ 120 mL/min) to give tert-butyl 4-(1-((tert-butoxycarbonyl)amino)-2-methoxy-2-oxoethylidene) piperidine- 1-carboxylate (39.0 g, 0.105 mol, 84% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.57 (s, 1H), 3.61 (s, 3H), 3.37-3.33 (m, 4H), 2.37-2.23 (m, 4H), 1.40 (s, 18H). Procedure for preparation of tert-butyl 4-(1-((tert-butoxycarbonyl)amino)-2-methoxy-2- oxoethyl)piperidine-1-carboxylate To a mixture of tert-butyl 4-(1-((tert-butoxycarbonyl)amino)-2-methoxy-2-oxoethylidene) piperidine-1- carboxylate (5.00 g, 13.5 mmol, 1.00 eq) in methanol (50.0 mL) was added wet palladium on carbon (500 mg, 10% purity) at 15 °C. After stirring at 15°C for 16 h under hydrogen (15 psi) atmosphere, the mixture was filtered through a pad of celite. The filter cake was washed with methanol (10.0 mL × 2). The combined filtrate was concentrated to give tert-butyl 4-(1-((tert-butoxycarbonyl)amino)-2-methoxy- 2-oxoethyl)piperidine-1-carboxylate (5.00 g, 13.4 mmol, 99.5% yield) as colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.27 (d, J = 8.4 Hz, 1H), 4.00 -3.90 (m, 3H), 3.62 (s, 3H), 2.65-2.57 (m, 2H), 1.87-1.81 (m, 1H), 1.56-1.44 (m, 2H), 1.43-1.31 (m, 18H), 1.27-1.02 (m, 2H). Procedure for preparation of tert-butyl 4-(1-((tert-butoxycarbonyl)amino)-2-methoxy-2- oxoethyl)-2-oxopiperidine-1-carboxylate To a mixture of sodium periodate (4.59 g, 21.5 mmol, 2.00 eq) and ruthenium (IV) oxide hydrate (162 mg, 1.07 mmol, 0.10 eq) in water (80.0 mL) was added a solution of tert-butyl 4-(1-((tert- butoxycarbonyl)amino)-2-methoxy-2-oxoethyl)piperidine-1-carb oxylate (4.00 g, 10.7 mmol, 1.00 eq) in acetonitrile (40.0 mL) at 0 °C. After stirring at 15 °C for 16 h, the reaction mixture was filtered. The filter cake was washed with ethyl acetate (20.0 mL). The combined filtrate was quenched with sodium sulfite solid (10.0 g) and extracted with ethyl acetate (50.0 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ether gradient @ 65 mL/min) to give tert-butyl 4-(1-((tert-butoxycarbonyl)amino)-2- methoxy-2-oxoethyl)-2-oxopiperidine-1-carboxylate (2.60 g, 6.73 mmol, 62.6% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.38 (d, J = 8.0 Hz, 1H), 4.09-3.93 (m, 1H), 3.73-3.55 (m, 4H), 3.45- 3.35 (m, 1H), 2.42-2.20 (m, 3H), 1.88-1.74 (m, 1H), 1.62-1.45 (m, 1H), 1.44-1.30 (m, 18H). Procedure for preparation of methyl 2-amino-2-(2-oxopiperidin-4-yl)acetate - To a mixture of tert-butyl 4-(1-((tert-butoxycarbonyl)amino)-2-methoxy-2-oxoethyl)-2-ox opiperidine-1- carboxylate (2.60 g, 6.73 mmol, 1.00 eq) in dichloromethane (20.0 mL) was added trifluoroacetic acid (10 mL, 135 mmol,, 20.0 eq) at 0 °C. After stirring at 15 °C for 2 h, the mixture was concentrated to give methyl 2-amino-2-(2-oxopiperidin-4-yl)acetate (2.00 g, 6.66 mmol, 99% yield, trifluoroacetic acid salt) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.55-8.34 (m, 3H), 7.61 (s, 1H), 4.06 (s, 1H), 3.76 (s, 3H), 3.25-3.01 (m, 2H), 2.33-2.24 (m, 1H), 2.22-2.15 (m, 1H), 1.91-1.75 (m, 1H), 1.57-1.43 (m, 1H), 1.42-1.30 (m, 1H). Procedure for preparation of methyl 2-((tert-butoxycarbonyl)amino)-2-(2-oxopiperidin-4- yl)acetate To a mixture of methyl 2-amino-2-(2-oxopiperidin-4-yl)acetate (2.00 g, 6.66 mmol, 1.00 eq, trifluoroacetic acid salt) in a mixed solvent of dichloromethane (25.0 mL) and water (1.00 mL) was added saturated sodium bicarbonate (1.68 g, 19.98 mmol, 3.00 eq) and di-tert-butyl dicarbonate (2.18 g, 9.99 mmol, 1.50 eq) at 15 °C. After stirring at 15 °C for 16 h, the mixture was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% (Ethyl acetate: Methanol=10:1)/Petroleum ether gradient @ 30 mL/min) to give methyl 2-((tert-butoxycarbonyl)amino)-2-(2-oxopiperidin-4-yl)acetat e (1.30 g, 4.54 mmol, 68.2% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.48 (s, 1H), 7.37 (t, J = 7.6 Hz, 1H), 4.07-3.90 (m, 1H), 3.64 (s, 3H), 3.21-2.93 (m, 2H), 2.23-1.85 (m, 3H), 1.73-1.61 (m, 1H), 1.48-1.28 (m, 10H). Procedure for preparation of methyl 2-((tert-butoxycarbonyl)amino)-2-(2-thioxopiperidin-4- yl)acetate A mixture of methyl 2-((tert-butoxycarbonyl)amino)-2-(2-oxopiperidin-4-yl)acetat e (1.30 g, 4.54 mmol, 1.00 eq) and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (1.10 g, 2.72 mmol, 0.600 eq) in toluene (20.0 mL) was stirred at 100 °C for 1 h. After concentration, the residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~35% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give methyl 2-((tert-butoxycarbonyl)amino)-2- (2-thioxopiperidin-4-yl)acetate (1.00 g, 3.31 mmol, 73% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.16 (s, 1H), 7.45-7.34 (m, 1H), 4.01-3.93 (m, 1H), 3.65 (s, 3H), 3.31-3.25 (m, 1H), 3.20-3.04 (m, 1H), 2.79-2.69 (m, 1H), 2.35-2.45 (m, 1H), 2.16-2.01 (m, 1H), 1.79- 1.68 (m, 1H), 1.55-1.30 (m, 10H). Procedure for preparation of methyl 2-((tert-butoxycarbonyl)amino)-2-(6-(methylthio)-2,3,4,5- tetrahydropyridin-4-yl)acetate To a mixture of methyl 2-((tert-butoxycarbonyl)amino)-2-(2-thioxopiperidin-4-yl)ace tate (1.00 g, 3.31 mmol, 1.00 eq) in tetrahydrofuran (10.0 mL) were added potassium carbonate (0.914 g, 6.61 mmol, 2.00 eq) and methyl iodide (0.939 g, 6.61 mmol, 2.00 eq) at 15 °C. After stirring at 15 °C for 4 h, the reaction mixture was filtered. The filter cake was washed with ethyl acetate (2.00 mL × 2). The combined filtrate was concentrated to give methyl 2-((tert-butoxycarbonyl)amino)-2-(6-(methylthio)-2,3,4,5- tetrahydropyridin-4-yl)acetate (1.00 g, crude) as yellow oil. Procedure for preparation of methyl 2-((tert-butoxycarbonyl)amino)-2-(5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyridin-7-yl)acetate A mixture of methyl 2-((tert-butoxycarbonyl)amino)-2-(6-(methylthio)-2,3,4,5-tet rahydropyridin-4- yl)acetate (1.00 g, 3.16 mmol, 1.00 eq) and formohydrazide (208 mg, 3.48 mmol, 1.10 eq) in methanol (15.0 mL) was stirred at 75 °C for 16 h. After concentration, the residue was purified by revered phase column (C18, 105 g, 15% of ACN in water with 0.1% FA) to give methyl 2-((tert-butoxycarbonyl)amino)- 2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)ace tate (840 mg, 2.36 mmol, 75% yield, formic acid salt) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.34 (s, 1H), 8.13 (s, 1H), 756-7.44 (m, 1H), 4.21-4.06 (m, 2H), 3.90- 3.75 (m, 1H), 3.67 (s, 3H), 2.96-2.84 (m, 1H), 2.71-2.61 (m, 1H), 2.32-2.18 (m, 1H), 2.02-1.90 (m, 1H), 1.78-1.61 (m, 1H), 1.40 (s, 9H). Procedure for preparation of tert-butyl (2-amino-2-oxo-1-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyridin-7-yl)ethyl)carbamate A mixture of methyl 2-((tert-butoxycarbonyl)amino)-2-(5,6,7,8-tetrahydro-[1,2,4] triazolo[4,3-a]pyridin-7- yl)acetate (840 mg, 2.71 mmol, 1.00 eq, formic acid salt) and ammonia (10 M in methanol, 20 mL, 73.9 eq) was stirred at 25 °C for 16 h. The mixture was concentrated to give tert-butyl (2-amino-2-oxo-1- (5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)ethyl )carbamate (700 mg, 2.37 mmol, 88% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.34 (s, 1H), 7.50-7.40 (m, 1H), 7.24-7.14 (m, 1H), 7.06-6.85 (m, 1H), 4.23-4.12 (m, 1H), 4.05-3.92 (m, 1H), 3.86-3.74 (m, 1H), 2.91-2.80 (m, 1H), 2.61-2.53 (m, 1H), 2.29-2.06 (m, 1H), 2.04-1.89 (m, 1H), 1.71-1.51 (m, 1H), 1.39 (s, 9H). Procedure for preparation of 2-amino-2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin- 7- yl)acetamide To a mixture of tert-butyl (2-amino-2-oxo-1-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]p yridin-7- yl)ethyl)carbamate (500 mg, 1.69 mmol, 1.00 eq) in dioxane (10.0 mL) was added hydrochloric acid (4 M in dioxane, 10 mL, 23.6 eq) at 0 °C. After stirring at 15 °C for 1 h, the reaction mixture was concentrated to give 2-amino-2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin- 7-yl)acetamide (400 mg, crude, hydrochloric acid salt) as a white solid. Procedure for preparation of (1R,2S,5S)-N-(2-amino-2-oxo-1-(5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyridin-7-yl)ethyl)-3-((S)-3,3-dimethy l-2-(2,2,2-trifluoroacetamido)butanoyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide - To a mixture of (1R,2S,5S)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)b utanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (629 mg, 1.73 mmol, 1.00 eq) in N,N-dimethylformamide (20.0 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexaflu orophosphate (984 mg, 2.59 mmol, 1.50 eq) and N,N-diisopropylethylamine (1.20 mL, 6.91 mmol, 4.00 eq) at 0 °C. After stirring for 5 min, 2-amino-2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin- 7-yl)acetamide (400 mg, crude, hydrochloric acid salt) was added at 0 °C. After stirring at 15 °C for 16 h, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*40 mm* 15 μm; mobile phase: [water(FA)-ACN]; B%: 20%-50%,10 min) to give peak1 (1R,2S,5S)-N-(2-amino-2-oxo-1-(5,6,7,8-tetrahydro-[1,2,4]tri azolo[4,3-a]pyridin-7-yl)ethyl)-3-((S)-3,3- dimethyl-2-(2,2,2-trifluoroacetamido) butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxami de (175 mg, 0.303 mmol, 17.6% yield, 94% purity) and peak2 (1R,2S,5S)-N-(2-amino-2-oxo-1-(5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)ethyl)-3-((S)- 3,3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ] hexane-2-carboxamide (410 mg, 0.719 mmol, 42% yield, 95% purity) as a yellow solid. LC-MS (Method C): R _t = 0.750 min; MS (ESIpos): m/z = 542.3 [M+H] ⁺ . LC-MS (Method C): R _t = 0.481 min; MS (ESIpos): m/z = 542.3 [M+H] ⁺ . Procedure for preparation of CPD0278001 - (1R,2S,5S)-N-(cyano(5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyridin-7-yl)methyl)-3-((S)-3,3-dimeth yl-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxamide - To a mixture of (1R,2S,5S)-N-(2-amino-2-oxo-1-(5,6,7,8-tetrahydro-[1,2,4]tri azolo[4,3-a]pyridin-7- yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)bu tanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (175 mg, 0.323 mmol, 1.00 eq) in dichloromethane (10.0 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (231 mg, 0.969 mmol, 3.00 eq) at 15 °C. After stirring at 15 °C for 2 h, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 μm; mobile phase: [water(FA)- ACN];B%: 27%-57%, 7 min) to give (1R,2S,5S)-N-(cyano(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyridin-7-yl)methyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluor oacetamido)butanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (129 mg, 0.227 mol, 70% yield, 92% purity) (mixture of 2 diastereoisomers) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.44-9.31 (m, 1H), 9.21-9.11 (m, 1H), 8.46-8.40 (m, 1H), 5.18-5.04 (m, 1H), 4.45-4.35 (m, 1H), 4.28-4.15 (m, 2H), 3.92-3.81 (m, 2H), 3.75-3.69 (m, 1H), 3.21-3.06 (m, 1H), 2.78-2.69 (m, 0.5 H), 2.48-2.35 (m, 1.5 H), 2.47-2.09 (m, 1H), 1.95-1.75 (m, 1H), 1.63-1.55 (m, 1H), 1.41-1.31 (m, 1H), 1.09-0.83 (m, 15H). LC-MS (Method C): R _t = 0.805 min; MS (ESIpos): m/z = 524.2 [M+H] ⁺ . HPLC (Method K): R _t = 1.671 min; purity: 92%. SFC: dr = 49: 51. Procedure for preparation of CPD0278002 - (1R,2S,5S)-N-(cyano(5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyridin-7-yl)methyl)-3-((S)-3,3-dimeth yl-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxamide - To a mixture of (1R,2S,5S)-N-(2-amino-2-oxo-1-(5,6,7,8-tetrahydro-[1,2,4]tri azolo[4,3-a]pyridin-7- yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)bu tanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (200 mg, 0.369 mmol, 1.00 eq) in dichloromethane (10.0 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (264 mg, 1.11 mmol, 3.00 eq) at 15 °C. After stirring at 15 °C for 2 h, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC(column: Unisil 3-100 C18 Ultra 150*50mm*3 μm; mobile phase: [water(FA)- ACN]; B%: 27%-57%, 7 min) to give (1R,2S,5S)-N-(cyano(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyridin-7-yl)methyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluor oacetamido)butanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (87.7 mg, 0.154 mol, 42% yield, 92% purity) ((mixture of 4 diastereoisomers) ) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.45-9.38 (m, 1H), 9.11-9.03 (m, 1H), 8.51-8.40 (m, 1H), 5.08-4.89 (m, 1H), 4.46-4.35 (m, 1H), 4.31-4.17 (m, 2H), 4.01-3.63 (m, 3H), 3.20-3.09 (m, 1H), 2.48-2.38 (m, 2 H), 2.23-2.11 (m, 1H), 1.90-1.69 (m, 1H), 1.63-1.53 (m, 1H), 1.41-1.32 (m, 1H), 1.13-0.84 (m, 15H). LC-MS (Method C): R _t = 0.800 min; MS (ESIpos): m/z = 524.2 [M+H] ⁺ . HPLC (Method K): R _t = 2.191 min; purity: 92%. SFC: dr = 12: 9: 39: 39. Preparation of CPD0186844 Procedure for preparation of 1-(3-bromo-5-vinyl-4-pyridyl)-N-methoxy-methanimine To a solution of 3,5-dibromopyridine-4-carbaldehyde (27.0 g, 102 mmol, 1.00 eq) in 1,2- dimethoxyethane (300 mL) and water (75.0 mL) were added potassium vinyltrifluoroborate (13.5 g, 101 mmol, 1 eq) and cesium carbonate (69.7 g, 214 mmol, 2.10 eq) and [1,1- bis(diphenylphosphino)ferrocene]palladium(II) chloride (832 mg, 1.02 mmol, 0.01 eq) at 20 °C. After stirring at 20 °C for 24 h, TLC showed some of the dibromide remained. Another batch of potassium vinyltrifluoroborate (8.00 g), cesium carbonate (35.0 g) and [1,1- bis(diphenylphosphino)ferrocene]palladium(II) chloride (450 mg) were added to the reaction mixture. The reaction mixture was stirred at 20 °C for another 14 h, followed by O-methylhydroxylamine (38.3 g, 459 mmol, 4.50 eq, hydrochloride). After stirring at 40 °C for 5 h, the reaction mixture was cooled to ambient temperature. The reaction mixture was extracted with ethyl acetate (150 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 0/1) to give 1-(3-bromo-5-vinyl-4-pyridyl)-N-methoxy-methanimine (11.2 g, crude) as colorless oil. Procedure for preparation of 4-bromo-2,6-naphthyridine A mixture of 1-(3-bromo-5-vinyl-4-pyridyl)-N-methoxy-methanimine (11.2 g, 46.3 mmol, 1.00 eq) in diphenyl ether (100 mL) was stirred at 200 °C for 2 h. The reaction mixture was cooled to 20 °C and diluted with hydrogen chloride (1 M in water, 200 mL). The mixture was washed with petroleum ether/ethyl acetate (v/v = 10/1, 150 mL × 3). Saturated sodium carbonate solution was added to the aqueous phase to adjust pH to 9-10. The mixture was extracted with ethyl acetate (150 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 0/1) to give 4-bromo-2,6-naphthyridine (1.60 g, 7.65 mmol, 17% yield) as a yellow solid. Procedure for preparation of methyl 2-(benzhydrylideneamino)-2-(2,6-naphthyridin-4-yl)acetate To a solution of 4-bromo-2,6-naphthyridine (200 mg, 957 μmol, 1.00 eq), methyl 2- (benzhydrylideneamino)acetate (364 mg, 1.44 mmol, 1.50 eq) and potassium phosphate (610 mg, 2.87 mmol, 3.00 eq) in N,N-dimethylformamide (5.00 mL) was added chloro[(tri-tert-butylphosphine)-2-(2- aminobiphenyl)]palladium (II) (25.0 mg, 48.8 μmol, 0.051 eq) at 20 °C under nitrogen atmosphere. After stirring at 90 °C for 16 h under nitrogen. (The Buchwald reaction is not suitable for scale, so carried out the reaction (8 batches) in parallel). The 8 batches reaction mixture were combined and filtered through a pad of celite. The filtrate was concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 0/1, then ethyl acetate/methanol = 10/1) to give methyl 2-(benzhydrylideneamino)-2-(2,6-naphthyridin-4-yl)acetate (2.50 g, 6.55 mmol, 86% yield) as brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.99 (s, 1H), 9.27 (s, 1H), 8.76-8.74 (m, 1H), 8.45 (s, 1H), 7.81-7.78 (m, 1H), 7.71 (d, J = 7.2 Hz, 2H), 7.51-7.49 (m, 3H), 7.40 (t, J = 7.2 Hz, 1H), 7.34-7.31 (m, 2H), 7.13-7.12 (m, 2H), 5.69 (s, 1H), 3.69 (s, 3H). Procedure for preparation of 2-(benzhydrylideneamino)-2-(2,6-naphthyridin-4-yl)acetamide A mixture of methyl 2-(benzhydrylideneamino)-2-(2,6-naphthyridin-4-yl)acetate (2.50 g, 6.55 mmol, 1.00 eq) in ammonia (7 M in methanol, 50 mL, 53.4 eq) was stirred at 20 °C for 16 h. The reaction mixture was triturated with tert-butyl methyl ether (30.0 mL) and filtered. The filter cake was washed with methanol (10.0 mL) and dried under vacuum to give 2-(benzhydrylideneamino)-2-(2,6- naphthyridin-4-yl)acetamide (2.00 g, 5.46 mmol, 83% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.75 (s, 1H), 9.34 (s, 1H), 7.71 (d, J = 5.6 Hz, 1H), 8.34 (s, 1H), 8.01 (d, J = 5.6 Hz, 1H), 7.70 (d, J = 7.6 Hz, 2H), 7.58-7.39 (m, 8H), 7.02 (d, J = 6.4 Hz, 2H), 5.42 (s, 1H). Procedure for preparation of 2-amino-2-(2,6-naphthyridin-4-yl)acetamide To a solution of 2-(benzhydrylideneamino)-2-(2,6-naphthyridin-4-yl)acetamide (2.00 g, 5.46 mmol, 1.00 eq) in a mixed solvent of dichloromethane (15.0 mL) and methanol (15.0 mL) was added hydrogen chloride (1 M in water, 30.0 mL, 5.50 eq). After stirring at 20 °C for 1 h, the reaction mixture was washed with dichloromethane (10.0 mL × 3). The aqueous phase was concentrated under vacuum to give 2- amino-2-(2,6-naphthyridin-4-yl)acetamide (0.75 g, 3.14 mmol, 58% yield, crude purity, hydrochloride) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.07 (s, 1H), 9.66 (s, 1H), 9.09-9.04 (m, 2H), 8.90-8.88 (m, 2H), 8.34 (d, J = 6.0 Hz, 1H), 8.11 (s, 1H), 7.81 (s, 1H), 5.95-5.93 (m, 1H). Procedure for preparation of (1R,2S,5S)-N-[2-amino-1-(2,6-naphthyridin-4-yl)-2-oxo-ethyl] -3- [(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl] -6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (250 mg, 686 μmol, 1.00 eq) in N,N-dimethylformamide (10 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (392 mg, 1.03 mmol, 1.50 eq) and N,N-diisopropylethylamine (275 mg, 2.13 mmol, 371 μL, 3.10 eq) at 0 °C. The mixture was stirred at 0 °C for 10 min,, and then 2-amino-2-(2,6-naphthyridin-4-yl)acetamide (150 mg, 742 μmol, 1.08 eq) was added. After stirring at 20 °C for 14 h, the reaction mixture was poured into ice-water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give residue. The residue was purified by prep-TLC (ethyl acetate/methanol = 10/1) to give (1R,2S,5S)-N-[2-amino-1- (2,6-naphthyridin-4-yl)-2-oxo-ethyl]-3-[(2S)-3,3-dimethyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (300 mg, 547 μmol, 80% yield) as a yellow solid. LC-MS (Method C): R _t = 0.726 min and 0.738 min; MS (ESIpos): m/z = 549.3 [M+H] ⁺ . Procedure for preparation of CPD0186844 - (1R,2S,5S)-N-[cyano-(3-methyl-2H-indazol-6- yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-[2-amino-1-(2,6-naphthyridin-4-yl)-2-oxo-ethyl] -3-[(2S)-3,3-dimethyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabi cyclo[3.1.0]hexane-2-carboxamide (300 mg, 547 μmol, 1.00 eq) in dichloromethane (8.00 mL) was added Burgess reagent (391 mg, 1.64 mmol, 3.00 eq) at 20 °C. After stirring at 20 °C for 14 h, the reaction mixture was diluted with saturated sodium bicarbonate aqueous solution (50.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 0/1) to give an impure product. The impure product was combined with EW33008-138-P1 and purified by prep-HPLC (column: Phenomenex Synergi C18 150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 33%-66%,11 min) to give (1R,2S,5S)-N-[cyano(2,6-naphthyridin-4-yl)methyl]-3- [(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl) amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (105 mg, 196 μmol, 99% purity) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.69 (d, J = 7.6 Hz, 0.3H), 9.59 (d, J = 7.2 Hz, 0.3H), 9.55-9.51 (m, 2H), 9.40-9.33 (m, 0.6H), 8.88-8.82 (m, 2H), 8.13 (t, J = 5.6 Hz, 1H), 7.13-7.07 (m, 1H), 4.38-4.34 (m, 1H), 4.21 (d, J = 11.6 Hz, 1H), 3.94-3.90 (m, 1H), 3.72-3.64 (m, 1H), 1.62-1.54 (m, 1H), 1.35-1.13 (m, 1H), 1.03-0.80 (m, 15H). LC-MS (Method C): R _t = 0.780 min; MS (ESIpos): m/z = 531.3 [M+H] ⁺ . HPLC (Method K): R _t = 2.135 min and 2.162 min. SFC: dr: 52: 48. Preparation of CPD0186845 and CPD0278796 Procedure for preparation of CPD018684 and CPD0278796 - (2S,4S)-N-[cyano(1,6-naphthyridin- 8-yl)methyl]-1-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl) amino]butanoyl]-4-propyl-pyrrolidine- 2-carboxamide To a solution of 2-amino-2-(1,6-naphthyridin-8-yl)acetonitrile (3.32 g, 18.0 mmol, 1.00 eq) and (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (6.57 g, 18.0 mmol, 1.00 eq) in dichloromethane (60.0 mL) were added diisopropylethylamine (6.99 g, 54.1 mmol, 9.42 mL, 3.00 eq) and O-(7-azabenzotriazol-1- yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (7.54 g, 19.8 mmol, 1.10 eq). After stirring at 25 °C for 12 h, the solvent was removed under reduced pressure to give a residue. The residue was partitioned between ethyl acetate (400 mL) and saturated ammonium chloride solution (400 mL). The separated aqueous phase was extracted with ethyl acetate (200 mL × 2). The combined extracts were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was purified by flash column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 3: 1 to 0: 1) followed by flash column chromatography (SiO ₂ , Dichloromethane: Tetrahydrofuran = 0: 1 to 5: 1) to give (1R,2S,5S)-N-[cyano(1,6-naphthyridin-8-yl)methyl]-3-[(2S)-3, 3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0] hexane-2- carboxamide (19.3 g, 35.9 mmol, 64% yield) as a white solid and (1R,2S,5S)-N-[cyano-(5-oxo-6H-1,6- naphthyridin-8-yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-tri fluoroacetyl)amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (490 mg, 889 μmol, 2% yield) as a white solid. CPD0186845 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.64-9.44 (m, 2H), 9.39-9.31 (m, 1H), 9.28-9.20 (m, 1H), 8.96 (d, J = 7.6 Hz, 1H), 8.72-8.67 (m, 1H), 7.88-7.81 (m, 1H), 6.87-6.81 (m, 1H), 4.44-4.32 (m, 2H), 3.95-3.89 (m, 1H), 3.75-3.68 (m, 1H), 2.08 (s, 1H), 1.60-1.48 (m, 1H), 1.48-1.40 (m, 1H), 1.28-1.20 (m, 1H), 1.08-0.88 (m, 12H), 0.88-0.81 (m, 3H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ = 171.22, 171.13, 167.96, 157.37 (q, J = 36.9 Hz, 1C), 155.75, 155.68, 155.44, 155.33, 146.94, 146.94, 145.61, 145.34, 137.22, 137.17, 125.47, 125.24, 124.32, 124.29, 123.47, 123.37, 118.49, 118.39, 117.73, 117.73, 114.87, 114.87, 60.47, 60.36, 58.85, 58.79, 48.07, 47.99, 38.81, 38.73, 35.06, 34.96, 30.80, 30.74, 27.67, 27.56, 26.76, 26.66, 26.28, 26.24, 19.27, 19.22, 12.78, 12.73. LC-MS (Method L): Rt = 9.998 min; MS (ESIpos): m/z = 531.3 [M+H] ⁺ . SFC : dr = 54: 46. CPD0278796 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.00-11.64 (m, 1H), 9.52-9.24 (m, 1H), 9.16 (d, J = 7.6 Hz, 1H), 9.12 (d, J = 7.6 Hz, 1H), 9.08-9.00 (m, 1H), 8.58-8.51 (m, 1H), 7.72 (d, J = 10.8 Hz, 1H), 7.65-7.57 (m, 1H), 6.48-6.24 (m, 1H), 4.36 (d, J = 9.2 Hz, 1H), 4.32 (d, J = 12.0 Hz, 1H), 3.92-3.87 (m, 1H), 3.76-3.69 (m, 1H), 1.54-1.48 (m, 1H), 1.40 (d, J = 7.6 Hz, 1H), 1.20 (d, J = 7.6 Hz, 1H), 1.08-0.92 (m, 12H), 0.84-0.80 (m, 3H). LC-MS (Method C): Rt = 0.710 min; MS (ESIpos): m/z = 547.2 [M+H] ⁺ . SFC: dr = 46: 53. Preparation of CPD0188253 Procedure for preparation of Compound CPD0188253 - (3S,3aS,6aR)-N-[cyano(1,6-naphthyridin- 8-yl)methyl]-2-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl) amino]butanoyl]-3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]pyrrole-3-carboxamide To a mixture of (3S,3aS,6aR)-2-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl) amino]butanoyl]- 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (329 mg, 903 umol, 1.00 eq) in N,N- dimethylformamide (1.00 mL) were added N-ethyl-N-isopropyl-propan-2-amine (233 mg, 1.81 mmol, 0.314 mL, 2.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (412 mg, 1.08 mmol, 1.20 eq). After stirring at 25 °C for 10 min, 2-amino-2-(1,6-naphthyridin-8- yl)acetonitrile (150 mg, 0.814 mmol, 9.01e-1 eq) was added to the reaction mixture above. The resulting mixture was stirred at 25 °C for 16 h. The mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)- ACN];B%: 36%-66%,2min), to give (3S,3aS,6aR)-N-[cyano(1,6-naphthyridin-8-yl)methyl]-2-[(2S)- 3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-3,3a,4,5, 6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3- carboxamide (135 mg, 0.251 mmol, 28% yield, 99% purity) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.51 (d, J = 2.0 Hz, 1H), 9.49-9.42 (m, 1H), 9.33-9.27 (m, 0.5H), 9.26-9.18 (m, 1.5H), 8.95 (s, 0.5H), 8.91 (s, 0.5H), 8.73-8.67 (m, 1H), 7.89-7.80 (m, 1H), 6.88-6.83 (m, 0.5H), 6.82-6.76 (m, 0.5H), 4.54-4.48 (m, 0.5H), 4.48-4.43 (m, 0.5H), 4.31 (d, J = 4.4 Hz, 1H), 4.24 (d, J = 4.4 Hz, 1H), 3.85-3.75 (m, 1H), 3.67-3.58 (m, 1H), 1.92-1.73 (m, 2H), 1.72-1.46 (m, 5H), 1.42-1.31 (m, 1H), 1.05-0.93 (m, 6H), 0.86 (s, 3H). LC-MS (Method C): Rt = 0.862 min; MS (ESIpos): m/z = 531.4 [M+H] ⁺ . SFC: dr = 50: 50. Preparation of CPD0188254 Procedure for preparation of 4-bromo-1-methyl-quinolin-2-one To a solution of 4-hydroxy-1-methyl-quinolin-2-one (23.0 g, 131 mmol, 1.00 eq) and phosphorus (V) oxide (55.9 g, 394 mmol, 24.0 mL, 3.00 eq) in toluene (500 mL) was added tetrabutylammonium;bromide (50.8 g, 157 mmol, 1.20 eq). After stirring at 100 °C for 2 h, the mixture was added to saturated sodium carbonate solution (1000 mL). The solution was extracted with ethyl acetate (2000 mL × 2). The combined organic layers were washed with brine (2000 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 1/1) to give 4-bromo-1-methyl- quinolin-2-one (15.0 g, 63.0 mmol, 24% yield) as a yellow solid. Procedure for preparation of 2-(benzhydrylideneamino) -2-(1-methyl-2-oxo-4-quinolyl) acetate To a solution of 4-bromo-1-methyl-quinolin-2-one (1.00 g, 4.20 mmol, 1.00 eq) and methyl 2- (benzhydrylideneamino) acetate (1.06 g, 4.20 mmol, 1.00 eq) in N,N-dimethylformamide (15.0 mL) were added potassium phosphate (2.67 g, 12.6 mmol, 3.00 eq) and [2-(2-aminophenyl) phenyl]-chloro- palladium;tritert-butylphosphane (430 mg, 840 μmol, 0.2 eq) under nitrogen atmosphere. After stirring at 90 °C for 3 h, the reaction mixture was added to water (50 mL). The solution was extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was triturated with ethyl acetate (10.0 mL) to give methyl 2-(benzhydrylideneamino) -2-(1-methyl-2-oxo-4- quinolyl) acetate (7.00 g, 7.67 mmol, 10% yield, 63% purity) as a white solid LC-MS (Method C): R _t = 0.973 min; MS (ESIpos): m/z = 220.0 [M+H] ⁺ . Procedure for preparation of 2-(benzhydrylideneamino) -2-(1-methyl-2-oxo-4-quinolyl) acetamide To a solution of methyl 2-(benzhydrylideneamino) -2-(1-methyl-2-oxo-4-quinolyl) acetate (6.50 g, 15.8 mmol, 1.00 eq) in ammonia gas/ Methanol (7 M, 260 mL, 115 eq) was added 3, 4, 6, 7, 8, 9-hexahydro- 2H-pyrimido[1, 2-a]pyrimidine (6.61 g, 47.5 mmol, 3.00 eq). After stirring at 40 °C for 12 h, precipitation was filtered. The filter cake was concentrated under vacuum to give 2-(benzhydrylideneamino)-2-(1- methyl-2-oxo-4-quinolyl) acetamide (4.50 g, 11.4 mmol, 72% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.86 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 7.2 Hz, 2H), 7.66-7.56 (m, 2H), 7.54-7.39 (m, 8H), 7.20 (t, J = 7.2 Hz, 1H), 7.13-7.06 (m, 2H), 6.62 (s, 1H), 5.17 (s, 1H), 3.60 (s, 3H). Procedure for preparation of 2-amino-2-(1-methyl-2-oxo-4-quinolyl) acetamide To a solution of 2-(benzhydrylideneamino)-2-(1-methyl-2-oxo-4-quinolyl) acetamide (4.50 g, 11.4 mmol, 1.00 eq) in methanol (30.0 mL) and dichloromethane (30.0 mL) was added hydrochloric acid (1 M, 15.6 mL, 1.38 eq). After stirring at 25 °C for 1 h, the mixture was filtered and the filter cake was concentrated under vacuum to give a residue. The residue was triturated with ethyl acetate (10.0 mL) to give 2-amino- 2-(1-methyl-2-oxo-4-quinolyl) acetamide (2.63 g, 11.4 mmol, 100% yield, 100% purity) as a white solid ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.06 (s, 2H), 8.27-8.08 (m, 2H), 7.84-7.55 (m, 3H), 7.35 (t, J = 7.8 Hz, 1H), 6.87 (s, 1H), 5.47 (s, 1H), 3.64 (s, 3H). Procedure for preparation of (3S, 3aS, 6aR) -N-[2-amino-1-(1-methyl-2-oxo-4-quinolyl) -2-oxo- ethyl]-2-[(2S) -3, 3-dimethyl-2-[(2, 2, 2-trifluoroacetyl) amino]butanoyl]-3, 3a, 4, 5, 6, 6a- hexahydro-1H-cyclopenta[c]pyrrole-3-carboxamide To a solution of (3S, 3aS, 6aR) -2-[(2S) -3, 3-dimethyl-2-[(2, 2, 2-trifluoroacetyl)amino]butanoyl]-3, 3a, 4, 5, 6, 6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (1.00 g, 2.74 mmol, 1.00 eq) and 2- amino-2-(1-methyl-2-oxo-4-quinolyl) acetamide (762 mg, 3.29 mmol, 1.20 eq) in N, N- dimethylformamide (20.0 mL) were added O-(7-azabenzotriazol-1-yl) -N, N, N, N-tetramethyluronium hexafluorophosphate (1.57 g, 4.12 mmol, 1.50 eq) and N,N-diisopropylethylamine (1.06 g, 8.23 mmol, 1.43 mL, 3.00 eq). After stirring at 25 °C for 12 h, the mixture was added to water (100 mL). The solution was extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by reversed phase (Instrument: 60 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-20 min 0-60% B; flow 50 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give (3S, 3aS, 6aR) -N-[2- amino-1-(1-methyl-2-oxo-4-quinolyl) -2-oxo-ethyl]-2-[(2S)-3, 3-dimethyl-2-[(2, 2, 2-trifluoroacetyl) amino]butanoyl]-3, 3a, 4, 5, 6, 6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxamide (1.00 g, 1.73 mmol, 63% yield, 100% purity) as a white solid. LC-MS (Method C): R _t = 0.882 min; MS (ESIpos): m/z = 220.0 [M+H] ⁺ . Procedure for preparation of CPD0188254 - (3S, 3aS, 6aR) -N-[cyano-(1-methyl-2-oxo-4-quinolyl) methyl]-2-[(2S) -3, 3-dimethyl-2-[(2, 2, 2-trifluoroacetyl) amino]butanoyl]-3, 3a, 4, 5, 6, 6a- hexahydro-1H-cyclopenta[c]pyrrole-3-carboxamide To a solution of (3S,3aS,6aR)-N-[2-amino-1-(1-methyl-2-oxo-4-quinolyl)-2-oxo- ethyl]-2-[(2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-3,3a,4,5, 6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3- carboxamide (1.00 g, 1.73 mmol, 1.00 eq) in dichloromethane (15.0 mL) was added methoxycarbonyl- (triethylammonio) sulfonyl-azanide (1.24 g, 5.19 mmol, 3.00 eq). After stirring at 20 °C for 15 h, the reaction mixture was concentrated under vacuum to give a residue. The residue was purified by prep- HPLC (column: Phenomenex luna C18150 × 40 mmx 15 μm; mobile phase: [water (FA) -ACN]; B%: 43%-73%, 10 min) to give (3S,3aS,6aR)-N-[cyano-(1-methyl-2-oxo-4-quinolyl)methyl]-2-[ (2S)-3,3- dimethyl-2-[(2, 2, 2-trifluoroacetyl) amino]butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrr ole- 3-carboxamide (902 mg, 1.61 mmol, 93% yield, 100% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.69-9.30 (m, 1H), 7.78-7.67 (m, 2H), 7.66-7.59 (m, 1H), 7.39-7.18 (m, 1H), 6.88-6.80 (m, 1H), 6.73 (s, 1H), 4.49 (d, J = 2.4 Hz, 1H), 4.15-4.06 (m, 1H), 3.84 (td, J = 10.4, 6.8 Hz, 1H), 3.65 (d, J = 1.0 Hz, 4H), 3.30 (s, 2H), 3.17 (d, J = 5.2 Hz, 1H), 2.83-2.69 (m, 1H), 2.44- 2.36 (m, 1H), 1.89-1.30 (m, 7H), 1.00 (s, 8H), 0.98-0.90 (m, 1H). LC-MS (Method C): R _t = 0.852 min; MS (ESIpos): m/z = 220.0 [M+H] ⁺ . Preparation of CPD0188256 Procedure for preparation of 2,2-dimethyl-N-(4-pyridyl)propanamide To a solution of pyridin-4-amine (17.6 g, 187 mmol, 31.4 mL, 1.00 eq) in dichloromethane (200 mL) were added dropwise 2,2-dimethylpropanoyl chloride (27.1 g, 224 mmol, 27.6 mL, 1.20 eq) and triethylamine (56.8 g, 561 mmol, 78.1 mL, 3.00 eq). After stirring at 25 °C for 12 h, the reaction mixture was partitioned between dichloromethane (100 mL) and water (200 mL). The separated aqueous phase was extracted with dichloromethane (100 mL × 2). The combined extracts were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was purified by flash column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 10: 1 to 5: 1) to afford 2,2-dimethyl-N-(4-pyridyl)propanamide (23.0 g, 116 mmol, 62% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.58-8.34 (m, 2H), 7.51 (d, J = 5.3 Hz, 2H), 1.45-1.17 (m, 9H). Procedure for preparation of 1,6-naphthyridine To a solution of 2,2-dimethyl-N-(4-pyridyl)propanamide (19.0 g, 107 mmol, 1.00 eq) in tetrahydrofuran (400 mL) was added n-butyllithium (2.5 M, 107 mL, 2.50 eq) dropwise at -70 °C over a period of 5 min under nitrogen. The reaction mixture was warmed to 0 °C and stirred at 0 °C for 3 h. The reaction mixture was cooled to -70 °C, (E)-3-(dimethylamino)prop-2-enal (11.6 g, 117 mmol, 11.7 mL, 1.10 eq) was dropwise added to the reaction mixture. The reaction mixture was stirred at -70 °C for 1 h, slowly warmed to 0 °C, and stirred at 0 °C for 2 h. Hydrochloric acid (4 M, 200 mL) was added to the reaction mixture above. The aqueous layer was separated and stirred at 90 °C for 3 h. The reaction mixture was cooled to 25 °C. The pH was adjusted to 8 with potassium carbonate (50.0 g). The resulting mixture was extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine (500 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 3/1 to 0/1) to give 1,6-naphthyridine (4.00 g, 27.7 mmol, 26% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.30 (d, J = 0.8 Hz, 3H), 9.11 (dd, J = 4.4, 1.6 Hz, 3H), 8.77 (d, J = 6.0 Hz, 3H), 8.34-8.28 (m, 3H), 7.94 (d, J = 6.0 Hz, 3H), 7.61-7.46 (m, 6H). Procedure for preparation of 8-bromo-1,6-naphthyridine To a solution of 1,6-naphthyridine (4.00 g, 30.7 mmol, 1.00 eq) in acetic acid (40.0 mL) was added bromine (2.50 g, 15.4 mmol, 792 μL, 0.50 eq). After stirring at 80 °C for 12 h, the reaction mixture was cooled to room temperature, poured into water (200 mL). Saturated sodium bicarbonate solution was added to the solution above to adjust pH = 8. The solution was extracted with ethyl acetate (100 mL × 3). The combined extracts were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was purified by flash column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 3: 1 to 0: 1) to afford 8-bromo-1,6-naphthyridine (2.00 g, 8.61 mmol, 28.0% yield) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.28-9.16 (m, 2H), 9.00 (s, 1H), 8.33 (dd, J = 8.4, 1.6 Hz, 1H), 7.63 (dd, J = 8.4, 4.4 Hz, 1H). Procedure for preparation of ethyl 3-(1,6-naphthyridin-8-yl)prop-2-enoate To a solution of 8-bromo-1,6-naphthyridine (2.00 g, 9.57 mmol, 1.00 eq), ethyl 3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)prop-2-enoate (2.60 g, 11.5 mmol, 1.20 eq) and potassium phosphate (4.06 g, 19.1 mmol, 2.00 eq) in a mixed solvent of tetrahydrofuran (40.0 mL) and water (10.0 mL) was added tetrakis[triphenylphosphine]palladium(0) (1.11 g, 957 μmol, 0.10 eq) under nitrogen atmosphere. After stirring at 80 °C for 2 h, the reaction mixture was cooled to room temperature and partitioned between ethyl acetate (100 mL) and water (100 mL). The separated aqueous phase was extracted with ethyl acetate (50 mL × 2). The combined extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was purified by flash column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 3: 0 to 0: 1) to afford ethyl 3-(1,6- naphthyridin-8-yl)prop-2-enoate (1.20 g, 4.21 mmol, 44% yield) as brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.30-9.10 (m, 2H), 8.98 (s, 1H), 8.58 (d, J = 16.0 Hz, 1H), 8.34 (dd, J = 8.4, 1.6 Hz, 1H), 7.62 (dd, J = 8.4, 4.4 Hz, 1H), 7.14 (d, J = 16.0 Hz, 1H), 4.34 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H). Procedure for preparation of 1,6-naphthyridine-8-carbaldehyde Ozone was bubbled into a solution of ethyl 3-(1,6-naphthyridin-8-yl)prop-2-enoate (600 mg, 2.63 mmol, 1.00 eq) in a mixed solvent of dichloromethane (20.0 mL) and methanol (5.00 mL) at -78 °C for 30 minutes. After purging by nitrogen, dimethyl sulfide (1.16 g, 18.7 mmol, 1.37 mL, 7.10 eq) was added at -78 °C. After stirring at 25 °C for 1 h, the reaction mixture was concentrated in vacuo at 40 °C to give a residue. The residue was triturated with methyl tert-butyl ether (30.0 mL). The solid was filtered and the filter cake was dried under vacuum to afford 1,6-naphthyridine-8-carbaldehyde (200 mg, 1.14 mmol, 43% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.26 (s, 1H), 9.70 (s, 1H), 9.32 (dd, J = 4.4, 1.6 Hz, 1H), 9.09 (s, 1H), 8.75 (dd, J = 8.4, 1.6 Hz, 1H), 7.87 (dd, J = 8.4, 4.4 Hz, 1H). Procedure for preparation of 2-amino-2-(1,6-naphthyridin-8-yl)acetonitrile Trimethylsilyl cyanide (163 mg, 1.64 mmol, 206 μL, 1.30 eq) was added to a mixture of 1,6- naphthyridine-8-carbaldehyde (200 mg, 1.26 mmol, 1.00 eq), ammonia 7 M in methanol (7 M, 632 uL, 3.50 eq) and titanium(iv)isopropoxide (431 mg, 1.52 mmol, 448 μL, 1.20 eq) in methanol (5.00 mL). After stirring at 20 °C for 1 h, the reaction mixture was quenched with saturated sodium bicarbonate solution (100 mL) at 5 °C. The solution was extracted with a mixed solvent of dichloromethane and methanol (v/v = 10/1, 50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 2-amino-2-(1,6-naphthyridin-8- yl)acetonitrile (230 mg, 874 μmol, 69% yield) as black oil. Procedure for preparation of 8-vinyl-1,6-naphthyridine To a solution of 8-bromo-1,6-naphthyridine (2.00 g, 9.57 mmol, 1.00 eq), potassium;trifluoro(vinyl)boranuide (1.54 g, 11.5 mmol, 1.20 eq) and sodium carbonate (3.04 g, 28.7 mmol, 3.00 eq) in a mixed solvent of water (8.00 mL) and dioxane (32.0 mL) was added [1,1- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (700 mg, 957 μmol, 0.100 eq) under nitrogen atmosphere. After stirring at 80 °C for 12 h, the reaction mixture was cooled to room temperature and partitioned between ethyl acetate (30.0 mL) and water (50.0 mL). The separated aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined extracts were washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was purified by flash column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 3: 0 to 0: 1) to afford 8-vinyl-1,6-naphthyridine (700 mg, 4.21 mmol, 44% yield) as a yellow solid. LC-MS (Method C): Rt = 0.260 min; MS (ESIpos): m/z = 157.1 [M+H] ⁺ . Procedure for preparation of 1,6-naphthyridine-8-carbaldehyde Ozone was bubbled into a solution of ethyl 8-vinyl-1,6-naphthyridine (700 mg, 4.48 mmol, 1.00 eq) in a mixed solvent of dichloromethane (25.0 mL) and methanol (5.00 mL) at -78 °C for 30 minutes. After purging by nitrogen, dimethyl sulfide (2.04 g, 32.8 mmol, 2.41 mL, 7.30 eq) was added at -78°C. After stirring at 25 °C for 1 h, the reaction mixture was concentrated under vacuum at 40 °C to give a residue. The residue was triturated with methyl tert-butyl ether (50.0 mL). The resulting precipitate was filtered and the filter cake was dried under vacuum to afford 1,6-naphthyridine-8-carbaldehyde (600 mg, 3.41 mmol, 76% yield) as a brown solid. Procedure for preparation of Compound CPD0188256 - (2S,4S)-N-[cyano(1,6-naphthyridin-8- yl)methyl]-1-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-4-propyl-pyrrolidine-2- carboxamide To a solution of (2S,4S)-1-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino ]butanoyl]-4-propyl- pyrrolidine-2-carboxylic acid (503 mg, 1.37 mmol, 1.10 eq) in dichloromethane (10.0 mL) were added 2-amino-2-(1,6-naphthyridin-8-yl)acetonitrile (230 mg, 1.25 mmol, 1.00 eq), diisopropylethylamine (484 mg, 3.75 mmol, 652 μL, 3.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (570 mg, 1.50 mmol, 1.20 eq). After stirring at 25 °C for 12 h, the reaction mixture was concentrated under vacuum at 50 °C to give a residue. The residue was purified by prep-HPLC (column: YMC Triart C18150*25mm*5 μm; mobile phase: [water(FA)-ACN]; B%: 48%-78%,10 min) to afford (2S,4S)-N-[cyano(1,6-naphthyridin-8-yl)methyl]-1-[(2S)-3,3-d imethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-4-propyl-pyrrolidine-2-carbo xamide (163 mg, 300 μmol, 24% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.59-9.37 (m, 2H), 9.31-9.19 (m, 2H), 8.99-8.88 (m, 1H), 8.70 (d, J = 8.4 Hz, 1H), 7.84 (dd, J = 8.4, 4.4 Hz, 1H), 6.90-6.75 (m, 1H), 4.60-4.48 (m, 1H), 4.45-4.31 (m, 1H), 4.03-3.79 (m, 1H), 3.08 (t, J = 10.0 Hz, 1H), 2.41-2.35 (m, 1H), 2.27-2.10 (m, 2H), 1.41-1.22 (m, 5H), 1.01-0.88 (m, 9H), 0.88-0.82 (m, 3H). LC-MS (Method C): Rt = 0.762 min; MS (ESIpos): m/z = 533.3 [M+H] ⁺ . Preparation of CPD0188257 Procedure for preparation of 1-(tert-butyl) 2-methyl (S)-4-(((trifluoromethyl)sulfonyl)oxy)-2,5- dihydro-1H-pyrrole-1,2-dicarboxylate To a solution of O1-tert-butyl O2-methyl (2S)-4-oxopyrrolidine-1,2-dicarboxylate (40.0 g, 164.4 mmol, 1.00 eq) in dichloromethane (400 mL) were added 4-dimethylaminopyridine (60.3 g, 493.3 mmol, 3.00 eq) and trifluoromethanesulfonic anhydride (69.6 g, 247 mmol, 40.7 mL, 1.50 eq) at 0 °C under nitrogen atmosphere. After stirring at 25 °C for 12 h, the reaction mixture was partitioned between dichloromethane (400 mL) and water (200 mL). After separation, the aqueous phase was extracted with dichloromethane (200 mL × 2). The combined extracts were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was purified by flash column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 10/1) to afford 1- (tert-butyl) 2-methyl (S)-4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrol e-1,2-dicarboxylate (41.0 g, 109 mmol, 66% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 6.18 (dd, J = 12.4, 1.6 Hz, 1H), 5.07-5.05 (m, 1H), 4.32-4.29 (m, 2H), 3.71-3.68 (m, 3H), 1.42-1.35 (m, 9H). Procedure for preparation of 1-(tert-butyl) 2-methyl (S)-4-allyl-2,5-dihydro-1H-pyrrole-1,2- dicarboxylate To a solution of 1-(tert-butyl) 2-methyl (S)-4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrol e-1,2- dicarboxylate (41.0 g, 109.2 mmol, 1.00 eq), potassium;allyl(trifluoro)boranuide (21.0 g, 142.0 mmol, 1.30 eq) and potassium carbonate (45.3 g, 328 mmol, 3.00 eq) in dioxane (400 mL) and water (100 mL) was added tetrakis[triphenylphosphine]palladium(0) (6.31 g, 5.46 mmol, 0.05 eq) under nitrogen atmosphere. After stirring at 90 °C for 12 h, the reaction mixture was cooled to room temperature and partitioned between ethyl acetate (300 mL) and water (500 mL). The separated aqueous phase was extracted with ethyl acetate (300 mL × 2). The combined extracts were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 5/1) to give 1-(tert-butyl) 2-methyl (S)-4-allyl-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate (28.0 g, 103 mmol, 94% yield) as yellow oil. LC-MS (Method C): Rt = 0.907 min; MS (ESIpos): m/z = 168.1[M+H-100] ⁺ . Procedure for preparation of 1-(tert-butyl) 2-methyl (2S,4S)-4-propylpyrrolidine-1,2- dicarboxylate To a solution of 1-(tert-butyl) 2-methyl (S)-4-allyl-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate (51.0 g, 191 mmol, 1.00 eq) in methanol (500 mL) was added palladium on carbon (3.97 g, 10% purity) at 25 °C. After stirring at 25 °C for 12 h under hydrogen (15 psi) atmosphere, the reaction mixture was diluted with methanol (1000 mL) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to afford 1-(tert-butyl) 2-methyl (2S,4S)-4-propylpyrrolidine-1,2-dicarboxylate (34.0 g, crude) as yellow oil. LC-MS (Method D): Rt = 0.885 min; MS (ESIpos): m/z = 172.3 [M+H-100] ⁺ . Procedure for preparation of methyl (2S,4S)-4-propylpyrrolidine-2-carboxylate A solution of 1-(tert-butyl) 2-methyl (2S,4S)-4-propylpyrrolidine-1,2-dicarboxylate (34.0 g, 125 mmol, 1.00 eq) in hydrogen chloride (4 M in 1,4-dioxane, 94 mL, 18.1 eq) was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure to afford methyl (2S,4S)-4-propylpyrrolidine-2- carboxylate (26.0 g, crude) as yellow oil. LC-MS (Method C): Rt = 0.936 min; MS (ESIpos): m/z = 172.1[M+H] ⁺ . Procedure for preparation of methyl (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3- dimethylbutanoyl)-4-isopropylpyrrolidine-2-carboxylate To a solution of methyl (2S,4S)-4-propylpyrrolidine-2-carboxylate (26.0 g, 125 mmol, 1.00 eq) and (2S)- 2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid (34.7 g, 150 mmol, 1.20 eq) in N,N- dimethylformamide (200 mL) were added N,N-diisopropylethylamine (80.9 g, 626 mmol, 109 mL, 5.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (71.4 g, 188 mmol, 1.50 eq) at 0 °C. After stirring at 25 °C for 12 h, the reaction mixture was cooled to room temperature and partitioned between ethyl acetate (400 mL) and water (800 mL). The separated aqueous phase was extracted with ethyl acetate (200 mL × 2). The combined extracts were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 10/1) to afford methyl (2S,4S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl- butanoyl]-4-propyl-pyrrolidine-2-carboxylate (42.0 g, 98.3 mmol, 78% yield) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.36-5.22 (m, 1H), 4.39 (dd, J = 10.0, 7.6 Hz, 1H), 4.28 (d, J = 10.0 Hz, 1H), 4.06-3.97 (m, 1H), 3.70 (s, 3H), 3.19-3.08 (m, 1H), 2.47-2.35 (m, 1H), 2.28-2.15 (m, 1H), 1.57-1.45 (m, 2H), 1.41 (s, 9H), 1.37-1.32 (m, 2H), 1.04-0.99 (m, 9H), 0.94-0.88 (m, 3H). Procedure for preparation of (2S,4S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl- butanoyl]-4-propyl-pyrrolidine-2-carboxylic acid To a solution of methyl (2S,4S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-bu tanoyl]-4-propyl- pyrrolidine-2-carboxylate (42.0 g, 109 mmol, 1.00 eq) in tetrahydrofuran (400 mL) were added lithium hydroxide hydrate (9.17 g, 218 mmol, 2.00 eq) and water (400 mL) at 25 °C. After stirring at 25 °C for 12 h, hydrogen chloride (1M in water) was added to the mixture to adjust pH = 7. The solution was extracted with ethyl acetate (300 mL × 3). The combined organic layers were concentrated to afford (2S,4S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-bu tanoyl]-4-propyl-pyrrolidine-2-carboxylic acid (40.0 g, crude) as yellow oil. LC-MS (Method C): Rt = 0.752 min; MS (ESIpos): m/z = 315.2 [M+H] ⁺ . Procedure for preparation of (2S,4S)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-propyl- pyrrolidine-2-carboxylic acid A solution of (2S,4S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-bu tanoyl]-4-propyl-pyrrolidine- 2-carboxylic acid (40.0 g, 108 mmol, 1.00 eq) in hydrogen chloride (4 M in 1,4-dioxane, 119 mL) was stirred at 25 °C for 12 h. The reaction mixture was concentrated to afford (2S,4S)-1-[(2S)-2-amino-3,3- dimethyl-butanoyl]-4-propyl-pyrrolidine-2-carboxylic acid (30.0 g, crude) as yellow oil. LC-MS (Method C): Rt = 0.415 min; MS (ESIpos): m/z = 271.2 [M+H] ⁺ . Procedure for preparation of (2S,4S)-1-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-4-propyl-pyrrolidine-2-carbo xylic acid To a solution of (2S,4S)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-propyl-pyrr olidine-2-carboxylic acid (30.0 g, 111 mmol, 1.00 eq) in methanol (300 mL) were added triethylamine (44.9 g, 444 mmol, 62.0 mL, 4.00 eq) and methyl 2,2,2-trifluoroacetate (28.4 g, 222 mmol, 22.4 mL, 2.00 eq) at 25 °C. After stirring at 50 °C for 12 h, the reaction mixture was concentrated under vacuum at 50 °C to give a residue. The residue was triturated with methyl tert-butyl ether (100 mL). The resulting suspension was filtered and the filter cake was dried under vacuum to afford (2S,4S)-1-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-4-propyl-pyrrolidine-2-carbo xylic acid (23.0 g, 60.9 mmol, 55% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.44 (br. s, 1H), 9.23 (d, J = 8.6 Hz, 1H), 4.59 (d, J = 8.4 Hz, 1H), 4.20 (dd, J = 9.6, 8.0 Hz, 1H), 4.04-3.93 (m, 1H), 3.14-3.04 (m, 1H), 2.44-2.33 (m, 1H), 2.23-2.11 (m, 1H), 1.44-1.22 (m, 5H), 1.01 (s, 9H), 0.93-0.80 (m, 4H). Procedure for preparation of (2S,4S)-N-(2-amino-1-(1-methyl-2-oxo-1,2-dihydroquinolin-4-y l)-2- oxoethyl)-1-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)bu tanoyl)-4-propylpyrrolidine-2- carboxamide To a solution of (2S,4S)-1-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino ]butanoyl]-4-propyl- pyrrolidine-2-carboxylic acid (500 mg, 1.36 mmol, 1.00 eq) in dichloromethane (15.0 mL) were added 2-amino-2-(1-methyl-2-oxo-4-quinolyl)acetamide (315 mg, 1.36 mmol, 1.00 eq), diisopropylethylamine (703 mg, 5.44 mmol, 948 μL, 4.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (1.03 g, 2.72 mmol, 2.00 eq). After stirring at 25 °C for 12 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Unisil 3- 100 C18 Ultra 150*50mm*3 μm; mobile phase: [water(FA)-ACN]; B%: 40%-70%,7min) to give (2S,4S)- N-(2-amino-1-(1-methyl-2-oxo-1,2-dihydroquinolin-4-yl)-2-oxo ethyl)-1-((S)-3,3-dimethyl-2-(2,2,2- trifluoroacetamido) butanoyl)-4-propylpyrrolidine-2-carboxamide (400 mg, 0.683 mmol, 50% yield, 99% purity) as a white solid. LC-MS (Method C): Rt = 0.739 min; MS (ESIpos): m/z = 580.0 [M+H] ⁺ . Procedure for preparation of Compound CPD0188257 - (2S,4S)-N-(cyano(1-methyl-2-oxo-1,2- dihydroquinolin-4-yl)methyl)-1-((S)-3,3-dimethyl-2-(2,2,2-tr ifluoroacetamido)butanoyl)-4- propylpyrrolidine-2-carboxamide To a solution of (2S,4S)-N-[2-amino-1-(1-methyl-2-oxo-4-quinolyl)-2-oxo-ethyl ]-1-[(2S)-3,3-dimethyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-4-propyl-pyrrolidine -2-carboxamide (350 mg, 0.604 mmol, 1.00 eq) in dichloromethane (7.00 mL) was added methoxycarbonyl-(triethylammonio)sulfonyl-azanide (432 mg, 1.81 mmol, 3.00 eq). After stirring at 25 °C for 3 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 3/2) to give (2S,4S)-N-[cyano-(1-methyl-2-oxo-4-quinolyl)methyl]-1- [(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl] -4-propyl-pyrrolidine-2-carboxamide (301 mg, 0.535 μmol, 89% yield, 100% purity) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.67-8.55 (m, 1H), 8.39-8.32 (m, 1H), 7.71-7.62 (m, 2H), 7.47 (d, J = 8.8 Hz, 1H), 7.30 (s, 1H), 7.19-7.11 (m, 1H), 7.06 (d, J = 8.8 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H), 4.74- 4.62 (m, 1H), 4.53 (q, J = 8.8 Hz, 1H), 4.08-3.94 (m, 1H), 3.74 (s, 1H), 3.34 (s, 2H), 3.25-3.15 (m, 1H), 2.61-2.41 (m, 1H), 2.33-2.22 (m, 1H), 2.00-1.84 (m, 1H), 1.53-1.29 (m, 5H), 1.10 (s, 1H), 1.07 (s, 3H), 1.02-0.88 (m, 8H). LC-MS (Method C): Rt = 0.988 min; MS (ESIpos): m/z = 562.2 [M+H] ⁺ . Preparation of CPD0188258 Procedure for preparation of 2-amino-2-(benzo[d]thiazol-5-yl)acetonitrile To a mixture of 1,3-benzothiazole-5-carbaldehyde (0.500 g, 3.06 mmol, 1.00 eq), ammonia 7 M in methanol (7 M, 1.50 mL, 3.43 eq) and titanium(iv)isopropoxide (1.06 g, 3.73 mmol, 1.10 mL, 1.22 eq) in methanol (5.00 mL) was added trimethylsilyl cyanide (396 mg, 4.00 mmol, 0.500 mL, 1.30 eq). After stirring at 20 °C for 2 h, the reaction mixture was quenched with saturated sodium bicarbonate solution (15.0 mL) at 5 °C. The solution was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-amino-2-(1,3-benzothiazol-5-yl)acetonitrile (570 mg, 3.01 mmol, 98% yield) as yellow oil. LC-MS (Method C): Rt = 1.054 min; MS (ESIpos): m/z= [M+H] ⁺ . Procedure for preparation of Compound CPD0188258 - (2S,4S)-N-(benzo[d]thiazol-5- yl(cyano)methyl)-1-((S)-3,3-dimethyl-2-(2,2,2-trifluoroaceta mido)butanoyl)-4-propylpyrrolidine- 2-carboxamide To a solution of (2S,4S)-1-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino ]butanoyl]-4-propyl- pyrrolidine-2-carboxylic acid (500 mg, 1.36 mmol, 1.00 eq) in dichloromethane (10.0 mL) were added 2-amino-2-(1,3-benzothiazol-5-yl)acetonitrile (387 mg, 2.05 mmol, 1.50 eq), diisopropylethylamine (706 mg, 5.46 mmol, 951 μL, 4.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (1.04 g, 2.73 mmol, 2.00 eq). After stirring at 25 °C for 12 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 48%-78%,10 min) to give (2S,4S)-N-[1,3-benzothiazol-5-yl(cyano)methyl]-1-[(2S)-3,3-d imethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-4-propyl-pyrrolidine-2-carbo xamide (375 mg, 691 μmol, 51 % yield, 99% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.51-9.41 (m, 2H), 9.24 (br. s, 1H), 8.38-8.08 (m, 2H), 7.69-7.49 (m, 1H), 6.52-6.32 (m, 1H), 4.69-4.50 (m, 1H), 4.42-4.26 (m, 1H), 4.12-3.91 (m, 1H), 3.20-3.04 (m, 1H), 2.52 (d, J = 2.0 Hz, 2H), 2.38-2.09 (m, 3H), 1.47-1.23 (m, 5H), 0.99 (d, J = 4.0 Hz, 9H), 0.87 (td, J = 16.0, 7.2 Hz, 3H). Preparation of CPD0188259 Procedure for preparation of Methyl (1R, 2S, 5S) -3-[(2S) -2-(tert-butoxycarbonylamino) -3, 3- dimethyl-butanoyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate To a solution of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid (20.0 g, 86.5 mmol, 1.00 eq), bromo(tripyrrolidin-1-yl)phosphonium;hexafluorophosphate (48.4 g, 104 mmol, 1.20 eq) and 4- methylmorpholine (21.9 g, 216 mmol, 23.8 mL, 2.50 eq) in dichloromethane (200 mL) was added methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (18.7 g, 90.8 mmol, 1.05 eq, HCl salt). After stirring at 20 °C for 15 h, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (400 mL) at 25 °C. The solution was extracted with ethyl acetate (300 mL × 3). The combined organic layers were washed with brine (200 mL ×2), dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (SiO ₂ , petroleum ether: ethyl acetate = 10: 1 to 5: 1) to afford methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl -butanoyl]-6, 6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (26.0 g, 68.0 mmol, 39% yield) as brown gum. ¹ H NMR (400 MHz, CD ₃ OD) δ = 6.43 (d, J = 9.6 Hz, 1H), 4.35 (s, 1H), 4.21 (d, J = 9.6 Hz, 1H), 4.05- 3.99 (m, 1H), 3.95-3.88 (m, 1H), 3.73 (s, 3H), 1.57 (dd, J = 7.2, 5.2 Hz, 1H), 1.47 (d, J = 7.2 Hz, 1H), 1.44-1.37 (m, 9H), 1.07 (s, 3H), 1.02 (s, 9H), 0.93 (s, 3H). Procedure for preparation of Methyl (1R, 2S, 5S) -3-[(2S) -2-amino-3, 3-dimethyl-butanoyl]-6, 6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate To a solution of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl -butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (4.80 g, 12.5 mmol, 1.00 eq) in dioxane (30.0 mL) was added hydrochloric acid (4 M in dioxane, 72.0 mL, 23.0 eq). After stirring at 20 °C for 3 h, the reaction mixture was concentrated to give methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (4.50 g, crude, HCl salt) as an off-white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ = 4.45 (s, 1H), 4.00-3.92 (m, 2H), 3.78 (br. s, 1H), 3.75 (s, 3H), 1.65- 1.60 (m, 1H), 1.58-1.53 (m, 1H), 1.15 (s, 9H), 1.09 (s, 3H), 1.02 (s, 3H). LC-MS (Method C): R _t = 0.369, 0.593 min; MS (ESIpos): m/z = 283.3, 283.2 [M+H] ⁺ . Procedure for preparation of Methyl (1R, 2S, 5S) -3-[(2S) -2-(2, 2-difluoropropanoylamino) -3, 3- dimethyl-butanoyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate To a solution of 2, 2-difluoropropanoic acid (414 mg, 3.76 mmol, 1.20 eq) in tetrahydrofuran (20.0 mL) was added di(imidazol-1-yl)methanone (610 mg, 3.76 mmol, 1.20 eq). After stirring at 20 °C for 6 h, methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimeth yl-3-azabicyclo[3.1.0]hexane-2- carboxylate (1.00 g, 3.14 mmol, 1.00 eq, HCl salt) was added. After stirring at 20 °C for 15 h, the reaction mixture was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~12% ethyl acetate/petroleum ether gradient @ 75 mL/min) to give methyl (1R,2S,5S)-3-[(2S)-2-(2,2-difluoropropanoylamino)-3,3-dimeth yl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyla te (800 mg, 2.14 mmol, 68% yield) as colorless oil. LC-MS (Method C): R _t = 0.886 min; MS (ESIpos): m/z = 375.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD3OD) δ = 4.57 (s, 1H), 4.37 (s, 1H), 4.00-3.88 (m, 2H), 3.74 (s, 3H), 1.75 (t, J = 19.2 Hz, 3H), 1.63-1.55 (m, 1H), 1.52-1.47 (m, 1H), 1.09-1.03 (m, 12H), 0.91 (s, 3H). Procedure for preparation of (1R, 2S, 5S) -3-[(2S) -2-(2, 2-difluoropropanoylamino) -3, 3-dimethyl- butanoyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-2-(2,2-difluoropropanoylamino)-3,3-dimeth yl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (800 mg, 2.14 mmol, 1.00 eq) in a mixed solvent of tetrahydrofuran (6.00 mL) and water (6.00 mL) was added lithium hydroxide monohydrate (89.7 mg, 2.14 mmol, 1.00 eq). After stirring at 20 °C for 15 h, the reaction mixture was quenched with hydrogen chloride (1M in water, 10.0 mL) at 25 °C. The solution was extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (10.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-3-[(2S)-2-(2,2- difluoropropanoylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (730 mg, 2.03 mmol, 95% yield) as a white solid. ¹ H NMR (400 MHz, CD3OD) δ = 7.85 (d, J = 8.8 Hz, 1H), 4.59 (d, J = 9.2 Hz, 1H), 4.35 (s, 1H), 4.02- 3.84 (m, 2H), 1.75 (t, J = 19.2 Hz, 3H), 1.61-1.55 (m, 1H), 1.55-1.50 (m, 1H), 1.11-0.95 (m, 12H), 0.91 (s, 3H). LC-MS (Method A): R _t = 0.827, 0.848 min; MS (ESIpos): m/z = 361.3 [M+H] ⁺ . Procedure for preparation of 2-amino-2-(1, 6-naphthyridin-8-yl) acetonitrile To a solution of 1,6-naphthyridine-8-carbaldehyde (300 mg, 1.90 mmol, 1.00 eq) in methanol (2.00 mL) were added titanium(IV) propan-2-olate (647 mg, 2.28 mmol, 0.672 mL, 1.20 eq) and NH ₃ (7 M in methanol, 1.90 mL, 7.00 eq) at 20 °C. After stirring at 20 °C for 1 h, trimethylsilylformonitrile (226 mg, 2.28 mmol, 285 μL, 1.2 eq) was added. After stirring at 20 °C for 2 h, the reaction mixture was quenched with water (80 mL) at 20 °C. The solution was extracted with dichloromethane/methanol (v/v = 10/1, 80.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-amino-2-(1, 6-naphthyridin-8-yl) acetonitrile (350 mg, 1.14 mmol, 60% yield, 60% purity) as black oil. LC-MS (Method A): R _t = 0.135 min; MS (ESIpos): m/z = 185.0 [M+H] ⁺ . Procedure for preparation of CPD0188259 - (1R, 2S, 5S) -N-[cyano (1, 6-naphthyridin-8-yl) methyl]-3-[(2S) -2-(2, 2-difluoropropanoylamino) -3, 3-dimethyl-butanoyl]-6, 6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-2-(2, 2-difluoropropanoylamino)-3,3-dimethyl-butanoyl]-6, 6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (500 mg, 1.39 mmol, 1.00 eq) in dichloromethane (5.00 mL) were added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]- dimethylazanium;hexafluorophosphate (633 mg, 1.66 mmol, 1.20 eq) and N-ethyl-N-isopropylpropan- 2-amine (538 mg, 4.16 mmol, 0.725 mL, 3.00 eq) at 20 °C. After stirring at 20 °C for 0.5 h, 2-amino-2- (1,6-naphthyridin-8-yl)acetonitrile (350 mg, 1.14 mmol, 60% purity, 0.822 eq) was added to the solution above. After stirring at 20 °C for 15 h, the reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex luna C18150*40 mm* 15 μm; mobile phase: [water (FA) -ACN]; B%: 37%-67%, 10 min) to give (1R,2S,5S)-N-[cyano(1,6- naphthyridin-8-yl)methyl]-3-[(2S)-2-(2,2-difluoropropanoylam ino)-3,3-dimethyl-butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxamide (230 mg, 0.437 mmol, 31% yield) as a pink solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.70-9.36 (m, 2H), 9.26 (td, J = 4.4, 1.2 Hz, 1H), 8.94 (d, J = 8.4 Hz, 1H), 8.71 (td, J = 8.4, 1.2 Hz, 1H), 8.22-8.06 (m, 1H), 7.85 (dd, J = 8.4, 4.4 Hz, 1H), 6.84 (dd, J = 16.8, 7.6 Hz, 1H), 4.46-4.29 (m, 2H), 3.94-3.83 (m, 1H), 3.77-3.65 (m, 1H), 1.74 (dt, J = 19.6, 6.0 Hz, 3H), 1.60-1.49 (m, 1H), 1.45-1.19 (m, 1H), 1.08-0.90 (m, 9H), 0.86 (s, 3H), 0.83 (d, J = 13.2 Hz, 3H). LC-MS (Method C): R _t = 0.865 min; MS (ESIpos): m/z = 527.3 [M+H] ⁺ . SFC: dr = 48: 45. Preparation of CPD0189006 Procedure for preparation of tert-butyl 7-bromo-2,3-dihydro-1,4-benzoxazine-4-carboxylate To a solution of 7-bromo-3,4-dihydro-2H-1,4-benzoxazine (5.00 g, 23.4 mmol, 1.00 eq) and tert- butoxycarbonyl tert-butyl carbonate (6.12 g, 28.0 mmol, 6.44 mL, 1.20 eq) in tetrahydrofuran (50.0 mL) were added 4-dimethylaminopyridine (1.43 g, 11.7 mmol, 0.500 eq) and triethylamine (4.73 g, 46.7 mmol, 6.50 mL, 2.00 eq). After stirring at 60 °C for 16 h, water (200 mL) was added to the solution above. The soluiton was extracted with ethyl acetate (200 mL×2). The combined organic layers were washed with brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 5: 1) to give tert-butyl 7-bromo-2,3-dihydro-1,4-benzoxazine-4-carboxylate (3.20 g, 10.1 mmol, 44% yield) as a white solid. Procedure for preparation of tert-butyl 7-[1-(benzhydrylideneamino)-2-methoxy-2-oxo-ethyl]- 2,3-dihydro-1,4-benzoxazine-4-carboxylate To a solution of tert-butyl 7-bromo-2,3-dihydro-1,4-benzoxazine-4-carboxylate (1.00 g, 3.18 mmol, 1.00 eq) and methyl 2-(benzhydrylideneamino)acetate (806 mg, 3.18 mmol, 1.00 eq) in N,N- dimethylformamide (15 mL) were added potassium phosphate (2.03 g, 9.55 mmol, 3.00 eq) and [2-(2- aminophenyl)phenyl]-chloro-palladium;tritert-butylphosphane (326 mg, 636 μmol, 0.20 eq) under nitrogen atmosphere. After stirring at 90 °C for 16 h, the mixture was filtered and the filter cake was concentrated under vacuum to give a residue. The residue was purified by reversed phase column (Instrument: 120 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.1% NH ₃ ^H ₂ O), eluent B: acetonitrile; gradient: 0-20 min 0-72% B; flow 85 ml/min; temperature: room temperature; Detector: UV 220/254 nm).to give tert-butyl 7-[1-(benzhydrylideneamino)-2-methoxy-2-oxo-ethyl]-2,3- dihydro-1,4-benzoxazine-4-carboxylate (900 mg, 1.72 mmol, 27% yield, 93% purity) as a yellow solid. LC-MS (Method G): R _t = 1.148 min; MS (ESIpos): m/z = 487.1 [M+H] ⁺ . Procedure for preparation of tert-butyl 7-[2-amino-1-(benzhydrylideneamino)-2-oxo-ethyl]-2,3- dihydro-1,4-benzoxazine-4-carboxylate To a solution of tert-butyl 7-[1-(benzhydrylideneamino)-2-methoxy-2-oxo-ethyl]-2,3-dihyd ro-1,4- benzoxazine-4-carboxylate (900 mg, 1.85 mmol, 1.00 eq) in ammonia/ methanol (7 M, 22.0 mL, 85.2 eq) was added 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine (772 mg, 5.55 mmol, 3.00 eq). After stirring at 40 °C for 12 h, the reaction mixture was filtered and the cake was concentrated under vacuum to give tert-butyl 7-[2-amino-1-(benzhydrylideneamino)-2-oxo-ethyl]-2,3-dihydro -1,4-benzoxazine-4- carboxylate (480 mg, 1.02 mmol, 55% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.87-7.83 (m, 1H), 7.72-7.70 (m, 2H), 7.70-7.55 (m, 2H), 7.50-7.35 (m, 7H), 7.25-7.15 (m, 1H), 7.20-7.15 (m, 1H), 6.62 (s, 1H), 5.17 (s, 1H), 3.60 (s, 3H). Procedure for preparation of tert-butyl 7-(1,2-diamino-2-oxo-ethyl)-2,3-dihydro-1,4-benzoxazine- 4-carboxylate To a solution of tert-butyl 7-[2-amino-1-(benzhydrylideneamino)-2-oxo-ethyl]-2,3-dihydro -1,4- benzoxazine-4-carboxylate (200 mg, 424 umol, 1.00 eq) in a mixed solvent of dichloromethane (2.00 mL) and methanol (2.00 mL) was added hydrogen chloride (1 M, 1.00 mL, 2.36 eq). After stirring at 25 °C for 1 h, the reaction mixture was concentrated under vacuum to give a residue. The residue was purified by reversed phase (Instrument: 120g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-10 min 0-60% B; flow 85 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give tert-butyl 7-(1,2-diamino-2-oxo-ethyl)-2,3-dihydro- 1,4-benzoxazine-4-carboxylate (60.0 mg, 195 umol, 46% yield) as a white solid. Procedure for preparation of tert-butyl 7-[2-amino-1-[ [( 1R,2S,5S)-3-[ (2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3 Azabicyclo [3.1.0]hexane-2-carbonyl]amino]-2- oxo-ethyl]-2,3-dihydro-1,4-benzoxazine-4-carboxylate To a solution of tert-butyl 7-(1,2-diamino-2-oxo-ethyl)-2,3-dihydro-1,4-benzoxazine-4-ca rboxylate (60.0 mg, 195 umol, 1.00 eq) and (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (85.4 mg, 234 μmol, 1.20 eq) in dichloromethane (2.00 mL) were added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]- dimethyl-ammonium;hexafluorophosphate (111 mg, 293 umol, 1.50 eq) and N,N-diisopropylethylamine (75.7 mg, 586 umol, 102 μL, 3.00 eq). After stirring at 20 °C for 2 h, the reaction mixture was concentrated under vacuum to give a residue. The residue was purified by reversed phase (Instrument: 30.0g Flash; Column: Welch Ultimate XB_C18 20-40 μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-15 min 0-60% B; flow 85 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give tert-butyl 7-[2-amino-1-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo [3.1.0]hexane-2-carbonyl]amino]-2-oxo- ethyl]-2,3-dihydro-1,4-benzoxazine-4-carboxylate (70.0 mg, 107 umol, 55% yield) as a white solid. Procedure for preparation of tert-butyl 7-[2-amino-1-[ [( 1R,2S,5S)-3-[ (2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3 Azabicyclo [3.1.0]hexane-2-carbonyl]amino]-2- oxo-ethyl]-2,3-dihydro-1,4-benzoxazine-4-carboxylate To a solution of tert-butyl 7-[2-amino-1-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carbonyl]amino]-2-oxo- ethyl]-2,3-dihydro-1,4-benzoxazine-4-carboxylate (60.0 mg, 91.8 μmol, 1.00 eq) in dichloromethane (2.00 mL) was added methoxycarbonyl-(triethylammonio)sulfonyl-azanide (65.6 mg, 275 μmol, 3.00 eq). After stirring at 25 °C for 16 h, the reaction mixture was concentrated under vacuum to give a residue. The residue was purified by reversed phase (Instrument: 30.0g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-10 min 0-60% B; flow 85 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give tert-butyl 7-[cyano- [[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl) amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carbonyl]amino]methyl]-2,3-dihydro -1,4-benzoxazine-4-carboxylate (30.0 mg, 47.2 μmol, 51% yield, 92% purity) as a white solid. LC-MS (Method C): R _t = 1.058 min; MS (ESIpos): m/z = 636.5 [M+H] ⁺ . Procedure for preparation of CPD0189006 - (1R,2S,5S)-N-[cyano(3,4-dihydro-2H-1,4-benzoxazin- 7-yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of tert-butyl 7-[cyano-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carbonyl]amino]methyl]-2,3- dihydro-1,4-benzoxazine-4-carboxylate (30.0 mg, 47.2 μmol, 1.00 eq) in acetonitrile (2.00 mL) was added hydrogen chloride (4 M in 1,4-dioxane, 35.4 μL, 3.00 eq). After stirring at 20 °C for 16 h, the mixture reaction was concentrated under vacuum to give a residue. The residue was purified by prep- HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN];B%: 48%- 78%,10 min). to give (1R,2S,5S)-N-[cyano(3,4-dihydro-2H-1,4-benzoxazin-7-yl)methy l]-3-[(2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (20.8 mg, 38.8 μmol, 82% yield,100% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.37 (d, J = 7.6 Hz, 1H), 9.18 (d, J = 7.6 Hz, 1H), 6.82-6.72 (m, 2H), 6.56 (dd, J = 8.0, 4.0 Hz, 1H), 6.00 (d, J = 2.4 Hz, 1H), 5.94-5.84 (m, 1H), 4.41 (d, J = 6.8 Hz, 1H), 4.28 (s, 1H), 4.11 (t, J = 4.0 Hz, 2H),3.89 (td, J = 10.4, 6.4 Hz, 1H), 3.70 (t, J = 10.4 Hz, 1H), 3.29-3.26 (m, 2H), 1.60-1.46 (m, 1H), 1.35-1.16 (m, 1H), 1.06-0.87 (m, 13H), 0.83 (d, J = 3.6 Hz, 3H). LC-MS (Method C): R _t = 0.851 min; MS (ESIpos): m/z = 558.3 [M+Na] ⁺ Preparation of CPD0189010 Procedure for preparation of pyrazolo[1,5-a]pyrimidine-3-carbaldehyde To a solution of pyrazolo[1,5-a]pyrimidine (4.80 g, 40.3 mmol, 1.00 eq) in N,N-dimethylformamide (45.6 g, 623 mmol, 48.0 mL, 15.4 eq) was added phosphoryl trichloride (18.5 g, 121 mmol, 11.2 mL, 3.00 eq). After stirring at 25 °C for 3 h, the mixture was filtered. The filter cake was added into anhydrous sodium hydrogen carbonate (200 mL). The mixture was stirred at 25 °C for 1 h and extracted with ethyl acetate (200 mL × 4). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (3.00 g, 20.4 mmol, 50% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.16 (s, 1H), 9.36 (dd, J = 7.2, 1.6 Hz, 1H), 8.89 (dd, J = 4.0, 1.6 Hz, 1H), 8.72 (s, 1H), 7.38 (dd, J = 7.2, 4.0 Hz, 1H). LC-MS (Method A): Rt = 0.257 min; MS (ESIpos): m/z = 148.0 [M+H] ⁺ . Procedure for preparation of 2-amino-2-(pyrazolo[1,5-a]pyrimidin-3-yl)acetonitrile To a solution of pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (200 mg, 1.36 mmol, 1.00 eq) in methyl alcohol (1.00 mL) and ammonia/methyl alcohol (7.00 M, 194 μL, 1.00 eq) was added isopropyl titanate (463 mg, 1.63 mmol, 481 μL, 1.20 eq). After stirring at 25 °C for 1 h, trimethylsilanecarbonitrile (162 mg, 1.63 mmol, 204 μL, 1.20 eq) was added. After stirring at 25 °C for 2 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved with ethyl acetate (20 mL). The resulting mixture was filtered. The filtrate was concentrated under vacuum to give 2-amino- 2-pyrazolo[1,5-a]pyrimidin-3-yl-acetonitrile (crude) as brown oil, and was used into the next step without further purification. LC-MS (Method A): Rt = 0.121 min; MS (ESIpos): m/z = 157.1 [M-NH2] ⁺ . Procedure for preparation of CPD0189010 - (1R,2S,5S)-N-(cyano(pyrazolo[1,5-a]pyrimidin-3- yl)methyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)b utanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (891 mg, 2.45 mmol, 1.00 eq) in N,N-dimethylformamide (6.00 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (1.40 g, 3.67 mmol, 1.50 eq) and diisopropylethylamine (632 mg, 4.89 mmol, 852 μL, 2.00 eq) at 25 °C. After stirring at 25 °C for 0.2 h, a solution of 2-amino-2-pyrazolo[1,5-a]pyrimidin-3-yl-acetonitrile (706 mg, 2.45 mmol, 60% purity, 1.00 eq) in N,N-dimethylformamide (1.00 mL) was added. After stirring at 25 °C for 2 h, the reaction mixture was quenched with water (10.0 mL) at 25 °C. The solution was extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition;column: Phenomenex luna C18150 × 40 mm × 15 μm; mobile phase: [water(FA)-ACN]; B%: 38%-68%,10min) to give (1R,2S,5S)-N-[cyano(pyrazolo[1,5-a]pyrimidin-3-yl)methyl]-3- [(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (297 mg, 550 μmol, 23% yield, 98% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.42-9.30 (m, 2H), 9.20 (d, J = 7.2 Hz, 1H), 8.71-8.66 (m, 1H), 8.38 (d, J = 10.4 Hz, 1H), 7.24-7.16 (m, 1H), 6.26 (d, J = 7.2 Hz, 1H), 4.40 (d, J = 8.0 Hz, 1H), 4.29 (d, J = 3.6 Hz, 1H), 3.90 (dd, J =10.0, 5.2 Hz, 1H), 3.75-3.67 (m, 1H), 1.61-1.48 (m, 1H), 1.38-1.27 (m, 1H), 1.00 (s, 6H), 0.97 (s, 6H), 0.83 (d, J = 5.6 Hz, 3H). LC-MS (Method C): Rt = 0.856 min; MS (ESIpos): m/z = 520.2 [M+H] ⁺ . SFC: 51:49. Preparation of CPD0189013 Procedure for preparation of 4-bromo-N-(2,2-dimethoxyethyl)-1H-pyrrole-2-carboxamide To a solution of 1-(4-bromo-1H-pyrrol-2-yl)-2,2,2-trichloro-ethanone (15.0 g, 51.48 mmol, 1.00 eq) in acetonitrile (150 mL) was added dropwise 2,2-dimethoxyethanamine (8.12 g, 77.22 mmol, 8.41 mL, 1.50 eq) at 20 °C. After stirring at 20 °C for 15 h, the reaction mixture was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 1: 0 to 3: 1) to afford 4-bromo-N-(2,2-dimethoxyethyl)-1H-pyrrole-2-carboxamide (11.5 g, 41.5 mmol, 81% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 10.42 (s, 1H), 6.92-6.91 (m, 1H), 6.64-6.63 (m, 1H), 6.32 (t, J = 4.8 Hz, 1H), 4.47 (t, J = 5.6 Hz, 1H), 3.57 (t, J = 5.6 Hz, 2H), 3.44 (s, 6H). Procedure for preparation of 7-bromo-4-hydroxy-3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one To a solution of 4-bromo-N-(2,2-dimethoxyethyl)-1H-pyrrole-2-carboxamide (14.5 g, 52.3 mmol, 1.00 eq) in a mixed solvent of water (29.0 mL) and acetone (145 mL) was added p-toluenesulfonic acid (63.07 g, 366 mmol, 7.00 eq) at 0 °C. After stirring at 80 °C for 15 h, the mixture was concentrated under vacuum to remove the organic solvent. The mixture was added dropwise into water (100 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ ^ petroleum ether: ethyl acetate = 10: 1 to 0: 1) to afford 7-bromo-4- hydroxy-3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one (3.08 g, 13.3 mmol, 25% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.76 (s, 1H), 7.00-6.99 (m, 1H), 6.65 (s, 1H), 5.59 (s, 1H), 3.61 (d, J = 12.0 Hz, 1H), 3.33-3.31 (m, 1H). Procedure for preparation of 7-bromo-2H-pyrrolo[1,2-a]pyrazin-1-one A solution of 7-bromo-4-hydroxy-3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one (4.63 g, 20.0 mmol, 1.00 eq) in methanesulfonic acid (30.0 mL) was stirred at 45 °C for 15 h. The reaction mixture was cooled to 20 °C, diluted with water (200 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 7- bromo-2H-pyrrolo[1,2-a]pyrazin-1-one (2.60 g, 12.2 mmol, 61% yield) as a gray solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.63 (s, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.27 (d, J = 5.6 Hz,1H), 6.92 (s, 1H), 6.62 (t, J = 6.0 Hz, 1H). Procedure for preparation of 7-bromo-2-methyl-pyrrolo[1,2-a]pyrazin-1-one To a solution of 7-bromo-2H-pyrrolo[1,2-a]pyrazin-1-one (2.60 g, 12.20 mmol, 1.00 eq) in tetrahydrofuran (30.0 mL) was added sodium hydride (976 mg, 24.4 mmol, 60% purity, 2.00 eq) at 0 °C under nitrogen atmosphere. After stirring at 0 °C for 10 min, methyl iodide (5.20 g, 36.61 mmol, 2.28 mL, 3.00 eq) was added at 0 °C. The reaction mixture was allowed to stir at 20 °C for 14 h under nitrogen atmosphere. The reaction mixture was poured into ice-water (30.0 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 20: 1 to 1: 1) to give 7-bromo-2-methyl-pyrrolo[1,2-a]pyrazin-1- one (2.2 g, 9.69 mmol, 79.39% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.59 (d, J = 1.6 Hz, 1H), 7.34 (m, J = 6.0 Hz, 1H), 6.93 (d, J = 1.2 Hz, 1H), 6.89 (m, J = 5.6 Hz, 1H), 3.34 (s, 3H). Procedure for preparation of 2-methyl-1-oxo-pyrrolo[1,2-a]pyrazine-7-carbaldehyde To a solution of 7-bromo-2-methyl-pyrrolo[1,2-a]pyrazin-1-one (0.8 g, 3.52 mmol, 1.00 eq) in tetrahydrofuran (10.0 mL) was added dropwise n-butyllithium (2.5 M in hexanes, 2.11 mL, 1.50 eq) at - 70 °C under nitrogen atmosphere. After stirring at -70 °C for 0.5 h under nitrogen atmosphere, N,N- dimethylformamide (773 mg, 10.6 mmol, 3.00 eq) was added dropwise. After stirring at -70 °C for 1 h, the reaction mixture was quenched with saturated ammonium chloride solution (15.0 mL) dropwise at - 70 °C. The reaction mixture was allowed to warm to 20 °C, diluted with water (10.0 mL) and extracted with ethyl acetate (12.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 20: 1 to 0: 1) to afford 2-methyl-1-oxo- pyrrolo[1,2-a]pyrazine-7-carbaldehyde (400 mg, 2.27 mmol, 64% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.40 (s, 1H), 8.48-8.46 (m, 1H), 7.23-7.20 (m, 2H), 6.66-6.64 (m, 1H), 3.60 (s, 3H). Procedure for preparation of 2-amino-2-(2-methyl-1-oxo-pyrrolo[1,2-a]pyrazin-7-yl)acetoni trile To a solution of 2-methyl-1-oxo-pyrrolo[1,2-a]pyrazine-7-carbaldehyde (500 mg, 2.84 mmol, 1.00 eq) in methanol (8.00 mL) were added ammonia (7 M in methanol, 2.03 mL, 5.00 eq) and titanium (IV) isopropoxide (968 mg, 3.41 mmol, 1.01 mL, 1.20 eq) at 20 °C. The reaction mixture was stirred at 20 °C for 2 h, followed by trimethylsilyl cyanide (338 mg, 3.41 mmol, 426 μL, 1.20 eq) at 20 °C. After stirring at 20 °C for 3 h, the reaction mixture was poured into ice-water (30.0 mL) and filtered. The filtrate was extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford 2-amino-2-(2-methyl-1-oxo- pyrrolo[1,2-a]pyrazin-7-yl)acetonitrile (573.9 mg, 2.84 mmol, 100.00% yield) as a yellow solid. Procedure for preparation of Compound CPD0189013 - (1R,2S,5S)-N-[cyano-(2-methyl-1-oxo- pyrrolo[1,2-a]pyrazin-7-yl)methyl]-3-[(2S)-3,3-dimethyl-2-[( 2,2,2-trifluoroacetyl)amino]butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (800 mg, 2.20 mmol, 1.00 eq) in N,N-dimethylformamide (10.0 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (1.25 g, 3.29 mmol, 1.50 eq) and N,N-diisopropylethylamine (568 mg, 4.39 mmol, 765 μL, 2.00 eq) at 0 °C. After stirring at 0 °C for 10 min, 2-amino-2-(2-methyl-1-oxo-pyrrolo[1,2-a]pyrazin-7-yl)acetoni trile (574 mg, 2.84 mmol, 1.29 eq) was added at 0 °C. After stirring at 20 °C for 14 h, the reaction mixture was added dropwise into ice-water (10.0 m L) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue (combined with: EW33008-438-P1) was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 36%-66%, 10 min) to afford (1R,2S,5S)-N-[cyano-(2-methyl-1-oxo-pyrrolo[1,2-a]pyrazin-7- yl)methyl]-3-[(2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (285 mg, 512 μmol, 23.33% yield, 99% purity) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.64 (d, J = 7.6 Hz, 0.5H), 9.49 (d, J = 7.6 Hz, 0.5H), 9.38 (d, J = 8.8 Hz, 1H), 7.28-7.27 (m, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.02-7.00 (m, 1H), 6.67-6.53 (m, 2H), 4.39 (d, J = 9.2 Hz, 1H), 4.23 (s, 1H), 3.95-3.91 (m, 1H), 3.70 (t, J = 10.4 Hz, 1H), 3.44 (s, 3H), 3.43 (s, 3H), 1.62- 1.54 (m, 1H), 1.35-1.13 (m, 1H), 1.03-0.82 (m, 15H). LC-MS (Method C): R _t = 0.597 min and 0.636 min; MS (ESIpos): m/z = 549.2 [M+H] ⁺ . HPLC (Method K): R _t = 2.027 min and 2.063 min, purity: 98%. SFC: dr: 50: 50. Preparation of CPD0189014 Procedure for preparation of ethyl (2E) -2-hydroxyimino-2-pyridazin-3-yl-acetate To a solution of ethyl 2-pyridazin-3-ylacetate (1.00 g, 6.02 mmol, 1.00 eq) in acetic acid (1.50 mL) was added a mixture of sodium nitrite (477 mg, 6.92 mmol, 1.15 eq) in water (5.00 mL) at 0 °C. After stirring at 0 °C for 1 h, water (4.00 mL) was added. The mixture was stirred at 20 °C for 2 h. The resulting precipitate was filtered and the filter cake was washed with water (15.0 mL), saturated sodium bicarbonate solution (15.0 mL), water (15.0 mL), concentrated under reduced pressure to give ethyl (2E) -2-hydroxyimino-2-pyridazin-3-yl-acetate (1.60 g, crude) as a gray solid. LCMS (Method C): R _t = 0.207 min; MS (ESIpos): m/z =196.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 13.02-12.60 (m, 1H), 9.25 (dd, J = 4.8, 1.6 Hz, 1H), 8.08 (dd, J = 8.8, 1.6, Hz, 1H), 7.83-7.74 (m, 1H), 4.35 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H). Procedure for preparation of ethyl 2-amino-2-pyridazin-3-yl-acetate To a solution of ethyl (2E) -2-hydroxyimino-2-pyridazin-3-yl-acetate (500 mg, 2.56 mmol, 1.00 eq) in methyl alcohol (5.00 mL) was added Pd/C (300 mg, 10% purity). The mixture was stirred at 20 °C for 16 h under hydrogen atmosphere (15 psi). The mixture was filtered through a pad of celite and the filtrate was concentrated under vacuum to give ethyl 2-amino-2-pyridazin-3-yl-acetate (400 mg, 2.21 mmol, 86% yield) as a black solid. LCMS (Method C): R _t = 0.135 min; MS (ESIpos): m/z =182.1 [M+H] ⁺ . Procedure for preparation of ethyl 2-((tert-butoxycarbonyl)amino)-2-(pyridazin-3-yl)acetate To a solution of ethyl 2-amino-2-pyridazin-3-yl-acetate (590 mg, 3.26 mmol, 1.00 eq) in dichloromethane (10.0 mL) were added tert-butyl (2-methylpropan-2-yl)oxycarbonyl carbonate (853 mg, 3.91 mmol, 0.898 mL, 1.20 eq) and triethylamine (659 mg, 6.51 mmol, 0.906 mL, 2.00 eq) at 0 °C. After stirring at 20 °C for 2 h, the mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (30.0 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 0: 1) to give ethyl 2-(tert-butoxycarbonylamino) -2-pyridazin-3-yl-acetate (120 mg, 0.427 mmol, 13% yield) as a white solid. LCMS (Method C): R _t = 0.175 min; MS (ESIpos): m/z =282.1 [M+H] ⁺ . Procedure for preparation of tert-butyl N-(2-amino-2-oxo-1-pyridazin-3-yl-ethyl)carbamate A solution of ethyl 2-(tert-butoxycarbonylamino) -2-pyridazin-3-yl-acetate (110 mg, 0.391 mmol, 1.00 eq) in ammonia/methyl alcohol (7 M, 16.5 mL, 0.295 eq) was stirred under at 60 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep- TLC (SiO ₂ , petroleum ether: ethyl acetate = 0: 1) to give tert-butyl N-(2-amino-2-oxo-1-pyridazin-3-yl- ethyl) carbamate (30.0 mg, 0.119 mmol, 30% yield) as a white solid. LCMS (Method G): R _t = 0.341 min; MS (ESIpos): m/z = 253.3 [M+H] ⁺ . Procedure for preparation of 2-amino-2-pyridazin-3-yl-acetamide To a solution of tert-butyl N-(2-amino-2-oxo-1-pyridazin-3-yl-ethyl) carbamate (80.0 mg, 0.317 mmol, 1.00 eq) in dioxane (0.500 mL) was added hydrochloric acid/dioxane (4 M, 0.500 mL, 6.31 eq) at 0 °C. After stirring at 20 °C for 2 h, the mixture was concentrated in vacuum to give 2-amino-2-pyridazin-3-yl- acetamide (60.0 mg, crude, HCl) as a gray solid. LCMS (Method C): R _t = 0.075 min; MS (ESIpos): m/z = 153.3 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-(2-amino-2-oxo-1-pyridazin-3-yl-ethyl)-3-[(2S)- 3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxamide To a solution of (1R, 2S, 5S) -3-[ (2S) -3, 3-dimethyl-2-[ (2, 2, 2-trifluoroacetyl) amino]butanoyl]-6, 6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (139 mg, 0.382 mmol, 1.20 eq) and O-(7- azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (181 mg, 0.477 mmol, 1.50 eq) in N,N-dimethylformamide (2.00 mL) was added diisopropylethylamine (82.2 mg, 0.636 mmol, 0.111 mL, 2.00 eq) at 0 °C. After stirring at 20 °C for 0.5 h, 2-amino-2-pyridazin-3-yl-acetamide (60.0 mg, 0.318 mmol, 1.00 eq, HCl) was added, and the mixture was stirred at 20 °C for 11.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (FA condition; column: Phenomenex luna C18150*25 mm* 10 μm; mobile phase: [water (FA) - ACN];B%: 25%-55%, 10 min) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-pyridazin-3-yl-ethyl)-3-[(2S)- 3,3- dimethyl-2-[(2,2,2-trifluoroacetyl) amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (76.0 mg, 0.152 mmol, 48% yield) as a pink solid. LCMS (Method C): R _t = 0.354 min; MS (ESIpos): m/z = 499.4 [M+H] ⁺ . Procedure for preparation of CPD0189014 - (1R,2S,5S)-N-[cyano(pyridazin-3-yl)methyl]-3-[(2S)- 3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-d imethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide To a solution of (1R,2S,5S)-N-(2-amino-2-oxo-1-pyridazin-3-yl-ethyl)-3-[(2S)- 3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (70.0 mg, 0.140 mmol, 1.00 eq) in dichloromethane (2.00 mL) was added methoxycarbonyl-(triethylammonio) sulfonyl- azanide (100 mg, 0.421 mmol, 3.00 eq). After stirring at 25 °C for 4 h, the reaction mixture was diluted with water (30.0 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (60 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex luna C18150*25 mm* 10 μm; mobile phase: [water (FA)-ACN];B%: 33%-63%, 10 min) to give (1R,2S,5S)-N-[cyano(pyridazin-3-yl)methyl]-3-[(2S)-3,3-dimet hyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (46.0 mg, 0.0950 mmol, 68% yield, 99% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.71 (dd, J = 13.2, 8.0 Hz, 1H), 9.40 (t, J = 7.2 Hz, 1H), 9.32-9.24 (m, 1H), 7.79-7.70 (m, 2H), 6.62-6.46 (m, 1H), 4.38 (d, J = 5.2 Hz, 1H), 4.31 (d, J = 18.0 Hz, 1H), 3.91 (dt, J = 10.0, 5.6 Hz, 1H), 3.70 (t, J = 10.0 Hz, 1H), 1.63-1.54 (m, 1H), 1.43-1.31 (m, 1H), 1.05-0.95 (m, 13H), 0.88-0.84 (m, 3H). LCMS (Method C): R _t = 1.438 min; MS (ESIpos): m/z = 481.2 [M+H] ⁺ . Preparation of CPD0189015 Procedure for preparation of 4-bromo-5-methyl-pyridin-2-ol Sulfuric acid (920 mg, 9.19 mmol, 0.500 mL, 98% purity, 3.44 eq) was added to water (5.00 mL) followed by 4-bromo-5-methyl-pyridin-2-amine (500 mg, 2.67 mmol, 1.00 eq). The resulting mixture was cooled to 0 °C. A solution of sodium nitrite (221 mg, 3.21 mmol, 1.20 eq) in water (1.00 mL) was added dropwise slowly to the mixture at 0 °C. The reaction mixture was warmed to 25 °C, and stirred at this temperature for 2 h. The resulting precipitate was filtered and the filter cake was dried under vacuum to give 4- bromo-5-methyl-pyridin-2-ol (500 mg, 2.66 mmol, 99% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.72 (br s, 1H), 7.36 (s, 1H), 6.71 (s, 1H), 2.05 (s, 3H). Procedure for preparation of 4-bromo-1-[(4-methoxyphenyl)methyl]-5-methyl-pyridin-2-one To a mixture of 4-bromo-5-methyl-pyridin-2-ol (500 mg, 2.66 mmol, 1 eq) and potassium carbonate (919 mg, 6.65 mmol, 2.50 eq) in N,N-dimethylformamide (5.00 mL) was added 1-(chloromethyl)-4-methoxy- benzene (625 mg, 3.99 mmol, 543 μL, 1.50 eq). After stirring at 80 °C for 32 h, the mixture was diluted with water (20.0 mL). The resulting mixture was extracted with ethyl acetate (20.0 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12.0 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient) to give 4- bromo-1-[(4-methoxyphenyl)methyl]-5-methyl-pyridin-2-one (460 mg, 1.49 mmol, 56% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.25 (d, J = 8.8 Hz, 2H), 7.06 (s, 1H), 6.95 (s, 1H), 6.91-6.85 (m, 2H), 5.02 (s, 2H), 3.80 (s, 3H), 2.08 (s, 3H). Procedure for preparation of methyl 2-(benzhydrylideneamino)-2-[1-[(4-methoxyphenyl)methyl]- 5-methyl-2-oxo-4-pyridyl]acetate To a mixture of 4-bromo-1-[(4-methoxyphenyl)methyl]-5-methyl-pyridin-2-one (1.76 g, 5.71 mmol, 1.00 eq), methyl 2-(benzhydrylideneamino)acetate (1.59 g, 6.28 mmol, 1.10 eq) and potassium hexafluorophosphate (2.42 g, 11.4 mmol, 2.00 eq) in N,N-dimethylformamide (20.0 mL) was added [2- (2-aminophenyl)phenyl]-chloro-palladium;tritert-butylphospha ne (293 mg, 571 μmol, 0.100 eq) under nitrogen atmosphere. After stirring at 90 °C for 16 h, the mixture was concentrated under vacuum to give a residue. The residue was purified by reverse phase HPLC (basic condition, column: 3_Phenomenex Luna C1875*30mm*3 μm; mobile phase: [water(0.0.01%ammonia hydroxide)-ACN]; B%: 45%-66%,5 min), followed by lyophilization to give methyl 2-(benzhydrylideneamino)-2-[1-[(4- methoxyphenyl)methyl]-5-methyl-2-oxo-4-pyridyl]acetate (1.50 g, 3.12 mmol, 55% yield) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.61-7.56 (m, 3H), 7.53 (dd, J = 4.4, 2.0 Hz, 3H), 7.44 (q, J = 7.2 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 7.12 (dd, J = 6.4, 2.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 6.41 (s, 1H), 4.96 (s, 1H), 4.94 (s, 2H), 3.71 (s, 3H), 3.63 (s, 3H), 1.75 (s, 3H). Procedure for preparation of 2-(benzhydrylideneamino)-2-[1-[(4-methoxyphenyl)methyl]-5- methyl-2-oxo-4-pyridyl]acetamide A mixture of methyl 2-(benzhydrylideneamino)-2-[1-[(4-methoxyphenyl)methyl]-5-me thyl-2-oxo-4- pyridyl]acetate (1.00 g, 2.08 mmol, 1.00 eq) and ammonium (7 M in methanol, 40.0 mL, 134 eq) was stirred at 25 °C for 16 h. The mixture was concentrated under vacuum to give 2- (benzhydrylideneamino)-2-[1-[(4-methoxyphenyl)methyl]-5-meth yl-2-oxo-4-pyridyl]acetamide (900 mg, 1.93 mmol, 93% yield) as light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.76-7.68 (m, 2H), 7.59 (s, 1H), 7.53-7.39 (m, 8H), 7.25 (d, J = 8.8 Hz, 2H), 7.11-7.00 (m, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.52 (s, 1H), 4.92 (q, J = 14.0 Hz, 2H), 4.69 (s, 1H), 3.71 (s, 3H), 1.66 (s, 3H). Procedure for preparation of 2-amino-2-[1-[(4-methoxyphenyl)methyl]-5-methyl-2-oxo-4- pyridyl]acetamide To a mixture of 2-(benzhydrylideneamino)-2-[1-[(4-methoxyphenyl)methyl]-5-me thyl-2-oxo-4- pyridyl]acetamide (900 mg, 1.93 mmol, 1.00 eq) in dioxane (2.00 mL) was added hydrochloride/dioxane (4 M, 5.00 mL, 10.3 eq). The mixture was stirred at 25 °C for 16 h. The mixture was concentrated to give a residue. The residue was triturated with methyl ethyl ether (20.0 mL) to give 2-amino-2-[1-[(4- methoxyphenyl)methyl]-5-methyl-2-oxo-4-pyridyl]acetamide (550 mg, 1.63 mmol, 84% yield, hydrochloride) as brown solid. Procedure for preparation of 2-amino-2-(5-methyl-2-oxo-1H-pyridin-4-yl)acetamide To a mixture of 2-amino-2-[1-[(4-methoxyphenyl)methyl]-5-methyl-2-oxo-4-pyri dyl]acetamide (400 mg, 1.33 mmol, 1 eq) in trifluoroacetic acid (5.00 mL) was added trifluoromethanesulfonic acid (598 mg, 3.98 mmol, 0.352 mL, 3.00 eq). The mixture was stirred at 60 °C for 48 h and 70 °C for 16 h. The mixture was concentrated to give a residue. The residue was purified by reverse phase (Instrument: 80 g Flash; Column: Welch Ultimate XB_C1820-40μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-3 min 0% B; flow 30 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give 2-amino-2-(5-methyl-2-oxo-1H-pyridin-4-yl)acetamide (300 mg, crude) as yellow oil and 2-amino- 2-[1-[(4-methoxyphenyl)methyl]-5-methyl-2-oxo-4-pyridyl]acet amide (150 mg, 498 μmol, 37% yield) as a yellow solid. Procedure for preparation of tert-butyl N-[2-amino-1-(5-methyl-2-oxo-1H-pyridin-4-yl)-2-oxo- ethyl]carbamate To a mixture of 2-amino-2-(5-methyl-2-oxo-1H-pyridin-4-yl)acetamide (300 mg, 1.66 mmol, 1.00 eq) and sodium hydrocarbonate (278 mg, 3.31 mmol, 0.129 mL, 2 eq) in methanol (5.00 mL) was added di-tert-butyldicarbonate (723 mg, 3.31 mmol, 0.761 mL, 2.00 eq). The mixture was stirred at 25 °C for 16 h. The mixture was concentrated to give a residue. The residue was purified by reversed phase (instrument: 120 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.1% NH ₃ ^H ₂ O), eluent B: acetonitrile; gradient: 0-10 min 0-60% B; flow 85 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give tert-butyl N-[2-amino-1-(5-methyl-2-oxo-1H-pyridin-4-yl)-2-oxo- ethyl]carbamate (80.0 mg, 0.284 mmol, 17% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.46-7.42 (m, 1H), 7.36-7.20 (m, 2H), 7.15 (s, 1H), 6.21 (s, 1H), 4.99 (d, J = 8.0 Hz, 1H), 2.00 (s, 3H), 1.43-1.24 (m, 9H). Procedure for preparation of 2-amino-2-(5-methyl-2-oxo-1H-pyridin-4-yl)acetamide To a mixture of tert-butyl N-[2-amino-1-(5-methyl-2-oxo-1H-pyridin-4-yl)-2-oxo-ethyl]ca rbamate (50.0 mg, 0.178 mmol, 1.00 eq) in dioxane (0.500 mL) was added hydrochloride/dioxane (4 M, 0.833 mL, 18.8 eq). After stirring at 25 °C for 2 h, the mixture was concentrated under vacuum to give 2-amino-2- (5-methyl-2-oxo-1H-pyridin-4-yl)acetamide (38.0 mg, 0.174 mmol, 98% yield, Hydrochloride) Procedure for preparation of (1R,2S,5S)-N-[2-amino-1-(5-methyl-2-oxo-1H-pyridin-4-yl)-2-o xo- ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino] butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide A mixture of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (70.0 mg, 0.192 mmol, 1.10 eq), [dimethylamino(triazolo[4,5- b]pyridin-3-yloxy)methylene]-dimethyl-ammonium;hexafluoropho sphate (86.3 mg, 0.227 mmol, 1.30 eq) and N-ethyl-N-isopropyl-propan-2-amine (67.7 mg, 0.524 mmol, 0.0912 mL, 3.00 eq) in dichloromethane (1 mL) was stirred at 25 °C for 10 min. 2-Amino-2-(5-methyl-2-oxo-1H-pyridin-4- yl)acetamide (38.0 mg, 0.175 mmol, 1.00 eq, hydrochloride) was added to the solution above. After stirring at 25 °C for 16 h, the mixture was concentrated to give a residue. The residue was purified by reversed phase (instrument: 6 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-25 min 0-30% B; flow 50 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)-N-[2-amino-1-(5-methyl-2-oxo-1H-pyridin- 4-yl)-2-oxo-ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroa cetyl) amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (70.0 mg, 0.133 mmol, 76% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 11.46-11.27 (m, 1H), 9.45-9.24 (m, 1H), 8.94-8.53 (m, 1H), 7.62- 7.48 (m, 1H), 7.40-7.23 (m, 1H), 7.18-7.13 (m, 1H), 6.28 (d, J = 13.6 Hz, 1H), 5.33-5.19 (m, 1H), 4.43- 4.37 (m, 1H), 4.35 (d, J = 4.4 Hz, 1H), 3.94-3.83 (m, 1H), 3.78-3.68 (m, 1H), 2.46-2.43 (m, 1H), 2.26 (t, J = 6.8 Hz, 1H), 2.04-1.98 (m, 3H), 1.79-1.62 (m, 1H), 1.55-1.49 (m, 1H), 1.41-1.20 (m, 1H), 1.05-0.96 (m, 12H), 0.85-0.84 (m, 3H). Procedure for preparation of Compound CPD0189015 - (1R,2S,5S)-N-[cyano-(5-methyl-2-oxo-1H- pyridin-4-yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluor oacetyl)amino]butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of (1R,2S,5S)-N-[2-amino-1-(5-methyl-2-oxo-1H-pyridin-4-yl)-2-o xo-ethyl]-3-[(2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (40.0 mg, 0.076 mmol, 1.00 eq) in dichloromethane (1.00 mL) was added burgess reagent (16.3 mg, 0.0682 mmol, 0.900 eq). The mixture was stirred at 25 °C for 16 h. Burgess reagent (18.1 mg, 0.0758 mmol, 1.00 eq) was added. The mixture was continue to stirring at 25 °C for 16 h. The mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Unisil 3- 100 C18 Ultra 150*50mm*3 μm; mobile phase: [water(FA)-ACN];B%: 34%-64%,7min) to give (1R,2S,5S)-N-[cyano-(5-methyl-2-oxo-1H-pyridin-4-yl)methyl]- 3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxamide (15.0 mg, 0.0290 mmol, 38% yield, 98% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.44-9.18 (m, 2H), 7.24 (s, 1H), 6.50 (d, J = 2.0 Hz, 1H), 6.14-6.03 (m, 1H), 4.38 (d, J = 8.4 Hz, 1H), 4.24 (d, J = 9.2 Hz, 1H), 3.95-3.82 (m, 1H), 3.75-3.63 (m, 1H), 1.98- 1.92 (m, 3H), 1.63-1.53 (m, 1H), 1.31-1.19 (m, 1H), 1.04-0.95 (m, 12H), 0.84-0.83 (m, 3H). LC-MS (Method C): Rt = 0.880 min; MS (ESIpos): m/z = 510.0 [M+H] ⁺ . SFC: dr = 36: 63. Preparation of CPD0189016 Procedure for preparation of (E)-tert-butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxabo rolan-2- yl)allyl)oxy)silane To a solution of pinacol borane (9.02 g, 70.5 mmol, 10.2 mL, 1.20 eq) and Schwartz's reagent (3.03 g, 11.7 mmol, 0.20 eq) in tetrahydrofuran (150 mL) was added N,N-diethylethanamine (1.19 g, 11.7 mmol, 1.63 mL, 0.20 eq). After stirring at 50 °C for 30 min, tert-butyl-dimethyl-prop-2-ynoxy-silane (10.0 g, 58.7 mmol, 11.9 mL, 1.00 eq) was added. The mixture was stirred at 50 °C for 15.5 h. The mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 100: 1 to 50: 1, petroleum ether: ethyl acetate = 10: 1) to afford tert-butyl-dimethyl- [3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyloxy]sil ane (15.6 g, 47.1 mmol, 80% yield, 90% purity) as yellow oil. ¹ H NMR (400 MHz, CD ₃ Cl): δ = 6.72-6.65 (m, 1H), 5.78-5.74 (m, 1H), 4.26-4.25 (m, 2H), 1.27 (s, 12H), 0.92 (s, 9H), 0.06 (s, 6H). Procedure for preparation of (E)-2-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-3,5- dichloropyrazine To a solution of 2-bromo-3,5-dichloro-pyrazine (4.00 g, 17.6 mmol, 1.00 eq) and tert-butyl-dimethyl-[3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyloxy]silane (10.5 g, 35.1 mmol, 2.00 eq) in dioxane (50.0 mL) were added water (1.58 g, 87.8 mmol, 1.58 mL, 5.00 eq), sodium carbonate (5.58 g, 52.7 mmol, 12.2 μL, 3.00 eq) and [1,1-bis(diphenylphosphino)ferrocene]palladium(II)dichloride (771 mg, 1.05 mmol, 0.06 eq). After stirring at 100 °C for 16 h under nitrogen atmosphere, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 100: 1 to 50: 1, Petroleum ether: Ethyl acetate = 10: 1) to afford tert-butyl-[3-(3,5-dichloropyrazin-2-yl)allyloxy]-dimethyl-s ilane (6.10 g, 15.3 mmol, 87% yield, 80% purity) as yellow oil. Procedure for preparation of 3-(3,5-dichloropyrazin-2-yl)propan-1-ol To a solution of tert-butyl-[3-(3,5-dichloropyrazin-2-yl)allyloxy]-dimethyl-s ilane (6.00 g, 15.0 mmol, 80% purity, 1.00 eq) in ethyl alcohol (100 mL) was added platinum(IV)oxygen (1.00 g, 4.40 mmol, 0.03 eq) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred at 25°C for 16 h under hydrogen (15 psi) atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silicon dioxide, Petroleum ether: Ethyl acetate = 3: 1 to 1: 1, Petroleum ether: Ethyl acetate = 1: 1) to afford 3-(3,5-dichloropyrazin-2-yl)propan-1-ol (1.30 g, 6.28 mmol, 42% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 8.76 (s, 1H), 4.63-4.47(m, 1H), 3.55-3.44(m, 2H), 3.04-2.85(m, 2H), 1.90-1.76(m, 2H). Procedure for preparation of 3-(2-chlorophenyl)cyclobutanone To a solution of 3-(3,5-dichloropyrazin-2-yl)propan-1-ol (1.30 g, 6.28 mmol, 1.00 eq) in tetrahydrofuran (30 mL) was added sodium tert-butoxide (905 mg, 9.42 mmol, 1.50 eq). The mixture was stirred at 25 °C for another 30 min. The reaction mixture was quenched with water (50 mL) at 0 °C, and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with water (30 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 10: 1 to 5: 1, Petroleum ether: Ethyl acetate = 3: 1) to afford 3-chloro-7,8-dihydro-6H-pyrano[2,3-b]pyrazine (940 mg, 4.96 mmol, 79% yield, 90% purity) as a white solid. ¹ H NMR (400 MHz, CD3Cl): δ = 8.29-7.92 (m, 1H), 4.47-4.23(m, 2H), 3.14-2.83(m, 2H), 2.24-2.04(m, 2H). Procedure for preparation of methyl 2-(7,8-dihydro-6H-pyrano[2,3-b]pyrazin-3-yl)-2- ((diphenylmethylene)amino)acetate To a solution of 3-chloro-7,8-dihydro-6H-pyrano[2,3-b]pyrazine (200 mg, 1.17 mmol, 1.00 eq) and methyl 2-(benzhydrylideneamino)acetate (297 mg, 1.17 mmol, 1.00 eq) in N,N-dimethylformamide (15.0 mL) were added tripotassium phosphate (746 mg, 3.52 mmol, 3.00 eq) and chloro[(tri-tetr- butylphosphine)-2-(2-aminobiphenyl)] palladium(II) (60.1 mg, 0.117 mmol, 0.10 eq). The reaction mixture was stirred at 100 °C for 15 h under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 10: 1 to 1: 1, Petroleum ether: Ethyl acetate = 1: 1) to afford methyl 2-(benzhydrylideneamino)-2-(7,8-dihydro-6H-pyrano[2,3-b]pyra zin-3-yl)acetate (400 mg, 1.03 mmol, 88% yield) as a yellow solid Procedure for preparation of 2-(7,8-dihydro-6H-pyrano[2,3-b]pyrazin-3-yl)-2- ((diphenylmethylene)amino)acetamide Methyl 2-(benzhydrylideneamino)-2-(7,8-dihydro-6H-pyrano[2,3-b]pyra zin-3-yl)acetate (500 mg, 1.29 mmol, 1.00 eq) was added to ammonia (7M in methanol, 10.0 mL, 54.2 eq). Yhe reaction mixture was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 3: 1 to 1: 1, Petroleum ether: Ethyl acetate = 1: 1) to give 2-(benzhydrylideneamino)-2-(7,8-dihydro-6H-pyrano[2,3- b]pyrazin-3-yl)acetamide (200 mg, crude) as a yellow solid. Procedure for preparation of 2-amino-2-(7,8-dihydro-6H-pyrano[2,3-b]pyrazin-3-yl)acetamid e 2-(Benzhydrylideneamino)-2-(7,8-dihydro-6H-pyrano[2,3-b]pyra zin-3-yl)acetamide (100 mg, 0.268 mmol, 1.00 eq) was added to trifluoroacetic acid (3.20 g, 28.1 mmol, 2.08 mL, 105 eq). The reaction mixture was stirred at 50 °C for 1 h. The mixture was concentrated under reduced pressure to give [2- amino-2-(7,8-dihydro-6H-pyrano[2,3-b]pyrazin-3-yl)acetamide (100 mg, crude) as yellow oil. Procedure for preparation of (1R,2S,5S)-N-(2-amino-1-(7,8-dihydro-6H-pyrano[2,3-b]pyrazin -3- yl)-2-oxoethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetam ido)butanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (175 mg, 0.480 mmol, 1.00 eq) and [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-d imethylazanium (192 mg, 0.504 mmol, 1.05 eq) in dichloromethane (5.00 mL) was added N-ethyl-N-isopropylpropan-2-amine (310.36 mg, 2.40 mmol, 0.418 mL, 5 eq). After stirring at 25 °C for 30 min, 2-amino-2-(7,8-dihydro-6H-pyrano[2,3- b]pyrazin-3-yl)acetamide (100 mg, 0.480 mmol, 1 eq) was added to the reaction mixture above. The reaction mixture was stirred at 25 °C for 30 min. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 10: 1 to 1: 1, Petroleum ether: Ethyl acetate = 1: 1) to give (1R,2S,5S)-N-[2-amino-1-(7,8- dihydro-6H-pyrano[2,3-b]pyrazin-3-yl)-2-oxo-ethyl]-3-[(2S)-3 ,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (100 mg, 0.135 mmol, 28% yield, 75% purity) as a yellow solid. Procedure for preparation of Compound CPD0189016 – (1R,2S,5S)-N-(cyano(7,8-dihydro-6H- pyrano[2,3-b]pyrazin-3-yl)methyl)-3-((S)-3,3-dimethyl-2-(2,2 ,2-trifluoroacetamido)butanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-[2-amino-1-(7,8-dihydro-6H-pyrano[2,3-b]pyrazin -3-yl)-2-oxo-ethyl]-3- [(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl] -6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (80.0 mg, 0.144 mmol, 1.00 eq) in dichloromethane (20.0 mL) was added Burgess reagent (68.8 mg, 0.289 mmol, 2.00 eq). After stirring at 25 °C 3 h, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC [column: Unisil 3-100 C18 Ultra 150*50mm*3 μm; mobile phase: [water(formic acid)-acetonitrile];B%: 44%-74%,7min] to give (1R,2S,5S)-N-[cyano(7,8-dihydro-6H-pyrano[2,3-b]pyrazin-3-yl )methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino] butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxami de (32.0 mg, 58.0 μmol, 40% yield, 97% purity) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ): δ = 9.63-9.49 (m, 1H), 9.44-9.33 (m, 1H), 8.29-8.21 (m, 1H), 6.33-6.17 (m, 1H), 4.43-4.37 (m, 3H), 4.35-4.29 (m, 1H), 3.96-3.84 (m, 1H), 3.75-3.66 (m, 1H), 3.46-3.38 (m, 1H), 3.28-3.24 (m, 1H), 2.99-2.92 (m, 2H), 2.65-2.55 (m, 1H), 2.55 (br s, 2H), 2.46-2.42 (m, 1H), 2.12-2.03 (m, 2H), 1.63-1.51 (m, 1H), 1.41-1.35 (d, 0.5H), 1.32-1.27 (d, 0.5H), 0.99 (s, 9H). LC-MS (Method C): Rt = 0.581 min; MS (ESIpos): m/z = 537.2 [M+H] ⁺ SFC: de% = 83%. Preparation of CPD0189018 Procedure for preparation of N'-(4-bromo-6-methyl-2-pyridyl)-N-hydroxy-formamidine To a solution of 4-bromo-6-methyl-pyridin-2-amine (4.50 g, 24.1 mmol, 1.00 eq) in isopropanol (40.0 mL) was added 1,1-dimethoxy-N,N-dimethyl-methanamine (8.60 g, 72.2 mmol, 9.59 mL, 3.00 eq). The mixture stirred at 80 °C for 1 h. Then hydroxylamine;hydrochloride (2.68 g, 38.5 mmol, 1.60 eq) was added. The mixture was stirred at 50 °C for 16 h. The reaction mixture was quenched with sodium hydrogen carbonate (30.0 mL) at 25 °C, then diluted with water (30.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers was dried over disodium sulfate, filtered and concentrated under reduced pressure to give N'-(4-bromo-6-methyl-2-pyridyl)-N-hydroxy-formamidine (2.40 g, 10.4 mmol, 43% yield) as a brown solid. LC-MS (Method A): R _t = 0.856 min; MS (ESIpos): m/z = 232.0 [M+H] ⁺ . Procedure for preparation of 7-bromo-5-methyl-[1,2,4]triazolo[1,5-a]pyridine To a solution of N'-(4-bromo-6-methyl-2-pyridyl)-N-hydroxy-formamidine (2.40 g, 10.4 mmol, 1.00 eq) in tetrahydrofuran (30.0 mL) was added (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (4.38 g, 20.9 mmol, 2.90 mL, 2.00 eq). After stirring at 40 °C for 7 h, the reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran. The residue was diluted with water (50.0 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether: ethyl acetate = 5: 1 to 3: 1) to afford 7-bromo-5-methyl- [1,2,4]triazolo[1,5-a]pyridine (1.40 g, 6.60 mmol, 63% yield) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d6) δ = 8.54 (s, 1H), 8.09 (s, 1H), 7.37 (s, 1H), 2.72 (s, 3H). LC-MS (Method A): R _t = 0.831 min; MS (ESIpos): m/z = 213.9 [M+H] ⁺ . Procedure for preparation of 5-methyl-7-vinyl-[1,2,4]triazolo[1,5-a]pyridine To a solution of 7-bromo-5-methyl-[1,2,4]triazolo[1,5-a]pyridine (0.600 g, 2.80 mmol, 1.00 eq) and potassium trifluoro(vinyl)boranuide (455 mg, 3.40 mmol, 1.20 eq) in dioxane (10.0 mL) and water (2.00 mL) were added sodium carbonate (900 mg, 8.50 mmol, 3.00 eq) and cyclopentyl(diphenyl)phosphane;dichloropalladium iron (207 mg, 283 μmol, 0.100 eq). After stirring at 90 °C for 15 h under nitrogen atmosphere, the reaction mixture was quenched with water (10 mL) at 25 °C, and filtered. The filtrate was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 5-methyl-7-vinyl-[1,2,4]triazolo[1,5-a]pyridine (222 mg, 1.40 mmol, 49% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.49-8.44 (m, 1H), 7.74-7.69 (m, 1H), 7.36 (s, 1H), 6.89-6.80 (m, 1H), 6.12 (d, J = 17.6 Hz, 1H), 5.55-5.49 (m, 1H), 2.72 (s, 3H). LC-MS (Method A): R _t = 0.829 min; MS (ESIpos): m/z = 160.1 [M+H] ⁺ . Procedure for preparation of 5-methyl-[1,2,4]triazolo[1,5-a]pyridine-7-carbaldehyde Ozone (15 psi) was bubbled into a solution of 5-methyl-7-vinyl-[1,2,4]triazolo[1,5-a]pyridine (222 mg, 1.40 mmol, 1.00 eq) in a mixed solvent of dichloromethane (0.500 mL) and methanol (2.00 mL). at -78 °C. After stirring for 30 min, methylsulfanylmethane (777 mg, 12.5 mmol, 918 μL, 9.00 eq) was added dropwise to the solution above, After stirring at-78 °C for 0.5 h, the mixture was warmed to 20 °C, and stirred for 2 h. The solution was concentrated to afford 5-methyl-[1,2,4]triazolo[1,5-a]pyridine-7- carbaldehyde (180 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.28 (d, J = 3.2 Hz, 3H), 4.43 (dd, J = 9.2, 4.8 Hz, 1H), 4.08-3.98 (m, 2H), 3.88-3.82 (m, 1H), 3.50-3.44 (m, 1H), 3.21 (s, 3H), 2.38-2.23 (m, 1H), 2.07-1.97 (m, 1H), 1.05 (s, 9H). LC-MS (Method H): R _t = 1.171 min; MS (ESIpos): m/z = 162.0 [M+H] ⁺ . Procedure for preparation of 2-amino-2-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)aceto nitrile To a solution of 5-methyl-[1,2,4]triazolo[1,5-a]pyridine-7-carbaldehyde (150 mg, 931 μmol, 1.00 eq) in methonal (5 mL) were added tetraisopropoxytitanium (317 mg, 1.10 mmol, 330 uL, 1.20 eq) and ammonia (7.00 M in methanol, 931 μL, 7 eq) at 25 °C for 20 min. Trimethylsilylformonitrile (111 mg, 1.10 mmol, 140 μL, 1.20 eq) was added dropwise to the solution above over 10 min. After stirring at 25 °C for 1.5 h, the reaction mixture was diluted with water (10.0 mL) and extracted with a mixed solvent of dichloromethane and methanol (v/v: 10/1, 10 mL × 6). The combined organic layers was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 2-amino-2-(5- methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)acetonitrile (83.0 mg, crude) as saffron yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.54 (s, 1H), 7.83-7.79 (m, 1H), 7.26-7.22 (m, 1H), 5.25-5.19 (m, 1H), 3.32-3.31 (m, 3H), 3.06-3.00 (m, 2H), 2.76 (s, 3H). LC-MS (Method A): R _t = 0.138 min; MS (ESIpos): m/z = 188.3 [M+H] ⁺ . Procedure for preparation of Compound CPD0189018 - (1R,2S,5S)-N-[cyano-(5-methyl- [1,2,4]triazolo[1,5-a]pyridin-7-yl)methyl]-3-[(2S)-3,3-dimet hyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide- To a solution of 2-amino-2-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)aceto nitrile (50.0 mg, 267 μmol, 1.00 eq) and (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (97.3 mg, 267 μmol, 1.00 eq) in dichloromethane (2.00 mL) were added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dim ethyl- ammonium;hexafluorophosphate (152 mg, 401 μmol, 1.50 eq) and N-ethyl-N-isopropyl-propan-2-amine (69.0 mg, 534 μmol, 93.1 μL, 2.00 eq). After stirring at 25 °C for 6 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition,column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: [water(FA)-ACN]; B%: 43%- 73%,7min) to afford (1R,2S,5S)-N-[cyano-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin- 7-yl)methyl]-3-[(2S)- 3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-d imethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (44.6 mg, 83.7 μmol, 31% yield, 100% purity) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.44 (d, J = 10.8 Hz, 1H), 8.24-8.18 (m, 1H), 7.96-7.92 (m, 1H), 7.92- 7.90 (m, 1H), 6.88 (s, 2H), 6.22-6.17 (m, 1H), 6.20 (d, J = 9.2 Hz, 1H), 4.62-4.55 (m, 1H), 4.54-4.48 (m, 1H), 4.44-4.37 (m, 1H), 3.94-3.82 (m, 2H), 2.81 (s, 2H), 2.85 (s, 1H), 1.84-1.70 (m, 1H), 1.69-1.57 (m, 1H), 1.11-1.08 (m, 3H), 1.06 (s, 6H), 0.90-0.85 (m, 3H), 0.82 (s, 3H). LC-MS (Method C): R _t = 0.774 min; MS (ESIpos): m/z = 534.2 [M+H] ⁺ . SFC : dr = 8: 50: 33. Preparation of CPD0189021 Procedure for preparation of 5-methyl-6,7-dihydrothieno[3,2-c]pyridin-4-one To a solution of 6,7-dihydro-5H-thieno[3,2-c]pyridin-4-one (3.50 g, 22.9 mmol, 1.00 eq) in tetrahydrofuran (25.0 mL) was added sodium hydride (2.74 g, 68.5 mmol, 60% purity, 3.00 eq) at 0 °C for 5min under nitrogen atmosphere. After stirring at this temperature for 10 min, iodomethane (19.5 g, 137 mmol, 8.53 mL, 6.00 eq) was added dropwise at 0 °C. After stirring at 20 °C for 16 h, the reaction mixture was quenched with saturated ammonia chloride solution (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The filtrate was concentrated under reduced pressure to afford 5-methyl-6,7-dihydrothieno[3,2-c]pyridin-4- one (2.40 g, 14.4 mmol, 63% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.35 (d, J = 5.2 Hz, 1H), 7.23 (d, J = 5.2 Hz, 1H), 3.60 (t, J = 6.8 Hz, 2H), 3.06 (t, J = 6.8 Hz, 2H), 2.95 (s, 3H). LC-MS (Method C): R _t = 0.278 min; MS (ESIpos): m/z = 167.9 [M+H] ⁺ . Procedure for preparation of 5-methyl-6,7-dihydrothieno[3,2-c]pyridin-4-one To a solution of 5-methyl-6,7-dihydrothieno[3,2-c]pyridin-4-one (1.50 g, 8.97 mmol, 1.00 eq) in acetic acid (10.0 mL) were added 1-bromopyrrolidine-2,5-dione (2.39 g, 13.5 mmol, 1.50 eq) and N,N- dimethylformamide (10.0 mL). After stirring at 20 °C for 16 h, the reaction mixture was diluted with ethyl acetate (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with bring (30.0 mL), dried over sodium sulfate, filtered. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 100: 1 to 1: 100) to afford 2-bromo-5-methyl- 6,7-dihydrothieno[3,2-c]pyridin-4-one (1.00 g, 4.06 mmol, 45% yield) as brown oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.27 (s, 1H), 3.60 (t, J = 6.8 Hz, 2H), 3.02 (t, J = 6.8 Hz, 2H), 2.95- 2.92 (m, 3H). LC-MS (Method C): R _t = 0.376 min; MS (ESIpos): m/z = 245.8 [M+H] ⁺ . Procedure for preparation of 5-methyl-2-vinyl-6,7-dihydrothieno[3,2-c]pyridin-4-one A mixture of 2-bromo-5-methyl-6,7-dihydrothieno[3,2-c]pyridin-4-one (1.60 g, 6.50 mmol, 1.00 eq), potassium;trifluoro(vinyl)boranuide (3.48 g, 26.0 mmol, 4.00 eq), cyclopenta-2,4-dien-1- yl(diphenyl)phosphane;dichloropalladium;iron(2+) (476 mg, 0.65 mmol, 0.100 eq), anhydrous sodium carbonate (2.07 g, 19.5 mmol, 3.00 eq) and H2O (0.300 mL) in dioxane (15.0 mL) was degassed and purged with nitrogen for 3 times. After stirring at 90 °C for 16 h under nitrogen atmosphere, the reaction mixture was diluted with H2O (30.0 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine (40.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 100: 1 to 1: 100) to afford 5-methyl-2-vinyl-6,7- dihydrothieno[3,2-c]pyridin-4-one (460 mg, 2.38 mmol, 37% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.15 (s, 1H), 6.78 (dd, J = 17.6, 10.8 Hz, 1H), 5.42 (d, J = 17.6 Hz, 1H), 5.09 (d, J = 10.8 Hz, 1H), 3.53 (t, J = 6.8 Hz, 2H), 2.97 (t, J = 6.8 Hz, 2H), 2.87 (s, 3H). LC-MS (Method C): R _t = 0.376 min; MS (ESIpos): m/z = 194.1 [M+H] ⁺ . Procedure for preparation of methyl-4-oxo-6,7-dihydrothieno[3,2-c]pyridine-2-carbaldehyde A solution of 5-methyl-2-vinyl-6,7-dihydrothieno[3,2-c]pyridin-4-one (460 mg, 2.38 mmol, 1.00 eq) in dichloromethane (20.0 mL) was cooled to -78 °C. Ozone (15 Psi) was bubbled to the mixture at -78 °C for 15 min. Methylsulfanylmethane (444 mg, 7.14 mmol, 524 μL, 3.00 eq) was added. The mixture was stirred at -78 °C for 0.5 h. After stirring at 20 °C for 0.5 h, the mixture was concentrated in vacuum to give 5-methyl-4-oxo-6,7-dihydrothieno[3,2-c]pyridine-2-carbaldehy de (460 mg, crude) as a brown solid. LC-MS (Method C): R _t = 0.284 min; MS (ESIpos): m/z = 195.8 [M+H] ⁺ . Procedure for preparation of 2-amino-2-(5-methyl-4-oxo-6,7-dihydrothieno[3,2-c]pyridin-2- yl)acetonitrile To a solution of 5-methyl-4-oxo-6,7-dihydrothieno[3,2-c]pyridine-2-carbaldehy de (460 mg, 2.36 mmol, 1.00 eq) in methyl alcohol (8.00 mL) were added to ammonia (7 M in methanol, 2.36 mL, 7.00 eq) and propan-2-olate;titanium(4+) (737 mg, 2.59 mmol, 765 uL, 1.10 eq). After stirring at 20 °C for 1 h. trimethylsilanecarbonitrile (280 mg, 2.83 mmol, 354 uL, 1.20 eq) was added. After stirring at 20 °C for 3 h, the reaction mixture was diluted with (H2O 30.0 mL) and extracted with dichloromethane (20.0 mL × 3). The combined organic layers were washed with bring (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-amino-2-(5-methyl-4-oxo-6,7- dihydrothieno[3,2-c]pyridin-2-yl)acetonitrile (350 mg, crude) as a brown solid. LC-MS (Method C): R _t = 0.159 min; MS (ESIpos): m/z = 221.9 [M+H] ⁺ . Procedure for preparation of CPD0189021 - (1R,2S,5S)-N-[cyano-(5-methyl-4-oxo-6,7- dihydrothieno[3,2-c]pyridin-2-yl)methyl]-3-[(2S)-3,3-dimethy l-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide - To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (692 mg, 1.90 mmol, 1.20 eq) in dichloromethane (15.0 mL) were added diisopropylethylamine (613 mg, 4.75 mmol, 827 μL, 3.00 eq) and O-(7- azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (722 mg, 1.90 mmol, 1.20 eq) at 0 °C. After stirring at 20 °C for 0.5 h, 2-amino-2-(5-methyl-4-oxo-6,7-dihydrothieno[3,2-c]pyridin- 2-yl)acetonitrile (350 mg, 1.58 mmol, 1.00 eq) was added. After stirring at 20 °C for 15 h, the mixture was concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water (formic acid) - acetonitrile]; B%: 40%- 70%, 10min) to give a residue (40.0 mg, crude). The residue (40.0 mg, crude) was purified by prep- HPLC (column: Phenomenex luna C18 150*25mm* 10 μm; mobile phase: [water (formic acid)- acetonitrile]; B%: 12%-42%, 8min) to afford (1R,2S,5S)-N-[cyano-(5-methyl-4-oxo-6,7- dihydrothieno[3,2-c]pyridin-2-yl)methyl]-3-[(2S)-3,3-dimethy l-2-[(2,2,2-trifluoroacetyl) amino]butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (20.0 mg, 32.7 μmol, 2% yield, 93% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.65 - 9.48 (m, 1H), 9.46-9.34 (m, 1H), 7.39-7.27 (m, 1H), 6.49-6.38 (m, 1H), 4.40 (d, J = 8.2 Hz, 1H), 4.26 (d, J = 4.8 Hz, 1H), 3.96-3.84 (m, 1H), 3.70 (br d, J = 10.4 Hz, 1H), 3.61 (t, J = 7.2 Hz, 2H), 3.06 (t, J = 6.8 Hz, 2H), 2.95 (s, 3H), 1.60-1.51 (m, 1H), 1.35-1.19 (m, 1H), 1.05 - 0.96 (m, 12H), 0.87-0.82 (m, 3H). LC-MS (Method C): R _t = 2.095 min; MS (ESIpos): m/z = 568.7 [M+H] ⁺ . Preparation of CPD0189022 Procedure for preparation of 4-chloro-6-methoxy-pyrimidine-5-carbaldehyde To a solution of 4, 6-dichloropyrimidine-5-carbaldehyde (7 g, 39.6 mmol, 1 eq) in methyl alcohol (100 mL) was added sodium methylate (1.92 g, 35.6 mmol, 0.90 eq). The mixture was stirred at 20 °C for 3 h. The reaction mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (100 mL×2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 1/0 to 5/1) to give 4-chloro-6-methoxy- pyrimidine-5-carbaldehyde (1.70 g, 9.85 mmol, 25% yield) as a white solid. LCMS (Method C): R _t = 0.655 min; MS (ESIpos): m/z = 173.0 [M+H] ⁺ . Procedure for preparation of 4-methoxypyrimidine-5-carbaldehyde To a solution of 4-chloro-6-methoxy-pyrimidine-5-carbaldehyde (1.60 g, 9.27 mmol, 1.00 eq) in methyl alcohol (20.0 mL) were added triethylamine (1.16 g, 11.5 mmol, 1.60 mL, 1.24 eq), Pd/C (140 mg, 9.27 mmol, 10% purity, 1.00 eq) under N2. The suspension was degassed under vacuum and purged with H ₂ for several times. The mixture was stirred under H2 (15 psi) at 20 °C for 1 h. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 1/0 to 3/1) to give 4- methoxypyrimidine-5-carbaldehyde (990 mg, 7.17 mmol, 77.3% yield) as a white solid. LCMS (Method C): R _t = 0.264 min; MS (ESIpos): m/z = 139.0 [M+H] ⁺ . Procedure for preparation of 2-amino-2-(4-methoxypyrimidin-5-yl)acetonitrile To a solution of 4-methoxypyrimidine-5-carbaldehyde (100 mg, 0.724 mmol, 1.00 eq) in methyl alcohol (2.00 mL) were added ammonia/methyl alcohol (7 M, 0.724 mL, 7.00 eq) and tetraisopropoxytitanium (247 mg, 0.869 mmol, 0.256 mL, 1.20 eq). The mixture was stirred at 20 °C for 1 h. Trimethylsilylformonitrile (86.2 mg, 0.869 mmol, 0.109 mL, 1.20 eq) was added dropwise. The mixture was stirred at 20 °C for 2 h. The reaction mixture was filtered and the filter cake was concentrated under reduced pressure to give 2-amino-2-(4-methoxypyrimidin-5-yl) acetonitrile ₂ -amino-2-(4- methoxypyrimidin-5-yl) acetonitrile (118 mg, crude) as a brown oil. LCMS (Method C): R _t = 0.139 min; MS (ESIpos): m/z = 165.0 [M+H] ⁺ . Procedure for preparation of CPD0189022 - (1R,2S,5S)-N-[cyano-(4-methoxypyrimidin-5- yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R, 2S, 5S) -3-[ (2S) -3, 3-dimethyl-2-[ (2, 2, 2-trifluoroacetyl) amino]butanoyl]-6, 6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (288 mg, 0.791 mmol, 1.10 eq) in N,N- dimethylformamide (2.00 mL) were added diisopropylethylamine (186 mg, 1.44 mmol, 0.250 mL, 2 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N’,N’- tetramethyluronium hexafluorophosphate (328 mg, 0.863 mmol, 1.2 eq). The mixture was stirred at 20 °C for 0.5 h. Then 2-amino-2-(4-methoxypyrimidin-5-yl) acetonitrile (118 mg, 0.719 mmol, 1 eq) was added. The mixture was stirred at 20 °C for 11.5 h. The reaction mixture was diluted with water (30.0 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (60 mL×2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition;column: Unisil 3-100 C18 μLtra 150*50 mm*3 um;mobile phase: [water (FA) -ACN];B%: 42%- 72%, 7 min) to give (1R, 2S, 5S) -N-[cyano-(4-methoxypyrimidin-5-yl) methyl]-3-[ (2S) -3, 3-dimethyl-2- [ (2, 2, 2-trifluoroacetyl) amino]butanoyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (96.49 mg, 0.186 mmol, 25.9% yield, 98.5% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 9.48-9.28 (m, 2H), 8.84 (s, 1H), 8.61 (d, J = 11.2 Hz, 1H), 6.13-6.01 (m, 1H), 4.38 (br d, J = 4.4 Hz, 1H), 4.28 (d, J = 3.2 Hz, 1H), 4.02 (d, J = 2.4 Hz, 3H), 3.94-3.84 (m, 1H), 3.70 (dd, J = 4.8, 10.4 Hz, 1H), 1.61-1.51 (m, 1H), 1.38 - 1.22 (m, 1H), 1.05-0.93 (m, 12H), 0.85 (d, J = 4.8 Hz, 3H) LCMS (Method C): R _t = 0.730 min; MS (ESIpos): m/z = 511.2 [M+H] ⁺ . SFC: 53:46 Preparation of CPD0189023 Procedure for preparation of Ethyl 2-pyridazin-3-ylacetate To a solution of 3-methylpyridazine (14.0 g, 148 mmol, 13.6 mL, 1.00 eq) in tetrahydrofuran (200 mL) was added dropwise lithium diisopropylamide (2 M in a mixture of n-heptane and tetrahydrofuran, 149 mL, 2.00 eq) at -78 °C in a period of 30 min. The mixture was warmed to 20 °C and stirred for 0.5 h. The reaction mixture was cooled to -78 °C and diethyl carbonate (35.2 g, 298 mmol, 36.1 mL, 2.00 eq) in tetrahydrofuran (50.0 mL) was added dropwise at -78 °C over 10 min. The mixture was warmed to 25 °C slowly and stirred for 16 h under N ₂ atmosphere. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (300 mL) and concentrated under reduced pressure to remove tetrahydrofuran. The solution was extracted with ethyl acetate (300 mL × 5). The combined organic layers were washed with brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 0 to 0: 1) to give ethyl 2-pyridazin-3-ylacetate (6.50 g, 39.1 mmol, 26% yield) as brown oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.16 (t, J = 3.2 Hz, 1H), 7.69 (d, J = 3.2 Hz, 2H), 4.13 (q, J = 7.2 Hz, 2H), 4.07 (s, 2H), 1.20 (t, J = 7.2 Hz, 3H). Procedure for preparation of amino 2, 4, 6-trimethylbenzenesulfonate A solution of tert-butyl (mesitylsulfonyl)oxycarbamate (20.0 g, 63.4 mmol, 1.00 eq) in 2,2,2- trifluoroacetic acid (80.0 mL) was stirred at 0 °C for 1 h. The reaction mixture was poured into ice water (300 mL). The resulting precipitate was filtered and the filter cake was dried to give amino 2, 4, 6- trimethylbenzenesulfonate (12.6 g, 58.5 mmol, 92% yield) as a white solid Procedure for preparation of methyl 6-(2-ethoxy-2-oxo-ethyl) pyrazolo[1, 5-b]pyridazine-3- carboxylate To a solution of ethyl 2-pyridazin-3-ylacetate (6.50 g, 39.1 mmol, 1.00 eq) in dichloromethane (30.0 mL) was added a solution of amino 2, 4, 6-trimethylbenzenesulfonate (12.6 g, 58.7 mmol, 1.50 eq) in dichloromethane (100 mL) at 20 °C. After stirring for 16 h, methanol (40.0 mL) was added and the solution was concentrated to remove dichloromethane. Methyl prop-2-ynoate (4.93 g, 58.7 mmol, 4.88 mL, 1.50 eq) and triethylamine (11.9 g, 117 mmol, 16.3 mL, 3.00 eq) were added to the residue above. After stirring at 20 °C for 2 h, the reaction mixture was quenched with water (150 mL) at 25 °C, and extracted with ethyl acetate (150 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~25% Ethyl acetate/Petroleum ethergradient @ 80 mL/min) to give methyl 6- (2-ethoxy-2-oxo-ethyl) pyrazolo[1, 5-b]pyridazine-3-carboxylate (3.80 g, 14.44 mmol, 37% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.58-8.50 (m, 2H), 7.58 (d, J = 9.2 Hz, 1H), 4.14 (q, J = 7.2 Hz, 2H), 4.07 (s, 2H), 3.86 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H). Procedure for preparation of 2-pyrazolo [1, 5-b] pyridazin-6-ylacetic acid To a solution of methyl 6-(2-ethoxy-2-oxo-ethyl) pyrazolo[1, 5-b]pyridazine-3-carboxylate (3.80 g, 14.4 mmol, 1.00 eq) in water (15.00 mL) was added sulfuric acid (8.74 g, 89.1 mmol, 4.75 mL, 6.17 eq). After stirring at 120 °C for 2 h, the reaction mixture was concentrated under reduced pressure give 2-pyrazolo [1, 5-b] pyridazin-6-ylacetic acid (11.0 g, crude) as brown oil (purity: 25%, with sulfuric acid). Procedure for preparation of methyl 2-pyrazolo[1, 5-b]pyridazin-6-ylacetate To a solution of 2-pyrazolo[1, 5-b]pyridazin-6-ylacetic acid (11.0 g, 15.5 mmol, 25% purity, 1.00 eq) in methanol (30.0 mL) was added sulfuric acid (1.52 g, 15.5 mmol, 0.84 mL, 1.00 eq). After stirring at 20 °C for 15 h, the reaction mixture was quenched with saturated sodium hydrogen carbonate aqueous solution (100 mL) at 25 °C. The solution was extracted with ethyl acetate (150 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give methyl 2-pyrazolo[1, 5-b]pyridazin-6-ylacetate (2.50 g, 13.1 mmol, 84% yield) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.25 (d, J = 9.2 Hz, 1H), 8.05 (d, J = 2.4 Hz, 1H), 7.20 (d, J = 9.2 Hz, 1H), 6.77 (d, J = 2.4 Hz, 1H), 3.99 (s, 2H), 3.67 (s, 3H). Procedure for preparation of methyl 2-(hydroxyimino)-2-(pyrazolo[1,5-b]pyridazin-6-yl)acetate To a solution of methyl 2-pyrazolo[1, 5-b]pyridazin-6-ylacetate (2.70 g, 14.12 mmol, 1.00 eq) in dichloromethane (50.0 mL) was added tert-butyl nitrite (2.18 g, 21.2 mmol, 2.52 mL, 1.50 eq) dropwise at 0 °C, then hydrogen chloride (2 M in ethyl acetate , 10.6 mL, 1.50 eq) was added over 10 min. After stirring at 20 °C for 15 h, the reaction mixture was directly concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~25% Ethyl acetate/Petroleum ethergradient @ 80 mL/min) to give methyl 2-(hydroxyimino)-2-(pyrazolo[1,5- b]pyridazin-6-yl)acetate (1 g, crude) and methyl 2-(hydroxyimino)-2-(pyrazolo[1,5-b]pyridazin-6- yl)acetate (400 mg, 1.82 mmol, 13% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 12.87 (s, 1H), 8.35 (d, J = 9.2 Hz, 1H), 8.17 (d, J = 2.4 Hz, 1H), 7.59 (d, J = 9.2 Hz, 1H), 6.89 (d, J = 2.4 Hz, 1H), 3.91 (s, 3H) LC-MS (Method C): R _t = 1.151 min; MS (ESIpos): m/z = 221.0 [M+H] ⁺ . Procedure for preparation of methyl 2-(tert-butoxycarbonylamino) -2-pyrazolo[1, 5-b]pyridazin- 6-yl-acetate To a solution of methyl 2-(hydroxyimino)-2-(pyrazolo[1,5-b]pyridazin-6-yl)acetate (300 mg, 1.36 mmol, 1.00 eq) in methanol (10.0 mL) were added Raney-Nickel (23.3 mg, 0.273 mmol, 0.20 eq), triethylamine (413 mg, 4.09 mmol, 0.569 mL, 3.00 eq) and di-tert-butyl dicarbonate (357 mg, 1.63 mmol, 0.376 mL, 1.20 eq) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen for 3 times. After stirring at 20 °C for 15 h under hydrogen (15 psi), the reaction mixture was filtered through a pad of celite. The filtered cake was washed with mixed solvent of ethyl acetate and methanol (v/v = 1/1, 300 mL). The combined filtrates were dried and purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ethergradient @ 40 mL/min) to give methyl 2-(tert-butoxycarbonylamino)-2-pyrazolo[1, 5-b]pyridazin-6-yl-acetate (280 mg, 0.914 mmol, 67% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.30 (d, J = 9.2 Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.27 (d, J = 9.2 Hz, 1H), 6.80 (d, J = 2.4 Hz, 1H), 6.77 (d, J = 2.4 Hz, 1H), 5.49 (br d, J = 8.4 Hz, 1H), 3.69 (s, 3H), 1.40 (s, 9H). Procedure for preparation of tert-butyl N-(2-amino-2-oxo-1-pyrazolo[1, 5-b]pyridazin-6-yl-ethyl) carbamate A solution of methyl 2-(tert-butoxycarbonylamino)-2-pyrazolo[1, 5-b]pyridazin-6-yl-acetate (280 mg, 0.914 mmol, 1.00 eq) in ammonia (7 M in methanol, 5.00 mL, 38.3 eq) was stirred at 20 °C for 15 h. The reaction mixture was directly concentrated in vacuo to give tert-butyl N-(2-amino-2-oxo-1- pyrazolo[1, 5-b]pyridazin-6-yl-ethyl) carbamate (250 mg, crude) as a yellow oil LC-MS (Method G): R _t = 0.520 min; MS (ESIpos): m/z = 292.1 [M+H] ⁺ . Procedure for preparation of 2-amino-2-pyrazolo[1, 5-b]pyridazin-6-yl-acetamide - To a solution of tert-butyl N-(2-amino-2-oxo-1-pyrazolo[1, 5-b]pyridazin-6-yl-ethyl) carbamate (250 mg, 0.858 mmol, 1.00 eq) in ethyl acetate (4.00 mL) was added hydrogen chloride (4 M in ethyl acetate, 4.00 mL, 18.6 eq). After stirring at 20 °C for 2 h, the reaction mixture was directly concentrated to give 2-amino-2-pyrazolo[1, 5-b]pyridazin-6-yl-acetamide (180 mg, crude, HCl) as an off-white solid. Procedure for preparation of (1R, 2S, 5S) -N-(2-amino-2-oxo-1-pyrazolo[1, 5-b]pyridazin-6-yl- ethyl) -3-[(2S) -3, 3-dimethyl-2-[(2, 2, 2-trifluoroacetyl) amino]butanoyl]-6, 6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R, 2S, 5S) -3-[(2S) -3, 3-dimethyl-2-[(2, 2, 2-trifluoroacetyl) amino]butanoyl]-6, 6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (230 mg, 0.631 mmol, 1.00 eq) in dichloromethane (10.00 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (288 mg, 0.757 mmol, 1.20 eq) and N,N-diisopropylethylamine (245 mg, 1.89 mmol, 0.33 mL, 3.00 eq) at 20 °C. After stirring for 0.5 h, 2-amino-2-pyrazolo[1, 5-b]pyridazin-6-yl- acetamide (172 mg, 0.757 mmol, 1.20 eq, HCl) was added. After stirring at 20 °C for 15 h, the reaction mixture was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~80% Ethyl acetate/Petroleum ethergradient @ 40 mL/min) to give (1R, 2S, 5S) -N-(2-amino-2-oxo-1-pyrazolo[1, 5-b]pyridazin-6-yl-ethyl) -3-[(2S) - 3, 3-dimethyl-2-[(2, 2, 2-trifluoroacetyl) amino]butanoyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (330 mg, 0.614 mmol, 97% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.44-9.29 (m, 1H), 9.14-8.83 (m, 1H), 8.35-8.17 (m, 1H), 8.14-8.02 (m, 1H), 7.88-7.65 (m, 1H), 7.63-7.35 (m, 1H), 7.32-7.19 (m, 1H), 6.79 (d, J = 2.4 Hz, 1H), 5.63-5.48 (m, 1H), 4.52-4.33 (m, 2H), 3.91-3.80 (m, 1H), 3.75-3.65 (m, 1H), 1.47 (t, J = 6.4 Hz, 1H), 1.42-1.35 (m, 1H), 1.00 (s, 9H), 0.92 (s, 3H), 0.86 (s, 3H). LC-MS (Method C): R _t = 1.641, 1.669 min; MS (ESIpos): m/z = 538.1 [M+H] ⁺ . Procedure for preparation of CPD0189023 - (1R, 2S, 5S) -N-[cyano (pyrazolo[1, 5-b]pyridazin-6- yl) methyl]-3-[(2S) -3, 3-dimethyl-2-[(2, 2, 2-trifluoroacetyl) amino]butanoyl]-6, 6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-(2-amino-2-oxo-1-pyrazolo[1, 5-b]pyridazin-6-yl-ethyl)-3-[(2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl) amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (330 mg, 0.614 mmol, 1.00 eq) in dichloromethane (15.0 mL) were added Burgess reagent (878 mg, 3.68 mmol, 6.00 eq). After stirring at 20 °C for 3 h, the reaction mixture was quenched by addition water (30.0 mL) at 25 °C, and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (30.0 mL ×2), dried over Sodium Sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex luna C18150*25 mm* 10 μm; mobile phase: [water (FA) -ACN];B%: 40%-70%, 10 min) to give (1R,2S,5S)-N-[cyano(pyrazolo[1,5-b]pyridazin-6-yl) methyl]-3-[(2S) -3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (140 mg, 0.267 mmol, 44% yield, 100% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.77-9.62 (m, 1H), 9.46-9.33 (m, 1H), 8.33 (d, J = 4.4 Hz, 0.5H), 8.30 (d, J = 4.4 Hz, 0.5H), 8.19-8.15 (m, 1H), 7.19 (d, J = 9.2 Hz, 0.5H), 7.14 (d, J = 9.2 Hz, 0.5H), 6.86 (d, J = 2.4 Hz, 1H), 6.59 (d, J = 8.0 Hz, 0.5H), 6.50 (d, J = 8.0 Hz, 0.5H), 4.31 (s, 0.5H), 4.26 (s, 0.5H), 3.97-3.87 (m, 1H), 3.75-3.65 (m, 1H), 1.63-1.53 (m, 1H), 1.44-1.36 (m, 1H), 1.06-0.94 (m, 12H), 0.90- 0.83 (m, 3H). LC-MS (Method C): R _t = 2.025 min; MS (ESIpos): m/z = 520.2 [M+H] ⁺ . SFC: dr = 9: 43: 48. Preparation of CPD0189027 Procedure for preparation of imidazo [1, 2-a] pyrimidine-6-carbaldehyde A solution of 2-aminopyrimidine-5-carbaldehyde (1.00 g, 8.12 mmol, 1.00 eq) and 2-chloroacetaldehyde (15.9 g, 81.2 mmol, 13.1 mL, 40% purity, 10.0 eq) in ethanol (30.0 mL) was stirred at 80 °C for 15 h. The reaction mixture was concentrated to give a residue. The residue was triturated with 2-methoxy-2- methylpropane (30.0 mL) at 20 °C for 30 min. The suspension was filtered and the filter cake was dried to give imidazo[1, 2-a]pyrimidine-6-carbaldehyde (1.00 g, 6.80 mmol, 84% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.14 (s, 1H), 9.89 (d, J = 2.0 Hz, 1H), 9.21 (d, J = 2.0 Hz, 1H), 8.37 (d, J = 2.0 Hz, 1H), 8.21 (d, J = 2.0 Hz, 1H). Procedure for preparation of 2-amino-2-imidazo[1, 2-a]pyrimidin-6-yl-acetonitrile To a solution of imidazo[1, 2-a]pyrimidine-6-carbaldehyde (1.00 g, 6.80 mmol, 1.00 eq) in methanol (15.0 mL) were added titanium(IV)propan-2-olate (2.12 g, 7.48 mmol, 2.21 mL, 1.10 eq) and ammonia (7M in methanol, 6.80 mL, 7.00 eq). After stirring at 20 °C for 1 h, trimethylsilanecarbonitrile (809 mg, 8.16 mmol, 1.02 mL, 1.20 eq) was added at 0 °C. After stirring at 20 °C for 2 h, the reaction mixture was quenched with water (60.0 mL). The resulting suspension was filtered and extracted with ethyl acetate (60.0 mL × 4). The combined organic layers were washed with brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-amino-2- imidazo[1, 2-a]pyrimidin-6-yl-acetonitrile (600 mg, crude) as a brown solid. Procedure for preparation of CPD0189027 - (1R,2S,5S)-N-[cyano(imidazo[1,2-a]pyrimidin-6- yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl) amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (600 mg, 1.65 mmol, 1.00 eq) in dichloroethane (30.0 mL) were added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]- dimethylazanium;hexafluorophosphate (751 mg, 1.98 mmol, 1.20 eq) and N-ethyl-N-isopropylpropan- 2-amine (638 mg, 4.94 mmol, 0.860 mL, 3.00 eq). After stirring at 20 °C for 0.5 h, 2-amino-2- imidazo[1,2-a]pyrimidin-6-yl-acetonitrile (600 mg, 3.46 mmol, 2.10 eq) was added. After stirring at 20 °C for 15 h, the reaction mixture was quenched with water (60.0 mL) and extracted with ethyl acetate (60.0 mL × 3). The combined organic layers were washed with brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (SiO ₂ , petroleum ether: ethyl acetate = 1: 0 to 0: 1) to afford 500 mg of crude product. The crude product was purified by prep-HPLC (FA condition; column: Phenomenex luna C18150*25 mm* 10 μm; mobile phase: [water (FA)-ACN];B%: 29%-59%, 10 min) to give (1R,2S,5S)-N-[cyano(imidazo[1,2-a]pyrimidin-6-yl)methyl]-3-[ (2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl) amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-car boxamide (130 mg, 0.250 mmol, 15% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.74-9.52 (m, 1H), 9.38-9.32 (m, 2H), 8.78-8.67 (m, 1H), 8.22-8.13 (m, 1H), 8.05-8.00 (m, 1H), 6.57-6.36 (m, 1H), 4.38 (t, J = 8.0 Hz, 1H), 4.24 (d, J = 2.8 Hz, 1H), 3.91 (d, J = 5.2 Hz, 1H), 3.70 (t, J = 10.8 Hz, 1H), 1.64-1.54 (m, 1H), 1.46-1.32 (m, 1H), 1.06-0.92 (m, 13H), 0.89-0.84 (m, 3H). LC-MS (Method C): R _t = 1.499, 1.500, 1.566 min; MS (ESIpos): m/z = 520.2 [M+H] ⁺ . SFC: dr = 6: 52: 38: 4. Preparation of CPD0189028 Procedure for preparation of N-[(E)-(5-bromo-2-pyridyl)methyleneamino]-4-methyl- benzenesulfonamide To a solution of 4-methylbenzenesulfonohydrazide (10.1 g, 54.3 mmol, 1.01 eq) in a mixed solvent of dichloromethane (100 mL) and methanol (100 mL) was added 5-bromopyridine-2-carbaldehyde (10.0 g, 53.8 mmol, 1.00 eq). After stirring at 25 °C for 1 h, the reaction mixture was concentrated under vacuum at 50 °C to afford N-[(E)-(5-bromo-2-pyridyl)methyleneamino]-4-methyl-benzenesu lfonamide (19.0 g, 53.6 mmol, 99% yield) as a white solid. LC-MS (Method C): Rt = 0.823 min; MS (ESIpos): m/z = 354.0 [M+H] ⁺ . Procedure for preparation of 6-bromotriazolo[1,5-a]pyridine A mixture of N-[(E)-(5-bromo-2-pyridyl)methyleneamino]-4-methyl-benzenesu lfonamide (19.0 g, 53.6 mmol, 1.0 eq) in morpholine (99.0 g, 1.14 mol, 100 mL, 21.2 eq) was stirred at 90 °C for 3 h. The reaction mixture was concentrated under vacuum at 50 °C to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: ethyl acetate = 4: 1 to 2: 1) to afford 6- bromotriazolo[1,5-a]pyridine (10.0 g, 50.0 mmol, 93% yield) as a light yellow solid. LC-MS (Method C): Rt = 0.410 min; MS (ESIpos): m/z = 198.1 [M+H] ⁺ . Procedure for preparation of ethyl (E)-3-(triazolo[1,5-a]pyridin-6-yl)prop-2-enoate To a solution of 6-bromotriazolo[1,5-a]pyridine (5.00 g, 25.3 mmol, 1.00 eq), ethyl (E)-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate (6.85 g, 30.3 mmol, 1.20 eq) and potassium phosphate (10.7 g, 50.5 mmol, 2.00 eq) in a mixed solvent of tetrahydrofuran (80.0 mL) and water (20.0 mL) was added tetrakis[triphenylphosphine]palladium(0) (2.92 g, 2.53 mmol, 0.100 eq) under nitrogen atmosphere. After stirring at 80 °C for 4 h, the reaction mixture was cooled to room temperature and partitioned between ethyl acetate (100 mL) and water (100 mL). The separated aqueous phase was extracted with ethyl acetate (50 mL × 2). The combined extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was triturated with methyl tert-butyl ether (30.0 mL). The resulting suspension was filtered and the filter cake was dried under vacuum to afford ethyl (E)-3-(triazolo[1,5-a]pyridin-6-yl)prop-2-enoate (3.00 g, 12.4 mmol, 49% yield) as a whiter solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.50 (s, 1H), 8.22 (s, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.89-7.72 (m, 2H), 7.55 (d, J = 6.4 Hz, 1H), 7.38-7.21 (m, 1H), 6.85 (d, J = 16.0 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 3.92 (s, 1H), 1.28 (t, J = 7.2 Hz, 3H). Procedure for preparation of triazolo[1,5-a]pyridine-6-carbaldehyde Ozone was bubbled into a solution of ethyl (E)-3-(triazolo[1,5-a]pyridin-6-yl)prop-2-enoate (3.00 g, 13.8 mmol, 1.00 eq) in dichloromethane (100 mL) and methanol (10.0 mL) at -78 °C for 30 minutes. After purging by nitrogen, dimethyl sulfide (4.29 g, 69.1 mmol, 5.07 mL, 5.00 eq) was added at -78 °C. After stirring at 25 °C for 1 h, the reaction mixture was concentrated under vacuum at 40 °C to give a residue. The residue was triturated with methyl tert-butyl ether (100 mL). The mixture was filtered and the filtrate was dried under vacuum to afford triazolo[1,5-a]pyridine-6-carbaldehyde (1.50 g, 8.16 mmol, 59% yield) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 10.07 (s, 1H), 9.25 (d, J = 0.8 Hz, 1H), 8.16 (s, 1H), 7.87-7.80 (m, 1H), 7.76-7.70 (m, 1H). Procedure for preparation of 2-amino-2-(triazolo[1,5-a]pyridin-6-yl)acetonitrile Trimethylsilyl cyanide (1.23 g, 12.4 mmol, 1.55 mL, 1.30 eq) was added to a mixture of triazolo[1,5- a]pyridine-6-carbaldehyde (1.40 g, 9.52 mmol, 1.00 eq), ammonia (7 M in methanol, 4.76 mL, 3.50 eq) and titanium(IV)isopropoxide (3.25 g, 11.4 mmol, 3.37 mL, 1.20 eq) in methanol (8.00 mL). After stirring at 20 °C for 2 h, the reaction mixture was quenched with water (200 mL) at 5 °C, and extracted with a mixed solvent of dichloromethane and methanol (v/v = 10/1, 200 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 2-amino-2-(triazolo[1,5-a]pyridin-6-yl)acetonitrile (1.50 g, 6.06 mmol, 64% yield) as yellow oil. LC-MS (Method C): Rt = 0.147 min; MS (ESIpos): m/z= 174.2 [M+H] ⁺ . Procedure for preparation of Compound CPD0189028 - (1R,2S,5S)-N-[cyano(triazolo[1,5- a]pyridin-6-yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-triflu oroacetyl)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (505 mg, 1.39 mmol, 0.800 eq) in dichloromethane (10.0 mL) were added 2-amino-2-(triazolo[1,5-a]pyridin-6-yl)acetonitrile (1.50 g, 1.73 mmol, 1.00 eq), diisopropylethylamine (671 mg, 5.20 mmol, 905 μL, 3.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluronium hexafluorophosphate (659 mg, 1.73 mmol, 1.00 eq). After stirring at 25 °C for 12 h, the reaction mixture was concentrated under vacuum at 40 °C to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge C18 150*50mm* 10 μm; mobile phase: [water( NH4HCO3)-ACN];B%: 34%-64%,10min) to afford (1R,2S,5S)-N-[cyano(triazolo[1,5-a]pyridin-6- yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (302 mg, 567 μmol, 33% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.73-9.56 (m, 1H), 9.41 (d, J = 8.0 Hz, 1H), 9.11 (d, J = 1.0 Hz, 1H), 8.26 (s, 1H), 8.06 (dd, J = 9.2, 1.6 Hz, 1H), 7.47 (d, J = 9.2 Hz, 1H), 6.51-6.32 (m, 1H), 4.38 (dd, J = 8.4, 1.2 Hz, 1H), 4.29 (d, J = 3.2 Hz, 1H), 3.96-3.86 (m, 1H), 3.77-3.64 (m, 1H), 1.63-1.51 (m, 1H), 1.46- 1.31 (m, 1H), 1.03 (d, J = 18.8 Hz, 3H), 0.99-0.92 (m, 9H), 0.89-0.85 (m, 3H). LC-MS (Method C): Rt = 0.715 min; MS (ESIpos): m/z = 520.3 [M+H] ^+. Preparation of CPD0189029 Procedure for preparation of dimethyl 2-(6-chloropyrazin-2-yl)propanedioate To a solution of 2,6-dichloropyrazine (25.0 g, 168 mmol, 1.00 eq), dimethyl propanedioate (20.0 g, 151 mmol, 17.4 mL, 0.90 eq) and Cesium carbonate (75.0 g, 230 mmol, 1.37 eq) in Dimethyl Formamide (250 mL). The mixture was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 20 °C for 16 h under nitrogen atmosphere. The reaction mixture was partitioned between water (500 mL) and Ethyl acetate (500 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=0/1) to give dimethyl 2-(6-chloropyrazin-2- yl)propanedioate (22.0 g, 89.9 mmol, 54% yield) as a yellow solid. Procedure for preparation of methyl 2-(6-chloropyrazin-2-yl)acetate To a solution of dimethyl 2-(6-chloropyrazin-2-yl) propanedioate (10.0 g, 40.9 mmol, 1.00 eq) in dimethylsulfoxide (200 mL) were added sodium chloride (2.39 g, 40.9 mmol, 1.00 eq) and water (12.5 mL). After stirring at 140 °C for 2 h, the reaction mixture was diluted with water (200 mL) and washed with ethyl acetate (50.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/1) to give methyl 2-(6-chloropyrazin-2-yl)acetate (5.00 g, 26.8 mmol, 66% yield) as yellow oil. LC-MS (Method C): R _t = 0.331 min; MS (ESIpos): m/z = 187.1 [M+H] ⁺ . Procedure for preparation of methyl 2-[6-(dimethylamino)pyrazin-2-yl]acetate To a solution of methyl 2-(6-chloropyrazin-2-yl)acetate (3.00 g, 16.1 mmol, 1.00 eq) was added dimethylamine tetrahydrofuran (7.00 M, 30.0 mL, 13.1 eq). After stirring at 20 °C for 16 h, the resulting mixture was concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 1: 1) to give methyl 2-[6-(dimethylamino) pyrazin-2-yl]acetate (2.00 g, 10.2 mmol, 64% yield) as yellow oil. LC-MS (Method C): R _t = 0.525 min; MS (ESIpos): m/z = 196.1 [M+H] ⁺ . Procedure for preparation of methyl (2E)-2-[6-(dimethylamino)pyrazin-2-yl]-2-hydroxyimino- acetate To a solution of methyl 2-[6-(dimethylamino)pyrazin-2-yl]acetate (2.00 g, 10.2 mmol, 1.00 eq) in acetic acid (3.00 mL) at 0 °C. Then a solution of sodium nitrite (813 mg, 11.8 mmol, 1.15 eq) in water (9.60 mL) was added to the reaction mixture above. After stirring at 0 °C for 1 h, water (7.20 mL) was added and the mixture was stirred at 20 °C for 2 h. A lot of solid precipitated out. The reaction mixture was washed with water (15.0 mL), saturated sodium bicarbonate solution (15.0 mL), water (15.0 mL), and filtered. The filtrate was concentrated under reduced pressure to give methyl (2E)-2-[6- (dimethylamino)pyrazin-2-yl]-2-hydroxyimino-acetate (2.00 g, crude) as a white solid. LC-MS (Method C): R _t = 0.433 min; MS (ESIpos): m/z = 225.2 [M+H] ⁺ . Procedure for preparation of methyl 2-(tert-butoxycarbonylamino)-2-[6-(dimethylamino)pyrazin- 2-yl]acetate To a solution of methyl (2E)-2-[6-(dimethylamino)pyrazin-2-yl]-2-hydroxyimino-acetat e (1.50 g, 6.69 mmol, 1.00 eq) and di-tert-butyl dicarbonate (1.61 g, 7.36 mmol, 1.69 mL, 1.10 eq) in methanol (40.0 mL) was added palladium (375 mg, 1.80 mmol, 10% purity on carbon) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen gas three times. The mixture was stirred at 20 °C for 16 h under hydrogen atmosphere (15 psi). The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 1: 1) to give methyl 2-(tert-butoxycarbonylamino)-2-[6-(dimethylamino)pyrazin-2-y l]acetate (2.00 g, 6.44 mmol, 96% yield) as a white solid. LC-MS (Method C): R _t = 0.856 min; MS (ESIpos): m/z = 311.3 [M+H] ⁺ . Procedure for preparation of tert-butyl N-[2-amino-1-[6-(dimethylamino)pyrazin-2-yl]-2-oxo- ethyl]carbamate A solution of methyl 2-(tert-butoxycarbonylamino)-2-[6-(dimethylamino)pyrazin-2-y l]acetate (1.50 g, 4.83 mmol, 1.00 eq) in ammonia and methanol (7.00 M, 15.0 mL, 21.7 eq) was stirred at 40 °C for 16 h. The reaction mixture was concentrated to give tert-butyl N-[2-amino-1-[6-(dimethylamino) pyrazin-2- yl]-2-oxo-ethyl] carbamate (1.40 g, crude) as yellow oil. LC-MS (Method D): R _t = 0.699 min; MS (ESIpos): m/z = 296.2 [M+H] ⁺ . Procedure for preparation of 2-amino-2-[6-(dimethylamino)pyrazin-2-yl]acetamide A solution of tert-butyl N-[2-amino-1-[6-(dimethylamino)pyrazin-2-yl]-2-oxo-ethyl]car bamate (1.10 g, 3.72 mmol, 1.00 eq) in dioxane hydrochloride (14.0 mL) was stirred at 20 °C for 2 h. The reaction mixture was concentrated to give 2-amino-2-[6-(dimethylamino)pyrazin-2-yl]acetamide (0.80 g, crude, HCl) as white solid. LC-MS (Method C): R _t = 0.110 min; MS (ESIpos): m/z = 196.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[2-amino-1-[6-(dimethylamino)pyrazin-2-yl]-2-ox o- ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino] butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of 2-amino-2-[6-(dimethylamino)pyrazin-2-yl]acetamide (700 mg, 3.59 mmol, 1.00 eq) in dichloromethane (10.0 mL) were added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene] - dimethyl-ammonium;hexafluorophosphate (2.05 g, 5.38 mmol, 1.50 eq), (1R,2S,5S)-3-[(2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.31 g, 3.59 mmol, 1.00 eq) and N-ethyl-N-isopropyl-propan-2-amine (1.85 g, 14.3 mmol, 2.50 mL, 4.00 eq). After stirring at 20 °C for 16 h, the resulting mixture was concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 2: 1) to give (1R,2S,5S)-N-[2-amino-1-[6-(dimethylamino)pyrazin-2-yl]- 2-oxo-ethyl]-3-[(2S)- 3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-d imethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (1.70 g, 3.14 mmol, 88% yield) as a yellow solid. LC-MS (Method G): R _t = 0.836 min; MS (ESIpos): m/z = 632.4[M+H] ⁺ . Procedure for preparation of CPD0189029 - (1R,2S,5S)-N-[cyano-[6-(dimethylamino)pyrazin-2- yl]methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-[2-amino-1-[6-(dimethylamino)pyrazin-2-yl]-2-ox o-ethyl]-3- [(2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (0.50 g, 923 umol, 1.00 eq) in dichloromethane (5 mL) was added methoxycarbonyl- (triethylammonio)sulfonyl-azanide (660 mg, 2.77 mmol, 3.00 eq). After stirring at 20 °C for 2 h, the resulting mixture was concentrated under vacuum to give a residue. The residue was further purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 μm; mobile phase: [water(FA)-ACN]; B%: 45%-75%, 7min) to give (1R,2S,5S)-N-[cyano-[6-(dimethylamino)pyrazin-2-yl]methyl] -3-[(2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (100 mg, 191 μmol, 21% yield, 100% purity ) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.54-9.37 (m, 2H), 8.15 (s, 1H), 7.87 (d, J = 9.2 Hz, 1H), 6.21-6.06 (m, 1H), 4.40 (br d, J = 8.0 Hz, 1H), 4.34 (d, J = 12.0 Hz, 1H), 3.90 (dt, J = 10.4, 5.6 Hz, 1H), 3.71 (dd, J = 10.4, 5.6 Hz, 1H), 3.11 (s, 6H), 1.63-1.51 (m, 1H), 1.42-1.29 (m, 1H), 1.04-0.97 (m, 12H), 0.90-0.81 (m, 3H). LC-MS (Method D): R _t = 0.904 min; MS (ESIpos): m/z = 524.3 [M+H] ⁺ . SFC: dr =55: 42. Preparation of CPD0189031 Procedure for preparation of tert-butyl (4S)-4-(cyclopropylidenemethyl)-2,2-dimethyl- oxazolidine-3-carboxylate To a solution of cyclopropyltriphenylphosphonium bromide (167 g, 436 mmol, 2.00 eq) in tetrahydrofuran (1000 mL) was added dropwise potassium bis(trimethylsilyl)amide (0.5 M in toluene, 829 mL, 1.90 eq) at 20 °C under nitrogen. After stirring at 20 °C for 1 h, tert-butyl (4R)-4-formyl-2,2- dimethyl-oxazolidine-3-carboxylate (50.0 g, 218 mmol, 1.00 eq) in tetrahydrofuran (100 mL) was added. After stirring at 70 °C for 2 h, the reaction mixture was cooled to ambient temperature. The reaction mixture was quenched with methanol (200 mL), diluted with ethyl acetate (800 mL) and washed with saturated potassium sodium tartrate (1000 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 0 to 10: 1) to give tert-butyl (4S)-4- (cyclopropylidenemethyl)-2,2-dimethyl-oxazolidine-3-carboxyl ate (40.0 g, 158 mmol, 72% yield) as yellow oil. Procedure for preparation of (2S)-2-amino-3-cyclopropylidene-propan-1-ol To a solution of tert-butyl (4S)-4-(cyclopropylidenemethyl)-2,2-dimethyl-oxazolidine-3-c arboxylate (29.0 g, 115 mmol, 1.00 eq) in methanol (100 mL) was added hydrogen chloride (4 M in methanol, 250 mL, 8.74 eq) at 20 °C. After stirring at 20 °C for 1 h, the reaction mixture was concentrated under vacuum to give (2S)-2-amino-3-cyclopropylidene-propan-1-ol (17.1 g, 1.15 mol, 100% yield, hydrochloride) as a white solid. Procedure for preparation of tert-butyl N-[2-[[(1S)-1-(cyclopropylidenemethyl)-2-hydroxy- ethyl]amino]-2-oxo-ethyl]carbamate To a solution of (2S)-2-amino-3-cyclopropylidene-propan-1-ol (17.1 g, 114 mmol, 1.00 eq, hydrochloride) in mixed solvent of tetrahydrofuran (65.0 mL) and methanol (65.0 mL) was added triethylamine (34.8 g, 343 mmol, 47.8 mL, 3.00 eq) at 0 °C, followed by (2,5-dioxopyrrolidin-1-yl) 2-(tert- butoxycarbonylamino)acetate (40.5 g, 149 mmol, 1.30 eq). After stirring at 20 °C for 1 h, the reaction mixture was concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 10: 1 to 0: 1) to afford tert-butyl N-[2-[[(1S)-1- (cyclopropylidenemethyl)-2-hydroxy-ethyl]amino]-2-oxo-ethyl] carbamate (30.0 g, 111 mmol, 97% yield) as yellow oil. Procedure for preparation of tert-butyl N-[2-[(4S)-4-(cyclopropylidenemethyl)-2,2-dimethyl- oxazolidin-3-yl]-2-oxo-ethyl]carbamate To a solution of tert-butyl N-[2-[[(1S)-1-(cyclopropylidenemethyl)-2-hydroxy-ethyl]amino ]-2-oxo- ethyl]carbamate (30.0 g, 111 mmol, 1.00 eq) and 2,2-dimethoxypropane (116 g, 1.11 mol, 136 mL, 10.0 eq) in acetone (300 mL) was added dropwise boron trifluoride diethyl etherate (3.45 g, 11.4 mmol, 3.00 mL, 47% purity, 0.001 eq) at 20 °C. After stirring at 20 °C for 5 h, the reaction mixture was concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 100: 1 to 10: 1) to afford tert-butyl N-[2-[(4S)-4-(cyclopropylidenemethyl)-2,2- dimethyl-oxazolidin-3-yl]-2-oxo-ethyl]carbamate (34.0 g, 110 mmol, 99% yield) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.87-5.84 (m, 1H), 5.40 (s, 1H), 4.45 (t, J = 6.8 Hz, 1H), 4.17-4.13 (m, 1H), 3.93-3.86 (m, 2H), 3.76-3.70 (m, 1H), 1.68 (s, 3H), 1.57 (s, 3H), 1.43 (s, 9 H), 1.33-1.31 (m, 1H), 1.21-1.13 (m, 3H). Procedure for preparation of 1-[(4S)-4-(cyclopropylidenemethyl)-2,2-dimethyl-oxazolidin-3 -yl]-2- diazo-ethanone To a solution of tert-butyl N-[2-[(4S)-4-(cyclopropylidenemethyl)-2,2-dimethyl-oxazolidi n-3-yl]-2-oxo- ethyl]carbamate (38.4 g, 124 mmol, 1.00 eq) in acetonitrile (400 mL) were added pyridine (29.4 g, 371 mmol, 30.0 mL, 3.00 eq) and nitridooxonium^tetrafluoroborate (28.8 g, 247 mmol, 1.99 eq) at -40 °C under nitrogen atmosphere. After stirring at 0 °C for 2.5 h, pyrrolidine (74.8 g, 1.05 mol, 87.8 mL, 8.50 eq) was added. The reaction mixture was allowed to warm to 20 °C and stirred at this temperature for 1 h. After concentration, the residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 20: 1 to 0: 1) to afford 1-[(4S)-4-(cyclopropylidenemethyl)-2,2-dimethyl-oxazolidin-3 -yl]-2- diazo-ethanone (27.4 g, 124 mmol, 100% yield) as yellow oil. Procedure for preparation of (1S,2R,4S)-7,7-dimethylspiro[8-oxa-6- azatricyclo[4.3.0.02,4]nonane-3,1'-cyclopropane]-5-one To a solution of 1-[(4S)-4-(cyclopropylidenemethyl)-2,2-dimethyl-oxazolidin-3 -yl]-2-diazo-ethanone (27.4 g, 124 mmol, 1.00 eq) in toluene (300 mL) was added palladium (II) acetate (1.43 g, 6.36 mmol, 0.051 eq) at 20 °C. After stirring at 110 °C for 1.5 h under nitrogen atmosphere, the reaction mixture was concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 100: 1 to 2: 1) to give (1S,2R,4S)-7,7- dimethylspiro[8-oxa-6-azatricyclo[4.3.0.02,4]nonane-3,1'-cyc lopropane]-5-one (5.70 g, 29.5 mmol, 24% yield,) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 4.00-3.96 (m, 1H), 3.92-3.88 (m, 1H), 3.52-3.48 (m, 1H), 2.34 (d, J = 5.6 Hz, 1H), 2.16 (d, J = 5.6 Hz, 1H), 1.74 (s, 3H), 1.39 (s, 3H), 1.14-1.02 (m, 2H), 0.95-0.84 (m, 2H). Procedure for preparation of (1S,4S,5R)-4-(hydroxymethyl)spiro[3-azabicyclo[3.1.0]hexane- 6,1'- cyclopropane]-2-one A mixture of (1S,2R,4S)-7,7-dimethylspiro[8-oxa-6-azatricyclo[4.3.0.02,4] nonane-3,1'-cyclopropane]-5- one (5.70 g, 29.5 mmol, 1.00 eq) in mixed solvent of hydrogen chloride (4 M in methanol, 20.0 mL, 2.71 eq) and methyl acetate (60.0 mL) was stirred at 20 °C for 1.5 h. The reaction mixture was concentrated under vacuum to give (1S,4S,5R)-4-(hydroxymethyl)spiro[3-azabicyclo[3.1.0]hexane- 6,1'- cyclopropane]-2-one (4.52 g, 29.5 mmol, 100% yield) as yellow oil. Procedure for preparation of 1-[(1R,2S,5S)-2-(hydroxymethyl)spiro[3-azabicyclo[3.1.0]hexa ne- 6,1'-cyclopropane]-3-yl]ethanone To a solution of (1S,4S,5R)-4-(hydroxymethyl)spiro[3-azabicyclo[3.1.0]hexane- 6,1'-cyclopropane]-2- one (4.52 g, 29.5 mmol, 1.00 eq) in tetrahydrofuran (100 mL) was added lithium aluminum hydride (3.36 g, 88.5 mmol, 3.00 eq) at 0 °C. The reaction mixture was stirred at 20 °C for 0.5 h, and then stirred at 80 °C for 5 h under nitrogen. The reaction mixture was quenched with sodium sulfate decahydrate until no gas was produced. The mixture was stirred at 20 °C for 0.5 h, and filtered under reduced pressure. The filter cake was washed with ethyl acetate (100 mL). The combined filtrate was concentrated under vacuum to give 1-[(1R,2S,5S)-2-(hydroxymethyl)spiro[3-azabicyclo[3.1.0]hexa ne-6,1'-cyclopropane]-3- yl]ethanone (4.20 g, 23.2 mmol, 79% yield) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 3.70-3.66 (m, 1H), 3.54-3.48 (m, 1H), 3.39-3.36 (m, 1H), 3.25-3.22 (m, 1H), 3.01 (d, J = 11.6 Hz, 1H), 1.97 (s, 2H), 1.93-1.91 (m, 1H), 1.70 (d, J = 6.0 Hz, 1H), 0.89-0.85 (m, 2H), 0.82-0.68 (m, 2H). Procedure for preparation of [(1R,2S,5S)-spiro[3-azabicyclo[3.1.0]hexane-6,1'-cyclopropan e]-2- yl]methanol To a solution of 1-[(1R,2S,5S)-2-(hydroxymethyl)spiro[3-azabicyclo[3.1.0]hexa ne-6,1'-cyclopropane]-3- yl]ethanone (0.500 g, 2.76 mmol, 1.00 eq) was added hydrogen chloride (4 M in methanol, 6.00 mL, 8.70 eq) at 20 °C. After stirring at 50 °C for 15 h, the mixture was concentrated under vacuum to afford [(1R,2S,5S)-spiro[3-azabicyclo[3.1.0]hexane-6,1'-cyclopropan e]-2-yl]methanol (484 mg, 2.76 mmol, 100% yield, hydrochloride) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.56 (s, 1H), 8.99 (s, 1H), 3.93-3.75 (m, 3H), 3.63-3.58 (m, 1H), 3.42- 3.37 (m, 1H), 2.14-2.12 (m, 1H), 1.86 (d, J = 5.6 Hz, 1H), 0.94 (s, 4H). Procedure for preparation of tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-(hydroxymethyl)spiro[3- azabicyclo[3.1.0]hexane-6,1'-cyclopropane]-3-carbonyl]-2,2-d imethyl-propyl]carbamate To a solution of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid (1.21 g, 5.22 mmol, 1.50 eq) in dichloromethane (10.0 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (2.12 g, 5.56 mmol, 1.60 eq) and N,N-diisopropylethylamine (1.35 g, 10.43 mmol, 1.82 mL, 3.00 eq) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 10 min. [(1R,2S,5S)-spiro[3-azabicyclo[3.1.0]hexane-6,1'-cyclopropan e]-2-yl]methanol (0.484 g, 3.48 mmol, 1.00 eq) in dichloromethane (5.00 mL) was added into the above mixture. After stirring at 20 °C for 15 h, the reaction mixture was diluted with dichloromethane (20.0 mL), washed with hydrochloric acid (0.5 M in water, 20.0 mL) and saturated sodium bicarbonate aqueous solution (20.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 50: 1 to 3: 1) to afford tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-(hydroxymethyl)spiro[3-azabicyclo[3. 1.0]hexane- 6,1'-cyclopropane]-3-carbonyl]-2,2-dimethyl-propyl]carbamate (650 mg, 1.84 mmol, 53% yield) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.20 (d, J = 10.4 Hz, 1H), 4.39-4.36 (m, 1H), 4.30-4.23 (m, 1H), 3.97 (d, J = 10.0 Hz, 1H), 3.81-3.77 (m, 1H), 3.71-3.64 (m, 3H), 1.94-1.87 (m, 1H), 1.42 (s, 9H), 1.00 (s, 9H), 0.93-0.82 (m, 2H), 0.65-0.60 (m, 1H), 0.52-0.47 (m, 1H). Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl - butanoyl]spiro[3-azabicyclo[3.1.0]hexane-6,1'-cyclopropane]- 2-carboxylic acid To a solution of tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-(hydroxymethyl)spiro[3-azabicyclo[3. 1.0]hexane- 6,1'-cyclopropane]-3-carbonyl]-2,2-dimethyl-propyl]carbamate (850 mg, 2.41 mmol, 1.00 eq), sodium dihydrogen phosphate (0.67 M, 4.57 mL, 1.27 eq) and disodium hydrogen phosphate (0.67 M, 4.57 mL, 1.27 eq) in mixed solvent of acetonitrile (8.00 mL) and water (8.00 mL) were added 2,2,6,6- tetramethylpiperidinooxy (37.9 mg, 0.241 mmol, 0.100 eq) and sodium chlorite (436 mg, 4.82 mmol, 2.00 eq) at 0 °C. After stirring at 0 °C for 0.5 h, sodium hypochlorite (180 mg, 0.241 mmol, 148 μL, 10% purity, 0.100 eq) was added into the reaction mixture at 0 °C. After addition, the reaction mixture was stirred at 20 °C for 14 h. The reaction mixture was diluted with hydrochloric acid (0.5 M in water, 20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were extracted with saturated sodium bicarbonate (20.0 mL). Hydrochloric acid (0.5 M in water) was added to the aqueous phase to adjust pH 2~3 and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give (1R,2S,5S)- 3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]s piro[3-azabicyclo[3.1.0]hexane-6,1'- cyclopropane]-2-carboxylic acid (590 mg, 1.61 mmol, 67% yield) as yellow oil. LC-MS (Method C): R _t = 0.799 min; MS (ESIpos): m/z = 367.1 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]spiro[3- azabicyclo[3.1.0]hexane-6,1'-cyclopropane]-2-carboxylic acid A solution of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl -butanoyl]spiro[3- azabicyclo[3.1.0]hexane-6,1'-cyclopropane]-2-carboxylic acid (640 mg, 1.75 mmol, 1.00 eq) in hydrochloric acid in (4 M in dioxane, 10.0 mL, 22.9 eq) was stirred at 20 °C for 2 h. The reaction mixture was concentrated in vacuum to give (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]spiro[3- azabicyclo[3.1.0]hexane-6,1'-cyclopropane]-2-carboxylic acid (529 mg, 1.75 mmol, 100% yield, hydrochloride) as white solid. Procedure for preparation of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]spiro[3-azabicyclo[3.1.0]hexa ne-6,1'-cyclopropane]-2- carboxylic acid To a solution of (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]spiro[3-aza bicyclo[3.1.0]hexane- 6,1'-cyclopropane]-2-carboxylic acid (529 mg, 1.75 mmol, 1.00 eq, hydrochloride) in methanol (8.00 mL) were added triethylamine (1.77 g, 17.5 mmol, 2.43 mL, 10.0 eq) and methyl 2,2,2-trifluoroacetate (1.79 g, 14.0 mmol, 1.41 mL, 8.00 eq) at 0 °C. After stirring at 20 °C for 14 h, the reaction mixture was concentrated in vacuum to give a residue. The residue was purified by reversed phase (instrument: 80 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.05% hydrogen chloride), eluent B: acetonitrile; gradient: 0-30 min 0-80% B; flow 60 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to afford (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]spiro[3-azabicyclo[3.1.0]hexa ne-6,1'-cyclopropane]-2-carboxylic acid (270 mg, 0.745 mmol, 43% yield) as a white solid. ¹ H NMR (400 MHz,DMSO-d ₆ ) δ = 12.82-12.77 (m, 1H), 9.47-9.08 (m, 1H), 4.62 (s, 0.3H), 4.56-4.44 (m, 1H), 4.37 (s, 0.7H), 3.82-3.72 (m, 1.5H), 3.55-3.38 (m, 0.5H), 2.14-1.89 (m, 2H), 1.00-0.84 (m, 11H), 0.66-0.58 (m, 0.5H), 0.46-0.38 (m, 1.5H). Procedure for preparation of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]spiro[3-az abicyclo[3.1.0]hexane-6,1'- cyclopropane]-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]spiro[3- azabicyclo[3.1.0]hexane-6,1'-cyclopropane]-2-carboxylic acid (100 mg, 276 μmol, 1.00 eq) in N,N- dimethylformamide (3.00 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (158 mg, 0.416 mmol, 1.51 eq) and N,N-diisopropylethylamine (143 mg, 1.10 mmol, 1.92 mL, 4.00 eq) at 0 °C. After stirring at 0 °C for 10 min, 2-amino-2-phthalazin-1-yl-acetamide (114 mg, 0.414 mmol, 1.50 eq, 2 hydrochloride) was added into the reaction mixture at 0 °C. After addition, the reaction was stirred at 20 °C for 14 h. The reaction mixture was slowly poured into ice- water (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 20: 1 to 0: 1) to afford (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]spiro[3-azabicyclo[3.1.0]hexa ne-6,1'-cyclopropane]-2-carboxamide (140 mg, 0.256 mmol, 93% yield) as a yellow solid. LC-MS (Method C): R _t = 0.760 min; MS (ESIpos): m/z = 547.2 [M+H] ⁺ . Procedure for preparation of CPD189031 - (1R,2S,5S)-N-[cyano(pyrazolo[1,5-b]pyridazin-2- yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]spiro[3-azabicyclo[3.1.0]hexa ne-6,1'-cyclopropane]-2-carboxamide (140 mg, 256 μmol, 1.00 eq) in dichloromethane (5.00 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (183 mg, 0.768 mmol, 3.00 eq) at 20 °C. After stirring at 20 °C for 3 h, the reaction mixture was poured into saturated sodium bicarbonate solution (10.0 mL) and extracted with dichloromethane (10.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)- ACN]; B%: 36%-66%, 10 min) to afford (1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]-3-[(2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]spiro[3-az abicyclo[3.1.0]hexane-6,1'-cyclopropane]- 2-carboxamide (59.2 mg, 112 μmol, 44% yield, 99% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.92 (s, 0.3H), 9.79-9.68 (m, 1.2H), 9.47-9.36 (m, 0.8H), 9.23 (s, 0.3H), 8.79-8.77 (m, 0.4H), 8.28-8.25 (m, 0.6H), 8.11-8.07 (m, 1.4H), 8.02-7.91 (m, 1H), 7.85-7.76 (m, 1.2H), 7.34-7.31 (m, 0.5H), 4.52-4.34 (m, 2H), 3.91-3.77 (m, 2H), 2.25 (d, J = 6.4 Hz, 0.4H), 2.13-2.11 (m, 0.7H), 2.04-2.02 (m, 0.3H), 1.92 (d, J = 5.6 Hz, 0.3H), 1.64 (d, J = 6.8 Hz, 0.3H), 1.02-0.76 (m, 11H), 0.52-0.34 (m, 2H). LC-MS (Method C): R _t = 0.804 min; MS (ESIpos): m/z = 529.2 [M+H] ⁺ . SFC: dr: 9: 5: 36: 50. HPLC (Method K): R _t = 2.236 min; purity: 99% Preparation of CPD0189516 Procedure for preparation of methyl (2E)-2-hydroxyimino-2-pyrazin-2-yl-acetate To a solution of methyl 2-pyrazin-2-ylacetate (9.00 g, 59.2 mmol, 1.00 eq) in acetic acid (15.0 mL) at 0 °C, Then a solution of sodium nitrite (4.69 g, 68.0 mmol, 1.15 eq) dissolved in water (50.0 mL) was added. The mixture was stirred at 0 °C for 1 h. After water (36.0 mL) was added, the mixture was stirred at 20 °C for 2 h. A lot of solid precipitated out. The reaction mixture was washed with water (15.0 mL), saturated sodium bicarbonate solution (15.0 mL), water (15.0 mL), then filtered and concentrated under reduced pressure to give a residue. The crude product methyl (2E)-2-hydroxyimino-2-pyrazin-2-yl- acetate (10.0 g, crude) as white solid was used into the next step without further purification. LC-MS (Method C): R _t = 0.356 min; MS (ESIpos): m/z = 182.2 [M+H] ⁺ . Procedure for preparation of methyl 2-(tert-butoxycarbonylamino)-2-pyrazin-2-yl-acetate To a solution of methyl (2E)-2-hydroxyimino-2-pyrazin-2-yl-acetate (8.00 g, 44.2 mmol, 1.00 eq) and Di-tert-butyl dicarbonate (10.6 g, 48.6 mmol, 11.2 mL, 1.10 eq) in methanol (200 mL) was added palladium on carbon (2.00 g, 9.62 mmol, 10% purity) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen three times. The mixture was stirred under hydrogen (15 psi) at 20 °C for 16 h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/1) to give methyl 2-(tert- butoxycarbonylamino)-2-pyrazin-2-yl-acetate (6.00 g, 22.5 mmol, 51% yield) as a white solid. LC-MS (Method D): R _t = 0.689 min; MS (ESIpos): m/z = 268.1 [M+H] ⁺ . Procedure for preparation of tert-butyl N-(2-amino-2-oxo-1-pyrazin-2-yl-ethyl)carbamate A solution of methyl 2-(tert-butoxycarbonylamino)-2-pyrazin-2-yl-acetate (5.00 g, 18.7 mmol, 1.00 eq) in ammonia and methanol (7.00 M, 50.0 mL, 18.7 eq) was stirred at 40 °C for 16 h. The reaction mixture was concentrated to give tert-butyl N-(2-amino-2-oxo-1-pyrazin-2-yl-ethyl)carbamate (4.50 g, crude) as yellow oil. LC-MS (Method D): R _t = 0.587 min; MS (ESIpos): m/z = 197.2 [M+H] ⁺ . Procedure for preparation of 2-amino-2-pyrazin-2-yl-acetamide A solution of tert-butyl N-(2-amino-2-oxo-1-pyrazin-2-yl-ethyl)carbamate (4.50 g, 17.9 mmol, 1.00 eq) in dioxane hydrochloride (45.0 mL) was stirred at 20 °C for 2 h. The reaction mixture was concentrated to give 2-amino-2-pyrazin-2-yl-acetamide (3.00 g, crude, hydrochloride) as white solid. LC-MS (Method C): R _t = 0.406 min; MS (ESIpos): m/z = 153.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-(2-amino-2-oxo-1-pyrazin-2-yl-ethyl)-3-[(2S)-3, 3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxamide To a solution of 2-amino-2-pyrazin-2-yl-acetamide (1.00 g, 6.57 mmol, 1.00 eq) in dichloromethane (20.0 mL) were added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dim ethyl- ammonium;hexafluorophosphate (3.75 g, 9.86 mmol, 1.50 eq), (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabi cyclo[3.1.0]hexane-2-carboxylic acid (2.39 g, 6.57 mmol, 1.00 eq) and N-ethyl-N-isopropyl-propan-2-amine (2.55 g, 19.7 mmol, 3.43 mL, 3.00 eq). The mixture was stirred at 20 °C for 16 h. The resulting mixture was concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 2/1) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-pyrazin-2-yl-ethyl)-3-[(2S)-3, 3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (2.00 g, 4.01 mmol, 61% yield) as a yellow solid. LC-MS (Method D): R _t = 0.806 min; MS (ESIpos): m/z = 499.2[M+H] ⁺ . Procedure for preparation of CPD0189516 - (1R,2S,5S)-N-[cyano(pyrazin-2-yl)methyl]-3-[(2S)- 3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-d imethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide To a solution of (1R,2S,5S)-N-(2-amino-2-oxo-1-pyrazin-2-yl-ethyl)-3-[(2S)-3, 3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (0.50 g, 1.00 mmol, 1.00 eq) in dichloromethane (5.00 mL) was added methoxycarbonyl-(triethylammonio)sulfonyl- azanide (717 mg, 3.01 mmol, 3.00 eq). The mixture was stirred at 20 °C for 2 h. The resulting mixture was concentrated in vacuum. The residue was further purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 um; mobile phase: [water(FA)-ACN]; B%: 39%-69%, 7min) to give (1R,2S,5S)-N- [cyano(pyrazin-2-yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-t rifluoroacetyl)amino]butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxamide (70.0 mg, 146 umol, 15% yield, 92.8% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.73-9.60 (m, 1H), 9.42 (br dd, J = 8.0, 2.4 Hz, 1H), 8.76-8.67 (m, 3H), 6.54-6.35 (m, 1H), 4.39 (dd, J = 8.4, 3.6 Hz, 1H), 4.31 (d, J = 16.0 Hz, 1H), 3.91 = 11.2, 5.6 Hz, 1H), 3.70 (br t, J = 10.8 Hz, 1H), 1.58 (ddd, J = 14.8, 7.6, 5.6 Hz, 1H), 1.44-1.31 (m, 1H), 1.05-0.96 (m, 12H), 0.86 (d, J = 5.6 Hz, 3H) LC-MS (Method G): R _t = 0.855 min; MS (ESIpos): m/z = 481.2 [M+H] ⁺ . SFC = 53 : 47 Preparation of CPD0220551 and CPD220552 Procedure for preparation of methyl 5-hydroxy-6-iodo-pyridine-3-carboxylate To a mixture of methyl 5-hydroxypyridine-3-carboxylate (10.0 g, 65.3 mmol, 1.00 eq) in a mixed solvent of tetrahydrofuran (100 mL) and water (100 mL) were added sodium carbonate (20.7 g, 195 mmol, 3.00 eq) and iodine (41.4 g, 163 mmol, 2.50 eq). After stirring at 20°C for 2 h, the reaction mixture was poured into saturated sodium sulfite (300 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were concentrated under vacuum to give methyl 5-hydroxy-6-iodo-pyridine-3- carboxylate (15.5 g, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.31 (d, J = 2.0 Hz, 1H), 7.52 (d, J = 2.0 Hz, 1H), 3.85 (s, 3H). Procedure for preparation of methyl furo[3,2-b]pyridine-6-carboxylate To a mixture of methyl 5-hydroxy-6-iodo-pyridine-3-carboxylate (15.5 g, 55.5 mmol, 1.00 eq), ethynyl(trimethyl)silane (6.55 g, 66.6 mmol, 9.23 mL, 1.20 eq), triethylamine (16.9 g, 166 mmol, 23.2 mL, 3.00 eq) and copper(I) iodide (1.06 g, 5.55 mmol, 0.100 eq) in N,N-dimethylformamide (300 mL) was added [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (4.06 g, 5.55 mmol, 0.100 eq). The mixture was purged with nitrogen for 3 times and then stirred at 100 °C for 12 h. After concentration, the residue was diluted with saturated ammonium chloride (300 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 5/1 to 1/1) to give methyl furo[3,2-b]pyridine-6-carboxylate (1.90 g, 10.2 mmol, 18% yield, 95% purity) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.23 (d, J = 1.6 Hz, 1H), 8.41 (s, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.08 (d, J = 1.6 Hz, 1H), 4.00 (s, 3H). Procedure for preparation of methyl 2,3-dihydrofuro[3,2-b]pyridine-6-carboxylate To a mixture of methyl furo[3,2-b]pyridine-6-carboxylate (2.00 g, 10.7 mmol, 95% purity, 1.00 eq) in acetic acid (50.0 mL) was added palladium (400 mg, 10% purity on carbon) under nitrogen atmosphere. The mixture was purged with hydrogen for 3 times and then stirred at 70 °C under hydrogen (15 psi) atmosphere for 12 h. After filtration, the filter cake was washed with methanol (100 mL). The combined filtrate was concentrated under vacuum to give a residue. The residue was poured into saturated sodium bicarbonate solution (200 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 5/1 to 1/1) to give methyl 2,3-dihydrofuro[3,2- b]pyridine-6-carboxylate (1.50 g, 7.95 mmol, 74% yield, 95% purity) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.70 (d, J = 1.6 Hz, 1H), 7.56 (d, J = 1.6 Hz, 1H), 4.73 (t, J = 9.0 Hz, 2H), 3.93 (s, 3H), 3.39 (t, J = 9.0 Hz, 2H). Procedure for preparation of 2,3-dihydrofuro[3,2-b]pyridin-6-ylmethanol To a mixture of methyl 2,3-dihydrofuro[3,2-b]pyridine-6-carboxylate (1.50 g, 7.95 mmol, 95% purity, 1.00 eq) in tetrahydrofuran (20.0 mL) was added lithium aluminum hydride (905 mg, 23.8 mmol, 3.00 eq) at -20 °C. After stirring at -20°C for 1 h, the reaction mixture was quenched with ethyl acetate (20.0 mL) and sodium hydroxide aqueous solution (15% weight percent, 2.00 mL). The suspension was stirred for 10 min, followed by addition of ethyl acetate (50.0 mL) and anhydrous sodium sulfate (30.0 g). After stirred at room temperature for 1 h, the resulting suspension was filtered. The filtrate was concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 2/1 to 0/1) to give 2,3-dihydrofuro[3,2-b]pyridin-6-ylmethanol (800 mg, 5.03 mmol, 63% yield, 95% purity) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.00 (d, J = 1.6 Hz, 1H), 7.07 (d, J = 1.6 Hz, 1H), 4.72-4.65 (m, 4H), 3.31 (t, J = 9.0 Hz, 2H), 2.22 (s, 1H). Procedure for preparation of 2,3-dihydrofuro[3,2-b]pyridine-6-carbaldehyde A mixture of 2,3-dihydrofuro[3,2-b]pyridin-6-ylmethanol (300 mg, 1.89 mmol, 95% purity, 1.00 eq) and (1,1,1-triacetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (879 mg, 2.07 mmol, 1.10 eq) in dichloromethane (10.0 mL) was stirred at 0 °C for 1 h. The reaction mixture was poured into a solution of saturated sodium bicarbonate and sodium thiosulfate (50.0 mL). The solution was extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were concentrated under vacuum to give residue. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 5: 1 to 0: 1) to give 2,3-dihydrofuro[3,2-b]pyridine-6-carbaldehyde (260 mg, 1.66 mmol, 87% yield, 95% purity) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 10.03 (s, 1H), 8.51 (d, J = 1.6 Hz, 1H), 7.43 (d, J = 1.6 Hz, 1H), 4.76 (t, J = 9.0 Hz, 2H), 3.43 (t, J = 9.0 Hz, 2H). Procedure for preparation of 2-amino-2-(2,3-dihydrofuro[3,2-b]pyridin-6-yl)acetonitrile To a mixture of 2,3-dihydrofuro[3,2-b]pyridine-6-carbaldehyde (260 mg, 1.66 mmol, 95% purity, 1.00 eq) in ammonia (7M in methanol, 10.0 mL) was added titanium (IV) isopropoxide (565 mg, 1.99 mmol, 1.20 eq) dropwise at 20 °C. After stirring at 20 °C for 2 h, trimethylsilylformonitrile (197 mg, 1.99 mmol, 1.20 eq) was added dropwise. After stirring at 20°C for 2 h, the mixture was poured into saturated sodium bicarbonate solution (50.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were concentrated under vacuum to give 2-amino-2-(2,3-dihydrofuro[3,2-b]pyridin-6- yl)acetonitrile (300 mg, crude) as yellow oil. LC-MS (Method I): R _t = 0.227 min; MS (ESIpos): m/z = 176.0 [M+H] ⁺ . Procedure for preparation of CPD0220551, CPD0220552 - (1R,2S,5S)-N-[cyano(2,3- dihydrofuro[3,2-b]pyridin-6-yl)methyl]-3-[(2S)-3,3-dimethyl- 2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide A mixture of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino] butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (686 mg, 1.88 mmol, 1.10 eq), O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (846 mg, 2.23 mmol, 1.30 eq) and N,N- diisopropylethylamine (885 mg, 6.85 mmol, 1.19 mL, 4.00 eq) in N,N-dimethylformamide (10.0 mL) was stirred at 20 °C for 0.5 h, followed by addition of 2-amino-2-(2,3-dihydrofuro[3,2-b]pyridin-6- yl)acetonitrile (300 mg, 1.71 mmol, 1.00 eq). After stirring at 20 °C for 11.5 h, the reaction mixture was poured into water (50.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25 mm* 10 μm; mobile phase: [water (FA)-ACN]; B%: 40%- 70%, 10 min) to give CPD0220551 (1R,2S,5S)-N-[cyano(2,3-dihydrofuro[3,2-b]pyridin-6-yl)methy l]-3- [(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl] -6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (79.5 mg, 0.147 mmol, 9% yield, 96% purity) and CPD0220552 (1R,2S,5S)-N-[cyano(2,3- dihydrofuro[3,2-b]pyridin-6-yl)methyl]-3-[(2S)-3,3-dimethyl- 2-[(2,2,2-trifluoroacetyl)amino]butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (250 mg, 0.431 mmol, 25% yield, 90% purity) as a white solid. 250 mg of impure CPD0220552 was further purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 43%-73%,10min) to give (1R,2S,5S)-N-[cyano(2,3-dihydrofuro[3,2-b]pyridin-6-yl) methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (188 mg, 0.357 mmol, 83% yield, 99% purity) as a yellow solid. CPD0220551: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.65-9.32 (m, 2H), 8.17-8.01 (m, 1H), 7.22-7.11 (m, 1H), 6.27 (d, J = 8.4 Hz, 0.15H), 6.18 (d, J = 7.6 Hz, 0.78H), 4.67 (t, J = 8.8 Hz, 2H), 4.39 (d, J = 8.2 Hz, 1H), 4.26 (s, 1H), 3.96-3.85 (m, 1H), 3.75-3.62 (m, 1H), 3.26 (t, J = 9.0 Hz, 2H), 1.62-1.50 (m, 1H), 1.38 (d, J = 7.6 Hz, 0.17H), 1.25 (d, J = 7.6 Hz, 0.89H), 1.07-0.93 (m, 12H), 0.88-0.81 (m, 3H). LC-MS (Method L): R _t = 0.578 min; MS (ESIpos): m/z = 522.2 [M+H] ⁺ . HPLC (Method M): R _t = 2.062 min; purity: 97%. CPD0220552: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.50-9.39 (m, 1H), 9.37-9.35 (m, 1H), 8.14-8.06 (m, 1H), 7.21-7.13 (m, 1H), 6.31-6.23 (m, 0.65H), 6.20-6.14 (m, 0.31H), 4.72-4.63 (m, 2H), 4.43-4.37 (m, 1H), 4.28-4.23 (m, 1H), 3.97-3.80 (m, 1H), 3.77-3.61 (m, 1H), 3.28-3.23 (m, 2H), 1.65-1.50 (m, 1H), 1.38 (d, J = 7.6 Hz, 0.65H), 1.25 (d, J = 7.6 Hz, 0.40H), 1.06-0.95 (m, 12H), 0.89-0.84 (m, 3H). LC-MS (Method C): R _t = 0.877 min; MS (ESIpos): m/z = 522.3 [M+H] ⁺ . HPLC (Method M): R _t = 2.108 min; purity: 99%. Preparation of CPD0277803, CPD0277804 Procedure for preparation of ethyl 2-(cyanomethyl)pyrazole-3-carboxylate To a mixture of ethyl 1H-pyrazole-5-carboxylate (20.0 g, 143 mmol, 1.00 eq) in dimethyl formamide (200 mL) was added cesium carbonate (60.4 g, 185 mmol, 1.30 eq). After stirring 10 min, 2- bromoacetonitrile (18.8 g, 157 mmol, 10.5 mL, 1.10 eq) was added. The mixture was stirred at 25 °C for 16 h. The mixture was diluted with water (250 mL), and extracted with ethyl acetate (200 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ethergradient @ 100 mL/min) to give ethyl 2-(cyanomethyl)pyrazole-3-carboxylate (13.7 g, 76.5 mmol, 54% yield) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.60 (d, J = 2.0 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 5.53 (s, 2H), 4.40 (q, J = 7.2 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H). Procedure for preparation of ethyl 2-(2-amino-2-oxo-ethyl)pyrazole-3-carboxylate To a mixture of ethyl 2-(cyanomethyl)pyrazole-3-carboxylate (13.7 g, 76.5 mmol, 1.00 eq) in trifluroacetic acid (130 mL) was added sulfuric acid (53.6 g, 535 mmol, 29.1 mL, 98% purity, 7.00 eq). The mixture was stirred at 25 °C for 16 h. The mixture was concentrated, and diluted with water (250 mL). Saturated sodium carbonate was added to adjust pH~7. The resulting mixture was extracted with ethyl acetate (250 mL × 5). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give ethyl 2-(2-amino-2-oxo-ethyl)pyrazole-3-carboxylate (15.0 g, 76.1 mmol, 99% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.55 (d, J = 2.0 Hz, 1H), 7.53 (s, 1H), 7.18 (s, 1H), 6.87 (d, J = 2.0 Hz, 1H), 5.09 (s, 2H), 4.25 (q, J = 7.2 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H). LC-MS (Method G): Rt = 0.358 min; MS (ESIpos): m/z = 198.0 [M+H] ⁺ . Procedure for preparation of 7H-pyrazolo[1,5-a]pyrazine-4,6-dione To a mixture of ethyl 2-(2-amino-2-oxo-ethyl)pyrazole-3-carboxylate (5.00 g, 25.4 mmol, 1.00 eq) in ethanol (100 mL) was added sodium tert-butoxide (2M in tetrahydrofuran, 25.4 mL, 2.00 eq). After stirring at 70 °C for 16 h, hydrochloride (1M) was added to the mixture to adjust pH~6. The mixture was concentrated to give a residue. The residue was triturated with ethanol (20.0 mL). The suspension was filtered and the filter cake was dried under vacuum to give 7H-pyrazolo[1,5-a]pyrazine-4,6-dione (2.50 g, 16.5 mmol, 65% yield) as a light green solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.80 (br s, 1H), 7.75 (d, J = 2.0 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 5.16 (s, 2H). Procedure for preparation of 4,6-dichloropyrazolo[1,5-a]pyrazine To a mixture of 7H-pyrazolo[1,5-a]pyrazine-4,6-dione (1 g, 6.62 mmol, 1 eq) in phosphorus oxychloride (16.5 g, 108 mmol, 10.0 mL, 16.3 eq) was added pyridine;hydrochloride (841 mg, 7.28 mmol, 1.10 eq). After stirring at 120 °C for 16 h, the mixture was concentrated to give a residue. The residue was diluted with ethyl acetate (50.0 mL). The mixture was poured into sodium phosphate monobasic hydrate (1M, 50.0 mL). The resulting mixture was filtered. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give 4,6-dichloropyrazolo[1,5-a]pyrazine (800 mg, 4.26 mmol, 64% yield) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.28 (s, 1H), 8.29 (d, J = 2.4 Hz, 1H), 7.15 (d, J = 2.4 Hz, 1H). Procedure for preparation of 6-chloropyrazolo[1,5-a]pyrazine To a mixture of 4,6-dichloropyrazolo[1,5-a]pyrazine (800 mg, 4.26 mmol, 1.00 eq) and sodium hydrogen carbonate (536 mg, 6.38 mmol, 0.248 mL, 1.50 eq) in ethanol (10.0 mL) was added palladium on carbon (50 mg, 10% purity) under nitrogen. The mixture was degassed and purged with hydrogen for three times. The mixture was stirred at 25 °C for 6 h under hydrogen (15 Psi). The mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 20.0 g SepaFlash® Silica Flash Column, Eluent of 0~19% Ethyl acetate/Petroleum ether gradient @ 75 mL/min) to give 6-chloropyrazolo[1,5-a]pyrazine (550 mg, 3.58 mmol, 84% yield) as yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.17 (d, J = 1.2 Hz, 1H), 9.12 (d, J = 1.2 Hz, 1H), 8.21 (d, J = 2.4 Hz, 1H), 7.13-0.06 (m, 1H). Procedure for preparation of ethyl 3-pyrazolo[1,5-a]pyrazin-6-ylprop-2-enoate To a mixture of 6-chloropyrazolo[1,5-a]pyrazine (150 mg, 0.977 mmol, 1.00 eq), ethyl 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate (442 mg, 1.95 mmol, 2.00 eq) and potassium hypophosphite (518 mg, 2.44 mmol, 2.50 eq) in dioxane (1.00 mL) and water (0.200 mL) was added chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphen yl)[2-(2-amino-1,1-biphenyl)]palladium(II) (76.8 mg, 97.7 μmol, 0.100 eq) under nitrogen atmosphere. The mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. The mixture was filtered. The filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ethergradient @ 55 mL/min) to give ethyl 3- pyrazolo[1,5-a]pyrazin-6-ylprop-2-enoate (210 mg, 0.967 mmol, 99% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.22 (d, J = 18.0 Hz, 2H), 8.24 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 15.2 Hz, 1H), 7.07 (d, J = 1.2 Hz, 1H), 6.84 (d, J = 15.2 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H), 1.20-1.15 (m, 3H). Procedure for preparation of pyrazolo[1,5-a]pyrazine-6-carbaldehyde To a solution of ethyl 3-pyrazolo[1,5-a]pyrazin-6-ylprop-2-enoate (210 mg, 0.967 mmol, 1.00 eq) in dichloromethane (5.00 mL) was bubbled ozone (13.23 mg, 275 μmol) at -70 °C for 0.5 h. Nitrogen was bubbled to the mixture for 10 min at -70 °C. The mixture was warmed to 25 °C. Dimethyl sulfide (630 mg, 10.1 mmol, 745 μL, 10.49 eq) was added. After stirring at 25 °C for 3 h, the mixture was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ethergradient @ 50 mL/min) to give pyrazolo[1,5-a]pyrazine-6-carbaldehyde (100 mg, 680 μmol, 70% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.00 (s, 1H), 9.48 (s, 1H), 9.33 (s, 1H), 8.43 (d, J = 2.0 Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H). Procedure for preparation of 2-amino-2-pyrazolo[1,5-a]pyrazin-6-yl-acetonitrile To a mixture of pyrazolo[1,5-a]pyrazine-6-carbaldehyde (100 mg, 0.680 mmol, 1.00 eq) in methanol (2.00 mL) were added ammonia (7 M in methanol, 0.485 mL, 5.00 eq) and titanium(iv)isopropoxide (290 mg, 1.02 mmol, 0.301 mL, 1.50 eq). After stirring for 0.5 h, trimethylsilyl cyanide (101 mg, 1.02 mmol, 0.127 mL, 1.50 eq) was added. The mixture was stirred at 25 °C for 2 h. The mixture reaction was diluted with water (20.0 mL), and extracted with ethyl acetate (10 mL × 4). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2- amino-2-pyrazolo[1,5-a]pyrazin-6-yl-acetonitrile (100 mg, 0.577 mmol, 93% yield) as a white solid. Procedure for preparation of Compound CPD0277804 & CPD0277803 - (1R,2S,5S)-N- (cyano(pyrazolo[1,5-a]pyrazin-6-yl)methyl)-3-((S)-3,3-dimeth yl-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxamide and (1R,2S,5S)-N-(cyano(pyrazolo[1,5-a]pyrazin-6-yl)methyl)-3-(( S)-3,3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxamide To a mixture of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (210 mg, 0.577 mmol, 1.00 eq) in dichloromethane (1.00 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (329 mg, 0.866 mmol, 1.50 eq) and diisopropylethylamine (336 mg, 2.60 mmol, 0.453 mL, 4.50 eq). After stirring at 25 °C for 10 min, 2-amino-2-pyrazolo[1,5-a]pyrazin-6-yl-acetonitrile (100 mg, 0.577 mmol, 1.00 eq) was added. The mixture was stirred at 25 °C for 16 h. The mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*40mm* 15 μm; mobile phase: [water(FA)-ACN];B%: 40%-70%,10 min) to give (1R,2S,5S)-N-((S)-cyano(pyrazolo[1,5- a]pyrazin-6-yl)methyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluor oacetamido)butanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (13.8 mg, 26.2 μmol, 4% yield, 98% purity) as a white solid and (1R,2S,5S)-N-((R)-cyano(pyrazolo[1,5-a]pyrazin-6-yl)methyl)- 3-((S)-3,3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxamide (16.8 mg, 32.2 μmol, 6% yield, 99% purity) as a white solid. CPD0277804 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.45 (d, J = 7.6 Hz, 1H), 9.35-9.28 (m, 2H), 8.89-8.81 (m, 1H), 8.28-8.20 (m, 1H), 7.08 (d, J = 2.4 Hz, 1H), 6.23 (d, J = 7.6 Hz, 1H), 4.53-4.46 (m, 1H), 4.27 (d, J = 4.4 Hz, 1H), 3.81 (dd, J = 10.4, 7.6, Hz, 1H), 3.63 (br dd, J = 10.6, 3.2 Hz, 1H), 1.85-1.73 (m, 2H), 1.70-1.33 (m, 5H), 1.04-0.91 (m, 10H). LC-MS (Method C): Rt = 0.920 min; MS (ESIpos): m/z = 520.3 [M+H] ⁺ . SFC: de% = 77%. CPD0277803 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.52 (d, J = 7.6 Hz, 1H), 9.37-9.23 (m, 2H), 8.87 (s, 1H), 8.28-8.20 (m, 1H), 7.08 (d, J = 2.4 Hz, 1H), 6.32 (d, J = 7.6 Hz, 1H), 4.50-4.44 (m, 1H), 4.26 (d, J = 4.4 Hz, 1H), 3.86-3.80 (m, 1H), 3.69-3.61 (m, 1H), 1.90-1.76 (m, 2H), 1.73-1.32 (m, 5H), 1.04-0.84 (m, 10H). LC-MS (Method C): Rt = 0.925 min; MS (ESIpos): m/z = 520.3 [M+H] ⁺ . SFC: de% = 100%. To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propanoic acid (2.00 g, 8.72 mmol, 1.00 eq) in dichloromethane (20.0 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluronium hexafluorophosphate (4.98 g, 13.1 mmol, 1.50 eq), diisopropylethylamine (2.25 g, 17.6 mmol, 3.04 mL, 2.00 eq) and methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylate (1.48 g, 8.72 mmol, 1.00 eq). After stirring at 25 °C for 2 h, the reaction mixture was concentrated under reduced pressure at 40 °C to give a residue. The residue was partitioned between ethyl acetate (20.0 mL) and water (20.0 mL). The separated aqueous phase was extracted with ethyl acetate (20.0 mL × 2). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was purified by flash column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 0 to 0: 1) to afford methyl (1R, 2S, 5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propa noyl]-6, 6-dimethyl-3- azabicyclo [3.1.0] hexane-2-carboxylate (5.00 g) as yellow oil. LCMS (Method C): Rt = 0.475 min; MS (ESIpos): m/z = 381.1 [M+H] ^+. Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropy l- propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropy l-propanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (5.00 g, 13.1 mmol, 1.00 eq) in methanol (20.0 mL) and water (20.0 mL) was added lithium hydroxide hydrate (1.65 g, 39.4 mmol, 3.00 eq) at 25 °C. After stirring at 25 °C for 2 h, the pH was adjusted to 7 with hydrogen chloride (1M). The reaction mixture was concentrated under reduced pressure to give (1R, 2S, 5S)-3-[(2S)-2-(tert-butoxycarbonylamino)- 3-cyclopropyl-propanoyl]-6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid (3.00 g, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 4.16-4.12 (m, 1H), 3.16 (s, 3H), 1.68 (s, 9H), 1.32 (s, 6H), 1.28-1.16 (m, 3H), 1.04 (t, J = 7.2 Hz, 1H), 0.96 (d, J = 3.2 Hz, 4H), 0.92-0.80 (m, 4H), 0.72-0.56 (m, 1H), 0.36 (d, J = 7.2 Hz, 2H), 0.16-0.04 (m, 3H). LC-MS (Method C): Rt = 0.437 min; MS (ESIpos): m/z = 367.1 [M+H] ⁺ . To a solution of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropy l-propanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (3.00 g, 8.19 mmol, 1.00 eq) in dichloromethane (15.0 mL) and trifluoroacetic acid (15.0 mL) at 25 °C. After stirring at 25 °C for 1 h, the reaction mixture was concentrated under reduced pressure at 40 °C to give (1R,2S,5S)-3-[(2S)-2-amino-3-cyclopropyl- propanoyl]-6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid (3.00 g, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 3.48-3.39 (m, 2H), 2.60-2.56 (m, 3H), 2.56 (s, 4H), 2.44 (d, J = 9.2 Hz, 2H), 2.32 (s, 1H), 2.28-2.16 (m, 1H), 1.88 (s, 2H), 1.60-1.52 (m, 1H), 1.44-1.32 (m, 6H), 1.24 (d, J = 6.4 Hz, 9H), 1.08 (s, 1H), 1.04-0.96 (m, 3H), 0.92-0.80 (m, 1H). LC-MS (Method C): Rt = 0.190 min and 0.259 min; MS (ESIpos): m/z = 267.0 [M+H] ^+. Procedure for preparation of (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[(2,2,2- trifluoroacetyl)amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3 .1.0]hexane-2-carboxylic acid To a solution of (1R,2S,5S)-3-[(2S)-2-amino-3-cyclopropyl-propanoyl]-6,6-dime thyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (3.00 g, 11.3 mmol, 1.00 eq) in methanol (10.0 mL) were added methyl 2,2,2-trifluoroacetate (4.33 g, 33.8 mmol, 3.41 mL, 3.00 eq) and triethylamine (3.42 g, 33.8 mmol, 4.70 mL, 3.00 eq) at 25 °C. After stirring at 25 °C for 16 h, the reaction mixture was concentrated at 40 °C to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10 μm; mobile phase: [water (FA)-ACN]; B%: 32%-62%, 8 min) to afford (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[(2,2,2-trifluoroacetyl)a mino]propanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (2.40 g, 6.62 mmol, 59% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.76 (d, J = 7.2 Hz, 1H), 4.52-4.40 (m, 1H), 4.12 (s, 1H), 3.92-3.72 (m, 2H), 1.72-1.60 (m, 1H), 1.60-1.48 (m, 2H), 1.44-1.36 (m, 1H), 1.12-0.88 (m, 6H), 0.84-0.76 (m, 1H), 0.48-0.32 (m, 2H), 0.28-0.16 (m, 1H), 0.12-0.04 (m, 1H). LC-MS (Method C): Rt = 0.399 min; MS (ESIpos): m/z = 363.0 [M+H] ^+. Procedure for preparation of Compound CPD0190783 - (1R,2S,5S)-N-[cyano(1,6-naphthyridin-8- yl)methyl]-3-[(2S)-3-cyclopropyl-2-[(2,2,2-trifluoroacetyl)a mino]propanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide - To a solution of 2-amino-2-(1,6-naphthyridin-8-yl)acetonitrile (100 mg, 271 umol, 1.00 eq) and (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[(2,2,2-trifluoroacetyl)a mino]propanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (90.0 mg, 0.248 mmol, 0.91 eq) in dichloromethane (1.00 mL) were added diisopropylethylamine (105 mg, 0.814 mmol, 142 uL, 3.00 eq) and O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (114 mg, 0.298 mmol, 1.10 eq). After stirring at 25 °C for 16 h, the reaction mixture was concentrated under reduce pressure at 40 °C to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10 μm; mobile phase: [water(FA)-ACN];B%: 38%-68%,10min) to afford (1R,2S,5S)-N- [cyano(1,6-naphthyridin-8-yl)methyl]-3-[(2S)-3-cyclopropyl-2 -[(2,2,2-trifluoroacetyl)amino]propanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (28.6 mg, 51.4 μmol, 19% yield) as yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.40-9.32 (m, 1H), 9.28-9.19 (m, 1H), 8.84 (d, J = 10.4 Hz, 1H), 8.56- 8.32 (m, 2H), 7.76-7.69 (m, 1H), 7.00 (d, J = 5.6 Hz, 1H), 6.60 (d, J = 8.8 Hz, 1H), 4.80-4.56 (m, 1H), 4.40 (d, J = 13.6 Hz, 1H), 3.96-3.64 (m, 2H), 1.84-1.76 (m, 1H), 1.72-1.64 (m, 2H), 1.52-1.40 (m, 1H), 1.40-1.24 (m, 1H), 1.12-1.00 (m, 3H), 0.96-0.84 (m, 3H), 0.80-0.72 (m, 1H), 0.64-0.48 (m, 1H), 0.32- 0.24 (m, 1H), 0.16-0.08 (m, 1H), 0.04-0.24 (m, 1H). LC-MS (Method C): Rt = 0.692 min; MS (ESIpos): m/z = 529.2 [M+H] ⁺ . To a solution of (2S)-3-amino-2-(tert-butoxycarbonylamino)propanoic acid (30.0 g, 147 mmol, 1.00 eq) in methanol (100 mL) was added formaldehyde (29.8 g, 367 mmol, 27.3 mL, 37% purity, 2.50 eq) and palladium in active carbon (3.00 g, 10% purity, 50 % in water) at 20 °C. After stirring at 20 °C for 16 h under hydrogen (15 psi) atmosphere, the reaction mixture was filtered. The filtrate was concentrated in vacuum to give (2S)-2-(tert-butoxycarbonylamino)-3-(dimethylamino)propanoic acid (33.0 g, 142 mmol, 97% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.82 (d, J = 4.0 Hz, 1H), 4.19-4.14 (m, 1H), 3.33-3.23 (m, 2H), 2.88 (s, 6H), 1.42 (s, 9H). Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3- (dimethylamino)propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]he xane-2-carboxylate To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-(dimethylamino)propanoic acid (5.00 g, 21.5 mmol, 1.00 eq) in N,N-dimethyl formamide (50.0 mL) were added 1-methyl-2-pyrrolidinone (6.53 g, 64.6 mmol, 7.10 mL, 3.00 eq), 1-hydroxybenzotriazole (4.36 g, 32.3 mmol, 1.50 eq) and N-(3- dimethylaminopropyl)-N-ethylcarbodiimide hyd,rochloride (6.19 g, 32.3 mmol, 1.50 eq) at 0 °C under nitrogen atmosphere. After stirring at 0 °C for 10 min, methyl (1R,2S,5S)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (5.31 g, 25.8 mmol, 1.20 eq, hydrochloride) was added into the reaction mixture at 0 °C. The reaction mixture was stirred at 20 °C for 16 h under nitrogen atmosphere. The reaction mixture was added dropwise into ice-water (50 mL). The mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®;120 g SepaFlash® Silica Flash Column, Eluent of 0~100%Ethyl acetate/Petroleum ethergradient @ 75 mL/min) to give methyl (1R,2S,5S)-3-[(2S)-2-(tert- butoxycarbonylamino)-3-(dimethylamino)propanoyl]-6,6-dimethy l-3-azabicyclo[3.1.0]hexane-2- carboxylate (6.50 g, 16.9 mmol, 81% yield) as yellow oil ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 6.95 (d, J = 7.2 Hz, 1H), 4.25-4.17 (m, 1H), 4.10-3.98 (m, 1H), 3.90- 3.82 (m, 1H), 3.79-3.71 (m, 1H), 3.63 (s, 2H), 2.46-2.28 (m, 2H), 2.16 (s, 5H), 1.41-1.30 (m, 9H), 1.01 (s, 3H), 0.94-0.88 (m, 3H). Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3- (dimethylamino)propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]he xane-2-carboxylic acid A mixture of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-(dimethyla mino)propanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (3.20 g, 8.34 mmol, 1.00 eq) and lithium;hydroxide;hydrate (1.05 g, 25.0 mmol, 3.00 eq) in ethanol (30.0 mL) and water (10.0 mL) was stirred at 25 °C for 4 h. The mixture was concentrated to give (1R,2S,5S)-3-[(2S)-2-(tert- butoxycarbonylamino)-3-(dimethylamino)propanoyl]-6,6-dimethy l-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (3.00 g, 8.12 mmol, 97% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 4.11-3.86 (m, 1H), 3.72-3.47 (m, 1H), 3.39-3.28 (m, 1H), 2.33 (s, 1H), 2.20-2.01 (m, 6H), 1.60 (s, 1H), 1.48-1.41 (m, 1H), 1.34-1.30 (m, 1H), 1.27-1.19 (m, 1H), 1.11 (s, 9H), 1.01-0.94 (m, 3H), 0.93-0.84 (m, 3H). Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-amino-3-(dimethylamino)propanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid - A mixture of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-(dimethyla mino)propanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.00 g, 2.71 mmol, 1.00 eq) and hydrochloric acid (4M in 1,4-dioxane, 10.0 mL, 14.8 eq) in 1,4-dioxane (10.0 mL) was stirred at 25 °C for 3 h. The mixture was concentrated to give (1R,2S,5S)-3-[(2S)-2-amino-3-(dimethylamino)propanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (800 mg, 2.62 mmol, 96% yield, hydrochloric acid) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.99 (br s, 1H), 4.95 (d, J = 6.8 Hz, 1H), 4.21 (s, 2H), 3.94-3.86 (m, 3H), 2.90 (s, 6H), 1.91 (s, 1H), 1.61-1.55 (m, 1H), 1.53-1.44 (m, 1H), 1.04 (s, 3H), 0.93 (s, 3H). Procedure for preparation of (1R,2S,5S)-3-[(2S)-3-(dimethylamino)-2-[(2,2,2- trifluoroacetyl)amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3 .1.0]hexane-2-carboxylic acid A mixture of (1R,2S,5S)-3-[(2S)-2-amino-3-(dimethylamino)propanoyl]-6,6-d imethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (700 mg, 2.60 mmol, 1.00 eq), methyl 2,2,2-trifluoroacetate (2.66 g, 20.8 mmol, 2.10 mL, 8.00 eq) and N,N-diethylethanamine (2.63 g, 26.0 mmol, 3.62 mL, 10.0 eq) in methanol (20.0 mL) was stirred at 25 °C for 16 h. Hydrochloric acid (1M) was added to the mixture to adjust pH~4. The mixture was concentrated to give a residue. The residue was purified by reversed phase (instrument: 330 g Flash; Column: Welch Ultimate XB_C1820-40μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-30min 40~60% B; flow 100 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give ((1R,2S,5S)-3-[(2S)-3-(dimethylamino)-2-[(2,2,2- trifluoroacetyl)amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3 .1.0]hexane-2-carboxylic acid (0.82 g, 2.02 mmol, 78% yield, 90% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.68 (br s, 1H), 4.55 (d, J = 6.8 Hz, 1H), 4.12 (s, 1H), 3.84-3.72 (m, 3H), 2.78-2.63 (m, 2H), 2.45-2.38 (m, 1H), 2.16 (s, 1H), 1.57-1.52 (m, 1H), 1.42 (d, J = 7.6 Hz, 1H), 1.02 (s, 3H), 0.95-0.92 (m, 1H), 0.90 (s, 3H). To a mixture of (1R,2S,5S)-3-[(2S)-3-(dimethylamino)-2-[(2,2,2-trifluoroacet yl)amino]propanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (350 mg, 958 umol, 1.00 eq), 2-amino-2-(1,6- naphthyridin-8-yl)acetonitrile (177 mg, 0.958 mmol, 1.00 eq) and N-ethyl-N-isopropyl-propan-2-amine (495 mg, 3.83 mmol, 0.667 mL, 4.00 eq) in dichloromethane (4.00 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dim ethyl-ammonium;hexafluorophosphate (364 mg, 0.958 mmol, 1.00 eq). After stirring at 25 °C for 16 h, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C1875*30mm*3 μm; mobile phase: [water(FA)-ACN]; B%: 15%-45%,7min) followed by reversed phase (column: Unisil 3-100 C18 Ultra 150*50mm*3 μm; mobile phase: [water(FA)-ACN];B%: 6%-36%,7min) to give (1R,2S,5S)-N- [cyano(1,6-naphthyridin-8-yl)methyl]-3-[(2S)-3-(dimethylamin o)-2-[(2,2,2- trifluoroacetyl)amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3 .1.0]hexane-2-carboxamide (38.9 mg, 66.6 μmol, 7% yield, 91% purity) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.11-9.96 (m, 1H), 9.77-9.68 (m, 1H), 9.62-9.50 (m, 2H), 9.45-9.22 (m, 2H), 8.92 (d, J = 2.4 Hz, 1H), 8.72 (dd, J = 8.4, 1.6 Hz, 1H), 7.89-7.82 (m, 1H), 6.86-6.81 (m, 1H), 5.04 - 4.87 (m, 1H), 4.37-4.25 (m, 1H), 3.98-3.91 (m, 1H), 3.72-3.60 (m, 1H), 3.57-3.43 (m, 2H), 2.97- 2.77 (m, 6H), 1.66-1.54 (m, 1H), 1.49-1.24 (m, 1H), 1.09-0.95 (m, 3H), 0.91-1.82 (m, 3H). LC-MS (Method C): Rt = 0.783 min; MS (ESIpos): m/z = 532.2 [M+H] ⁺ . SFC: dr = 53: 64. Preparation of CPD0190791 Procedure for preparation of methyl (2S)-2-(tert-butoxycarbonylamino)-3-pyrrolidin-1-yl- propanoate To a solution of pyrrolidine (4.32 g, 60.8 mmol, 5.07 mL, 2.00 eq) in dimethyl formamide (50.0 mL) were added potassium carbonate (8.40 g, 60.8 mmol, 2.00 eq) and methyl (2R)-2-(tert- butoxycarbonylamino)-3-iodo-propanoate (10.0 g, 30.4 mmol, 1.00 eq). After stirring at 25 °C for 2 h, the reaction mixture was quenched with water (50.0 mL), diluted with ethyl acetate (50.0 mL) and washed with water (30.0 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 5: 1 to 1: 1) to afford methyl (2S)-2-(tert- butoxycarbonylamino)-3-pyrrolidin-1-yl-propanoate (6.00 g, 19.8 mmol, 65% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.12-7.00 (m, 1H), 4.12 (q, J = 7.2 Hz, 1H), 3.60 (s, 3H), 2.76-2.68 (m, 1H), 2.64-2.60(m, 1H), 2.44 (br s, 4H), 1.64 (br t, J = 2.8 Hz, 4H), 1.40-1.32 (m, 9H). LCMS (Method C): Rt = 0.216 min; MS (ESIpos): m/z = 273.2 [M+H] ⁺ . Procedure for preparation of (2S)-2-(tert-butoxycarbonylamino)-3-pyrrolidin-1-yl-propanoi c acid To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-pyrrolidin-1-yl-propanoa te (6.00 g, 22.0 mmol, 1.00 eq) in water (25.0 mL) and methanol (25.0 mL) was added lithium hydroxide hydrate (2.77 g, 66.1 mmol, 3.00 eq). After stirring at 25 °C for 12 h, the reaction mixture was concentrated under reduced pressure to give (2S)-2-(tert-butoxycarbonylamino)-3-pyrrolidin-1-yl-propanoi c acid (9.00 g, 20.9 mmol, 95% yield) as colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 6.36 (d, J =7.2 Hz, 1H), 3.04-2.84 (m, 6H), 1.80 (br. s, 4H), 1.36 (s, 9H). LC-MS (Method C): Rt = 0.190 min; MS (ESIpos): m/z = 259.2 [M+H] ⁺ . Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3- pyrrolidin-1-yl-propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]h exane-2-carboxylate To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-pyrrolidin-1-yl-propanoi c acid (4.00 g, 10.1 mmol, 65% purity, 1.00 eq) in dichloromethane (50.0 mL) were added methyl (1R,2S,5S)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (3.41 g, 20.1 mmol, 2.00 eq), diisopropylethylamine (2.60 g, 20.1 mmol, 3.51 mL, 2.00 eq) and (benzotriazol-1- yloxy)tripyrrolidinophosphonium,hexafluorophosphate (7.86 g, 15.1 mmol, 1.50 eq) at 25 °C. After stirring at 25 °C for 2 h, the reaction mixture was concentrated under vacuum at 50 °C to give a residue. The residue was partitioned between ethyl acetate (30.0 mL) and water (30.0 mL). The separated aqueous phase was extracted with ethyl acetate (30.0 mL × 2). The combined extracts were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was purified by flash column chromatography (SiO ₂ , dichloromethane: methanol = 100: 1 to 4: 1) to afford methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3- pyrrolidin-1-yl-propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]h exane-2-carboxylate (9.00 g, crude) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 4.20-4.16 (m, 1H), 4.16-4.08 (m, 1H), 3.88-3.84 (m, 2H), 3.64 (s, 3H), 3.12-3.08 (m, 2H), 2.76-2.72 (m, 4H), 1.84-1.80 (m, 4H), 1.60-1.52 (m, 1H), 1.48-1.44 (m, 1H), 1.28 (s, 9H), 1.24-1.20 (m, 3H), 1.04-1.00 (m, 3H). LC-MS (Method C): Rt = 0.318 min; MS (ESIpos): m/z = 410.3 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-pyrrolidin -1-yl- propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-pyrrolidin -1-yl-propanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (9.00 g, 22.0 mmol, 1.00 eq) in methanol (30.0 mL) and water (30.0 mL) was added lithium hydroxide hydrate (2.77 g, 65.9 mmol, 3.00 eq) at 25 °C. After stirring at 25 °C for 2 h, hydrochloric acid (1M) was added to the mixture to adjust pH = 7. The solution was concentrated under reduced pressure to give (1R,2S,5S)-3-[(2S)-2-(tert- butoxycarbonylamino)-3-pyrrolidin-1-yl-propanoyl]-6,6-dimeth yl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (8.00 g, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 4.36-4.28 (m, 1H), 4.08-4.04 (m, 1H), 3.76-3.72 (m, 2H), 2.84-2.76 (m, 2H), 2.72-2.64 (m, 4H), 1.84-1.76 (m, 4H), 1.60-1.56 (m, 1H), 1.56-1.48 (m, 1H), 1.36 (br. s, 9H), 0.96-0.84 (m, 6H). LC-MS (Method C): Rt = 0.309 min; MS (ESIpos): m/z = 396.3 [M+H] ^+. To a solution of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-pyrrolidin -1-yl-propanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (8.00 g, 20.2 mmol, 1.00 eq) in dichloromethane (40.0 mL) and trifluoroacetic acid (40.0 mL) at 25 °C After stirring at 25 °C for 2 h, the reaction mixture was concentrated in vacuo at 50 °C to give (1R,2S,5S)-3-[(2S)-2-amino-3-pyrrolidin-1-yl-propanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (6.00 g, crude) as yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 4.64-4.56 (m, 1H), 4.20-4.16 (m, 1H), 4.04-3.96 (m, 1H), 3.84-3.76 (m, 1H), 3.68-3.64 (m, 1H), 3.56-3.48 (m, 2H), 3.24-3.20 (m, 1H), 2.48-2.28 (m, 4H), 2.00-1.94 (m, 4H), 1.52-1.48 (m, 1H), 1.48-1.40 (m, 1H), 1.08-1.00 (m, 6H) LC-MS (Method C): Rt = 0.195 min; MS (ESIpos): m/z = 296.2 [M+H] ^+. Procedure for preparation of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-pyrrolidin-1-yl-2-[(2,2,2- trifluoroacetyl)amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2 -carboxylic acid To a solution of (1R,2S,5S)-3-[(2S)-2-amino-3-pyrrolidin-1-yl-propanoyl]-6,6- dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (6.00 g, 20.3 mmol, 1.00 eq) in methanol (60.0 mL) were added methyl 2,2,2-trifluoroacetate (7.80 g, 60.9 mmol, 6.14 mL, 3.00 eq) and triethylamine (6.17 g, 60.9 mmol, 8.48 mL, 3.00 eq) at 25 °C. After stirring at 25 °C for 16 h, the reaction mixture was concentrated under vacuum at 50 °C to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water (FA)-ACN];B%: 5%-35%,8min) to afford Compound (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-pyrrolidin-1-yl-2-[(2,2,2- trifluoroacetyl)amino]propanoyl]-3-azabicyclo[3.1.0] hexane-2-carboxylic acid (188 mg, 480 μmol) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.00-9.68 (m, 1H), 4.64-4.56 (m, 1H), 4.12 (s, 1H), 3.84-3.76 (m, 1H), 3.76-3.64 (m, 1H), 3.12-2.92 (m, 2H), 2.72-2.60 (m, 4H), 1.76-1.68 (m, 4H), 1.56-1.52 (m, 1H), 1.48-1.40 (m, 1H), 1.00 (s, 3H), 0.88 (s, 3H). LC-MS (Method C): Rt = 0.273 min; MS (ESIpos): m/z = 392.2 [M+H] ^+. . SFC: dr = 84: 16. To a solution of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-pyrrolidin-1-yl-2-[(2,2,2- trifluoroacetyl)amino] propanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (70.0 mg, 179 μmol, 1.00 eq) in dichloromethane (1.00 mL) were added 2-amino-2-(1,6-naphthyridin-8-yl)acetonitrile (36.2 mg, 197 μmol, 1.10 eq), diisopropylethylamine (69.3 mg, 536 μmol, 93.5 μL, 3.00 eq) and O-(7-azabenzotriazol- 1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (74.8 mg, 197 μmol, 1.10 eq). After stirring at 25 °C for 12 h, the reaction mixture was concentrated under vacuum at 50 °C to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 μm; mobile phase: [water(FA)-ACN]; B%: 9%-39%,7min) and followed by prep-TLC (dichloromethane: tetrahydrofuran = 10: 1) to give (1R,2S,5S)-N-[cyano(1,6-naphthyridin-8-yl)methyl]-6,6-dimeth yl-3-[(2S)-3-pyrrolidin-1-yl- 2-[(2,2,2-trifluoroacetyl) amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide (19.0 mg, 31.2 μmol, 17% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.96-9.64 (m, 1H), 9.60-9.36 (m, 2H), 9.28 (td, J = 3.6, 2.0 Hz, 1H), 8.88 (d, J = 8.0 Hz, 1H), 8.72 (br d, J = 6.8 Hz, 1H), 8.12 (s, 1H), 7.84 (dd, J = 8.2, 4.4 Hz, 1H), 6.92- 6.76 (m, 1H), 4.60-4.48 (m, 1H), 4.36-4.24 (m, 1H), 3.92-3.80 (m, 1H), 3.72 (br d, J = 10.4 Hz, 1H), 2.96-2.76 (m, 1H), 2.64-2.60 (m, 1H), 2.44-2.36 (m, 2H), 1.72-1.52 (m, 5H), 1.48-1.20 (m, 3H), 1.08- 0.88 (m, 6H). LC-MS (Method C): Rt = 0.692 min; MS (ESIpos): m/z = 529.2 [M+H] ⁺ . SFC: dr = 67: 33. A mixture of (2S)-2-(tert-butoxycarbonylamino)-3-(3-pyridyl)propanoic acid (1.00 g, 3.76 mmol, 1.00 eq), methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (772 mg, 3.76 mmol, 1.00 eq, hydrochloric acid), O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (2.14 g, 5.63 mmol, 1.50 eq) and N,N-diisopropylethylamine (1.46 g, 11.3 mmol, 1.96 mL, 3.00 eq) in N,N-dimethylformamide (10.0 mL) was stirred at 20 °C for 12 h. The mixture was poured into water (40.0 mL) and extracted with ethyl acetate (40.0 mL × 3). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1 to 0: 1) to afford methyl (1R,2S,5S)-3-[(2S)-2- (tert-butoxycarbonylamino)-3-(3-pyridyl)propanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxylate (1.50 g, 3.56 mmol, 95% yield, 99% purity) as light yellow gum. LC-MS (Method O): Rt = 0.351 min; MS (ESIpos): m/z = 418.0 [M+H] ⁺ . SFC: de% = 100%. Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-(3- pyridyl)propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid To a mixture of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-(3-pyridyl )propanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.50 g, 3.59 mmol, 1.00 eq) in a mixed solvent of methanol (10.0 mL) and water (10.0 mL) was added lithium hydroxide hydrate (452 mg, 10.8 mmol, 3.00 eq) at 0 °C. After stirring at 20 °C for 12 h, the mixture was concentrated under vacuum to remove methanol. The residue was diluted with water (20.0 mL), adjusted to pH = 7 with hydrochloric acid (1.00 M) and extracted with ethyl acetate (30.0 mL × 4). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-(3-pyridyl )propanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (1.4 g, crude) as a light yellow solid. The crude product was used for the next step reaction directly. LC-MS (Method C): R _t = 0.414 min; MS (ESIpos): m/z = 404.0 [M+H] ⁺ . To a mixture of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-(3-pyridyl )propanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (0.600 g, 1.49 mmol, 1.00 eq) in ethyl acetate (5.00 mL) was added hydrochloric acid (4 M in ethyl acetate, 6.00 mL, 16.1 eq) at 20 °C. After stirring at 20 °C for 3 h, the mixture was concentrated under vacuum to afford (1R,2S,5S)-3-[(2S)-2-amino-3-(3- pyridyl)propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (500 mg, 1.37 mmol, 92% yield, 93% purity, hydrochloric acid) as an off-white solid. LC-MS (Method C): R _t = 0.197 min; MS (ESIpos): m/z = 303.9 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2- carboxylic acid A mixture of (1R,2S,5S)-3-[(2S)-2-amino-3-(3-pyridyl)propanoyl]-6,6-dimet hyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (500 mg, 1.37 mmol, 93% purity, 1.00 eq, hydrochloric acid), methyl 2,2,2-trifluoroacetate (263 mg, 2.05 mmol, 1.50 eq) and triethylamine (415 mg, 4.11 mmol, 3.00 eq) in methanol (5.00 mL) was stirred at 20 °C for 12 h. The mixture was concentrated under vacuum to give a residue. The residue was diluted with water (10.0 mL), adjusted to pH = 7 with hydrochloric acid (0.50 M) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-(3-pyridyl)-2-[(2,2,2-trif luoroacetyl)amino]propanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (460 mg, 968 μmol, 71% yield, 84% purity) as light yellow gum. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 13.00-12.58 (m, 1H), 9.96 (d, J = 8.0 Hz, 1H), 8.54 (d, J = 1.2 Hz, 1H), 8.44 (d, J = 3.6 Hz, 1H), 7.79-7.75 (m, 1H), 7.32 (dd, J = 4.8, 7.6 Hz, 1H), 4.73-4.67 (m, 1H), 4.16 (s, 1H), 3.85-3.79 (m, 1H), 3.76-3.71 (m, 1H), 3.04 (d, J = 4.8 Hz, 1H), 3.00-2.95 (m, 1H), 1.56-1.52 (m, 1H), 1.45 (d, J = 7.5 Hz, 1H), 1.03 (s, 3H), 0.88 (s, 3H). LC-MS (Method O): R _t = 0.293 min; MS (ESIpos): m/z = 399.9 [M+H-100] ⁺ . A mixture of 2-amino-2-(1,6-naphthyridin-8-yl)acetonitrile (100 mg, 543 umol, 1.00 eq), (1R,2S,5S)-6,6- dimethyl-3-[(2S)-3-(3-pyridyl)-2-[(2,2,2-trifluoroacetyl)ami no]propanoyl]-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (217 mg, 543 μmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (310 mg, 814 μmol, 1.5 eq), N,N-diisopropylethylamine (140 mg, 1.09 mmol, 0.190 mL, 2.00 eq) in N,N-dimethylformamide (1.50 mL) was stirred at 20 °C for 12 h. The reaction mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (20.0 mL × 2). The combined organic layers were washed with brine (10.0 mL × 2), dried over anhydrous sodium sulfate filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition;n column: Waters Xbridge C18150*50mm* 10 μm; mobile phase: [water( NH ₄ HCO ₃ )-ACN]; B%: 28%) to give (1R,2S,5S)-N-[cyano(1,6-naphthyridin-8-yl)methyl]-6,6-dimeth yl-3- [(2S)-3-(3-pyridyl)-2-[(2,2,2-trifluoroacetyl)amino]propanoy l]-3-azabicyclo[3.1.0]hexane-2-carboxamide (36.7 mg, 63.5 μmol, 12% yield, 98% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.99-9.92 (m, 0.6H), 9.64 (d, J = 7.8 Hz, 0.4H), 9.53 (s, 1H), 9.51- 9.49 (m, 0.4H), 9.29-9.27 (m, 1H), 8.94 (d, J = 11.2 Hz, 1H), 8.73-8.71 (m, 1H), 8.55-8.48 (m, 1H), 8.45- 8.43 (m, 0.5H), 8.41-8.39 (m, 0.5H), 7.87-7.84 (m, 1H), 7.77-7.75 (m, 0.5H), 7.69-7.67 (m, 0.5H), 7.34- 7.31 (m, 0.5H), 7.26-7.23 (m, 0.5H), 6.93-6.91 (m, 0.5H), 6.86-6.84 (m, 0.5H), 4.72-4.63 (m, 1H),4.36- 4.30 (m, 1H), 3.94-3.86 (m, 1H), 3.76-3.72 (m, 1H), 3.13-2.88 (m, 2H), 1.61-1.55 (m, 1H), 1.44-1.43 (m, 0.5H), 1.30-1.28 (m, 0.5H), 1.06-1.04 (m, 1.5H), 0.97 (s, 1.5H), 0.88 (d, J = 15.2 Hz, 3H). LC-MS (Method C): R _t = 0.449 min; MS (ESIpos): m/z = 566.3 [M+H] ⁺ . HPLC (Method K): R _t = 1.449 min; purity: 98%. SFC: dr = 48: 48. Preparation of CPD0190794 Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-phenyl- propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate To a mixture of (2S)-2-(tert-butoxycarbonylamino)-3-phenyl-propanoic acid (2.00 g, 7.54 mmol, 1.00 eq), N,N-diisopropylethylamine (2.92 g, 22.62 mmol, 3.94 mL, 3 eq) and O-(7-Aza-1H-benzotriazol-1- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.30 g, 11.31 mmol, 1.50 eq) in acetonitrile (20.0 mL) was added methyl (1S,2S,5R)-6-methyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.52 g, 7.92 mmol, 1.05 eq, hydrochloric acid) at 0 °C. After addition, the mixture was stirred at 20 °C for 12 h. The mixture was poured into water (20.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified silica gel column chromatography (petroleum ether: ethyl acetate= 10: 1 to 5: 1) to afford methyl (1R,2S,5S)-3-[(2S)-2- (tert-butoxycarbonylamino)-3-phenyl-propanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2- carboxylate (1.30 g, 2.87 mmol, 38% yield, 92% purity) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.24-7.20 (m, 2H), 7.18-7.15 (m, 3H), 5.07 (d, J = 9.2 Hz, 1H), 4.58- 4.49 (m, 1H), 3.73-3.70 (m, 1H), 3.67 (s, 3H), 3.42-3.35 (m, 1H), 3.02 (dd, J = 13.6, 7.2 Hz, 1H), 2.79 (dd, J = 13.6, 7.2 Hz, 1H), 1.30 (s, 9H), 1.27-1.22 (m, 1H), 0.96 (s, 3H), 0.85 (s, 3H), 0.82-0.69 (m, 2H). LC-MS (Method O): R _t = 0.486 min; MS (ESIpos): m/z = 316.9 [M+H-Boc] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-phenyl- propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ic acid To a mixture of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-phenyl-pro panoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.30 g, 2.88 mmol, 92% purity, 1.00 eq) in methanol (10.0 mL) and water (10.0 mL) was added lithium hydroxide hydrate (242 mg, 5.76 mmol, 2.00 eq) at 20 °C. After stirring at 20 °C for 12 h, the mixture was concentrated under vacuum. The residue was diluted with water (20.0 mL) and washed with ethyl acetate (20.0 mL × 2). The aqueous phase was adjusted to pH= 7 with hydrochloric acid (1.00 mol/L) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3- phenyl-propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-c arboxylic acid (960 mg, 2.27 mmol, 79% yield, 95% purity) as light yellow gum. The crude product was used for next step directly. LC-MS (Method S): R _t = 0.579 min; MS (ESIpos): m/z = 303.1 [M+H-Boc] ⁺ . A mixture of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-phenyl-pro panoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (960 mg, 2.39 mmol, 1.00 eq) in hydrochloric acid (4 mol/L in ethyl acetate, 5.00 mL, 8.39 eq) and ethyl acetate (5.00 mL) was stirred at 20 °C for 12 h. The mixture was concentrated under vacuum to afford (1R,2S,5S)-3-[(2S)-2-amino-3-phenyl-propanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (800 mg, 2.24 mmol, 94% yield, 95% purity, hydrochloric acid) as an off-white solid which was used for the next step reaction directly. LC-MS (Method S): R _t = 0.348&0.406 min; MS (ESIpos): m/z = 303.1 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-phenyl-2-[(2,2,2- trifluoroacetyl)amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2 -carboxylic acid To a mixture of (1R,2S,5S)-3-[(2S)-2-amino-3-phenyl-propanoyl]-6,6-dimethyl- 3- azabicyclo[3.1.0]hexane-2-carboxylic acid (800 mg, 2.36 mmol, 1.00 eq, hydrochloric acid) and triethylamine (717 mg, 7.08 mmol, 3.00 eq) in methanol (10.0 mL) was added methyl 2,2,2- trifluoroacetate (454 mg, 3.54 mmol, 1.50 eq) at 20 °C. After stirring at 20 °C for 12 h, the mixture was concentrated under vacuum to give a residue. The residue was diluted with water (10.0 mL), adjusted to pH= 7 with hydrochloric acid (0.50 mol/L) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-phenyl-2-[(2,2,2- trifluoroacetyl)amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2 -carboxylic acid (770 mg, 1.72 mmol, 73% yield, 89% purity) as a light yellow solid which was used for the next step directly. LC-MS (Method S): R _t = 0.545 min; MS (ESIpos): m/z = 399.0 [M+H] ⁺ . A mixture of 2-amino-2-(1,6-naphthyridin-8-yl)acetonitrile (120 mg, 651 umol, 1.00 eq) , (1R,2S,5S)- 6,6-dimethyl-3-[(2S)-3-phenyl-2-[(2,2,2-trifluoroacetyl)amin o]propanoyl]-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (259 mg, 651 μmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (247 mg, 651 μmol, 1.00 eq) , N,N-diisopropylethylamine (84.20 mg, 651 μmol, 1.00 eq) in N,N-dimethylformamide (1.2 mL) was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (20.0 mL × 2). The combined organic layers were washed with brine (10.0 mL × 2), dried over anhydrous sodium sulfate filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (FA condition; column: Phenomenex Synergi C18150*25mm* 10 μm; mobile phase: [water(FA)- ACN]; B%: 39%-69%, 10 min) to give (1R,2S,5S)-N-[cyano(1,6-naphthyridin-8-yl)methyl]-6,6-dimeth yl- 3-[(2S)-3-phenyl-2-[(2,2,2-trifluoroacetyl)amino]propanoyl]- 3-azabicyclo[3.1.0]hexane-2-carboxamide (159.32 mg, 275 μmol, 42.19% yield, 97.4% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.95-9.88 (m, 1H), 9.63 (d, J = 7.7 Hz, 0.5H), 9.53 (s, 1H), 9.49 (d, J = 7.95 Hz, 0.5H), 9.29-9.27 (m, 1H), 8.94 (d, J = 11.37 Hz, 1H), 8.73-8.70 (m, 1H), 7.87-7.84 (m, 1H), 7.33-7.23 (m, 5H), 6.93-6.85 (m, 1H), 4.67-4.56 (m, 1H), 4.36-4.30 (m, 1H), 3.93-3.83 (m, 1H), 3.73- 3.70 (m, 1H), 3.09-2.87 (m, 2H), 1.61-1.56 (m, 1H), 1.44-1.43 (m, 0.5H), 1.30-1.28 (m, 0.5H), 1.06 (s, 1.5H), 0.97-0.96 (m, 1.5H), 0.88 (d, J = 14.5 Hz, 3H). LC-MS (Method C): R _t = 0.900 min; MS (ESIpos): m/z = 565.2 [M+H] ⁺ . SFC: de= 50%. To a mixture of (2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoic acid (1.00 g, 4.60 mmol, 1.00 eq) and N,N-diisopropylethylamine (1.78 g, 13.8 mmol, 3.00 eq) in N,N-dimethylformamide (10.0 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexaflu orophosphate (2.63 g, 6.90 mmol, 1.50 eq) at 0 °C. After stirring at 0 °C for 0.1 h, methyl (1R,2S,5S)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (1.04 g, 5.06 mmol, 1.10 eq, hydrochloric acid) was added. After stirring at 20 °C for 12 h, the mixture was poured into water (200 mL) and extracted with ethyl acetate (300 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 10: 1 to 1: 1) to give methyl (1R,2S,5S)- 3-[(2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylate (680 mg, 1.83 mmol, 40% yield, 99% purity) as light yellow gum. LC-MS (Method C): R _t = 0.551 min; MS (ESIpos): m/z = 269.0 [M+H-Boc] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-methyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyli c acid To a mixture of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-methyl-but anoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (680 mg, 1.85 mmol, 1.00 eq) in a mixed solvent of methanol (5.00 mL) and water (5.00 mL) was added lithium hydroxide hydrate (116 mg, 2.77 mmol, 1.50 eq) at 0 °C. After stirring at 20 °C for 12 h, the mixture was concentrated under vacuum to remove methanol. The solution was diluted with water (20.0 mL), adjusted to pH = 5 with hydrochloric acid (1.00 M) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-methyl-but anoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (560 mg, 1.58 mmol, 86% yield, 99% purity) as an off-white solid which was used for next step directly. LC-MS (Method C): R _t = 0.506 min; MS (ESIpos): m/z = 255.0 [M+H-Boc] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-amino-3-methyl-butanoyl]-6,6-dimethyl-3 - azabicyclo[3.1.0]hexane-2-carboxylic acid To a mixture of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-methyl-but anoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (560 mg, 1.58 mmol, 1.00 eq) in ethyl acetate (5.00 mL) was added hydrochloric acid (4.00 M in ethyl acetate, 5.00 mL, 12.7 eq) at 20 °C. After stirring at 20 °C for 12 h, the mixture was concentrated under vacuum to give (1R,2S,5S)-3-[(2S)-2-amino-3-methyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyli c acid (460 mg, crude, hydrochloric acid) as a light yellow solid. LC-MS (Method N): R _t = 0.369 min; MS (ESIpos): m/z = 254.9 Procedure for preparation of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2- carboxylic acid To a mixture of (1R,2S,5S)-3-[(2S)-2-amino-3-methyl-butanoyl]-6,6-dimethyl-3 - azabicyclo[3.1.0]hexane-2-carboxylic acid (460 mg, 1.58 mmol, crude purity, 1.00 eq, hydrochloric acid) and triethylamine (480 mg, 4.75 mmol, 3.00 eq) in methanol (10.0 mL) was added methyl 2,2,2- trifluoroacetate (304 mg, 2.37 mmol, 1.50 eq) at 20 °C. After stirring at 20 °C for 12 h, the mixture was concentrated under vacuum to give a residue. The residue was diluted with water (20.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give (1R,2S,5S)- 6,6-dimethyl-3-[(2S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amin o]butanoyl]-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (668 mg, crude) as a light yellow solid. LC-MS (Method C): R _t = 0.437 min; MS (ESIpos): m/z = 351.0 [M+H-100] ⁺ . Procedure for preparation of CPD0190795 - (1R,2S,5S)-N-[cyano(1,6-naphthyridin-8-yl)methyl]- 6,6-dimethyl-3-[(2S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amin o]butanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxamide A mixture of 2-amino-2-(1,6-naphthyridin-8-yl)acetonitrile (150 mg, 814 umol, 1.00 eq), (1R,2S,5S)-6,6- dimethyl-3-[(2S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]bu tanoyl]-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (286 mg, 814 umol, 1.00 eq), O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (464.46 mg, 1.22 mmol, 1.5 eq) and N,N- diisopropylethylamine (210 mg, 1.63 mmol, 0.28 mL, 2.00 eq) in N,N-dimethylformamide (1.5 mL) was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 35%-65%, 10 min) to give (1R,2S,5S)-N-[cyano(1,6- naphthyridin-8-yl)methyl]-6,6-dimethyl-3-[(2S)-3-methyl-2-[( 2,2,2-trifluoroacetyl)amino]butanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxamide (236 mg, 442 μmol, 54% yield, 97% purity) as a yellow solid ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.84-9.78 (m, 1H), 9.64 (d, J = 7.6 Hz, 0.5H), 9.52 (d, J = 2.8 Hz, 1H), 9.48 (d, J = 7.6 Hz, 0.5H), 9.27-9.26 (m, 1H), 8.94 (d, J = 10.2 Hz, 1H), 8.72-8.70 (m, 1H), 7.87- 7.84 (m, 1H), 6.88-6.84 (m, 1H), 4.33 (d, J = 15.6 Hz, 1H), 4.18-4.10 (m, 1H), 3.89-3.81 (m, 2H), 2.14- 2.00 (m, 1H), 1.60-1.52 (m, 1H), 1.42 (d, J = 8.4 Hz, 0.5H), 1.21 (d, J = 7.2 Hz, 0.5H), 1.05 (s, 1H), 0.95-0.94 (m, 3H), 0.91-0.87 (m, 8H). LC-MS (Method C): R _t = 0.806 min; MS (ESIpos): m/z = 517.3 [M+H] ⁺ . SFC: dr = 50: 50. Preparation of CPD0190796 Procedure for preparation of methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3- hydroxy-3-methylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]he xane-2-carboxylate A mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-methylbutanoi c acid (2.00 g, 8.57 mmol, 1.00 eq), methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (2.29 g, 11.2 mmol, 1.30 eq, HCl salt), benzotriazol-1-yloxy(tripyrrolidin-1-yl)phosphanium;hexafluo rophosphate (6.69 g, 12.9 mmol, 1.50 eq) and 4-methylmorpholine (2.17 g, 21.4 mmol, 2.36 mL, 2.50 eq) in dichloromethane (10.0 mL) was stirred at 20 °C for 12 h. The mixture was poured into water (50.0 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed by brine (20.0 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 1: 0 to 3: 1) to afford methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3 -methylbutanoyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.60 g, 3.75 mmol, 44% yield) as light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.49 (d, J = 10.0 Hz, 1H), 4.44 (s, 1H), 4.31 (s, 1H), 4.21 (t, J = 9.2 Hz, 2H), 3.94-3.87 (m, 1H), 3.82-3.76 (m, 3H), 1.49-1.40 (m, 11H), 1.31 (s, 3H), 1.22 (s, 3H), 1.06 (s, 3H), 0.95 (s, 3H). LC-MS (Method C): R _t = 0.737 min; MS (ESIpos): m/z = 385.1 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3 - methylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-car boxylic acid To a solution of methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino) -3-hydroxy-3- methylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-car boxylate (1.60 g, 4.16 mmol, 1.00 eq) in methanol (10.0 mL) was added a solution of lithium hydroxide monohydrate (305 mg, 7.27 mmol, 5.00 eq) in water (2.00 mL). After stirring at 25 °C for 12 h, the mixture was poured into water (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). Hydrochloric acid (1M in water) was added to the aqueous phase to adjust pH to 5 and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed by brine (20.0 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3 - methylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-car boxylic acid (1.50 g, 4.05 mmol, 97% yield) as light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.55 (d, J = 9.6 Hz, 1H), 4.44 (s, 1H), 4.25-4.19 (m, 2H), 3.92-3.85 (m, 1H), 1.64-1.58 (m, 1H), 1.54-1.50 (m, 1H), 1.41 (s, 9H), 1.30-1.28 (m, 3H), 1.22 (s, 3H), 1.07 (s, 3H), 0.95 (s, 3H). LC-MS (Method C): R _t = 0.875 min; MS (ESIpos): m/z = 371.1 [M+H] ⁺ . To a solution of (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3 -methylbutanoyl)- 6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.00 g, 2.70 mmol, 1.00 eq) in acetonitrile (5.00 mL) was added hydrochloric acid (4 M in dioxane, 10.0 mL) at 0 °C. After stirring at 20 °C for 1 h, the mixture was concentrated under vacuum to give (1R,2S,5S)-3-((S)-2-amino-3-hydroxy-3- methylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-car boxylic acid (1.00 g crude, HCl salt) as light yellow gum. Procedure for preparation of (1R,2S,5S)-3-((S)-3-hydroxy-3-methyl-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxylic acid A mixture of (1R,2S,5S)-3-((S)-2-amino-3-hydroxy-3-methylbutanoyl)-6,6-di methyl-3-azabicyclo [3.1.0]hexane-2-carboxylic acid (1.00 g, 3.26 mmol, 1.00 eq, HCl salt), methyl 2,2,2-trifluoroacetate (626 mg, 4.89 mmol, 493 μL, 1.50 eq) and triethylamine (1.32 g, 13.0 mmol, 1.81 mL, 4.00 eq) in dichloromethane (10.0 mL) was stirred at 20 °C for 1 h. The mixture was poured into water (20.0 mL), adjusted pH to 5 with hydrochloric acid (1M in water) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed by brine (20.0 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-3-((S)-3-hydroxy-3-methyl-2- (2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxylic acid (1.00 g, crude) as light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.38-9.28 (m, 1H), 4.51-4.47 (m, 1H), 4.14 (s, 1H), 3.94-3.88 (m, 1H), 3.70 (d, J = 8.0 Hz, 1H), 1.55-1.51 (m, 1H), 1.45-1.43 (m, 1H), 1.21 (s, 3H), 1.17 (s, 3H), 1.01 (s, 3H), 0.85 (s, 3H). LC-MS (Method C): R _t = 0.833 min; MS (ESIpos): m/z = 367.2 [M+H] ⁺ . SFC: dr = 1: 9. To a solution of (1R,2S,5S)-3-((S)-3-hydroxy-3-methyl-2-(2,2,2-trifluoroaceta mido) butanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (398 mg, 1.09 mmol, 1.00 eq) and 2-amino-2- (1,6-naphthyridin-8-yl)acetonitrile (200 mg, 1.09 mmol, 1.00 eq) in N,N-dimethylformamide (2.00 mL) were added benzotriazol-1-yloxy(tripyrrolidin-1-yl)phosphanium;hexafluo rophosphate (848 mg, 1.63 mmol, 1.50 eq) and 4-methylmorpholine (220 mg, 2.17 mmol, 239 μL, 2.00 eq). After stirring at 20 °C for 12 h, the mixture was poured into water (30.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (neutral condition: column: Waters Xbridge 150*25mm* 5 μm; mobile phase: [water (ammonium hydrogen carbonate)- acetonitrile]; B%: 36%-66%, 10 min) to give (1R,2S,5S)-N-(cyano(1,6- naphthyridin-8-yl)methyl)-3-((S)-3-hydroxy-3-methyl-2-(2,2,2 -trifluoroacetamido)butanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (83.2 mg, 147 μmol, 14% yield, 94% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.54-9.50 (m, 1H), 9.37-9.22 (m, 2H), 8.93-8.89 (m, 1H), 8.70 (d, J = 8.0 Hz, 1H), 7.89-7.79 (m, 1H), 6.88-6.84 (m, 1H), 4.92 (d, J = 5.6 Hz, 1H), 4.46 (s, 1H), 4.39-4.31 (m, 1H), 4.03-3.92 (m, 1H), 3.73-3.62 (m, 1H), 1.59-1.51 (m, 1H), 1.46-1.26 (m, 1H), 1.22-0.81 (m, 12H). LC-MS (Method C): R _t = 0.823 min; MS (ESIpos): m/z = 533.2 [ ⁺ . HPLC (Method S): R _t = 1.517 min. SFC: dr = 52: 48 Preparation of CPD0190797 Procedure for preparation of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3- methylbutanoate To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-methylbutanoi c acid (10.0 g, 42.9 mmol, 1.00 eq) in dichloromethane (200 mL) and methanol (50.0 mL) was added (diazomethyl)trimethylsilane (2 M in n-hexane, 50.0 mL, 1.17 eq) at 0 °C. After stirring at 20 °C for 12 h, the mixture was concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 1: 0 to 1: 1) to give methyl (S)-2-((tert- butoxycarbonyl) amino)-3-hydroxy-3-methylbutanoate (9.20 g, 37.2 mmol, 87% yield) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.70 (d, J = 9.6 Hz, 1H), 4.69 (s, 1H), 3.94 (d, J = 8.8 Hz, 1H), 3.61 (s, 3H), 1.38 (s, 9H), 1.14 (s, 6H). Procedure for preparation of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3- methylbutanoate A mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-methylbutanoa te (1.25 g, 5.05 mmol, 1 eq) and silver (I) oxide (2.34 g, 10.1 mmol, 2.00 eq) in methyl iodide (20.0 mL) was stirred at 40 °C for 72 h. The mixture was poured into water (50.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (20.0 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 1: 0 to 0: 1) to give methyl (S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-methylbutanoa te (380 mg, 1.45 mmol, 7% yield) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.89 (d, J = 8.4 Hz, 1H), 4.17 (d, J = 8.4 Hz, 1H), 3.62 (s, 3H), 3.10 (s, 3H), 1.38 (s, 9H), 1.18-1.12 (m, 6H). Procedure for preparation of (S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-methylbutanoi c acid To a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-methylbutanoa te (380 mg, 1.45 mmol, 1.00 eq) in methanol (3.00 mL) was added a solution of lithium hydroxide (305 mg, 7.27 mmol, 5.00 eq) in water (0.500 mL). After stirring at 20 °C for 12 h, the mixture was poured into water (20.0 mL), adjusted pH~5 with hydrochloric acid (1M in water) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (20.0 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (S)-2-((tert-butoxycarbonyl) amino)-3- methoxy-3-methylbutanoic acid (340 mg, 1.24 mmol, 85% yield) as light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.60 (d, J = 8.8 Hz, 1H), 4.10-4.05 (m, 1H), 3.10 (s, 3H), 1.38 (s, 9H), 1.16 (d, J = 5.2 Hz, 6H). Procedure for preparation of methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3- methoxy-3-methylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]he xane-2-carboxylate A mixture of (2S)-2-(tert-butoxycarbonylamino)-3-methoxy-3-methyl-butanoi c acid (0.300 g, 1.21 mmol, 1.00 eq), methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (324 mg, 1.58 mmol, 1.30 eq, HCl salt), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexaflu orophosphate (692 mg, 1.82 mmol, 1.50 eq) and N,N-diisopropylethylamine (470 mg, 3.64 mmol, 634 μL, 3.00 eq) in dichloromethane (2.00 mL) was stirred at 20 °C for 12 h. The mixture was poured into water (30.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed by brine (20.0 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 1: 0 to 3: 1) to give methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy- 3-methylbutanoyl) -6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (430 mg, 971 μmol, 80% yield) as light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.34 (t, J = 9.6 Hz, 1H), 4.52-4.40 (m, 1H), 4.16-4.10 (m, 1H), 4.03-3.91 (m, 1H), 3.78-3.74 (m, 3H), 3.61 (s, 1H), 3.27-3.11 (m, 3H), 1.49-1.38 (m, 11H), 1.27-1.11 (m, 6H), 1.06-0.92 (m, 6H). Procedure for preparation of (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3 - methylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-car boxylic acid To a solution of methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl) amino)-3-methoxy-3- methylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-car boxylate (420 mg, 1.05 mmol, 1.00 eq) in methanol (2.00 mL) was added a solution of lithium hydroxide (177 mg, 4.22 mmol, 4.00 eq) in water (0.500 mL). After stirring at 20 °C for 12 h, the mixture was poured into water (20.0 mL), adjusted pH~5 with hydrochloric acid (1 N in water) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (20.0 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3- methoxy-3-methylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]he xane-2-carboxylic acid (350 mg, 819 μmol, 78% yield) as light yellow oil ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.33-5.24 (m, 1H), 4.58-4.44 (m, 2H), 3.96-3.87 (m, 2H), 3.24 (s, 3H), 1.47-1.40 (m, 12H), 1.21 (s, 3H), 1.08 (s, 3H), 0.93 (s, 3H). Procedure for preparation of (1R,2S,5S)-3-((S)-2-amino-3-methoxy-3-methylbutanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid To a solution of (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl) amino)-3-methoxy-3-methylbutanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (350 mg, 910 μmol, 1.00 eq) in acetonitrile (2.00 mL) was added hydrochloric acid (4 M in dioxane, 2.00 mL) at 0 °C. After stirring at 20 °C for 1 h, the mixture was concentrated under vacuum to give (1R,2S,5S)-3-((S)-2-amino-3-methoxy-3- methylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-car boxylic acid (400 mg, crude, HCl salt) as light yellow gum. LC-MS (Method C): R _t = 0.322 min; MS (ESIpos): m/z = 285.2 [ . Procedure for preparation of (1R,2S,5S)-N-(1-amino-3-((S)-1-methyl-2-oxopyrrolidin-3-yl)- 1- oxopropan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetam ido)butanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide A mixture of (1R,2S,5S)-3-((S)-2-amino-3-methoxy-3-methylbutanoyl)-6,6-di methyl -3- azabicyclo[3.1.0]hexane-2-carboxylic acid (400 mg, 1.41 mmol, 1.00 eq), methyl 2,2,2-trifluoroacetate (270 mg, 2.11 mmol, 1.50 eq) and triethylamine (569 mg, 5.63 mmol, 4.00 eq) in dichloromethane (5.00 mL) was stirred at 20 °C for 12 h. The mixture was poured into water (50.0 mL). Hydrochloric acid (1 M in water) was added to adjust pH~5 and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (20.0 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-3-((S)-3-methoxy-3-methyl-2-(2,2,2- trifluoroacetamido) butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyli c acid (500 mg, crude) as light yellow oil. LC-MS (Method C): R _t = 0.871, 0.892 min; MS (ESIpos): m/z = 381.2 [M+H] ⁺ . A mixture of 2-amino-2-(1,6-naphthyridin-8-yl)acetonitrile (120 mg, 651 μmol, 1 eq), (1R,2S,5S)-3-((S)- 3-methoxy-3-methyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6 -dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (275 mg, 652 μmol, 1.00 eq), benzotriazol-1-yloxy (tripyrrolidin-1- yl)phosphanium;hexafluorophosphate (509 mg, 977 μmol, 1.50 eq), 4-methylmorpholine (132 mg, 1.30 mmol, 143 μL, 2.00 eq) in N,N-dimethylformamide (2.00 mL) was stirred at 20 °C for 12 h. After concentration, the residue was purified by silica gel column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 1: 0 to 2: 3) and prep-HPLC (FA condition ^column: Phenomenex luna C18150*25mm* 100.892 μm; mobile phase: [water(FA)-ACN]; B%: 41%-71%, 10 min) to give (1R,2S,5S)-N-(cyano(1,6- naphthyridin-8-yl)methyl)-3-((S)-3-methoxy-3-methyl-2-(2,2,2 -trifluoroacetamido)butanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (24.14 mg, 41.9 μmol, 6% yield, 95% purity) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.53-9.44 (m, 1H), 9.39-9.25 (m, 2H), 8.97-8.84 (m, 1H), 7.90-7.81 (m, 1H), 6.90-6.68 (m, 1H), 4.81-4.55 (m, 1H), 4.40-4.12 (m, 1H), 4.01-3.89 (m, 1H), 3.78-3.66 (m, 1H), 3.13-3.03 (m, 3H), 2.43-2.36 (m, 1H), 1.60-1.48 (m, 1H), 1.46-1.34 (m, 1H), 1.28-0.95 (m, 10H), 0.89- 0.85 (m, 2H). LC-MS (Method C): R _t = 0.859 min; MS (ESIpos): m/z = 547.3 [M+H] ⁺ . HPLC: (Method S): R _t = 2.000 min; purity: 94%. SFC: dr = 49: 51. To a solution of (2S)-2-(tert-butoxycarbonylamino)pentanoic acid (2.00 g, 9.21 mmol, 1.00 eq), 4- methylmorpholine (2.33 g, 23.0 mmol, 2.53 mL, 2.50 eq) in dichloromethane (20.0 mL) were added O- (7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluor ophosphate (3.68 g, 9.67 mmol, 1.05 eq) and methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (1.99 g, 9.67 mmol, 1.05 eq, HCl) at 0 °C. After stirring at 25 °C for 12 h, the reaction was poured into water (30.0 mL) and washed with hydrochloric acid (1 M in water, 20.0 mL). The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 4/1) to give methyl (1R,2S,5S)-3-[(2S)- 2-(tert-butoxycarbonylamino)pentanoyl]-6,6-dimethyl-3-azabic yclo[3.1.0]hexane-2-carboxylate (3.20 g, 8.60 mmol, 93% yield, 99% purity) as light yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ =7.07 (d, J = 7.6 Hz, 1H), 4.19 (s, 1H), 4.14-4.04 (m, 1H), 3.90 (d, J = 10.4 Hz, 1H), 3.69-3.78 (m, 1H), 3.64 (s, 3H), 1.58-1.54 (m, 2H), 1.47-1.30 (m, 13H), 1.02 (s, 3H), 0.90- 0.83 (m, 6H). LC-MS (Method C): R _t = 0.861 min, MS (ESIpos): m/z = 369.3 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)pentanoyl]-6, 6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid To a mixture of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)pentanoyl]-6, 6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (3.20 g, 8.68 mmol, 1.00 eq) in a mixed solvent of methanol (15.0 mL) and water (15.0 mL) was added lithium hydroxide hydrate (547 mg, 13.0 mmol, 1.50 eq). After stirring at 20 °C for 2 h, the reaction mixture was concentrated under reduced pressure to remove most of the organic solvent. The resulting solution was washed with ethyl acetate (30.0 mL). Hydrochloric acid (1 M in water) was added to the aqueous phase to adjust pH~5.0, and extracted with ethyl acetate (30.0 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)pentanoyl]-6, 6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (3.0 g, 8.46 mmol, 98% yield) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.72 (s, 1H), 5.30 (d, J = 9.2 Hz, 1H), 4.47 (s, 1H), 4.42-4.22 (m, 1H), 3.97-3.61 (m, 2H), 2.09 (s, 0.5H), 1.73-1.45 (m, 4H), 1.41-1.24 (m, 11.5H), 1.06 (s, 3H), 0.95-0.88 (m, 6H). LC-MS (Method A): R _t = 1.021 min, MS (ESIpos): m/z = 355.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-((S)-2-aminopentanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid A mixture of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)pentanoyl]-6, 6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (3.00 g, 8.46 mmol, 1.00 eq) in hydrochloric acid (4 M in dioxane, 30.0 mL) was stirred at 20 °C for 12 h. The reaction was concentrated under reduced pressure to give (1R,2S,5S)-3-((S)-2-aminopentanoyl)-6,6-dimethyl-3-azabicycl o[3.1.0]hexane-2-carboxylic acid (2.60 g, 7.95 mmol, 94% yield, 2HCl) as colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ =12.60 (s, 1H), 8.39 (s, 3H), 4.18-4.08 (m, 2H), 3.71 (d, J = 2.4 Hz, 2H), 1.72-1.54 (m, 3H), 1.46-1.40 (m, 3H), 1.02-0.86 (m, 9H). LC-MS (Method A): R _t = 0.954 min, MS (ESIpos): m/z = 351.2 [M+H] ⁺ . Procedure for preparation of Compound 5- (1R,2S,5S)-6,6-dimethyl-3-((S)-2-(2,2,2- trifluoroacetamido)pentanoyl)-3-azabicyclo[3.1.0]hexane-2-ca rboxylic acid A mixture of (1S,2S,5R)-3-[(2S)-2-aminopentanoyl]-6-methyl-3-azabicyclo[3 .1.0]hexane-2-carboxylic acid (2.60 g, 7.95 mmol, 1.00 eq, 2HCl), triethylamine (2.81, 29.1 mmol, 3.50 eq) and methyl 2,2,2- trifluoroacetate (1.59 g, 12.4 mmol, 1.26 mL, 1.50 eq) in methanol (20.0 mL) was stirred at 20 °C for 12 h. After concentration, the residue was diluted with ethyl acetate (50.0 mL) and washed with hydrochloric acid (1 M in water, 30.0 mL × 3). The separated organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give (1R,2S,5S)-6,6- dimethyl-3-((S)-2-(2,2,2-trifluoroacetamido)pentanoyl)-3-aza bicyclo[3.1.0]hexane-2-carboxylic acid (2.30 g, 6.50 mmol, 82% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.71 (d, J = 6.8 Hz, 1H), 4.46-4.36 (m, 1H), 4.13 (s, 1H), 3.75-3.45 (m, 1H), 1.67-1.15 (m, 7H), 1.02-0.80 (m, 9H). LC-MS (Method A): R _t = 0.951 min, MS (ESIpos): m/z = 351.2 [M+H] ⁺ . Procedure for preparation of CPD0190801 - (1R,2S,5S)-N-[cyano(1,6-naphthyridin-8-yl)methyl]- 6,6-dimethyl-3-[(2S)-2-[(2,2,2-trifluoroacetyl)amino]pentano yl]-3-azabicyclo[3.1.0]hexane-2- carboxamide A mixture of 2-amino-2-(1,6-naphthyridin-8-yl)acetonitrile (150 mg, 814 μmol, 1.00 eq), (1R,2S,5S)-6,6- dimethyl-3-[(2S)-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (285 mg, 814 μmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (464 mg, 1.22 mmol, 1.50 eq) and N,N-diisopropylethylamine (210 mg, 1.63 mmol, 0.28 mL, 2.00 eq) in N,N-dimethylformamide (1.50 mL) was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (20.0 mL × 2). The combined organic layers were washed with brine (10.0 mL × 2), dried over anhydrous sodium sulfate filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi C18 150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 34%-64%, 10 min) to give (1R,2S,5S)-N-[cyano(1,6-naphthyridin-8-yl)methyl]- 6,6-dimethyl-3-[(2S)-2-[(2,2,2-trifluoroacetyl)amino]pentano yl]-3-azabicyclo[3.1.0]hexane-2- carboxamide (203 mg, 388 μmol, 48% yield, 99% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.77-9.69 (m, 1H), 9.6 (d, J = 7.6 Hz, 0.5H), 9.52 (d, J = 2.2 Hz, 1H), 9.45 (d, J = 7.6 Hz, 0.5H), 9.28-9.26 (m, 1H), 8.91 (d, J = 10.2 Hz, 1H), 8.72-8.70 (m, 1H), 7.87-7.83 (m, 1H), 6.89-6.81 (m, 1H), 4.41-4.35 (m, 1H), 4.33 (s, 0.5H), 4.28 (s, 0.5H), 3.87-3.79 (m, 1H), 3.74- 3.70 (m, 1H), 1.72-1.55 (m, 3.5H), 1.42-1.21 (m, 3.5H), 1.06 (s, 1H), 0.96 (s, 1H), 0.92-0.91 (m, 1H), 0.92-0.91 (m, 1.5H), 0.89-0.88 (m, 2H), 0.84-0.81 (m, 1.5H). LC-MS (Method A): R _t = 0.865 min, MS (ESIpos): m/z = 317.1 [M+H] ⁺ . SFC: dr: 51: 49. Preparation of CPD0277802 Procedure for preparation of (1-methylcyclopropyl) methanol Lithium aluminum hydride (8.53 g, 225 mmol, 1.50 eq) was added to a solution of 1- methylcyclopropanecarboxylic acid (15.0 g, 150 mmol, 1.00 eq) in tetrahydrofuran (100 mL) in portions at 0 °C. After stirring at 20 °C for 12 h, the reaction mixture was quenched with water (8.60 mL), followed by addition of sodium hydroxide (8.60 mL, 15% purity in water) and water (25.8 mL). The suspension was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give (1-methylcyclopropyl) methanol (11.2 g, 130 mmol, crude) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 3.39 (s, 2H), 1.15 (s, 3H), 0.42-0.37 (m, 2H), 0.36-0.30 (m, 2H). Procedure for preparation of 1-methylcyclopropanecarbaldehyde To a suspension of (1-methylcyclopropyl) methanol (8.00 g, 92.9 mmol, 1.00 eq) and silica gel (8.00 g, 133 mmol, 1.43 eq) in dichloromethane (20.0 mL) was added pyridinium chlorochromate (22.0 g, 102 mmol, 1.10 eq) at 20 °C. After stirring at 20 °C for 4 h, the mixture was filtered. The filter cake was washed with dichloromethane/methanol (v/v = 20/1, 200 mL × 2). The combined filtrate was concentrated under vacuum to give a residue. The residue was distilled (44 °C, 0.09 MPa) to give 1- methylcyclopropanecarbaldehyde (1.10 g, 11.8 mmol, 13% yield, 90% purity) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.64 (s, 1H), 1.25 (s, 3H), 1.19-1.14 (m, 2H), 0.96-0.90 (m, 2H). Procedure for preparation of (S)-2-methyl-N-((1-methylcyclopropyl)methylene)propane-2- sulfinamide To a mixture of 1-methylcyclopropanecarbaldehyde (950 mg, 11.3 mmol, 1 eq) and titanium (IV) propan- 2-olate (6.42 g, 22.6 mmol, 6.67 mL, 2.00 eq) in dichloromethane (15.0 mL) was added (S)-2- methylpropane-2-sulfinamide (1.51 g, 12.4 mmol, 1.10 eq) at 20 °C under nitrogen in portions. After stirring at 20 °C for 12 h, the mixture was poured into water (10.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 40: 1 to 10: 1) to give (S)-2-methyl-N- ((1-methylcyclopropyl)methylene)propane-2-sulfinamide (1.00 g, 5.23 mmol, 46% yield, 98% purity) as colorless oil. 7.36 (s, 1H), 1.34 (s, 3H), 1.19 (s, 9H), 1.10-1.06 (m, 2H), 0.96-0.89 (m, LC-MS (Method S): R _t = 0.489 min; MS (ESIpos): m/z = 132.1 [M+H-t-Bu] ⁺ . Procedure for preparation of (2S)-2-amino-2-(1-methylcyclopropyl) acetic acid hydrochloride To a mixture of (S)-2-methyl-N-((1-methylcyclopropyl)methylene)propane-2-sul finamide (1.00 g, 5.34 mmol, 1.00 eq) and cesium fluoride (81.1 mg, 534 μmol, 0.100 eq) in acetonitrile (20.0 mL) was added trimethylsilanecarbonitrile (636 mg, 6.41 mmol, 1.20 eq) at 20 °C. After stirring at 20 °C for 1 h, the mixture was poured into water (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give (S)-N-[(S)-cyano-(1-methylcyclopropyl)methyl]-2-methyl-propa ne- 2-sulfinamide (0.900 g, 3.99 mmol, 75% yield, 95% purity) as a light yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 3.40 (d, J = 4.8 Hz, 1H), 1.30-1.24 (m, 12H), 0.86-0.67 (m, 2H), 0.64- 0.53 (m, 2H). Procedure for preparation of (2S)-2-amino-2-(1-methylcyclopropyl) acetic acid hydrochloride A mixture of (S)-N-[(S)-cyano-(1-methylcyclopropyl)methyl]-2-methyl-propa ne-2-sulfinamide (900 mg, 4.20 mmol, 1.00 eq) in hydrochloric acid (20.0 mL, 36% purity) was stirred at 80 °C for 12 h. The mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The aqueous phase was concentrated under vacuum to give (2S)-2-amino-2-(1-methylcyclopropyl) acetic acid (870 mg, 4.09 mmol, 97% yield, 95% purity, 2 hydrochloric acid) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ +D ₂ O) δ = 8.45 (s, 1H), 3.25 (s, 1H), 0.98 (s, 3H), 0.81-0.64 (m, 2H), 0.55- 0.41 (m, 2H). A mixture of (2S)-2-amino-2-(1-methylcyclopropyl)acetic acid (770 mg, 3.81 mmol, 1.00 eq, 2 hydrochloric acid), methyl 2,2,2-trifluoroacetate (732 mg, 5.72 mmol, 1.50 eq) and triethylamine (1.54 g, 15.2 mmol, 4.00 eq) in methanol (10.0 mL) was stirred at 20 °C for 12 h. The mixture was poured into hydrochloric acid (40.0 mL, 1.00 M) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give (2S)-2-(1-methylcyclopropyl)-2-[(2,2,2-trifluoroacetyl)amino ]acetic acid (850 mg, 3.59 mmol, 94% yield, 95% purity) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.76 (d, J = 7.2 Hz, 1H), 3.77 (d, J = 7.2 Hz, 1H), 1.06 (s, 3H), 0.76- 0.68 (m, 1H), 0.56-0.48 (m, 1H), 0.46-0.29 (m, 2H). Procedure for preparation of methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-2-(1-methylcyclopropyl)-2- [(2,2,2-trifluoroacetyl)amino]acetyl]-3-azabicyclo[3.1.0]hex ane-2-carboxylate To a mixture of (2S)-2-(1-methylcyclopropyl)-2-[(2,2,2-trifluoroacetyl)amino ]acetic acid (950 mg, 4.22 mmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexaflu orophosphate (2.41 g, 6.33 mmol, 1.50 eq) and N,N-diisopropylethylamine (2.20 mL, 12.7 mmol, 3.00 eq) in acetonitrile (10.0 mL) was added methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (1.04 g, 5.06 mmol, 1.20 eq, hydrochloride) at 0 °C. After stirring at 20 °C for 12 h, the mixture was poured into water (20.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate= 15: 1 to 10: 1) to give methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-2-(1-methylcyclopropyl)-2- [(2,2,2-trifluoroacetyl)amino]acetyl]-3-azabicyclo[3.1.0]hex ane-2-carboxylate (720 mg, 1.82 mmol, 43% yield, 95% purity) as colorless gum. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 4.48-4.40 (m, 1H), 4.40 (s, 1H), 4.13-4.11 (m, 1H), 4.02-3.98 (m, 1H), 3.84-3.63 (m, 4H), 1.60-1.53 (m, 1H), 1.50-1.45 (m, 1H), 1.16-0.92 (m, 9H), 0.88-0.70 (m, 2H), 0.52- 0.33 (m, 2H). LC-MS (Method S): R _t = 0.544 min; MS (ESIpos): m/z = 377.1 [M+H] ⁺ . SFC: de% = 100%. Procedure for preparation of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-2-(1-methylcyclopropyl)-2-[( 2,2,2- trifluoroacetyl)amino]acetyl]-3-azabicyclo[3.1.0]hexane-2-ca rboxylic acid To a mixture of methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-2-(1-methylcyclopropyl)-2-[( 2,2,2- trifluoroacetyl)amino]acetyl]-3-azabicyclo[3.1.0]hexane-2-ca rboxylate (620 mg, 1.48 mmol, 90% purity, 1.00 eq) in methanol (1.00 mL) was added a solution of lithium hydroxide hydrate (93.3 mg, 2.22 mmol, 1.50 eq) in water (1.00 mL) at 0 °C. After stirring at 20 °C for 12 h, the mixture was poured into water (20.0 mL) and washed with ethyl acetate (20.0 mL × 2). Hydrochloric acid (1 M) was added to the aqueous phase to adjust pH~5 and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give (1R,2S,5S)-6,6-dimethyl-3-[2-(1-methylcyclopropyl)-2-[(2,2,2 - trifluoroacetyl)amino]acetyl]-3-azabicyclo[3.1.0]hexane-2-ca rboxylic acid (350 mg, 869 μmol, 59% yield, 90% purity) as colorless gum. LC-MS (Method S): R _t = 0.502 min; MS (ESIpos): m/z = 363.0 [M+H] ⁺ . A mixture of 2-amino-2-(1,6-naphthyridin-8-yl)acetonitrile (150 mg, 814μmol, 1.00 eq), (1R,2S,5S)-6,6- dimethyl-3-[2-(1-methylcyclopropyl)-2-[(2,2,2-trifluoroacety l)amino]acetyl]-3-azabicyclo [3.1.0]hexane- 2-carboxylic acid (295 mg, 814 μmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (464 mg, 1.22 mmol, 1.50 eq), N,N-diisopropylethylamine (210 mg, 1.63 mmol, 2.00 eq) in N,N-dimethylformamide (1.50 mL) was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (30.0 mL) and extracted with ethyl acetate (30.0 mL × 2). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Shim-pack C18150*25*10 μm; mobile phase: [water(FA)-ACN]; B%: 40%-70%, 10 min) and prep-HPLC (column: Shim-pack C18150*25*10 μm; mobile phase: [water(NH4HCO3)-ACN]; B%: 34%-64%, 10 min) for twice to give (1R,2S,5S)-N-(cyano(1,6-naphthyridin-8-yl)methyl)-6,6-dimeth yl-3- (2-(1-methylcyclopropyl)-2-(2,2,2-trifluoroacetamido)acetyl) -3-azabicyclo[3.1.0]hexane-2-carboxamide (95.4 mg, 177 μmol, 22% yield, 98% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.69-9.66 (m, 1H), 9.55-9.51 (m, 1H), 9.40-9.26 (m 1H), 9.00-8.70 (m, 1H), 8.71-8.69 (m, 1H), 7.86-7.28 (m, 1H), 6.90-6.80 (m, 1H), 4.54-4.22 (m, 2H), 3.82-3.55 (m, 2H), 1.70-1.21 (m, 2H), 1.08-0.62 (m, 10H), 0.60-0.20 (m, 3H). LC-MS (Method C): R _t = 0.583 min; MS (ESIpos): m/z = 529.5 [M+H] ⁺ . HPLC: Method S: R _t = 1.985 min; purity: 98%. SFC: dr: 25: 26: 30: 19. To a mixture of (2S)-2-(tert-butoxycarbonylamino)-4,4-difluoro-butanoic acid (500 mg, 2.09 mmol, 1 eq) in dichloromethane (5.00 mL) were added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]- dimethyl-ammonium;hexafluorophosphate (1.19 g, 3.14 mmol, 1.50 eq) and N-ethyl-N-isopropyl- propan-2-amine (946 mg, 7.32 mmol, 1.27 mL, 3.50 eq) at 25 °C. After stirring at 25 °C for 10 min, methyl (1R, 2S, 5S) -6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (516 mg, 2.51 mmol, 1.2 eq, Hydrogen chloride) was added. The mixture was stirred at 25 °C for 16 h and concentrated to give a residue. The residue was purified by reversed phase column (Instrument: 80 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-15 min 45% B; flow 30 mL/min; temperature: room temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)-3- [(2S)-2-(tert-butoxycarbonylamino)-4,4-difluoro-butanoyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylate (650 mg, 1.61 mmol, 77% yield, 97% purity) as yellow oil. Procedure for preparation of (1R, 2S, 5S) -3-[(2S) -2-(tert-butoxycarbonylamino) -4, 4-difluoro- butanoyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-4,4-difluoro -butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (600 mg, 1.54 mmol, 1.00 eq) in methanol (16.0 mL) and water (4.00 mL) was added lithium hydroxide monohydrate (129 mg, 3.07 mmol, 2.00 eq). The mixture was stirred at 25 °C for 16 h and concentrated in vacuo to give (1R, 2S, 5S) -3-[(2S) -2-(tert- butoxycarbonylamino) -4, 4-difluoro-butanoyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (550 mg, 1.46 mmol, 95% yield) as a yellow solid. Procedure for preparation of (1R, 2S, 5S) -3-[(2S) -2-amino-4, 4-difluoro-butanoyl]-6, 6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid To a solution of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-4,4-difluoro -butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (550 mg, 1.46 mmol, 1.00 eq) in dioxane (10.0 mL) was added hydrogen chloride (4 M in dioxane, 6.88 mL, 18.8 eq). After stirring at 25 °C for 1 h, the reaction mixture was concentrated to give (1R,2S,5S)-3-[(2S)-2-amino-4,4-difluoro-butanoyl]-6,6-dimeth yl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (587 mg, crude, Hydrogen chloride) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.80-8.42 (m, 3H), 6.59-6.11 (m, 1H), 4.29 (br s, 1H), 4.22 (s, 1H), 3.95-3.88 (m, 1H), 3.53-3.48 (m, 1H), 2.41-2.24 (m, 2H), 1.65-1.56 (m, 1H), 1.52-1.45 (m, 1H), 1.08- 0.86 (m, 6H). Procedure for preparation of (1R, 2S, 5S) -3-[(2S) -4, 4-difluoro-2-[(2, 2, 2-trifluoroacetyl) amino]butanoyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid To a solution of (1R,2S,5S)-3-[(2S)-2-amino-4,4-difluoro-butanoyl]-6,6-dimeth yl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (587 mg, 1.88 mmol, 1 eq, Hydrogen chloride) and methyl 2,2,2-trifluoroacetate (1.68 g, 13.1 mmol, 1.32 mL, 6.98 eq) in methanol (15.0 mL) was added N,N- diethylethanamine (1.14 g, 11.3 mmol, 1.57 mL, 6.00 eq). After stirring at 25 °C for 12 h, the reaction mixture was concentrated to give a residue. The residue was purified by reversed phase column (80 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-30 min 0-100% B; flow 55 mL/min; temperature: room temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)-3-[(2S)-4,4-difluoro-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (230 mg, 617 μmol, 33% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 13.21-12.71 (m, 1H), 10.09-9.93 (m, 1H), 6.42-5.93 (m, 1H), 4.85- 4.41 (m, 1H), 4.36-4.04 (m, 1H), 3.86-3.74 (m, 1H), 3.73-3.66 (m, 1H), 3.60-3.49 (m, 1H), 2.41-2.15 (m, 2H), 1.64-1.53 (m, 1H), 1.48-1.40 (m, 1H), 1.09-0.80 (m, 6H). Procedure for preparation of (1R, 2S, 5S) -N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl) -3-[(2S) -4, 4-difluoro-2-[(2, 2, 2-trifluoroacetyl) amino]butanoyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide To a solution of (1R,2S,5S)-3-[(2S)-4,4-difluoro-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (220 mg, 591 μmol, 1.00 eq) and 2-amino-2-phthalazin-1- yl-acetamide (179 mg, 650 μmol, 1.10 eq, 2Hydrogen chloride) in dichloromethane (6.00 mL) were added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dim ethyl- ammonium;hexafluorophosphate (337 mg, 886 μmol, 1.50 eq) and N-ethyl-N-isopropyl-propan-2-amine (229 mg, 1.77 mmol, 308 μL, 3.00 eq). After stirring at 25 °C for 16 h, the reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (instrument: 80 g Flash; Column: Welch ultimate XB_C1820-40 μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-50 min 0-100% B; flow 55 mL/min; temperature: room temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -4,4-difluoro-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (130 mg, 233 μmol, 39% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.99 (br. s, 1H), 9.67 (s, 1H), 9.24 (d, J = 8.4 Hz, 0.5H), 9.06 (d, J = 8.4 Hz, 0.3H), 8.37-8.18 (m, 2H), 8.12-7.97 (m, 2H), 7.61-7.21 (m, 2H), 6.40-6.29 (m, 1H), 6.27-5.91 (m, 1H), 4.66-4.54 (m, 1H), 4.48-4.44 (m, 0.6H), 4.33 (s, 0.3H), 3.90-3.80 (m, 1H), 3.70-3.63 (m, 1H), 2.29-2.11 (m, 2H), 1.57-1.46 (m, 1H), 1.31-1.21 (m, 1H), 1.11-0.82 (m, 6H). To a solution of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -4,4-difluoro-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (80.0 mg, 144 μmol, 1.00 eq) in dichloromethane (2.00 mL) was added methoxycarbonyl-(triethylammonio) sulfonyl- azanide (103 mg, 432 μmol, 3.00 eq). After stirring at 25 °C for 16 h, the reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150 × 50 mm ×3 μm; mobile phase: [water (FA)-ACN]; B%: 38%-68%, 7 min) to give (1R,2S,5S)-N- [cyano(phthalazin-1-yl)methyl]-3-[(2S)-4, 4-difluoro-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (66.9 mg, 124 μmol, 86% yield, 100% purity) as a yellow solid. LC-MS (Method C): R _t = 0.882 min, MS (ESIpos): m/z = 539.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ = 10.50-10.38 (m, 0.3H), 10.06-9.78 (m, 0.8H), 9.77-9.73 (m, 0.5H), 9.64-9.47 (m, 0.5H), 9.14 (s, 0.3H), 8.79 (d, J = 8.0 Hz, 0.4H), 8.31-8.20 (m, 0.5H), 8.18-7.96 (m, 2H), 7.88-7.72 (m, 1H), 7.26-7.13 (m, 0.5H), 6.40-5.78 (m, 1H), 4.88-4.48 (m, 1H), 4.31-4.25 (m, 0.6H), 4.23- 4.20 (m, 0.2H), 4.01-3.83 (m, 0.9H), 3.77-3.60 (m, 0.9H), 3.59-3.47 (m, 0.2H), 2.43-2.29 (m, 1.5H), 2.21-2.00 (m, 0.6H), 1.72-1.53 (m, 1.4H), 1.41-1.33 (m, 0.3H), 1.22-1.17 (m, 0.3H), 1.12-1.02 (m, 2H), 1.00-0.90 (m, 2H), 0.89-0.81 (m, 2H). SFC: dr =14: 28: 21: 36. To a solution of methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-4-hydroxy-3 ,3- dimethylbutanoyl) -6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (2.00 g, 5.02 mmol, 1.00 eq) in a mixed solvent of methanol (2.00 mL) and tetrahydrofuran (2.00 mL) was added a solution of lithium hydroxide monohydrate (842 mg, 20.1 mmol, 4.00 eq) in water (1.00 mL) at 0 °C. After stirring at 20 °C for 2 h, the mixture was poured into water (50.0 mL), adjusted pH to 5 with hydrochloric acid (1M in water) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed by brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 0 to 0: 1) to give (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-4-hydroxy-3 ,3- dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-c arboxylic acid (1.20 g, crude) as a light yellow solid. LC-MS (Method C): R _t = 0.543&0.552 min MS (ESIpos): m/z = 385.0 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-((S)-2-amino-4-hydroxy-3,3-dimethylbutanoyl)-6, 6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid A mixture of (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-4-hydroxy-3 ,3-dimethylbutanoyl) -6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.00 g, 2.60 mmol, 1.00 eq) in hydrochloric acid (4 M in dioxane, 10.0 mL, 15.4 eq) was stirred at 20 °C for 2 h. The mixture was concentrated under reduced pressure to give (1R,2S,5S)-3-((S)-2-amino-4-hydroxy-3,3-dimethylbutanoyl)-6, 6-dimethyl-3- azabicyclo [3.1.0]hexane-2-carboxylic acid (1.00 g, crude, hydrochloric acid salt) as a light yellow solid. LC-MS (Method C): R _t = 0.356 min; MS (ESIpos): m/z = 285.1 [M +H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-((S)-4-hydroxy-3,3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxylic acid A mixture of (1R,2S,5S)-3-((S)-2-amino-4-hydroxy-3,3-dimethylbutanoyl)-6, 6-dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxylic acid (1.00 g, 3.12 mmol, 1.00 eq, hydrochloric acid salt), methyl 2,2,2- trifluoroacetate (1.20 g, 9.35 mmol, 0.943 mL, 3 eq), triethylamine (1.26 g, 12.5 mmol, 1.74 mL, 4.00 eq) in methanol (5.00 mL) was stirred at 20 °C for 12 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (FA condition: 55g Flash Column SEPAFLASH_C1840-63μm; 60 A; mobile phase: [water (0.225%FA)-ACN]; B%: 30-50%, 10 min) to give (1R,2S,5S)-3-((S)-4-hydroxy-3,3-dimethyl-2-(2,2,2-trifluoroa cetamido)butanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.10 g, 2.46 mmol, 79% yield) as light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.74 (s, 1H), 9.57 (d, J = 7.2 Hz, 1H), 5.26 (s, 1H), 4.50 (d, J = 7.2 Hz, 1H), 4.17-4.12 (m, 1H), 3.92-3.85 (m, 1H), 3.83-3.77 (m, 1H), 3.57-3.51 (m, 1H), 3.19-3.13 (m, 1H), 1.55-1.52 (m, 1H), 1.45-1.41 (m, 1H), 1.03 (d, J = 4.4 Hz, 6H), 0.93 (s, 3H), 0.86 (s, 3H). LC-MS (Method C): R _t = 0.535 min; MS (ESIpos): m/z = 381.1 [M +H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-(2-amino-2-oxo-1-(phthalazin-1-yl)ethyl)-3-((S) -4- hydroxy-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6 ,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-((S)-4-hydroxy-3,3-dimethyl-2-(2,2,2-trifluoroa cetamido)butanoyl) -6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (450 mg, 1.18 mmol, 1.00 eq), benzotriazol-1- yloxy(tripyrrolidin-1-yl)phosphanium;hexafluorophosphate (924 mg, 1.77 mmol, 1.50 eq) and 4- methylmorpholine (479 mg, 4.73 mmol, 520 μL, 4.00 eq) in N,N-dimethylformamide (3.00 mL) was added 2-amino-2-(phthalazin-1-yl)acetamide (282 mg, 1.18 mmol, 1.00 eq, hydrochloric acid salt). After stirring at 20 °C for 12 h, the mixture was poured into water (50.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: (ethyl acetate: methanol = 10: 1) = 1: 0 to 70: 30) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-(phthalazin-1-yl)ethyl)-3-((S) -4-hydroxy-3,3-dimethyl-2- (2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicycl o[3.1.0]hexane-2-carboxamide (480 mg, 765 μmol, 65% yield) as yellow oil. LC-MS (Method C): R _t = 0.841 min; MS (ESIpos): m/z = 565.3 [M +H] ⁺ . To a solution of (1R,2S,5S)-N-(2-amino-2-oxo-1-(phthalazin-1-yl)ethyl)-3-((S) -4-hydroxy-3,3-dimethyl - 2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicy clo[3.1.0]hexane-2-carboxamide (50.0 mg, 53.1 μmol, 1.00 eq) in dichloromethane (3.00 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (19.0 mg, 79.7 μmol, 1.50 eq). After stirring at 20 °C for 12 h, 5 batches of the reaction mixture were combined and workup together. The mixture was poured into water (20.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were washed with brine (20.0 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (ethyl acetate: methanol = 20: 1) and prep-HPLC (FA condition: column: Phenomenex C1875*30 mm*3 μm; mobile phase: [water(FA)-ACN]; B%: 38%-68%, 7 min) to give (1R,2S,5S)-N-(cyano(phthalazin-1-yl) methyl)- 3-((S)-4-hydroxy-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)bu tanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (11.8 mg, 21.6 μmol, 6% yield, 99% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.07-10.55 (m, 0.5H), 10.05-9.21 (m, 2.3H), 9.09-8.72 (m, 0.5H), 8.36-8.21 (m, 0.5H), 8.16-7.91 (m, 2H), 7.89-7.69 (m, 1.5H), 7.39-7.19 (m, 0.5H), 5.41-5.26 (m, 1H), 4.73-4.40 (m, 1H), 4.35-4.12 (m, 1H), 4.08-3.91 (m, 1H), 3.88-3.72 (m, 1H), 3.67-3.61 (m, 0.5H), 3.15- 3.09 (m, 0.5H), 1.74-1.27 (m, 2H), 1.14-0.76 (m, 12H). LC-MS (Method C): R _t = 0.877 min; MS (ESIpos): m/z = 547.3 [M+H] ⁺ . HPLC (Method S): R _t = 1.965 min. SFC: dr = 7: 30: 44: 19. Preparation of CPD0277847 Procedure for preparation of (R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl trifluoromethanesulfonate To a solution of (R)-3-hydroxy-4,4-dimethyldihydrofuran-2(3H)-one (25.0 g, 192 mmol, 1.00 eq) in dichloromethane (100 mL) were added pyridine (19.5 g, 246 mmol, 19.9 mL, 1.28 eq) and trifluoromethanesulfonic anhydride (56.9 g, 202 mmol, 33.3 mL, 1.05 eq) at 0 °C. After stirring at 20 °C for 2 h, the mixture was poured into hydrochloric acid (1M in water, 50.0 mL) and extracted with dichloromethane (50.0 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (R)-4,4- dimethyl-2-oxotetrahydrofuran-3-yl trifluoromethanesulfonate (40.0 g, 137 mmol, 71% yield, 90% purity) as brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.08 (s, 1H), 4.19-4.05 (m, 2H), 1.32 (s, 3H), 1.24 (s, 3H). Procedure for preparation of (S)-3-azido-4,4-dimethyldihydrofuran-2(3H)-one To a solution of (R)-3-hydroxy-4,4-dimethyldihydrofuran-2(3H)-one (40.0 g, 153 mmol, 1.00 eq) in tetrahydrofuran (100 mL) was added tetrabutylammonium fluoride (1M in tetrahydrofuran, 168 mL, 1.10 eq) and azido trimethylsilane (19.3 g, 168 mmol, 22.1 mL, 1.10 eq) at 0 °C. After stirring at 20 °C for 12 h, the mixture was poured into saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 0 to 95: 5) to afford (S)-3-azido-4, 4-dimethyldihydrofuran-2(3H)-one (16.0 g, 103 mmol, 68% yield) as light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 4.65 (s, 1H), 4.09-4.02 (m, 2H), 1.14 (s, 3H), 0.96 (s, 3H). Procedure for preparation of tert-butyl (S)-(4,4-dimethyl-2-oxotetrahydrofuran-3-yl)carbamate To a solution of (S)-3-azido-4,4-dimethyldihydrofuran-2(3H)-one (8.00 g, 51.6 mmol, 1.00 eq) in methanol (50.0 mL) were added di-tert-butyldicarbonate (13.5 g, 61.9 mmol, 14.2 mL, 1.20 eq) and palladium on carbon (2.00 g, 10% purity) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen for 3 times. After stirring at 20 °C for 12 h under hydrogen atmosphere (15 psi), the reaction mixture was filtered. The filtrate was concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 0 to 90: 10) to give tert-butyl (S)-(4, 4-dimethyl-2-oxotetrahydrofuran-3-yl)carbamate (14.0 g, 61.1 mmol, 59% yield) as light yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.33 (d, J = 9.6 Hz, 1H), 4.7 (d, J = 9.6 Hz, 1H), 4.07-4.04 (m, 2H), 1.41 (s, 9H), 1.05 (s, 3H), 0.85 (s, 3H). Procedure for preparation of methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-4- hydroxy-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1. 0]hexane-2-carboxylate To a solution of tert-butyl (S)-(4,4-dimethyl-2-oxotetrahydrofuran-3-yl)carbamate (8.00 g, 34.9 mmol, 1.00 eq) and methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (5.90 g, 34.9 mmol, 1.00 eq) in dichloromethane (50.0 mL) was added trimethyl aluminum (2M in toluene, 17.5 mL, 1.00 eq) at 0 °C. After stirring at 25 °C for 16 h, the mixture was diluted with saturated ammonium chloride (100 mL). Hydrochloric acid (1M in water) was added to adjust pH to 3 and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 0 to 85: 15) to give methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-4-hydroxy-3 ,3-dimethylbutanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (7.00 g, 14.1 mmol, 40% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 6.84-6.60 (m, 1H), 4.78-4.68 (m, 1H), 4.36-4.18 (m, 2H), 3.99-3.92 (m, 1H), 3.88-3.81 (m, 1H), 3.68-3.61 (m, 3H), 3.41-3.48 (m, 1H), 3.14-3.09 (m, 1H), 1.55-1.50 (m, 1H), 1.46-1.42 (m, 1H), 1.38-1.33 (m, 9H), 1.08-1.03 (m, 3H), 0.96-0.93 (m, 3H), 0.88-0.82 (m, 6H). LC-MS (Method C): R _t = 0.554 min; MS (ESIpos): m/z = 399.2 [M+H] ⁺ . Procedure for preparation of methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-4- methoxy-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1. 0]hexane-2-carboxylate To a solution of methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-4-hydroxy-3 ,3- dimethylbutanoyl) -6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.00 g, 2.51 mmol, 1.00 eq) in iodomethane (10.0 mL) was added silver (I) oxide (1.16 g, 5.02 mmol, 2.00 eq) (carried out 6 batches in parallel). After stirring at 40 °C for 96 h, the mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (50.0 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 0 to 85: 15) to give methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-4-methoxy-3 ,3-dimethylbutanoyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (400 mg, 776 μmol, 5% yield) as light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.71 (d, J = 10.0 Hz, 1H), 4.51-4.44 (m, 1H), 4.16-4.09 (m, 2H), 3.93- 3.84 (m, 1H), 3.76-3.74 (m, 4H), 3.35 (s, 3H), 3.09-3.03 (m, 1H), 1.46-1.39 (m, 11H), 1.06-1.03 (s, 3H), 1.02-0.99 (m, 3H), 0.96-0.93 (m, 3H), 0.89-0.88 (m, 3H). LC-MS (Method C): R _t = 1.014 min; MS (ESIpos): m/z = 413.3 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-4-methoxy-3 ,3- dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-c arboxylic acid To a solution of methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-4-methoxy-3 ,3- dimethylbutanoyl) -6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (400 mg, 970 μmol, 1.00 eq) in methanol (4.00 mL) was added a solution of lithium hydroxide monohydrate (163 mg, 3.88 mmol, 4.00 eq) in water (1.00 mL) at 0 °C. After stirring at 20 °C for 2 h, the mixture was poured into water (50.0 mL), adjusted pH to 5 with hydrochloric acid (1M in water) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-4- methoxy-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1. 0]hexane-2-carboxylic acid (400 mg, 753 μmol, 78% yield) as light yellow oil. LC-MS (Method C): R _t = 0.887 min; MS (ESIpos): m/z = 399.2 [ . Procedure for preparation of (1R,2S,5S)-3-((S)-2-amino-4-methoxy-3,3-dimethylbutanoyl)-6, 6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid A mixture of (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-4-methoxy-3 ,3-dimethylbutanoyl) -6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (350 mg, 878 μmol, 1.00 eq) in hydrochloric acid (4M in dioxane, 10 mL, 45.5 eq) was stirred at 0 °C for 2 h. The mixture was concentrated under vacuum to give (1R,2S,5S)-3-((S)-2-amino-4-methoxy-3,3-dimethylbutanoyl)-6, 6-dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxylic acid (350 mg, crude, hydrochloric acid salt) as light yellow oil. Procedure for preparation of (1R,2S,5S)-3-((S)-4-methoxy-3,3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxylic acid To a solution of (1R,2S,5S)-3-((S)-2-amino-4-methoxy-3,3-dimethylbutanoyl)-6, 6-dimethyl-3- azabicyclo [3.1.0]hexane-2-carboxylic acid (350 mg, 1.05 mmol, 1.00 eq, hydrochloric acid salt) in methanol (10.0 mL) were added triethylamine (1.06 g, 10.5 mmol, 1.45 mL, 10.0 eq) and methyl 2,2,2- trifluoroacetate (669 mg, 5.23 mmol, 527 μL, 5.00 eq). After stirring at 25 °C for 16 h, the mixture was poured into water (50.0 mL) and washed with ethyl acetate (50.0 mL × 2). Hydrochloric acid (1M in water) was added to the aqueous phase to adjust pH to 5 and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed by brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (FA condition: 55g Flash Column SEPAFLASH_C1840-63μm; 60 A; mobile phase: [water(0.225%FA)-ACN]; B%: 40-60%, 10 min) to give (1R,2S,5S)-3-((S)-4-methoxy-3,3-dimethyl-2- (2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicycl o[3.1.0]hexane-2-carboxylic acid (120 mg, 304 μmol, 29% yield) as a yellow solid. LC-MS (Method C): R _t = 0.920 min; MS (ESIpos): m/z = 491.4 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-(2-amino-2-oxo-1-(phthalazin-1-yl)ethyl)-3-((S) -4- methoxy-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6 ,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-((S)-4-methoxy-3,3-dimethyl-2-(2,2,2-trifluoroa cetamido) butanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (100 mg, 253 μmol, 1.00 eq), benzotriazol-1- yloxy(tripyrrolidin-1-yl)phosphanium;hexafluorophosphate (198 mg, 380 μmol, 1.50 eq), 4- methylmorpholine (103 mg, 1.01 mmol, 112 μL, 4.00 eq) in N,N-dimethylformamide (3.00 mL) was added 2-amino-2-(phthalazin-1-yl)acetamide (60.5 mg, 253 μmol, 1.00 eq, hydrochloric acid salt). After stirring at 20 °C for 12 h, the mixture was poured into water (20.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were washed with brine (20.0 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: (ethyl acetate: methanol = 10: 1) = 1: 0 to 60: 40) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-(phthalazin-1-yl)ethyl)-3-((S) -4-methoxy-3,3-dimethyl- 2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicy clo[3.1.0]hexane-2-carboxamide (160 mg, 249 μmol, 98% yield) as a yellow solid. LC-MS (Method C): R _t = 0.844 min; MS (ESIpos): m/z = 579.3 [M+H] ⁺ . To a mixture of (1R,2S,5S)-N-(2-amino-2-oxo-1-(phthalazin-1-yl)ethyl)-3-((S) -4-methoxy -3,3-dimethyl- 2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicy clo[3.1.0]hexane-2-carboxamide (40.0 mg, 69.1 μmol, 1.00 eq) in dichloromethane (1.00 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (33.0 mg, 138 μmol, 2.00 eq). (Carried out the dehydration three batches in parallel.) After stirring at 25 °C for 12 h , the mixture was poured into water (20.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: UniSil 3-100 C18 UItra (150*25mm*3 μm); mobile phase: [water(FA)-ACN];B%: 44%-74%, 7 min) to give (1R,2S,5S)-N-(cyano(phthalazin-1-yl)methyl)-3-((S)-4-methoxy -3,3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxamide (23.20 mg, 41.4 μmol, 20% yield, 99% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.69 (s, 0.5H), 9.90-9.66 (m, 0.6H), 9.50-9.22 (m, 1.4H), 8.86-8.69 (m, 0.6H), 8.33-8.21 (m, 0.3H), 8.16-7.71 (m, 3.5H), 7.39-7.23 (m, 0.3H), 4.61-4.51 (m, 1H), 4.35-4.13 (m, 1H), 4.00-3.88 (m, 1H), 3.81-3.67 (m, 1H), 3.38-3.35 (m, 1H), 3.29-3.24 (m, 3H), 3.11-3.05 (m, 1H), 1.70-1.55 (m, 1.5H), 1.37-1.21 (m, 0.5H), 1.11-0.75 (m, 12H). A mixture of ethyl 3-methylbut-2-enoate (30.0 g, 234 mmol, 1.00 eq), 3-chlorobenzenecarboperoxoic acid (47.5 g, 234 mmol, 85% purity, 1.00 eq) in tetrahydrofuran (200 mL) was stirred at 60 °C for 12 h under nitrogen atmosphere. The mixture was poured into water (200 mL) and extracted with petroleum ether (150 mL × 3). The separated organic phase was washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether (200 mL) and filtered. The filtrate was concentrated under reduced pressure to give a residue and then purified by silica gel column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 6/1) to give ethyl 3,3-dimethyloxirane-2-carboxylate (8.20 g, 56.9 mmol) as colorless oil. ¹ H NMR (CDCl ₃ , 400 MHz) δ = 4.15-4.40 (m, 3H), 3.35 (s, 1H), 1.45 (s, 3H), 1.40 (s, 3H), 1.33 (t, J =7.20 Hz, 3H). Procedure for preparation of ethyl 3-ethoxy-2-hydroxy-3-methylbutanoate To a solution of ethyl 3,3-dimethyloxirane-2-carboxylate (6.30 g, 43.7 mmol, 1.00 eq) in ethanol (20.0 mL) was added boron trifluoride-ethyl ether complex (7.44 g, 52.4 mmol, 6.47 mL, 1.20 eq) at 0 °C. After stirring at 25 °C for 12 h, the mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give crude ethyl 3-ethoxy-2-hydroxy-3-methyl-butanoate (7.40 g, 38.9 mmol, 89% yield) as light yellow oil. The crude product was used for next step without purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 4.32-4.17 (m, 2H), 4.02 (d, J = 6.8 Hz, 1H), 3.49-3.38 (m, 2H), 3.07 (d, J = 6.4 Hz, 1H), 1.29 (t, J = 6.8 Hz, 3H), 1.26 (s, 3H), 1.22 (s, 3H), 1.13 (t, J = 6.8 Hz, 3H). Procedure for preparation of ethyl 3-ethoxy-3-methyl-2- (((trifluoromethyl)sulfonyl)oxy)butanoate To a solution of ethyl 3-ethoxy-2-hydroxy-3-methyl-butanoate (7.40 g, 38.9 mmol, 1.00 eq) in dichloromethane (30.0 mL) were added pyridine (7.38 g, 93.4 mmol, 7.54 mL, 2.40 eq) and trifluoromethylsulfonyl trifluoromethanesulfonate (24.1 g, 85.6 mmol, 14.1 mL, 2.20 eq) at 0 °C. After stirring at 20 °C for 1 h, the mixture was diluted with saturated ammonium chloride (200 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give ethyl 3-ethoxy-3-methyl-2- (trifluoromethylsulfonyloxy)butanoate (10.7 g, 33.2 mmol, 85% yield) as black brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 4.99 (s, 1H), 4.36-4.28 (m, 2H), 3.53-3.47 (m, 2H), 1.39-1.32 (m, 9H), 1.15 (t, J = 7.2 Hz, 3H). Procedure for preparation of ethyl 2-azido-3-ethoxy-3-methylbutanoate To a solution of ethyl 3-ethoxy-3-methyl-2-(trifluoromethylsulfonyloxy)butanoate (9.70 g, 30.1 mmol, 1.00 eq) in N,N-dimethylformamide (100 mL) was added sodium azide (2.97 g, 45.7 mmol, 1.52 eq). After stirring at 50 °C for 12 h, the reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether) to give ethyl 2-azido-3- ethoxy-3-methyl-butanoate (2.50 g, 9.29 mmol, 31% yield, 80% purity) as colorless oil. 4.22 (m, 2H), 3.86 (s, 1H), 3.54-3.39 (m, 2H), 1.35-1.23 (m, Procedure for preparation of ethyl 2-((tert-butoxycarbonyl)amino)-3-ethoxy-3-methylbutanoate To a solution of ethyl 2-azido-3-ethoxy-3-methyl-butanoate (2.40 g, 11.2 mmol, 1.00 eq) in ethanol (20.0 mL) were added di-tert-butyl dicarbonate (2.92 g, 13.4 mmol, 3.07 mL, 1.20 eq) and palladium on carbon (0.500 g, 11.2 mmol, 10% purity, 1.00 eq) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen for 3 times. After stirring at 20 °C for 12 h under hydrogen atmosphere (15 psi), the reaction mixture was filtered. The filtrate was concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (SiO ₂ , petroleum ether then petroleum ether: ethyl acetate = 95: 5) to give ethyl 2-(tert-butoxycarbonylamino)- 3-ethoxy-3-methyl-butanoate (2.80 g, 8.71 mmol, 78% yield, 90% purity) as light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.32 (d, J = 8.0 Hz, 1H), 4.34-4.16 (m, 3H), 3.53-3.33 (m, 2H), 1.45 (s, 9H), 1.32-1.25 (m, 9H), 1.14 (t, J = 6.8 Hz, 3H). Procedure for preparation of 2-((tert-butoxycarbonyl)amino)-3-ethoxy-3-methylbutanoic acid To a solution of ethyl 2-(tert-butoxycarbonylamino)-3-ethoxy-3-methyl-butanoate (1.00 g, 3.46 mmol, 1.00 eq) in tetrahydrofuran (10.0 mL) and methanol (5.00 mL) was added a solution of lithium hydroxide hydrate (725 mg, 17.3 mmol, 5.00 eq) in water (2.00 mL) at 0 °C. After stirring at 20 °C for 12 h, the mixture was poured into water (20.0 mL). Hydrochloric acid (1M) was added to the mixture to adjust pH to 4~5 and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 2-(tert-butoxycarbonylamino)-3-ethoxy-3-methyl-butanoic acid (1.00 g, crude) as light yellow oil. The crude product was used for next step without purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.3 (s, 1H), 6.60 (d, J = 8.8 Hz, 1H), 4.12 (d, J = 8.8 Hz, 1H), 3.43- 3.35 (m, 2H), 1.38 (s, 12H), 1.17 (s, 3H), 1.15(s, 3H). Procedure for preparation of methyl (1R,2S,5S)-3-(2-((tert-butoxycarbonyl)amino)-3-ethoxy-3- methylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane -2-carboxylate A mixture of 2-(tert-butoxycarbonylamino)-3-ethoxy-3-methyl-butanoic acid (744 mg, 2.85 mmol, 1.00 eq), methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (626 mg, 3.70 mmol, 1.30 eq), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexaflu orophosphate (1.62 g, 4.27 mmol, 1.50 eq), N,N-diisopropylethylamine (1.10 g, 8.54 mmol, 1.49 mL, 3.00 eq) in dichloromethane (10.0 mL) was stirred at 20 °C for 12 h. The mixture was poured into water (50.0 mL) and extracted with dichloromethane (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 10: 1 to 4: 1) to give methyl (1R,2S,5S)-3-[2-(tert-butoxycarbonylamino)-3-ethoxy-3-methyl -butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (998 mg, 2.06 mmol, 72% yield) as light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.37-5.23 (m, 1H), 4.49-4.30 (m, 2H), 4.08-4.00 (m, 1H), 3.94-3.86 (m, 1H), 3.78-3.72 (m, 3H), 3.51-3.34 (m, 2H), 1.69-1.64 (m, 1H), 1.53-1.48(m, 1H), 1.47-1.36 (m, 12H), 1.24-1.20 (m, 3H), 1.19-1.15 (m, 3H), 1.09-1.02 (m, 6H). LCMS (Method C): R _t = 0.694 & 0.705 min; MS (ESIpos): m/z =413.3 [M+H] ⁺ . SFC: dr = 51: 49. Procedure for preparation of (1R,2S,5S)-3-(2-((tert-butoxycarbonyl)amino)-3-ethoxy-3- methylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxylic acid To a solution of methyl (1R,2S,5S)-3-[2-(tert-butoxycarbonylamino)-3-ethoxy-3-methyl -butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (998 mg, 2.42 mmol, 1.00 eq) in methanol (10.0 mL) was added lithium hydroxide hydrate (508 mg, 12.1 mmol, 5.00 eq) in water (2.00 mL) at 0 °C. After stirring at 25 °C for 16 h, the mixture was poured into water (20.0 mL), adjusted pH to 4~5 with hydrochloric acid aqueous solution (1M) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-3-[2-(tert-butoxycarbonylamino)-3-ethoxy-3- methyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-ca rboxylic acid (1.00 g, 2.38 mmol, 98% yield) as a light yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.40-5.26 (m, 1H), 4.53-4.34 (m, 2H), 4.07-3.87 (m, 2H), 3.52-3.33 (m, 2H), 1.80-1.66 (m, 1H), 1.49-1.39 (m, 10H), 1.31-1.18 (m, 9H), 1.11-1.01 (m, 6H). LCMS (Method C): R _t = 0.645; 0.663 min; MS (ESIpos): m/z =399.3 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-(2-amino-3-ethoxy-3-methylbutanoyl)-6,6-dimethy l-3- azabicyclo[3.1.0]hexane-2-carboxylic acid To a solution of (1R,2S,5S)-3-[2-(tert-butoxycarbonylamino)-3-ethoxy-3-methyl -butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (900 mg, 2.26 mmol, 1.00 eq) in dioxane (15.0 mL) was added hydrochloric acid (4.00 M in dioxane, 18.0 mL) at 0 °C. After stirring at 20 °C for 1 h, the mixture was concentrated under reduced pressure to give (1R,2S,5S)-3-(2-amino-3-ethoxy-3-methyl-butanoyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (750 mg, 2.02 mmol, 89% yield, hydrochloric acid ) as light yellow oil. LCMS (Method C): R _t = 0.454 & 0.482 min; MS (ESIpos): m/z =299.1 [M+H] ⁺ Procedure for preparation of (1R,2S,5S)-3-(3-ethoxy-3-methyl-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxylic acid To a solution of (1R,2S,5S)-3-(2-amino-3-ethoxy-3-methyl-butanoyl)-6,6-dimeth yl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (750 mg, 2.51 mmol, 1.00 eq) in methanol (10.0 mL) were added triethylamine (1.27 g, 12.6 mmol, 1.75 mL, 5.00 eq) and methyl 2,2,2-trifluoroacetate (966 mg, 7.54 mmol, 0.760 mL, 3.00 eq) at 20 °C. After stirring at 20 °C for 12 h, the mixture was concentrated under reduced pressure to give a residue. The residue was diluted with ethyl acetate (30.0 mL), poured into water (20.0 mL) and then adjusted pH to 4~5 with hydrochloric acid aqueous solution (1M). The mixture was extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-3- [(2S)-3-ethoxy-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]buta noyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (835 mg, 1.48 mmol, 59% yield) as light yellow oil. LCMS (Method C): R _t = 0.594 and 0.613 min; MS (ESIpos): m/z =395.2 [M+H] ⁺ To a solution of (1R,2S,5S)-3-[(2S)-3-ethoxy-3-methyl-2-[(2,2,2-trifluoroacet yl)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (300 mg, 761 μmol, 1.00 eq), O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (578 mg, 1.52 mmol, 2.00 eq) and N,N-diisopropylethylamine (393 mg, 3.04 mmol, 4.00 eq) in N,N-dimethylformamide (2.00 mL) was added 2-amino-2-phthalazin-1-yl-acetamide (182 mg, 761 μmol, 1.00 eq, hydrochloric acid) at 0 °C. After stirring at 20 °C for 12h, the mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with saturated calcium chloride aqueous (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 1: 1 to dichloromethane: methanol = 10: 1) to give (1R,2S,5S)-N-(2-amino-2-oxo-1- phthalazin-1-yl-ethyl)-3-[(2S)-3-ethoxy-3-methyl-2-[(2,2,2-t rifluoroacetyl)amino]butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxamide (263 mg, 364 μmol, 48% yield) as light yellow oil. LCMS (Method C): R _t = 0.580 min; MS (ESIpos): m/z =579.2 [M+H] ⁺ . Procedure for preparation of CPD0279111 - (1R,2S,5S)-N-(cyano(phthalazin-1-yl)methyl)-3-(3- ethoxy-3-methyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-di methyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide To a solution of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -3-ethoxy-3-methyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabi cyclo[3.1.0]hexane-2-carboxamide (243 mg, 420 μmol, 1.00 eq) in dichloromethane (5.00 mL) was added (methoxycarbonylsulfamoyl)triethylammonium hydroxide (300 mg, 1.26 mmol, 3.00 eq). After stirring at 20 °C for 1 h, the mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 1: 1 to dichloromethane: ethyl acetate = 7: 3) and prep-HPLC (FA condition: column: Phenomenex luna C18150×40.0 mm× 15.0 μm; mobile phase: [water (FA)-ACN]; B%: 54%-84%, 10 min). to give (1R,2S,5S)-N-[cyano(phthalazin-1- yl)methyl]-3-[(2S)-3-ethoxy-3-methyl-2-[(2,2,2-trifluoroacet yl)amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (15.0 mg, 26.5 μmol, 6% yield) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.74-10.62 (m, 1H), 9.94-9.20 (m, 2H), 8.84-8.21 (m, 1H), 8.13- 7.94 (m, 2H), 7.88-7.28 (m, 2H), 4.73-4.58 (m, 1H), 4.36-4.15 (m, 1H), 4.11-3.95 (m, 1H), 3.76-3.61 (m, 1H), 3.50-3.37 (m, 2H), 1.69-1.56 (m, 2H), 1.40- 0.76 (m, 15H). LCMS (Method C): R _t = 0.854 min; MS (ESIpos): m/z =561.3 [M+H] ⁺ . SFC: dr = 7: 20: 39: 34 To a mixture of methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimeth yl-3- azabicyclo[3.1.0]hexane-2-carboxylate (1.20 g, 3.76 mmol, 1.00 eq, hydrochloric acid), 3,3- difluorocyclobutanecarboxylic acid (614 mg, 4.52 mmol, 1.20 eq) and O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (1.86 g, 4.89 mmol, 1.30 eq) in dichloromethane (20.0 mL) was added N,N-diisopropylethylamine (1.95 g, 15.1 mmol, 4.00 eq). After stirring at 20 °C for 12 h, the reaction mixture was poured into saturated ammonium chloride aqueous (100 mL) and extracted with ethyl acetate (80.0 mL × 3). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 3: 1 to 2: 1) to give methyl (1R,2S,5S)-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino ]-3,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyla te (1.30 g, 3.08 mmol, 82% yield) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.16-5.97 (m, 1H), 4.60 (d, J=9.6 Hz, 1H), 4.46 (s, 1H), 3.97-3.87 (m, 2H), 3.82-3.73 (m, 4H), 2.80-2.64 (m, 4H), 1.50-1.42 (m, 2H), 1.06-1.02 (m, 12H), 0.90-0.85 (m, 3H). LC-MS (Method C): R _t = 0.904 min; MS (ESIpos): m/z = 400.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino ]-3,3- dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino ]-3,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyla te (1.30 g, 3.25 mmol, 1.00 eq) in a mixed solution of water (3.00 mL) and methanol (3.00 mL) was added lithium hydroxide ( 311 mg, 13.0 mmol, 4.00 eq) at 0 °C. After stirring at 20 °C for 12 h, the reaction mixture was adjusted to pH~5 with hydrochloric acid (1 M in water) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-3-[(2S)-2-[(3,3- difluorocyclobutanecarbonyl)amino]-3,3-dimethyl-butanoyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (1.00 g, 2.59 mmol, 80% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.21-7.15 (m, 1H), 6.31 (d, J = 9.6 Hz, 1H), 4.63 (d, J = 9.6 Hz, 1H), 4.45 (s, 1H), 4.06-3.97 (m, 1H), 3.94-3.85 (m, 1H), 2.98-2.64 (m, 5H), 1.78-1.62 (m, 1H), 1.58-1.47 (m, 1H), 1.08 (s, 3H), 1.02 (s,.9H), 0.88 (s, 3H). LC-MS (Method C): R _t = 0.872 min; MS (ESIpos): m/z = 387.2 [M+H] ⁺ . Procedure for preparation of CPD0190963 (1R,2S,5S)-N-[1-cyano-2-(3-oxo-4H-1,4-benzoxazin-2- yl)ethyl]-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino] -3,3-dimethyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino ]-3,3-dimethyl-butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (300 mg, 776 μmol, 1.00 eq), N,N- diisopropylethylamine (301 mg, 2.33 mmol, 3.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (443 mg, 1.16 mmol, 1.50 eq) in N,N-dimethylformamide (3.00 mL) was added 2-amino-3-(3-oxo-4H-1,4-benzoxazin-2-yl)propanenitrile (169 mg, 776 μmol, 1.00 eq). After stirring at 20 °C for 15 h, the reaction mixture was poured into saturated sodium bicarbonate (30.0 mL) and extracted with ethyl acetate (15.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-N-[1- cyano-2-(3-oxo-4H-1,4-benzoxazin-2-yl)ethyl]-3-[(2S)-2-[(3,3 -difluorocyclobutanecarbonyl)amino]-3,3- dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (204 mg, 344 μmol, 44% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.2-10.7 (m, 1H), 9.30-8.98 (m, 1H), 8.37-8.04 (m, 1H), 7.18-6.95 (m, 4H), 5.31-5.03 (m, 1H), 4.85-4.62 (m, 1H), 4.55-4.44 (m, 1H), 4.57-4.37 (m, 1H), 4.02-3.87 (m, 2H), 3.26-3.10 (m, 1H), 2.86-2.67 (m, 4H), 2.59-2.52 (m, 1H), 2.43-2.30 (m, 1H), 1.69-1.56 (m, 1H), 1.47- 1.36(m, 1H), 1.16-0.84 (m, 15H). LC-MS (Method C): R _t = 0.823 min; MS (ESIpos): m/z = 533.2 HPLC (Method S): R _t = 2.655 min. SFC: dr = 17: 26: 42: 15. Preparation of CPD0190964 Procedure for preparation of methyl (2S)-3,3-dimethyl-2-(thiazol-5-ylamino)butanoate A mixture of 5-bromothiazole (9.00 g, 54.8 mmol, 1.00 eq), methyl (2S)-2-amino-3,3-dimethyl-butanoate (19.9 g, 109.7 mmol, 2.00 eq, HCl), cesium carbonate (71.5 g, 219 mmol, 4.00 eq) and [2-(2- aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[2-(2,6-di isopropoxyphenyl)phenyl]phosphane (4.26 g, 5.49 mmol, 0.100 eq) in dioxane (200 mL) was degassed and purged with nitrogen for 3 times. After stirring at 110 °C for 12 h under nitrogen atmosphere, the reaction mixture was filtered. The filter cake was washed with ethyl acetate (100 mL × 3). The filtrate was concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 5: 1 to 1: 1) followed by reversed phase column (40%-60% ACN in water (additive: 0.1% FA)) to give methyl (2S)-3,3-dimethyl-2-(thiazol-5-ylamino)butanoate (340 mg, 1.41 mmol, 3% yield, 95% purity) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.12 (s, 1H), 7.06 (s, 1H), 4.33 (d, J = 10.4 Hz, 1H), 3.73 (s, 3H), 3.54 (d, J = 10.4 Hz, 1H), 1.05 (s, 9H). LC-MS (Method L): R _t = 0.490 min; MS (ESIpos): m/z = 229.1 [M+H] ⁺ . Procedure for preparation of (2S)-3,3-dimethyl-2-(thiazol-5-ylamino)butanoic acid To a mixture of methyl (2S)-3,3-dimethyl-2-(thiazol-5-ylamino)butanoate (340 mg, 1.41 mmol, 95% purity, 1.00 eq) in a mixed solvent of methanol (5.00 mL) and water (5.00 mL) was added lithium hydroxide monohydrate (593 mg, 14.2 mmol, 10.0 eq) at 20 °C. After stirring at 50 °C for 12 h, the reaction mixture was poured into water (50.0 mL), adjusted pH to 4~5 with hydrochloric acid (1M in water) and extracted with (ethyl acetate: methanol = 10: 1, 20.0 mL × 5). The combined organic layers were concentrated under vacuum to give (2S)-3,3-dimethyl-2-(thiazol-5-ylamino)butanoic acid (280 mg, crude) as a yellow solid. LC-MS (Method C): R _t = 0.423 min; MS (ESIpos): m/z = 215.0 [M+H] ⁺ . Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(thiazol-5- ylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-c arboxylate A mixture of (2S)-3,3-dimethyl-2-(thiazol-5-ylamino)butanoic acid (280 mg, 1.31 mmol, 1.00 eq), O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (745 mg, 1.96 mmol, 1.50 eq) and N,N-diisopropylethylamine (675 mg, 5.23 mmol, 4.00 eq) in N,N-dimethylformamide (10.0 mL) was stirred at 20 °C for 0.5 h. Methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (322 mg, 1.57 mmol, 1.20 eq, HCl) was added to the solution above. After stirring at 20°C for 11.5 h, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 5: 1 to 0: 1) to give methyl (1R,2S,5S)- 3-[(2S)-3,3-dimethyl-2-(thiazol-5-ylamino)butanoyl]-6,6-dime thyl-3-azabicyclo[3.1.0]hexane-2- carboxylate (240 mg, 0.590 mmol, 45% yield, 90% purity) as brown oil. LC-MS (Method L): R _t = 0.541 min; MS (ESIpos): m/z = 366.3 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(thiazol-5-ylamino)butanoy l]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid To a mixture of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(thiazol-5-ylamino) butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (240 mg, 0.590 mmol, 90% purity, 1.00 eq) in a mixed solvent of methanol (5.00 mL) and water (5.00 mL) was added lithium hydroxide monohydrate (74.4 mg, 1.77 mmol, 3.00 eq) at 20 °C. After stirring at 20°C for 12 h, the reaction mixture was poured into water (50.0 mL), adjusted pH to 4~5 with hydrochloric acid (1mol/L in water) and extracted with ethyl acetate (20.0 mL × 5). The combined organic layers were concentrated under vacuum to give (1R,2S,5S)-3-[(2S)- 3,3-dimethyl-2-(thiazol-5-ylamino)butanoyl]-6,6-dimethyl-3-a zabicyclo[3.1.0]hexane-2-carboxylic acid (200 mg, crude) as a brown solid. LC-MS (Method L): R _t = 0.497 min; MS (ESIpos): m/z = 352.1 [M+H] ⁺ . Procedure for preparation of CPD0190964 - (1R,2S,5S)-N-[1-cyano-2-(3-oxo-4H-1,4-benzoxazin- 2-yl)ethyl]-3-[(2S)-3,3-dimethyl-2-(thiazol-5-ylamino)butano yl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide A mixture of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(thiazol-5-ylamino) butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (200 mg, 0.569 mmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (324 mg, 0.853 mmol, 1.50 eq) and N,N- diisopropylethylamine (220 mg, 1.71 mmol, 3.00 eq) in N,N-dimethylformamide (5.00 mL) was stirred at 20°C for 0.5 h.2-Amino-3-(3-oxo-4H-1,4-benzoxazin-2-yl)propanenitrile (151 mg, 0.625 mmol, 90% purity, 1.10 eq) was added to the solution above. After stirring at the same temperature for 11.5 h, the reaction mixture was poured into water (50.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm*5 μm; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B%: 35%-62%, 9 min) to give (1R,2S,5S)-N-[1-cyano-2-(3-oxo-4H-1,4-benzoxazin-2-yl) ethyl]-3-[(2S)-3,3-dimethyl-2-(thiazol-5-ylamino)butanoyl]-6 ,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (25.4 mg, 0.042 mmol, 7% yield, 93% purity) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98-10.67 (m, 1H), 9.24-8.91 (m, 1H), 8.25-7.97 (m, 1H), 7.09- 6.82 (m, 5H), 6.16-5.95 (m, 1H), 5.27-4.84 (m, 1H), 4.79-4.46 (m, 1H), 4.27-4.03 (m, 1H), 3.89-3.85 (m, 1H), 3.75-3.59 (m, 2H), 2.43-2.38 (m, 1H), 2.28-2.18 (m, 1H), 1.57-1.47 (m, 1H), 1.34-1.24 (m, 1H), 1.08-0.59 (m, 15H). LC-MS (Method C): R _t = 0.856 min; MS (ESIpos): m/z = 551.3 [M+H] ⁺ . HPLC (Method M): R _t = 1.970 min. Preparation of CPD0191305 Procedure for preparation of dimethyl (2S,4R)-2-((tert-butoxycarbonyl)amino)-4- hydroxypentanedioate To a solution of O1-tert-butyl O2-methyl (2S, 4R) - 4-acetoxy-5-oxo-pyrrolidine-1, 2-dicarboxylate (9.00 g, 29.9 mmol, 1.00 eq) in methanol (100 mL) was added sodium carbonate (949.81 mg, 8.96 mmol, 0.3 eq) at 0 °C. After stirring at 20 °C for 3 h, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ethergradient @ 50 mL/min) to give compound dimethyl (2S,4R)-2-(tert- butoxycarbonylamino)-4-hydroxy-pentanedioate (7.00 g, 24.0 mmol, 80% yield) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.25 (d, J = 6.0 Hz, 1H), 4.65-4.50 (m, 1H), 4.40-4.30 (m, 1H), 3.83- 3.75 (m, 6H), 2.49-2.34 (m, 1H), 2.21-2.08 (m, 1H), 1.46 (s, 9H). Procedure for preparation of dimethyl (2S,4S)-2-((tert-butoxycarbonyl)amino)-4-(5-fluoro-2- nitrophenoxy)pentanedioate To a solution of dimethyl (2S, 4R) - 2 -(tert-butoxycarbonylamino) -4-hydroxy-pentanedioate (1.00 g, 3.43 mmol, 1.00 eq) and 3-fluoro-2-nitro-phenol (647 mg, 4.12 mmol, 1.20 eq) in tetrahydrofuran (20.0 mL) were added triphenylphosphine (1.35 g, 5.15 mmol, 1.50 eq) and diisopropyl azodicarboxylate (1.04 g, 5.15 mmol, 1.00 mL, 1.50 eq) at 0 °C. After stirring at 20 °C for 16 h, the reaction mixture was quenched with water (20.0 mL) at 25 °C. The solution was extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~35% Ethyl acetate/Petroleum ethergradient @ 50 mL/min) to give dimethyl (2S,4S)-2-(tert-butoxycarbonylamino)- 4-(3-fluoro-2-nitro-phenoxy)pentanedioate (1.40 g, crude) as yellow oil. LC-MS (Method G): Rt = 0.737 min; MS (ESIpos): m/z = 331.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.38-7.35 (m, 1H), 6.92-6.87 (m, 1H), 6.75-6.71 (m, 1H), 5.03-4.97 (m, 1H), 4.92-4.87 (m, 1H), 3.75 (s, 3H), 3.73 (s, 3H), 2.57-2.54 (m, 1H), 2.53-2.50 (m, 1H), 1.40 (s, 9H). Procedure for preparation of methyl (2S)-2-(tert-butoxycarbonylamino) -3-[(2S)-5-fluoro-3-oxo- 4H-1,4-benzoxazin-2-yl]propanoate To a solution of dimethyl (2S,4S)-2-(tert-butoxycarbonylamino)-4-(3-fluoro-2-nitro- phenoxy)pentanedioate (1.40 g, 3.25 mmol, 1.00 eq) in methanol (20.0 mL) was added Pd/C (200 mg, 10% purity) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen for 3 times. After stirring at 20 °C for 2 h under hydrogen atmosphere (15 psi). The reaction mixture was filtered and the filter filtrate was concentrated to give methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(2S)- 5-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]propanoate (1.20 g, crude) as yellow oil. Procedure for preparation of tert-butyl N-[(1S)-2-amino-1-[[(2S)-5-fluoro-3-oxo-4H-1,4- benzoxazin-2-yl]methyl]-2-oxo-ethyl]carbamate To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(2S)-5-fluoro-3-oxo-4H- 1,4-benzoxazin-2- yl]propanoate (800 mg, 2.17 mmol, 1.00 eq) was added ammonia (7M in methanol, 20.0 mL, 64.5 eq). After stirring at 25 °C for 36 h, the reaction mixture was concentrated under reduced pressure to get a residue. The residue was purified by flash silica gel chromatography (20 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ethergradient @ 60 mL/min) to give tert-butyl N- [(1S)-2-amino-1-[[(2S)-5-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl ]methyl]-2-oxo-ethyl]carbamate (395 mg, 1.11 mmol, 51% yield, 99% purity) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.30-7.93 (m, 1H), 7.00-6.88 (m, 1H), 6.87-6.72 (m, 2H), 6.57-6.35 (m, 1H), 5.72-5.34 (m, 2H), 4.87-4.72 (m, 1H), 4.65-4.41 (m, 1H), 2.75-2.24 (m, 2H), 1.54-1.32 (m, 9H). LC-MS (Method R): Rt = 0.711 min; MS (ESIpos): m/z = 254.1 [M-100+H]+. Procedure for preparation of (2S)-2-amino-3-[(2S)-5-fluoro-3-oxo-4H-1,4-benzoxazin-2- yl]propanamide To a solution of tert-butyl N-[(1S)-2-amino-1-[[(2S)-5-fluoro-3-oxo-4H-1,4-benzoxazin-2- yl]methyl]-2- oxo-ethyl]carbamate (200 mg, 0.566 mmol, 1 eq) in dioxane (1.00 mL) was added hydrochloric acid (4M in dioxane, 0.141 mL, 1.00 eq). After stirring at 20 °C for 1 h, the reaction mixture was concentrated under reduced pressure to give (2S)-2-amino-3-[(2S)-5-fluoro-3-oxo-4H-1,4-benzoxazin-2- yl]propanamide (160 mg, 525 umol, 93% yield, 95% purity, Hydrogen chloride) as a white solid. LC-MS (Method A): Rt = 0.308 min; MS (ESIpos): m/z = 254.1 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[(1S)-2-amino-1-[[(2S)-5-fluoro-3-oxo-4H-1,4- benzoxazin-2-yl]methyl]-2-oxo-ethyl]-3-[(2S)-3,3-dimethyl-2- [(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (230 mg, 632 umol, 1.00 eq) in dimethyl formamide (2.00 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (360 mg, 0.948 mmol, 1.50 eq) and diisopropylethylamine (408 mg, 3.16 mmol, 0.550 mL, 5.00 eq). After stirring at 25 °C for 1 h, (2S)-2-amino-3-[(2S)-5-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]p ropanamide (160 mg, 0.632 mmol, 1.00 eq) was added. After stirring at 25 °C for another 16 h, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (20 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ethergradient @ 60 mL/min) to give (1R,2S,5S)-N-[(1S)-2-amino-1- [[(2S)-5-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]methyl]-2-oxo-e thyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (172 mg, 0.241 mmol, 38% yield, 84% purity) as red oil. LC-MS (Method A ): Rt = 0.717 min; MS (ESIpos): m/z = 600.4 [M+H] ⁺ . To a solution of (1R,2S,5S)-N-[(1S)-2-amino-1-[[(2S)-5-fluoro-3-oxo-4H-1,4-be nzoxazin-2-yl]methyl]-2- oxo-ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxamide (172 mg, 0.287 mmol, 1.00 eq) in dichloromethane (3.00 mL) was added Burgess reagent (88.9 mg, 0.373 mmol, 1.30 eq) at 0 °C. After stirring at 25 °C for 18 h, the reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (20 ml × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 45%-75%, 10 min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-5-fluoro-3-oxo-4H-1,4-ben zoxazin-2-yl]ethyl]-3- [(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl] -6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (35.9 mg, 61.2 μmol, 21% yield, 99% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.99 (br. s, 1H), 9.45-9.28 (m, 1H), 9.13-9.01 (m, 1H), 7.00-6.86 (m, 2.35H), 6.80-6.73 (m, 0.65H), 5.20-5.10 (m, 1H), 4.77-4.50 (m, 1H), 4.41-4.30 (m, 1H), 4.23-4.08 (m, 1H), 3.93-3.83 (m, 1H), 3.72-3.63 (m, 1H), 2.56-2.54 (m, 1H), 2.33-2.27 (m, 1H), 1.59-1.50 (m, 1H), 1.39-1.32 (m, 1H), 1.04-0.92 (m, 6H), 0.86-0.81 (m, 3H), 0.76 (s, 6H). LC-MS (Method S): Rt = 2.315 min; MS (ESIpos): m/z = 582.3 [M+H] ⁺ . SFC: dr = 39: 61. Preparation of CPD0191314 Procedure for preparation of dimethyl (2S,4S)-2-(tert-butoxycarbonylamino)-4-(3-cyano-2-nitro- phenoxy)pentanedioate To a solution of dimethyl (2S,4R)-2-(tert-butoxycarbonylamino)-4-hydroxy-pentanedioate (1.50 g, 5.15 mmol, 1.0 eq), 3-hydroxy-2-nitro-benzonitrile (887 mg, 5.41 mmol, 1.05 eq) and triphenylphosphine (2.03 g, 7.72 mmol, 1.50 eq) in tetrahydrofuran (30.0 mL) was added diisopropylazodicarboxylate (1.56 g, 7.72 mmol, 1.50 mL, 1.50 eq) at 0 °C. After stirring at 25 °C for 16 h, the mixture was diluted with water (100 mL) and saturated ammonium chloride (50.0 mL), and extracted with ethyl acetate (40.0 mL × 3). The combined organic layers were washed with water (80.0 mL), brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 50 mL/min) to give dimethyl (2S,4S)-2-(tert- butoxycarbonylamino)-4- (3-cyano-2-nitro-phenoxy)pentanedioate (4.0 g, 89% yield, 50% purity) as yellow oil. LC-MS (Method C): R _t = 0.439 min; MS (ESIpos): m/z = 460.1 [M+Na] ⁺ , m/z = 338.2 [M-Boc+H] ⁺ . 4.2. Procedure for preparation of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(2S)-5-cyano-3- oxo-4H-1,4-benzoxazin-2-yl]propanoate To a solution of dimethyl (2S,4S)-2-(tert-butoxycarbonylamino)-4-(3-cyano-2-nitro- phenoxy)pentanedioate (4.00 g, 4.57 mmol, 50% purity, 1.00 eq) in a mixed solvent of methanol (40 mL) and acetic acid (20 mL) was added iron powder (1.28 g, 22.9 mmol, 5 eq) in portions at 60 °C. After stirring at the same temperature for 16 h, the mixture was filtered. The filtrate was diluted with water (200 mL). Sodium bicarbonate was added to the solution to adjust pH = 7~8 and extracted with ethyl acetate (60.0 mL × 3). The combined organic layers were washed with water (100 mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ethergradient @ 25 mL/min) to give methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(2S)-5-cyano-3-oxo-4H- 1,4-benzoxazin-2-yl]propanoate (800 mg, 42% yield, 90% purity) as a yellow solid. LC-MS (Method C): R _t = 0.393 min; MS (ESIpos): m/z = 398.1 [M+Na] ⁺ , m/z = 319.9 [M-56+H] ⁺ , m/z = 276.2 [M-Boc+H] ⁺ . Procedure for preparation of tert-butyl N-[(1S)-2-amino-1-[[(2S)-5-cyano-3-oxo-4H-1,4- benzoxazin-2-yl]methyl]-2-oxo-ethyl]carbamate To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3- [(2S)-5-cyano-3-oxo-4H-1,4-benzoxazin- 2-yl]propanoate (800 mg, 2.13 mmol, 1.00 eq) in methanol (5.00 mL) was added ammonia (10 M in methanol, 20 mL, 93.8 eq) at 25 °C. After stirring at the same temperature for 64 h, the mixture was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give tert-butyl N-[(1S)-2-amino-1-[[(2S)-5-cyano-3-oxo-4H -1,4-benzoxazin-2-yl]methyl]-2- oxo-ethyl]carbamate (600 mg, 77.3% yield, 99% purity) as a brown solid. LC-MS (Method C): R _t = 0.345 min; MS (ESIpos): m/z = 383.0 [M+Na] ⁺ , m/z = 305.0 [M-56+H] ⁺ , m/z = 261.0 [M-100+H] ⁺ . HPLC (Method: K): R _t = 1.322 min; purity: 99%. SFC: de% = 100%. Procedure for preparation of (2S)-2-amino-3-[(2S)-5-cyano-3-oxo-4H-1,4-benzoxazin-2- yl]propanamide To a solution of tert-butyl N-[(1S)-2-amino-1-[[(2S)-5-cyano-3-oxo-4H-1,4-benzoxazin-2-y l]methyl] -2- oxo-ethyl]carbamate (0.550 g, 1.53 mmol, 1.00 eq) in acetonitrile (5.00 mL) was added dropwise trifluoroacetic acid (1.5 mL) at 25 °C. After stirring at the same temperature for 3 h, trifluoroacetic acid (1.0 mL) was added to the mixture, and the resulting mixture was stirred at 25 °C for another 16 h. The solution was concentrated at 38 °C to give a residue. The residue was diluted with ethyl acetate (50.0 mL), extracted with saturated sodium bicarbonate (25.0 mL × 2). The aqueous phase was concentrated under oil pump (38 °C) to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 5 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ethergradient @ 10 mL/min) to give (2S)-2-amino-3- [(2S)-5-cyano-3-oxo-4H-1,4-benzoxazin-2-yl]propanamide (300 mg, 72% yield, 95% purity) as a yellow solid. LC-MS (Method C): R _t = 0.187 min; MS (ESIpos): m/z = 260.9 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[(1S)-2-amino-1-[[(2S)-5-cyano-3-oxo-4H-1,4- benzoxazin-2-yl]methyl]-2-oxo-ethyl]-3-[(2S)-3,3-dimethyl-2- [(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide - To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl] -6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (200 mg, 0.549 mmol, 1.00 eq) and N,N- diisopropylethylamine (213 mg, 1.65 mmol, 0.287 mL, 3 eq) in N,N-dimethylformamide (4 mL) was added o-(7-azabenzotriazol-1-yl)-n,n,n,n-tetramethyluronium hexafluorophosphate (250 mg, 0.659 mmol, 1.2 eq) at 0 °C. After stirring at the same temperature for 10 min, (2S)-2-amino-3-[(2S)-5-cyano- 3-oxo-4H-1,4- benzoxazin-2-yl]propanamide (143 mg, 0.549 mmol, 1 eq) was added to the above mixture. After stirring at 25 °C for 2 h, the reaction was diluted with water (40.0 mL) and saturated ammonium chloride (20.0 mL), and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with water (50.0 mL) and brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~90% Ethyl acetate/Petroleum ethergradient @ 15 mL/min) to give (1R,2S,5S)-N-[(1S)-2-amino-1-[[(2S)-5-cyano- 3-oxo-4H-1,4-benzoxazin-2-yl]methyl]-2-oxo-ethyl] -3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (200 mg, 54% yield, 90% purity) as brown oil. LC-MS (Method C): R _t = 0.399 min; MS (ESIpos): m/z = 607.3 [M+H] ⁺ . Procedure for preparation of Compound cyano-3-oxo-4H-1,4-benzoxazin-2-yl]ethyl]- trifluoroacetyl)amino]butanoyl]-6,6-dimethy To a solution of (1R,2S,5S)-N-[(1S)-2-amino-1-[[(2S)-5-cyano-3-oxo-4H-1,4-ben zoxazin-2-yl] methyl]- 2-oxo-ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl) amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (200 mg, 0.330 μmol, 1.00 eq) in dichloromethane (4.00 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (157 mg, 0.659 mmol, 2.00 eq) at 0 °C. After stirring at 25 °C for 4 h, the reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (20.0 mL × 3). The combined organic layers were washed with water (40.0 mL), brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 48%-78%, 10 min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2- [(2S)-5-cyano-3-oxo-4H-1,4-benzoxazin-2-yl]ethyl]-3-[(2S)-3, 3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (72.3 mg, 37% yield, 99% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.32 (s, 1H), 9.35 (d, J = 8.4 Hz, 1H), 9.14 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 7.11 (t, J = 8.0 Hz, 1H), 5.24-5.14 (m, 1H), 4.51 (dd, J = 10.4, 2.4 Hz, 1H), 4.33 (d, J = 8.0 Hz, 1H), 4.09 (s, 1H), 3.91-3.82 (m, 1H), 3.67 (d, J = 10.4 Hz, 1H), 2.43-2.29 (m, 2H), 1.57 (dd, J = 7.2, 6.0 Hz, 1H), 1.35 (d, J = 8.0 Hz, 1H), 1.02 (s, 3H), 0.83 (s, 3H), 0.74 (s, 9H). LC-MS (Method C): R _t = 0.461 min; MS (ESIpos): m/z = 589.5 [M+H] ⁺ . HPLC (Method K): R _t = 2.303 min. SFC: de%= 82%. Preparation of CPD0191315 Procedure for preparation of dimethyl (2S,4S)-2-(tert-butoxycarbonylamino)-4-(5-fluoro-2-nitro- phenoxy)pentanedioate To a solution of dimethyl (2S,4R)-2-(tert-butoxycarbonylamino)-4-hydroxy-pentanedioate (1.00 g, 3.43 mmol, 1.00 eq), 5-fluoro-2-nitro-phenol (593 mg, 3.78 mmol, 1.10 eq) and triphenylphosphine (1.35 g, 5.15 mmol, 1.50 eq) in tetrahydrofuran (10.0 mL) was added diisopropyl azodicarboxylate (1.04 g, 5.15 mmol, 1.00 mL, 1.50 eq) at 0 °C. After stirring at 20 °C for 3 h, the reaction mixture was diluted with water (30.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed phase column (water: acetonitrile = 60: 1 to 40: 1, 0.01% FA condition) to afford dimethyl (2S, 4S)-2-(tert- butoxycarbonylamino)-4-(5-fluoro-2-nitro-phenoxy)pentanedioa te (0.80 g, 1.77 mmol, 51% yield, 95.0% purity) as colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.08-8.04 (m, 1H), 7.37-7.34 (m, 1H), 7.28-7.26 (m, 1H), 7.03-7.00 (m, 1H), 5.08-5.04 (m, 1H), 4.34-4.30 (m, 1H), 3.70 (s, 3H), 3.64 (s, 3H), 2.34-2.29 (m, 2H), 1.25 (s, 9H). LC-MS (Method C): R _t = 0.602 min; MS (ESIpos): m/z = 331.0 [M-Boc+H] ⁺ . Procedure for preparation of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(2S)-7-fluoro-3-oxo- 4H-1,4-benzoxazin-2-yl]propanoate To a solution of dimethyl (2S,4S)-2-(tert-butoxycarbonylamino)-4-(5-fluoro-2-nitro- phenoxy)pentanedioate (0.80 g, 1.86 mmol, 1.00 eq) in methanol (10.0 mL) was added palladium on carbon (100 mg, 2.32 mmol, 10% purity) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen for 3 times. After stirring at 20 °C for 16 h under hydrogen atmosphere (15 psi), the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(2S)-7-fluoro-3-oxo-4H- 1,4-benzoxazin-2-yl]propanoate (515 mg, 1.26 mmol, 68% yield, 90% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.80 (s, 1H), 7.42 (d, J = 8.2 Hz, 1H), 6.90-6.81 (m, 3H), 4.57-4.53 (m, 1H), 4.30-4.24 (m, 1H), 3.61 (s, 3H), 2.22-2.08 (m, 2H), 1.37 (s, 9H). LC-MS (Method C): R _t = 0.575 min; MS (ESIpos): m/z = 269.0 [M-Boc+H] ⁺ . 4Procedure for preparation of tert-butyl N-[(1S)-2-amino-1-[[(2S)-7-fluoro-3-oxo-4H-1,4- benzoxazin-2-yl]methyl]-2-oxo-ethyl]carbamate A mixture of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(2S)-7-fluoro-3-oxo-4H- 1,4-benzoxazin-2- yl]propanoate (510 mg, 1.38 mmol, 1.00 eq) in ammonium (15.0 M in methanol, 9.00 mL) was stirred at 25 °C for 36 h. The reaction mixture was concentrated under reduced pressure to give tert-butyl N- [(1S)-2-amino-1-[[(2S)-7-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl ]methyl]-2-oxo-ethyl]carbamate (450 mg, 1.18 mmol, 86% yield, 93% purity) as a light yellow solid, which was used for next step reaction directly. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.29-7.26 (m, 1H), 7.10-7.07 (m, 1H), 6.99 (d, J = 8.8 Hz, 1H), 6.91- 6.81 (m, 4H), 4.51-4.47 (m, 1H), 4.16-4.13 (m, 2H), 1.37 (s, 9H). LC-MS (Method C): R _t = 0.537 min; MS (ESIpos): m/z = 254.1 [M-Boc+H] ⁺ . SFC: de%= 75% Procedure for preparation of (2S)-2-amino-3-[(2S)-7-fluoro-3-oxo-4H-1,4-benzoxazin-2- yl]propanamide To a solution of tert-butyl N-[(1S)-2-amino-1-[[(2S)-7-fluoro-3-oxo-4H-1,4-benzoxazin-2- yl]methyl]-2- oxo-ethyl]carbamate (450 mg, 1.27 mmol, 1.00 eq) in dioxane (1.50 mL) was added dropwise hydrochloric acid (4 M in dioxane, 3.00 mL) at 25 °C. After stirring at 25 °C for 4 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with methyl tertiary butyl ether (10.0 ml) at 25 °C for 30 min and filtered. The filter cake was dried under reduced pressure to give (2S)-2-amino-3-[(2S)-7-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]p ropanamide (380 mg, 1.11 mmol, 88% yield, 85% purity, hydrochloric acid) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.90 (s, 1H), 8.40-8.37 (m, 2H), 8.03 (s, 1H), 7.64 (s, 1H), 6.99- 6.83 (m, 3H), 4.76-4.74 (m, 1H), 4.03-3.98 (m, 1H), 2.45-2.41 (m, 1H), 2.25-2.18 (m, 1H). LC-MS (Method A): R _t = 0.121 min; MS (ESIpos): m/z = 254.1 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[(1S)-2-amino-1-[[(2S)-7-fluoro-3-oxo-4H-1,4- benzoxazin-2-yl]methyl]-2-oxo-ethyl]-3-[(2S)-3,3-dimethyl-2- [(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide A mixture of (2S)-2-amino-3-[(2S)-7-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]p ropanamide (350 mg, 1.21 mmol, 1.00 eq, hydrochloric acid), (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxylic acid (440 mg, 1.21 mmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexaflu orophosphate (689 mg, 1.81 mmol, 1.50 eq), N,N-diisopropylethylamine (469 mg, 3.62 mmol, 0.630 mL, 3.00 eq) in N,N- dimethylformamide (3.00 mL) was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (30.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 20: 1 to 5: 1) to give (1R,2S,5S)-N-[(1S)-2-amino-1-[[(2S)-7-fluoro-3-oxo-4H-1,4- benzoxazin-2-yl]methyl]-2-oxo-ethyl]-3-[(2S)-3,3-dimethyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6- dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxamide (550 mg, 844 μmol, 70% yield, 92% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.7 (s, 1H), 9.31 (d, J = 8.44 Hz, 1H), 8.37 (d, J = 8.8 Hz, 1H), 7.37 (s, 0.5H), 7.14 (s, 0.5H), 6.87-6.78 (m, 2H), 6.71-6.68 (m, 1H), 4.63-4.57 (m, 1H), 4.50-4.47 (m, 1H), 4.36-4.34 (m, 1H), 4.22 (s, 1H), 3.87-3.83 (m, 1H), 3.68-3.65 (m, 1H), 3.64-3.60 (m, 1H), 3.16-3.13 (m, 1H), 2.25-2.19 (m, 1H), 2.13-2.06 (m, 1H), 1.51-1.44 (m, 2H), 1.22-1.16 (m, 4H), 1.01 (s, 2H), 0.82 (s, 2H), 0.77 (s, 6H). LC-MS (Method C): R _t = 0.553 min; MS (ESIpos): m/z = 600.1 [M+H] ⁺ Procedure for preparation of CPD0191315 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-7-fluoro-3-oxo- 4H-1,4-benzoxazin-2-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2 -trifluoroacetyl)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-[(1S)-2-amino-1-[[(2S)-7-fluoro-3-oxo-4H-1,4-be nzoxazin-2-yl]methyl]-2- oxo-ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0] hexane-2-carboxamide (200 mg, 334 μmol, 1.00 eq) in dichloromethane (2.00 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (397 mg, 1.67 mmol, 5.00 eq) at 25 °C. After stirring at 25 °C for 12 h, the reaction mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (20.0 mL ×2). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex luna C18150*25 mm* 10 μm; mobile phase: [water(FA)-ACN];B%: 48%-68%, 10 min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2- [(2S)-7-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]ethyl]-3-[(2S)-3 ,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (101 mg, 173 μmol, 52% yield, 99% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.9-10.8 (m, 1H), 9.33 (d, J = 8.44 Hz, 1H), 9.10-9.05 (m, 1H), 6.90- 6.80 (m, 2H), 6.76-6.73 (m, 1H), 5.18-5.12 (m, 1H), 4.56-4.52 (m, 1H), 4.36-4.34 (m, 1H), 4.12 (s, 1H), 3.90-3.86 (m, 1H), 3.69-3.67 (m, 1H), 2.35-2.27 (m, 2H), 1.58-1.55 (m, 1H), 1.35-1.33 (m, 1H), 1.04- 0.93 (m, 4H), 0.84-0.79 (m, 11H). LC-MS (Method C): R _t = 0.610 min; MS (ESIpos): m/z = 582.2 [M+H] ⁺ . SFC: de% = 66%. Preparation of CPD0191316 Procedure for preparation of dimethyl (2S,4S)-2-((tert-butoxycarbonyl)amino)-4-(4-fluoro-2- nitrophenoxy)pentanedioate To a solution of dimethyl (2S)-2-((tert-butoxycarbonyl)amino)-4-hydroxypentanedioate (1.00 g, 3.43 mmol, 1.00 eq), 4-fluoro-2-nitrophenol (593 mg, 3.78 mmol, 1.10 eq), triphenylphosphine (1.35 g, 5.15 mmol, 1.50 eq) in tetrahydrofuran (10.0 mL) was added diisopropyl azodicarboxylate (1.04 g, 5.15 mmol, 1.00 mL, 1.50 eq) at 0°C. After stirring at 20 °C for 16 h, the mixture was diluted with saturated ammonium chloride (50.0 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ ethyl acetate = 1/0 to 3/1) to give dimethyl (2S, 4S)-2-((tert- butoxycarbonyl)amino)-4-(4-fluoro-2-nitrophenoxy)pentanedioa te (900 mg, 1.99 mmol, 58% yield) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.65 (dd, J = 8.0, 3.2 Hz, 1H), 7.26-7.20 (m, 1H), 7.01-6.94 (m, 1H), 5.50-5.27 (m, 1H), 4.84 (dd, J = 10.0, 3.2 Hz, 1H), 4.73-4.61 (m, 1H), 3.78-3.76 (s, 3H), 3.76-3.74 (s, 3H), 2.64-2.50 (m, 1H), 2.40-2.30 (m, 1H), 1.40 (s, 9H). LC-MS (Method C): R _t = 0.600 min; MS (ESIpos): m/z = 331 [M-Boc+H] ⁺ . A mixture of dimethyl (2S, 4S)-2-((tert-butoxycarbonyl)amino)-4-(4-fluoro-2- nitrophenoxy)pentanedioate (900 mg, 2.09 mmol, 1.00 eq) in methanol (10.0 mL) was added palladium on carbon (0.100 g, 10% purity). The suspension was degassed under vacuum and purged with hydrogen for 3 times. After stirring at 20 °C for 16 h under hydrogen atmosphere (15 psi), the reaction mixture was filtered. The filtrate was concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ ethyl acetate = 1/0 to 2/1) to afford methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-6-fluoro-3-oxo-3,4 -dihydro-2H-benzo[b][1,4]oxazin-2- yl)propanoate (760 mg, 1.65 mmol, 79% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.90-8.25 (m, 1H), 6.75-6.66 (m, 1H), 6.62-6.55 (m, 1H), 5.41-5.19 (m, 1H), 4.75-4.56 (m, 2H), 3.83-3.68 (m, 3H), 2.47-2.28 (m, 2H), 1.44 (s, 9H). LC-MS (Method C): R _t = 0.786 min; MS (ESIpos): m/z = 269.0 [M-Boc+H] ⁺ . Procedure for preparation of tert-butyl ((S)-1-amino-3-((S)-6-fluoro-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)-1-oxopropan-2-yl)carbamate To a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-6-fluoro-3-oxo-3,4 -dihydro-2H- benzo[b][1,4]oxazin-2-yl)propanoate (700 mg, 1.90 mmol, 1.00 eq) in methanol (3.00 mL) was added ammonium (10 M in methanol, 10.0 mL). After stirring at 20 °C for 24 h, the mixture was concentrated under vacuum to give tert-butyl ((S)-1-amino-3-((S)-6-fluoro-3-oxo-3,4-dihydro-2H-benzo[b][1 ,4]oxazin- 2-yl)-1-oxopropan-2-yl) carbamate (580 mg, 1.49 mmol, 78% yield) as light yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.42 (s, 1H), 6.92 (dd, J = 8.8, 4.8 Hz, 1H), 6.76-6.63 (m, 2H), 6.62-6.54 (m, 1H), 6.07-5.86 (m, 1H), 5.59 (d, J = 8.0 Hz, 1H), 4.79-4.64 (m, 1H), 4.62-4.47 (m, 1H), 2.45-2.31 (m, 2H), 1.50-1.38 (m, 9H). Procedure for preparation of (S)-2-amino-3-((S)-6-fluoro-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)propanamide To a solution of tert-butyl ((S)-1-amino-3-((S)-6-fluoro-3-oxo-3,4-dihydro-2H-benzo[b][1 ,4] oxazin-2-yl)- 1-oxopropan-2-yl)carbamate (580 mg, 1.64 mmol, 1.00 eq) in dioxane (5.00 mL) was added hydrochloric acid (4 M in dioxane, 5.00 mL, 12.2 eq)at 0 °C. After stirring at 20 °C for 2 h, the mixture was concentrated under vacuum to give (S)-2-amino-3-((S)-6-fluoro-3-oxo-3,4-dihydro-2H- benzo[b][1,4] oxazin-2-yl)propanamide (430 mg, 1.48 mmol, 90% yield, HCl salt) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (s, 1H), 8.52-8.27 (m, 3H), 8.00 (s, 1H), 7.64 (s, 1H), 7.15- 7.02 (m, 1H), 6.87-6.65 (m, 2H), 4.69 (dd, J = 10.0, 2.4 Hz, 1H), 4.03-3.92 (m, 1H), 2.46-2.39 (m, 1H), 2.28-2.16 (m, 1H). Procedure for preparation of (1R,2S,5S)-N-((S)-1-amino-3-((S)-6-fluoro-3-oxo-3,4-dihydro- 2H- benzo[b][1,4]oxazin-2-yl)-1-oxopropan-2-yl)-3-((S)-3,3-dimet hyl-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxamide A mixture of (S)-2-amino-3-((S)-6-fluoro-3-oxo-3,4-dihydro-2H-benzo[b][1, 4]oxazin-2-yl)propanamide (400 mg, 1.38 mmol, 1.00 eq, HCl salt), (1R,2S,5S)-3-((S)-3,3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxylic acid (503 mg, 1.38 mmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexaflu orophosphate (788 mg, 2.07 mmol, 1.50 eq), N,N-diisopropylethylamine (535 mg, 4.14 mmol, 722 μL, 3.00 eq) in N,N- dimethylformamide (5.00 mL) was stirred at 20 °C for 12 h. The mixture was poured into water (50.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (20.0 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 1: 0 to 50: 1) to give (1R,2S,5S)-N-((S)-1-amino-3-((S)-6-fluoro-3-oxo-3,4-dihydro- 2H- benzo[b][1,4]oxazin-2-yl)-1-oxopropan-2-yl)-3-((S)-3,3-dimet hyl-2-(2,2,2-trifluoroacetamido)butanoyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (600 mg, 951 μmol, 69% yield) as light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.12-8.98 (m, 1H), 7.47-7.37 (m, 1H), 7.17-7.06 (m, 1H), 6.94-6.86 (m, 1H), 6.70-6.62 (m, 2H), 6.59-6.53 (m, 1H), 6.05-5.92 (m, 1H), 4.90-4.75 (m, 1H), 4.62-4.57 (m, 1H), 4.53 (d, J = 8.0 Hz, 1H), 4.33 (s, 1H), 4.02-3.93 (m, 1H), 3.89-3.80 (m, 1H), 2.53-2.30 (m, 2H), 1.58- 1.52 (m, 1H), 1.51-1.44 (m, 1H), 1.03 (s, 3H), 0.93 (s, 9H), 0.86 (s, 3H). LC-MS (Method C): R _t = 0.863 min; MS (ESIpos): m/z = 600.2 [M+H] ⁺ . Procedure for preparation of CPD0191316 - (1R,2S,5S)-N-((S)-1-cyano-2-((S)-6-fluoro-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-3-((S)-3,3-dimeth yl-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-((S)-1-amino-3-((S)-6-fluoro-3-oxo-3,4-dihydro- 2H-benzo[b][1,4] oxazin- 2-yl)-1-oxopropan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluo roacetamido)butanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (200 mg, 333 μmol, 1.00 eq) in dichloromethane (3.00 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (398 mg, 1.67 mmol, 5.00 eq). After stirring at 25 °C for 2 h, the mixture was poured into water (50.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex C18 75*30mm*3 μm; mobile phase: [water(FA)-ACN];B%: 50%-80%,7min) to give (1R,2S,5S)-N-((S)-1-cyano-2-((S)-6-fluoro-3-oxo-3,4- dihydro-2H-benzo[b][1,4] oxazin-2-yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroace tamido)butanoyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (89.11 mg, 153 μmol, 46% yield, 99% purity) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.88 (s, 1H), 9.33 (s, 1H), 9.09 (d, J = 8.0 Hz, 1H), 6.94-6.87 (m, 1H), 6.79-6.72 (m, 1H), 6.70-6.64 (m, 1H), 5.18-5.10 (m, 1H), 4.50 (dd, J = 10.4, 2.4 Hz, 1H), 4.34 (s, 1H), 4.12 (s, 1H), 3.92-3.84 (m, 1H), 3.67 (d, J = 10.8 Hz, 1H), 2.48-2.42 (m, 1H), 2.32-2.25 (m, 1H), 1.60-1.52 (m, 1H), 1.34 (d, J = 7.6 Hz, 1H), 1.04-0.99 (m, 3H), 0.86-0.77 (m, 12H). LC-MS (Method C): R _t = 0.641 min; MS (ESIpos): m/z = 582.1 [M+H] ⁺ . HPLC (Method S): R _t = 2.256 min. SFC: de%: 67%. Preparation of CPD0191317 Procedure for preparation of 1-(tert-butyl) 2-methyl (2S,4R)-4-acetoxypyrrolidine-1,2- dicarboxylate To a solution of 1-(tert-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (50.0 g, 204 mmol, 1.00 eq) in tetrahydrofuran (500 mL) were added pyridine (32.3 g, 408 mmol, 32.9 mL, 2.00 eq) and acetic anhydride (31.2 g, 306 mmol, 28.6 mL, 1.50 eq) at 25 °C. After stirring at the same temperature for 16 h, dimethylaminopyridine (498 mg, 4.08 mmol, 0.020 eq) was added to the above mixture, and the resulting mixture was stirred at 25 °C for another 4 h. The solution was diluted with mixed solvent of water (1300 mL) and hydrochloric acid (50 mL, 1 M in water), extracted with ethyl acetate (400 mL × 3). The combined organic layers were washed with water (400 mL × 2), brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1- (tert-butyl) 2-methyl (2S,4R)-4-acetoxypyrrolidine-1,2-dicarboxylate (52.0 g, 181 mmol, 89% yield) as colorless oil. LC-MS (Method C): R _t = 0.545 min; MS (ESIpos): m/z = 310.2 [M+Na] ⁺ , m/z = 232.2 [M-56+H] ⁺ , m/z = 188.2 [M-100+H] ⁺ . To a solution of sodium periodate (96.8 g, 452 mmol, 2.50 eq) in water (500 mL) was added ruthenium (III) chloridetrihydrate (9.46 g, 36.2 mmol, 0.200 eq) at 0 °C. After stirring at 25 °C for 10 min, a solution of 1-(tert-butyl) 2-methyl (2S,4R)-4-acetoxypyrrolidine-1,2-dicarboxylate (52.0 g, 181 mmol, 1.00 eq) in ethyl acetate (500 mL) was added dropwise to the above mixture. After stirring at 25 °C for 40 h, the mixture was filtered and the filter cake was washed with ethyl acetate (400 mL). The filtrate was extracted with ethyl acetate (300 mL × 2). The combined organic layers were washed with water (500 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: ethyl acetate = 5: 1 then 3: 1) to give 1-(tert-butyl) 2-methyl (2S,4R)-4-acetoxy-5-oxopyrrolidine-1,2- dicarboxylate (37.0 g, 123 mmol, 68% yield) as colorless oil. LC-MS (Method C): R _t = 0.512 min; MS (ESIpos): m/z = 324.1 [M+Na] ⁺ , m/z = 246.1 [M-56+H] ⁺ , m/z = 202.2 [M-100+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 5.37 (ABq, J = 10.8Hz, 1H), 4.72 (ABq, J = 9.6, 1H), 3.75 (s, 3H), 2.56-2.46 (m, 1H), 2.43-2.32 (m, 1H), 2.11 (s, 3H), 1.43 (s, 9H). Procedure for preparation of dimethyl (2S,4R)-2-(tert-butoxycarbonylamino)-4-hydroxy- pentanedioate To a solution of 1-(tert-butyl) 2-methyl (2S,4R)-4-acetoxy-5-oxopyrrolidine-1,2-dicarboxylate (31.5 g, 105 mmol, 1.00 eq) in methanol (700 mL) was added sodium bicarbonate (17.6 g, 209 mmol, 2.00 eq) at 25 °C. After stirring at 25 °C for 21 h, the reaction mixture was poured into ice water (600 mL), adjusted pH = 6 with hydrochloric acid aqueous solution (1 M) and extracted with ethyl acetate (500 mL × 3). The combined organic layers were washed with water (800 mL), brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 5: 1 to 3: 1 then 2: 1) to give dimethyl (2S,4R)-2- (tert-butoxycarbonylamino)-4-hydroxy-pentanedioate (25.0 g, 85.8 mmol, 82% yield) as colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.20 (d, J = 8.0 Hz, 1H), 5.59 (d, J = 6.0 Hz, 1H), 4.21-4.08 (m, 2H), 3.63 (s, 6H), 2.13-2.02 (m, 1H), 1.93-1.81 (m, 1H), 1.38 (s, 9H). Procedure for preparation of dimethyl (2S,4S)-2-(tert-butoxycarbonylamino)-4-(2- nitrophenoxy)pentanedioate To a solution of dimethyl (2S,4R)-2-(tert-butoxycarbonylamino)-4-hydroxy-pentanedioate (15.0 g, 51.5 mmol, 1.00 eq), 2-nitrophenol (7.88 g, 56.6 mmol, 1.10 eq) and triphenylphosphine (20.3 g, 77.2 mmol, 1.50 eq) in tetrahydrofuran (200 mL) was added dropwise diisopropylazodicarboxylate (15.6 g, 77.2 mmol, 15.0 mL, 1.50 eq) at 0 °C. After stirring at 25 °C for 16 h, the reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (80 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 3: 1 then 1: 1) to give dimethyl (2S,4S)-2-(tert-butoxycarbonylamino)- 4-(2-nitrophenoxy)pentanedioate (21.0 g, 47.4 mmol, 92% yield, 93% purity) as yellow gum. LC-MS (Method C): R _t = 0.575 min; MS (ESIpos): m/z = 435.2 [M+Na] ⁺ , m/z = 357.2 [M-56+H] ⁺ , m/z = 313.2 [M-Boc+H] ⁺ . SFC de% = 88%. Procedure for preparation of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(2S)-3-oxo-4H-1,4- benzoxazin-2-yl]propanoate To a solution of dimethyl (2S,4S)-2-(tert-butoxycarbonylamino)-4-(2-nitrophenoxy)penta nedioate (21.0 g, 47.4 mmol, 93.0% purity, 1.00 eq) in methanol (300 mL) was added palladium on carbon (2.00 g, 10% purity) at 25 °C. After stirring at 25 °C for 16 h under hydrogen atmosphere (15 psi), the mixture was filtered. The filtrate was concentrated to give a residue and then purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~45% Ethyl acetate/Petroleum ether gradient @ 80 mL/min) to give methyl (2S)-2-(tert-butoxycarbonylamino)-3- [(2S)-3-oxo-4H-1,4-benzoxazin-2-yl]propanoate (16.0 g, 45.7 mmol, 96% yield, 99% purity) as yellow oil. LC-MS (Method C): R _t = 0.846 min; MS (ESIpos): m/z = 373.1 [M+Na] ⁺ , m/z = 251.0 [M-Boc+H] ⁺ . Procedure for preparation of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(2S)-4-methyl-3-oxo- 1,4-benzoxazin-2-yl]propanoate To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(2S)-3-oxo-4H-1,4-benzo xazin-2-yl] propanoate (0.40 g, 1.14 mmol, 1.0 eq) and sodium carbonate (181.5 mg, 1.71 mmol, 1.50 eq) in N,N- dimethylformamide (5.00 mL) was added dropwise methyl iodide (324 mg, 2.28 mmol, 2.00 eq) at 0 °C. After stirring at 25 °C for 16 h, additional methyl iodide (324 mg, 2.28 mmol, 0.142 mL, 2.00 eq) was added. The mixture was stirred at 25 °C for another 24 h. The mixture (combined with EW35622-35- P1) was diluted with water (30.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with water (20.0 mL), brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 20 mL/min) to give methyl (2S)-2- (tert-butoxycarbonylamino)-3- [(2S)-4-methyl-3-oxo-1,4-benzoxazin-2-yl]propanoate (250 mg, 0.690 mmol, 40% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.44 (d, J = 8.0 Hz, 1H), 7.21-7.15 (m, 1H), 7.13-6.97 (m, 3H), 4.56 (ABq, J = 10.2, 2.8 Hz, 1H), 4.34-4.25 (m, 1H), 3.61 (s, 3H), 3.29 (s, 3H), 2.26-2.05 (m, 2H), 1.38 (s, 9H). LC-MS (Method C): R _t = 0.569 min; MS (ESIpos): m/z = 387.2 [M+Na] ⁺ , m/z = 309.2 [M-56+H] ⁺ , m/z = 265.2 [M-Boc+H] ⁺ . Procedure for preparation of tert-butyl N-[(1S)-2-amino-1-[[(2S)-4-methyl-3-oxo-1,4-benzoxazin- 2-yl]methyl]-2-oxo-ethyl]carbamate To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(2S)-4-methyl-3-oxo-1,4 -benzoxazin-2-yl] propanoate (0.230 g, 0.631 mmol, 1.00 eq) in methanol (2.00 mL) was added ammonium (7 M in methanol, 3.00 mL) at 25 °C. After stirring at 25 °C for 40 h, additional ammonium (7 M in methanol, 3.00 mL) was added. The resulting mixture was stirred at the same temperature for another 24 h. The mixture was concentrated to give tert-butyl N-[(1S)-2-amino-1- [[(2S)-4-methyl-3-oxo-1,4-benzoxazin- 2-yl] methyl]-2-oxo-ethyl]carbamate (0.200 g, 0.572 mmol, 91% yield) as a white solid. LC-MS (Method C): R _t = 0.512 min; MS (ESIpos): m/z = 372.2 [M+Na] ⁺ , m/z = 294.2 [M-56+H] ⁺ , m/z = 250.2 [M-Boc+H] ⁺ . Procedure for preparation of (2S)-2-amino-3-[(2S)-4-methyl-3-oxo-1,4-benzoxazin-2- yl]propanamide To a solution of tert-butyl N-[(1S)-2-amino-1-[[(2S)-4-methyl-3-oxo-1,4-benzoxazin-2-yl] methyl] -2-oxo- ethyl]carbamate (0.200 g, 0.572 mmol, 1.00 eq) in dioxane (2.00 mL) was added hydrochloric acid (4 M in dioxane, 4.00 mL) at 25 °C. After stirring at 25 °C for 1 h, the mixture was concentrated to give (2S)-2-amino-3-[(2S)-4-methyl-3-oxo-1,4-benzoxazin-2-yl]prop anamide (0.140 g, 0.562 mmol, 98% yield) as a white solid. LC-MS (Method A): R _t = 0.680 min; MS (ESIpos): m/z = 249.9 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[(1S)-2-amino-1-[[(2S)-4-methyl-3-oxo-1,4- benzoxazin-2-yl]methyl]-2-oxo-ethyl]-3-[(2S)-3,3-dimethyl-2- [(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6- dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (200 mg, 0.549 mmol, 1.00 eq) and N,N- diisopropylethylamine (213 mg, 1.65 mmol, 3.00 eq) in N,N-dimethylformamide (3.00 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (250 mg, 0.659 mmol, 1.20 eq) at 0 °C. After stirring at the same temperature for 10 min, (2S)-2-amino-3-[(2S)-4-methyl-3- oxo-1,4-benzoxazin-2-yl]propanamide (137 mg, 0.549 mmol, 1.0 eq) was added. After stirring at 25 °C for 16 h, the resulting mixture was diluted with water (80.0 mL) and saturated ammonium chloride (20.0 mL) and extracted with dichloromethane (30.0 mL × 3). The combined organic layers were washed with water (50.0 mL), brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~80% Ethyl acetate/Petroleum ether gradient @ 15 mL/min) to give (1R,2S,5S)-N-[(1S)-2-amino-1 -[[(2S)-4-methyl-3-oxo-1,4-benzoxazin-2- yl]methyl]-2-oxo-ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifl uoroacetyl)amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (250 mg, 0.420 mmol, 77% yield) as yellow oil. LC-MS (Method C): R _t = 0.561 min; MS (ESIpos): m/z = 596.2 [M+H] ⁺ . To a solution of (1R,2S,5S)-N-[(1S)-2-amino-1-[[(2S)-4-methyl-3-oxo-1,4-benzo xazin-2-yl]methyl] -2- oxo-ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (250 mg, 0.420 mmol, 1.0 eq) in dichloromethane (3.00 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (130 mg, 0.546 mmol, 1.30 eq) at 0 °C. After stirring at 25 °C for 2 h, additional (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (100 mg, 0.420 mmol, 1.00 eq) was added at 25 °C. After stirring for 16 h, the reaction mixture was diluted with water (50.0 mL), saturated ammonium chloride (10.0 mL) and extracted with dichloromethane (20.0 mL × 3). The combined organic layers were washed with water (30.0 mL), brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 μm; mobile phase: [water(FA)-ACN];B%: 50%-80%,7 min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2- [(2S)-4-methyl-3-oxo- 1,4-benzoxazin-2-yl] ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino] butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0] hexane-2-carboxamide (121 mg, 0.207 mmol, 49% yield, 99% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.36 (d, J = 7.2 Hz, 1H), 9.11 (d, J = 7.2 Hz, 1H), 7.20-7.15 (m, 1H), 7.10 (td, J = 12.8, 1.2 Hz, 1H), 7.03 (td, J = 12.8, 1.2 Hz, 1H), 6.99-6.94 (m, 1H), 5.20-5.11 (m, 1H), 4.56 (ABq, J = 10.4 Hz, 1H), 4.37-4.30 (m, 1H), 4.13 (s, 1H), 3.93-3.84 (m, 1H), 3.67 (d, J = 10.4 Hz, 1H), 3.28 (s, 3H), 2.53-2.58 (m, 1H), 2.33-2.26 (m, 1H), 1.57 (dd, J = 7.6, 5.6 Hz, 1H), 1.34 (d, J = 7.6 Hz, 1H), 1.02 (s, 3H), 0.83 (s, 3H), 0.74 (s, 9H). LC-MS (Method C): R _t = 0.618 min; MS (ESIpos): m/z = 600.2 [M+Na] ⁺ , m/z = 578.2 [M+H] ⁺ . HPLC: R _t = 2.375 min. SFC: de% = 60%. Preparation of CPD0329495 Procedure for preparation of dimethyl (2S)-2-((tert-butoxycarbonyl)amino)-4-((2-chloro-5- nitropyrimidin-4-yl)oxy)pentanedioate To a solution of dimethyl (2S, 4R) - 2 -(tert-butoxycarbonylamino ) -4-hydroxy-pentanedioate (2.00 g, 6.87 mmol, 1.00 eq) and 2, 4-dichloro-5-nitro-pyrimidine (4.00 g, 20.60 mmol, 3.00 eq) in tetrahydrofuran (20.0 mL) was added potassium tert-butyl alcohol (1.00 M, 13.7 mL, 2.00 eq) (in tetrahydrofuran) at 0 °C. The mixture was stirred at 25 °C for 2 hr. The reaction mixture was quenched by water (25.0 mL) at 0 °C, and extracted with ethyl acetate (80.0 mL × 2). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80.00 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ethergradient @ 60 mL/min) to give dimethyl (2S, 4R)-2-(tert-butoxycarbonylamino)-4-(2-chloro-5-nitro- pyrimidin-4-yl)oxy-pentanedioate (2.00 g, 4.06 mmol, 59% yield, 91% purity) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.15-9.12 (m, 1H), 5.74 (dd, J = 9.2, 3.6 Hz, 1H), 5.30 (br. s, 1H), 4.56 (d, J = 4.0 Hz, 1H), 3.83-3.75 (m, 6H), 2.75-2.65 (m, 1H), 2.63-2.54 (m, 1H), 1.47-1.44 (m, 9H). Procedure for preparation of dimethyl (4S)-2-((5-aminopyrimidin-4-yl)oxy)-4-((tert- butoxycarbonyl)amino)pentanedioate To a solution of dimethyl (2S)-2(tert-butoxycarbonyl) amino)-4-((2-chloro-5-nitropyrimidin-4-yl)oxy) pentanedioate (2.00 g, 4.46 mmol, 1.00 eq) in methanol (100 mL) was added palladium on activated carbon (500 mg, 10% purity) (wetted with 55% water) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen for 3 times. The mixture was stirred at 20 °C for 2 hours under hydrogen (15 psi) atmosphere. After stirring for another 16 hours, the reaction mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20.00 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ethergradient @ 50 mL/min) to give dimethyl (4S) -2-(5-aminopyrimidin-4-yl) oxy-4- (tert-butoxycarbonylamino) pentanedioate (800 mg, 1.87 mmol, 54% yield, 90% purity) as a yellow solid. To a solution of dimethyl (4S) - 2 -(5-aminopyrimidin-4-yl) oxy-4-(tert-butoxycarbonylamino) pentanedioate (800 mg, 2.08 mmol, 1.00 eq) in N,N-dimethyl formamide (10.0 mL) was added potassium carbonate (863 mg, 6.24 mmol, 3.00 eq). After stirring at 80 °C for 16 h, the reaction mixture was quenched with water (20.0 mL) at 0 °C, extracted with ethyl acetate (40.0 mL × 2). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12.00 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ethergradient @ 50.00 mL/min) to give methyl (2S) -2-(tert-butoxycarbonylamino) - 3-(6-oxo-5H-pyrimido[4, 5-b][1, 4]oxazin-7-yl) propanoate (300 mg, 766 μmol, 37% yield, 90% purity) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.49-8.38 (m, 1H), 8.14-8.10 (m, 1H), 5.31-5.21 (m, 1H), 5.05-5.02 (m, 1H), 4.60-4.57 (m, 1H), 3.75-3.65 (m, 3H), 2.67-2.44 (m, 2H), 1.39-1.26 (m, 9H). LC-MS (Method A): Rt = 0.599 min; MS (ESIpos): m/z = 353.2 [M+H] ⁺ . Procedure for preparation of tert-butyl ((2S)-1-amino-1-oxo-3-(6-oxo-6,7-dihydro-5H- pyrimido[4,5-b][1,4]oxazin-7-yl)propan-2-yl)carbamate To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(6-oxo-5H-pyrimido[4,5-b ][1,4]oxazin-7-yl) propanoate (300 mg, 851 μmol, 1.00 eq) in methanol (1.00 mL) was added ammonia (7.00 M in methanol, 3.65 mL, 30.0 eq). After stirring at 20 °C for 18 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12.00 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ethergradient @ 50.00 mL/min) to give tert-butyl N-[(1S)-2-amino-2-oxo-1-[(6-oxo-5H-pyrimido[4,5- b][1,4]oxazin-7-yl) methyl]ethyl]carbamate (170.00 mg, 453.56 μmol, 53.27% yield, 90% purity) as a white solid. LC-MS (Method A): Rt = 0.466 min; MS (ESIpos): m/z = 338.3 [M+H] ⁺ . Procedure for preparation of (2S)-2-amino-3-(6-oxo-6,7-dihydro-5H-pyrimido[4,5-b][1,4]oxa zin-7- yl)propanamide To a solution of tert-butyl N-[(1S)-2-amino-2-oxo-1-[(6-oxo-5H-pyrimido[4,5-b][1,4]oxazi n-7-yl) methyl]ethyl]carbamate (170 mg, 504 μmol, 1.00 eq) in dioxane (1.00 mL) was added hydrogen chloride in dioxane (4.00 M, 630 μL, 5.00 eq). After stirring at 25 °C for 1 h, the reaction mixture was concentrated under reduced pressure to give (2S)-2-amino-3-(6-oxo-5H-pyrimido[4,5-b][1,4]oxazin-7- yl)propanamide (130 mg, crude, HCl) as a white solid. LC-MS (Method B): Rt = 0.200 min; MS (ESIpos): m/z = 238.6 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-((2S)-1-amino-1-oxo-3-(6-oxo-6,7-dihydro-5H- pyrimido[4,5-b][1,4]oxazin-7-yl)propan-2-yl)-3-((S)-3,3-dime thyl-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxamide A mixture of (2S)-2-amino-3-(6-oxo-5H-pyrimido[4,5-b][1,4]oxazin-7-yl)pro panamide (130 mg, 475 μmol, 1.00 eq, hydrochloride), (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxylic acid (164 mg, 451 μmol, 0.95 eq), diisopropylethylamine (307 mg, 2.38 mmol, 414 μL, 5.00 eq), and 2-(7-azabenzotriazol- 1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (271 mg, 713 μmol, 1.50 eq) in dimethyl formamide (1.00 mL) was degassed and purged with nitrogen for 3 times. After stirring at 25 °C for 16 h under nitrogen atmosphere, the reaction mixture was quenched with water (20.0 mL) at 0 °C, extracted with ethyl acetate (40.0 mL × 2). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12.00 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ethergradient @ 50.00 mL/min) to give (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[(6-oxo-5H-pyrimido[4,5-b ][1,4]oxazin-7-yl) methyl]ethyl]-3-[(2S)- 3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-d imethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (150 mg, 211 μmol, 44% yield, 82% purity) as a white solid. LC-MS (Method B): Rt = 0.640 min; MS (ESIpos): m/z = 584.3 [M+H] ⁺ . Procedure for preparation of CPD0329495 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(7S)-6-oxo-5H- pyrimido[4,5-b][1,4]oxazin-7-yl]ethyl]-3-[(2S)-3,3-dimethyl- 2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[(6-oxo-5H-pyrimido[4,5-b ][1,4]oxazin-7- yl)methyl] ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino] butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0] hexane-2-carboxamide (0.11 g, 189 μmol, 1.00 eq) in dichloromethane (5.00 mL) was added dropwise a solution of burgess reagent (67.4 mg, 283 μmol, 1.50 eq) in dichloromethane (1.00 mL).at 0 °C. After stirring at 20 °C for 6 h, the mixture was added dropwise into saturated sodium bicarbonate solution (100 mL) at 0 °C. The mixture was extracted with dichloromethane (50.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by prep-TLC (petroleum ether: ethyl acetate = 1: 3) to give a residue. The residue was further purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10 μm; mobile phase: [water(FA)-ACN];B%: 40%-60%,10 min) to give (1R,2S,5S)-N-[(1S)- 1-cyano-2-[(7S)-6-oxo-5H-pyrimido[4,5-b][1,4]oxazin-7-yl]eth yl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (15.6 mg, 27.3 μmol, 14% yield, 99% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.23-11.06 (m, 1H), 9.37 (s, 1H), 9.12-9.06 (m, 1H), 8.44 (s, 1H), 8.14 (s, 1H), 5.16-5.00 (m, 2H), 4.41-4.35 (m 1H), 4.30-4.13 (m, 1H).3.92-3.88 (m 1H), 3.68-3.65 (m, 1H).2.71-2.57 (m 2H), 1.61-1.55 (m, 1H).1.39-1.36 (m 1H), 1.05-0.81 (m, 15H). LC-MS (Method C): R _t = 0.528 min; MS (ESIpos): m/z = 566.2 [M+H] ⁺ . HPLC (Method K): R _t = 2.000 min. Preparation of CPD0279114 Procedure for preparation of dimethyl (2S,4R)-2-(tert-butoxycarbonylamino)-4-[(3-nitro-4- pyridyl)oxy]pentanedioate To a solution of dimethyl (2S,4R)-2-(tert-butoxycarbonylamino)-4-hydroxy-pentanedioate (2.20 g, 7.55 mmol, 1.00 eq) and 4-chloro-3-nitro-pyridine (1.56 g, 9.82 mmol, 1.30 eq) in dimethyl formamide (50.0 mL) was added potassium carbonate (1.57 g, 11.3 mmol, 1.50 eq). The mixture was stirred at 80 °C for 2 h, diluted with saturated ammonium chloride (50.0 mL) and extracted with ethyl acetate (50.0 mL × 3), and washed with brine (50.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ethergradient @60 mL/min) to give dimethyl (2S,4R)-2-(tert- butoxycarbonylamino)-4-[(3-nitro-4-pyridyl)oxy]pentanedioate (1.57 g, 3.60 mmol, 48% yield, 95% purity) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.03 (s, 1H), 8.68-8.50 (m, 1H), 6.96-6.74 (m, 1H), 5.53-5.31 (m, 1H), 5.16-4.94 (m, 1H), 4.67-4.44 (m, 1H), 3.80 (s, 3H), 3.70 (s, 3H), 2.78-2.44 (m, 2H), 1.30 (s, 9H). LC-MS (Method A): Rt = 0.844 min; MS (ESIpos): m/z =414.1 [M+H] ⁺ . Procedure for preparation of dimethyl (2R,4S)-2-[(3-amino-4-pyridyl)oxy]-4-(tert- butoxycarbonylamino)pentanedioate To a solution of dimethyl (2S,4R)-2-(tert-butoxycarbonylamino)-4-[(3-nitro-4-pyridyl)o xy]pentanedioate (1.40 g, 3.39 mmol, 1.00 eq) in methanol (20.0 mL) was added Pd/C (355 mg, 0.339 mmol, 10% purity, 0.10 eq.) at 25 °C under nitrogen atmosphere. The suspension was degassed and purged with hydrogen for 3 times and stirred at 25 °C for 2 h. The reaction mixture was filtrated through a pad of celite and concentrated under reduced pressure to afford dimethyl (2R,4S)-2-[(3-amino-4-pyridyl)oxy]- 4-(tert-butoxycarbonylamino)pentanedioate (1.3 g, crude) as yellow oil. LC-MS (Method A): Rt = 0.693 min; MS (ESIpos): m/z = 384.1 [M+H] ⁺ . Procedure for preparation of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(2R)-3-oxo-4H- pyrido[4,3-b][1,4]oxazin-2-yl]propanoate To a solution of dimethyl (2R,4S)-2-[(3-amino-4-pyridyl)oxy]-4-(tert- butoxycarbonylamino)pentanedioate (1.30 g, 3.39 mmol, 1.00 eq) in dimethyl formamide (20.0 mL) was added potassium carbonate (937 mg, 6.78 mmol, 2.00 eq). After stirring at 80 °C for 16 h, the reaction mixture was quenched with saturated ammonium chloride (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a residue. The residue was purified by flash silica gel chromatography (20 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ethergradient @ 60 mL/min) to give methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(2R)-3-oxo-4H-pyrido[4, 3-b][1,4]oxazin-2- yl]propanoate (400 mg, 1.14 mmol, 33% yield) as yellow oil. Procedure for preparation of tert-butyl N-[(1S)-2-amino-2-oxo-1-[[(2R)-3-oxo-4H-pyrido[4,3- b][1,4]oxazin-2-yl]methyl]ethyl]carbamate To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(2R)-3-oxo-4H-pyrido[4, 3-b][1,4]oxazin-2- yl]propanoate (400 mg, 1.14 mmol, 1.00 eq) in methanol (15.0 mL) was added ammonia (7M in methanol, 4.07 mL, 25 eq). After stirring at 25 °C for 16 h, ammonia (10M in methanol, 20 mL, 175 eq) was added. The mixture was stirred at 25 °C for 16 h, and concentrated under reduced pressure to give tert-butyl N-[(1S)-2-amino-2-oxo-1-[[(2R)-3-oxo-4H-pyrido[4,3-b][1,4]ox azin-2- yl]methyl]ethyl]carbamate (333 mg, 0.970 mmol, 85% yield, 98% purity) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.12-8.01 (m, 2H), 7.13-6.94 (m, 1H), 4.48-4.34 (m, 1H), 2.55-2.13 (m, 2H), 1.44-1.41 (m, 9H). LC-MS (Method B): Rt = 0.415 min, 0.611 min; MS (ESIpos): m/z =337.1 [M+H] ⁺ . Procedure for preparation of (2S)-2-amino-3-[(2R)-3-oxo-4H-pyrido[4,3-b][1,4]oxazin-2- yl]propanamide To a solution of tert-butyl N-[(1S)-2-amino-2-oxo-1-[[(2R)-3-oxo-4H-pyrido[4,3-b][1,4]ox azin-2- yl]methyl]ethyl]carbamate (120 mg, 0.357 mmol, 1.00 eq) in dioxane (8.00 mL) was added hydrochloric acid /dioxane (4 M, 0.356 mL, 1.00 eq). After stirring at 25 °C for 1 h, the reaction mixture was concentrated under reduced pressure to give (2S)-2-amino-3-[(2R)-3-oxo-4H-pyrido[4,3-b][1,4]oxazin- 2-yl]propanamide (95.0 mg, 0.341 mmol, 96% yield, 98% purity, hydrochloric acid) as a white solid. LC-MS (Method C): Rt = 0.111 min; MS (ESIpos): m/z =237.1 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(2R)-3-oxo-4H-pyrido[4, 3- b][1,4]oxazin-2-yl]methyl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2, 2,2-trifluoroacetyl)amino]butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (2S)-2-amino-3-[(2R)-3-oxo-4H-pyrido[4,3-b][1,4]oxazin-2-yl] propanamide (95.0 mg, 0.402 mmol, 1.00 eq) and (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (146 mg, 0.402 mmol, 1.00 eq) in dimethyl formamide (2.00 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (229 mg, 0.603 mmol, 1.50 eq) and diisopropylethylamine (259 mg, 2.01 mmol, 0.350 mL, 5.00 eq). The mixture was stirred at 25 °C for 16 h, diluted with saturated ammonium chloride solution and extracted with ethyl acetate (4.00 mL × 3). The combined organic layers were washed with brine (4.00 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, Eluent of 0~10% Methanol/Ethyl acetate @ 60 mL/min) to give (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(2R)-3-oxo-4H-pyrido[4, 3-b][1,4]oxazin-2-yl]methyl]ethyl]-3- [(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl] -6,6-dimethyl-3-azabicyclo [3.1.0]hexane-2- carboxamide (222 mg, 381 umol, 95% yield) as a yellow solid. LC-MS (Method C): Rt = 0.835 min; MS (ESIpos): m/z =583.3 [M+H] ⁺ . Procedure for preparation of Compound CPD279114 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-3-oxo- 4H-pyrido[4,3-b][1,4]oxazin-2-yl]ethyl]-3-[(2S)-3,3-dimethyl -2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide A mixture of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(2R)-3-oxo-4H-pyrido[4, 3-b][1,4]oxazin-2- yl]methyl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroace tyl)amino]butanoyl]-6,6-dimethyl-3- azabicyclo [3.1.0]hexane-2-carboxamide (220 mg, 0.377 mmol, 1.00 eq) and burgess reagent (178 mg, 0.755 mmol, 2.00 eq) in dichloromethane (4.00 mL) was stirred at 25 ^ for 16 h. The reaction mixture was diluted with saturated ammonium chloride (12.0 mL) and extracted with of ethyl acetate (4.00 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25 mm* 10 μm; mobile phase: [water(FA)-ACN];B%: 22%-52%,10min) to afford (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-3-oxo-4H-pyrido[4,3-b][1, 4]oxazin-2-yl]ethyl]-3-[(2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (16.6 mg, 29.4 μmol, 9% yield, 100% purity) as a white solid. LC-MS (Method B): Rt = 2.273 min; MS (ESIpos): m/z =565.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.05 (br. s, 1H), 9.47-9.30 (m, 1H), 9.18-8.98 (m, 1H), 8.18-8.05 (m, 2H), 7.11-6.88 (m, 1H), 5.21-4.67 (m, 2H), 4.48-4.31 (m, 1H), 4.24-4.10 (m, 1H), 3.95-3.84 (m, 1H), 3.74-3.64 (m, 1H), 2.43-2.36 (m, 1H), 2.33-2.18 (m, 1H), 1.62-1.48 (m, 1H), 1.40-1.28 (m, 1H), 1.03- 0.93 (m, 9H), 0.91-0.71 (m, 6H). Preparation of CPD0220119 Procedure for preparation of 7-hydroxyimidazo[1,2-a]pyrimidin-5(1H)-one A mixture of 1H-imidazol-2-amine (5.00 g, 18.9 mmol, 1.00 eq, 1/2 sulfuric acid salt), dimethyl propanedioate (5.00 g, 37.8 mmol, 2.00 eq) and sodium methoxide (17.0 g, 94.6 mmol, 5.00 eq, 30% purity in methanol) in methanol (50.0 mL) was stirred at 75 °C for 16 h. After concentration, the residue was suspended into ethyl acetate (100 mL) and stirred at 15 °C for 0.5 h. After filtration, the filter cake was dried to give 7-hydroxyimidazo[1,2-a]pyrimidin-5(1H)-one (10.0 g, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.01 (d, J = 1.6 Hz, 1H), 6.63 (d, J = 1.6 Hz, 1H), 4.02 (s, 1H). Procedure for preparation of 5,7-dichloroimidazo[1,2-a]pyrimidine A mixture of 7-hydroxyimidazo[1,2-a]pyrimidin-5(1H)-one (9.00 g, 59.5 mmol, 1.00 eq) and phosphorus oxychloride (29.7 g, 194 mmol, 3.25 eq) was heated to 90 °C and stirred at this temperature for 3 h. The mixture was concentrated to remove phosphorus oxychloride to give a residue. The residue was diluted with ethyl acetate (100 mL) and water (100 mL), adjusted to pH = 7~8 with sodium bicarbonate solid and extracted with ethyl acetate (100 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 5,7-dichloroimidazo[1,2-a]pyrimidine (2.60 g, 13.8 mmol, 23% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.14 (d, J = 1.6 Hz, 1H), 7.95 (d, J = 1.6 Hz, 1H), 7.80 (s, 1H). Procedure for preparation of 7-chloroimidazo[1,2-a]pyrimidin-5(1H)-one A mixture of 5,7-dichloroimidazo[1,2-a]pyrimidine (2.60 g, 13.8 mmol, 1.00 eq) and sodium hydroxide (1 M in water, 41.5 mL, 3.00 eq) was stirred at100 °C for 0.5 h. Hydrochloric acid (1 M in water) was added to the mixture to adjust pH to 1~2 and extracted with ethyl acetate (100 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 7- chloroimidazo[1,2-a]pyrimidin-5(1H)-one 7 (600 mg, 3.54 mmol, 26% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 13.14 (s, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 5.91 (s, 1H). Procedure for preparation of 7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,2- a]pyrimidin-5(1H)-one To a mixture of 7-chloroimidazo[1,2-a]pyrimidin-5(1H)-one (540 mg, 3.18 mmol, 1.00 eq) and potassium carbonate (880 mg, 6.37 mmol, 2.00 eq) in N,N-dimethylformamide (10.0 mL) was added 2- (chloromethoxy)ethyl-trimethyl-silane (637 mg, 3.82 mmol, 1.20 eq) dropwise at 0 °C. After stirring at 25 °C for 2 h, the mixture was poured into water (50.0 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~27% Ethyl acetate/Petroleum ether gradient @ 45 mL/min) to give 7- chloro-1-((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,2-a]pyr imidin-5(1H)-one (750 mg, 2.50 mmol, 79% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.79 (d, J = 2.8 Hz, 1H), 7.74 (d, J = 2.8 Hz, 1H), 6.03 (s, 1H), 5.45 (s, 2H), 3.60 (t, J = 8.0 Hz, 2H), 0.875 (d, J = 8.0 Hz, 2H), -0.05 (s, 9H). Procedure for preparation of methyl 2-((diphenylmethylene)amino)-2-(5-oxo-1-((2- (trimethylsilyl)ethoxy)methyl)-1,5-dihydroimidazo[1,2-a]pyri midin-7-yl)acetate To a mixture of 7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,2-a]p yrimidin-5(1H)-one (700 mg, 2.33 mmol, 1.00 eq) and methyl 2-((diphenylmethylene)amino)acetate (710 mg, 2.80 mmol, 1.20 eq) in N,N-dimethylformamide (10.0 mL) were added potassium phosphate (1.49 g, 7.00 mmol, 3.00 eq) and [2-(2-aminophenyl)phenyl]-chloro-palladium;tritert-butylphos phane (59.8 mg, 0.117 mmol, 0.05 eq) at 15 °C. After stirring at 90 °C for 16 h under nitrogen atmosphere, the mixture was poured into water (50.0 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 60 mL/min) to give methyl 2-((diphenylmethylene)amino)-2-(5-oxo- 1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydroimidazo[1,2- a]pyrimidin-7-yl)acetate (650 mg, 1.26 mmol, 54% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.76-7.72 (m, 1H), 7.71-7.68 (m, 1H), 7.64-7.60 (m, 2H), 7.57-7.41(m, 6H), 7.24-7.14 (m, 2H), 6.11 (s, 1H), 5.39 (s, 2H), 5.00 (s, 1H), 3.63 (s, 3H), 3.58-3.51 (m, 2H), 0.85- 0.78 (m, 2H), -0.12 (s, 9H). Procedure for preparation of 2-((diphenylmethylene)amino)-2-(5-oxo-1-((2- (trimethylsilyl)ethoxy)methyl)-1,5-dihydroimidazo[1,2-a]pyri midin-7-yl)acetamide A mixture of methyl 2-((diphenylmethylene)amino)-2-(5-oxo-1-((2-(trimethylsilyl) ethoxy)methyl)-1,5- dihydroimidazo[1,2-a]pyrimidin-7-yl)acetate (650 mg, 1.26 mmol, 1.00 eq) in ammonia (7 M in methanol, 30 mL, 167 eq) was stirred at 15 °C for 16 h. The mixture was concentrated to give 2- ((diphenylmethylene) amino)-2-(5-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dih ydroimidazo[1,2- a]pyrimidin-7-yl)acetamide (600 mg, 1.20 mmol, crude) as yellow oil. Procedure for preparation of 2-amino-2-(5-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5- dihydroimidazo[1,2-a]pyrimidin-7-yl)acetamide A mixture of 2-((diphenylmethylene)amino)-2-(5-oxo-1-((2-(trimethylsilyl) ethoxy)methyl)-1,5- dihydroimidazo[1,2-a]pyrimidin-7-yl)acetamide (600 mg, 1.20 mmol, crude) in hydrochloric acid (1M in water, 5 mL, 4.18 eq) was stirred at 20 °C for 1 h. The mixture was washed with ethyl acetate (10.0 mL). The separated aqueous phase was adjusted to pH = 7~8 with saturated sodium bicarbonate solution and extracted with ethyl acetate (20.0 mL × 4). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 2-amino-2-(5-oxo-1-((2- (trimethylsilyl)ethoxy)methyl)-1,5-dihydroimidazo[1,2-a]pyri midin-7-yl)acetamide (350 mg, crude) as yellow oil. To a mixture of (1R,2S,5S)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)b utanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (291 mg, 0.800 mmol) and 2-amino-2-(5-oxo-1-((2- (trimethylsilyl)ethoxy)methyl)-1,5-dihydroimidazo[1,2-a]pyri midin-7-yl)acetamide (300 mg, crude) in N,N-dimethylformamide (10.0 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (507 mg, 1.33 mmol, 1.50 eq) and N,N-diisopropylethylamine (460 mg, 3.56 mmol, 4.00 eq) at 15 °C. After stirring at 15 °C for 16 h, the mixture was poured into water (50.0 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-(5-oxo-1-((2- (trimethylsilyl)ethoxy)methyl)-1,5-dihydroimidazo[1,2-a]pyri midin-7-yl)ethyl)-3-((S)-3,3-dimethyl-2- (2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicycl o[3.1.0]hexane-2-carboxamide (350 mg, 0.491 mmol, 55% yield, 96% purity) as a white solid. LC-MS (Method C): R _t = 0.615 min; MS (ESIpos): m/z = 684.3 [M+H] ⁺ . To a mixture of (1R,2S,5S)-N-(2-amino-2-oxo-1-(5-oxo-1-((2-(trimethylsilyl)e thoxy)methyl)-1,5- dihydroimidazo[1,2-a]pyrimidin-7-yl)ethyl)-3-((S)-3,3-dimeth yl-2-(2,2,2-trifluoroacetamido)butanoyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (330 mg, 0.483 mmol, 1.00 eq) in dichloromethane (10.0 mL) was added trifluoroacetic acid (5.00 mL) at 15 °C. After stirring at 15 °C for 16 h, the mixture was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~100% (Ethyl acetate ^ methanol=10:1)/Petroleum ether gradient @ 30 mL/min) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-(5- oxo-1,5-dihydroimidazo[1,2-a]pyrimidin-7-yl)ethyl)-3-((S)-3, 3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ] hexane-2-carboxamide (300 mg) as yellow oil. LC-MS (Method C): R _t = 0.500 min; MS (ESIpos): m/z = 554.3 Procedure for preparation of CPD0220199 - (1R,2S,5S)-N-(cyano(5-oxo-1,5-dihydroimidazo[1,2- a]pyrimidin-7-yl)methyl)-3-((S)-3,3-dimethyl-2-(2,2,2-triflu oroacetamido)butanoyl)-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of (1R,2S,5S)-N-(2-amino-2-oxo-1-(5-oxo-1,5-dihydroimidazo[1,2- a]pyrimidin-7-yl)ethyl)- 3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (200 mg, 0.361 mmol, 1.00 eq) and trimethylamine (219 mg, 2.17 mmol, 6.00 eq) in dichloromethane (10.0 mL) was added trifluoroacetic anhydride (379 mg, 1.81 mmol, 5.00 eq) at 25 °C. After stirring at 25 °C for 2 h, the mixture was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) and prep-HPLC(column: UniSil 3-100 C18 UItra (150*25mm*3μm); mobile phase: [water(FA)-ACN]; B%: 39%-59%, 7 min) to give (1R,2S,5S)-N- (cyano(5-oxo-1,5-dihydroimidazo[1,2-a]pyrimidin-7-yl)methyl) -3-((S)-3,3-dimethyl-2-(2,2,2- trifluoroacetamido) butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxami de (16.7 mg, 30.6 μmol, 8% yield, 98% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 13.11 (s, 1H), 9.57-9.35 (m, 2H), 7.72-7.55 (m, 2H), 6.08-5.92 (m, 2H), 4.45-4.39 (m, 1H), 4.29-4.38 (m, 1H), 3.98-3.62 (m, 2H), 1.63-1.53 (m, 1H), 1.41-1.21 (m, 1H), 1.08-0.79 (m, 15H). LC-MS (Method C): R _t = 0.793 min; MS (ESIpos): m/z = 536.3 [M+H] ⁺ . HPLC (Method K): R _t = 1.833 min; purity: 98%. Preparation of CPD0220200 Procedure for preparation of 7-hydroxythiazolo[3,2-a]pyrimidin-5-one A mixture of thiazol-2-amine (10.0 g, 99.9 mmol, 1.00 eq) and bis(2,4,6-trichlorophenyl) propanedioate (46.2 g, 99.9 mmol, 1.00 eq) in tetrahydrofuran (50.0 mL) was stirred at 50 °C for 12 h. After filtration, the filter cake was washed with ethyl acetate (100 mL × 2) and dried under vacuum to give 7- hydroxythiazolo[3,2-a]pyrimidin-5-one (12.0 g, 71.4 mmol, 72% yield) as a gray solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.65 (s, 1H), 7.92 (d, J = 4.8 Hz, 1H), 7.40 (d, J = 4.8 Hz, 1H), 5.30 (s, 1H). LC-MS (Method C): R _t = 0.855 min; MS (ESIpos): m/z = 169.2 [M+H] ⁺ . Procedure for preparation of 7-chlorothiazolo[3,2-a]pyrimidin-5-one A mixture of 7-hydroxythiazolo[3,2-a]pyrimidin-5-one (12.0 g, 71.4 mmol, 1.00 eq) in phosphorus oxychloride (80.0 mL) was stirred at 100 °C for 12 h. After concentration, the residue was diluted with ethyl acetate (200 mL), adjusted to pH = 7 with ice saturated sodium bicarbonate solution and extracted with ethyl acetate (500 mL × 3). The combined organic layers were washed with brine (200 mL) and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 4: 1 to 2: 1) to give 7-chlorothiazolo[3,2-a]pyrimidin-5-one (8.80 g, 44.8 mmol, 63% yield, 95% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.09 (d, J = 4.0 Hz, 1H), 7.65 (d, J = 4.0 Hz, 1H), 6.43 (s, 1H). LC-MS (Method C): R _t = 0.407 min; MS (ESIpos): m/z = 187.0 [M+H] ⁺ . Procedure for preparation of methyl 2-(benzhydrylideneamino)-2-(5-oxothiazolo[3,2- a]pyrimidin-7-yl)acetate A mixture of 7-chlorothiazolo[3,2-a]pyrimidin-5-one (5.65 g, 30.3 mmol, 1.00 eq), methyl 2- (benzhydrylideneamino)acetate (7.67 g, 30.3 mmol, 1.00 eq) and cesium carbonate (14.8 g, 45.4 mmol, 1.50 eq) in N,N-dimethylacetamide (40.0 mL) was stirred at 90 °C for 12 h. After cooling to 20 °C, the reaction mixture poured into saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate (150 mL × 4). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 5: 1 to 3: 1) to give methyl 2-(benzhydrylideneamino)-2-(5-oxothiazolo[3,2-a]pyrimidin-7- yl)acetate (4.00 g, 8.92 mmol, 29 % yield, 90% purity) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.07 (d, J = 4.8 Hz, 1H), 7.67-7.51 (m, 7H), 7.48-7.43 (m, 2H), 7.22- 7.17 (m, 2H), 6.41(s, 1H), 5.00 (s, 1H), 3.64 (s, 3H). LC-MS (Method P): R _t = 0.578 min; MS (ESIpos): m/z = 404.1 [M+H] ⁺ . Procedure for preparation of 2-(benzhydrylideneamino)-2-(5-oxothiazolo[3,2-a]pyrimidin-7- yl)acetamide A mixture of methyl 2-(benzhydrylideneamino)-2-(5-oxothiazolo[3,2-a]pyrimidin-7- yl)acetate (4.00 g, 9.91 mmol, 1.00 eq) in ammonia (10M in methanol, 40 mL) was stirred at 40 °C for 12 h in a sealed tube. After cooling to 20 °C, the mixture was concentrated to give a residue. The residue was triturated with mixed solvent of methyl tert-butyl ether and ethyl acetate (v/v = 1/1, 20.0 mL) and filtered. The filter cake was collected and dried to give 2-(benzhydrylideneamino)-2-(5-oxothiazolo[3,2-a]pyrimidin-7- yl)acetamide (2.50 g, 4.51 mmol, 45% yield, 70% purity) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.07-8.01 (m, 1H), 7.58-7.41 (m, 10H), 7.19-7.13 (m, 2H), 6.33 (s, 1H), 4.69 (s, 1H). LC-MS (Method P): R _t = 0.505 min; MS (ESIpos): m/z = 389.1 [M+H] ⁺ . Procedure for preparation of 2-amino-2-(5-oxothiazolo[3,2-a]pyrimidin-7-yl)acetamide A mixture of 2-(benzhydrylideneamino)-2-(5-oxothiazolo[3,2-a]pyrimidin-7- yl)acetamide (1.00 g, 2.57 mmol, 1.00 eq) in a mixed solvent of hydrochloric acid (4 M in water, 40.0 mL) and tetrahydrofuran (10.0 mL) was stirred at 25 °C for 0.5 h .The mixture was diluted with water (10.0 mL) and washed with ethyl acetate (10.0 mL × 2). The aqueous phase was concentrated under reduced pressure to give a 2- amino-2-(5-oxothiazolo[3,2-a]pyrimidin-7-yl)acetamide (750 mg, crude, 2 hydrochloric acid) as a brown solid. LC-MS (Method P): R _t = 0.630 min; MS (ESIpos): m/z = 224.9 [M+H] ⁺ . To a mixture of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (920 mg, 2.52 mmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (1.25 g, 3.28 mmol, 1.30 eq) and N,N- diisopropylethylamine (1.63 g, 12.6 mmol, 5.00 eq) in N,N-dimethylformamide (3.00 mL) was added 2- amino-2-(5-oxothiazolo[3,2-a]pyrimidin-7-yl)acetamide (750 mg, 2.52 mmol, 1.00 eq, 2 hydrochloric acid). After stirring at 20 °C for 2 h, the mixture was poured into saturated ammonium chloride (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 3: 1 to 1: 1) to give (1R,2S,5S)-N-[2-amino-2-oxo-1-(5-oxothiazolo[3,2-a]pyrimidin -7-yl)ethyl]-3-[(2S)-3,3-dimethyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabi cyclo[3.1.0]hexane-2-carboxamide (500 mg, 798 μmol, 32% yield, 91% purity) as a brown solid. LC-MS (Method P): R _t = 0.512 min; MS (ESIpos): m/z = 571.2 [M+H] ⁺ . To a solution of (1R,2S,5S)-N-[2-amino-2-oxo-1-(5-oxothiazolo[3,2-a]pyrimidin -7-yl)ethyl]-3-[(2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (450 mg, 749 μmol, 95% purity, 1.00 eq) in dichloromethane (5.00 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (268 mg, 1.12 mmol, 1.50 eq). After stirring at 25 °C for 2 h, the mixture was poured into saturated sodium bicarbonate solution (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: [water(FA)-ACN]; B%: 41%-71%, 7 min) to give (1R,2S,5S)-N-[cyano-(5-oxothiazolo[3,2- a]pyrimidin-7-yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trif luoroacetyl)amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (252 mg, 447 μmol, 60% yield, 98% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.67-9.49 (m, 1H), 9.48-9.40 (m, 1H), 8.12-8.07 (m, 1H), 7.64 (d, J = 4.8 Hz, 1H), 6.40-6.30 (m, 1H), 6.18-6.07 (m, 1H), 4.43-4.39 (m, 1H), 4.37-4.34 (m, 1H), 3.96-3.85 (m, 1H), 3.77-3.67 (m, 1H), 1.63-1.52 (m, 1H), 1.42-1.31 (m, 1H), 1.09-0.93 (m, 12H), 0.90-0.83 (m, 3H). LC-MS (Method P): R _t = 0.571 min; MS (ESIpos): m/z = 533.2 [M+H] ⁺ . HPLC (Method S): R _t = 1.991&2.014 min. SFC: dr: 54: 46. Preparation of CPD0220203 Procedure for preparation of 2-hydroxy-9-methoxy-pyrido[1, 2-a]pyrimidin-4-one A solution of 3-methoxypyridin-2-amine (8.00 g, 64.4 mmol, 1.00 eq) and bis(2,4,6-trichlorophenyl) propanedioate (29.8 g, 64.4 mmol, 1.00 eq) in acetone (200 mL) was stirred at 20 °C. After stirring for 0.5 h, triethylamine (13.0 g, 129 mmol, 17.9 mL, 2.00 eq) was added. After stirring at 20 °C for 11.5 h, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a 2- hydroxy-9-methoxy-pyrido[1, 2-a]pyrimidin-4-one (7.50 g, crude) as a white solid. LCMS (Method A): R _t = 0.681 min; MS (ESIpos): m/z =193.1 [M+H] ⁺ . Procedure for preparation of 2-chloro-9-methoxy-pyrido[1, 2-a]pyrimidin-4-one A solution of 2-hydroxy-9-methoxy-pyrido[1, 2-a]pyrimidin-4-one (7.50 g, 39.0 mmol, 1.00 eq) and phosphorus oxychloride (124 g, 807 mmol, 75.0 mL, 20.7 eq) was stirred at 110 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 0 to 0: 1) to give 2-chloro- 9-methoxy-pyrido[1, 2-a]pyrimidin-4-one (4.89 g, 23.2 mmol, 59% yield) as a white solid. LCMS (Method B): R _t = 1.425 min; MS (ESIpos): m/z =211.0 [M+H] ⁺ . To a solution of 2-chloro-9-methoxy-pyrido[1,2-a]pyrimidin-4-one (4.69 g, 22.3 mmol, 1.00 eq) and methyl 2-(benzhydrylideneamino) acetate (6.20 g, 24.5 mmol, 1.10 eq) in N,N-dimethylformamide (100 mL) was added cesium carbonate (21.8 g, 66.8 mmol, 3.00 eq). After stirring at 100 °C for 12 h, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (300 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with methyl tert-butyl ether at 20 ^o C for 30 min, followed by filtration to give methyl 2- (benzhydrylideneamino)-2-(9-methoxy-4-oxo-pyrido[1,2-a]pyrim idin-2-yl) acetate (2.80 g, 6.55 mmol, 29% yield) as a yellow solid. LCMS (Method C): R _t = 3.082 min; MS (ESIpos): m/z = 428.1 Procedure for preparation of 2-(benzhydrylideneamino)-2-(9-methoxy-4-oxo-pyrido[1,2- a]pyrimidin-2-yl)acetamide To a solution of methyl 2-(benzhydrylideneamino)-2-(9-methoxy-4-oxo-pyrido[1,2-a]pyr imidin-2- yl)acetate (2.60 g, 6.08 mmol, 1.00 eq) in tetrahydrofuran (20.0 mL) was added ammoniumhydroxide (18.2 g, 130 mmol, 20.0 mL, 25% purity, 21.3 eq). After stirring at 20 °C for 12 h, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 2- (benzhydrylideneamino)-2-(9-methoxy-4-oxo-pyrido[1,2-a]pyrim idin-2-yl)acetamide (2.20 g, 5.33 mmol, 88% yield) as a yellow solid. LCMS (Method F): R _t = 2.702 min; MS (ESIpos): m/z = 413.3 [M+H] ⁺ . Procedure for preparation of 2-amino-2-(9-methoxy-4-oxo-pyrido[1, 2-a]pyrimidin-2-yl) acetamide To a solution of 2-(benzhydrylideneamino)-2-(9-methoxy-4-oxo-pyrido[1,2-a]pyr imidin-2-yl)acetamide (2.20 g, 5.33 mmol, 1.00 eq) in mixed solvent of dichloromethane (5.00 mL) and methyl alcohol (5.00 mL) was added hydrochloric acid (1M, 10.0 mL, 1.87 eq). After stirring at 20 °C for 1 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (instrument: 90g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.1% NH ₃ ^H ₂ O), eluent B: acetonitrile; gradient: 0-50min 0-100% B; flow 50 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give 2-amino-2-(9-methoxy-4-oxo-pyrido[1,2- a]pyrimidin-2-yl) acetamide (830 mg, 2.92 mmol, 55% yield, hydrochloride) as a yellow solid. LCMS (Method B): R _t = 0.889 min; MS (ESIpos): m/z = 249.1 [M+H] ⁺ . Procedure for preparation of (1R, 2S, 5S) -N-[2-amino-1-(9-methoxy-4-oxo-pyrido[1, 2- a]pyrimidin-2-yl) -2-oxo-ethyl]-3-[ (2S) -3, 3-dimethyl-2-[ (2, 2, 2-trifluoroacetyl) amino]butanoyl]- 6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-[ (2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl) amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (734 mg, 2.01 mmol, 1.00 eq) in N,N- dimethylformamide (10.0 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (1.15 g, 3.02 mmol, 1.50 eq). After stirring at 20 °C for 0.5 h, diisopropylethylamine (781 mg, 6.04 mmol, 1.05 mL, 3.00 eq) and 2-amino-2-(9-methoxy-4-oxo-pyrido[1, 2-a]pyrimidin-2-yl) acetamide (500 mg, 2.01 mmol, 1.00 eq) were added. After stirring at 20 °C for 11.5 h, the reaction mixture was purified by reversed phase column (instrument: 90g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.1% FA condition), eluent B: acetonitrile; gradient: 0-50min 0- 100% B; flow 50 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)- N-[2-amino-1-(9-methoxy-4-oxo-pyrido[1,2-a]pyrimidin-2-yl)-2 -oxo-ethyl]-3-[(2S)-3,3-dimethyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabi cyclo[3.1.0] hexane-2-carboxamide (540 mg, 0.908 mmol, 45% yield) as a white solid. LCMS (Method C): R _t = 1.385 min; MS (ESIpos): m/z = 595.5 [M+H] ⁺ . Procedure for preparation of CPD0220203 - (1R, 2S, 5S) -N-[cyano-(9-methoxy-4-oxo-pyrido[1, 2- a]pyrimidin-2-yl) methyl]-3-[ (2S) -3, 3-dimethyl-2-[ (2, 2, 2-trifluoroacetyl) amino]butanoyl]-6, 6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-[2-amino-1-(9-methoxy-4-oxo-pyrido[1,2-a]pyrimi din-2-yl)-2-oxo-ethyl]-3- [(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl] -6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (540 mg, 0.908 mmol, 1.00 eq) in dichloromethane (5.00 mL) was added methoxycarbonyl-(triethylammonio) sulfonyl-azanide (1.30 g, 5.45 mmol, 6.00 eq). After stirring at 20 °C for 4 h, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Welch Ultimate C18 150*25 mm*5 μm; mobile phase: [water (FA)-ACN]; B%: 40%-70%, 10 min) to give (1R,2S,5S)-N- [cyano-(9-methoxy-4-oxo-pyrido[1,2-a]pyrimidin-2-yl)methyl]- 3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (145 mg, 0.249 mmol, 27% yield, 99% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.71-9.55 (m, 1H), 9.43 (t, J = 8.0 Hz, 1H), 8.61-8.55 (m, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.39-7.29 (m, 1H), 6.54 (d, J = 9.6 Hz, 1H), 6.16 - 6.08 (m, 1H), 4.40 (d, J = 7.2 Hz, 1H), 4.36 (d, J = 6.4 Hz, 1H), 3.98 (d, J = 2.4 Hz, 3H), 3.90 (td, J = 10.4, 5.2 Hz, 1H), 3.71 (dd, J = 10.4, 6.4 Hz, 1H), 1.60-1.51 (m, 1H), 1.42 (dd, J = 10.4, 7.6 Hz, 1H), 1.04 (d, J = 10.4 Hz, 3H), 0.98 (d, J = 8.0 Hz, 9H), 0.87 (d, J = 6.4 Hz, 3H). LCMS (Method C): R _t = 1.511 min; MS (ESIpos): m/z = 577.4 [M+H] ⁺ . SFC: dr = 7: 92. Preparation of CPD0220204 Procedure for preparation of 2-hydroxy-7-methoxy-pyrido[1,2-a]pyrimidin-4-one A mixture of 5-methoxypyridin-2-amine (10.0 g, 80.6 mmol, 1.00 eq) and bis(2,4,6-trichlorophenyl) propanedioate (37.3 g, 80.6 mmol, 1.00 eq) in acetone (200 mL) was stirred for 0.5 h. Triethylamine (16.3 g, 161 mmol, 22.4 mL, 2.00 eq) was added into the mixture. After stirring at 20 °C for 1 h, the resulting precipitate was collected by filtration. The filter cake was washed with ethyl acetate (20.0 mL) and dried under vacuum to give 2-hydroxy-7-methoxy-pyrido[1,2-a]pyrimidin-4-one (15.0 g, 78.1 mmol, 97% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.47-8.39 (m, 1H), 7.90-7.84 (m, 1H), 7.42-7.41 (m, 1H), 7.41-7.38 (m, 1H), 5.16-5.05 (m, 1H), 3.89 (s, 3H). LCMS (Method C): Rt = 0.191 min; MS (ESIpos): m/z = 193.2 [M+H] ⁺ . Procedure for preparation of 2-chloro-7-methoxy-pyrido[1,2-a]pyrimidin-4-one To a solution of 2-hydroxy-7-methoxy-pyrido[1,2-a]pyrimidin-4-one (15.0 g, 78.1 mmol, 1.00 eq) in phosphoryl trichloride (100 mL) at 25 °C. The mixture was stirred at 100 °C for 4 h. The reaction mixture was concentrated under reduced pressure to remove phosphoryl trichloride to give a residue. The residue was diluted with ethyl acetate (100 mL) and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ethergradient @ 80 mL/min) to give 2-chloro- 7-methoxy-pyrido[1,2-a]pyrimidin-4-one (7.50 g, 35.6 mmol, 46% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.46-8.40 (m, 1H), 7.96-7.88 (m, 1H), 7.74-7.67 (m, 1H), 6.51-6.40 (m, 1H), 3.96-3.82 (m, 3H). LC-MS (Method L): Rt = 0.990 min; MS (ESIpos): m/z = 211.0 [M+H] ⁺ . A mixture of 2-chloro-7-methoxy-pyrido[1,2-a]pyrimidin-4-one (5.60 g, 26.6 mmol, 1.00 eq), methyl 2- (benzhydrylideneamino)acetate (7.41 g, 29.3 mmol, 1.10 eq) and cesium carbonate (26.0 g, 79.8 mmol, 3.00 eq) in N,N-dimethylformamide (100 mL) was stirred at 100 °C for 12 h. The reaction mixture was diluted with ethyl acetate (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 80 mL/min) to give methyl 2-(benzhydrylideneamino)-2-(7- methoxy-4-oxo-pyrido[1,2-a]pyrimidin-2-yl)acetate (650 mg, 1.52 mmol, 6% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.49-8.42 (m, 1H), 7.78 (d, J = 2.8 Hz, 1H), 7.66-7.62 (m, 3H), 7.56- 7.52 (m, 3H), 7.46 (d, J = 7.6 Hz, 3H), 7.22-7.18 (m, 2H), 6.59-6.53 (m, 1H), 5.10-5.04 (m, 1H), 3.93- 3.92 (m, 3H), 3.66-3.61 (m, 3H). LC-MS (Method K): Rt = 0.840 min; MS (ESIpos): m/z = 428.3 [M+H] ⁺ . Procedure for preparation of 2-(benzhydrylideneamino)-2-(7-methoxy-4-oxo-pyrido[1,2- a]pyrimidin-2-yl)acetamide To a solution of methyl 2-(benzhydrylideneamino)-2-(7-methoxy-4-oxo-pyrido[1,2-a]pyr imidin-2- yl)acetate (650 mg, 1.52 mmol, 1.00 eq) in terahydrofuran (6.00 mL) was added ammonia water (10.9 g, 77.9 mmol, 12.0 mL, 25% purity, 51.2 eq) at 20 °C. After stirring at 20 °C for 24 h, the reaction mixture was filtered and the filter cake was dried under vacuum to give 2-(benzhydrylideneamino)-2-(7- methoxy-4-oxo-pyrido[1,2-a]pyrimidin-2-yl)acetamide (500 mg, 1.21 mmol, 80% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.49-8.39 (m, 1H), 7.76 (d, J = 2.8 Hz, 1H), 7.73-7.69 (m, 2H), 7.64 (s, 1H), 7.62 (s, 1H), 7.52-7.50 (m, 3H), 7.40 (d, J = 3.6 Hz, 2H), 7.18-7.14 (m, 2H), 6.59-6.52 (m, 1H), 4.80-4.73 (m, 1H), 3.92-3.91 (m, 3H). LC-MS (Method A): Rt = 2.061 min; MS (ESIpos): m/z = 413.3 [M+H] ⁺ . Procedure for preparation of 2-amino-2-(7-methoxy-4-oxo-pyrido[1,2-a]pyrimidin-2- yl)acetamide To a solution of 2-(benzhydrylideneamino)-2-(7-methoxy-4-oxo-pyrido[1,2-a]pyr imidin-2-yl)acetamide (500 mg, 1.21 mmol, 1.00 eq) in mixed solvent of dichloromethane (4.00 mL) and methyl alcohol (4.00 mL) was added hydrogen chloride (1M, 8.00 mL, 6.60 eq) at 20 °C. After stirring at 20 °C for 3 h, ethyl acetate (10.0 mL) and water (10.0 mL) were added and layers were separated. The aqueous phase was washed with ethyl acetate (5 mL × 2). The aqueous phase was lyophilized to give 2-amino-2-(7- methoxy-4-oxo-pyrido[1,2-a]pyrimidin-2-yl)acetamide (345 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.72 (d, J = 4.4 Hz, 2H), 8.49 (d, J = 2.8 Hz, 1H), 8.20-8.12 (m, 1H), 7.92-7.88 (m, 1H), 7.75-7.69 (m, 2H), 6.79-6.76 (m, 1H), 5.03-4.95 (m, 1H), 3.95 (s, 3H). LC-MS (Method F): Rt = 1.113 min; MS (ESIpos): m/z = 249.1 [M+H] ⁺ . Procedure for preparation 2-yl)-2-oxo-ethyl]-3-[(2S)-3, azabicyclo[3.1.0]hexane-2- To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (506 mg, 1.39 mmol, 1.00 eq) in N,N-dimethylformamide (6.00 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (793 mg, 2.08 mmol, 1.50 eq) and N,N- diisopropylethylamine (539 mg, 4.17 mmol, 0.726 mL, 3.00 eq). After stirring at 20 °C for 0.5 h, 2-amino-2-(7-methoxy-4-oxo-pyrido[1,2-a]pyrimidin-2-yl)aceta mide (345 mg, 1.39 mmol, 1.00 eq) was added. The mixture was stirred at 20 °C for 11.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (Instrument: 40 g Flash; Column: Welch Ultimate XB_C1820-40μm; eluent A: water (0.05% formic acid), eluent B: acetonitrile; gradient: 0-20 min 0-60% B; flow 40 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)-N-[2-amino-1-(7-methoxy-4-oxo-pyrido[1,2- a]pyrimidin-2-yl)-2-oxo-ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2, 2-trifluoroacetyl)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (384 mg, 0.646 mmol, 46% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.42-9.38 (m, 1H), 8.71-8.60 (m, 1H), 8.48-8.40 (m, 1H), 7.88-7.80 (m, 1H), 7.68 (d, J = 10.0 Hz, 1H), 7.57-7.45 (m, 1H), 7.32 (s, 1H), 6.60-6.45 (m, 1H), 5.37-5.26 (m, 1H), 4.56-4.47 (m, 1H), 4.44-4.41 (m, 1H), 3.94-3.92 (m, 3H), 3.91-3.80 (m, 1H), 3.76-3.71 (m, 1H), 1.53-1.49 (m, 1H), 1.42-1.37 (m, 1H), 0.99 (s, 9H), 0.82 (s, 6H). LC-MS (Method B): Rt = 3.133 and 3.190 min; MS (ESIpos): m/z = 595.1 [M+H] ⁺ . Procedure for preparation of Compound CPD0220204- (1R,2S,5S)-N-[cyano-(7-methoxy-4-oxo- pyrido[1,2-a]pyrimidin-2-yl)methyl]-3-[(2S)-3,3-dimethyl-2-[ (2,2,2-trifluoroacetyl) amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-car boxamide To a solution of (1R,2S,5S)-N-[2-amino-1-(7-methoxy-4-oxo-pyrido[1,2-a]pyrimi din-2-yl)-2-oxo-ethyl]-3- [(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl] -6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (384 mg, 0.645 mmol, 1.00 eq) in dichloromethane (7.00 mL) was added methoxycarbonyl-(triethylammonio)sulfonyl-azanide (616 mg, 2.58 mmol, 4.00 eq) at 20 °C. After stirring at 20 °C for 4 h, the reaction mixture was quenched with water (10 mL) at 20 °C and extracted with dichloromethane (10 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um; mobile phase: [water (FA)-ACN]; B%: 42%-72%,10 min) to give (1R,2S,5S)-N-[cyano-(7-methoxy-4-oxo-pyrido[1,2-a]pyrimidin- 2- yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl) amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (249 mg, 0.432 mmol, 66% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.66-9.50 (m, 1H), 9.48-9.39 (m, 1H), 8.49-8.44 (m, 1H), 7.88 (dd, J = 9.6, 2.8 Hz, 1H), 7.79-7.70 (m, 1H), 6.50-6.46 (m, 1H), 6.26-6.07 (m, 1H), 4.44-4.39 (m, 1H), 4.38- 4.35 (m, 1H), 3.94 (s, 3H), 3.93-3.87 (m, 1H), 3.75-3.66 (m, 1H), 1.64-1.52 (m, 1H), 1.43-1.34 (m, 1H), 1.09-1.01 (m, 3H), 1.01-0.96 (m, 9H), 0.89-0.85 (m, 3H). LC-MS (Method L): Rt = 2.087 min; MS (ESIpos): m/z = 577.6 [M+H] ⁺ . Preparation of CPD0220205 Procedure for preparation of 2-fluoropropanedioic acid To a solution of lithium hydrate (12.8 g, 533 mmol, 4.00 eq) in water (50 mL) was added tetrahydrofuran (50 mL) and the temperature was raised to 40 °C. Dimethyl 2-fluoropropanedioate (20.0 g, 133 mmol, 1.00 eq) was slowly added dropwise to the reaction mixture. After stirring at 40 °C for 24 h, the reaction mixture was extracted with ethyl acetate (200 mL). The combined organic layers were washed with water (200 mL). Hydrogen chloride was added to the aqueous phase to adjust pH to 1. The solution was extracted with methyl tertiary butyl ether (500 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-fluoropropanedioic acid (11.0 g, crude) as colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.88-7.49 (m, 2H), 5.58-5.33 (m, 1H). Procedure for preparation of 2-chloro-3-fluoro-pyrido[1,2-a]pyrimidin-4-one To a solution of 2-fluoropropanedioic acid (11.0 g, 90.1 mmol, 1.00 eq) and benzyl(triethyl)ammonium;chloride (41.1 g, 180 mmol, 2.00 eq) in acetonitrile (120 mL) was added dropwise phosphorus oxychloride (138 g, 901 mmol, 83.8 mL, 10.0 eq) at 20 °C. After stirring at 20 °C until the solid was dissolved, a solution of pyridin-2-amine (8.91 g, 94.6 mmol, 1.05 eq) in acetonitrile (50 mL) was added dropwise at 20 °C over 15 min. The resulting mixture was stirred at 80 °C for 16 h. The mixture was concentrated under vacuum to give a residue. The residue was neutralized with saturated sodium bicarbonate until pH to 7 and extracted with dichloromethane (50 mL * 3). The organic phase was washed with brine (50 mL), dried with sodium sulfate and concentrated in vacuo to give residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ethergradient @ 120 mL/min). Compound 2- chloro-3-fluoro-pyrido[1,2-a]pyrimidin-4-one (9 g, 27.2 mmol, 30.2% yield, 60.0% purity) was obtained as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 8.94 (d, J=6.8 Hz, 1H), 8.04 (ddd, J = 1.2, 6.8, 8.6 Hz, 1H), 7.84- 7.73 (m, 1H), 7.47 (dt, J = 1.2, 7.2 Hz, 1H). LCMS (Method C): R _t = 0.325 min; MS (ESIpos): m/z =199.2 [M+H] ⁺ . Procedure for preparation of methyl 2-(benzhydrylideneamino)-2-(3-fluoro-4-oxo-pyrido[1,2- a]pyrimidin-2-yl)acetate A mixture of 2-chloro-3-fluoro-pyrido[1,2-a]pyrimidin-4-one (0.800 g, 4.03 mmol, 1.00 eq) , methyl 2- (benzhydrylideneamino)acetate (1.02 g, 4.03 mmol, 1.00 eq), [2-(2-aminophenyl)phenyl]-chloro- palladium;tritert-butylphosphane (206 mg, 403 umol, 0.100 eq), potassium phosphate (2.57 g, 12.1 mmol, 3.00 eq) in N,N-dimethylformamide (10 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 90 °C for 16 hr under nitrogen atmosphere. The mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (30.0 mL*3), then the organicphase was dried with anhydrous sodium sulfate and concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ethergradient @ 50 mL/min). Compound methyl 2-(benzhydrylideneamino)-2- (3-fluoro-4-oxo-pyrido[1,2-a]pyrimidin-2-yl)acetate (1.30 g, crude) was obtained as a brown oil. ¹ H NMR (400 MHz, DMSO-d6) δ = 8.91 (d, J = 6.8 Hz, 1H), 7.96-7.88 (m, 1H), 7.79-7.73 (m, 1H), 7.60- 7.52 (m, 7H), 7.50-7.45 (m, 2H), 7.43-7.34 (m, 6H), 7.22-7.15 (m, 3H), 5.40 (s, 1H), 3.67 (s, 3H). LCMS (Method C): R _t = 3.131 min; MS (ESIpos): m/z =416.3 [M+H] ⁺ . Procedure for preparation of 2-(benzhydrylideneamino)-2-(3-fluoro-4-oxo-pyrido[1,2- a]pyrimidin-2-yl)acetamide A mixture of methyl 2-(benzhydrylideneamino)-2-(3-fluoro-4-oxo-pyrido[1,2-a]pyri midin-2-yl)acetate (1.30 g, 3.13 mmol, 1.00 eq) in ammonia water (8 mL) and terahydrofuran (4 mL) was stirred at 25 °C for 16 h. The mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were driedover anhydrous sodium sulfate and concentrated to give 2- (benzhydrylideneamino)-2-(3-fluoro-4-oxo-pyrido[1,2-a]pyrimi din-2-yl)acetamide (770 mg, 1.35 mmol, 43% yield, 70% purity) as a white solid. LCMS (Method G): R _t = 0.814 min; MS (ESIpos): m/z = 401.3 [M+H] ⁺ . Procedure for preparation of 2-amino-2-(3-fluoro-4-oxo-pyrido[1,2-a]pyrimidin-2-yl)acetam ide To a solution of 2-(benzhydrylideneamino)-2-(3-fluoro-4-oxo-pyrido[1,2-a]pyri midin-2-yl)acetamide (770 mg, 1.92 mmol, 1.00 eq) in methyl alcohol (5 mL) and dichloromethane (5 mL) was added hydrogen chloride (1.00 M, 10.0 mL, 5.20 eq). After stirring at 20 °C for 1 h, the reaction mixture was extracted with ethyl acetate (20 mL), and extracted with water (10 mL × 3). The aqueous phase was lyophilized to give 2-amino-2-(3-fluoro-4-oxo-pyrido[1,2-a]pyrimidin-2-yl)acetam ide (400 mg, 1.13 mmol, 59% yield, 67% purity) as a yellow solid. LCMS (Method C): R _t = 0.298 min; MS (ESIpos): m/z = 273.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[2-amino-1-(3-fluoro-4-oxo-pyrido[1,2-a]pyrimid in-2- yl)-2-oxo-ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroace tyl)amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (617 mg, 1.69 mmol, 1.00 eq) in N,N-dimethylformamide (5 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (966 mg, 2.54 mmol, 1.50 eq). After stirring at 25 °C for 30 min, a solution of 2-amino-2-(3-fluoro-4-oxo- pyrido[1,2-a]pyrimidin-2-yl)acetamide (400 mg, 1.69 mmol, 1.00 eq) and diisopropylethylamine (657 mg, 5.08 mmol, 0.885 mL, 3.00 eq) in N,N-dimethylformamide (5 mL) was added dropwise at 25 °C. The resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (Instrument: 40 g Flash; Column: Welch Ultimate XB_C18 20-40μm; eluent A: water (0.1% formic acid), eluent B: acetonitrile; gradient: 0-10 min 0-50% B; flow 45 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)-N-[2-amino-1-(3-fluoro-4-oxo-pyrido[1,2-a]pyrimid in-2-yl)-2-oxo-ethyl]- 3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoy l]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide (270 mg, 0.440 mmol, 26% yield, 95% purity) as a yellow solid. LCMS (Method C): R _t = 0.435 min; MS (ESIpos): m/z = 583.4 [M+H] ⁺ . Procedure for preparation of CPD0220205 - (1R,2S,5S)-N-[cyano-(3-fluoro-4-oxo-pyrido[1,2- a]pyrimidin-2-yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trif luoroacetyl)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-[2-amino-1-(3-fluoro-4-oxo-pyrido[1,2-a]pyrimid in-2-yl)-2-oxo-ethyl]-3- [(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl] -6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (270 mg, 46.0 μmol, 1.00 eq) in dichloromethane (2 mL) was added methoxycarbonyl- (triethylammonio)sulfonyl-azanide (442 mg, 1.85 mmol, 4.00 eq). After stirring at 25 °C for 4 h, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate 90 mL (30 mL × 3). The combined organic layers were washed with brine (60 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Welch Ultimate C18150*25mm*5 μm; mobile phase: [water (formic acid)- acetonitrile]; B%: 43%-73%,10min) to give (1R,2S,5S)-N-[cyano-(3-fluoro-4-oxo-pyrido[1,2-a]pyrimidin-2 -yl)methyl]- 3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoy l]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide (120 mg, 213 umol, 45.9% yield, 100% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.61-9.47 (m, 1H), 9.43-9.29 (m, 1H), 8.97 (d, J = 7.2 Hz, 1H), 8.11- 7.97 (m, 1H), 7.89-7.82 (m, 1H), 7.48 (t, J = 6.8 Hz, 1H), 6.52-6.44 (m, 1H), 4.45-4.29 (m, 2H), 3.92- 3.84 (m, 1H), 3.72-3.66 (m, 1H), 1.63-1.45 (m, 1H), 1.38-1.30 (m, 1H), 1.06-0.93 (m, 12H), 0.83 (s, 3H). LCMS (Method C): R _t = 2.059 min; MS (ESIpos): m/z = 565.3 [M+H] ⁺ . Preparation of CPD0220206 Procedure for preparation of 5-fluoropyridin-2-amine A mixture of 5-fluoropyridin-2-amine (4.00 g, 35.7 mmol, 1.00 eq), bis(2,4,6-trichlorophenyl) propanedioate (18.2 g, 39.3 mmol, 1.10 eq) in tetrahydrofuran (120 mL) was heated at 80 °C for 3 h. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran. The resulting precipitate was filtered and washed with petroleum ether. The filter cake was dried to give 7- fluoro-2-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (6.30 g, 345 mmol, 98% yield) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.0 (br s, 1H), 8.91-8.86 (m, 1H), 8.18-8.12 (m, 1H), 7.56-7.50 (m), 5.50-4.92 (m, 1H). Procedure for preparation of 2-chloro-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one A solution of 7-fluoro-2-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one (5.00 g, 27.8 mmol, 1.00 eq) in phosphorus oxychloride (50.0 mL) was heated at 110 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was quenched with water (100 mL) at 10 °C. The resulting precipitate was filtered and washed with methylbenzene ether, filtered and concentrated under reduced pressure to give 2chloro-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one (4.70 g, 22.5 mmol, 81% yield, 95% purity) as a red solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.06-8.98 (m, 1H), 8.40-8.11 (m, 1H), 7.92-7.82 (m, 1H), 6.57 (s, 1H). Procedure for preparation of methyl 2-((diphenylmethylene)amino)-2-(7-fluoro-4-oxo-4H- pyrido[1,2-a]pyrimidin-2-yl)acetate To a solution of 2-chloro-7-fluoro-pyrido[1,2-a]pyrimidin-4-one (1.50 g, 7.55 mmol, 1.00 eq), methyl 2- (benzhydrylideneamino) acetate (1.91 g, 7.55 mmol, 1.00 eq) in N,N-dimethylformamide (20.0 mL) was added cesium carbonate (7.38 g, 22.7 mmol, 3.00 eq). After heating to 100 °C, and stirred for 12 h, the reaction mixture was quenched with water (50.0 mL) and extracted with ethyl acetate (40.0 mL × 3). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 4: 1 to 3: 1) to give methyl 2- (benzhydrylideneamino)-2-(7-fluoro-4-oxo-pyrido[1,2-a]pyrimi din-2-yl)acetate (910 mg, 2.08 mmol, 28% yield, 95% purity) as a red solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.99-8.88 (m, 1H), 8.17-8.07 (m, 1H), 7.96 (s, 4H), 7.78-7.67 (m, 1H), 7.65-7.40 (m, 11H), 7.24-7.18 (m, 4H), 6.61 (s, 1H), 5.09 (s, 1H), 3.64 (s, 3H). Procedure for preparation of 2-((diphenylmethylene)amino)-2-(7-fluoro-4H-pyrido[1,2- a]pyrimidin-2-yl)acetamide To a mixture of methyl 2-(benzhydrylideneamino)-2-(7-fluoro-4-oxo-pyrido[1,2-a]pyri midin-2-yl)acetate (910 mg, 2.19 mmol, 1.00 eq) in ammonia in methanol (50.0 mL, 7M) in the flask was added 3,4,6,7,8,9- hexahydro-2H-pyrimido[1,2-a]pyrimidine (150 mg, 8.90 mmol, 4.00 eq) at 20 °C. After stirring at 20 °C for 16 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (10.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (instrument: 20.0 g Flash; Column: Welch Ultimate XB_C18 20-40 μm; eluent A: water (0.05% NH ₃ •H ₂ O), eluent B: acetonitrile; gradient: 0-20 min 0-80% B; flow 40 ml/min; temperature; Detector: UV 220/254 nm) and lyophilized to give 2-(benzhydrylideneamino)-2-(7-fluoro-4-oxo-pyrido[1,2- a]pyrimidin-2-yl)acetamide (210 mg, 0.498 mmol, 23% yield, 95% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.15-8.91 (m, 1H), 8.25-8.05 (m, 1H), 7.92-7.74 (m, 3H), 7.67-7.39 (m, 11H), 7.32-7.12 (m, 3H), 6.66 (s, 1H), 4.85 (s, 1H). Procedure for preparation of 2-amino-2-(7-fluoro-4-oxo-4H-pyrido[1,2-a]pyrimidin-2- yl)acetamide A mixture of 2-(benzhydrylideneamino)-2-(7-fluoro-4-oxo-pyrido[1,2-a]pyri midin-2-yl)acetamide (200 mg, 0.500 mmol, 1.00 eq) and hydrogen chloride (1M, 1.50 mL, 3.00 eq) in tetrahydrofuran (2.00 mL) was stirred at 25 °C for 4 h. The reaction mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The aqueous phase was lyophilized to give 2-amino-2-(7-fluoro-4-oxo- pyrido[1,2-a]pyrimidin-2-yl)acetamide (80.0 mg, 0.305 mmol, 61% yield, 90% purity) as a red oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.05-8.98 (m, 1H), 8.86-8.76 (m, 1H), 8.85-8.79 (m, 1H), 8.34-8.15 (m, 2H), 7.91-7.71 (m, 2H), 7.56-7.21 (m, 2H), 6.88 (s, 1H), 6.66-6.60 (m, 1H), 5.08-5.02 (m, 1H), 4.54- 4.23 (m, 11H), 2.00-1.88 (m, 1H), 1.96-1.84 (m, 1H). A mixture of 2-amino-2-(7-fluoro-4-oxo-pyrido[1,2-a]pyrimidin-2-yl)acetam ide (60.0 mg, 0.254 mmol, 1.00 eq), (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (111 mg, 0.305 mmol, 1.20 eq), [dimethylamino(triazolo[4,5- b]pyridin-3-yloxy)methylidene]-dimethylazanium; hexafluorophosphate (145 mg, 0.381 mmol, 1.50 eq) and diisopropylethylamine (164 mg, 1.27 mmol, 0.221 mL, 5.00 eq) in dichloromethane (5.00 mL) was stirred at 25 °C for 6 h. The reaction mixture was partitioned between water (30.0 mL) and ethyl acetate (30.0 mL). The organic phase was separated, washed with water (10.0 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (instrument: 20 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.05% FA), eluent B: acetonitrile; gradient: 0-20 min 0-80% B; flow 40 ml/min; temperature; Detector: UV 220/254 nm) and lyophilized to give (1R,2S,5S)-N-[2-amino-1-(7-fluoro-4-oxo-pyrido[1,2- a]pyrimidin-2-yl)-2-oxo-ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2, 2-trifluoroacetyl)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (120 mg, 0.185 mmol, 73% yield, 90% purity) as a red oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.44-9.38 (m, 1H), 9.06-8.84 (m, 1H), 8.73-8.68 (m, 1H), 8.18-8.10 (m, 1H), 7.90-7.69 (m, 1H), 7.63-7.28 (m, 1H), 6.96 (s, 1H), 6.63-6.44 (m, 1H), 5.34 (d, J = 8.4 Hz, 1H), 4.64-4.35 (m, 1H), 4.15 (s, 1H), 3.96-3.62 (m, 1H), 1.62-1.31 (m, 1H), 1.14-0.76 (m, 1H). Procedure for preparation of Compound CPD0220206 (1R,2S,5S)-N-(cyano(7-fluoro-4-oxo-4H- pyrido[1,2-a]pyrimidin-2-yl)methyl)-3-((S)-3,3-dimethyl-2-(2 ,2,2-trifluoroacetamido)butanoyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide A mixture of (1R,2S,5S)-N-[2-amino-1-(7-fluoro-4-oxo-pyrido[1,2-a]pyrimid in-2-yl)-2-oxo-ethyl]-3-[(2S)- 3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-d imethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (100 mg, 0.172 mmol, 1.00 eq) and Burgess reagent (164 mg, 0.687 mmol, 4.00 eq) in dichloromethane (10.0 mL) was stirred at 20 °C for 16 h. The reaction mixture was partitioned between water (30.0 mL) and dichloromethane (30.0 mL). The organic phase was separated, washed with water (10.0 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 42%-72%,10min) to give (1R,2S,5S)-N-[cyano-(7-fluoro- 4-oxo-pyrido[1,2-a]pyrimidin-2-yl)methyl]-3-[(2S)-3,3-dimeth yl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (50.6 mg, 87.8 μmol, 51% yield, 98% purity) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.04-8.98 (m, 1H), 8.21-8.11 (m, 1H), 7.85-7.76 (m, 2H), 7.76-7.68 (m, 1H), 6.93-6.77 (m, 1H), 6.59 (d, J = 7.6 Hz, 1H), 6.04-6.94 (m, 1H), 4.47 (s, 1H), 4.53-4.41 (m, 1H), 3.91-3.90 (m, 1H), 3.89-3.89 (m, 1H), 3.96-3.83 (m, 1H), 1.84 (d, J = 7.6 Hz, 1H), 1.91-1.71 (m, 1H), 1.94-1.69 (m, 1H), 1.66-1.61 (m, 1H), 1.60-1.59 (m, 1H), 1.58-1.57 (m, 1H), 1.53 (br s, 1H), 1.68-1.49 (m, 9H), 1.14-1.05 (m, 7H), 0.92-0.84 (m, 7H). LC-MS (Method C): R _t = 0.734 min; MS (ESIpos): m/z = 565.2 [M+H] ⁺ . A mixture of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl -butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (15.0 g, 39.2 mmol, 1.00 eq) in hydrochloric acid (100 mL, 4 M in dioxane) was stirred at 25 °C for 16 h. The mixture was concentrated to afford methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimeth yl-3-azabicyclo[3.1.0]hexane-2- carboxylate (11.0 g, 34.5 mmol, 88% yield, hydrochloric acid salt) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.23-8.12 (m, 2H), 4.26 (s, 1H), 3.93-3.73 (m, 3H), 3.67 (s, 3H), 1.62- 1.61-1.57 (m, 1H), 1.51-1.47 (m, 1H), 1.06 (s, 12H), 0.96 (m, 3H). LC-MS (Method C): R _t = 0.673 min; MS (ESIpos): m/z = 283.3 [M+H] ⁺ . Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-2-[(2-ethoxyacetyl)amino]-3,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyla te To a mixture of 2-ethoxyacetic acid (588 mg, 5.65 mmol, 1.20 eq), benzotriazol-1-yloxy(tripyrrolidin-1- yl)phosphanium;hexafluorophosphate (3.18 g, 6.12 mmol, 1.30 eq) and N-methylmorpholine (1.43 g, 14.1 mmol, 3.00 eq) in dichloromethane (20.0 mL) was added methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3- dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylate (1.50 g, 4.70 mmol, 1.00 eq, hydrochloric acid) at 25 °C. After stirring at 25 °C for 16 h, the reaction mixture was diluted with saturated ammonium chloride solution (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®;40 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @80 mL/min). to afford methyl (1R,2S,5S)-3-[(2S)-2-[(2-ethoxyacetyl)amino]-3,3-dimethyl-bu tanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.20 g, 3.26 mmol, 69% yield) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.21 (d, J = 8.0 Hz, 1H), 4.60-4.54 (m, 1H), 4.46 (s, 1H), 4.00-3.91 (m, 3H), 3.91-3.88 (m, 1H), 3.76 (s, 3H), 3.60-3.50 (m, 2H), 2.09-2.02 (m, 1H), 1.48-1.42 (m, 1H), 1.29-1.25 (m, 1H), 1.23 (t, J = 6.8 Hz, 3H), 1.09-1.01 (m, 11H), 0.98-0.88 (m, 4H). LC-MS (Method C): R _t = 0.899 min; MS (ESIpos): m/z = 369.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-[(2-ethoxyacetyl)amino]-3,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyli c acid To a solution of methyl (1R,2S,5S)-3-[(2S)-2-[(2-ethoxyacetyl)amino]-3,3-dimethyl-bu tanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.20 g, 3.26 mmol, 1.00 eq) in tetrahydrofuran (5.00 mL) and methanol (5.00 mL) was added a solution of lithium hydroxide hydrate (312 mg, 13.0 mmol, 4.00 eq) in water (5.00 mL). After stirring at 25 °C for 16 h, the reaction mixture was adjusted to pH~3 with hydrochloric acid solution (2 M) and extracted with ethyl acetate (50.0 mL ×3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give (1R,2S,5S)-3-[(2S)-2-[(2-ethoxyacetyl)amino]-3,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxylic acid (1.00 g, 2.82 mmol, 87% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.21-7.02 (m, 1H), 4.63-4.54 (m, 1H), 4.52-4.45 (m, 1H), 4.01-3.91 (m, 2H), 3.91-3.83 (m, 1H), 3.61-3.48 (m, 2H), 1.85-1.73 (m, 1H), 1.61-1.41 (m, 1H), 1.30-1.18 (m, 3H), 1.17-0.96 (m, 12H), 0.93 (s, 3H). LC-MS (Method C): R _t = 0.846 min; MS (ESIpos): m/z = 355.9 [M+H] ⁺ . To a mixture of (1R,2S,5S)-3-[(2S)-2-[(2-ethoxyacetyl)amino]-3,3-dimethyl-bu tanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (300 mg, 0.846 mmol, 1.00 eq) in dimethyl formamide (5.00 mL) were added N,N-diisopropylethylamine (438 mg, 3.39 mmol, 4.00 eq) and O-(7-azabenzotriazol-1- yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (418 mg, 1.10 mmol, 1.30 eq) at 25 °C, followed by (2S)-2-amino-3-[(2S)-3-oxo-4H-1,4-benzoxazin-2-yl]propanamid e (261 mg, 0.846 mmol, 1.00 eq, 2HCl salt). After stirring at 25 °C for 16 h, the reaction mixture was diluted with saturated ammonium chloride solution (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL ), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®;12g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate/Petroleum ether gradient @ 60 mL/min) to give (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4-benzo xazin-2- yl]methyl]ethyl]-3-[(2S)-2-[(2-ethoxyacetyl) amino]-3,3-dimethyl-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (450 mg, 0.764 mmol, 90% yield, 97% purity) as a yellow solid. LC-MS (Method C): R _t = 0.468min; MS (ESIpos): m/z = 572.4 [M+H] ⁺ . To a solution of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4-benzo xazin-2- yl]methyl]ethyl]-3-[(2S)-2-[(2-ethoxyacetyl)amino]-3,3-dimet hyl-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (400 mg, 0.700 mmol, 1.00 eq) in dichloromethane (5.00 mL) was added methoxycarbonyl-(triethylammonio)sulfonyl-azanide (334 mg, 1.40 mmol, 2.00 eq) at 0 °C. After stirring at 25 °C for 2 h, the reaction mixture was diluted with water (30.0 mL), and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C1875*30mm*3 μm; mobile phase: [water(formic acid)-acetonitrile]; B%: 46%-66%, 8 min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-3- oxo-4H-1,4-benzoxazin-2-yl]ethyl]-3-[(2S)-2-[(2-ethoxyacetyl )amino]-3,3-dimethyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (115 mg, 0.204 mmol, 29% yield, 98% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.78 (s, 1H), 9.07 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 9.2 Hz, 1H), 7.00- 6.86 (m, 4H), 5.17-5.09 (m, 1H), 4.57-4.51 (m, 1H), 4.31 (d, J = 9.2 Hz, 1H), 4.12 (s, 1H), 3.91-3.72 (m, 4H), 3.47-3.39 (m, 2H), 2.48-2.47 (m, 1H), 2.32-2.23 (m, 1H), 1.60-1.52 (m, 1H), 1.39-1.29 (m, 1H), 1.10 (t, J = 6.8 Hz, 1H), 1.02 (s, 3H), 0.86-0.69 (m, 12H). LC-MS (Method C): R _t = 0.857 min; MS (ESIpos): m/z = 554.2 [M+H] ⁺ . SFC: de%: 94%. Preparation of CPD0220263 Procedure for preparation of methyl (2S)-3,3-dimethyl-2-(pyrimidin-5-ylamino)butanoate To a mixture of 5-bromopyrimidine (2.00 g, 12.6 mmol, 1.00 eq), methyl (2S)-2-amino-3,3-dimethyl- butanoate (2.19 g, 12.1 mmol, 1.00 eq, hydrochloric acid salt) and cesium carbonate (9.02 g, 27.7 mmol, 2.20 eq) in toluene (20.0 mL) was added [2-(2-aminophenyl)phenyl]-chloro- palladium;dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]pho sphane (488 mg, 629 μmol, 0.05 eq). The mixture was purged with nitrogen for 3 times and stirred at 100 °C for 16 h. After filtration, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 3: 1 to 2: 1) to give methyl (2S)-3,3-dimethyl- 2-(pyrimidin-5-ylamino)butanoate (1.37 g, 6.14 mmol, 49% yield) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.64 (s, 1H), 8.17 (s, 2H), 4.25 (d, J = 10.0 Hz, 1H), 3.80 (d, J = 12.0 Hz, 1H), 3.73 (s, 3H), 1.08 (s, 9H). LC-MS (Method C): R _t = 0.651 min; MS (ESIpos): m/z = 224.1 [M+H] ⁺ . Procedure for preparation of (2S)-3,3-dimethyl-2-(pyrimidin-5-ylamino)butanoic acid To a solution of methyl (2S)-3,3-dimethyl-2-(pyrimidin-5-ylamino)butanoate (1.37 g, 6.14 mmol, 1.00 eq) in mixed solvent of tetrahydrofuran (5.00 mL), water (5.00 mL) and methanol (5.00 mL) was added lithium hydroxide (588 mg, 24.5 mmol, 4.00 eq) at 0 °C. After stirring at stirred at 25 °C for 16 h, hydrochloric acid (1 M) was added to the reaction mixture to adjust pH to 5~6 and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (2S)-3,3-dimethyl-2-(pyrimidin-5-ylamino)butanoic acid (837 mg, 4.00 mmol, 65% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.72 (m, 1H), 8.41 (s, 1H), 8.24 (s, 2H), 6.11 (d, J=9.6 Hz, 1H), 3.81 (d, J=9.6 Hz, 1H), 1.04 (s, 9H). LC-MS (Method C): R _t = 0.532 min; MS (ESIpos): m/z = 210.1 [M+H] ⁺ Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(pyrimidin-5- ylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-c arboxylate To a solution of (2S)-3,3-dimethyl-2-(pyrimidin-5-ylamino)butanoic acid (737 mg, 3.52 mmol, 1.00 eq), N,N-diisopropylethylamine (1.37 g, 10.6 mmol, 3.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (2.01 g, 5.28 mmol, 1.50 eq) in N,N-dimethylformamide (10.0 mL) was added methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxylate (869 mg, 4.23 mmol, 1.20 eq, hydrochloric acid salt) at 0 °C. After stirring at 25 °C for 16 h, the reaction mixture was poured into saturated ammonium chloride aqueous (10.0 mL) and extracted with ethyl acetate (5.00 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (petroleum ether: ethyl acetate = 4: 1 to 3: 1) to give methyl (1R,2S,5S)-3-[(2S)-3,3- dimethyl-2-(pyrimidin-5-ylamino)butanoyl]-6,6-dimethyl-3-aza bicyclo[3.1.0]hexane-2-carboxylate (1.10 g, 2.75 mmol, 78% yield) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.60 (s, 1H), 8.18 (s, 2H), 8.14-8.11 (m, 1H), 4.40 (s, 1H), 4.00-3.95 (m, 1H), 3.76 (s, 3H), 3.61 (d, J=10.0 Hz, 1H), 1.50-1.42 (m, 2H), 1.07-1.06 (m, 2H), 1.19-1.03 (m, 13H). To a solution of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(pyrimidin-5-ylamino) butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylate (1.10 g, 2.75 mmol,1.00 eq) in water (5.00 mL), methanol (5.00 mL) and tetrahydrofuran (5.00 mL) was added lithium hydroxide (197 mg, 8.24 mmol, 3.00 eq) at 0 °C. After stirring at 25 °C for 12 h, hydrochloric acid (1 M) was added to the reaction mixture to adjust pH to 6~7 and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-3- [(2S)-3,3-dimethyl-2-(pyrimidin-5-ylamino)butanoyl]-6,6-dime thyl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (687 mg, 1.78 mmol, 65% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.40-8.32 (m, 3H), 5.86 (d, J = 10.4 Hz, 1H), 4.26-4.04 (m, 2H), 3.90- 3.75 (m, 2H), 1.57-1.48 (m, 1H), 1.41-1.36 (m, 1H), 1.08-0.91 (m, 15H). LC-MS (Method C): R _t = 0.814 min; MS (ESIpos): m/z = 347.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4- benzoxazin-2-yl]methyl]ethyl]-3-[(2S)-3,3-dimethyl-2-(pyrimi din-5-ylamino)butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(pyrimidin-5-ylamino) butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (200 mg, 577 μmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (329 mg, 866 μmol, 1.50 eq) and N,N- diisopropylethylamine (298 mg, 2.31 mmol, 4.00 eq) in N,N-dimethylformamide (2.00 mL) was added (2S)-2-amino-3-[(2S)-3-oxo-4H-1,4-benzoxazin-2-yl]propanamid e (235 mg, 866 μmol, 1.50 eq, hydrochloric acid salt) at 0 °C. After stirring at 25 °C for 12 h, the reaction mixture was poured into saturated ammonium chloride solution (5.00 mL) and extracted with ethyl acetate (3.00 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 48~58% Ethyl acetate/Petroleum ether gradient @ 70 mL/min) to give (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4-benzo xazin-2- yl]methyl] ethyl]-3-[(2S)-3,3-dimethyl-2-(pyrimidin-5-ylamino)butanoyl] -6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (235 mg, 417 μmol, 72% yield) as a white solid. LC-MS (Method P): R _t = 0.509 min; MS (ESIpos): m/z = 564.4 [M+H] ⁺ . To a solution of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4-benzo xazin-2-yl] methyl]ethyl]-3-[(2S)-3,3-dimethyl-2-(pyrimidin-5-ylamino)bu tanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (185 mg, 328 μmol, 1.00 eq) in dichloromethane (5.00 mL) was added (methoxycarbonylsulfamoyl)triethylammonium hydroxide (156 mg, 656 μmol, 2.00 eq) at 0 °C. After stirring at 25 °C for 12 h, the reaction mixture was poured into saturated sodium bicarbonate solution (5.00 mL) and extracted with ethyl acetate (5.00 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 μm; mobile phase: [water(FA)-ACN]; B%: 37%-67%, 7 min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)- 3-oxo-4H-1,4-benzoxazin-2-yl] ethyl]-3-[(2S)-3,3-dimethyl-2-(pyrimidin-5-ylamino)butanoyl] -6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (139 mg, 253 μmol, 77 % yield) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.8 (s, 1H), 9.07 (d, J = 8.4 Hz, 1H), 8.41-8.34 (m, 1H), 8.33-8.27 (m, 2H), 7.03-6.79 (m, 4H), 5.73 (d, J = 10.8 Hz, 1H), 5.22-5.08 (m, 1H), 4.58-4.47 (m, 1H), 4.12-4.01 (m, 2H), 3.94-3.83 (m, 1H), 3.81-3.76 (m, 1H), 2.48-2.44 (m, 1H), 2.35-2.23 (m, 1H), 1.61-1.53 (m, 1H), 1.33-1.27 (m, 1H), 1.09-0.73 (m, 12H), 0.70-0.57 (m, 3H). LC-MS (Method P): R _t = 0.499 min; MS (ESIpos): m/z = 546.4 [M+H] ⁺ . SFC: de% = 97%. Preparation of CPD0220264 Procedure for preparation of methyl 2-(cyclopropoxy)acetate To a mixture of cyclopropanol (10.0 g, 172 mmol, 1.00 eq) in tetrahydrofuran (100 mL) was added sodium hydride (8.26 g, 206 mmol, 60% purity, 1.20 eq) at 0 °C. After stirring at 0 °C for 1 h, methyl 2- bromoacetate (28.9 g, 189 mmol, 1.10 eq) was added. The resulting mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 10: 1 to 5: 1) to give methyl 2-(cyclopropoxy)acetate (4.10 g, 29.9 mmol, 17% yield, 95% purity) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 4.12 (s, 2H), 3.77 (s, 3H), 3.59-3.43 (m, 1H), 0.70-0.61 (m, 2H), 0.54- 0.46 (m, 2H). Procedure for preparation of 2-(cyclopropoxy)acetic acid To a mixture of methyl 2-(cyclopropoxy)acetate (4.10 g, 29.9 mmol, 95% purity, 1.00 eq) in a mixed solvent of methanol (10.0 mL) and water (10.0 mL) was added lithium hydroxide monohydrate (3.77 g, 89.8 mmol, 3.00 eq) at 20 °C. After stirring at 20°C for 12 h, the reaction mixture was poured into water (50.0 mL). Hydrochloric acid (1M) was added to adjust pH to 3~4 and extracted with ethyl acetate (40.0 mL × 7). The combined organic layers were concentrated under vacuum to give 2-(cyclopropoxy)acetic acid (1.65 g, 12.8 mmol, 42% yield, 90% purity) as light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 10.67 (s, 1H), 4.18 (s, 2H), 3.58-3.51 (m, 1H), 0.72-0.62 (m, 2H), 0.52- 0.50 (m, 2H). Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-2-[[2-(cyclopropoxy)acetyl]amino]-3,3- dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylate A mixture of 2-(cyclopropoxy)acetic acid (500 mg, 3.88 mmol, 90% purity, 1.00 eq), O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (2.21 g, 5.81 mmol, 1.50 eq) and N,N-diisopropylethylamine (2.00 g, 15.5 mmol, 4.00 eq) in N,N-dimethylformamide (10.0 mL) was stirred at 20 °C for 0.5 h. Methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl- butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (1.48 g, 4.65 mmol, 1.20 eq, HCl) was added to the solution above. After stirring at 20 °C for 11.5 h, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 5: 1 to 1: 1) to give methyl (1R,2S,5S)-3-[(2S)-2-[[2-(cyclopropoxy)acetyl] amino]-3,3- dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylate (850 mg, 2.01 mmol, 51% yield, 90% purity) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.99 (d, J = 9.6 Hz, 1H), 4.56 (d, J = 9.6 Hz, 1H), 4.47-4.43 (m, 1H), 4.06-3.99 (m, 1H), 3.98-3.93 (m, 1H), 3.92-3.89 (m, 2H), 3.76 (s, 3H), 3.40-3.33 (m, 1H), 1.52-1.42 (m, 2H), 1.11-0.98 (m, 12H), 0.90 (s, 3H), 0.67-0.58 (m, 2H), 0.55-0.45 (m, 2H). LC-MS (Method L): R _t = 0.595,0.611 min; MS (ESIpos): m/z = 403.3 [M+Na] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-[[2-(cyclopropoxy)acetyl]amino]-3,3-dim ethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyli c acid To a mixture of methyl (1R,2S,5S)-3-[(2S)-2-[[2-(cyclopropoxy)acetyl] amino]-3,3-dimethyl-butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (850 mg, 2.01 mmol, 90% purity, 1.00 eq) in a mixed solvent of methanol (5.00 mL) and water (5.00 mL) was added lithium hydroxide (144 mg, 6.03 mmol, 3.00 eq) at 25 °C. After stirring at 25 °C for 12 h, hydrochloric acid (1M in water) was added to the reaction mixture to adjust pH to 4~5. The solution was extracted ethyl acetate (20 mL × 5). The combined organic layers were concentrated under vacuum to give (1R,2S,5S)-3-[(2S)-2-[[2- (cyclopropoxy)acetyl]amino]-3,3-dimethyl-butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (800 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.23-6.95 (m, 1H), 4.57 (d, J = 9.6 Hz, 1H), 4.46 (s, 1H), 4.07-3.94 (m, 3H), 3.92-3.74 (m, 1H), 3.43-3.33 (m, 1H), 1.76-1.59 (m, 1H), 1.55-1.38 (m, 1H), 1.12-0.88 (m, 15H), 0.70-0.60 (m, 2H), 0.55-0.45 (m, 2H). Procedure for preparation of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4- benzoxazin-2-yl]methyl]ethyl]-3-[(2S)-2-[[2-(cyclopropoxy)ac etyl]amino]-3,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxami de A mixture of (1R,2S,5S)-3-[(2S)-2-[[2-(cyclopropoxy)acetyl]amino]-3,3-dim ethyl-butanoyl] -6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (200 mg, 0.545 mmol, 1.00 eq), O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (311 mg, 0.818 mmol, 1.50 eq) and N,N-diisopropylethylamine (282 mg, 2.18 mmol, 4.00 eq) in N,N-dimethylformamide (5.00 mL) was stirred at 0 °C for 0.5 h. (2S)-2-amino-3-[(2S)-3-oxo-4H-1,4-benzoxazin-2-yl]propanamid e (192 mg, 0.709 mmol, 1.30 eq, HCl) was added to the solution above. After stirring at 25 °C for 11.5 h, the reaction mixture was poured into water (30.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 50~100% Ethyl acetate/Petroleum ether gradient @ 50 mL/min) to give (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(2S)-3- oxo-4H-1,4-benzoxazin-2-yl]methyl]ethyl]-3-[(2S)-2-[[2-(cycl opropoxy)acetyl]amino]-3,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxami de (260 mg, 0.400 mmol, 73% yield, 90% purity) as a yellow solid. LC-MS (Method C): R _t = 0.789 min; MS (ESIpos): m/z = 584.4 [M+H] ⁺ . Ammonia was bubbled into a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(2S)-3-oxo-4H- 1,4-benzoxazin-2-yl]propanoate (29.0 g, 82.7 mmol, 1.00 eq) in methanol (500 mL) at -70 °C for 0.5 h. After stirring at 20 °C for 16 h, the reaction was concentrated under reduced pressure to give a residue. The crude product was triturated with ethyl acetate at 25 °C for 1 h. The reaction mixture was filtered. The filter cake was dried under vacuum to give tert-butyl N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4- benzoxazin-2-yl]methyl]ethyl]carbamate (9.60 g, 27.8 mmol, 33% yield, 97% purity) as a white solid. LC-MS (Method L): Rt = 0.590 min; MS (ESIpos): m/z = 236.0 [M-99] ⁺ . Procedure for preparation of (2S)-2-amino-3-[(2S)-3-oxo-4H-1,4-benzoxazin-2-yl]propanamid e A mixture of tert-butyl N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4-benzoxazin-2-yl] methyl]ethyl]carbamate (1.00 g, 2.98 mmol, 1.00 eq) in hydrochloric acid (4 M in dioxine, 10.0 mL) was stirred at 0 °C for 1 h. The reaction mixture was concentrated under vacuum to give (2S)-2-amino-3- [(2S)-3-oxo-4H-1,4-benzoxazin-2-yl]propanamide (1.00 g, crude, HCl) as an off-white solid. LC-MS (Method L): R _t = 0.308 min; MS (ESIpos): m/z = 236.3 [M+H] ⁺ . A mixture of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4-benzo xazin-2-yl]methyl] ethyl]- 3-[(2S)-2-[[2-(cyclopropoxy)acetyl]amino]-3,3-dimethyl-butan oyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (260 mg, 0.400 mmol, 90% purity, 1.00 eq) and (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (191 mg, 0.801 mmol, 2.00 eq) in dichloromethane (5.00 mL) was stirred at 25 °C for 2h. The reaction mixture was poured into saturated sodium bicarbonate aqueous solution (10.0 mL) and extracted with ethyl acetate (3.00 mL × 3). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5 μm; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B%: 37%-67%, 9 min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-3-oxo-4H-1,4- benzoxazin-2-yl]ethyl]-3-[(2S)-2- [[2-(cyclopropoxy)acetyl]amino]-3,3-dimethyl-butanoyl]-6,6-d imethyl- 3-azabicyclo[3.1.0]hexane-2-carboxamide (93.2 mg, 0.161 mmol, 40% yield, 97% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.01-10.65 (m, 1H), 9.05 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 7.04-6.83 (m, 4H), 5.19-5.05 (m, 1H), 4.54-4.51 (m, 1H), 4.38-4.26 (m, 1H), 4.11 (s, 1H), 3.95-3.87 (m, 2H), 3.86-3.80 (m, 1H), 3.74 (d, J = 10.4 Hz, 1H), 3.46-3.36 (m, 1H), 2.47-2.45 (m, 1H), 2.32-2.23 (m, 1H), 1.60-1.44 (m, 1H), 1.32 (d, J = 7.6 Hz, 1H), 1.05-0.68 (m, 15H), 0.56-0.35 (m, 4H). LC-MS (Method L): R _t = 0.623 min; MS (ESIpos): m/z = 566.5 [M+H] ⁺ . HPLC (Method M): R _t = 2.127 min; HPLC purity: 99.02%. To a solution of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid (10.0 g, 43.2 mmol, 1.05 eq), 4-methylmorpholine (10.4 g, 103 mmol, 11.3 mL, 2.50 eq) and (benzotriazol-1- yloxy)tripyrrolidinophosphonium,hexafluorophosphate (23.6 g, 45.3 mmol, 1.10 eq) in dichloromethane (200 mL) was added methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (6.97 g, 41.2 mmol, 1.00 eq) at 0 °C. After stirring at 25 °C for 12 h, the reaction mixture was partitioned between dichloromethane (100 mL) and water (400 mL). The separated aqueous phase was extracted with dichloromethane (200 mL × 2). The combined extracts were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was purified by flash column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 0 to 10: 1) to afford methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl -butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (14.0 g, 33.0 mmol, 80% yield) as colorless oil. LC-MS (Method C): Rt = 0.793 min; MS (ESIpos): m/z = 383.3 [M+H] ⁺ . Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate To a solution of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl -butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (23.0 g, 60.1 mmol, 1.00 eq) in hydrochloride (4 M in dioxane, 200 mL, 13.3 eq) was stirred at 25 °C for 1 h. The reaction mixture was concentrated under vacuum at 50 °C to give methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimeth yl-3- azabicyclo[3.1.0]hexane-2-carboxylate (20.0 g, 56.3 mmol, 94% yield, 2 hydrochloride) as a white solid. Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2-tetrahydropyran-4- ylacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxylate To a solution of methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimeth yl-3- azabicyclo[3.1.0]hexane-2-carboxylate (1.00 g, 2.81 mmol, 1.00 eq, 2 hydrochloride) in dimethyl formamide (10.0 mL) were added 2-tetrahydropyran-4-ylacetic acid (406 mg, 2.81 mmol, 1.00 eq), tetramethylurea hexafluorophosphate (2.14 g, 5.63 mmol, 2.00 eq) and diisopropylethylamine (2.18 g, 16.9 mmol, 2.94 mL,6.00 eq). After stirring at 25 °C for 15 h, the reaction mixture was partitioned between water (100 mL) and ethyl acetate (200 mL). The organic layer was washed with brine (100 mL × 2), dried over anhydrous sodium sulfate anhydrous, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 0: 1) to afford methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2-tetrahydropyran-4- ylacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxylate (950 mg, 2.33 mmol, 83% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.88 (d, J = 8.8 Hz, 1H), 4.40 (d, J = 8.8 Hz, 1H), 4.16 (s, 1H), 3.92- 3.84 (m, 1H), 3.84-3.78 (m, 3H), 3.64 (s, 3H), 3.28-3.16 (m, 2H), 2.12 (d, J = 7.2 Hz, 2H), 1.88-1.79 (m, 1H), 1.56-1.44 (m, 2H), 1.44-1.40 (m, 2H), 1.20-1.08 (m, 2H), 1.00 (s, 3H), 0.96 (s, 9H), 0.80 (s, 3H). LC-MS (Method C): Rt = 0.545 min; MS (ESIpos): m/z = 409.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2-tetrahydropyran-4- ylacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2-tetrahydropyran-4- ylacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxylate (0.850 g, 2.08 mmol, 1.00 eq) in methanol (10.0 mL) and water (2.00 mL) was added lithium hydroxide (99.7 mg, 4.16 mmol, 2.00 eq). The mixture was stirred at 25 °C for 2 h. Hydrochloric acid (1M, 15 mL) was added to the reaction mixture. The solution was partitioned between water (100 mL) and ethyl acetate (200 mL). The organic layer was washed with brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2-tetrahydropyran-4- ylacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxylic acid (700 mg, 1.77 mmol, 85% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.52 (s, 1H), 7.88 (d, J = 9.2 Hz, 1H), 4.40 (d, J = 9.2 Hz, 1H), 4.12 (s, 1H), 3.88-3.80 (m, 1H), 3.80-3.76 (m, 2H), 3.24-3.16 (m, 2H), 2.12 (d, J = 7.2 Hz, 2H), 2.00 (s, 1H), 1.92 (s, 2H), 1.88-1.76 (m, 1H), 1.48-1.44 (m, 2H), 1.40 (d, J = 7.6 Hz, 1H), 1.16-1.12 (m, 2H), 1.00 (s, 3H), 0.96 (s, 9H), 0.80 (s, 3H). LC-MS (Method C): Rt = 0.745 min; MS (ESIpos): m/z = 395 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4- benzoxazin-2-yl]methyl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2-tet rahydropyran-4- ylacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2-tetrahydropyran-4-ylac etyl)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (300 mg, 0.760 mmol, 1.00 eq) in dimethyl formamide (3 mL) were added (2S)-2-amino-3-[(2S)-3-oxo-4H-1,4-benzoxazin-2-yl]propanamid e (248 mg, 0.913 mmol, 1.20 eq, hydrochloride), tetramethylurea hexafluorophosphate (578 mg, 1.52 mmol, 2 eq) and diisopropylethylamine (590 mg, 4.56 mmol, 0.795 mL, 6.00 eq). After stirring at 20 °C for 15 h, the reaction mixture was partitioned between water (50.0 mL) and ethyl acetate (100 mL). The organic layer was washed with brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (instrument: 25 g Flash; Column: Welch Ultimate XB_C1820-40μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-50min 0-100% B; flow 35 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to afford (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4- benzoxazin-2-yl]methyl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2-tet rahydropyran-4-ylacetyl)amino]butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (120 mg, 0.196 mmol, 26% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.60 (s, 1H), 8.32-8.24 (m, 1H), 7.79-7.68 (m, 1H), 7.32-7.24 (m, 1H), 7.12 (br s, 1H), 6.96-6.80 (m, 5H), 4.56-4.44 (m, 2H), 4.38-4.30 (m, 1H), 4.24-4.12 (m, 1H), 3.84- 3.68 (m, 5H), 2.12-2.04 (m, 3H), 1.85-1.79 (m, 1H), 1.48-1.32 (m, 5H), 1.16-1.08 (m, 2H), 1.00 (s, 3H), 0.80 (s, 3H), 0.72 (s, 9H). LC-MS (Method C): Rt = 0.548 min; MS (ESIpos): m/z = 612 [M+H] ⁺ . Procedure for preparation of Compound CPD0220270 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-3- oxo-4H-1,4-benzoxazin-2-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2 -tetrahydropyran-4- ylacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxamide To a solution of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4-benzo xazin-2- yl]methyl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2-tetrahydropyran- 4-ylacetyl)amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0] hexane-2-carboxamide (170 mg, 0.278 mmol, 1.00 eq) in methylene chloride (2.00 mL) was added Burgess reagent (166 mg, 0.695 mmol, 2.50 eq). After stirring at 25 °C for 2 h, the reaction mixture was partitioned between water (100 mL) and ethyl acetate (200 mL). The combined organic layers were washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 0:1) to afford (1R,2S,5S)-N-[(1S)-1-cyano-2- [(2S)-3-oxo-4H-1,4-benzoxazin-2-yl]ethyl]-3-[(2S)-3,3-dimeth yl-2-[(2-tetrahydropyran-4- ylacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxamide (60.0 mg, 98.0 μmol, 35% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.76 (s, 1H), 9.04 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 9.2 Hz, 1H), 6.96- 6.80 (m, 4H), 5.20-5.08 (m, 1H), 4.56 (dd, J = 10.4, 2.4 Hz, 1H), 4.32 (d, J = 9.0 Hz, 1H), 4.08 (s, 1H), 3.88-3.80 (m, 2H), 3.79-7.71 (m, 2H), 3.24-3.16 (m, 2H), 2.59-2.49 (m, 1H), 2.40-2.20 (m, 2H), 2.08 (d, J = 6.8 Hz, 2H), 1.82-1.72 (m, 1H), 1.59-1.48 (m, 1H), 1.44-1.36 (m, 2H), 1.28 (d, J = 7.6 Hz, 1H), 1.16- 1.04 (m, 2H), 1.00 (s, 3H), 0.80 (s, 3H), 0.72 (s, 9H). LC-MS (Method C): Rt = 0.572 min; MS (ESIpos): m/z = 594.3 [M+H] ⁺ . SFC: de% = 95%. To a mixture of tetrahydrofuran-3-carboxylic acid (500 mg, 4.31 mmol, 0.413 mL, 1.00 eq) in dichloromethane (5.00 mL) were added benzotriazol-1-yloxy(tripyrrolidin-1- yl)phosphonium;hexafluorophosphate (3.36 g, 6.46 mmol, 1.50 eq) and 4-methylmorpholine (1.96 g, 19.4 mmol, 2.13 mL, 4.50 eq). After stirring for 10 min, methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyla te (1.82 g, 5.72 mmol, 1.33 eq, hydrochloric acid) was added. The reaction mixture was stirred at 25 °C for 16 h. The mixture reaction was diluted with water (20.0 mL).and extracted with ethyl acetate (20.0 mL × 5). The combined organic layers were dried over anhydrous sodium sulfate anhydrous, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®;20.0 g SepaFlash® Silica Flash Column, Eluent of 0~60% Ethyl acetate/Petroleum ethergradient @ 45 mL/min) followed by reversed phase (Instrument:80.0 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.5% FA), eluent B: acetonitrile; gradient: 0-20 min 60-80% B; flow 45 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give methyl (1R,2S,5S)-3-[(2S)-3,3- dimethyl-2-(tetrahydrofuran-3-carbonylamino)butanoyl]-6,6-di methyl-3-azabicyclo[3.1.0]hexane-2- carboxylate (1.20 g, 2.71 mmol, 63% yield, 86% purity) as brown oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.09-7.98 (m, 1H), 4.19 (d, J = 3.6 Hz, 1H), 3.91-3.74 (m, 3H), 3.73- 3.58 (m, 5H), 3.18-3.12 (m, 1H), 2.05-1.80 (m, 2H), 1.55-1.48 (m, 1H), 1.48-1.39 (m, 1H), 1.00 (s, 3H), 0.98-0.92 (m, 9H), 0.89-0.82 (m, 1H), 0.84-0.77 (m, 3H). Procedure for preparation of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(tetrahydrofuran-3- carbonylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexa ne-2-carboxylic acid A mixture of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(tetrahydrofuran-3-carbony lamino)butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (600 mg, 1.58 mmol, 1.00 eq) and lithium hydroxide (114 mg, 4.73 mmol, 3.00 eq) in methanol (10.0 mL) and water (5.00 mL) was stirred at 25 °C for 16 h. The mixture was concentrated to give a residue. The residue was purified by reversed phase (Instrument: 80.0 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.5% FA), eluent B: acetonitrile; gradient: 0-20 min 40~60 % B; flow 45 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give ((1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(tetrahydrofuran-3- carbonylamino)butanoyl]-6,6-dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxylic acid (380 mg, 0.896 mmol, 57% yield, 86% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.08-8.01 (m, 1H), 4.46-1.39 m, 1H), 4.11 (d, J = 3.6 Hz, 1H), 3.85- 3.77 (m, 2H), 3.73-3.57 (m, 2H), 3.17-3.04 (m, 1H), 2.02-1.80 (m, 2H), 1.56-1.45 (m, 1H), 1.44-1.36 (m, 1H), 1.00 (s, 3H), 0.98-0.89 (m, 9H), 0.80-0.78 (m, 3H). Procedure for preparation of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4- benzoxazin-2-yl]methyl]ethyl]-3-[(2S)-3,3-dimethyl-2-(tetrah ydrofuran-3- carbonylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexa ne-2-carboxamide To a mixture of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(tetrahydrofuran-3-carbony lamino)butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (150 mg, 0.409 mmol, 1.00 eq) in dichloromethane (2.00 mL) were added N,N-diisopropylethylamine (212 mg, 1.64 mmol, 0.285 mL, 4.00 eq) and [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dim ethyl- ammonium;hexafluorophosphate (233 mg, 0.614 mmol, 1.50 eq). After stirring for 10 min, (2S)-2-amino- 3-[(2S)-3-oxo-4H-1,4-benzoxazin-2-yl]propanamide (96.3 mg, 0.409 mmol, 1.00 eq) was added. The reaction mixture was stirred for 25 °C at 16 h. The mixture was concentrated to give a residue. The residue was purified by reversed phase (instrument: 25.0 g Flash; Column: Welch Ultimate XB_C18 20-40μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-15 min 40-70% B; flow 40 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)-N-[(1S)-2-amino-2-oxo- 1-[[(2S)-3-oxo-4H-1,4-benzoxazin-2-yl]methyl]ethyl]-3-[(2S)- 3,3-dimethyl-2-(tetrahydrofuran-3- carbonylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexa ne-2-carboxamide (130 mg, 0.216 mmol, 53% yield, 97% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.62 (s, 1H), 8.30 (d, J = 8.8 Hz, 1H), 7.92-7.85 (m, 1H), 7.30 (s, 1H), 7.12 (s, 1H), 6.95-6.81 (m, 4H), 4.59-4.46 (m, 2H), 4.38-4.28 (m, 1H), 4.21-4.14 (m, 1H), 3.83-3.74 (m, 3H), 3.68-3.59 (m, 3H), 2.29-2.04 (m, 2H), 1.92-1.86 (m, 1H), 0.99-0.88 (m, 3H), 0.81-0.77 (m, 3H), 0.71-0.70 (m, 9H). Procedure for preparation of tert-butyl N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4-benzoxazin- 2-yl]methyl]ethyl]carbamate A mixture of tert-butyl-N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4-benzo xazin-2- yl]methyl]ethyl]carbamate (1.00 g, 2.98 mmol, 1 eq) and hydrochloric acid (4 M in 1,4-dioxane, 10.0 mL, 13.4 eq) in 1,4-dioxane (10.0 mL) was stirred at 25 °C for 2 h. The mixture was concentrated to give (2S)-2-amino-3-[(2S)-3-oxo-4H-1,4-benzoxazin-2-yl]propanamid e (700 mg, 1.80 mmol, 60% yield, 70% purity, hydrochloric acid) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.85 (s, 1H), 8.36-8.17 (m, 2H), 7.97 (s, 1H), 7.67 (s, 1H), 7.16- 6.76 (m, 4H), 4.69-4.61 (m, 1H), 3.99-3.91 (m, 1H), 2.43-2.39 (m, 1H), 2.28-2.21 (m, 1H). Procedure for preparation of Compound CPD0220275 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-3- oxo-4H-1,4-benzoxazin-2-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-(te trahydrofuran-3- carbonylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexa ne-2-carboxamide A mixture of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4-benzo xazin-2-yl]methyl]ethyl]-3- [(2S)-3,3-dimethyl-2-(tetrahydrofuran-3-carbonylamino)butano yl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (130 mg, 0.223 mmol, 1.00 eq) and methoxycarbonyl- (triethylammonio)sulfonyl-azanide (80.0 mg, 0.334 mmol, 1.50 eq) in dichloromethane (1.00 mL) was stirred 25 °C for 3 h. The mixture was concentrated to give a residue. The residue was purified by reversed phase (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: [water(FA)- ACN];B%: 36%-66%,10min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-3-oxo-4H-1,4-benzoxazin-2 - yl]ethyl]-3-[(2S)-3,3-dimethyl-2-(tetrahydrofuran-3-carbonyl amino)butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (60.0 mg, 0.104 mmol, 47% yield, 98% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.75 (s, 1H), 9.02 (d, J = 8.5 Hz, 1H), 7.95-7.84 (m, 1H), 6.98-6.85 (m, 4H), 5.19-5.08 (m, 1H), 4.59-4.51 (m, 1H), 4.35-4.28 (m, 1H), 4.09 (d, J = 4.4 Hz, 1H), 3.89-3.74 (m, 3H), 3.71-3.58 (m, 3H), 3.44-3.37 (m, 1H), 3.14-3.02 (m, 1H), 2.29-2.22 (m, 1H), 1.95-1.75 (m, 3H), 1.60-1.49 (m, 1H), 1.37-1.29 (m, 1H), 1.01 (s, 3H), 0.88-0.79 (m, 3H), 0.74-0.67 (m, 9H). LC-MS (Method C): Rt = 0.513 min; MS (ESIpos): m/z = 565.3 [M+H] ^+. SFC: dr = 47: 53. To a solution of methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimeth yl-3- azabicyclo[3.1.0]hexane-2-carboxylate (1.00 g, 3.54 mmol, 1.00 eq) in dichloromethane (20.0 mL) was added dropwise diisopropylethylamine (2.29 g, 17.7 mmol, 3.08 mL, 5.00 eq) at 0 °C over 1 min. After addition, the mixture was stirred at this temperature for 10 min. Cyclopropanecarbonyl chloride (407 mg, 3.90 mmol, 354 uL, 1.10 eq) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with hydrochloric acid (1M, 1.00 mL) at 0 °C, diluted with water (5.00 mL) and extracted with ethyl acetate (10.0 mL). The combined organic layer were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give methyl (1R,2S,5S)-3-[(2S)-2-(cyclopropanecarbonylamino)-3,3-dimethy l- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyla te (1.02 g, 2.62 mmol, 74% yield, 90% purity) as colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.13 (d, J = 9.2 Hz, 1H), 5.76 (s, 1H), 4.40 (d, J = 9.2 Hz, 1H), 4.20 (s, 1H), 3.66 (s, 3H), 3.61-3.53 (m, 2H), 3.33 (s, 3H), 1.93-1.67 (m, 2H), 1.56-1.32 (m, 2H), 1.25-1.18 (m, 1H), 1.05-0.91 (m, 16H), 0.80 (s, 3H), 0.65-0.45 (m, 3H). Procedure for preparation of (1R,2S,5S)-3-((S)-2-(cyclopropanecarboxamido)-3,3- dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-c arboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-2-(cyclopropanecarbonylamino)-3,3-dimethy l-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (960 mg, 2.74 mmol, 1.00 eq) in methanol (6 mL) and water (3 mL) was added lithium hydrate (197 mg, 8.22 mmol, 3.00 eq). After stirring at 20 °C for 16 h, the reaction mixture was quenched with water (10.0 mL) at 25 °C. Hydrochloric acid (1M) was added to adjust pH to 5. The resulting mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were washed with water (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-3-[(2S)-2- (cyclopropanecarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (640 mg, 1.81 mmol, 66% yield, 95% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.12 (d, J = 9.2 Hz, 1H), 4.41 (d, J = 9.2 Hz, 1H), 4.12 (s, 1H), 3.87- 3.73 (m, 2H), 1.88-1.77 (m, 1H), 1.55-1.31 (m, 2H), 1.56-1.15 (m, 1H), 0.97-0.89 (m, 13H), 0.88-0.75 (m, 1H), 0.84-0.71 (m, 4H), 0.71-0.48 (m, 4H). Procedure for preparation of (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)propan-2-yl)-3-((S)-2-(cyclopropane carboxamido)-3,3- dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-c arboxamide To a solution of (1R,2S,5S)-3-[(2S)-2-(cyclopropanecarbonylamino)-3,3-dimethy l-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (640 mg, 1.90 mmol, 1.00 eq) in dichloromethane (5.00 mL) were added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dim ethyl- ammonium;hexafluorophosphate (1.08 g, 2.85 mmol, 1.50 eq) and N-ethyl-N-isopropyl-propan-2-amine (1.48 g, 11.4 mmol, 1.99 mL, 6.00 eq) at 20 °C. After stirring at this temperature for 10 min, (2S)-2- amino-3-[(2S)-3-oxo-4H-1,4-benzoxazin-2-yl]propanamide (492 mg, 2.09 mmol, 1.10 eq) was added dropwise at 20 °C. The resulting mixture was stirred at 20 °C for 16 h. The reaction mixture was partitioned between water (30.0 mL) and ethyl acetate (50.0 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (instrument: 20g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.05% FA), eluent B: acetonitrile; gradient: 0-20 min 0-80% B; flow 40 ml/min; temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(2S)- 3-oxo-4H-1,4-benzoxazin-2-yl]methyl]ethyl]-3-[(2S)-2-(cyclop ropanecarbonylamino)-3,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxami de (557 mg, 0.905 mmol, 48% yield, 90% purity) as red oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.63 (s, 1H), 8.46-8.32 (m, 1H), 8.06-7.93 (m, 1H), 7.30 (s, 1H), 7.13 (s, 1H), 6.96-6.80 (m, 1H), 4.53 (s, 1H), 4.30-4.18 (m, 1H), 4.09-4.01 (m, 1H), 3.78 (s, 1H), 1.99 (s, 1H), 1.32-1.05 (m, 1H), 0.92-0.50 (m, 1H). Procedure for preparation of Compound CPD0220277 - (1R,2S,5S)-N-((S)-1-cyano-2-((S)-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-3-((S)-2-(cyc lopropanecarboxamido)-3,3- dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-c arboxamide A mixture of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4-benzo xazin-2-yl]methyl]ethyl]-3- [(2S)-2-(cyclopropanecarbonylamino)-3,3-dimethyl-butanoyl]-6 ,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide (300 mg, 0.542 mmol, 1.00 eq) and Burgess reagent (194 mg, 0.813 mmol, 1.50 eq) in ethyl acetate (3.00 mL) was stirred at 20 °C for 6 h. The reaction mixture was partitioned between water (30.0 mL) and ethyl acetate (30.0 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10 μm; mobile phase: [water(FA)- ACN];B%: 35%-65%,10min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-3-oxo-4H-1,4-benzoxazin-2 - yl]ethyl]-3-[(2S)-2-(cyclopropanecarbonylamino)-3,3-dimethyl -butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (107 mg, 0.196 mmol, 36% yield, 98% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.76 (br s, 1H), 9.02 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 6.99-6.86 (m, 5H), 5.19-5.11 (m, 1H), 4.56 (dd, J = 2.4, 10.2 Hz, 1H), 4.29 (d, J = 8.8 Hz, 1H), 4.09- 4.05 (m, 1H), 3.85-3.78 (m, 2H), 2.34-2.23 (m, 2H), 1.86-1.75 (m, 1H), 1.56-1.47 (m, 1H), 1.30 (d, J = 7.6 Hz, 1H), 1.05-0.95 (m, 5H), 0.82-0.71 (m, 15H), 0.69-0.49 (m, 6H). LC-MS (Method C): R _t = 0.56 min; MS (ESIpos): m/z = 536.4 [M+H] ⁺ . SFC: de% = 100%. A mixture of (1R,2S,5S)-3-[(2S)-2-[[2-(cyclopropoxy)acetyl]amino]-3,3-dim ethyl-butanoyl] -6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (300 mg, 0.818 mmol, 1.00 eq), O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (466 mg, 1.23 mmol, 1.50 eq) and N,N-diisopropylethylamine (423 mg, 3.27 mmol, 4.00 eq) in N,N-dimethylformamide (5.00 mL) was stirred at 25 °C for 0.5 h.2-Amino-2-phthalazin-1-yl-acetamide (195 mg, 0.818 mmol, 1.00 eq, HCl) was added to the solution above. After stirring at 25 °C for 11.5 h, the reaction mixture was poured into saturated sodium bicarbonate aqueous (30.0 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 50%-70% (Ethyl acetate:methnol = 10: 1)/Petroleum ether gradient @ 80 mL/min) to give (1R,2S,5S)-N-(2-amino- 2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S)-2-[[2-(cyclopropoxy)a cetyl]amino]-3,3-dimethyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (320 mg, 0.552 mmol, 67% yield, 95% purity) as a yellow solid. LC-MS (Method C): R _t = 0.755 min; MS (ESIpos): m/z = 551.4 [M+H] ⁺ . A mixture of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -2-[[2-(cyclopropoxy) acetyl]amino]-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyc lo[3.1.0]hexane-2-carboxamide (320 mg, 0.552 mmol, 95% purity, 1.00 eq) and (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (394 mg, 1.66 mmol, 3.00 eq) in dichloromethane (5.00 mL) was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*40mm* 15 μm; mobile phase: [water(FA)-ACN]; B%: 43%-73%, 9 min) to give (1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]-3-[(2S)-2-[[2-(c yclopropoxy)acetyl]amino]- 3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan e-2-carboxamide (58.5 mg, 0.107 mmol, 19% yield, 97% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.69 (s, 0.2H), 9.85-9.41 (m, 1.4H), 8.84-8.75 (m, 0.4H), 8.31-7.74 (m, 3.8H), 7.47 (d, J = 8.4 Hz, 0.4H), 7.40-7.23 (m, 0.7H), 4.47-4.32 (m, 1H), 4.30-4.12 (m, 1H), 4.03- 3.87 (m, 3H), 3.85-3.70 (m, 1H), 3.44-3.40 (m, 1H), 3.36-3.31 (m, 1H), 1.69-1.10 (m, 2H), 1.08-0.74 (m, 15H), 0.59-0.34 (m, 4H). LC-MS (Method C): R _t = 0.562 min; MS (ESIpos): m/z = 533.2 [M+H] ⁺ . SFC: dr = 1: 1. HPLC (Method M): R _t = 2.058 min; purity: 98%. Preparation of CPD0277851 Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[[2-(3- pyridyl)acetyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1 .0]hexane-2-carboxylate A mixture of 2-(3-pyridyl)acetic acid (1.00 g, 5.76 mmol, 1.00 eq, HCl), methyl (1R,2S,5S)-3-[(2S)-2- amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxylate (2.02 g, 6.34 mmol, 1.10 eq, HCl), benzotriazol-1-yloxy(tripyrrolidin-1-yl) phosphanium;hexafluorophosphate (3.90 g, 7.49 mmol, 1.30 eq) and 4-methylmorpholine (2.33 g, 23.0 mmol, 2.53 mL, 4.00 eq) in dichloromethane (30.0 mL) was stirred at 25°C for 12 h. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were concentrated under vacuum and purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 50~100% Ethyl acetate/Petroleum ether gradient @ 60 mL/min) to give methyl (1R,2S,5S)-3- [(2S)-3,3-dimethyl-2-[[2-(3-pyridyl)acetyl]amino] butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylate (2.10 g, 4.71 mmol, 81% yield, 90% purity) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.45-8.38 (m, 2H), 8.30 (d, J = 9.0 Hz, 1H), 7.63-7.60 (m, 1H), 7.35- 7.25 (m, 1H), 4.38 (d, J = 9.0 Hz, 1H), 4.18 (s, 1H), 3.80 (d, J = 2.8 Hz, 2H), 3.66 (s, 3H), 3.61-3.55 (m, 1H), 3.54-3.49 (m, 1H), 1.56-1.47 (m, 1H), 1.44-1.37 (m, 1H), 0.98-0.68 (m, 15H). LC-MS (Method L): R _t = 0.456 min; MS (ESIpos): m/z = 402.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[[2-(3- pyridyl)acetyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1 .0]hexane-2-carboxylic acid A mixture of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[[2-(3-pyridyl)acetyl]amin o]butanoyl] -6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (2.10 g, 4.71 mmol, 90% purity, 1.00 eq) and lithium hydroxide monohydrate (592 mg, 14.1 mmol, 3.00 eq) in mixed solvent of methanol (20.0 mL) and water (20.0 mL) was stirred at 25 °C for 12 h. The reaction mixture was poured into water (50.0 mL) and washed with ethyl acetate (20.0 mL × 2). Hydrochloric acid (1M in water) was added to the aqueous phase to adjust pH~7 and extracted with mixed solvent of ethyl acetate and methanol (v/v = 5/1, 30.0 mL × 5). The combined organic layers were concentrated under vacuum to give (1R,2S,5S)-3-[(2S)- 3,3-dimethyl-2-[[2-(3-pyridyl)acetyl]amino]butanoyl]-6,6-dim ethyl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (2.00 g, crude) as an off-white solid. LC-MS (Method G): R _t = 0.222 min; MS (ESIpos): m/z = 388.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -3,3- dimethyl-2-[[2-(3-pyridyl)acetyl]amino]butanoyl]-6,6-dimethy l-3-azabicyclo[3.1.0]hexane-2- carboxamide A mixture of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[[2-(3-pyridyl)acetyl]amin o]butanoyl] -6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (800 mg, 2.06 mmol, 1.00 eq), benzotriazol-1- yloxy(tripyrrolidin-1-yl)phosphanium;hexafluorophosphate (1.29 g, 2.48 mmol, 1.20 eq) and 4- methylmorpholine (835 mg, 8.26 mmol, 4.00 eq) in dichloromethane (20.0 mL) was stirred at 0 °C for 0.5 h, followed by 2-amino-2-phthalazin-1-yl-acetamide (492 mg, 2.06 mmol, 1.00 eq, HCl). After stirring at 25 °C for 11.5 h, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-20% methanol/Ethyl acetate @ 60 mL/min) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1- yl-ethyl)-3-[(2S)-3,3-dimethyl-2-[[2-(3-pyridyl)acetyl]amino ]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (700 mg, 1.10 mmol, 53% yield, 90% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.79-9.55 (m, 1H), 9.30-8.88 (m, 1H), 8.57-8.36 (m, 2H), 8.35-8.14 (m, 3H), 8.12-8.01 (m, 2H), 7.72-7.45 (m, 3H), 7.31-7.28 (m, 1H), 6.41-6.06 (m, 1H), 4.49-4.29 (m, 2H), 3.93-3.70 (m, 2H), 3.65-3.47 (m, 2H), 1.49-1.40 (m, 1H), 1.17-1.10 (m, 1H), 0.99-0.66 (m, 15H). LC-MS (Method C): R _t = 0.395 min; MS (ESIpos): m/z = 572.4 [M+H] ⁺ . A mixture of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -3,3-dimethyl-2-[[2- (3- pyridyl)acetyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1 .0]hexane-2-carboxamide (180 mg, 0.283 mmol, 90% purity, 1.00 eq) and (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (101 mg, 0.425 mmol, 1.50 eq) in dichloromethane (10.0 mL) was stirred at 25°C for 2 h. The reaction mixture was poured into water (20.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge C18150*50mm* 10 μm; mobile phase: [water( NH4HCO3)-ACN]; B%: 25%-55%, 10 min) to give (1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]-3-[(2S)-3,3-dime thyl-2-[[2-(3- pyridyl)acetyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1 .0]hexane-2-carboxamide (78.2 mg, 0.137 mmol, 16% yield, 97% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.71 (s, 0.4H), 9.84-9.73 (m, 0.8H), 8.63 (d, J = 8.0 Hz, 0.2H), 8.43 (s, 0.4H), 8.83-8.69 (m, 0.4H), 8.49-8.36 (m, 2H), 8.35-8.16 (m, 1.5H), 8.13-8.05 (m, 1.2H), 8.04-7.87 (m, 1H), 7.86-7.73 (m, 1.3H), 7.70-7.53 (m, 1H), 7.37-7.20 (m, 1.4H), 4.41-4.28 (m, 1H), 4.27-4.09 (m, 1H), 3.96-3.85 (m, 1H), 3.83-3.67 (m, 1H), 3.65-3.40 (m, 2H), 1.64-1.43 (m, 1.4H), 1.32-1.18 (m, 0.5H), 1.09-0.56 (m, 15H). LC-MS (Method C): R _t = 0.763 min; MS (ESIpos): m/z = 554.3 [M+H] ⁺ . HPLC (Method M): R _t = 1.501 min; HPLC purity: 97.33%. SFC: dr: 2: 21: 10: 45: 22. Preparation of CPD0277852 Procedure for preparation of methyl (2S)-2-[(6-methoxy-3-pyridyl)amino]-3,3-dimethyl- butanoate To a solution of (6-methoxy-3-pyridyl)boronic acid (5.00 g, 32.7 mmol, 1.00 eq), methyl (2S)-2-amino- 3,3-dimethyl-butanoate (6.53 g, 36.0 mmol, 1.10 eq, Hydrogen chloride) and cesium carbonate (42.6 g, 130 mmol, 4.00 eq) in acetonitrile (100 mL) was added copper acetate (5.94 g, 32.7 mmol, 1.00 eq). After stirring at 20 °C for 12 h under oxygen atmosphere, the reaction mixture was filtered. The filtrate was concentrated under vacuum to give a residue. The residue was purified by flash column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 0 to 10: 1) to afford methyl (2S)-2-[(6- methoxy-3-pyridyl)amino]-3,3-dimethyl-butanoate (3.50 g, 12.5 mmol, 38% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.61 (d, J = 2.8 Hz, 1H), 7.03 (dd, J = 8.8, 2.8 Hz, 1H), 6.62 (d, J = 8.8 Hz, 1H), 3.86 (s, 3H), 3.68 (s, 3H), 3.63 (br d, J = 7.6 Hz, 1H), 1.06 (s, 9H). A solution of methyl (2S)-2-[(6-methoxy-3-pyridyl)amino]-3,3-dimethyl-butanoate (1.00 g, 3.96 mmol, 1.00 eq) in hydrogen bromide/water (16.0 g, 79.3 mmol, 10.8 mL, 40% purity, 20.0 eq) was stirred at 80 °C for 12 h. The solution was diluted with water (10.0 mL). Sodium hydroxide (2M) aqueous solution was added to adjust pH = 2 at 25 °C. The resulting precipitation was filtered and the filter cake was concentrated under reduced pressure to afford (2S)-3,3-dimethyl-2-[(6-oxo-1H-pyridin-3- yl)amino]butanoic acid (800 mg, 3.57 mmol, 90% yield) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.69 (br. s, 1H), 7.29 (dd, J = 9.6, 2.8, 1H), 6.58 (d, J = 2.8 Hz, 1H), 6.27 (d, J = 9.6 Hz, 1H), 4.80 (br. s, 1H), 1.00 (s, 9H). Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(6-oxo-1H-pyridin-3- yl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylate To a solution of (2S)-3,3-dimethyl-2-[(6-oxo-1H-pyridin-3-yl)amino]butanoic acid (1.10 g, 4.91 mmol, 1.00 eq) and methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate;hydrochloride (1.11 g, 5.40 mmol, 1.10 eq) in dichloromethane (20.0 mL) were added diisopropylethylamine (2.54 g, 19.6 mmol, 3.42 mL, 4.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (2.05 g, 5.40 mmol, 1.10 eq). After stirring at 20 °C for 2 h, the reaction mixture was concentrated under vacuum at 50 °C to give a residue. The residue was purified by flash column chromatography (SiO ₂ , Dichloromethane: Methanol = 100: 1 to 10: 1) to afford methyl (1R,2S,5S)-3- [(2S)-3,3-dimethyl-2-[(6-oxo-1H-pyridin-3-yl)amino]butanoyl] -6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxylate (1.30 g, 3.46 mmol, 70% yield) as colorless oil. Procedure for preparation of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(6-oxo-1H-pyridin-3- yl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(6-oxo-1H-pyridin-3-yl)am ino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.30 g, 3.46 mmol 1.00 eq) in mixed solvent of methanol (10.0 mL) and water (1.00 mL) was added lithium hydroxide hydrate (291 mg, 6.92 mmol, 2.00 eq). After stirring at 25 °C for 16 h, the reaction mixture was concentrated under vacuum to afford (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(6-oxo-1H-pyridin-3-yl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (1.10 g, 3.04 mmol, 88% yield) as a brown solid. LC-MS (Method C): Rt = 0.535 min and 0.618 min; MS (ESIpos): m/z = 362.2 [M+H] ^+. To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(6-oxo-1H-pyridin-3-yl)am ino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.10 g, 3.04 mmol, 1.00 eq) and 2-amino-2- phthalazin-1-yl-acetamide (739 mg, 3.65 mmol, 1.20 eq, Hydrogen chloride) in dichloromethane (10.0 mL) were added diisopropylethylamine (1.57 g, 12.2 mmol, 2.12 mL, 4.00 eq) and O-(7-azabenzotriazol- 1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (1.27 g, 3.35 mmol, 1.10 eq). After stirring at 20 °C for 12 h, the reaction mixture was concentrated under vacuum at 50 °C to give a residue. The residue was purified by reversed phase column (instrument: 80g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-50min 0-100% B; flow 50 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to afford (1R,2S,5S)-N-(2-amino- 2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S)-3,3-dimethyl-2-[(6-ox o-1H-pyridin-3-yl)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (400 mg, 0.733 mmol, 24% yield) as a brown solid. LC-MS (Method C): Rt = 0.560 min; MS (ESIpos): m/z = 546.4 [M+H] ^+. Procedure for prepa yl)methyl]-3-[(2S)-3,3- azabicyclo[3.1.0]hexa To a solution of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -3,3-dimethyl-2-[(6-oxo- 1H-pyridin-3-yl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (400 mg, 0.733 mmol, 1.00 eq) in dimethyl formamide (4.00 mL) was added dropwise trifluoroacetic anhydride (616 mg, 2.93 mmol, 0.408 mL, 4.00 eq). After stirring at 20 °C for 0.5 h, the reaction mixture was concentrated under vacuum at 30 °C to give a residue. The residue was purified by reversed phase column (instrument: 80 g Flash; Column: Welch Ultimate XB_C1820-40μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-50 min 0-100% B; flow 55 ml/min; temperature: room temperature; Detector: UV 220/254 nm) and prep-HPLC (column: UniSil 3-100 C18 UItra (150*25mm*3 μm); mobile phase: [water(FA)-ACN];B%: 26%-56%,7min) to afford (1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]-3- [(2S)-3,3-dimethyl-2-[(6-oxo-1H-pyridin-3-yl)amino] butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide (29.5 mg, 54.4 μmol) as a green solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.95 (br. s, 1H), 10.66 (s, 0.5H), 9.81-9.71 (m, 1H), 9.64 (d, J = 8.8 Hz, 0.2H), 9.45 (s, 0.5H), 8.76 (dd, J = 7.2, 2.4 Hz, 0.4H), 8.31-8.19 (m, 0.6H), 8.14-8.05 (m, 1.2H), 8.03-7.96 (m, 0.6H), 7.94-7.85 (m, 0.4H), 7.85-7.72 (m, 1.5H), 7.37-7.20 (m, 1.5H), 6.92-6.61 (m, 1H), 6.28-6.12 (m, 1H), 4.42-4.23 (m, 1H), 4.22-4.15 (m, 1H), 4.08 (s, 0.3H), 3.90-3.80 (m, 1H), 3.69-3.47 (m, 2H), 1.65-1.53 (m, 1H), 1.48 (d, J = 7.8 Hz, 0.7H), 1.26 (d, J = 7.6 Hz, 0.3H), 1.05 (s, 3H), 1.00 (d, J = 2.1 Hz, 5H), 0.97 (br s, 1.5H), 0.94 (s, 1.5H), 0.83 (s, 1H), 0.62 (s, 1.5H), 0.52-0.44 (m, 0.5H). LC-MS (Method C): Rt = 0.618 min; MS (ESIpos): m/z = 528.3 [M+H] ⁺ . SFC: dr 38: 62. Preparation of CPD0277853 Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-2-[(2-ethoxyacetyl)amino]-3,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyla te To a mixture of 2-ethoxyacetic acid (588 mg, 5.65 mmol, 1.20 eq) in dichloromethane (20.0 mL) were added benzotriazol-1-yloxy(tripyrrolidin-1-yl)phosphanium;hexafluo rophosphate (3.18 g, 6.12 mmol, 1.30 eq) and N-methylmorpholine (1.43 g, 14.1 mmol, 1.55 mL, 3.00 eq) at 0 °C followed by methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimeth yl-3-azabicyclo[3.1.0]hexane-2- carboxylate (1.50 g, 4.70 mmol, 1.00 eq, hydrochloride). After stirring at 25 °C for 16 h, the mixture was diluted with saturated ammonium chloride aqueous solution (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 80 mL/min) to afford methyl (1R,2S,5S)-3-[(2S)-2-[(2- ethoxyacetyl)amino]-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-az abicyclo[3.1.0]hexane-2-carboxylate (670 mg, 1.82 mmol, 39% yield) as colorless liquid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.14 (d, J = 9.6 Hz, 1H), 4.58 (d, J = 9.6 Hz, 1H), 4.46 (s, 1H), 3.95-3.86 (m, 2H), 3.91-3.87 (m, 1H), 3.77 (s, 3H), 3.54 (q, J = 7.2 Hz, 2H), 1.51-1.43 (m, 1H), 1.32-1.27 (m, 1H), 1.23 (t, J =7.2 Hz, 3H), 1.09-0.86 (m, 15H). LC-MS (Method C): R _t = 0.841 min; MS (ESIpos): m/z = 369.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-[(2-ethoxyacetyl)amino]-3,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyli c acid - To a solution of methyl (1R,2S,5S)-3-[(2S)-2-[(2-ethoxyacetyl)amino]-3,3-dimethyl-bu tanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (670 mg, 1.82 mmol, 1.00 eq) in methanol (5.00 mL) was added a solution of lithium hydroxide (174 mg, 7.27 mmol, 4.00 eq) in water (5.00 mL). After stirring at 25 °C for 16 h, hydrochloric acid (0.5M in water) was added to the reaction mixture to adjust pH~3 and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give (1R,2S,5S)-3-[(2S)-2-[(2-ethoxyacetyl)amino]-3,3-dimethyl-bu tanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxylic acid (440 mg, 1.24 mmol, 68 % yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.15 (d, J = 9.6 Hz, 1H), 4.59 (d, J = 9.6 Hz, 1H), 4.49 (s, 1H), 4.12-4.00 (m, 2H), 3.96-3.89 (m, 2H), 3.60-3.55 (m, 2H), 1.76-1.65(m, 1H), 1.43-1.56 (m, 1H), 1.31-1.22 (t, J = 6.8 Hz, 3H), 1.08-0.90 (m, 15H). LC-MS (Method C): R _t = 0.468 min; MS (ESIpos): m/z = 355.1 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -2-[(2- ethoxyacetyl)amino]-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-az abicyclo[3.1.0]hexane-2- carboxamide To a mixture of (1R,2S,5S)-3-[(2S)-2-[(2-ethoxyacetyl)amino]-3,3-dimethyl-bu tanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (300 mg, 0.846 mmol, 1.00 eq), N,N-diisopropylethylamine (438 mg, 3.39 mmol, 4.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (418 mg, 1.10 mmol, 1.30 eq) in N,N-dimethylformamide (5.00 mL) was added 2-amino-2-phthalazin-1-yl-acetamide (233 mg, 0.846 mmol, 1.00 eq, 2 hydrochloride). After stirring at 25 °C for 16 h, the reaction mixture was diluted with saturated ammonium chloride (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®;12g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate/Petroleum ether gradient @ 60 mL/min) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -2-[(2-ethoxyacetyl)amino]-3,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxami de (400 mg, 0.743 mmol, 88% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.62-9.37 (m, 1H), 8.66-8.41 (m, 2H), 8.12-7.81 (m, 3H), 7.15-7.02 (m, 1H), 6.45-6.41 (m, 1H), 5.48 (s, 1H), 4.60-4.50 (m, 1H), 4.31 (s, 1H), 4.15-4.05 (m, 2H),3.97-3.93 (m, 2H), 3.61-3.55 (m, 2H), 1.66-1.58 (m, 1H), 1.40-1.34 (m, 1H), 1.28-1.23 (m, 3H), 1.12-0.98 (m, 15H). LC-MS (Method C): Rt = 0.535 min; MS (ESIpos): m/z = 539.2 [M+H] ⁺ . To a solution of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -2-[(2- ethoxyacetyl)amino]-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-az abicyclo[3.1.0]hexane-2-carboxamide (350 mg, 0.650 mmol, 1.00 eq) in dichloromethane (5.00 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (232 mg, 0.975 mmol, 1.50 eq) at 0 °C. After stirring at 25 °C for 2 h, the reaction mixture was diluted with saturated ammonium chloride (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 80 mL/min) and prep- HPLC (column: Waters X bridge C18 150*50mm* 10 μm; mobile phase: [water(ammonium bicarbonate)-acetonitrile ]; B%: 30%-60%,10min) to give (1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]- 3-[(2S)-2-[(2-ethoxyacetyl)amino]-3,3-dimethyl-butanoyl]-6,6 -dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (31.8 mg, 58.6 μmol, 9% yield, 96% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.71 (s, 0.6H), 9.91-9.74 (m, 0.5H), 9.44 (s, 0.6H), 8.94-8.61(m, 0.7H), 8.34-7.96 (m, 2H), 7.94-7.21(m, 4H), 4.44-4.36 (m, 1H), 4.29-4.16 (m, 1H), 3.98-3.79 (m, 4H), 3.52-3.45 (m, 2H), 1.66-1.53 (m, 2H), 1.15 (t, J = 6.8 Hz, 3H), 1.17-1.01 (m, 3H), 1.05-0.99 (m, 3H), 0.96 (s, 6H), 0.91 (s, 3H). LC-MS (Method C): R _t = 0.596 min; MS (ESIpos): m/z = 521.3 [M+H] ⁺ . HPLC (Method S): R _t = 2.052 min; purity: 96%. SFC: dr = 29: 30: 13: 28. To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(pyrimidin-5-ylamino) butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (300 mg, 0.866 mmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (494 mg, 1.30 mmol, 1.50 eq) and N,N- diisopropylethylamine (448 mg, 3.46 mmol, 0.603 mL, 4.00 eq) in N,N-dimethylformamide (3.00 mL) was added 2-amino-2-phthalazin-1-yl-acetamide (248 mg, 1.04 mmol, 1.20 eq, hydrochloride) at 0 °C. After stirring at 25 °C for 12 h, the reaction mixture was poured into saturated sodium carbonate aqueous (5.00 mL) and then extracted with ethyl acetate (3.00 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether; gradient @60 mL/min) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -3,3-dimethyl-2-(pyrimidin-5- ylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-c arboxamide (336 mg, 633 μmol, 73% yield) as a light yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ= 9.57-9.41 (m, 1H), 8.70-8.50 (m, 2H), 8.27-8.14 (m, 2H), 8.09-7.89 (m, 3H), 7.65-7.53 (m, 1H), 6.50-6.40 (m, 1H), 4.28 (s, 1H), 4.21-4.15 (m, 1H), 3.96-3.90 (m, 1H), 3.74-3.63 (m, 1H), 1.54-1.51 (m, 1H), 1.47-1.43 (m, 1H), 1.18-1.07 (m, 9H), 0.98 (s, 3H), 0.76 (s, 3H). LC-MS (Method Q): R _t = 0.475 min; MS (ESIpos): m/z = 531.4 [M+H] ⁺ . To a solution of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -3,3-dimethyl-2- (pyrimidin-5-ylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1 .0]hexane-2-carboxamide (200 mg, 37.0 μmol, 1.00 eq) in dichloromethane (3.00 mL) was added (methoxycarbonyl)[(triethylazaniumyl) sulfonyl]azanide (180 mg, 0.754 mmol, 2.00 eq) at 0 °C. After stirring at 25 °C for 12 h, the reaction mixture was poured into saturated ammonium chloride aqueous solution (3.00 mL) and extracted with ethyl acetate (3.00 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 μm; mobile phase: [water(FA)-ACN]; B%: 33%- 63%, 7 min) to give (1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]-3-[(2S)-3,3-dime thyl-2-(pyrimidin-5- ylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-c arboxamide (102 mg, 197 μmol, 52% yield, 99.6% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.66 (s, 0.5H), 9.81-9.75 (m, 0.5H), 9.45 (s, 0.5H), 8.84-8.73 (m, 0.5H), 8.44-8.32 (m, 2.5H), 8.31-8.23 (m, 1H), 8.13-8.06 (m, 1H), 8.06-7.88 (m, 0.6H), 7.87-7.74 (m, 2H), 7.28-7.34 (m, 0.3H), 5.98-5.74 (m, 1H), 4.32-4.06 (m, 2H), 4.06-3.89 (m, 1H), 3.86-3.70 (m, 1H), 1.74-1.60 (m, 1H), 1.59-1.51 (m, 1H), 1.13-0.96 (m, 11H), 0.87 (s, 1H). LC-MS (Method Q): R _t = 0.472 min; MS (ESIpos): m/z = 513.3 [M+H] ⁺ . HPLC (Method S): R _t = 1.936 min; purity: 99%. SFC: dr = 62: 38. Synthetic Scheme of CPD0277855 Procedure for preparation of 4-bromo-5-fluoro-1-(4-methoxybenzyl)pyridin-2(1H)-one To a mixture of 4-bromo-5-fluoropyridin-2(1H)-one (4.00 g, 20.8 mmol, 1.00 eq) and potassium carbonate (4.32 g, 31.3 mmol, 1.50 eq) in N,N-dimethylformamide (40.0 mL) was added 1- (chloromethyl)-4-methoxybenzene (3.59 g, 22.9 mmol, 1.10 eq) at 15 °C. After stirring at 50 °C for 2 h, the mixture was poured into water (200 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 5: 1 to 2: 1) to give 4-bromo-5-fluoro-1-(4-methoxybenzyl)pyridin-2(1H)-one (6.00 g, 19.2 mmol, 92% yield) as a white solid. To a mixture of 4-bromo-5-fluoro-1-(4-methoxybenzyl)pyridin-2(1H)-one (6.00 g, 19.2 mmol, 1.00 eq) and methyl (S)-2-amino-3,3-dimethylbutanoate (4.19 g, 23.1 mmol, 1.20 eq, hydrochloric acid salt) in dioxane (100 mL) were added tris(dibenzylideneacetone)dipalladium (0) (552 mg, 0.961 mmol, 0.05 eq), (±)-2,2'-bis(diphenylphosphino)-1,1’-binaphthalene (1.20 g, 1.92 mmol, 0.100 eq) and cesium carbonate (18.8 g, 57.7 mmol, 3.00 eq) at 15 °C. After stirring at 100 °C for 16 h under nitrogen atmosphere, the mixture was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 60 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 80 mL/min) to give methyl (S)-2-((5-fluoro-1-(4-methoxybenzyl)-2- oxo-1,2-dihydropyridin-4-yl)amino)-3,3-dimethylbutanoate (5.30 g, 14.1 mmol, 73% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.82 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 5.72 (d, J = 9.2 Hz, 1H), 5.40 (d, J = 8.4 Hz, 1H), 4.82 (s, 2H), 3.94 (d, J = 9.2 Hz, 1H), 3.73 (s, 3H), 3.67 (s, 3H), 1.01 (s, 9H). Procedure for preparation of methyl (S)-2-((5-fluoro-2-oxo-1,2-dihydropyridin-4-yl)amino)-3,3- dimethylbutanoate A mixture of methyl (S)-2-((5-fluoro-1-(4-methoxybenzyl)-2-oxo-1,2-dihydropyridi n-4-yl)amino)-3,3- dimethylbutanoate (2.00 g, 5.31 mmol, 1.00 eq) in trifluoromethanesulfonic acid (20.0 mL) was stirred at 25°C for 16 h. The mixture was poured into cooled water (200 mL) at 0 °C, adjusted to pH 8~9 with sodium bicarbonate solid and extracted with ethyl acetate (50.0 mL × 4). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~80% Ethyl acetate/Petroleum ether gradient @ 60 mL/min) to give methyl (S)-2-((5-fluoro-2-oxo-1,2- dihydropyridin-4-yl)amino)-3,3-dimethylbutanoate (1.20 g, 4.68 mmol, 88% yield) as a gray solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.45 (s, 1H), 7.35 (d, J = 6.8 Hz, 1H), 5.61 (d, J = 9.2 Hz, 1H), 5.31 (d, J = 8.0 Hz, 1H), 3.92 (d, J = 9.2 Hz, 1H), 3.68 (s, 3H), 1.02 (s, 9H). Procedure for preparation of (S)-2-((5-fluoro-2-oxo-1,2-dihydropyridin-4-yl)amino)-3,3- dimethylbutanoic acid A mixture of methyl (S)-2-((5-fluoro-2-oxo-1,2-dihydropyridin-4-yl)amino)-3,3-di methylbutanoate (500 mg, 1.95 mmol, 1.00 eq) and lithium hydroxide monohydrate (409 mg, 9.76 mmol, 5.00 eq) in mixed solvent of methanol (5.00 mL) and water (5.00 mL) was stirred at 25 °C for 16 h. Hydrochloric acid solution (1M in water) was added to adjust pH to 4~5 and concentrated to give a residue. The residue was purified by reversed phase HPLC (C18, 105 g, 0-10% of ACN in water with 0.1% FA condition) to give (S)-2-((5-fluoro-2-oxo-1,2-dihydropyridin-4-yl)amino)-3,3-di methylbutanoic acid (200 mg, 0.826 mmol, 42% yield, 99% purity) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.33 (d, J = 6.8 Hz, 1H), 5.48 (d, J = 9.2 Hz, 1H), 5.30 (d, J = 7.6 Hz, 1H), 3.73 (d, J = 8.8 Hz, 1H), 1.02 (s, 9H). LC-MS (Method C): R _t = 0.638 min; MS (ESIpos): m/z = 243.2 [M+H] ⁺ . Procedure for preparation of tert-butyl (1R,2S,5S)-2-[(2-amino-2-oxo-1-phthalazin-1-yl- ethyl)carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-ca rboxylate To a solution of 2-amino-2-phthalazin-1-yl-acetamide (1.00 g, 4.19 mmol, 1.00 eq, hydrochloride), O- (7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluor ophosphate (1.91 g, 5.03 mmol, 1.20 eq) and N,N-diisopropylethylamine (1.62 g, 12.6 mmol, 2.19 mL, 3.00 eq) in N,N-dimethylformamide (10.0 mL) was added (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3 .1.0]hexane-2- carboxylic acid (1.07 g, 4.19 mmol, 1.00 eq). After stirring at 25 °C for 12 h, the reaction mixture was poured into water (20.0 mL) and extracted with ethyl acetate (50.0 mL × 5). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 100% Ethyl acetate/Petroleum ether gradient @ 80 mL/min) to give tert- butyl (1R,2S,5S)-2-[(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)carbamo yl]-6,6-dimethyl-3-aza bicyclo[3.1.0]hexane-3-carboxylate (1.66 g, 3.78 mmol, 90 % yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.51 (d, J = 12.4 Hz, 1H), 8.57-8.45 (m, 2H), 8.09-7.94 (m, 3H), 7.79 (s, 0.5H), 7.60 (s, 0.5H), 6.51-6.37 (m, 1H), 5.51-5.23 (m, 1H), 3.85-3.67 (m, 2H), 3.18 (m, 1H), 1.47-1.41 (m, 9H), 1.31-1.21 (m, 2H), 1.06-0.94 (m, 6H). LC-MS (Method C): R _t = 0.481 min; MS (ESIpos): m/z = 440.2 [M+H] ⁺ . Procedure for preparation of tert-butyl (1R,2S,5S)-2-[[cyano(phthalazin-1-yl)methyl]carbamoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate To a solution of tert-butyl (1R,2S,5S)-2-[(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)carbamo yl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.00 g, 2.28 mmol, 1.00 eq) in dichloromethane (10.0 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (1.08 g, 4.55 mmol, 2.00 eq) at 0 °C. After stirring at 25 °C for 2 h, the reaction mixture was poured into saturated ammonium chloride (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 58% Ethyl acetate/Petroleum ether gradient @ 70 mL/min) to give tert-butyl (1R,2S,5S)-2-[[cyano(phthalazin-1-yl)methyl]carbamoyl]-6,6-d imethyl-3-aza bicyclo[3.1.0]hexane-3- carboxylate (700 mg, 1.63 mmol, 72% yield) as yellow oil. LC-MS (Method C): R _t = 0.600 min; MS (ESIpos): m/z = 422.4 [M+H] ⁺ . To a solution of tert-butyl (1R,2S,5S)-2-[[cyano(phthalazin-1-yl)methyl]carbamoyl]-6,6-d imethyl-3- azabicyclo[3.1.0]hexane-3-carboxylate (500 mg, 1.19 mmol, 1.00 eq) in acetonitrile (2.00 mL) was added hydrochloric acid (4M in dioxane, 2.00 mL) at 0 °C. After stirring at 25°C for 1 h, the reaction mixture was concentrated under reduced pressure to give (1R, 2S, 5S)-N-[cyano(phthalazin-1- yl)methyl]-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxamide (460 mg, crude, hydrochloride) as a yellow solid. LC-MS (Method C): R _t = 0.416 min; MS (ESIpos): m/z = 322.2 Procedure for preparation of CPD0277855 - (1R,2S,5S)-N-(cyano(phthalazin-1-yl)methyl)-3-((S)- 2-((5-fluoro-2-oxo-1,2-dihydropyridin-4-yl)amino)-3,3-dimeth ylbutanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of (S)-2-((5-fluoro-2-oxo-1,2-dihydropyridin-4-yl)amino)-3,3-di methylbutanoic acid (140 mg, 0.578 mmol, 1.00 eq) and (1R,2S,5S)-N-(cyano(phthalazin-1-yl)methyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (207 mg, 0.578 mmol, 1.00 eq, hydrochloric acid salt) in N,N- dimethylformamide (5.00 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (330 mg, 0.867 mmol, 1.50 eq) and N,N- diisopropylethylamine (299 mg, 2.31 mmol, 4.00 eq) at 25 °C. After stirring at 25 °C for 16 h, the mixture was poured into water (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 22%-52%, 10 min) and column chromatography (SiO ₂ , Dichloromethane: Methanol = 100: 1 to 20: 1) to give (1R,2S,5S)-N-(cyano(phthalazin-1-yl)methyl)-3-((S)-2-((5-flu oro-2- oxo-1,2-dihydropyridin-4-yl)amino)-3,3-dimethylbutanoyl)-6,6 -dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (67.7 mg, 0.123 mmol, 21% yield, 99% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.70 (s, 0.5H), 10.4-10.31 (m, 1H), 9.86-9.69 (m, 1H), 9.42 (s, 0.5H), 8.80-8.76 (m, 0.5H), 8.30-8.22 (m, 0.5H), 8.14-7.88 (m, 2H), 7.86-7.74 (m, 1H), 7.35-7.23 (m, 1.5H), 5.65-5.52 (m, 1H), 5.18-4.99 (m, 1H), 4.29 (d, J = 19.6 Hz, 1H), 4.19-4.08 (m, 1H), 4.01-3.89 (m, 1H), 3.86-3.75 (m, 1H), 1.71-1.54 (m, 1.5H), 1.37-1.31 (m, 0.5H), 1.12-0.69 (m, 15H). LC-MS (Method C): R _t = 0.488 min; MS (ESIpos): m/z = 546.3 [M+H] ⁺ . HPLC: (Method K): R _t = 1.753 min; purity: 99%. SFC: dr: 18: 54: 27. Synthetic Scheme of CPD0277857 Procedure for preparation of methyl (1R,2S,5S)-3-((S)-3,3-dimethyl-2-(oxetan-3- ylamino)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-c arboxylate To a mixture of oxetan-3-one (1.00 g, 13.9 mmol, 2.00 eq) and methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3- dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylate (2.21 g, 6.94 mmol, 1.00 eq, hydrochloride) in methanol (40.0 mL) were added sodium acetate (1.14 g, 13.9 mmol, 2.00 eq) and sodium cyanoborohydride (2.18 g, 34.7 mmol, 5.00 eq). After stirring at 25 °C for 16 h, saturated sodium hydrogen carbonate solution (50.0 mL) was added to adjust pH to 9 and extracted with ethyl acetate (60.0 mL × 2). The combined organic layers were washed with brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether; gradient @ 40 mL/min) to give methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2- (oxetan-3-ylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxylate (1.50 g, 4.08 mmol, 58% yield) as colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 4.53 (t, J = 6.4 Hz, 1H), 4.40 (t, J = 6.4 Hz, 1H), 4.29 (t, J = 6.4 Hz, 1H), 4.20-4.15 (m, 2H), 3.80-3.72 (m, 1H), 3.71-3.66 (m, 1H), 3.64 (s, 3H), 3.62-3.56 (m, 1H), 2.99-2.89 (m, 1H), 1.59-1.52 (m, 1H), 1.43-1.41 (m, 1H), 1.03 (s, 3H), 0.94 (s, 9H), 0.91 (s, 3H). LC-MS (Method C): R _t = 0.446 min; MS (ESIpos): m/z = 339.2 [M+H] ⁺ . SFC: dr = 6: 94 Procedure for preparation of (1R,2S,5S)-3-((S)-3,3-dimethyl-2-(oxetan-3-ylamino)butanoyl) -6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(oxetan-3-ylamino)butanoyl ]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (1.30 g, 3.84 mmol, 1.00 eq) in methanol (5.00 mL) was added a solution of lithium hydroxide monohydrate (806 mg, 19.2 mmol, 5.00 eq) in water (5.00 mL) at 20 °C. After stirring at 20 °C for 12 h, hydrochloric acid (1M in water) was added to the mixture to adjust pH to 4~5 and to give a residue. The residue was suspended into a mixed solvent of (dichloromethane/methanol, v/v = 20/1, 30.0 mL). After filtration, the filtrare was concentrated to give (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(oxetan-3-ylamino)butanoyl ]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (1.90 g, 3.51 mmol, 91% yield) as light yellow oil. LC-MS (Method C): R _t = 0.461 min and R _t = 0.485 min; MS (ESIpos): m/z = 325.2 [M+H] ⁺ . To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(oxetan-3-ylamino)butanoyl ]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (370 mg, 684 μmol, 60% purity, 1.00 eq), O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (520 mg, 1.37 mmol, 2.00 eq) and N,N-diisopropylethylamine (354 mg, 2.74 mmol, 477 μL, 4.00 eq) in N,N-dimethylformamide (3.00 mL) was added 2-amino-2-phthalazin-1-yl-acetamide (163 mg, 684 μmol, 1.00 eq, hydrochloride) at 0 °C. After stirring at 20 °C for 12 h, the mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase chromatography (C18, 50 g; condition: H2O/CH3CN = 1:0 to 7:3, 0.1% formic acid) to give (1R,2S,5S)- N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S)-3,3-dimeth yl-2-(oxetan-3-ylamino)butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (160 mg, 283 μmol, 41% yield) as light yellow oil. LC-MS (Method C): R _t = 0.413 & 0.431 min; MS (ESIpos): m/z = 509.3 [M+H] ⁺ . To a solution of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -3,3-dimethyl-2-(oxetan- 3-ylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2 -carboxamide (140 mg, 275 μmol, 1.00 eq) in dichloromethane (3.00 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (164 mg, 688 μmol, 2.50 eq). After stirring at 20 °C for 14 h, the mixture was concentrated under reduced pressure to give residue. The residue was purified by reversed phase column: (Phenomenex luna C18 150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 18%-48%, 8 min to give (1R,2S,5S)-N- [cyano(phthalazin-1-yl)methyl]-3-[(2S)-3,3-dimethyl-2-(oxeta n-3-ylamino)butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (7.00 mg, 13.4 μmol, 5% yield) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.68 (s, 0.4H), 9.83-9.66 (m, 0.9H), 9.50 (s, 0.6H), 8.81-8.74 (m, 0.6H), 8.30-8.22 (m, 0.5H), 8.14-7.96 (m, 1.9H), 7.94-7.74 (m, 2.2H), 7.42-7.23 (m, 0.6H), 4.60-4.42 (m, 2H), 4.36-4.20 (m, 3H), 4.19-4.08 (m, 1H), 3.88-3.79 (m, 1H), 3.63-3.56 (m, 1H), 3.01-2.88 (m, 1H), 1.68-1.59 (m, 1H), 1.58-1.49 (m, 1H), 1.09-1.04 (m, 3H), 1.00-0.97 (m, 3H), 0.95-0.86 (m, 9H). LC-MS (Method C): R _t = 0.680 min; MS (ESIpos): m/z = 491.4 [M+H] ⁺ . HPLC (Method M): R _t = 1.425 min; purity: 94%. SFC: dr = 65: 35. A mixture of cyclopropanecarbonyl chloride (500 mg, 4.78 mmol, 0.435 mL, 1.00 eq), methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimeth yl-3-azabicyclo[3.1.0]hexane-2- carboxylate (1.49 g, 5.26 mmol, 1.10 eq) and diisopropylethylamine (3.71 g, 28.7 mmol, 5.00 mL, 6.00 eq) in dichloromethane (10.0 mL) was stirred at 20 °C for 2 h. The reaction mixture was quenched with water (30.0 mL) at 10 °C and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give methyl (1R,2S,5S)-3-[(2S)-2-(cyclopropanecarbonylamino)-3,3-dimethy l-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (1.34 g, 2.94 mmol, 62% yield, 77% purity) as red oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.14 (d, J = 9.2 Hz, 1H), 4.41 (d, J = 9.2 Hz, 1H), 4.20 (s, 1H), 3.93- 3.86 (m, 1H), 3.81 (s, 1H), 3.66 (s, 3H), 1.91-1.81 (m, 1H), 1.55-1.49 (m, 1H), 1.48-1.38 (m, 1H), 0.97 (s, 12H), 0.80 (s, 3H), 0.69-0.52 (m, 4H). Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-(cyclopropanecarbonylamino)-3,3-dimethy l- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyli c acid A mixture of methyl (1R,2S,5S)-3-[(2S)-2-(cyclopropanecarbonylamino)-3,3-dimethy l-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.34 g, 3.82 mmol, 1.00 eq), lithium hydrate (275 mg, 11.5 mmol, 3.00 eq) in mixed solvent of methanol (5.00 mL) and water (0.10 mL) was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with ethyl acetate (30.0 mL) and extracted with water (10.0 mL × 2). Hydrochloric acid (1 M) was added to the aqueous phase to adjust pH to 3 and extracted with ethyl acetate (30.0 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-3-[(2S)-2-(cyclopropanecarbonylamino)-3,3-dimethy l- butanoyl]-6,6-dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxylic acid (950 mg, 2.40 mmol, 63% yield, 85% purity) as red oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.54 (s, 1H), 8.13 (d, J = 9.2 Hz, 1H), 4.41 (d, J = 9.2 Hz, 1H), 4.12 (s, 1H), 3.89-3.83 (m, 1H), 3.81-3.74 (m, 1H), 1.89-1.81 (m, 1H), 1.51-1.45 (m, 1H), 1.41-1.37 (m, 1H), 1.03-0.95 (m, 12H), 0.79 (s, 3H), 0.71 - 0.49 (m, 4H). A mixture of (1R,2S,5S)-3-[(2S)-2-(cyclopropanecarbonylamino)-3,3-dimethy l-butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (760 mg, 2.26 mmol, 1.00 eq), hexafluorophosphate (1.29 g, 3.39 mmol, 1.50 eq) and diisopropylethylamine (1.46 g, 11.3 mmol, 1.97 mL, 5.00 eq) in dichloromethane (2.00 mL) was stirred at 25 °C for 30 min.2-Amino-2-phthalazin-1-yl-acetamide (746 mg, 2.71 mmol, 1.20 eq, 2 hydrogen chloride) was added to the solution above. After stirring at 25 °C for 16 h, the reaction mixture was partitioned between water (30.0 mL) and dichloromethane (30.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -2- (cyclopropanecarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0] hexane-2- carboxamide (600 mg, 1.06 mmol, 47% yield, 92% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.68 (s, 1H), 9.22 (d, J = 8.8 Hz, 1H), 8.37-8.28 (m, 1H), 8.26-8.20 (m, 1H), 8.15-8.03 (m, 3H), 7.62 (s, 1H), 7.55 (s, 1H), 6.32 (d, J = 8.4 Hz, 1H), 4.44 (s, 1H), 4.37 (d, J = 8.8 Hz, 1H), 3.68-3.57 (m, 1H), 3.18-3.10 (m, 1H), 1.92-1.83 (m, 1H), 1.50-1.41 (m, 1H), 1.23 (d, J = 4.0 Hz, 1H), 0.99-0.91 (m, 12H), 0.81 (s, 3H), 0.72-0.51 (m, 4H). Procedure for preparation of CPD0277860 - (1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]-3-[(2S)- 2-(cyclopropanecarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dim ethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide A mixture of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -2- (cyclopropanecarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (550 mg, 1.06 mmol, 1.00 eq), Burgess reagent (629 mg, 2.64 mmol, 2.50 eq) in dichloromethane (3.00 mL) was stirred at 25 °C for 16 h. The reaction mixture was partitioned between dichloromethane (20.0 mL) and water (20.0 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN];B%: 36%-66%,10min) to give (1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]-3-[(2S)-2- (cyclopropanecarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (138 mg, 264 μmol, 25% yield, 96% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.73 (s, 0.37H), 9.83-9.71 (m, 0.70H), 9.62 (d, J = 8.8 Hz, 0.16H), 9.44 (s, 0.37H), 8.81-8.72 (m, 0.45H), 8.29-8.22 (m, 0.48H), 8.18-8.12 (m, 0.53H), 8.11-8.06 (m, 1.30H), 8.05-7.96 (m, 0.78H), 7.93-7.87 (m, 0.29H), 7.86-7.80 (m, 0.86H), 7.80-7.76 (m, 0.50H), 7.37-7.24 (m, 0.41H), 4.42-4.29 (m, 1H), 4.26-4.19 (m, 0.63H), 4.13 (s, 0.27H), 3.96-3.73 (m, 1.87H), 1.95-1.73 (m, 1H), 1.64-1.45 (m, 1.43H), 1.32-1.27 (m, 0.27H), 1.09- 0.81 (m, 13.5H), 0.78-0.74 (m, 1.5H), 0.71-0.46 (m, 4H). LC-MS (Method C): R _t = 0.844 min; MS (ESIpos): m/z = 503.3 [M+H] ⁺ . SFC: dr = 17:52:30. To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2-tetrahydropyran-4-ylac etyl)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (500 mg, 1.27 mmol, 1.00 eq) in dichloromethane (5.00 mL) were added 2-amino-2-phthalazin-1-yl-acetamide (349 mg, 1.27 mmol, 1.00 eq, 2hydrochloride), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]- dimethylazanium;hexafluorophosphate (963 mg, 2.53 mmol, 2.00 eq) and N,N-diethylpropan-2-amine (819 mg, 6.34 mmol, 1.10 mL, 5.00 eq). After stirring at 20 °C for 16 h, the reaction mixture was partitioned between water (100 mL) and ethyl acetate (200 mL). The organic phase was separated, washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition, instrument: 40 g Flash; Column: Welch Ultimate XB_C1820-40μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-50min 0-100% B; flow 55 ml/min; temperature: room temperature; Detector: UV 220/254 nm) and lyophilized to give (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -3,3-dimethyl- 2-[(2-tetrahydropyran-4-ylacetyl)amino]butanoyl]-6,6-dimethy l-3-azabicyclo[3.1.0] hexane-2- carboxamide (300 mg, 0.518 mmol, 41% yield) as a white solid. LC-MS (Method C): Rt = 0.752 min; MS (ESIpos): m/z = 579.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.67-9.65 (m, 1H), 9.21 (d, J = 8.4 Hz, 0.8H), 8.92 (d, J = 8.4 Hz, 0.3H), 8.31-8.19 (m, 2H), 8.11-8.00 (m, 2H), 7.88 (d, J = 8.8 Hz, 1H), 7.62 (s, 1H), 7.52 (br s, 1H), 6.34- 6.29 (m, 1H), 4.43-4.33 (m, 2H), 3.85-3.70 (m, 3H), 3.26-3.18 (m, 3H), 2.18-2.05 (m, 3H), 1.89-1.76 (m, 1H), 1.48-1.36 (m, 3H), 1.27 (d, J = 6.4 Hz, 1H), 1.18 (d, J = 6.8 Hz, 1H), 0.95 - 0.91 (m, 9H), 0.86 (s, 3H), 0.80 (s, 3H). Procedure for 3,3-dimethyl-2 azabicyclo[3.1 To a solution of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -3,3-dimethyl-2-[(2- tetrahydropyran-4-ylacetyl)amino]butanoyl]-6,6-dimethyl-3-az abicyclo[3.1.0]hexane-2-carboxamide (300 mg, 0.518 mmol, 1.00 eq) in dichloromethane (4.00 mL) was added Burgess reagent (247 mg, 1.04 mmol, 2.00 eq). After stirring at 20 °C for 2 h, the reaction mixture was partitioned between water (50.0 mL) and dichloromethane (100 mL). The organic phase was separated, washed with brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex luna C18150 × 25mm × 10 μm; mobile phase: [water(FA)-ACN]; B%: 38%-68%,10min) to give a residue. The residue was purified by prep-TLC (Ethyl acetate: Methanol = 20: 1) to give (1R,2S,5S)-N-[cyano(phthalazin-1- yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(2-tetrahydropyran-4-ylac etyl)amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (25.8 mg, 44.7 μmol, 9% yield, 97% purity) as a yellow solid. LC-MS (Method C): Rt = 0.796 min; MS (ESIpos): m/z = 561.3 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 10.70 (s, 0.3H), 9.76-9.74 (m, 0.85H), 9.63 (d, J = 8.8 Hz, 0.3H), 9.43 (s, 0.3H), 8.78-8.76 (m, 0.32H), 8.27- 8.24 (m, 0.6H), 8.10-8.06 (m, 1.22H), 8.00-7.84 (m, 1.3H), 7.82- 7.75 (m, 1.57H), 7.33-7.25 (m, 0.5H), 4.40- 4.32 (m, 1H), 4.24 (d, J = 12.8 Hz, 0.6H), 4.12 (s, 0.31H), 3.96-3.85 (m, 2H), 3.80- 3.67 (m, 2H), 3.29-3.14 (m, 2H), 2.15-2.04 (m, 2H), 1.86-1.75 (m, 1H), 1.62- 1.44 (m, 3H), 1.31-1.09 (m, 3H), 1.05-0.70 (m, 15H). A mixture of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl -butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (15.0 g, 39.2 mmol, 1.00 eq) in hydrochloric acid (4 M in dioxane, 100 mL) was stirred at 25 °C for 16 h. The mixture was concentrated to afford methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimeth yl-3-azabicyclo[3.1.0]hexane-2- carboxylate (11.0 g, 34.5 mmol, 88% yield, hydrochloric acid) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.16 (s, 2H), 4.26 (s, 1H), 3.87-3.78 (m, 3H), 3.67 (s, 3H), 1.62-1.57 (m, 1H), 1.52-1.47 (m, 1H), 1.06-0.93 (m, 15H). LC-MS (Method C): R _t = 0.673 min; MS (ESIpos): m/z = 283.3 [M+H] ⁺ . Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2- (phenoxycarbonylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxylate A solution of methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimeth yl-3- azabicyclo[3.1.0]hexane-2-carboxylate (3.00 g, 9.41 mmol, 1.00 eq, hydrochloric acid) and N,N- diisopropylethylamine (3.65 g, 28.23 mmol, 3.00 eq) in dichloromethane (50.0 mL) was cooled to 0 °C followed by phenyl chloroformate (1.62 g, 10.4 mmol, 1.10 eq) dropwise. After stirring at 25 °C for 16 h, the mixture was diluted with saturated ammonium chloride aqueous solution (50.0 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®;40 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether; gradient @45 mL/min) to afford methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(phenoxycarbonylamino)buta noyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (2.50 g, 6.21 mmol, 66% yield) as colorless gum. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.94 (d, J = 8.8 Hz, 1H), 7.40-7.36 (m, 2H), 7.23-7.19 (m, 1H), 7.04 (d, J = 7.6 Hz, 3H), 4.25 (s, 1H), 4.13 (d, J = 8.8 Hz, 1H), 3.88-3.77 (m, 2H), 3.67 (s, 3H), 1.59-1.51 (m, 1H), 1.47-1.42(m, 1H), 1.04 (s, 9H), 1.01 (s, 3H), 0.86 (s,3H). LC-MS (Method C): R _t = 0.587 min; MS (ESIpos): m/z = 403.2 [M+H] ⁺ . Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-2-[(3-fluoro-3-methyl-azetidine-1- carbonyl)amino]-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabic yclo[3.1.0]hexane-2-carboxylate To a mixture of 3-fluoro-3-methyl-azetidine (1.01 g, 8.07 mmol, 1.30 eq, hydrochloric acid) and N,N- diisopropylethylamine (2.41 g, 18.6 mmol, 3.00 eq) in acetonitrile (50.0 mL) was added methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(phenoxycarbonylamino)buta noyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (2.50 g, 6.21 mmol, 1.00 eq). After stirring at 80 °C for 12 h, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 30% Ethyl acetate/Petroleum ether gradient @ 60 mL/min). to give methyl (1R,2S,5S)-3-[(2S)-2-[(3-fluoro-3- methyl-azetidine-1-carbonyl)amino]-3,3-dimethyl-butanoyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylate (2.30 g, 5.79 mmol, 93% yield) as brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 4.73 (d, J = 9.6 Hz, 1H), 4.44 (s, 1H), 4.38 (d, J = 9.6 Hz, 1H), 4.14-4.09 (m, 4H), 3.92-3.90 (m, 2H), 3.75 (s, 3H), 1.60 (d, J = 21.6 Hz, 3H), 1.44 (s, 1H), 1.24-1.27 (t, J = 5.6 Hz, 4H), 1.02 (s, 12H). LC-MS (Method C): R _t = 0.538 min; MS (ESIpos): m/z = 398.1 [M+H] ⁺ . To a solution of methyl (1R,2S,5S)-3-[(2S)-2-[(3-fluoro-3-methyl-azetidine-1-carbony l)amino]-3,3- dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylate (2.30 g, 5.79 mmol, 1.00 eq) in methanol (30.0 mL) was added a solution of lithium hydroxide (555 mg, 23.2 mmol, 4.00 eq) in water (20.0 mL) at 0 °C. After stirring at 25 °C for 16 h, hydrochloric acid (0.5M in water) was added to the reaction mixture to adjust to pH~3 with and extracted with ethyl acetate (60.0 mL × 3). The combined organic layers were washed with brine (60.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give (1R,2S,5S)-3-[(2S)-2-[(3-fluoro-3-methyl-azetidine-1-carbony l)amino]- 3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan e-2-carboxylic acid (2.00 g, 5.22 mmol, 90% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 6.23 (d, J = 9.2 Hz, 1H), 4.19 (d, J = 9.2 Hz, 1H), 4.12 (s, 1H), 3.98- 3.93 (m, 1H), 3.98-3.93 (m, 1H), 3.91-3.84 (m, 2H), 3.80-3.76 (m, 1H), 3.46-3.41 (m, 2H), 1.54-1.49 (m, 4H), 1.40-1.38 (m, 1H), 1.01-0.84 (m, 15H). LC-MS (Method C): R _t = 0.554min; MS (ESIpos): m/z = 384.1 [M+H] ⁺ . Procedure for p fluoro-3-methyl- azabicyclo[3.1.0 To a mixture of (1R,2S,5S)-3-[(2S)-2-[(3-fluoro-3-methyl-azetidine-1-carbony l)amino]-3,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyli c acid (400 mg, 1.04 mmol, 1.00 eq) in dichloromethane (10.0 mL) were added N,N-diisopropylethylamine (539 mg, 4.17 mmol, 4.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexaflu orophosphate (476 mg, 1.25 mmol, 1.20 eq), followed by 2-amino-2-phthalazin-1-yl-acetamide (211 mg, 1.04 mmol, 1.00 eq) at 0 °C. After stirring at 25 °C for 16 h, the reaction mixture was diluted with saturated ammonium chloride aqueous (20.0 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~40% ethyl acetate / Petroleum ether gradient @ 45 mL/min) and reversed-phase column (C18, 55 g, 0~40% acetonitrile in water with 0.1% formic acid condition) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -2-[(3-fluoro-3- methyl-azetidine-1-carbonyl)amino]-3,3-dimethyl-butanoyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide(150 mg, 0.254 mmol, 24% yield, 96% purity) as a yellow solid. LC-MS (Method C): R _t = 0.543 min; MS (ESIpos): m/z = 568.4 [M+H] ⁺ . To a solution of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -2-[(3-fluoro-3-methyl- azetidine-1-carbonyl)amino]-3,3-dimethyl-butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (130 mg, 229 μmol, 1.00 eq) in dichloromethane (5.00 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (218 mg, 916 μmol, 4.00 eq) at 0 °C. After stirring at 25 °C for 4 h, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C1875*30mm*3 μm; mobile phase: [water (formic acid)- acetonitrile]; B%: 35%-65%, 7 min) to give (1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]- 3-[(2S)-2-[(3-fluoro-3-methyl-azetidine-1-carbonyl)amino]-3, 3-dimethyl-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (34.3 mg, 60.0 μmol, 26% yield, 96% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.68 (s, 0.3H), 9.76-9.60 (m, 1H), 9.42 (s, 0.4H), 8.78-8.76 (m, 1H), 8.30-8.20 (m, 0.4H), 8.09-8.05 (m, 1H), 8.01-7.97 (m, 0.5H), 7.91-7.75 (m, 1.6H), 7.32-7.27 (m, 0.5H), 6.28-6.11 (m, 1H), 4.24-4.10 (m, 2H), 4.03-3.73 (m, 6H), 1.61-1.30 (m, 5H), 1.10-0.78 (m, 15H). LC-MS (Method C): Rt = 0.577 min; MS (ESIpos): m/z = 550.4 [M+H] ⁺ . HPLC (Method S): R _t = 1.882 min; purity: 96%. SFC: dr = 28: 43: 27. Preparation of CPD0277863 Procedure for preparation of ethyl 2-cyclopropyl-2-hydroxyacetate To a mixture of ethyl 2-oxoacetate (15.0 g, 147 mmol, 1.00 eq) in tetrahydrofuran (150 mL) was added cyclopropylmagnesium chloride (1M, 176 mL, 1.20 eq) dropwise at -40 °C under nitrogen atmosphere.After stirring at -40 ~-20 °C for 6 h, the reaction mixture was quenched with saturated ammonium chlorine solution (50.0 mL), extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 20: 1 to 3: 1) to give ethyl 2-cyclopropyl-2-hydroxy-acetate (1.80 g, 12.5 mmol, 9% yield) as colorless liquid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 4.35-4.20 (m, 2H), 3.80-3.70 (m, 1H), 2.71 (d, J = 6.4 Hz, 1H), 1.32 (t, J = 7.2 Hz, 3H), 1.16-1.05 (m, 1H), 0.61-0.37 (m, 4H). Procedure for preparation of ethyl 2-cyclopropyl-2-methoxyacetate To a mixture of ethyl 2-cyclopropyl-2-hydroxy-acetate (1.80 g, 12.5 mmol, 1.00 eq) in acetonitrile (20.0 mL) were added silver oxide (8.68 g, 37.5 mmol, 3.00 eq) and methyl iodide (5.32 g, 37.5 mmol, 2.33 mL, 3.00 eq). The mixture was heated to 60 °C and stirred for 16 h. The mixture was filtered and washed with ethyl acetate (30.0 mL). The filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 20: 1 to 5: 1) to give ethyl 2- cyclopropyl-2-methoxy-acetate (870 mg, 5.50 mmol, 44% yield) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 4.29-4.21 (m, 2H), 3.39 (s, 3H), 3.19 (d, J = 8.0 Hz, 1H), 1.31 (t, J = 7.2 Hz, 3H), 1.18-1.08 (m, 1H), 0.67-0.60 (m, 1H), 0.58-0.50 (m, 1H), 0.49-0.42 (m, 2H). Procedure for preparation of 2-cyclopropyl-2-methoxyacetic acid To a mixture of ethyl 2-cyclopropyl-2-methoxy-acetate (870 mg, 5.50 mmol, 1.00 eq) in mixed solvent of methanol (5.00 mL) and water (1.00 mL) was added lithium hydroxide monohydrate (462 mg, 11.0 mmol, 2.00 eq). The mixture was stirred at 20 °C for 16 h. The reaction mixture was diluted with water (10.0 mL), concentrated. The resulting solution was washed with ethyl acetate (20.0 mL). Hydrochloric acid (1M) was added to the aqueous layer to adjust pH = 3. The solution was extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 2-cyclopropyl-2-methoxy-acetic acid (540 mg, 4.15 mmol, 75% yield) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 3.46 (s, 3H), 3.29 (d, J = 8.0 Hz, 1H), 1.20-1.14 (m, 1H), 0.69-0.41 (m, 4H). Procedure for preparation of (1R,2S,5S)-methyl 3-((2S)-2-(2-cyclopropyl-2-methoxyacetamido)- 3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane -2-carboxylate To a mixture of 2-cyclopropyl-2-methoxy-acetic acid (440 mg, 3.38 mmol, 1.00 eq) and methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimeth yl-3-azabicyclo[3.1.0]hexane-2- carboxylate (1.62 g, 5.07 mmol, 1.50 eq) in dichloromethane (10.0 mL) were added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-d imethylazanium;hexafluorophosphate (1.93 g, 5.07 mmol, 1.50 eq) and N,N-diethylpropan-2-amine (2.18 g, 16.9 mmol, 2.94 mL, 5.00 eq). After stirring at 20 °C for 16 h, the reaction mixture was concentrated to give a residue. The residue was purified by reversed phase (0.5% FA condition, instrument: 20 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.5% FA^H ₂ O), eluent B: acetonitrile; gradient: 0-20 min 0-100% B; flow 100 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give methyl (1R,2S,5S)-3-[(2S)-2-[(2-cyclopropyl-2-methoxy-acetyl)amino] -3,3-dimethyl-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (1.20 g, 3.04 mmol, 90% yield) as gray oil. LC-MS (Method C): R _t = 0.568 min and 0.594 min; MS (ESIpos): m/z = 395.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.01-6.94 (m, 1H), 4.60-4.47 (m, 1H), 4.50-4.44 (m, 1H), 3.99-3.88 (m, 2H), 3.79-3.75 (m, 3H), 3.41-3.30 (m, 3H), 3.29-3.21 (m, 1H), 1.52-1.43 (m, 2H), 1.09-1.01 (m, 12H), 0.98-0.94 (m, 1H), 0.91-0.85 (m, 3H), 0.57-0.32 (m, 4H). Procedure for preparation of (1R,2S,5S)-3-((2S)-2-(2-cyclopropyl-2-methoxyacetamido)-3,3- dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-c arboxylic acid To a mixture of methyl (1R,2S,5S)-3-[(2S)-2-[(2-cyclopropyl-2-methoxy-acetyl)amino] -3,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyla te (1.10 g, 2.79 mmol, 1.00 eq) in methanol (20.0 mL) and water (5.00 mL) was added lithium hydroxide monohydrate (351 mg, 8.36 mmol, 3.00 eq). After stirring at 20 °C for 16 h, the reaction mixture was diluted with water (15.0 mL), concentrated to remove methanol and washed with ethyl acetate (30.0 mL × 2). Hydrochloric acid (1M, 30.0 mL) was added to the aqueous layer to adjust pH = 3 and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give (1R,2S,5S)-3-[(2S)-2-[(2-cyclopropyl-2-methoxy- acetyl)amino]-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyc lo[3.1.0]hexane-2-carboxylic acid (940 mg, 2.47 mmol, 89% yield) as colorless oil. LC-MS (Method C): R _t = 0.537 min; MS (ESIpos): m/z = 381.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.42 (s, 1H), 7.66 (d, J = 9.6 Hz, 0.5H), 7.49 (d, J = 9.6 Hz, 0.5H), 4.49-4.46 (m, 1H), 4.13 (s, 1H), 3.86-3.77 (m, 2H), 3.27-3.24 (m, 1H), 3.16 (s, 1.5H), 3.14 (s, 1.5H), 1.53-1.50 (m, 1H), 1.42-1.39 (m, 1H), 1.01-0.90 (m, 13H), 0.79 (s, 3H), 0.52-0.24 (m, 4H). Procedure for preparation of 1-chlorophthalazine To a solution of phosphorus oxychloride (944 g, 6.16 mol, 572 mL, 3.00 eq) in toluene (2.50 L) was added phthalazin-1-ol (300 g, 2.05 mol, 1.00 eq) in portions at 20 °C for 30 min. The mixture was heated to 100 °C and stirred for 6 h. The reaction mixture was concentrated under reduced pressure to remove phosphorus oxychloride. The residue was triturated with ethyl acetate/methanol (1.50 L, ethyl acetate: methanol = 3: 1) at 20 °C for 2 h, filtered and the filter cake was washed with mixed solvent of ethyl acetate and methanol (v/v = 3/1, 1.00 L) and dried under vacuum to give 1-chlorophthalazine (370 g, crude) as a yellow solid. LC-MS (Method C): Rt = 0.538 min; MS (ESIpos): m/z = 165.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.77 (s, 1H), 8.38-8.27 (m, 2H), 8.24-8.13 (m, 2H). Procedure for preparation of methyl 2-((diphenylmethylene)amino)-2-(phthalazin-1-yl)acetate To a mixture of 1-chlorophthalazine (100 g, 608 mmol, 1.00 eq) and methyl 2- (benzhydrylideneamino)acetate (185 g, 729 mmol, 1.20 eq) in N,N-dimethylacetamide (1.00 L) was added cesium carbonate (792 g, 2.43 mol, 4.00 eq). After stirring at 20 °C for 16 h, the reaction mixture was quenched with water (1.00 L) and extracted with ethyl acetate (1.00 L × 3). The combined organic layers were washed with brine (1.00 L × 3), dried over anhydrous sodium sulfate, filtered and concentrated at 40 °C to give methyl 2-(benzhydrylideneamino)-2-phthalazin-1-yl-acetate (500 g, crude) as brown oil. LC-MS (Method P): Rt = 0.664 min; MS (ESIpos): m/z = 382.3 [M+H] ⁺ . Procedure for preparation of methyl 2-amino-2-(phthalazin-1-yl)acetate hydrochloride To a solution of methyl 2-(benzhydrylideneamino)-2-phthalazin-1-yl-acetate (500 g, 1.31 mol, 1.00 eq) in ethyl acetate (1.50 L) was added hydrogen chloride (4M in dioxane, 500 mL, 1.53 eq) at 25 °C. After stirring at 25 °C for 1 h, the reaction mixture was concentrated under reduced pressure to give methyl 2-amino-2-phthalazin-1-yl-acetate (300 g, crude) as yellow oil. Procedure for preparation of methyl 2-(tert-butoxycarbonylamino)-2-phthalazin-1-yl-acetate To a solution of methyl 2-amino-2-phthalazin-1-yl-acetate (300 g, 1.18 mol, 1.00 eq) in methanol (2.00 L) was added triethylamine (359 g, 3.55 mol, 494 mL, 3.00 eq) at 25 °C to adjust pH to about 8. Tert- butyl (2-methylpropan-2-yl)oxycarbonyl carbonate (310 g, 1.42 mol, 326 mL, 1.20 eq) was added to the solution above. After stirring at 25 °C for 1 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 3: 1 to 1: 1, Petroleum ether: Ethyl acetate = 1: 1) to give methyl 2-(tert- butoxycarbonylamino)-2-phthalazin-1-yl-acetate (110 g, 312 mmol, 26% yield, 90% purity) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.67 (s, 1H), 8.26-8.22 (m, 1H), 8.21-8.17 (m, 1H), 8.09-8.08 (m, 1H), 8.14-8.07 (m, 1H), 8.04-7.98 (m, 1H), 6.24 (d, J = 8.8 Hz, 1 H), 3.71 (s, 3H), 1.41 (s, 9H). Procedure for preparation of tert-butyl N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)carbamate To a solution of methyl 2-(tert-butoxycarbonylamino)-2-phthalazin-1-yl-acetate (80.0 g, 252 mmol, 1.00 eq) was added to ammonia (7 M in methanol, 500 mL, 13.9 eq) at 25 °C. After stirring at 25 °C for 16 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with ethyl acetate (300 mL), filtered and washed with ethyl acetate (100 mL) to give tert-butyl N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)carbamate (70.0 g, 208 mmol, 83% yield, 90% purity) as a gray solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.64 (s, 1H), 8.35 (d, J = 7.6 Hz, 1H), 8.24-8.18 (m, 1H), 8.10-8.01 (m, 2H), 7.60 (s, 1H), 7.57- 7.52 (m, 1H), 7.32 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 4.19-3.99 (m, 1H), 3.18- 3.15 (m, 3H), 1.39 (s, 9H). Procedure for preparation of 2-amino-2-(phthalazin-1-yl)acetamide hydrochloride Hydrogen chloride (4M in ethyl acetate, 120 mL, 12.0 eq) was added to tert-butyl N-(2-amino-2-oxo-1- phthalazin-1-yl-ethyl)carbamate (12.6 g, 41.7 mmol, 1.00 eq) at 25 °C. After stirring at 25 °C for 1 h, the resulting precipicate was filtered and the filter cake was washed with ethyl acetate (30.0 mL) to give 2- amino-2-phthalazin-1-yl-acetamide (13.0 g, crude, hydrogen chloride) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.88 (s, 1H), 9.28-9.02 (m, 3H), 8.73 (d, J = 7.6 Hz, 1H), 8.40-8.29 (m, 2H), 8.24-8.12 (m, 2H), 7.86 (s, 1H), 6.08 (d, J = 4.0 Hz, 1H). Procedure for prepa cyclopropyl-2-meth azabicyclo[3.1.0]he To a mixture of (1R,2S,5S)-3-[(2S)-2-[(2-cyclopropyl-2-methoxy-acetyl)amino] -3,3-dimethyl-butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (200 mg, 0.526 mmol, 1.00 eq) and 2-amino- 2-phthalazin-1-yl-acetamide (174 mg, 0.631 mmol, 1.20 eq, 2 hydrogen chloride) in dichloromethane (4.00 mL) were added N,N-diethylpropan-2-amine (340 mg, 2.63 mmol, 0.458 mL, 5.00 eq) and [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-d imethylazanium;hexafluorophosphate (400 mg, 1.05 mmol, 2.00 eq). After stirring at 20 °C for 2 h, the reaction mixture was diluted with dichloromethane (50.0 mL), washed with water (30.0 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , dichloromethane: tetrahydrofuran = 1: 0 to 5: 1) to give (1R,2S,5S)-N- (2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S)-2-[(2-cyclop ropyl-2-methoxy-acetyl)amino]-3,3- dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (280 mg, 0.496 mmol, 94% yield) as a yellow solid. LC-MS (Method C): Rt = 0.834 min; MS (ESIpos): m/z = 565.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.76-9.62 (m, 1H), 9.24-9.21 (m, 0.65H), 8.97-8.94 (m, 0.25H), 8.32- 8.30 (m, 0.69H), 8.26-8.19 (m, 1.31H), 8.10-7.93 (m, 2H), 7.65-7.60 (m, 1H), 7.53-7.46 (m, 1H), 6.31 (d, J = 8.4 Hz, 1H), 4.48-4.35 (m, 2H), 3.92-3.73 (m, 2H), 3.30-3.22 (m, 1H), 3.18-3.10 (m, 3H), 1.53- 1.43 (m, 1H), 1.30-1.22 (m, 1H), 1.03–1.00 (m, 1H), 0.97-0.93 (m, 10H), 0.88-0.84 (m, 2H), 0.80-0.77 (m, 3H). To a mixture of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -2-[(2-cyclopropyl-2- methoxy-acetyl)amino]-3,3-dimethyl-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (270 mg, 0.478 mmol, 1.00 eq) in dichloromethane (10.0 mL) was added Burgess reagent (285 mg, 1.20 mmol, 2.50 eq). After stirring at 20 °C for 2 h, the reaction mixture was quenched with water (20.0 mL), extracted with dichloromethane (30 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep- HPLC (FA condition, column: Waters Xbridge BEH C18 150*25mm*5 μm; mobile phase: [water( NH ₄ HCO ₃ )-ACN]; B%: 36%-66%,9 min) to give (1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]-3-[(2S)-2- [(2-cyclopropyl-2-methoxy-acetyl)amino]-3,3-dimethyl-butanoy l]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (90.0 mg, 165 μmol, 34% yield) as a yellow solid. LC-MS (Method C): Rt = 0.587 min; MS (ESIpos): m/z = 547.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.70 (s, 0.4H), 9.79-9.77 (m, 0.8H), 9.66 (t, J = 8.8 Hz, 0.2H), 9.42 (s, 0.4H), 8.78-8.76 (m, 0.5H), 8.26-8.24 (m, 0.6H), 8.12-7.88 (m, 2H), 7.83-7.52 (m, 2H), 7.46-7.27 (m, 1H), 4.49-4.39 (m, 1H), 4.30-4.15 (m, 1H), 3.95–3.92 (m, 1H), 3.87-3.79 (m, 1H), 3.26-3.09 (m, 4H), 1.63-1.48 (m, 1.5H), 1.33-1.32 (m, 0.5H), 1.10-0.75 (m, 16H), 0.48-0.23 (m, 4H). SFC: dr = 25: 46: 29. Preparation of CPD0277864 Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(tetrahydrofuran-3- carbonylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexa ne-2-carboxylate To a mixture of tetrahydrofuran-3-carboxylic acid (500 mg, 4.31 mmol, 413 uL, 1.00 eq) in dichloromethane (5.00 mL) were added benzotriazol-1-yloxy(tripyrrolidin-1- yl)phosphonium;hexafluorophosphate (3.36 g, 6.46 mmol, 1.50 eq) and 4-methylmorpholine (1.96 g, 19.4 mmol, 2.13 mL, 4.50 eq). After stirring for 10 min, methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyla te (1.82 g, 5.72 mmol, 1.33 eq, hydrochloric acid) was added. The reaction mixture was stirred at 25 °C for 16 h. The mixture reaction was diluted with water (20.0 mL), extracted with ethyl acetate (20.0 mL × 5). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®;20.0 g SepaFlash® Silica Flash Column, Eluent of 0~60% Ethyl acetate/Petroleum ether gradient @ 45 mL/min) followed by reversed phase (Instrument:80.0 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.5% FA), eluent B: acetonitrile; gradient: 0-20 min 60-80% B; flow 45 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2- (tetrahydrofuran-3-carbonylamino)butanoyl]-6,6-dimethyl-3-az abicyclo[3.1.0]hexane-2-carboxylate (1.20 g, 2.71 mmol, 63% yield, 86% purity) as brown oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.10-8.00 (m, 1H), 4.50-4.35 (m, 1H), 4.21-4.18 (m, 1H), 3.90-3.75 (m, 3H), 3.72-3.68 (m, 1H), 3.65 (s, 3H), 3.64-3.60 (m, 1H), 3.57-3.43 (m, 1H), 3.18-3.08 (m, 1H), 2.02- 1.80 (m, 2H), 1.56-1.47 (m, 1H), 1.47-1.39 (m, 1H), 1.05-0.90 (m, 12H), 0.81 (s, 1.5H), 0.79 (s, 1.5H). Procedure for preparation of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(tetrahydrofuran-3- carbonylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexa ne-2-carboxylic acid A mixture of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(tetrahydrofuran-3-carbony lamino)butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (600 mg, 1.58 mmol, 1.00 eq) and lithium hydroxide (114 mg, 4.73 mmol, 3.00 eq) in mixed solvent of methanol (10.0 mL) and water (5.00 mL) was stirred at 25 °C for 16 h. The mixture was concentrated to give a residue. The residue was purified by reversed phase (Instrument: 80.0 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.5% FA), eluent B: acetonitrile; gradient: 0-20 min 40~60 % B; flow 45 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give ((1R,2S,5S)-3-[(2S)-3,3-dimethyl-2- (tetrahydrofuran-3-carbonylamino)butanoyl]-6,6-dimethyl-3-az abicyclo[3.1.0]hexane-2-carboxylic acid (380 mg, 0.896 mmol, 57% yield, 86% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.64 (s, 1H), 8.06-8.00 (m, 1H), 4.47-4.39 (m, 1H), 4.11-4.10 (m, 1H), 3.90-3.72 (m, 3H), 3.71-3.60 (m, 2H), 3.57-3.42 (m, 1H), 3.18-3.05 (m, 1H), 2.01-1.79 (m, 2H), 1.53-1.46 (m, 1H), 1.42-1.36 (m, 1H), 1.05-0.92 (m, 12H), 0.87-0.75 (m, 3H). To a mixture of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(tetrahydrofuran-3-carbony lamino)butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (100 mg, 0.273 mmol, 1.00 eq), 2-amino-2- phthalazin-1-yl-acetamide (55.2 mg, 0.273 mmol, 1.00 eq) and N,N-diisopropylethylamine (106 mg, 0.819 mmol, 143 uL, 3.00 eq) in dichloromethane (1.00 mL) was added [dimethylamino(triazolo[4,5- b]pyridin-3-yloxy)methylene]-dimethyl-ammonium;hexafluoropho sphate (156 mg, 409 umol, 1.50 eq). After stirring for 10 min, 2-amino-2-phthalazin-1-yl-acetamide (55.2 mg, 0.273 mmol, 1.00 eq) was added. After stirring at 25 °C for 16 h, the reaction mixture was concentrated to give a residue. The residue was purified by reversed phase reversed phase (instrument: 40.0 g Flash; Column: Welch Ultimate XB_C1820-40μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-15 min 20- 40% B; flow 40 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)- N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S)-3,3-dimeth yl-2-(tetrahydrofuran-3- carbonylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexa ne-2-carboxamide (110 mg, 188 μmol, 69% yield, 94% purity) as a white solid. Procedure for preparation of Compound CPD0277864 - (1R,2S,5S)-N-[cyano(phthalazin-1- yl)methyl]-3-[(2S)-3,3-dimethyl-2-(tetrahydrofuran-3-carbony lamino)butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide A mixture of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -3,3-dimethyl-2- (tetrahydrofuran-3-carbonylamino)butanoyl]-6,6-dimethyl-3-az abicyclo[3.1.0]hexane-2-carboxamide (380 mg, 690 μmol, 1.00 eq) and methoxycarbonyl-(triethylammonio)sulfonyl-azanide (494 mg, 2.07 mmol, 3.00 eq) in dichloromethane (5.00 mL) was stirred 25 °C for 16 h. The reaction mixture was concentrated to give a residue. The residue was purified by reversed phase reversed phase (column: 3_Phenomenex Luna C18 75*30mm*3 μm; mobile phase: [water(FA)-ACN];B%: 36%-56%,8min) followed by reverse phase (column: 3_Phenomenex Luna C18 75*30mm*3 μm; mobile phase: [water(FA)-ACN]; B%: 34%-54%,8min) to give (1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]-3-[(2S)- 3,3-dimethyl-2-(tetrahydrofuran-3-carbonylamino) butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (77.1 mg, 137 μmol, 20% yield, 95% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.70 (s, 0.3H), 9.81-9.58 (m, 0.63H), 9.42 (s, 0.3H), 8.83-8.73 (m, 0.37H), 8.30-8.23 (m, 0.4H), 8.16-8.03 (m, 1.5H), 8.02-7.96 (m, 0.5H), 7.95-7.88 (m, 0.5H), 7.86-7.80 (m, 1H), 7.80-7.75 (m, 0.5H), 7.39-7.21 (m, 0.3H), 4.67-4.60 (m, 0.1H), 4.42-4.28 (m, 1H), 4.26-4.24 (m, 0.3H), 4.23-4.20 (m, 0.2H), 4.15-4.10 (m, 0.2H), 3.96-3.75 (m, 3H), 3.74-3.52 (m, 3H), 3.26-3.03 (m, 1H), 2.05-1.77 (m, 2H), 1.73-1.46 (m, 1.5H), 1.35-1.21 (m, 0.5H), 1.14-0.71 (m, 15H). To a solution of 2-tetrahydrofuran-3-ylacetic acid (500 mg, 3.84 mmol, 1.00 eq), 4-methylmorpholine (1.55 g, 15.8 mmol, 1.69 mL, 4.00 eq) and (benzotriazol-1- yloxy)tripyrrolidinophosphonium,hexafluorophosphate (2.20 g, 4.23 mmol, 1.10 eq) in dichloromethane (10.0 mL) was added methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimeth yl-3- azabicyclo[3.1.0]hexane-2-carboxylate (1.64 g, 4.61 mmol, 1.20 eq, 2 hydrogen chloride). After stirring at 25 °C for 12 h, the reaction mixture was partitioned between dichloromethane (20.0 mL) and water (30.0 mL). The separated aqueous phase was extracted with dichloromethane (20.0 mL × 2). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 0: 1 to 10: 1) to afford methyl (1R,2S,5S)-3- [(2S)-3,3-dimethyl-2-[(2-tetrahydrofuran-3-ylacetyl)amino]bu tanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (1.50 g, 3.78 mmol, 98% yield) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.08 (d, J = 9.2 Hz, 1H), 4.60 (d, J = 2.4 Hz, 0.5H), 4.58 (d, J = 2.4 Hz, 0.5H), 4.45 (s, 1H), 3.99-3.82 (m, 4H), 3.80-3.70 (m, 4H), 3.45-3.30 (m, 1H), 2.68-2.55 (m, 1H), 2.31- 2.23 (m, 2H), 2.13-2.05 (m, 1H), 1.60-1.48 (m, 1H), 1.46 (s, 1H), 1.06-1.01 (m, 12H), 0.94 (s, 1H), 0.88 (s, 3H). LC-MS (Method C): Rt = 0.781 min; MS (ESIpos): m/z = 395.3 [ SFC: dr = 47: 53. Procedure for preparation of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2-tetrahydrofuran-3- ylacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2-tetrahydrofuran-3- ylacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxylate (1.50 g, 3.80 mmol, 1.00 eq) in mixed solvent of methanol (15.0 mL) and water (1.50 mL) was added lithium hydroxide hydrate (319 mg, 7.60 mmol, 2.00 eq). After stirring at 25 °C for 16 h, the solvent was removed under reduced pressure and the residue was dissolved in water (50.0 mL). Hydrochloric acid (2M) was added to the mixture at 25 °C to adjust pH = 2. The solution was extracted with ethyl acetate (20.0 mL × 2). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2-tetrahydrofuran-3-ylac etyl)amino]butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.10 g, 2.89 mmol, 76% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.63 (s, 1H), 8.00-7.90 (m, 1H), 4.40 (br d, J = 9.2 Hz, 1H), 4.11 (s, 1H), 3.94-3.83 (m, 1H), 3.81-3.76 (m, 1H), 3.72-3.64 (m, 2H), 3.63-3.53 (m, 1H), 3.25-3.16 (m, 1H), 2.46-2.35 (m, 1H), 2.32-2.14 (m, 2H), 1.95-1.79 (m, 1H), 1.56-1.35 (m, 3H), 1.00 (s, 3H), 0.95 (s, 9H), 0.81 (s, 3H). To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2-tetrahydrofuran-3-ylac etyl)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (400 mg, 1.05 mmol, 1.00 eq) and 2-amino-2- phthalazin-1-yl-acetamide (251 mg, 1.05 mmol, 1.00 eq, hydrogen chloride) in dichloromethane (8.00 mL) were added diisopropylethylamine (543 mg, 4.21 mmol, 0.732 mL, 4.00 eq) and O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (440 mg, 1.16 mmol, 1.10 eq). After stirring at 20 °C for 12 h, the reaction mixture was concentrated at 50 °C to give a residue. The residue was purified by flash column chromatography (SiO ₂ , dichloromethane: tetrahydrofuran = 1: 2) to afford (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -3,3-dimethyl-2-[(2- tetrahydrofuran-3-ylacetyl)amino]butanoyl]-6,6-dimethyl-3-az abicyclo[3.1.0]hexane-2-carboxamide (300 mg, 531 μmol, 51% yield) as colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.66 (s, 1H), 9.21 (dd, J = 8.4, 2.4 Hz, 1H), 8.32-8.27 (m, 1H), 8.24- 8.19 (m, 1H), 8.10-8.02 (m, 2H), 7.94 (t, J = 8.4 Hz, 1H), 7.61 (s, 1H), 7.51 (s, 1H), 6.30 (d, J = 8.4 Hz, 1H), 4.43 (s, 1H), 4.37 (d, J = 8.8 Hz, 1H), 3.90-3.80 (m, 2H), 3.73-3.65 (m, 2H), 3.64-3.54 (m, 1H), 3.26-3.18 (m, 1H), 2.44-2.35 (m, 1H), 2.30-2.20 (m, 2H), 1.94-1.83 (m, 1H), 1.49-1.42 (m, 2H), 1.28- 1.23 (m, 1H), 0.96-0.90 (m, 12H), 0.81 (s, 3H). Procedure for preparation of Compound CPD0277865 - (1R,2S,5S)-N-[cyano(phthalazin-1- yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(2-tetrahydrofuran-3-ylac etyl)amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -3,3-dimethyl-2-[(2- tetrahydrofuran-3-ylacetyl)amino]butanoyl]-6,6-dimethyl-3-az abicyclo[3.1.0]hexane-2-carboxamide (200 mg, 354 μmol, 1.00 eq) in dichloromethane (2.00 mL) was added dropwise a solution of Burgess reagent (169 mg, 708 μmol, 2.00 eq) in dichloromethane (0.50 mL). After stirring at 20 °C for 1 h, the reaction mixture was concentrated under vacuum at 40 °C to give a residue. The residue was purified by prep-TLC (SiO ₂ , dichloromethane: tetrahydrofuran = 1: 1) and prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 μm; mobile phase: [water(FA)-ACN];B%: 34%-64%,7min) to afford (1R,2S,5S)-N- [cyano(phthalazin-1-yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(2-te trahydrofuran-3-ylacetyl)amino]butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (26.0 mg, 46.8 μmol, 13% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.75-10.65 (m, 0.4H), 9.80-9.72 (m, 0.8H), 9.63 (d, J = 8.6 Hz, 0.2H), 9.43 (s, 0.4H), 8.82-8.73 (m, 0.5H), 8.30-8.22 (m, 0.5H), 8.12-8.05 (m, 1H), 8.03-7.96 (m, 1H), 7.94-7.85 (m, 0.8H), 7.84-7.80 (m, 0.9H), 7.80-7.74 (m, 0.5H), 7.32 (d, J = 8.4 Hz, 0.3H), 7.28 (d, J = 8.4 Hz, 0.2H), 4.37 (d, J = 8.8 Hz, 0.8H), 4.32 (d, J = 8.8 Hz, 0.2H), 4.25 (s, 0.4H), 4.22 (s, 0.2H), 4.14 (s, 0.28H), 3.97-3.77 (m, 2H), 3.73-3.53 (m, 3H), 3.27-3.11 (m, 1H), 2.47-2.11 (m, 3H), 1.98-1.76 (m, 1H), 1.66-1.28 (m, 3H), 1.09-1.05 (m, 1.5H), 1.02 (s, 1H), 1.00 (s, 2H), 0.95 (s, 4H), 0.93-0.86 (m, 3H), 0.83 (s, 2H), 0.79-0.73 (m, 1.5H). LC-MS (Method C): Rt = 0.836 min; MS (ESIpos): m/z = 547.3 [M+H] ⁺ . SFC: dr = 23: 30: 22: 26. To a solution of (2S)-2-methoxypropanoic acid (300 mg, 2.88 mmol, 1.00 eq), 4-methylmorpholine (1.17 g, 11.5 mmol, 1.27 mL, 4.00 eq) and (benzotriazol-1- yloxy)tripyrrolidinophosphonium,hexafluorophosphate (1.65 g, 3.17 mmol, 1.10 eq) in dichloromethane (10.0 mL) was added methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimeth yl-3- azabicyclo[3.1.0]hexane-2-carboxylate (1.23 g, 3.46 mmol, 1.20 eq, 2Hydrochloride). After stirring at 25 °C for 12 h, the reaction mixture was quenched with water (20.0 mL), diluted with dichloromethane (10.0 mL) and extracted with dichloromethane (20.0 mL × 2). The combined extracts were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 0: 1 to 1: 1) to afford methyl (1R,2S,5S)-3-[(2S)-2-[[(2S)-2-methoxypropanoyl]amino]-3,3- dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylate (1.00 g, 2.20 mmol, 76% yield) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ -d) δ = 4.52 (d, J = 9.6 Hz, 1H), 4.44 (s, 1H), 4.00-3.92 (m, 2H), 3.80 (s, 1H), 3.76 (s, 3H), 3.72-3.68 (m, 1H), 3.40 (s, 1H), 3.32 (s, 3H), 1.52-1.44 (m, 2H), 1.40 (d, J = 6.8 Hz, 3H), 1.08-1.04 (m, 12H), 0.92 (s, 3H) Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-[[(2S)-2-methoxypropanoyl]amino]-3,3- dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-2-[[(2S)-2-methoxypropanoyl]amino]-3,3-di methyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyla te (1.00 g, 2.71 mmol, 1.00 eq) in methanol (10.0 mL) and water (1.00 mL) was added lithium hydroxide hydrate (228 mg, 5.43 mmol, 2.00 eq). After stirring at 25 °C for 16 h, the solvent was removed under reduced pressure and the residue was dissolved in water (30.0 mL). Hydrochloric acid (2M) was added to the mixture at 25 °C to adjust pH = 2. The separated aqueous phase was extracted with ethyl acetate (10.0 mL × 2). The combined extracts were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*40mm* 15 μm; mobile phase: [water (FA)-ACN];B%: 30%-60%,9 min) to afford (1R,2S,5S)-3-[(2S)-2-[[(2S)-2-methoxypropanoyl]amino]-3,3-di methyl-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (600 mg, 1.46 mmol, 54% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.72 (s, 1H), 7.48 (d, J = 9.2 Hz, 1H), 4.44 (br d, J = 9.2 Hz, 1H), 4.12 (s, 1H), 3.88-3.72 (m, 3H), 3.24-3.16 (m, 3H), 1.56-1.50 (m, 1H), 1.44 (d, J = 7.6 Hz, 1H), 1.16 (d, J = 6.4 Hz, 3H), 1.00 (s, 3H), 0.96 (s, 9H), 0.80 (s, 3H). Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3- pyrrolidin-1-yl-propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]h exane-2-carboxylate To a solution of (1R,2S,5S)-3-[(2S)-2-[[(2S)-2-methoxypropanoyl]amino]-3,3-di methyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (300 mg, 0.846 mmol, 1.00 eq) and (2S)-2- amino-3-[(2S)-3-oxo-4H-1,4-benzoxazin-2-yl]propanamide (230 mg, 0.846 mmol, 1.00 eq, hydrochloride) in dichloromethane (10.0 mL) were added diisopropylethylamine (328 mg, 2.54 mmol, 0.442 mL, 3.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (354 mg, 0.931 mmol, 1.10 eq). After stirring at 20 °C for 12 h, the reaction mixture was concentrated in vacuo at 50 °C to give a residue. The residue was purified by flash column chromatography (SiO ₂ , dichloromethane: tetrahydrofuran = 1: 1) to afford (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo- 4H-1,4-benzoxazin-2-yl]methyl]ethyl]-3-[(2S)-2-[[(2S)-2-meth oxypropanoyl]amino]-3,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxami de (500 mg, 0.770 mmol, 91% yield) as colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.64 (s, 1H), 8.32 (d, J = 8.8 Hz, 1H), 7.40-7.24 (m, 2H), 7.12 (s, 1H), 6.96-6.84 (m, 5H), 4.64-4.40 (m, 3H), 4.32 (d, J = 9.6 Hz, 1H), 4.20 (s, 1H), 3.88-3.68 (m, 4H), 3.16 (s, 3H), 1.48-1.42 (m, 1H), 1.16-1.12 (m, 3H), 1.00 (s, 3H), 0.92 (s, 1H), 0.80 (s, 3H), 0.72 (s, 9H). Procedure for preparation of Compound CPD0278003 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-3- oxo-4H-1,4-benzoxazin-2-yl]ethyl]-3-[(2S)-2-[[(2S)-2-methoxy propanoyl]amino]-3,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxami de To a solution of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4-benzo xazin-2- yl]methyl]ethyl]-3-[(2S)-2-[[(2S)-2-methoxypropanoyl]amino]- 3,3-dimethyl-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0] hexane-2-carboxamide (500 mg, 0.875 mmol, 1.00 eq) in dichloromethane (10.0 mL) was added burgess reagent (417 mg, 1.75 mmol, 2.00 eq). After stirring at 20 °C for 2 h, the reaction mixture was concentrated in vacuo at 40 °C to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10 μm; mobile phase: [water(FA)-ACN];B%: 39%- 69%,10min) to afford (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-3-oxo-4H-1,4-benzoxazin-2 -yl]ethyl]-3-[(2S)- 2-[[(2S)-2-methoxypropanoyl]amino]-3,3-dimethyl-butanoyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide (177 mg, 0.318 mmol, 36% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.76 (br s, 1H), 9.08 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 9.2 Hz, 1H), 7.00-6.80 (m, 4H), 5.20-5.04 (m, 1H), 4.52 (d, J = 10.0 Hz, 1H), 4.32 (d, J = 9.2 Hz, 1H), 4.12 (s, 1H), 3.91-3.84 (m, 1H), 3.80-3.72 (m, 2H), 3.20-3.12 (m, 3H), 2.37-2.22 (m, 1H), 1.60-1.52 (m, 1H), 1.36- 1.28 (m, 1H), 1.12 (d, J = 6.4 Hz, 3H), 1.00 (s, 3H), 0.98-0.95 (m, 1H), 0.84-0.64 (m, 12H). LC-MS (Method C): Rt = 0.702 min; MS (ESIpos): m/z = 554.2 [M+H] ^+. SFC: de%: 94%. Preparation of CPD0279112 and CPD0279113 Procedure for preparation of methyl (1R,2S,5S)-3-((S)-2-(3-methoxycyclobutane-1- carboxamido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxylate To a solution of 3-methoxycyclobutanecarboxylic acid (612 mg, 4.70 mmol, 1.00 eq), benzotriazol-1- yloxy(tripyrrolidin-1-yl)phosphanium;hexafluorophosphate (3.18 g, 6.12 mmol, 1.30 eq) and 4- methylmorpholine (1.90 g, 18.8 mmol, 2.07 mL, 4.00 eq) in dichloromethane (10.0 mL) was added methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimeth yl-3-azabicyclo[3.1.0]hexane-2- carboxylate (1.50 g, 4.70 mmol, 1.00 eq, hydrochloric acid salt) at 0 °C. After stirring at 20 °C for 16 h, the mixture was poured into water (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 10: 1 to 2: 1) to give methyl (1R,2S,5S)-3-[(2S)- 2-[(3-methoxycyclobutanecarbonyl)amino]-3,3-dimethyl-butanoy l]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (733 mg, 1.67 mmol, 36% yield) as light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.12-5.91 (m, 1H), 4.64-4.55 (m, 1H), 4.47-4.42 (m, 1H), 3.99-3.91 (m, 2H), 3.81-3.77 (m, 1H), 3.75(s, 3H), 3.24-3.21 (m, 3H), 2.49-2.42 (m, 2H), 2.20-2.06 (m, 2H), 1.48-1.43 (m, 2H), 1.05-1.01 (m, 12H), 0.89-0.86 (m, 3H). LC-MS (Method C): R _t = 0.563 min; MS (ESIpos): m/z = 395.5 [M+H] ⁺ . SFC: dr: 37: 63. Procedure for preparation of (1R,2S,5S)-3-((S)-2-(3-methoxycyclobutane-1-carboxamido)-3,3 - dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-c arboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-2-[(3-methoxycyclobutanecarbonyl)amino]-3 ,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyla te (398 mg, 1.01 mmol, 1.00 eq) in methanol (10.0 mL) was added a solution of lithium hydroxide hydrate (212 mg, 5.04 mmol, 5.00 eq) in water (5.00 mL). After stirring at 20 °C for 12 h, the mixture was diluted with water (20.0 mL), adjusted pH to 4~5 with hydrochloric acid aqueous (1M) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-3-[(2S)-2-[(3- methoxycyclobutanecarbonyl)amino]-3,3-dimethyl-butanoyl]-6,6 -dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxylic acid (429 mg, crude) as light yellow oil. The crude product was used for the next step directly without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.44 (d, J = 9.6 Hz, 1H), 4.63 (d, J = 9.6 Hz, 1H), 4.45 (s, 1H), 4.04-3.99 (m, 1H), 3.92-3.86 (m, 1H), 3.83-3.74 (m, 1H), 3.24 (s, 3H), 2.56-2.41 (m, 2 H), 2.27-2.11 (m, 2H), 1.67- 1.60 (m, 1H), 1.53-1.48 (m, 1H), 1.06 (s, 3H), 1.02 (s, 9H), 0.88 (s, 3H). Procedure for preparation of (1R,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)propan-2-yl)-3-((S)-2-(3-methoxycyc lobutane-1-carboxamido)-3,3- dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-c arboxamide To a solution of (1R,2S,5S)-3-[(2S)-2-[(3-methoxycyclobutanecarbonyl)amino]-3 ,3-dimethyl-butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (270 mg, 709 μmol, 1.00 eq) and N,N- diisopropylethylamine (367 mg, 2.84 mmol, 494 μL, 4.00 eq) in N,N-dimethylformamide (2.00 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexaflu orophosphate (540 mg, 1.42 mmol, 2.00 eq) at 0 °C, followed by (2S)-2-amino-3-[(2S)-3-oxo-4H-1,4-benzoxazin-2-yl]propanamid e (230 mg, 745 μmol, 1.05 eq, hydrochloric acid salt). After stirring at 20 °C for 12 h, the mixture was poured into water (20.0 mL), washed with ethyl acetate (20.0 mL × 3). The aqueous phase was lyophilized to give a residue. The residue was purified by column chromatography (SiO ₂ , dichloromethane: methanol = 1: 0 to 10: 1) to give (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo- 4H-1,4-benzoxazin-2-yl]methyl]ethyl]-3-[(2S)-2-[(3-methoxycy clobutanecarbonyl)amino]-3,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxami de (264 mg, 424 μmol, 60% yield) as a light yellow solid. ¹ H NMR (400 MHz, DMSO) δ = 10.61 (s, 1H), 8.28 (d, J = 8.4 Hz, 1H), 7.80-7.62 (m, 1H), 7.35 (s, 1H), 7.12 (s, 1H), 6.96-6.82 (m, 4H), 4.61-4.46 (m, 2H), 4.34-4.26 (m, 1H), 4.21-4.13 (m, 1H), 3.84-3.74 (m, 2H), 3.07 (s, 3H), 3.05-2.96(m, 1H), 2.24-2.19 (m, 2H), 2.14-2.01 (m, 2H), 1.97-1.83 (m, 2H), 1.52-1.38 (m, 2H), 1.00 (s, 3H), 0.81 (s, 3H), 0.70 (s, 9H). LC-MS (Method C): R _t = 0.554 min; MS (ESIpos): m/z = 598.3 [M+H] ⁺ . Procedure for preparation of CPD0279112 & CPD0279113 - (1R,2S,5S)-N-((S)-1-cyano-2-((S)-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-3-((S)-2- (3-methoxycyclobutane-1- carboxamido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4-benzo xazin-2- yl]methyl]ethyl]-3-[(2S)-2-[(3-methoxycyclobutanecarbonyl)am ino]-3,3-dimethyl-butanoyl]-6,6- dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxamide (234 mg, 392 μmol, 1.00 eq) in dichloromethane (3.00 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (140 mg, 587 μmol, 1.50 eq). After stirring at 20 °C for 16 h, the mixture was poured into water (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 10: 1 to dichloromethane: methanol = 10: 1) followed by prep-HPLC (FA condition:column: Phenomenex luna C18 150*25.0 mm*10.0 μm; mobile phase: [water(FA)-ACN];B%: 34%-64%, 10 min) to give CPD0279112 (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-3-oxo-4H-1,4-benzoxazin-2 -yl]ethyl]-3-[(2S)-2-[(3- methoxycyclobutanecarbonyl)amino]-3,3-dimethyl-butanoyl]-6,6 -dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide (53.5 mg, 91.4 μmol, 23% yield, dr = 93: 7) and CPD0279113 (1R,2S,5S)-N-[(1S)-1- cyano-2-[(2S)-3-oxo-4H-1,4-benzoxazin-2-yl]ethyl]-3-[(2S)-2- [(3-methoxycyclobutanecarbonyl)amino]- 3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan e-2-carboxamide (56.1 mg, 95.8 μmol, 25% yield, dr = 78: 22) as a white solid. CPD0279112: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.75 (s, 1H), 9.09-8.94 (m, 1H), 7.84-7.63 (m, 1H), 6.98-6.85 (m, 4H), 5.17-5.08 (m, 1H), 4.60-4.48 (m, 1H), 4.34-4.24 (m, 1H), 4.11-4.06 (m, 1H), 3.95- 3.87 (m, 1H), 3.87-3.77 (m, 2H), 3.07 (s, 3H), 3.06-2.97 (m, 1H), 2.54-2.63 (m, 1H), 2.30-2.16 (m, 2H), 2.13-1.73 (m, 3H), 1.57-1.50 (m, 1H), 1.34-1.27 (d, J =8.00 Hz, 1H), 1.01 (s, 3H), 0.82 (s, 3H), 0.70 (s, 9H). LC-MS (Method C): R _t = 0.830 min; MS (ESIpos): m/z = 580.4 [M+H] ⁺ . HPLC (Method S): R _t = 2.053 min; purity: 99% SFC: dr = 93: 7. CPD0279113: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.76 (s, 1H), 9.08-8.95 (d, J = 8.0 Hz, 1H), 7.80-7.66 (d, J = 8.0 Hz, 1H), 7.04-6.83 (m, 4H), 5.22-5.07 (m, 1H), 4.60-4.50 (m, 1H), 4.31-4.22 (d, J = 8.0 Hz, 1H), 4.1 (s, 1H), 3.87-3.77 (m, 2H), 3.73-3.60 (m, 1H), 3.07 (s, 3H), 2.31-2.18 (m, 4H), 2.12-1.73 (m, 3H), 1.93-1.74 (m, 3H), 1.56-1.50 (m, 1H), 1.30 (d, J = 8.0 Hz, 1H), 1.05-0.98 (s, 3H), 0.85-0.79 (s, 3H), 0.76-0.66 (s, 9H). LC-MS (Method C): R _t = 0.823 min; MS (ESIpos): m/z = 580.5 [M+H] ⁺ . SFC: dr = 78: 22. A mixture of (2R)-2-methoxypropanoic acid (500 mg, 4.80 mmol, 1.00 eq), methyl (1R,2S,5S)-3-[(2S)- 2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1 .0]hexane-2-carboxylate (2.05 g, 5.76 mmol, 1.20 eq, 2Hydrogen chloride), N-methylmorpholine (1.94 g, 19.2 mmol, 2.11 mL, 4.00 eq) and benzotriazol-1-yloxy(tripyrrolidin-1-yl)phosphonium;hexafluo rophosphate (2.75 g, 5.28 mmol, 1.10 eq) in dichloromethane (5.00 mL) was stirred at 20 °C for 16 h. The reaction mixture was partitioned between dichloromethane (30.0 mL) and water (30.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ethergradient @ 40 mL/min) to give methyl (1R,2S,5S)-3-[(2S)-2- [[(2R)-2-methoxypropanoyl]amino]-3,3-dimethyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylate (1.38 g, 3.37 mmol, 70% yield, 90% purity) as red oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.59 (d, J = 9.6 Hz, 1H), 4.45 (d, J = 9.6 Hz, 1H), 4.22 (s, 1H), 3.91- 3.83 (m, 3H), 3.67 (s, 3H), 3.34-3.27 (m, 2H), 1.58-1.50 (m, 1H), 1.47-1.42 (m, 1H), 1.21-1.11 (m, 3H), 1.03-0.94 (m, 11H), 0.90-0.78 (m, 4H). Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-[[(2R)-2-methoxypropanoyl]amino]-3,3- dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid A mixture of methyl (1R,2S,5S)-3-[(2S)-2-[[(2R)-2-methoxypropanoyl]amino]-3,3-di methyl-butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.58 g, 4.29 mmol, 1.00 eq), lithium hydroxide hydrate (308.1 mg, 12.9 mmol, 3.00 eq) in methanol (4.00 mL) was stirred at 20 °C for 4 h. The reaction mixture was concentrated under reduced pressure to remove methanol. The residue was diluted with water (30 mL) and washed with ethyl acetate (20.0 mL). Hydrochloric acid (1M, 2.00 ml) was added to the aqueous phase to adjust pH to 3. The solution was extracted with ethyl acetate (30.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-3-[(2S)-2-[[(2R)-2-methoxypropanoyl]amino]-3,3-di methyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.08 g, 2.44 mmol, 57% yield, 80% purity) as red oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.70 (br. s, 1H), 7.57 (d, J = 9.6 Hz, 1H), 4.45 (d, J = 9.6 Hz, 1H), 4.14 (s, 1H), 3.87 (q, J = 6.8 Hz, 1H), 3.83 (d, J = 2.8 Hz, 2H), 3.19 (s, 3H), 1.57-1.49 (m, 1H), 1.42 (d, J = 7.6 Hz, 1H), 1.14 (d, J = 6.8 Hz, 3H), 1.04-0.89 (m, 12H), 0.79 (s, 3H). A mixture of (1R,2S,5S)-3-[(2S)-2-[[(2R)-2-methoxypropanoyl]amino]-3,3-di methyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.00 g, 2.82 mmol, 1.00 eq), hexafluorophosphate (1.61 g, 4.23 mmol, 1.50 eq), diisopropylethylamine (1.82 g, 14.1 mmol, 2.46 mL, 5.00 eq) in dichloromethane (2.00 mL) was stirred at 25 °C for 30 min. 2-Amino-2-phthalazin-1-yl- acetamide (931 mg, 3.39 mmol, 1.20 eq, 2Hydrogen chloride) was added. After stirring at 25 °C for 16 h, the reaction mixture was partitioned between water (30.0 mL) and dichloromethane (30.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ethergradient @ 40 mL/min) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -2-[[(2R)-2- methoxypropanoyl]amino]-3,3-dimethyl-butanoyl]-6,6-dimethyl- 3-azabicyclo [3.1.0]hexane-2- carboxamide (940 mg, 1.55 mmol, 55% yield, 89% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.70-9.63 (m, 1H), 9.23 (d, J = 8.4 Hz, 0.7H), 8.96 (d, J = 8.6 Hz, 0.3H), 8.32-8.29 (m, 0.5H), 8.26-8.16 (m, 1.5H), 8.11-8.02 (m, 2H), 7.98-7.90 (m, 0.3H), 7.61 (s, 0.7H), 7.58-7.49 (m, 1.6H), 7.43 (d, J = 9.6 Hz, 0.4H), 6.35-6.27 (m, 1H), 4.46 (s, 0.7H), 4.42 (d, J = 9.6 Hz, 1H), 4.35 (s, 0.3H), 3.93-3.86 (m, 1H), 3.85-3.77 (m, 1H), 3.70-3.50 (m, 1H), 3.20 (s, 2H), 3.14 (s, 1H), 1.51-1.43 (m, 1H), 1.16-1.13 (m, 3H), 1.11-1.07 (m, 1H), 0.99-0.91 (m, 9H), 0.87 (s, 2H), 0.82-0.74 (m, 3H). A mixture of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -2-[[(2R)-2- methoxypropanoyl]amino]-3,3-dimethyl-butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2- carboxamide (890 mg, 1.65 mmol, 1.00 eq), Burgess reagent (788 mg, 3.30 mmol, 2.00 eq) in dichloromethane (3.00 mL) was stirred at 25 °C for 16 h. The reaction mixture was partitioned between dichloromethane (20.0 mL) and water (20.0 mL). The organic phase was separated, washed with water (10.0 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN];B%: 41%-65%,8min) to give (1R,2S,5S)-N-[cyano(phthalazin- 1-yl)methyl]-3-[(2S)-2-[[(2R)-2-methoxypropanoyl]amino]-3,3- dimethyl-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (260 mg, 479 μmol, 29% yield, 96% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.72 (s, 0.3H), 9.85-9.74 (m, 0.7H), 9.67 (d, J = 8.0 Hz, 0.2H), 9.43 (s, 0.4H), 8.88-8.70 (m, 0.4H), 8.35-8.21 (m, 0.5H), 8.16-8.05 (m, 1H), 8.04-7.95 (m, 0.5H), 7.94-7.88 (m, 0.3H), 7.87-7.75 (m, 1H), 7.68-7.67 (m, 0.4H), 7.55-7.44 (m, 0.5H), 7.36-7.25 (m, 0.5H), 4.53-4.34 (m, 1H), 4.29 (s, 0.4H), 4.25 (s, 0.2H), 4.16 (s, 0.3H), 4.04-3.73 (m, 3H), 3.26-3.07 (m, 3H), 1.71-1.49 (m, 1.5H), 1.38-1.30 (m, 0.5H), 1.21-0.71 (m, 18H). LC-MS (Method C): R _t = 0.843 min; MS (ESIpos): m/z = 521.3 [M+H] ⁺ . Preparation of CPD0329497 Procedure for preparation of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -2- [[(2S)-2-methoxypropanoyl]amino]-3,3-dimethyl-butanoyl]-6,6- dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-2-[[(2S)-2-methoxypropanoyl]amino]-3,3-di methyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (400 mg, 1.13 mmol, 1.00 eq) and 2-amino-2- phthalazin-1-yl-acetamide (269.35 mg, 1.13 mmol, 1.00 eq, Hydrogen chloride) in dichloromethane (8.00 mL) was added diisopropylethylamine (583 mg, 4.51 mmol, 0.786 mL, 4.00 eq) and O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (472 mg, 1.24 mmol, 1.10 eq). After stirring at 20 °C for 12 h, the reaction mixture was concentrated under vacuum at 50 °C to give a residue. The residue was purified by flash column chromatography (SiO ₂ , Dichloromethane: Tetrahydrofuran = 1: 1) to afford (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -2-[[(2S)- 2-methoxypropanoyl]amino]-3,3-dimethyl-butanoyl]-6,6-dimethy l-3-azabicyclo[3.1.0]hexane-2- carboxamide (400 mg, 0.743 mmol, 66% yield) as colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.70-9.65 (m, 1H), 9.30-8.91 (m, 1H), 8.34-8.29 (m, 1H), 8.268.17 (m, 2H), 8.11-8.03 (m, 2H), 7.60-7.44 (m, 2H), 6.37-6.28 (m, 1H), 4.47-4.31 (m, 2H), 3.94-3.79 (m, 2H), 3.77-3.73 (m, 1H), 3.21 (s, 3H), 1.56-1.42 (m, 2H), 1.35 (s, 3H), 0.97-0.92 (m, 9H), 0.88 (s, 3H), 0.80 (s, 3H). To a solution of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -2-[[(2S)-2- methoxypropanoyl]amino]-3,3-dimethyl-butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2- carboxamide (350 mg, 649.79 umol, 1.00 eq) in dichloromethane (7.00 mL) was added burgess reagent (310 mg, 1.30 mmol, 2.00 eq). After stirring at 20 °C for 1 h, the reaction mixture was concentrated under reduced pressure at 40 °C to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN];B%: 42%-72%,10min) to afford (1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]-3-[(2S)-2-[[(2S) -2-methoxypropanoyl]amino]-3,3- dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxamide (190 mg, 0.359 mmol, 55% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.71 (s, 0.4H), 9.83-9.75 (m, 0.8H), 9.67 (d, J = 8.8 Hz, 0.2H), 9.43 (s, 0.4H), 8.83-8.73 (m, 0.4H), 8.32-8.22 (m, 0.6H), 8.13-8.07 (m, 1H), 8.05-7.96 (m, 0.6H), 7.94-7.87 (m, 0.3H), 7.85-7.75 (m, 1H), 7.53 (d, J = 9.2 Hz, 0.4H), 7.46 (d, J = 9.4 Hz, 0.2H), 7.39 (d, J = 9.4 Hz, 0.3H), 7.35-7.25 (m, 0.5H), 4.42 (d, J = 9.2 Hz, 0.7H), 4.38 (d, J = 9.2 Hz, 0.3H), 4.3 (s, 0.4H), 4.25 (s, 0.2H), 4.16 (s, 0.3H), 3.99-3.90 (m, 1H), 3.88-3.70 (m, 2H), 3.24 (s, 1H), 3.19(s, 1H), 3.14 (s, 1H), 1.67- 1.56 (m, 1H), 1.55-1.49 (m, 0.3H), 1.34 (d, J = 7.6 Hz, 0.4H), 1.19 (d, J = 6.8 Hz, 1H), 1.16 (d, J = 6.8 Hz, 0.7H), 1.13 (d, J = 6.8 Hz, 0.8H), 1.11-1.09 (m, 0.4H), 1.07-1.03 (m, 2H), 1.01 (s, 3H), 0.96 (s, 4H), 0.92-0.88 (m, 2H), 0.86 (s, 2H), 0.80-0.75 (m, 2H). LC-MS (Method C): Rt = 0.677 min; MS (ESIpos): m/z = 521.3 [M+H] ⁺ . SFC: dr = 51: 49. A mixture of 2-amino-3-(3-oxo-4H-1,4-benzoxazin-2-yl)propanenitrile (120 mg, 552 μmol, 1.00 eq), (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-[(2,2,2-trifluoro acetyl)amino]butanoyl]-3-azabicyclo[3.1.0] hexane-2-carboxylic acid (194 mg, 552 μmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (315 mg, 829 μmol, 1.50 eq) and N,N-diisopropylethylamine (143 mg, 1.10 mmol, 2.00 eq) in N,N-dimethylformamide (1.50 mL) was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (30.0 mL) and extracted with ethyl acetate (30.0 mL × 2). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (FA condition; column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 42%-72%, 10 min) to give (1R,2S,5S)-N-[1-cyano-2-(3-oxo-4H-1,4-benzoxazin- 2-yl)ethyl]-6,6-dimethyl-3-[(2S)-3-methyl-2-[(2,2,2-trifluor oacetyl)amino]butanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxamide (97.1 mg, 175 μmol, 32% yield, 99% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.83-10.77(m, 1H), 9.80-9.76 (m, 1H), 9.07-9.01 (m 1H), 7.05- 6.90(m, 4H), 5.07-4.99 (m, 1H), 4.70-4.68 (m, 1H),4.19-4.13 (m, 2H), 3.87-3.80 (m, 2H), 2.30-2.26 (m, 1H), 2.07-2.04 (m, 1H), 1.57-1.34 (m, 1H), 1.33-1.31 (m, 1H), 1.00-0.82 (m, 13H). A mixture of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-[(2,2,2-trifluoro acetyl)amino] butanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (300 mg, 0.856 mmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (488 mg, 1.28 mmol, 1.50 eq) and N,N- diisopropylethylamine (332 mg, 2.57 mmol, 3.00 eq) in N,N-dimethylformamide (5.00 mL) was stirred at 0 °C for 0.5 h.2-Amino-2-phthalazin-1-yl-acetamide (225 mg, 0.941 mmol, 1.10 eq, HCl) was added to the solution above. After stirring at 25 °C for 11.5 h, the reaction mixture was poured into water (30.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 60~100% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-6,6-dim ethyl-3-[(2S)-3- methyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-3-azabicyclo[3.1.0]h exane-2-carboxamide (300 mg, 0.505 mmol, 59% yield, 90% purity) as a yellow solid. LC-MS (Method L): R _t = 0.523 min; MS (ESIpos): m/z = 535.2 [M+H] ⁺ . Procedure for preparation of CPD0220615 - (1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]-6,6- dimethyl-3-[(2S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]bu tanoyl]-3-azabicyclo[3.1.0]hexane-2- carboxamide A mixture of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-6,6-dim ethyl-3-[(2S)-3-methyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-3-azabicyclo[3.1.0]h exane-2-carboxamide (300 mg, 0.505 mmol, 90% purity, 1.00 eq) and (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (240 mg, 1.01 mmol, 2.00 eq) in dichloromethane (5.00 mL) was stirred at 25 °C for 2 h. The reaction mixture was poured into water (20.0 mL) and extracted with ethyl acetate (8.00 mL × 3). The combined organic layers were concentrated in vacuum to give a residue and purified by prep-HPLC (column: Phenomenex luna C18150*40mm* 15 μm; phase: [water(FA)-ACN]; B%: 34%-64%, 9 min) to give (1R,2S,5S)-N- [cyano(phthalazin-1-yl)methyl]-6,6-dimethyl-3-[(2S)-3-methyl -2-[(2,2,2-trifluoroacetyl)amino]butanoyl]- 3-azabicyclo[3.1.0]hexane-2-carboxamide (72.8 mg, 0.140 mmol, 28% yield, 99% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.70 (s, 0.3H), 10.07-9.62 (m, 1.7H), 9.46 (s, 0.3H), 8.83-8.72 (m, 0.4H), 8.34-8.21 (m, 0.5H), 8.13-7.88 (m, 2H), 7.86-7.73 (m, 1.2H), 7.33-7.25 (m, 0.4H), 4.41-4.05 (m, 2H), 3.97-3.74 (m, 2H), 2.26-1.99 (m, 1H), 1.71-1.20 (m, 2H), 1.16-0.68 (m, 12H). To a solution of (3S,3aS,6aR)-2-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl) amino]butanoyl]- 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (500 mg, 1.37 mmol, 1.00 eq) in dichloromethane (5.00 mL) were added 2-amino-2-phthalazin-1-yl-acetamide (333 mg, 1.65 mmol, 1.20 eq), tetramethylurea hexafluorophosphate (1.04 g, 2.74 mmol, 2.00 eq) and diisopropylethylamine (887 mg, 6.86 mmol, 1.20 mL, 5 eq). The mixture was stirred at 20 °C for 16 h. The reaction mixture was partitioned between water (50.0 mL) and ethyl acetate (100 mL). The organic phase was separated, washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; instrument: 40 g Flash; Column: Welch Ultimate XB_C18 20-40 μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-50min 0-100% B; flow 55 ml/min; temperature: room temperature; Detector: UV 220/254 nm)) to afford (3S,3aS,6aR)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-2-[(2 S)-3,3-dimethyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-3,3a,4,5,6,6a-hexahy dro-1H-cyclopenta[c]pyrrole-3- carboxamide (350 mg, 638 μmol, 46% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.68-9.64 (m, 1H), 9.34 (d, J = 8.0 Hz, 0.6H), 9.26-9.18 (m, 1H), 8.87 (d, J = 8.8 Hz, 0.3H), 8.29-8.18 (m, 2H), 8.11-7.99 (m, 2H), 7.57 (s, 0.6H), 7.52 (s, 0.7H),, 6.39-6.25 (m, 1H), 4.54-4.45 (m, 1H), 4.40-4.30 (m, 1H), 3.90-3.74 (m, 1H), 3.68-3.51 (m, 1H), 2.77-2.59 (m, 1.4H), 2.47-2.39 (m, 0.6H), 1.91-1.69 (m, 1H), 1.64-1.47 (m, 4H), 1.41-1.23 (m, 1H), 1.00 (s, 6H), 0.90 (s, 3H). LC-MS (Method C): Rt = 0.796 min; MS (ESIpos): m/z = 549 [M+H] ⁺ . Procedure for preparation of CPD0278004 - (3S,3aS,6aR)-N-[cyano(phthalazin-1-yl)methyl]-2- [(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl] -3,3a,4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrole-3-carboxamide To a solution of (3S,3aS,6aR)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-2-[(2 S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-c yclopenta[c]pyrrole-3-carboxamide (300 mg, 547 μmol, 1.00 eq) in dichloromethane (4.00 mL) was added burgess reagent (521 mg, 2.19 mmol, 4.00 eq). The mixture was stirred at 20 °C for 1 h. The reaction mixture was partitioned between water (50.0 mL) and dichloromethane (100 mL). The organic phase was separated, washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed phase column (0.1% FA condition; column: Phenomenex Luna C18150×25mm×10um;mobile phase: [water (FA)-acetonitrile];B%: 40%-70%,9min) to afford (3S,3aS,6aR)-N-[cyano(phthalazin-1-yl)methyl]-2-[(2S)-3,3-di methyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-c yclopenta[c]pyrrole-3-carboxamide (176 mg, 329 μmol, 60% yield, 99% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.72 (s, 0.38H), 9.80-9.75 (m, 0.55H), 9.73 (d, J = 8.4 Hz, 0.28H), 9.64 (d, J = 8.8 Hz, 0.24H), 9.46 (s, 0.4H), 9.42-9.17 (m, 1H), 8.82-8.73 (m, 0.4H), 8.31-8.22 (m, 0.6H), 8.12-8.06 (m, 1H), 8.04-7.98 (m, 0.3H), 7.97-7.88 (m, 0.5H), 7.87-7.81 (m, 0.8H), 7.80-7.75 (m, 0.5H), 7.35-7.25 (m, 0.53H), 4.58-4.42 (m, 1H), 4.18-4.09 (m, 0.6H), 4.08-4.02 (m, 0.3H), 3.93-3.81 (m, 1H), 3.77-3.70 (m, 0.4H), 3.68-3.55 (m, 0.6H), 2.80-2.63 (m, 1.5H), 2.59-2.53 (m, 0.4H), 2.40-2.31 (m, 0.2H), 1.89-1.30 (m, 6H), 1.10-0.92 (m, 9H). LC-MS (Method C): Rt = 0.578 min; MS (ESIpos): m/z = 531 [M+H] ⁺ . To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propanoic acid (4.75 g, 20.7 mmol, 1.00 eq) in dichloromethane (60.0 mL) were added bis(2-oxo-3-oxazolidinyl)phosphinic chloride (6.33 g, 24.7 mmol, 1.20 eq) and N,N- diisopropylethylamine (8.03 g, 62.2 mmol, 10.8 mL, 3.00 eq). After stirring at 20 °C for 0.5 h, methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (4.26 g, 20.7 mmol, 1.00 eq, hydrogen chloride) was added. The mixture was stirred at 20 °C for 11.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ethergradient @ 80 mL/min) to give methyl (1R,2S,5S)-3-[(2S)-2-(tert- butoxycarbonylamino)-3-cyclopropyl-propanoyl]-6,6-dimethyl-3 -azabicyclo[3.1.0]hexane-2-carboxylate (6.00 g, 15.8 mmol, 76.1% yield) as colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.08 (d, J = 7.6 Hz, 1H), 4.19 (s, 1H), 4.17-4.10 (m, 1H), 3.99-3.90 (m, 1H), 3.80-3.75 (m, 1H), 3.62 (s, 3H), 1.58-1.49 (m, 2H), 1.41-1.38 (m, 1H), 1.36-1.32 (m, 9H), 1.29- 1.21 (m, 1H), 1.03-0.90 (m, 6H), 0.80-0.72 (m, 1H), 0.41-0.31 (m, 2H), 0.17-0.10 (m, 1H), 0.08--0.03 (m, 1H) LCMS (Method L): Rt = 1.637 min; MS (ESIpos): m/z = 281.4 [M-99] ⁺ , 325.1[M-55] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropy l- propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropy l-propanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (4.00 g, 10.5 mmol, 1.00 eq) in methyl alcohol (20.0 mL) and water (20.0 mL) was added lithium hydrate (1.32 g, 31.5 mmol, 3.00 eq). After stirring at 20 °C for 2 h, hydrogen chloride (1M) was added to the reaction mixture to adjust pH~4. The reaction mixture was diluted with water (20.0 mL), and extracted with ethyl acetate (20.0 mL × 2). The combined organic layers were washed with brine (10.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3- cyclopropyl-propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan e-2-carboxylic acid (5.20 g, crude) as a white solid. LC-MS (Method L): Rt = 1.463 min; MS (ESIpos): m/z = 267.3 [M-99] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-amino-3-cyclopropyl-propanoyl]-6,6-dime thyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid A solution of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropy l-propanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (5.20 g, 14.2 mmol, 1.00 eq) in hydrogen chloride (40 mL in ethyl acetate) was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give (1R,2S,5S)-3-[(2S)-2-amino-3-cyclopropyl-propanoyl]-6,6-dime thyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (5.00 g, crude) as a yellow solid. LC-MS (Method A): Rt = 0.988 min; MS (ESIpos): m/z = 267.1 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[(2,2,2- trifluoroacetyl)amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3 .1.0]hexane-2-carboxylic acid To a solution of (1R,2S,5S)-3-[(2S)-2-amino-3-cyclopropyl-propanoyl]-6,6-dime thyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (4.50 g, 16.9 mmol, 1.00 eq) in dichloromethane (40.0 mL) were added methyl 2,2,2-trifluoroacetate (2.16 g, 16.9 mmol, 1.70 mL, 1.00 eq) and triethylamine (6.84 g, 67.6 mmol, 9.41 mL, 4.00 eq). After stirring at 20 °C for 6 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase column (Instrument: 300 g Flash; Column: Welch Ultimate XB_C1820-40μm; eluent A: water (0.05% formic acid), eluent B: acetonitrile; gradient: 0-30 min 0-100% B; flow 80 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[(2,2,2- trifluoroacetyl)amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3 .1.0]hexane-2-carboxylic acid (2.50 g, 6.21 mmol, 37% yield, 90% purity) as a gray solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.75 (d, J = 6.8 Hz, 1H), 4.54-4.37 (m, 1H), 4.15-4.02 (m, 1H), 3.84- 3.71 (m, 2H), 1.72-1.60 (m, 1H), 1.59-1.46 (m, 2H), 1.44-1.35 (m, 1H), 1.16-1.06 (m, 1H), 1.05-0.86 (m, 6H), 0.85-0.77 (m, 1H), 0.49-0.31 (m, 2H), 0.25-0.14 (m, 1H), 0.12--0.04 (m, 1H). LC-MS (Method L): Rt = 1.878 min; MS (ESIpos): m/z = 363.3 [M+H] ^+. Procedure for preparation of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -3- cyclopropyl-2-[(2,2,2-trifluoroacetyl)amino]propanoyl]-6,6-d imethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[(2,2,2-trifluoroacetyl)a mino]propanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (560 mg, 1.55 mmol, 1.00 eq) in dichloromethane (15.0 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (881 mg, 2.32 mmol, 1.50 eq) and N,N- diisopropylethylamine (599 mg, 4.64 mmol, 808 μL, 3.00 eq) After stirring at 20 °C for 0.5 h, 2-amino-2-phthalazin-1-yl-acetamide (313 mg, 1.55 mmol, 1.00 eq) was added and the mixture was stirred at 20 °C for 11.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (Instrument: 80 g Flash; Column: Welch Ultimate XB_C1820-40μm; eluent A: water (0.05% formic acid), eluent B: acetonitrile; gradient: 0-12 min 0-50% B; flow 50 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -3-cyclopropyl-2- [(2,2,2-trifluoroacetyl)amino]propanoyl]-6,6-dimethyl-3-azab icyclo[3.1.0]hexane-2-carboxamide (490 mg, 897 μmol, 58% yield) as a white solid. LC-MS (Method L): Rt = 1.672 min; MS (ESIpos): m/z = 547.1 [M+H] ⁺ . To a solution of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -3-cyclopropyl-2-[(2,2,2- trifluoroacetyl)amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3 .1.0]hexane-2-carboxamide (390 mg, 714 μmol, 1.00 eq) in dichloromethane (2 mL) was added methoxycarbonyl-(triethylammonio)sulfonyl- azanide (680 mg, 2.85 mmol, 4.00 eq). After stirring at 20 °C for 4 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Ultimate C18150× 25mm × 5 μm; mobile phase: [water(formic acid)- acetonitrile]; B%: 37%-67%,10 min) to give (1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]-3-[(2S)-3-cyclop ropyl-2-[(2,2,2- trifluoroacetyl)amino] propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxam ide (120 mg, 227 μmol, 31% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.65 (s, 0.3H), 9.95-9.85 (m, 0.4H), 9.79-9.73 (m, 1H), 9.71 (d, J = 8.4 Hz, 0.3H), 9.61 (d, J = 8.4 Hz, 0.3H), 9.33 (s, 0.3H), 8.81-8.71 (m, 0.4H), 8.33-8.20 (m, 0.6H), 8.14- 8.04 (m, 1H), 8.01-7.92 (m, 0.7H), 7.87-7.73 (m, 1.2H), 7.24 (d, J = 8.4 Hz, 0.4H), 4.52-4.42 (m, 0.7H), 4.43-4.36 (m, 0.3H), 4.28 (s, 0.4H), 4.22 (s, 0.3H), 4.18 (s, 0.3H), 4.00-3.85 (m, 1H), 3.83-3.74 (m, 0.7H), 3.71-3.68 (m, 0.3H), 1.80-1.40 (m, 3.5H), 1.38-1.29 (m, 0.5H), 1.11 (d, J = 7.6 Hz, 0.3H), 1.09- 1.01 (m, 2H), 0.98-0.91 (m, 2H), 0.88-0.82 (m, 1.8H), 0.51-0.29 (m, 2H), 0.22--0.07 (m, 2H). LC-MS (Method L): Rt = 2.143 min; MS (ESIpos): m/z = 529.1 [M+H] ^+. To a solution of ethyl (3S,3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole -3-carboxylate (569 mg, 2.59 mmol, 1.20 eq, hydrochloric acid) and (2S) -2-(tert-butoxycarbonylamino)-3,3-dimethyl- butanoic acid (500 mg, 2.16 mmol, 1.00 eq) in dichloromethane (20.0 mL) were added 4- methylmorpholine (874 mg, 8.64 mmol, 0.950 mL, 4.00 eq) and benzotriazol-1-yloxy(tripyrrolidin-1- yl)phosphonium;hexafluorophosphate (1.11 g, 2.38 mmol, 1.10 eq). After stirring at 25 °C for 2 h, the reaction mixture was diluted with water (100 mL). The solution was extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 4: 1) to give ethyl (3S,3aS,6aR)-2-[(2S) -2-(tert- butoxycarbonylamino)-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-he xahydro-1H-cyclopenta[c]pyrrole-3- carboxylate (600 mg, 1.51 mmol, 70% yield) as a yellow solid. LC-MS (Method C): Rt = 0.702 min; MS (ESIpos): m/z = 397.3 [M+H] ⁺ . Procedure for preparation of ethyl (3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-butanoyl]- 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylat e To a solution of ethyl (3S,3aS,6aR)-2-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimeth yl-butanoyl]- 3,3a,4,5, 6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate (600 mg, 1.51 mmol, 1.00 eq) in dioxane (8.00 mL) was added hydrochloric acid (4.00 M in 1,4-dioxane, 8.00 mL, 21.1 eq). After stirring at 25 °C for 2 h, the reaction mixture was concentrated under vacuum to give ethyl (3S, 3aS, 6aR) -2- [(2S) -2-amino-3, 3-dimethyl-butanoyl]-3, 3a, 4, 5, 6, 6a-hexahydro-1H-cyclopenta[c]pyrrole-3- carboxylate (760 mg, crude) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.21 (br. s, 3H), 4.18-4.15 (m, 1H), 4.15-4.06 (m, 2H), 4.00-3.91 (m, 1H), 3.79-3.71 (m, 1H), 3.71-3.62 (m, 1H), 2.75-2.66 (m, 1H), 2.65-2.57 (m, 1H), 1.95-1.85 (m, 1H), 1.84-1.68 (m, 2H), 1.67-1.55 (m, 2H), 1.54-1.43 (m, 1H), 1.18 (t, J = 7.2 Hz, 3H), 1.03 (s, 9H). Procedure for preparation of ethyl (3S,3aS,6aR)-2-[(2S)-2-(2,2-difluoropropanoylamino)-3,3- dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]p yrrole-3-carboxylate To a mixture of 2, 2-difluoropropanoic acid (827 mg, 7.51 mmol, 1 eq), ethyl (3S,3aS,6aR)-2-[(2S)-2- amino-3, 3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c ]pyrrole-3-carboxylate (2.50 g, 7.51 mmol, 1.00 eq, hydrochloric acid) and N,N-diisopropylethylamine (2.91 g, 22.5 mmol, 3.92 mL, 3.00 eq) in dichloromethane (30.0 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3- yloxy)methylene]-dimethyl-ammonium;hexafluorophosphate (4.28 g, 11.3 mmol, 1.5 eq). After stirring at 25 °C for 16 h, the reaction mixture was concentrated to give a residue. The residue was purified by reversed phase (instrument: 80 g Flash; Column: Welch Ultimate XB_C ₁₈ 20-40 μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-20 min 40-60% B; flow 80 mL/min; temperature: room temperature; Detector: UV 220/254 nm) to give ethyl (3S,3aS,6aR)-2-[(2S)-2-(2,2- difluoropropanoylamino)-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a -hexahydro-1H-cyclopenta[c]pyrrole-3- carboxylate (1.92 g, 4.45 mmol, 59% yield, 90% purity) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.05 (d, J = 8.6 Hz, 1H), 4.51 (d, J = 8.6 Hz, 1H), 4.15-4.12 (m, 1H), 4.12-4.05 (m, 2H), 3.82-3.73 (m, 1H), 3.67-3.62 (m, 1H), 2.74-2.65 (m, 1H), 2.63-2.54 (m, 1H), 1.98- 1.83 (m, 1H), 1.82-1.69 (m, 4H), 1.69-1.50 (m, 3H), 1.43-1.31 (m, 1H), 1.21-1.14 (m, 3H), 0.99 (s, 8H), 0.92 (s, 1H). Procedure for preparation of (3S,3aS,6aR)-2-[(2S)-2-(2,2-difluoropropanoylamino)-3,3-dime thyl- butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3- carboxylic acid A mixture of ethyl (3S,3aS,6aR)-2-[(2S)-2-(2,2-difluoropropanoylamino)-3,3-dime thyl-butanoyl]- 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylat e (1.92 g, 4.94 mmol, 1.00 eq) and lithium hydroxide (207mg, 4.94 mmol, 1.00 eq) in tetrahydrofuran (20.0 mL) and water (1.00 mL) was stirred at 25 °C for 16 h. The reaction mixture was concentrated to give a residue. The residue was purified by reversed phase (instrument: 120 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-15 min 40-60% B; flow 80 mL/min; temperature: room temperature; Detector: UV 220/254 nm) to give (3S,3aS,6aR)-2-[(2S)-2-(2,2- difluoropropanoylamino)-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a -hexahydro-1H-cyclopenta[c]pyrrole-3- carboxylic acid (500 mg, 1.26 mmol, 26% yield, 91% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.56 (br. s, 1H), 8.02 (d, J = 8.6 Hz, 1H), 4.51 (d, J = 8.8 Hz, 1H), 4.09 (d, J = 4.4 Hz, 1H), 3.82-3.72 (m, 1H), 3.67-3.60 (m, 1H), 2.85-2.55 (m, 2H), 2.01-1.83 (m, 1H), 1.83-1.69 (m, 4H), 1.67-1.47 (m, 3H), 1.42-1.29 (m, 1H), 1.02-0.91 (m, 9H). To a solution of (3S,3aS,6aR)-2-[(2S)-2-(2, 2-difluoropropanoylamino)-3,3-dimethyl-butanoyl]- 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (500 mg, 1.39 mmol, 1.00 eq) and 2-amino-2-phthalazin-1-yl-acetamide (364 mg, 1.53 mmol, 1.10 eq, hydrochloric acid) in dichloromethane (10.0 mL) were added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]- dimethyl-ammonium;hexafluorophosphate (791 mg, 2.08 mmol, 1.50 eq) and N-ethyl-N-isopropyl- propan-2-amine (537 mg, 4.16 mmol, 0.724 mL, 3.00 eq). After stirring at 25 °C for 2 h, the reaction mixture was concentrated to give a residue. The residue was purified by reversed phase column (instrument: 80 g Flash; Column: Welch μLtimate XB_C1820-40 μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-30 min 0-100% B; flow 55 mL/min; temperature: room temperature; Detector: UV 220/254 nm) to give (3S,3aS,6aR)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-2-[(2 S)-2-(2,2- difluoropropanoylamino)-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a -hexahydro-1H-cyclopenta[c]pyrrole-3- carboxamide (700 mg, 1.29 mmol, 93% yield) as a yellow solid. Procedure for preparation of Compound CPD0278006 - (3S,3aS,6aR)-N-[cyano (phthalazin-1-yl) methyl]-2-[(2S)-2-(2,2-difluoropropanoylamino)-3,3-dimethyl- butanoyl]-3,3a,4,5,6,6a-hexahydro- 1H-cyclopenta[c]pyrrole-3-carboxamide To a solution of (3S,3aS,6aR)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-2-[(2 S)-2-(2,2- difluoropropanoylamino)-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a -hexahydro-1H-cyclopenta[c]pyrrole-3- carboxamide (230 mg, 422 μmol, 1.00 eq) in dichloromethane (2.00 mL) was added methoxycarbonyl- (triethylammonio)sulfonyl-azanide (301 mg, 1.27 mmol, 3.00 eq). After stirring at 25 °C for 16 h, the reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: UniSil 3-100 C18 UItra (150 × 25 mm × 3 μm); mobile phase: [water (FA)-ACN];B%: 40%-70%, 7 min) to give (3S,3aS,6aR)-N-[cyano(phthalazin-1-yl)methyl]-2-[(2S)-2-(2,2 -difluoropropanoylamino)-3,3- dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]p yrrole-3-carboxamide (94.6 mg, 179 μmol, 42% yield, 100% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.74 (s, 0.4H), 9.77 (d, J = 4.0 Hz, 0.5H), 9.72 (d, J = 8.8 Hz, 0.3H), 9.64 (d, J = 8.8 Hz, 0.2H), 9.46 (s, 0.4H), 8.84-8.71 (m, 0.5H), 8.32-8.23 (m, 0.6H), 8.17-7.74 (m, 4H), 7.37-7.23 (m, 0.5H), 4.55-4.41 (m, 1H), 4.16-4.09 (m, 0.6H), 4.04 (d, J = 4.4 Hz, 0.3H), 3.93-3.83 (m, 1H), 3.75-3.68 (m, 0.4H), 3.66-3.56 (m, 0.5H), 2.83-2.65 (m, 1H), 2.58-2.52 (m, 0.3H), 2.40-2.30 (m, 0.2H), 1.93-1.65 (m, 6H), 1.63-1.27 (m, 3H), 1.03-0.95 (m, 9H). LC-MS (Method C) : R _t = 0.893 min, MS (ESIpos) : m/z = 527.3 [M+H] ⁺ . To a mixture of 3,3-difluorocyclobutanecarboxylic acid (1.00 g, 7.35 mmol, 1.10 eq) in dichloromethane (2.00 mL) were added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyri dinium 3-Oxide hexafluorophosphate (3.81 g, 10.0 mmol, 1.50 eq) and diisopropylethylamine (4.32 g, 33.4 mmol, 5.82 mL, 5.00 eq). After stirring at 20 °C for 30 min, methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyla te (2.37 g, 6.68 mmol, 1.00 eq, 2Hydrogen chloride) was added. The mixture was stirred at 20 °C for 16 h, and partitioned between water (30.0 mL) and dichloromethane (30.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 10: 1 to 4: 1) to give methyl (1R,2S,5S)-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino ]-3,3-dimethyl-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (1.94 g, 4.36 mmol, 65% yield, 90% purity) as red oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.16 (d, J = 9.2 Hz, 1H), 4.42 (d, J = 9.2 Hz, 1H), 4.20 (s, 1H), 3.91- 3.79 (m, 2H), 3.69-3.63 (m, 3H), 3.14-3.04 (m, 1H), 2.70-2.52 (m, 4H), 1.65-1.50 (m, 1H), 1.45-1.40 (m, 1H), 1.05-0.92 (m, 11H), 0.88-0.79 (m, 4H). Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino ]-3,3- dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid A mixture of methyl (1R,2S,5S)-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino ]-3,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyla te (1.94 g, 4.84 mmol, 1.00 eq) and lithium hydrate (610 mg, 14.5 mmol, 3.00 eq) in mixed solvent of methanol (4.00 mL) and water (0.100 mL) was stirred at 20 °C for 16 h. The reaction mixture was concentrated and diluted with water (20.0 mL). The solution was washed with ethyl acetate (30.0 mL × 2). Hydrochloric acid (1M, 2.00 mL) was added to the aqueous phase to adjust pH to 3~4. The solution was extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with water (10.0 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-3-[(2S)-2-[(3,3- difluorocyclobutanecarbonyl)amino]-3,3-dimethyl-butanoyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (1.55 g, 3.81 mmol, 79% yield, 95% purity) as red oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.46 (br. s, 1H), 8.15 (d, J = 9.2 Hz, 1H), 4.42 (d, J = 9.2 Hz, 1H), 4.12 (s, 1H), 3.88-3.78 (m, 2H), 3.13-3.02 (m, 1H), 2.77-2.55 (m, 4H), 1.91 (s, 1H), 1.52-1.47 (m, 1H), 1.41-1.36 (m, 1H), 1.03-0.93 (m, 12H), 0.87-0.79 (m, 3H). Procedure for preparation of methyl (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3- [(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino]-3,3-dimethy l-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of (1R,2S,5S)-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino ]-3,3-dimethyl-butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.30 g, 3.36 mmol, 1.00 eq) in dichloromethane (2.00 mL) were added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-Oxide hexafluorophosphate (1.92 g, 5.05 mmol, 1.50 eq) and diisopropylethylamine (2.17 g, 16.8 mmol, 2.93 mL, 5.00 eq). After stirring at 25 °C for 30 min, 2-amino-2-phthalazin-1-yl- acetamide (1.11 g, 4.04 mmol, 1.20 eq, 2Hydrogen chloride) was added. The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (nstrument: 40g Flash; Column: Welch Ultimate XB_C1820- 40 μm; eluent A: water (0.05% FA), eluent B: acetonitrile; gradient: 0-20 min 0-70% B; flow 70 ml/min; temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)- 3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino]-3,3-dimet hyl-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (1.02 g, 1.64 mmol, 49% yield, 92% purity) as a yellow solid. LC-MS (Method C): R _t = 0.538 min; MS (ESIpos): m/z = 571.3 [M+H] ⁺ . Procedure for preparation of Compound CPD0278007 - (1R,2S,5S)-N-[cyano(phthalazin-1- yl)methyl]-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino ]-3,3-dimethyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -2-[(3,3- difluorocyclobutanecarbonyl)amino]-3,3-dimethyl-butanoyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (900 mg, 1.58 mmol, 1.00 eq) in dichloromethane (4.00 mL) was added Burgess reagent (1.50 g, 6.31 mmol, 4.00 eq). After stirring at 25 °C for 16 h, the reaction mixture was partitioned between dichloromethane (30.0 mL) and water (30.0 mL). The organic phase was washed with water (10.0 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN];B%: 31%-71%,10min) to give (1R,2S,5S)-N-[cyano(phthalazin- 1-yl)methyl]-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)ami no]-3,3-dimethyl-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (240 mg, 417 μmol, 26% yield, 96% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.70 (s, 0.35H), 9.81-9.73 (m, 0.71H), 9.63 (d, J = 8.8 Hz, 0.17H), 9.43 (s, 0.37H), 8.82-8.72 (m, 0.44H), 8.30-8.22 (m, 0.48H), 8.21-8.13 (m, 0.50H), 8.13-8.06 (m, 1.33H), 8.05-7.96 (m, 0.73H), 7.94-7.88 (m, 0.28H), 7.87-7.81 (m, 0.78H), 7.80-7.75 (m, 0.44H), 7.33 (d, J = 8.8 Hz, 0.25H), 7.29 (d, J = 8.8 Hz, 0.16H), 4.45-4.33 (m, 1H), 4.26 (s, 0.39H), 4.23 (s, 0.20H), 4.14 (s, 0.28H), 4.01-3.73 (m, 2H), 3.18-2.96 (m, 1H), 2.75-2.57 (m, 4H), 1.68-1.57 (m, 0.66H), 1.57-1.53 (m, 0.42H), 1.52-1.46 (m, 0.25H), 1.43-1.29 (m, 0.35H), 1.10-0.89 (m, 12H), 0.87-0.72 (m, 3H). Preparation of CPD0278008 Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-methyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyla te To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoic acid (10.0 g, 46.0 mmol, 1.0 eq) in dichloromethane (80.0 mL) were added benzotriazol-1-yloxy(tripyrrolidin-1- yl)phosphanium;hexafluorophosphate (27.4 g, 52.6 mmol, 1.20 eq) and diisopropylethylamine (17.0 g, 132 mmol, 22.9 mL, 3.00 eq). After stirring at 20 °C for 0.5 h, to the mixture was added methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (7.42 g, 36.1 mmol, 1.0eq). The solution was stirred at 20 °C for 16 h. The reaction mixture was diluted with water (120 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 12% Ethyl acetate/Petroleum ether gradient @ 130 mL/min) to afford methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-methyl-but anoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (6.50 g, 16.1 mmol, 37% yield, 92% purity) as white oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.06 (d, J = 8.4 Hz, 1H), 4.18 (s, 1H), 4.02-3.97 (m, 1H), 3.86-3.73 (m, 2H), 3.64 (s, 3H), 1.93-1.81 (m, 1H), 1.56-1.49 (m, 1H), 1.40 (br d, J = 7.6 Hz, 1H), 1.38-1.28 (m, 9H), 1.01 (s, 3H), 0.91-0.82 (m, 9H). LC-MS (Method C): R _t = 1.599 min; MS (ESIpos): m/z = 369.2 [M+Na] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-methyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyli c acid To a solution of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-methyl-but anoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (3.00 g, 8.14 mmol, 1.00 eq) in mixed solvent of tetrahydrofuran (15.0 mL) and water (15.0 mL) was added lithium hydroxide hydrate (1.02 g, 24.4 mmol, 3.00 eq). After stirring at 20 °C for 16 h, hydrochloric acid (1M) was added to adjust pH to 4. The reaction mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (20.0 × 3 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford (1R,2S,5S)-3-[(2S)-2-(tert- butoxycarbonylamino)-3-methyl-butanoyl]-6,6-dimethyl-3-azabi cyclo[3.1.0]hexane-2-carboxylic acid (2.80 g, crude) as a white solid. LC-MS (Method C): R _t = 2.179 min; MS (ESIpos): m/z = 355.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-amino-3-methyl-butanoyl]-6,6-dimethyl-3 - azabicyclo[3.1.0]hexane-2-carboxylic acid To a solution of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-methyl-but anoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (2.80 g, 7.90 mmol, 1.00 eq) in hydrogen chloride (4M in ethyl acetate, 20.0 mL). After stirring at 20 °C for 2 h, the reaction mixture was concentrated under reduced pressure to give (1R,2S,5S)-3-[(2S)-2-amino-3-methyl-butanoyl]-6,6-dimethyl-3 - azabicyclo[3.1.0]hexane-2-carboxylic acid (2.00 g, crude) as a white solid. LC-MS (Method C): R _t = 0.503 min; MS (ESIpos): m/z = 255.1 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2- carboxylic acid To a solution of (1R,2S,5S)-3-[(2S)-2-amino-3-methyl-butanoyl]-6,6-dimethyl-3 - azabicyclo[3.1.0]hexane-2-carboxylic acid (2.00 g, 7.86 mmol, 1.00 eq) in dichloromethane (20.0 mL) were added methyl 2,2,2-trifluoroacetate (3.02 g, 23.6 mmol, 2.38 mL, 3.00 eq) and diisopropylethylamine (3.05 g, 23.6 mmol, 4.11 mL, 3.00 eq). After stirring at 20 °C 12 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (Instrument: 200 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.05% formic acid), eluent B: acetonitrile; gradient: 55% B; flow 90 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to afford (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (2.20 g, 5.92 mmol, 75% yield, 94% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.83 (d, J = 8.0 Hz, 1H), 4.22-4.09 (m, 2H), 3.91-3.77 (m, 2H), 2.16- 2.09 (m, 1H), 1.54-1.52 (m, 1H), 1.47-1.35 (m, 1H), 1.11-0.76 (m, 12H). To a solution of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-[(2,2,2-trifluoro acetyl)amino]butanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (800 mg, 2.28 mmol, 1.00 eq) in N,N-dimethylformamide (10.0 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (1.04 g, 2.74 mmol, 1.20 eq) and diisopropylethylamine (885 mg, 6.85 mmol, 1.19 mL, 3.00 eq). After stirring at 20 °C for 0.5 h, 2-amino-2-cinnolin-4-yl-acetamide (654 mg, 2.74 mmol, 1.20 eq, HCl) was added to the reaction mixture at 25 °C. After stirring at 25 °C for 16 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (Instrument: 220 g Flash; Column: Welch Ultimate XB_C1820-40μm; eluent A: water (0.05% formic acid), eluent B: acetonitrile; gradient: 12 min 50% B; flow 80 mL/min; temperature: room temperature; Detector: UV 220/254 nm) to afford (1R,2S,5S)-N-(2-amino-1-cinnolin-4-yl-2-oxo-ethyl)-6,6-dimet hyl-3- [(2S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl] -3-azabicyclo[3.1.0]hexane-2-carboxamide (700 mg, 1.28 mmol, 56% yield, 98% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.89-9.71 (m, 1H), 9.36-9.32 (m, 1H), 9.32-9.15 (m, 1H), 8.55-8.47 (m, 1H), 8.39-8.21 (m, 1H), 8.03-7.96 (m, 1H), 7.95-7.85 (m, 1H), 6.20-6.10 (m, 1H), 4.44-4.37 (m, 1H), 4.16-4.04 (m, 1H), 3.87-3.76 (m, 2H), 2.15-1.98 (m, 1H), 1.44 (br d, J = 7.6 Hz, 1H), 0.98-0.75 (m, 12H). LC-MS (Method C): R _t = 1.697 and 1.765 min; MS (ESIpos): m/z = 535.6 [M+H] ⁺ . 4.6. dim carb To a solution of (1R,2S,5S)-N-(2-amino-1-cinnolin-4-yl-2-oxo-ethyl)-6,6-dimet hyl-3-[(2S)-3-methyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-3-azabicyclo[3.1.0]h exane-2-carboxamide (650 mg, 1.22 mmol, 1.00 eq) in dichloromethane (12.0 mL) was added methoxycarbonyl-(triethylammonio)sulfonyl-azanide (1.45 g, 6.08 mmol, 5.00 eq) at 20 °C. After stirring at 20 °C for 4 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C18250*50mm*10 μm; mobile phase: [water( ammonium hydrogen carbonate)- acetonitrile]; B%: 32%-62%,8min) to afford (1R,2S,5S)-N-[cinnolin-4-yl(cyano)methyl]-6,6-dimethyl-3- [(2S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-3-a zabicyclo[3.1.0]hexane-2-carboxamide (380 mg, 0.719 mmol, 59% yield, 98% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.55 (s, 0.6H), 12.40 (s, 0.3H), 9.92 (s, 0.3H), 9.85 (d, J = 7.6 Hz, 1H), 9.68 (s, 0.7H), 8.52 (d, J = 8.4 Hz, 0.6H), 8.28 (d, J = 8.4 Hz, 0.3H), 7.72 (s, 0.3H), 7.69 (s, 0.6H), 7.60 (t, J = 7.6 Hz, 0.6H), 7.53 (t, J = 7.6 Hz, 0.3H), 7.33-7.25 (m, 1.2H), 7.23-7.08 (m, 0.7H), 4.39 (s, 0.3H), 4.33 (s, 0.6H), 4.21-4.12 (m, 1H), 3.95-3.88 (m, 1H), 3.88-3.80 (m, 1H), 2.20-2.07 (m, 1H), 1.68- 1.59 (m, 1H), 1.43 (d, J = 7.6 Hz, 0.7H), 1.36 (d, J = 7.6 Hz, 0.3H), 1.07 (s, 3H), 0.98-0.80 (m, 9H). LC-MS (Method C): R _t = 1.982 min; MS (ESIpos): m/z = 517.1 [M+H] ⁺ . Preparation of CPD0278009 Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-2-amino-3-methyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate A mixture of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-methyl-but anoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylate (2.00 g, 5.43 mmol, 1.00 eq) in hydrogen chloride (20.0 mL in ethyl acetate) was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to afford methyl (1R,2S,5S)-3-[(2S)-2-amino-3-methyl-butanoyl]-6,6-dimethyl-3 - azabicyclo[3.1.0]hexane-2-carboxylate (1.40 g, crude) as a white solid. Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-2-(2,2-difluoropropanoylamino)-3- methyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-ca rboxylate To a solution of 2,2-difluoropropanoic acid (902 mg, 8.20 mmol, 1.10 eq) in tetrahydrofuran (20.0 mL) was added di(imidazol-1-yl)methanone (1.45 g, 8.94 mmol, 1.20 eq). After stirring at 25 °C for 4 h, methyl (1R,2S,5S)-3-[(2S)-2-amino-3-methyl-butanoyl]-6,6-dimethyl-3 -azabicyclo[3.1.0]hexane-2- carboxylate (2.00 g, 7.45 mmol, 1.00 eq) was added at 25 °C. After stirring at 25 °C for 12 h, the reaction mixture was diluted with water (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (60.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~40% Ethylacetate/Petroleum ethergradient @ 60 mL/min) to afford (1R,2S,5S)-3-[(2S)-2-(2,2- difluoropropanoylamino)-3-methyl-butanoyl]-6,6-dimethyl-3-az abicyclo [3.1.0]hexane-2-carboxylate (1.60 g, 4.00 mmol, 54% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.85 (br d, J = 8.0 Hz, 1H), 4.19 (s, 1H), 4.14 (t, J = 8.8 Hz, 1H), 3.93-3.88 (d, 1H), 3.84-3.76 (m, 1H), 3.66 (s, 3H), 2.16-2.04 (m, 1H), 1.71 (t, J = 19.2 Hz, 3H), 1.58- 1.51 (m, 1H), 1.43 (d, J = 7.6 Hz, 1H), 1.01 (s, 3H), 0.92 (d, J = 6.4 Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H), 0.84 (s, 3H). LCMS (Method C): R _t = 1.884 min; MS (ESIpos): m/z = 361.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-(2,2-difluoropropanoylamino)-3-methyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyli c acid To a solution of methyl (1R,2S,5S)-3-[(2S)-2-(2,2-difluoropropanoylamino)-3-methyl-b utanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.60 g, 4.44 mmol, 1.00 eq) in methanol (10.0 mL) and water (10.0 mL) was added lithium hydroxide hydrate (559 mg, 13.3 mmol, 3.00 eq). After stirring at 25 °C for 2 h, hydrogen chloride (1M) was added to the reaction mixture to adjust pH~4. The solution was diluted with water (30.0 mL) and extracted with ethyl acetate 60 mL (20 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (1R,2S,5S)-3-[(2S)-2-(2,2-difluoropropanoylamino)-3- methyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-ca rboxylic acid (1.20 g, 3.12 mmol, 70.2% yield) as colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.44 (br. s, 1H), 8.82 (d, J = 8.0 Hz, 1H), 4.21-4.08 (m, 2H), 3.94- 3.85 (m, 1H), 3.84-3.75 (m, 1H), 2.16- 2.04 (m, 1H), 1.71 (t, J = 19.2 Hz, 3H), 1.55-1.50 (m, 1H), 1.44- 1.39 (m, 1H), 1.01 (s, 3H), 0.92 (br d, J = 6.4 Hz, 3H), 0.86 (d, J = 6.4 Hz, 3H), 0.83 (s, 3H). LCMS (Method A): R _t = 0.511 min; MS (ESIpos): m/z =347.3 [M+H] ⁺ . To a solution of 2-amino-2-(1,6-naphthyridin-8-yl)acetonitrile (50.5 mg, 274 umol, 0.95 eq) and (1R,2S,5S)-3-[(2S)-2-(2,2-difluoropropanoylamino)-3-methyl-b utanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (100 mg, 289 μmol, 1 eq) in dichloromethane (1.00 mL) were added diisopropylethylamine (112 mg, 866 μmol, 151 μL, 3.00 eq) and O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluronium hexafluorophosphate (121 mg, 318 μmol, 1.10 eq). After stirring at 20 °C for 2 h, the reaction mixture was concentrated to give a residue. The residue was purified by prep-TLC (SiO ₂ , petroleum ether: ethyl acetate = 0: 1), followed by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 μm; mobile phase: [water(FA)-ACN];B%:37%-67%, 7min) afford (1R,2S,5S)-N- [cyano(1,6-naphthyridin-8-yl)methyl]-3-[(2S)-2-(2,2-difluoro propanoylamino)-3-methyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (83.9 mg, 157 μmol, 55% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.61 (d, J = 7.6 Hz, 0.5H), 9.53 (d, J = 2.8 Hz, 1H), 9.46 (d, J = 7.6 Hz, 0.5H), 9.29-9.25 (m, 1H), 8.95 (s, 0.5H), 8.93 (s, 0.5H), 8.84-8.79 (m, 1H), 8.71 (dd, J = 8.4, 1.6 Hz, 1H), 7.85 (dd, J = 8.4, 4.4 Hz, 1H), 6.93-6.79 (m, 1H), 4.34 (s, 0.5H), 4.30 (s, 0.5H), 4.42-4.20 (m, 1H), 3.90-3.81 (m, 2H), 2.19-1.94 (m, 1H), 1.80-1.61 (m, 3H), 1.61-1.49 (m, 1H), 1.41 (d, J = 7.6 Hz, 0.5H), 1.22 (d, J = 7.6 Hz, 0.5H), 1.06 (s, 1.5H), 0.96 (s, 1.5H), 0.93-0.89 (m, 2H), 0.88-0.84 (m, 3H), 0.84-0.80 (m, 4H). LC-MS (Method C): Rt = 0.652 min; MS (ESIpos): m/z = 513.2 [M+H] ⁺ . 50: 50. Preparation of CPD0278010 Procedure for preparation of 2-amino-2-cinnolin-4-yl-acetamide To a solution of tert-butyl N-(2-amino-1-cinnolin-4-yl-2-oxo-ethyl)carbamate (500 mg, 1.65 mmol, 1.00 eq) in hydrochloric acid (4M in dioxane, 5.00 mL) at 20 °C. After stirring at 20 °C for 2 h, the reaction mixture was concentrated under reduced pressure to give 2-amino-2-cinnolin-4-yl-acetamide (450 mg, 1.62 mmol, 98% yield, 73% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.51 (s, 1H), 9.21-9.20 (m, 2H), 8.61-8.53 (m, 2H), 8.19 (s, 1H), 8.10- 8.00 (m, 2H), 7.85 (s, 1H), 5.82-5.81 (m, 1H). Procedure for preparation difluorocyclobutanecarbo azabicyclo[3.1.0]hexane-2 To a solution of (1R,2S,5S)-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino ]-3,3-dimethyl-butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (500 mg, 1.29 mmol, 1.00 eq) in dichloromethane (10.0 mL) were added 2-amino-2-cinnolin-4-yl-acetamide (371 mg, 1.55 mmol, 1.20 eq, hydrochloride), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]- dimethylazanium;hexafluorophosphate (984 mg, 2.59 mmol, 2.00 eq) and N,N-diethylpropan-2-amine (836 mg, 6.47 mmol, 1.13 mL, 5.00 eq). After stirring at 20 °C for 16 h, the reaction mixture was partitioned between water (100 mL) and ethyl acetate (200 mL). The organic phase was washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Dichloromethane: Tetrahydrofuran = 4: 1 to 1: 1) to give (1R,2S,5S)-N-(2-amino-1-cinnolin-4-yl-2-oxo- ethyl)-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino]-3, 3-dimethyl-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (380 mg, 0.666 mmol, 52% yield) as a white solid. LC-MS (Method C): Rt = 0.849 min; MS (ESIpos): m/z = 571.3 [M+H] ^+. To a solution of (1R,2S,5S)-N-(2-amino-1-cinnolin-4-yl-2-oxo-ethyl)-3-[(2S)-2 -[(3,3- difluorocyclobutanecarbonyl)amino]-3,3-dimethyl-butanoyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (200 mg, 0.351 mmol, 1.00 eq) in dichloromethane (3.00 mL) was added Burgess reagent (334 mg, 1.40 mmol, 4.00 eq). After stirring at 20 °C for 2 h, the reaction mixture was partitioned between water (50.0 mL) and dichloromethane (100 mL). The organic phase was washed with brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition, column: Phenomenex Luna C18150 × 25 mm × 10 μm; mobile phase: [water(FA)-ACN]; B%: 36%-66%, 9min) to give a residue. The residue was purified by SFC separation (column: DAICEL CHIRALPAK AD (250mm ×30 mm, 10 μm); mobile phase: [Neu-IPA]; B%: 45%-45%, 2.8min) to give (1R,2S,5S)-N-[cinnolin-4- yl(cyano)methyl]-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl ) amino]-3,3-dimethyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (21.3 mg, 38.6 μmol, 71% yield) as a yellow solid. LC-MS (Method C): Rt = 0.559 min; MS (ESIpos): m/z = 553.3 [ +H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.57-12.38 (m, 1H), 9.86 (s, 0.5H), 9.64 (s, 0.3H), 8.51 (d, J = 8.0 Hz, 0.4H), 8.32 (d, J = 8.4 Hz, 0.6H), 8.16-8.10 (m, 1H), 7.71 (d, J = 4.0 Hz, 1H), 7.62-7.50 (m, 1H), 7.31-7.24 (m, 1H), 7.18-7.10 (m, 1H), 4.42-4.30 (m, 2H), 3.93-3.80 (m, 2H), 3.14-3.06 (m, 1H), 2.72- 2.57 (m, 4H), 1.62-1.54 (m, 1H), 1.40-1.38 (m, 1H), 1.35-1.30 (m, 1H), 1.05 (s, 3H), 0.97-0.86 (m, 13H). Preparation of CPD0278011 Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-2-(2,2-difluoropropanoylamino)-3,3- dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylate - To a mixture of 2,2-difluoropropanoic acid (690 mg, 6.27 mmol, 1.00 eq) in dichloromethane (50.0 mL) were added benzotriazol-1-yloxy(tripyrrolidin-1-yl)phosphanium;hexafluo rophosphate (3.92 g, 7.53 mmol, 1.20 eq) and N-methylmorpholine (2.54 g, 25.1 mmol, 4.00 eq) followed by methyl (1R,2S,5S)- 3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabic yclo[3.1.0]hexane-2-carboxylate (2.00 g, 6.27 mmol, 1.00 eq, hydrochloric acid) at 0 °C. After stirring at 25 °C for 16 h, the reaction mixture was diluted with saturated ammonium chloride aqueous solution (50.0 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®;20 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ether gradient @60 mL/min) to afford methyl (1R,2S,5S)-3-[(2S)-2-(2,2-difluoropropanoylamino)-3,3-dimeth yl-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (1.60 g, 4.27 mmol, 68% yield) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.90 (d, J = 8.0 Hz, 1H), 4.56 (d, J = 12.0 Hz, 1H), 4.48 (s, 1H), 3.98- 3.85 (m, 2H), 3.78 (s, 3H), 1.78 (t, J = 19.2 Hz, 3H), 1.52-1.46 (m, 2H), 1.08 (s, 9H), 1.07(s, 3H), 0.90 (s, 3H). LC-MS (Method C): R _t = 0.656 min; MS (ESIpos): m/z = 375.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-(2,2-difluoropropanoylamino)-3,3-dimeth yl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyli c acid To a solution of methyl (1R,2S,5S)-3-[(2S)-2-(2,2-difluoropropanoylamino)-3,3-dimeth yl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.60 g, 4.27 mmol, 1.00 eq) in methanol (10.0 mL) was added a solution of lithium hydroxide hydrate (409 mg, 17.1 mmol, 4.00 eq) in water (10.0 mL) at 0 °C. After stirring at 25 °C for 16 h, hydrochloric acid (0.5M in water) was added to the reaction mixture to adjust pH~3. The solution was extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was triturated with methyl tert-butyl ether (20.0 mL). The mixture was filtered. The filter cake was dried under vacuum to give (1R,2S,5S)-3-[(2S)- 2-(2,2-difluoropropanoylamino)-3,3-dimethyl-butanoyl]-6,6-di methyl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (450 mg, 1.04 mmol, 24% yield, 83% purity) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.92 (d, J = 9.6 Hz, 1H), 4.58 (d, J = 9.6 Hz, 1H), 4.50 (s, 1H), 3.98-3.89 (m, 2H), 1.79 (t, J = 19.2 Hz, 3H), 1.73-1.66 (m, 1H), 1.59-1.52 (m, 1H), 1.09 (s, 3H), 1.07 (s, 9H), 0.90 (s, 3H). LC-MS (Method C): R _t = 0.528 min; MS (ESIpos): m/z = 361.1 [M+H] ⁺ . To a mixture of (1R,2S,5S)-3-[(2S)-2-(2,2-difluoropropanoylamino)-3,3-dimeth yl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (300 mg, 0.832 mmol, 1.00 eq) in dichloromethane (10.0 mL) were added N,N-diisopropylethylamine (430 mg, 3.33 mmol, 4.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexaflu orophosphate (380 mg, 0.999 mmol, 1.20 eq) followed by 2-amino-2-phthalazin-1-yl-acetamide (168 mg, 0.705 mmol, 1.00 eq, hydrochloric acid salt) at 0 °C After stirring at 25 °C for 16 h, the reaction mixture was diluted with saturated ammonium chloride aqueous solution (20.0 mL) and extracted with ethyl acetate (20.0 mL× 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®;4g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate/Petroleum ether gradient @ 60 mL/min) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1- yl-ethyl)-3-[(2S)-2-(2,2-difluoropropanoylamino)-3,3-dimethy l-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0] hexane-2-carboxamide (400 mg, 0.734 mmol, 88% yield) as a yellow solid. LC-MS (Method C): R _t = 0.559min; MS (ESIpos): m/z = 545.3 [M+H] ⁺ . Procedure 2-(2,2-diflu 2-carboxa To a solution of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -2-(2,2- difluoropropanoylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2- carboxamide (400 mg, 0.734 mmol, 1.00 eq) in dichloromethane (5.00 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (350 mg, 1.47 mmol, 2.00 eq) at 0 °C. After stirring at 25 °C for 2 h, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC column: (Waters Xbridge 150*25mm* 5 μm; mobile phase: [water( ammonium bicarbonate)- acetonitrile]; B%: 39%-69%, 8 min).to give (1R,2S,5S)-N-[cyano(phthalazin- 1-yl)methyl]-3-[(2S)-2-(2,2-difluoropropanoylamino)-3,3-dime thyl-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (52.0 mg, 89.9 μmol, 12% yield, 91% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.68 (s, 0.3H), 9.83-9.75 (m, 0.7H), 9.70-9.65 (m,0.2H), 9.43 (s, 0.3H), 8.81-8.73 (m, 0.4H), 8.33-8.21 (m, 0.9H), 8.15-8.05 (m, 1.5H), 8.04-7.87(m, 0.8H),7.86-7.75(m, 0.8H), 7.36-7.27 (m, 0.4H), 4.44-4.33 (m, 1H), 4.31-4.15 (m, 1H), 3.94-3.96 (m, 1H), 3.71-3.74 (m, 1H), 1.52-1.82 (m, 5H), 0.87-1.02 (m, 15H). LC-MS (Method C): R _t = 0.557 min; MS (ESIpos): m/z = 527.3 [M+H] ⁺ . HPLC (Method S): R _t = 1.983 min; purity: 92%. SFC: dr = 54: 46. To a mixture of (1R,2S,5S)-3-[(2S)-2-(2,2-difluoropropanoylamino)-3-methyl-b utanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (177 mg, 0.512 mol, 1.00 eq), N,N-diisopropylethylamine (264 mg, 2.05 mmol, 4.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (253 mg, 0.665mol, 1.30 eq) in dichloromethane (5.00 mL) was added 2-amino-2-cinnolin-4-yl-acetamide (103 mg, 0.433 mol, 1.00 eq, hydrochloric acid salt). After stirring at 25 °C for 16 h, the mixture was diluted with saturated ammonium chloride solution (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~90% Ethyl acetate/Petroleum ether gradient @ 60 mL/min). to afford (1R,2S,5S)-N-(2-amino-1-cinnolin-4-yl-2-oxo-ethyl)-3-[(2S)-2 -(2,2-difluoropropanoylamino)-3-methyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxami de (200 mg, 377 μmol, 74% yield) as a yellow solid. LC-MS (Method C): R _t = 0.553 min; MS (ESIpos): m/z = 531.3 [M+H] ⁺ . To a solution of (1R,2S,5S)-N-(2-amino-1-cinnolin-4-yl-2-oxo-ethyl)-3-[(2S)-2 -(2,2- difluoropropanoylamino)-3-methyl-butanoyl]-6,6-dimethyl-3-az abicyclo[3.1.0]hexane-2-carboxamide (150 mg, 0.283 mmol, 1.00 eq) in dichloromethane (3.00 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (87.6 mg, 0.368 mmol, 1.30 eq) at 0 °C. After stirring at 25 °C for 2 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 0.01mm; mobile phase: [water (formic acid)-acetonitrile]; B%: 37%-67%, 10 min) to afford (1R,2S,5S)-N-[cinnolin-4- yl(cyano)methyl]-3-[(2S)-2-(2,2-difluoropropanoylamino)-3-me thyl-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (46.7 mg, 0.087 mmol, 31% yield, 96% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.59 (s, 0.5H), 12.40 (s, 0.25H), 9.89 (s, 0.3H), 9.66 (s, 0.6H), 8.95- 8.80 (m, 1H), 8.52 (d, J = 8.4 Hz, 0.6H), 8.29 (d, J = 8.4 Hz, 0.4H), 7.72 (s, 0.4H), 7.68 (s, 0.6H), 7.64- 7.57 (m, 0.6H), 7.56-7.50 (m, 0.6H), 7.33-7.24 (m, 1.2H), 7.20-7.10 (m, 0.6H), 4.38 (s, 0.3H), 4.32 (s,0.6H), 4.19-4.08 (m, 1H), 3.95-3.81 (m, 2H), 2.19-2.05 (m, 1H), 1.83-1.66 (m, 3H), 1.65-1.58 (m, 1H), 1.44-1.32 (m, 1H), 1.07 (s, 3H), 0.99-0.81 (m, 9H). LC-MS (Method C): R _t = 0.543 min; MS (ESIpos): m/z = 513.2 [M+H] ⁺ . HPLC (Method S): R _t = 2.068 min; purity: 96%. SFC: dr = 69: 31. Preparation of CPD0278013 Procedure for preparation of ethyl (3S,3aS,6aR)-2-[(2S)-2-(tert-butoxycarbonylamino)-3-methyl- butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3- carboxylate A mixture of (2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoic acid (3.00 g, 13.8 mmol, 1.00 eq), O- (7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluor ophosphate (6.30 g, 16.5 mmol, 1.20 eq), N,N-diisopropylethylamine (4.46 g, 34.5 mmol, 6.01 mL, 2.50 eq) in N,N -dimethylformamide (30.0 mL) was stirred at 25 °C for 0.5 h, followed by ethyl (3S,3aS,6aR)-1,2,3,3a,4,5,6,6a- octahydrocyclopenta[c]pyrrole-3-carboxylate (3.03 g, 13.8 mmol, 1.00 eq, hydrochloric acid). After stirring at 25 °C for 11.5 h, the reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (30.0 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 0 to 5: 1) to give ethyl(3S,3aS,6aR)-2-[(2S)-2-(tert-butoxycarbonylamino)-3-met hyl- butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3- carboxylate (4.50 g, 10.5 mmol, 76% yield, 90% purity) as colorless oil. LC-MS (Method L): R _t = 0.629 min; MS (ESIpos): m/z = 383.3 [M+1] ⁺ . Procedure for preparation of (3S,3aS,6aR)-2-[(2S)-2-(tert-butoxycarbonylamino)-3-methyl- butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3- carboxylic acid To a solution of ethyl (3S,3aS,6aR)-2-[(2S)-2-(tert-butoxycarbonylamino)-3-methyl-b utanoyl] - 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylat e (4.50 g, 10.5 mmol, 90% purity, 1.00 eq) in a mixed solvent of methanol (20.0 mL) and water (20.0 mL) was added lithium hydroxide monohydrate (1.33 g, 31.7 mmol, 3.00 eq) at 0 °C. After stirring at 25 °C for 12 h, hydrochloric acid (1M) was added to the reaction mixture to adjust pH to 4~5 to give a suspension. After filtration, the filter cake was washed with water (100 mL), dried under vacuum to give (3S,3aS,6aR)-2-[(2S)-2-(tert- butoxycarbonylamino) -3-methyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c] pyrrole-3- carboxylic acid (3.70 g, 9.92 mmol, 93% yield, 95% purity) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.25 (d, J = 9.2 Hz 1H), 4.42 (d, J = 3.6 Hz, 1H), 4.28-4.24 (m, 1H), 3.82-3.71 (m, 2H), 2.95-2.86 (m, 1H), 2.85-2.74 (m, 1H), 2.08-1.94 (m, 2H), 1.94-1.84 (m, 1H), 1.83- 1.71 (m, 1H), 1.71-1.58 (m, 2H), 1.57-1.50 (m, 1H), 1.48-1.39 (m, 9H), 0.98 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H). Procedure for preparation of (3S,3aS,6aR)-2-[(2S)-2-amino-3-methyl-butanoyl]-3,3a,4,5,6,6 a- hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid A mixture of (3S,3aS,6aR)-2-[(2S)-2-(tert-butoxycarbonylamino)-3-methyl-b utanoyl] -3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (3.70 g, 9.92 mmol, 95% purity, 1.00 eq) in hydrochloric acid (4M in dioxane, 40.0 mL) was stirred at 20 °C for 1 h. The reaction mixture was concentrated under vacuum to give (3S,3aS,6aR)-2-[(2S)-2-amino-3-methyl-butanoyl] -3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (3.00 g, crude, hydrochloric acid) as a white solid. LC-MS (Method L): R _t = 0.454 min; MS (ESIpos): m/z = 255.1 [M+1] ⁺ . Procedure for preparation of (3S,3aS,6aR)-2-[(2S)-3-methyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-c yclopenta[c]pyrrole-3-carboxylic acid To a mixture of (3S,3aS,6aR)-2-[(2S)-2-amino-3-methyl-butanoyl]-3,3a,4,5,6,6 a-hexahydro-1H- cyclopenta [c]pyrrole-3-carboxylic acid (3.00 g, 10.3 mmol, 1.00 eq, HCl) and methyl 2,2,2- trifluoroacetate (1.98 g, 15.4 mmol, 1.56 mL, 1.50 eq) in methanol (30.0 mL) was added triethylamine (3.13 g, 30.9 mmol, 4.31 mL, 3.00 eq). After stirring at 20 °C for 12 h, hydrochloric acid (1M) was added to the reaction mixture to adjust pH to 4~5, diluted with water (150 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 3: 1 to 1: 1) to give (3S,3aS,6aR)-2-[(2S)-3- methyl-2-[(2,2,2-trifluoroacetyl)amino] butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3- carboxylic acid (2.30 g, 6.24 mmol, 60% yield, 95% purity) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.74 (d, J = 8.0 Hz , 1H), 4.61 (t, J = 8.0 Hz, 1H), 4.40-4.38 (m, 1H), 3.89-3.84 (m, 1H), 3.73-3.68 (m, 1H), 2.82 (s, 2H), 2.22-2.13 (m, 1H), 2.08-1.99 (m, 1H), 1.98-1.88 (m, 1H), 1.85-1.72 (m, 1H), 1.71-1.57 (m, 2H), 1.56-1.42 (m, 1H), 1.04 (d, J = 6.8 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H). A mixture of (3S,3aS,6aR)-2-[(2S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amin o]butanoyl] -3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (500 mg, 1.43 mmol, 1.00 eq), benzotriazol-1- yloxy(tripyrrolidin-1-yl)phosphanium;hexafluorophosphate (1.11 g, 2.14 mmol, 1.50 eq) and 4- methylmorpholine (577 mg, 5.71 mmol, 4.00 eq) in dichloromethane (5.00 mL) was stirred at 0 °C of 0.5 h, followed by 2-amino-2-phthalazin-1-yl-acetamide (340 mg, 1.43 mmol, 1.00 eq, HCl). After stirring at 25°C for 11.5 h, the reaction mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 1 to 0: 1) to give (3S,3aS,6aR)-N-(2-amino- 2-oxo-1-phthalazin-1-yl-ethyl)-2-[(2S)-3-methyl-2-[(2,2,2-tr ifluoroacetyl)amino]butanoyl]-3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]pyrrole-3-carboxamide (600 mg, 1.01 mmol, 70% yield, 90% purity) as a yellow solid. LC-MS (Method C): R _t = 0.489 min; MS (ESIpos): m/z = 535.2 [M+H] ⁺ . To a solution of (3S,3aS,6aR)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-2-[(2 S)-3-methyl -2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-c yclopenta[c]pyrrole-3-carboxamide (300 mg, 0.561 mmol, 1.00 eq) in dichloromethane (3.00 mL) was added burgess reagent (200 mg, 0.841 mmol, 1.50 eq). After stirring at 25 °C for 12 h, the reaction mixture was poured into water (20.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 41%-71%,10min) to give (3S,3aS,6aR)-N- [cyano(phthalazin-1-yl) methyl]-2-[(2S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]but anoyl]- 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxamid e (87.5 mg, 0.167 mmol, 29% yield, 98% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.77 (s, 0.32H), 9.96-9.63 (m, 1.73H), 9.43 (s, 0.36H), 8.81-8.72 (m, 0.39H), 8.32-8.23 (m, 0.53H), 8.14-8.04 (m, 1.18H), 8.03-7.89 (m, 0.78H), 7.87-7.72 (m, 1.26H), 7.33-7.24 (m, 0.41H), 4.33-4.04 (m, 2H), 3.94-3.68 (m, 2H), 2.82-2.71 (m, 1H), 2.45-2.41 (m, 1H), 2.23- 2.06 (m, 1H), 1.95-1.28 (m, 6H), 1.12-0.75 (m, 6H). LC-MS (Method C): R _t = 0.544 min; MS (ESIpos): m/z = 517.3 [M+H] ⁺ . HPLC (Method M): R _t = 2.038 min; purity: 99%. Preparation of CPD0278014 Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-2-amino-3-methyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate Hydrochloric acid (4.00 M in dioxane, 33.9 mL, 10.0 eq) was added into methyl (1R,2S,5S)-3-[(2S)-2- (tert-butoxycarbonylamino)-3-methyl-butanoyl]-6,6-dimethyl-3 -azabicyclo[3.1.0]hexane-2-carboxylate (5.00 g, 13.6 mmol, 1.00 eq) at 0°C. After stirring at 20 °C for 2 h, the mixture was concentrated under reduced pressure to give methyl (1R,2S,5S)-3-[(2S)-2-amino-3-methyl -butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (3.00 g, 7.47 mmol, 55% yield, 85% purity, 2HCl) as light yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.32 (s, 2H), 4.26 (s, 1H), 3.95 (d, J = 4.4 Hz, 1H), 3.82-3.70 (m, 2H), 3.66 (s, 3H), 2.18-2.07 (m, 1H), 1.61-1.56 (m, 1H), 1.48 (d, J = 7.6 Hz, 1H), 1.07-0.99 (m, 6H), 0.98-0.90 (m, 6H). Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-2-(2,2-difluoropropanoylamino)-3- methyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-ca rboxylate To a solution of 2,2-difluoropropanoic acid (0.450 g, 4.09 mmol, 1.00 eq) in tetrahydrofuran (10.0 mL) was added 1,1'-carbonyldiimidazole (795 mg, 4.91 mmol, 1.20 eq). After stirring at 25 °C for 2 h, methyl (1R,2S,5S)-3-[(2S)-2-amino-3-methyl-butanoyl]-6,6-dimethyl-3 -azabicyclo[3.1.0]hexane-2-carboxylate (1.25 g, 4.09 mmol, 1.00 eq, HCl) and N,N-diisopropylethylamine (2.11 g, 16.3 mmol, 2.85 mL, 4.00 eq) were added. After stirring at 25 °C for 12 h, the reaction mixture was poured into saturated ammonium chloride solution (10.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 8: 1 to 3: 1) to give methyl (1R,2S,5S)-3-[(2S)-2-(2,2- difluoropropanoylamino)-3-methyl-butanoyl]-6,6-dimethyl-3-az abicyclo[3.1.0]hexane-2-carboxylate (0.800 g, 2.11 mmol, 51% yield, 95% purity) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.93 (d, J = 8.0 Hz, 1H), 4.57-4.50 (m, 1H), 4.49-4.45 (m, 1H), 4.20- 4.09 (m, 1H), 3.99-3.90 (m, 1H), 3.86-3.81 (m, 1H), 3.80-3.77 (m, 3H), 2.25-2.13 (m, 1H), 1.80 (t, J = 19.0 Hz, 3H), 1.53-1.50 (m, 1H), 1.33-1.23 (m, 1H), 1.10-1.04 (m, 6H), 0.98-0.90 (m, 6H). LC-MS (Method L): R _t = 0.628 min; MS (ESIpos): m/z = 361.0 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-(2,2-difluoropropanoylamino)-3-methyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyli c acid To a mixture of methyl (1R,2S,5S)-3-[(2S)-2-(2,2-difluoropropanoylamino)-3-methyl -butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (800 mg, 2.11 mmol, 95% purity, 1.00 eq) in methanol (5.00 mL) and water (5.00 mL) was added lithium hydroxide monohydrate (265 mg, 6.33 mmol, 3.00 eq). After stirring at 25 °C for 16 h, hydrochloric acid (1M) was added to the reaction mixture to adjust pH to 4~5. The solution was diluted with water (10.0 mL) and extracted with dichloromethane (10.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-3-[(2S)-2-(2,2-difluoropropanoylamino)-3- methyl-butanoyl] -6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (560 mg, crude) as colorless gum. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.67 (s, 1H), 8.83 (d, J = 8.2 Hz, 1H), 4.17-4.09 (m, 2H), 3.90-3.85 (m, 1H), 3.82-3.76 (m, 1H), 2.19-2.05 (m, 1H), 1.75-1.66 (m, 3H), 1.53-1.50 (m, 1H), 1.41 (d, J = 7.6 Hz, 1H), 1.01 (s, 3H), 0.92 (d, J = 6.4 Hz, 3H), 0.86 (d, J = 6.4 Hz, 3H), 0.83 (s, 3H). To a mixture of (1R,2S,5S)-3-[(2S)-2-(2,2-difluoropropanoylamino)-3-methyl-b utanoyl] -6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (300 mg, 0.866 mmol, 1.00 eq), benzotriazol-1- yloxy(tripyrrolidin-1-yl)phosphanium;hexafluorophosphate (676 mg, 1.30 mmol, 1.50 eq) and 4- methylmorpholine (350 mg, 3.46 mmol, 4.00 eq) in dichloromethane (3.00 mL) was added 2-amino-2- phthalazin-1-yl-acetamide (206. mg, 0.866 mmol, 1.00 eq, HCl). After stirring at 25 °C for 12 h, the reaction mixture was diluted with water (10.0 mL) and extracted with dichloromethane (5.00 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 1: 1 to 0: 1) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl- ethyl)-3-[(2S)-2-(2,2-difluoropropanoylamino)-3-methyl-butan oyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (370 mg, 0.662 mmol, 76% yield, 95% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.71-9.63 (m, 1H), 9.30-8.96 (m, 1H), 8.95-8.69 (m, 1H), 8.35-8.26 (m, 1H), 8.25-8.17 (m, 1H), 8.13-7.90 (m, 2H), 7.62-7.25 (m, 2H), 6.38-6.24 (m, 1H), 4.52-4.32 (m, 1H), 4.11 (t, J = 8.8 Hz, 1H), 3.93-3.78 (m, 2H), 2.18-2.02 (m, 1H), 1.79-1.66 (m, 3H), 1.53-1.47 (m, 1H), 1.07-0.99 (m, 1H), 0.98-0.79 (m, 12H). LC-MS (Method L): Rt = 0.515 min; MS (ESIpos): m/z = 531.2 [M+H] ⁺ . To a solution of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -2-(2,2- difluoropropanoylamino)-3-methyl-butanoyl]-6,6-dimethyl-3-az abicyclo[3.1.0]hexane-2-carboxamide (340 mg, 0.608 mmol, 95% purity, 1.00 eq) in dichloromethane (4.00 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (217 mg, 0.913 mmol, 1.50 eq). After stirring at 25 °C for 2 h, the reaction mixture was poured into water (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 μm; mobile phase: [water(FA)-ACN]; B%: 37%-67%, 7 min) to give (1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]-3-[(2S)- 2-(2,2 -difluoropropanoylamino)-3-methyl-butanoyl]-6,6-dimethyl-3-a zabicyclo[3.1.0]hexane-2- carboxamide (161 mg, 0.314 mmol, 51% yield, 99% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.95-10.49 (m, 0.59H), 9.84-9.62 (m, 0.42H), 9.56-9.29 (m, 0.60H), 8.99 (d, J = 7.8 Hz, 0.63H), 8.85-8.69 (m, 0.86H), 8.34-7.90 (m, 1.68H), 7.88-7.66 (m, 2.03H), 7.30- 7.27 (m, 1H), 4.40-4.04 (m, 2H), 3.97-3.77 (m, 1.82H), 3.50-3.41 (m, 0.23H), 2.26-2.00 (m, 1H), 1.87- 1.47 (m, 4.55H), 1.21-0.64 (m, 12H). LC-MS (Method C): R _t = 0.857 min; MS (ESIpos): m/z = 513.3 [M+H] ⁺ . To a solution of (3S,3aS,6aR)-2-[(2S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amin o]butanoyl]-3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (300 mg, 856 μmol, 1.00 eq), O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (488 mg, 1.28 mmol, 1.50 eq) and N,N-diisopropylethylamine (443 mg, 3.43 mmol, 4.00 eq) in N,N-dimethylformamide (3.00 mL) was added 2-amino-2-cinnolin-4-yl-acetamide (204 mg, 856 μmol, 1.00 eq, hydrochloric acid salt) at 0 °C. After stirring at 20 °C for 12 h, the mixture was poured into saturated ammonium chloride (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by chromatography on silica gel (Petroleum ether: (Ethyl acetate: Methanol = 10: 1) = 10: 1 to 2: 1) to give (3S,3aS,6aR)-N-(2-amino-1-cinnolin-4-yl-2-oxo-ethyl)-2-[(2S) -3-methyl-2- [(2,2,2-trifluoroacetyl)amino] butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3- carboxamide (377 mg, 670 μmol, 78% yield) as light yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.80-9.71 (m, 1H), 9.38-9.25 (m, 2H), 8.54-8.49 (m, 1H), 8.39-8.25 (m, 1H), 8.01-7.89 (m, 3H), 7.66-7.49 (m, 1H), 6.21-6.09 (m, 1H), 4.41-4.31 (m, 1H), 4.25-4.17 (m, 1H), 3.80-3.65 (m, 2H), 2.65-2.54 (m, 2H), 1.86-1.77 (m, 1H),1.66-1.46 (m, 4H ), 1.45-1.23 (m, 2H), 0.95- 0.91 (m, 3H), 0.85-0.75 (m, 3H). LC-MS (Method C): R _t = 0.784 min; MS (ESIpos): m/z = 535.3 [M+H] ⁺ . Procedure for preparation of CPD0278015 - (1S,3aR,6aS)-N-(cinnolin-4-yl(cyano)methyl)-2- ((2,2,2-trifluoroacetyl)-L-valyl)octahydrocyclopenta[c]pyrro le-1-carboxamide To a solution of (3S,3aS,6aR)-N-(2-amino-1-cinnolin-4-yl-2-oxo-ethyl)-2-[(2S) -3-methyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-c yclopenta[c]pyrrole-3-carboxamide (355 mg, 664 μmol, 1.00 eq) in dichloromethane (5.00 mL) was added Burgess reagent (396 mg, 1.66 mmol, 2.50 eq) at 0 °C. After stirring at 20 °C for 24 h, the mixture was poured into saturated sodium bicarbonate (20.0 mL), extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25 mm* 10 μm; mobile phase: [water (FA)-ACN]; B%: 42%-62%, 10 min to give (3S,3aS,6aR)-N-[cinnolin-4- yl(cyano)methyl]-2-[(2S)-3-methyl-2-[(2,2,2-trifluoroacetyl) amino]butanoyl]-3,3a,4,5,6,6a-hexahydro- 1H-cyclopenta[c]pyrrole-3-carboxamide (106 mg, 195 μmol, 29% yield, purity:95%) as an orange solid. ¹ H NMR (400 MHz, DMSO) δ = 12.52 (s, 0.5H), 12.37 (s, 0.3H), 9.85 (s, 0.3H), 9.80 (d, J = 7.2 Hz, 1H), 9.60 (s, 0.6H), 8.50 (d, J = 8.4 Hz, 0.6H), 8.25 (d, J = 8.4 Hz, 0.3H), 7.70 (s, 0.3H), 7.68 (s, 0.6H), 7.58 (t, J = 7.2 Hz, 0.6H), 7.52 (t, J = 7.2 Hz, 0.4H), 7.33-7.09 (m, 2H), 4.29-4.20 (m, 2H), 3.87-3.71 (m, 2H), 2.83-2.72 (m, 1H), 2.64-2.55 (m, 1H), 2.19-2.05 (m, 1H), 1.93-1.78 (m, 2H), 1.75-1.58 (m, 3H), 1.37- 1.47 (m, 1H), 0.95-0.86 (m, 6H). LC-MS (Method C): R _t = 0.844 min; MS (ESIpos): m/z = 517.3 [M+H] ⁺ . HPLC (Method S): R _t = 2.082 min; purity: 96%. SFC: dr = 67: 33. To a mixture of (2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propanoic acid (3.00 g, 13.1 mmol, 1.00 eq) and ethyl (3S,3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole -3-carboxylate (2.87 g, 13.1 mmol, 1.00 eq, hydrochloride) in dichloromethane (100 mL) were added N-methylmorpholine (3.97 g, 39.3 mmol, 4.32 mL, 3.00 eq) and benzotriazol-1-yloxy(tripyrrolidin-1-yl)phosphanium hexafluorophosphate (8.17 g, 15.7 mmol, 1.20 eq). After stirring at 25 °C for 16 h, the mixture was diluted with saturated ammonium chloride (45.0 mL) and extracted with ethyl acetate (45.0 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®;20.0 g SepaFlash® Silica Flash Column, Eluent of 0~40% Ethyl acetate/Petroleum ether; gradient @45.0 mL/min) to afford ethyl (3S,3aS,6aR)-2-[(2S)-2-(tert-butoxycarbonylamino)-3- cyclopropyl-propanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta [c]pyrrole-3-carboxylate (2.14 g, 5.42 mmol, 42% yield) as a colorless gum. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 5.33 (d, J = 8.8 Hz, 1H), 4.55-4.53 (m, 1H), 4.38 (d, J = 3.6 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.88-3.83 (m, 1H), 3.67-3.63 (m, 1H), 2.80-2.76 (m, 1H), 2.67-2.62 (m, 1H), 2.01-1.95 (m, 1H), 1.91-1.87 (m, 1H), 1.82-1.59 (m, 4H), 1.54-1.40 (m, 11H), 1.26 (t, J = 7.2 Hz, 3H), 0.93-0.78 (m, 1H), 0.58-0.44 (m, 2H), 0.23-0.01 (m, 2H). LC-MS (Method C): R _t = 0.674 min; MS (ESIpos): m/z = 395.1 [M+H] ⁺ . Procedure for preparation of (3S,3aS,6aR)-2-[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopro pyl- propanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3 -carboxylic acid To a mixture of ethyl (3S,3aS,6aR)-2-[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopro pyl-propanoyl]- 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylat e (2.14 g, 5.42 mmol, 1.00 eq) in methanol (10.0 mL) was added a solution of lithium hydroxide monohydrate (911 mg, 21.7 mmol, 4.00 eq) in water (10.0 mL). After stirring at 20 C for 2 h, the reaction mixture was diluted with water (30.0 mL), adjusted pH~5 with hydrochloric acid (1M in water) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrate to afford (3S,3aS,6aR)-2-[(2S)-2-(tert-butoxycarbonylamino)-3- cyclopropyl-propanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta [c]pyrrole-3-carboxylic acid (1.05 g, 2.87 mmol, 53% yield) as colorless gum. LC-MS (Method C): R _t = 0.588 min; MS (ESIpos): m/z = 367.2 [M+H] ⁺ . Procedure for preparation of (3S,3aS,6aR)-2-[(2S)-2-amino-3-cyclopropyl-propanoyl]- 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid A mixture of (3S,3aS,6aR)-2-[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopro pyl-propanoyl]- 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (1.05 g, 2.87 mmol, 1.00 eq) in hydrochloric acid (4.00 M in dioxane, 20.0 mL) was stirred at 25 °C for 16 h. The mixture was concentrated to afford (3S,3aS,6aR)-2-[(2S)-2-amino-3-cyclopropyl-propanoyl]-3,3a,4 ,5,6,6a- hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (850 mg, 2.81 mmol, 98% yield, hydrochloride) as colorless gum. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 12.66 (s, 1H), 8.20 (s, 3H), 4.21-4.19 (m, 1H), 4.15-4.14 (d, J = 4.0 Hz, 1H), 3.67-3.64 (m, 2H), 2.74-2.70 (m, 1H), 2.63-2.60 (m, 1H), 1.79-1.42 (m, 7H), 0.87-0.81 (m, 1H), 0.45-0.43 (m, 2H), 0.21-0.12 (m, 2H). Procedure for preparation of (3S,3aS,6aR)-2-[(2S)-3-cyclopropyl-2-[(2,2,2- trifluoroacetyl)amino]propanoyl]-3,3a,4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrole-3-carboxylic acid To a solution of (3S,3aS,6aR)-2-[(2S)-2-amino-3-cyclopropyl-propanoyl]-3,3a,4 ,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrole-3-carboxylic acid (850 mg, 2.81 mmol, 1.00 eq, hydrochloride) and triethylamine (1.14 g, 11.2 mmol, 4.00 eq) in methanol (20.0 mL) was added methyl 2,2,2-trifluoroacetate (539 mg, 4.21 mmol, 1.50 eq) at 25 °C. After stirring at 25 °C for 12 h, the reaction mixture was diluted with saturated ammonium chloride (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®;12.0 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate/Petroleum ether; gradient @ 40.0 mL/min) to give (3S,3aS,6aR)-2-[(2S)-3-cyclopropyl-2-[(2,2,2- trifluoroacetyl)amino]propanoyl]-3,3a,4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrole-3-carboxylic acid (700 mg, 1.93 mmol, 69% yield) as colorless gum. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.71 (d, J = 7.2 Hz, 1H), 4.60-4.56 (m, 1H), 4.10-4.01(d, J = 3.2 Hz, 1H), 3.76-3.71 (m, 1H), 3.62-3.59 (m, 1H), 2.73-2.67 (m, 2H), 1.91-1.39 (m, 8H), 0.86-0.79 (m, 1H), 0.42- 0.34 (m, 2H), 0.22-0.06 (m, 2H). LC-MS (Method C): R _t = 0.642 min; MS (ESIpos): m/z = 363.1 [M+H] ⁺ . Procedure for preparation of (3S,3aS,6aR)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-2-[(2 S)-3- cyclopropyl-2-[(2,2,2-trifluoroacetyl)amino]propanoyl]-3,3a, 4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrole-3-carboxamide To a solution of (3S,3aS,6aR)-2-[(2S)-3-cyclopropyl-2-[(2,2,2-trifluoroacetyl )amino]propanoyl]- 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (100 mg, 276 μmol, 1.00 eq) and 2- amino-2-phthalazin-1-yl-acetamide (65.9 mg, 276 μmol, 1.00 eq, hydrochloride) in N,N- dimethylformamide (2.00 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (126 mg, 331 μmol, 1.20 eq) and N,N-diisopropylethylamine (143 mg, 1.10 mmol, 192 μL, 4.00 eq). After stirring at 20 °C for 10 h, the reaction was diluted with saturated ammonium chloride (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was residue purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~75% Ethyl acetate: Methanol (10:1)/ Petroleum ether; gradient @ 40.0 mL/min). to afford ethyl (3S,3aS,6aR)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-2-[(2 S)-3-cyclopropyl-2-[(2,2,2-trifluoroacetyl) amino]propanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyr role-3-carboxamide (117 mg, 214 μmol, 78% yield) as a light yellow solid. LC-MS (Method C): R _t = 0.527 min; MS (ESIpos): m/z = 547.2 [M+H] ⁺ . To a solution of (3S,3aS,6aR)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-2-[(2 S)-3-cyclopropyl-2- [(2,2,2-trifluoroacetyl)amino]propanoyl]-3,3a,4,5,6,6a-hexah ydro-1H-cyclopenta[c]pyrrole-3- carboxamide (97.0 mg, 177 μmol, 1.00 eq) in dichloromethane (3.00 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (63.4 mg, 266 μmol, 1.50 eq). After stirring at 25 °C for 12 h, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18150*25mm*10 μm; mobile phase: [water(formic acid)- acetonitrile]; B%: 40.0%-70.0%, 10 min).to give (3S,3aS,6aR)-N-[cyano(phthalazin-1-yl)methyl]-2-[(2S)-3- cyclopropyl-2-[(2,2,2-trifluoroacetyl)amino]propanoyl]-3,3a, 4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrole-3-carboxamide (39.0 mg, 72.3 μmol, 41% yield, 98% purity) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.74 (s, 0.4H), 9.91-9.86 (m, 0.4H), 9.85-9.77 (m, 0.4H), 9.76-9.65 (m, 0.5H), 9.65-9.57 (m, 0.3H), 9.30 (s, 0.4H), 8.84-8.69 (m, 0.4H), 8.30-8.23 (m, 0.4H), 8.18-8.10 (m, 0.4H), 8.10-8.07 (m, 0.7H), 8.03-7.96 (m, 0.4H), 7.95-7.76 (m, 1.6H), 7.25-7.22 (m, 0.4H), 4.60-4.55 (m, 1H), 4.19-4.11, (m, 1H), 3.91-3.83 (m, 1H), 3.74-3.58 (m, 1H), 2.83-2.67 (m, 2H), 1.76-1.38 (m, 8H), 0.79-0.76 (m, 1H), 0.44-0.38 (m, 2H), 0.37-0.14 (m, 2H). LC-MS (Method C): R _t = 0.606 min; MS (ESIpos): m/z = 529.1 [M+H] ⁺ . HPLC (Method S): R _t = 2.079 min; purity: 98%. SFC: dr = 31: 26: 9: 33. Preparation of CPD0279200 Procedure for preparation of (2S,4S)-dimethyl 2-((tert-butoxycarbonyl)amino)-4-(5-fluoro-2- nitrophenoxy)pentanedioate To a mixture of dimethyl (2S,4R)-2-(tert-butoxycarbonylamino)-4-hydroxy-pentanedioate (3.50 g, 12.0 mmol, 1.00 eq) and 5-fluoro-2-nitro-phenol (1.89 g, 12.0 mmol, 1.00 eq) in tetrahydrofuran (30.0 mL) was added triphenylphosphine (3.78 g, 14.4 mmol, 1.20 eq) at 0 °C under nitrogen atmosphere. After addition, diisopropyl azodicarboxylate (2.92 g, 14.4 mmol, 2.80 mL, 1.20 eq) in tetrahydrofuran (10.0 mL) was added dropwise at 0 °C under nitrogen atmosphere. The mixture was warmed to 20 °C and stirred for 16 h. The reaction mixture was quenched with brine (50.0 mL), extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 10: 1 to 3: 1) to give dimethyl (2S,4S)-2-(tert- butoxycarbonylamino)-4-(5-fluoro-2-nitro-phenoxy)pentanedioa te (6.20 g, crude) as a colorless oil. LC-MS (Method C): R _t = 0.536 min; MS (ESIpos): m/z = 331.0 [M-100+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.06 (dd, J = 9.2, 6.0 Hz, 1H), 7.41-7.32 (m, 1H), 7.30-7.22 (m, 1H), 7.12-6.94 (m, 1H), 5.38-5.31 (m, 0.07H), 5.20-5.13 (m, 0.13H), 5.06 (dd, J = 9.6, 4.0 Hz, 1H), 5.11-4.99 (m, 1H), 4.40-4.25 (m, 1H), 3.69 (s, 2.9H), 3.67 (s, 0.2H), 3.64 (s, 2.9H), 3.58 (s, 0.2H), 2.37-2.24 (m, 2H), 1.36 (s, 0.7H), 1.25 (s, 8H). To a solution of dimethyl (2S,4S)-2-(tert-butoxycarbonylamino)-4-(5-fluoro-2-nitro- phenoxy)pentanedioate (6.00 g, 13.9 mmol, 1.00 eq) in methanol (50.0 mL) was added palladium on carbon (1.00 g, 10% purity) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred at 20 °C for 16 h under hydrogen (15.0 psi) atmosphere. The reaction mixture was filtered and washed with methanol (20.0 mL), concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 10: 1 to 3: 1) to give methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(2S)-7-fluoro- 3-oxo-4H-1,4-benzoxazin-2-yl]propanoate (3.80 g, 10.3 mmol, 74% yield) as yellow oil. LC-MS (Method C): R _t = 0.589 min; MS (ESIpos): m/z = 269 [M-99] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ = 10.77 (br. s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 6.92-6.81 (m, 3H), 4.56 (dd, J = 10.0, 3.2 Hz, 1H), 4.31-4.26 (m, 1H), 3.62 (s, 3H), 2.21-2.09 (m, 2H), 1.38 (s, 9H). Procedure for preparation of tert-butyl ((S)-1-amino-3-((S)-7-fluoro-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)-1-oxopropan-2-yl)carbamate To a mixture of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(2S)-7-fluoro-3-oxo-4H- 1,4-benzoxazin-2- yl]propanoate (3.80 g, 10.3 mmol, 1.00 eq) was added ammonia (7 M in methanol, 50.0 mL, 33.9 eq). The mixture was stirred at 20 °C for 48 h and concentrated to give tert-butyl N-[(1S)-2-amino-1-[[(2S)- 7-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]methyl]-2-oxo-ethyl]ca rbamate (3.30 g, 9.34 mmol, 91% yield) as an off-white solid. LC-MS (Method C): R _t = 0.485 min; MS (ESIpos): m/z = 254 [M-99] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.73 (br. s, 1H), 7.26 (br. s, 1H), 7.07 (br. s, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.92-6.88 (m, 1H), 6.86-6.82 (m, 2H), 4.51-4.48 (m, 1H), 4.19-4.13 (m, 1H), 2.10-2.00 (m, 2H), 1.38 SFC: Procedure for preparation of tert-butyl ((S)-1-amino-3-((S)-7-fluoro-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)-1-oxopropan-2-yl)carbamate A mixture of tert-butyl N-[(1S)-2-amino-1-[[(2S)-7-fluoro-3-oxo-4H-1,4-benzoxazin-2- yl]methyl]-2-oxo- ethyl]carbamate (3.30 g, 9.34 mmol, 1.00 eq) in ethyl acetate (45.0 mL) was heated to 70 °C and stirred for 1 h. The mixture was cooled to 20 °C and stirred for 16 h. The reaction mixture was filtered and washed with ethyl acetate (10.0 mL). The filter cake was dried to give tert-butyl N-[(1S)-2-amino-1- [[(2S)-7-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]methyl]-2-oxo-e thyl]carbamate (2.70 g, 7.64 mmol, 82% yield) as a white solid. Checked by SFC (SFC ₁ of Compound 5). Tert-butyl N-[(1S)-2-amino-1-[[(2S)-7-fluoro-3-oxo-4H-1,4-benzoxazin-2- yl]methyl]-2-oxo- ethyl]carbamate (2.70 g, 7.64 mmol, 1.00 eq) was suspended in ethyl acetate (40.0 mL) at 20 °C. The reaction mixture was heated to 70 °C and stirred for 15 min. Methanol (10.0 mL) was added and the suspension turned clean. The solution was cooled to 20 °C and concentrated under reduced pressure to remove methanol. The solid was appeared during concentration. Ethyl acetate (20.0 ml) was added, and the mixture was stirred at 20 °C for 16 h. The precipitate was filtered and washed with ethyl acetate (30.0 mL). The filter cake was dried to give tert-butyl N-[(1S)-2-amino-1-[[(2S)-7-fluoro-3-oxo-4H-1,4- benzoxazin-2-yl]methyl]-2-oxo-ethyl]carbamate (2.50 g, 7.08 mmol, 93% yield) as a white solid. Checked by SFC (SFC2 of Compound 5). LC-MS (Method C): R _t = 0.532 min; MS (ESIpos): m/z = 254.0 [M-99] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ = 10.74 (br s, 1H), 7.27 (br s, 1H), 7.08 (br s, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.91-6.81 (m, 3H), 4.51-4.48 (m, 1H), 4.19-4.13 (m, 1H), 2.07-2.02 (m, 2H), 1.38 (s, 9H). SFC: de = 98.5% Procedure for preparation of (S)-2-amino-3-((S)-7-fluoro-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)propanamide Hydrochloride (4M in dioxane, 10.0 mL, 23.6 eq) was added to tert-butyl N-[(1S)-2-amino-1-[[(2S)-7- fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]methyl]-2-oxo-ethyl]carb amate (600 mg, 1.70 mmol, 1.00 eq). After stirring at 20 °C for 1 h, the reaction mixture was concentrated to give (2S)-2-amino-3-[(2S)-7- fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]propanamide (600 mg, crude) as a yellow solid. LC-MS (Method B): R _t = 0.184 min; MS (ESIpos): m/z = 254.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.92 (s, 1H), 8.40 (br. s, 3H), 8.05 (br. s, 1H), 7.64 (s, 1H), 7.00- 6.93 (m, 2H), 6.88-6.83 (m, 1H), 4.84-4.68 (m, 1H), 4.00-3.97 (m, 1H), 2.48-2.43 (m, 1H), 2.26-2.18 (m, 1H). Procedure for preparation of (1R,2S,5S)-N-((S)-1-amino-3-((S)-7-fluoro-3-oxo-3,4-dihydro- 2H- benzo[b][1,4]oxazin-2-yl)-1-oxopropan-2-yl)-3-((S)-2-(3,3-di fluorocyclobutanecarboxamido)-3- methylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-car boxamide To a mixture of (2S)-2-amino-3-[(2S)-7-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]p ropanamide (263 mg, 0.806 mmol, 1.00 eq, 2Hydrogen chloride) and (1R,2S,5S)-3-[(2S)-2-[(3,3- difluorocyclobutanecarbonyl)amino]-3-methyl-butanoyl]-6,6-di methyl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (300 mg, 0.806 mmol, 1.00 eq) in dichloromethane (10.0 mL) were added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-d imethylazanium;hexafluorophosphate (613 mg, 1.61 mmol, 2.00 eq) and N,N-diethylpropan-2-amine (521 mg, 4.03 mmol, 0.702 mL, 5.00 eq).After stirring at 20 °C for 2 h, the reaction mixture was diluted with dichloromethane (40.0 mL), washed with water (20.0 mL) and brine (20.0 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 10: 1 to 1: 4) and concentrated to give (1R,2S,5S)-N-[(1S)-2- amino-1-[[(2S)-7-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]methyl] -2-oxo-ethyl]-3-[(2S)-2-[(3,3- difluorocyclobutanecarbonyl)amino]-3-methyl-butanoyl]-6,6-di methyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (490 mg, crude) as a yellow solid. LC-MS (Method C): Rt = 0.853 min; MS (ESIpos): m/z = 608.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.81-10.55 (m, 1H), 8.31 (d, J = 8.4 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.31 (s, 1H), 7.12 (s, 1H), 6.91-6.77 (m, 2H), 6.75-6.70 (m, 1H), 4.62-4.49 (m, 2H), 4.23-4.14 (m, 1H), 4.10-3.98 (m, 1H), 3.92-3.74 (m, 2H), 2.98-2.86 (m, 1H), 2.68-2.56 (m, 4H), 2.26-2.04 (m, 2H), 1.71-1.57 (m, 1H), 1.50-1.45 (m, 1H), 1.44-1.40 (m, 1H), 1.00 (s, 3H), 0.84 (s, 3H), 0.77-0.66 (m, 6H). Procedure for preparation of CPD0279200 - (1R,2S,5S)-N-((S)-1-cyano-2-((S)-7-fluoro-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-3-((S)-2-(3,3-dif luorocyclobutanecarboxamido)-3- methylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-car boxamide To a mixture of (1R,2S,5S)-N-[(1S)-2-amino-1-[[(2S)-7-fluoro-3-oxo-4H-1,4-be nzoxazin-2-yl]methyl]-2- oxo-ethyl]-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino ]-3-methyl-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (440 mg, 0.724 mmol, 1.00 eq) in dichloromethane (10.0 mL) was added Burgess reagent (345 mg, 1.45 mmol, 2.00 eq). After stirring at 20 °C for 4 h, Burgess reagent (345 mg, 1.45 mmol, 2.00 eq) was added. The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with dichloromethane (50.0 mL), washed with water (30.0 mL) and brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-HPLC (column: UniSil 3-100 C18 UItra (150*25mm*3 μm); mobile phase: [water(FA)-ACN]; B%: 45%-65%, 7min) and lyophilized to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-7- fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]ethyl]-3-[(2S)-2-[(3,3-d ifluorocyclobutanecarbonyl)amino]-3- methyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxamide (150 mg, 0.254 mmol, 35% yield) as a white solid. LC-MS (Method C): Rt = 0.570 min; MS (ESIpos): m/z = 590.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.86 (br. s, 1H), 9.07 (d, J = 8.4 Hz, 1H), 8.32 (d, J = 8.4 Hz, 1H), 6.99-6.87 (m, 2H), 6.86-6.80 (m, 1H), 5.20-5.15 (m, 1H), 4.65 (dd, J = 10.4, 2.8 Hz, 1H), 4.15-4.09 (m, 2H), 3.94-3.86 (m, 2H), 3.01-2.96 (m, 1H), 2.74-2.62 (m, 4H), 2.40-2.33 (m, 1H), 1.75-1.69 (m, 1H), 1.62-1.59 (m, 1H), 1.37 (d, J = 7.6 Hz, 1H), 1.13-1.08 (m, 3.4H), 0.98-0.91 (m, 3.6H), 0.86-0.77 (m, 6H). SFC: dr = 75: 15: 10. A mixture of methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3 -methylbutanoyl) - 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.10 g, 2.86 mmol, 1.00 eq) in hydrochloric acid (4 M in dioxane, 10.0 mL, 14.0 eq) was stirred at 0 °C for 2 h. The mixture was concentrated under vacuum to give methyl (1R,2S,5S)-3-((S)-2-amino-3-hydroxy-3-methylbutanoyl)-6,6-di methyl-3- azabicyclo [3.1.0]hexane-2-carboxylate (1.2 g, crude, hydrochloric acid) as light yellow oil. To a solution of 3,3-difluorocyclobutane-1-carboxylic acid (535 mg, 3.93 mmol, 1.05 eq), O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (2.13 g, 5.61 mmol, 1.50 eq), N,N-diisopropylethylamine (1.93 g, 15.0 mmol, 2.61 mL, 4.00 eq) in N,N-dimethylformamide (5.00 mL) was added methyl (1R,2S,5S)-3-((S)-2-amino-3-hydroxy-3-methylbutanoyl)-6,6-di methyl-3-azabicyclo [3.1.0]hexane-2-carboxylate (1.20 g, 3.74 mmol, 1.00 eq, hydrochloric acid salt). After stirring at 20 °C for 12 h, the mixture was poured into water (50.0 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine (20.0 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (100~200 mesh, Petroleum ether: Ethyl acetate = 1: 0 to 1: 1) to give methyl (1R,2S,5S)-3-((S)-2-(3,3-difluorocyclobutane-1-carboxamido)- 3-hydroxy-3-methylbutanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.00 g, 2.36 mmol, 63% yield) as light yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 6.81-6.61 (m, 1H), 4.76-4.70 (m, 1H), 4.34-4.17 (m, 2H), 3.97-3.90 (m, 1H), 3.88-3.79 (m, 1H), 3.67-3.62 (m, 3H), 3.41-3.36 (m, 1H), 3.12-3.03 (m, 1H), 1.57-1.49 (m, 1H), 1.43-1.40 (m, 1H), 1.37-1.31 (m, 9H), 1.00 (s, 3H), 0.93-0.90 (m, 3H), 0.85-0.83 (m, 6H). LC-MS (Method C): R _t = 0.835 min; MS (ESIpos): m/z = 403.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-((S)-2-(3,3-difluorocyclobutane-1-carboxamido)- 3- hydroxy-3-methylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]he xane-2-carboxylic acid To a solution of methyl (1R,2S,5S)-3-((S)-2-(3,3-difluorocyclobutane-1-carboxamido)- 3-hydroxy -3- methylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-car boxylate (1.00 g, 2.48 mmol, 1.00 eq) in methanol (10.0 mL) was added a solution of lithium hydroxide monohydrate (521 mg, 12.4 mmol, 5.00 eq) in water (2.00 mL) at 0 °C. After stirring the mixture at 20 °C for 12 h, the mixture was poured into water (20.0 mL). Hydrochloric acid (1M) was added to adjust pH to 5 and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (FA condition: 108 g Flash Column SEPAFLASH_C1840-63μm; 60 A; mobile phase: [water(0.225%FA)-ACN]; B%: 30-50%,10 min) to give (1R,2S,5S)-3-((S)-2-(3,3- difluorocyclobutane-1-carboxamido)-3-hydroxy-3-methylbutanoy l)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (100 mg, 245 μmol, 10% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.26 (d, J = 8.8 Hz, 1H), 4.47 (d, J = 8.8 Hz, 1H), 4.10 (s, 1H), 3.87 (s, 2H), 3.14-3.04 (m, 1H), 2.74-2.55 (m, 5H), 1.55-1.37 (m, 2H), 1.16 (s, 3H), 1.09 (s, 3H), 1.03-1.00 (m, 3H), 0.82 (s, 3H). LC-MS (Method C): R _t = 0.794 min; MS (ESIpos): m/z = 389.2 [M+H] ⁺ . Procedure for preparation of tert-butyl ((S)-1-cyano-2-((S)-6-fluoro-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)ethyl)carbamate To a mixture of tert-butyl ((S)-1-amino-3-((S)-6-fluoro-3-oxo-3,4-dihydro-2H-benzo[b] [1,4]oxazin-2-yl)- 1-oxopropan-2-yl)carbamate (800 mg, 2.26 mmol, 1.00 eq) in dichloromethane (4.00 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (809 mg, 3.40 mmol, 1.50 eq). After stirring at 25 °C for 12 h, the mixture was poured into saturated sodium bicarbonate (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 10: 1 to 3: 1) to give tert-butyl N-[(1S)-1-cyano-2-[(2S)-6-fluoro-3-oxo-4H-1,4-benzoxazin-2-y l]ethyl]carbamate (760 mg, 2.04 mmol, 90% yield) as a white solid. LCMS (Method C) = 0.766, m/z =358.3 [M+Na] ⁺ . Procedure for preparation of (S)-2-amino-3-((S)-6-fluoro-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)propanenitrile To a mixture of tert-butyl ((S)-1-cyano-2-((S)-6-fluoro-3-oxo-3, 4-dihydro-2H-benzo[b][1,4]oxazin-2- yl)ethyl)carbamate (760 mg, 2.27 mmol, 1.00 eq) in acetonitrile (3.00 mL) was added hydrochloric acid (4 M in dioxane, 3.00 mL). After stirring at 0 °C for 1 h, the mixture was concentrated to give a residue, diluted with ethyl acetate (20.0 mL). The mixture was washed with saturated sodium bicarbonate (10.0 mL), brine (10.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 3: 1 to 1: 1) to give (S)-2-amino-3-((S)-6-fluoro-3-oxo-3, 4-dihydro-2H-benzo[b][1,4]oxazin-2- yl)propanenitrile (420 mg, 1.70 mmol, 75% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.03-8.30 (m, 1H), 7.02-6.90 (m, 1H), 6.75-6.65 (m, 1H), 6.68-6.55 (m, 1H), 4.93-4.82 (m, 1H), 4.11-1.03 (m, 1H), 2.52-2.28 (m, 2H). To a solution of (1R,2S,5S)-3-((S)-2-(3,3-difluorocyclobutane-1-carboxamido)- 3-hydroxy-3- methylbutanoyl) -6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (90.0 mg, 232 μmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexaflu orophosphate (132 mg, 348 μmol, 1.50 eq), and N,N-diisopropylethylamine (89.8 mg, 695 μmol, 3.00 eq) in N,N-dimethylformamide (2.00 mL) was added (2S)-2-amino-3-[(2S)-6-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]p ropanenitrile (65.4 mg, 278 μmol, 1.20 eq) at 0 °C. After stirring the mixture at 20 °C for 12 h, the mixture was poured into water (20.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were washed with brine (20.0 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex luna C18 150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 39%-61%, 10 min) to give (1R,2S,5S)-N-((S)-1-cyano-2-((S)-6-fluoro-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-2-yl)ethyl)-3- ((S)-2-(3,3-difluorocyclobutane-1-carboxamido)-3-hydroxy-3-m ethylbutanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (42.7 mg, 69.3 μmol, 30% yield, 98% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.90 (s, 1H), 8.85 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 6.98- 6.87 (m, 1H), 6.81-6.73 (m, 1H), 6.68 (dd, J = 9.2, 2.8 Hz, 1H), 5.15-5.01 (m, 1H), 4.91 (s, 1H), 4.53 (dd, J = 9.2, 2.8 Hz, 1H), 4.42 (d, J = 8.2 Hz, 1H), 4.14 (s, 1H), 4.00-3.90 (m, 1H), 3.81-3.75 (m, 1H), 3.13-3.00 (m, 1H), 2.70-2.60 (m, 3H), 2.45-2.41 (m, 1H), 2.38-2.28 (m, 2H), 1.47-1.40 (m, 1H), 1.34- 1.29 (m, 1H), 1.05-0.97 (m, 9H), 0.84 (s, 3H). LC-MS (Method R): R _t = 1.937 min; MS (ESIpos): m/z = 606.3 [M+H] ⁺ . SFC: de%: 94%. To a solution of (1R,2S,5S)-3-((3,3-difluorocyclobutane-1-carbonyl)-L-valyl)- 6,6-dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxylic acid (300 mg, 806 μmol, 1.00 eq), O-(7-azabenzotriazol-1-yl) -N,N,N,N- tetramethyluroniumhexafluorophosphate (460 mg, 1.21 mmol, 1.50 eq) and N,N-diisopropylethylamine (312 mg, 2.42 mmol, 421 μL, 3.00 eq) in N,N-dimethylformamide (5.00 mL) was added (S)-2-amino-3- ((S)-6-fluoro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl) propanamide (233 mg, 806 μmol, 1.00 eq, hydrochloric acid) at 0 °C. After stirring at 25 °C for 12 h, the mixture was poured into water (20.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 0 to 4: 1) to give (1R,2S,5S)-N-((S)-1-amino-3-((S)-6-fluoro-3-oxo-3,4-dihydro- 2H-benzo [b][1,4]oxazin-2-yl)-1-oxopropan-2-yl)-3-((3,3-difluorocyclo butane-1-carbonyl)-L-valyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (330 mg, 516 μmol, 64% yield) as light yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.73 (s, 1H), 8.32-8.21 (m, 2H), 7.29 (s, 1H), 7.12 (s, 1H), 6.92- 6.85 (m, 1H), 6.78-6.63 (m, 2H), 4.57-4.45 (m, 2H), 4.17 (s, 1H), 3.88-3.73 (m, 2H), 3.52-3.45 (m, 1H), 3.44-3.38 (m, 1H), 2.97-2.86 (m, 1H), 2.70-2.52 (m, 4H), 2.26-2.03 (m, 2H), 1.72-1.58 (m, 1H), 1.51- 1.39 (m, 2H), 1.00 (s, 3H), 0.84 (s, 3H), 0.76-0.68 (m, 6H). LC-MS (Method C): R _t = 0.850 min; MS (ESIpos): m/z = 608.3 [M+H] ⁺ . To a solution of (1R,2S,5S)-N-((S)-1-amino-3-((S)-6-fluoro-3-oxo-3,4-dihydro- 2H-benzo [b][1,4]oxazin- 2-yl)-1-oxopropan-2-yl)-3-((3,3-difluorocyclobutane-1-carbon yl)-L-valyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (300 mg, 494 μmol, 1.00 eq) in dichloromethane (2.00 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (294 mg, 1.23 mmol, 2.50 eq). After stirring at 20 °C for 2 h, the mixture was poured into water (20.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex C18 75*30mm*3 μm; mobile phase: [water(FA)-ACN]; B%: 45%-75%, 7 min) to give (1R,2S,5S)-N-((S)-1-cyano-2-((S)-6-fluoro-3-oxo-3,4- dihydro-2H-benzo [b][1,4]oxazin-2-yl)ethyl)-3-((3,3-difluorocyclobutane-1-car bonyl)-L-valyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (138 mg, 233 μmol, 47% yield, 99% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.87 (s, 1H), 8.99 (d, J = 8.4 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 6.98- 6.89 (m, 1H), 6.80-6.73 (m, 1H), 6.71-6.66 (m, 1H), 5.13-5.04 (m, 1H), 4.59-4.51 (m, 1H), 4.38-4.30 (m, 1H), 4.09 (s, 1H), 4.05 (t, J = 8.8 Hz, 1H), 3.88-3.78 (m, 2H), 3.49-3.39 (m, 1H), 2.97-2.87 (m, 1H), 2.70-2.57 (m, 3H), 2.48-2.42 (m, 1H), 2.34-2.24 (m, 1H), 1.74-1.61 (m, 1H), 1.56-1.50 (m, 1H), 1.33- 1.27 (m, 1H), 1.05 (t, J = 6.8 Hz, 1H), 1.01 (s, 3H), 0.93-0.87 (m, 1H), 0.84 (s, 3H), 0.79-0.66 (m, 6H). LC-MS (Method R): R _t = 2.043 min; MS (ESIpos): m/z = 590.2 [M+H] ⁺ . SFC: dr = 73: 12: 6: 9. Preparation of CPD0279197 Procedure for preparation of (1R,2S,5S)-N-((S)-1-amino-3-((S)-7-fluoro-3-oxo-3,4-dihydro- 2H- benzo[b][1,4]oxazin-2-yl)-1-oxopropan-2-yl)-3-((S)-3-cyclopr opyl-2-(3,3- difluorocyclobutanecarboxamido)propanoyl)-6,6-dimethyl-3-aza bicyclo[3.1.0]hexane-2- carboxamide To a mixture of (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[(3,3- difluorocyclobutanecarbonyl)amino]propanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (400 mg, 1.04 mmol, 1.00 eq) and (2S)-2-amino-3-[(2S)-7-fluoro-3-oxo-4H-1,4-benzoxazin-2- yl]propanamide (339 mg, 1.04 mmol, 1.00 eq, 2 hydrochloride) in dichloromethane (5.00 mL) were added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]- dimethylazanium;hexafluorophosphate (593mg, 1.56 mmol, 1.50 eq) and N,N-diethylpropan-2-amine (672 mg, 5.20 mmol, 0.906 mL, 5.00 eq). After stirring at 20 °C for 4 h, the reaction mixture was diluted with dichloromethane (40.0 mL), washed with water (30.0 mL) and brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 5: 1 to 1: 5) to give (1R,2S,5S)-N-[(1S)- 2-amino-1-[[(2S)-7-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]methy l]-2-oxo-ethyl]-3-[(2S)-3-cyclopropyl-2- [(3,3-difluorocyclobutanecarbonyl) amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (510 mg, 0.823 mmol, 79% yield) as a white solid. LC-MS (Method C): Rt = 0.864 min; MS (ESIpos): m/z = 620.3 [M+H] ⁺ . To a mixture of (1R,2S,5S)-N-[(1S)-2-amino-1-[[(2S)-7-fluoro-3-oxo-4H-1,4-be nzoxazin-2-yl]methyl]-2- oxo-ethyl]-3-[(2S)-3-cyclopropyl-2-[(3,3-difluorocyclobutane carbonyl)amino]propanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (460 mg, 0.742 mmol, 1.00 eq) in dichloromethane (10.0 mL) was added burgess reagent (531 mg, 2.23 mmol, 3.00 eq). After stirring at 20 °C for 16 h, the reaction mixture was diluted with dichloromethane (50.0 mL), washed with water (30.0 mL) and brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water (FA)- ACN];B%: 45%-65%,9 min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-7-fluoro-3-oxo-4H-1,4- benzoxazin-2-yl]ethyl]-3-[(2S)-3-cyclopropyl-2-[(3,3-difluor ocyclobutanecarbonyl)amino]propanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxamide (200 mg, 0.332 mmol, 45% yield) as a white solid. LC-MS (Method C): Rt = 0.897 min; MS (ESIpos): m/z = 602.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.82 (br. s, 1H), 8.94 (d, J = 8.0 Hz 1H), 8.28 (d, J = 7.8 Hz, 1H), 6.90-6.76 (m, 3H), 5.07-5.01 (m, 1H), 4.63-4.57 (m, 1H), 4.39-4.27 (m, 1H), 4.08 (s, 1H), 3.89-3.78 (m, 2H), 2.91-2.85 (m, 1H), 2.67-2.58 (m, 4H), 2.33-2.25 (m, 1H), 1.71-1.70 (m, 0.36H), 1.56-1.52 (m, 1.38H), 1.41-1.34 (m, 1.17H), 1.30 (d, J = 7.8 Hz, 1H), 1.13-1.06 (m, 1H), 1.01 (s, 3H), 0.88-0.84 (m, 3H), 0.70-0.64 (m, 1H), 0.40-0.32 (m, 2H), 0.067-0.033 (m, 1H), -0.034--0.066 (m, 1H). SFC: dr = 3: 93: 4. Preparation of CPD0279335 Procedure for preparation of methyl (2S) -3, 3-dimethyl-2-(pyrimidin-5-ylamino) butanoate To a solution of 5-bromopyrimidine (5.00 g, 31.4 mmol, 1.00 eq) and methyl (2S) -2-amino-3, 3- dimethyl-butanoate;hydrochloride (6.28 g, 34.6 mmol, 1.10 eq) in toluene. (100 mL) were added [2-(2- aminophenyl) phenyl]-chloro-palladium;dicyclohexyl-[2-(2, 6-diisopropoxyphenyl) phenyl]phosphane (1.22 g, 1.57 mmol, 0.05 eq) and cesium carbonate (22.5 g, 69.2 mmol, 2.20 eq). After stirring at 100 °C for 16 h, the reaction mixture was diluted with water (300 mL). The solution was extracted with ethyl acetate (300 mL × 2). The combined organic layers were washed with brine (300 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 3: 1) to give methyl (2S)-3,3-dimethyl-2-(pyrimidin-5-ylamino)butanoate (2.70 g, 8.22 mmol, 26% yield, 68% purity) as a yellow oil. Procedure for preparation of (2S) -3, 3-dimethyl-2-(pyrimidin-5-ylamino) butanoic acid To a solution of methyl (2S) -3, 3-dimethyl-2-(pyrimidin-5-ylamino) butanoate (2.60 g, 11.6 mmol, 1.00 eq) in mixed solvent of methanol (20.0 mL) and water (5.00 mL) was added lithium hydroxide monohydrate (977 mg, 23.3 mmol, 2 eq). After stirring at 25 °C for 16 h, the reaction mixture was concentrated to give a residue. The residue was purified by reversed phase (instrument: 80 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.1% NH3^H2O), eluent B: acetonitrile; gradient: 0-50 min 0-100% B; flow 55 mL/min; temperature: room temperature; Detector: UV 220/254 nm) to give (2S) -3, 3-dimethyl-2-(pyrimidin-5-ylamino)butanoic acid (1.70 g, 8.12 mmol, 70% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.27 (s, 1H), 8.15 (s, 2H), 5.69 (d, J = 8.0 Hz, 1H), 3.31 (br d, J = 7.2 Hz, 1H), 1.63 (s, 1H), 0.97 (s, 9H). Procedure for preparation of methyl (1R, 2S, 5S) -3-[(2S) -3, 3-dimethyl-2-(pyrimidin-5-ylamino) butanoyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate To a solution of (2S)-3,3-dimethyl-2-(pyrimidin-5-ylamino)butanoic acid (1.70 g, 8.12 mmol, 1.00 eq) and methyl (1R,2S,5S)-6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate;hydrochlo ride (2.51 g, 12.2 mmol, 1.50 eq) in N,N-dimethylformamide (30.0 mL) were added [dimethylamino(triazolo[4,5- b]pyridin-3-yloxy)methylene]-dimethyl-ammonium;hexafluoropho sphate (4.63 g, 12.2 mmol, 1.50 eq) and N-ethyl-N-isopropyl-propan-2-amine (3.15 g, 24.4 mmol, 4.25 mL, 3.00 eq). After stirring at 25 °C for 16 h, the reaction mixture was purified by reversed phase column (instrument: 80 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-50 min 0-100% B; flow 55 mL/min; temperature: room temperature; Detector: UV 220/254 nm) to give methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(pyrimidin-5-ylamino)butan oyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (2.00 g, 5.55 mmol, 68% yield) as yellow oil. Procedure for preparation of (1R, 2S, 5S) -3-[(2S) -3, 3-dimethyl-2-(pyrimidin-5-ylamino) butanoyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(pyrimidin-5-ylamino) butanoyl]-6, 6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (500 mg, 1.39 mmol, 1.00 eq) in mixed solvent of methanol (5.00 mL) and water (1.00 mL) was added lithium hydroxide monohydrate (117 mg, 2.77 mmol, 2.00 eq). After stirring at 25 °C for 16 h, the reaction mixture was purified by reversed phase column (instrument: 80 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.1% NH ₃ ^H ₂ O), eluent B: acetonitrile; gradient: 0-50 min 0-100% B; flow 55 mL/min; temperature: room temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(pyrimidin-5- ylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxylic acid (220 mg, 413 μmol, 30% yield, 65% purity) as yellow oil. LC-MS (Method C): R _t = 0.439 ^0.469 min, MS (ESIpos): m/z = 347.1 [M+H] ⁺ . Procedure for preparation of Compound CPD0279335 - (1R, 2S, 5S) -N-[cyano (1, 6-naphthyridin- 8-yl) methyl]-3-[(2S) -3, 3-dimethyl-2-(pyrimidin-5-ylamino) butanoyl]-6, 6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(pyrimidin-5-ylamino)butan oyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (252 mg, 0.727 mmol, 1 eq) and 2-amino-2-(1, 6- naphthyridin-8-yl) acetonitrile (134 mg, 0.607 mmol, 0.84 eq, Hydrogen chloride) in dichloromethane (5.00 mL) were added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dim ethyl- ammonium;hexafluorophosphate (414 mg, 1.09 mmol, 1.50 eq) and N-ethyl-N-isopropyl-propan-2- amine (282.mg, 2.18 mmol, 0.380 mL, 3.00 eq). After stirring at 25 °C for 12 h, the reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 × 25 mm × 10 μm; mobile phase: [water (FA) -ACN];B%: 33%-53%, 9 min) to give (1R,2S,5S)- N-[cyano(1,6-naphthyridin-8-yl)methyl]-3-[(2S)-3,3-dimethyl- 2-(pyrimidin-5-ylamino)butanoyl]-6, 6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (60.0 mg, 116 μmol, 16 % yield, 99% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.60 (d, J = 7.6 Hz, 0.5H), 9.51 (d, J = 3.2 Hz, 1H), 9.44 (d, J = 7.6 Hz, 0.5H), 9.28-9.23 (m, 1H), 9.00-8.91 (m, 1H), 8.73-8.68 (m, 1H), 8.38 (d, J = 2.0 Hz, 1H), 8.34 (s, 1H), 8.32 (s, 1H), 7.91-7.79 (m, 1H), 6.90-6.76 (m, 1H), 5.90-5.75 (m, 1H), 4.33 (s, 0.5H), 4.28 (s, 0.5H), 4.19-4.06 (m, 1H), 3.96-3.85 (m, 1H), 3.83-3.76 (m, 1H), 1.63-1.49 (m, 1H), 1.41 (d, J = 7.6 Hz, 0.5H). 1.19 (d, J = 7.6 Hz, 0.5H), 1.08-0.99 (m, 6H), 0.97 - 0.88 (m, 6H), 0.70-0.60 (m, 3H). LC-MS (Method C): R _t = 0.417 min, MS (ESIpos): m/z = 513.2 [M+H] ⁺ . Preparation of CPD187907 Procedure for preparation of (2S)-2-amino-3-[(2S)-3-oxo-4H-1,4-benzoxazin-2-yl]propanamid e A solution of tert-butyl N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4-benzoxazin-2- yl]methyl]ethyl]carbamate (2.00 g, 5.96 mmol, 1.00 eq) in hydrochloric acid/dioxane (20.0 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford (2S)- 2-amino-3-[(2S)-3-oxo-4H-1,4-benzoxazin-2-yl]propanamide (1.30 g, 5.53 mmol, 93% yield, hydrochloride) as a white solid. LC-MS (Method C): Rt = 0.294 min; MS (ESIpos): m/z = 236.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 10.86 (s, 1H), 8.43-8.33 (m, 2H), 8.01 (s, 1H), 7.65 (s, 1H), 7.00- 6.92 (m, 4H), 4.70 (dd, J = 10.0, 2.8 Hz, 1H), 3.98-3.97 (m, 1H), 2.46-2.42 (m, 1H), 2.26-2.18 (m, 1H). Procedure for preparation of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4- benzoxazin-2-yl]methyl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2 -trifluoroacetyl)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.50 g, 4.12 mmol, 1.00 eq) in dichloromethane (15.0 mL) were added (2S)-2-amino-3-[(2S)-3-oxo-4H-1,4-benzoxazin-2-yl]propanamid e (1.16 g, 4.94 mmol, 1.20 eq), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-d imethylazanium;hexafluorophosphate (2.35 g, 6.18 mmol, 1.50 eq) and diisopropylethylamine (3.72 g, 28.8 mmol, 5.02 mL, 7.00 eq). After stirring at 25 °C for 16 h, the reaction mixture was partitioned between water (100 mL) and ethyl acetate (200 mL). The organic phase was separated, washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 0: 1) to afford (1R,2S,5S)- N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4-benzoxazin-2-yl] methyl]ethyl]-3-[(2S)-3,3-dimethyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabi cyclo[3.1.0]hexane-2-carboxamide (1.80 g, 3.10 mmol, 75% yield) as a yellow solid. LC-MS (Method C): Rt = 0.797 min; MS (ESIpos): m/z = 582.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.63 (s, 1H), 9.30 (d, J = 8.4 Hz, 1H), 8.36 (d, J = 8.8 Hz, 1H), 7.33 (s, 1H), 7.13 (s, 1H), 6.93-6.84 (m, 4H), 4.61-4.54 (m, 1H), 4.54-4.47 (m, 1H), 4.34 (d, J = 8.4 Hz, 1H), 4.23 (s, 1H), 3.89-3.81 (m, 1H), 3.66 (d, J = 10.4 Hz, 1H), 2.29-2.16 (m, 1H), 2.13-2.08 (m, 1H), 1.51- 1.42 (m, 2H), 1.01 (s, 3H), 0.82 (s, 3H), 0.78 (s, 9H). Procedure for preparation of Compound CPD0187907 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-3- oxo-4H-1,4-benzoxazin-2-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2 ,2,2-trifluoroacetyl)amino]butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4-benzo xazin-2- yl]methyl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroace tyl)amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (1.60 g, 2.75 mmol, 1.00 eq) in dichloromethane (5.00 mL) was added burgess reagent (1.31 g, 5.50 mmol, 2.00 eq). After stirring at 20 °C for 4 h, the reaction mixture was partitioned between water (100 mL) and ethyl acetate (200 mL). The organic phase was separated, washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (FA condition; column: Phenomenex luna C18150 × 40 mm × 15 μm; mobile phase: [water(FA)-ACN]; B%: 45%-75%,10 min.) to give(1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-3-oxo-4H-1,4-benzoxaz in-2-yl]ethyl]-3-[(2S)-3,3-dimethyl- 2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-aza bicyclo[3.1.0]hexane-2-carboxamide (1.10 g, 1.95 mmol, 35% yield) followed by prep-SFC (column: daicel chiralpak ad (250 mm × 30 mm,10um);mobile phase: [Neu-IPA];B%: 30%-30%,2.5min,Rt = 1.35) to give (1R,2S,5S)-N-[(1S)-1- cyano-2-[(2S)-3-oxo-4H-1,4-benzoxazin-2-yl]ethyl]-3-[(2S)-3, 3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (212 mg, 0.375 mmol, 14% yield, 99% purity) as a white solid. LC-MS (Method C): Rt = 0.593 min; MS (ESIpos): m/z = 564.3 [M+H] ⁺ . NMR (400 MHz, DMSO-d ₆ ) δ = 10.80 (s, 1H), 9.32 (s, 1H), 9.10-9.07 (m, 1H), 6.95-6.88 (m, 4H), 5.19-5.12 (m, 1H), 4.53 (dd, J = 10.4, 2.8 Hz, 1H), 4.39-4.24 (m, 1H), 4.14 (s, 1H), 3.92-3.86 (m, 1H), 3.68 (d, J = 10.4 Hz, 1H), 2.53 (d, J = 2.8 Hz, 1H), 2.47 (d, J = 2.8 Hz, 1H), 1.62-1.54 (m, 1H), 1.34 (d, J = 7.6 Hz, 1H), 1.07-0.98 (m, 3H), 0.96-0.66 (m, 12H). ¹³ C NMR (100 MHz, DMSO- d ₆ ) δ = 171.1, 167.9, 165.8, 157.4 (q, J = 36.3 Hz), 142.9, 127.9, 123.6, 123.2, 120.6, 119.4, 117.7, 117.0, 116.1, 114.8, 112.0, 73.3, 72.2, 60.6, 58.6, 57.9, 56.5, 48.0, 39.3, 36.5, 34.8, 30.6, 27.8, 26.5, 26.2, 19.7, 19.3, 19.0, 13.4, 12.7. To a mixture of (1R,2S,5S)-3-[(2S)-3-(dimethylamino)-2-[(2,2,2-trifluoroacet yl)amino]propanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (100 mg, 0.274 mmol, 1.00 eq), 2-amino-2- phthalazin-1-yl-acetamide (55.4 mg, 0.274 mmol, 1.00 eq) and N,N-diisopropylethylamine (35.4 mg, 0.274 mmol, 47.7 μL, 1.00 eq) in dichloromethane (1.00 mL) was added [dimethylamino(triazolo[4,5- b]pyridin-3-yloxy)methylene]-dimethyl-ammonium;hexafluoropho sphate (104 mg, 0.274 mmol, 1.00 eq). After stirring at 25 °C for 16 h, the reaction mixture was purified by reversed phase (instrument: 40 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-15 min 20-40% B; flow 40 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -3-(dimethylamino)-2-[(2,2,2- trifluoroacetyl)amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3 .1.0]hexane-2-carboxamide (50.0 mg, 90.0 μmol, 33% yield, 99% purity) as a white solid LC-MS (Method C): Rt = 0.440 min; MS (ESIpos): m/z = 550.3 [M+H] ⁺ . A mixture of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -3-(dimethylamino)-2- [(2,2,2-trifluoroacetyl)amino]propanoyl]-6,6-dimethyl-3-azab icyclo[3.1.0]hexane-2-carboxamide (200 mg, 0.364 mmol, 1.00 eq) in dichloromethane (5.00 mL) was added methoxycarbonyl- (triethylammonio)sulfonyl-azanide (260 mg, 1.09 mmol, 3.00 eq). After stirring 25 °C for 16 h, the reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25 mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 11%-41%,10min) and (column: 3_Phenomenex Luna C1875*30mm*3 μm; mobile phase: [water(TFA)-ACN];B%: 19%-39%,9 min) to give (1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]-3-[(2S)-3-(dimet hylamino)-2-[(2,2,2- trifluoroacetyl)amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3 .1.0]hexane-2-carboxamide (70.0 mg, 0.119 mmol, 33% yield, 90% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.77 (s, 0.4H), 10.22-10.14 (m, 0.4H), 10.11-10.04 (m, 0.5H), 9.84- 9.69 (m, 1H), 9.67-9.48 (m, 0.7H), 9.28 (s, 0.4H), 8.85-8.72 (m, 0.5H), 8.34-8.23 (m, 0.6H), 8.14-8.06 (m, 1.4H), 8.06-7.95 (m, 0.8H), 7.87-7.73 (m, 1.4H), 7.30-7.15 (m, 0.6H), 5.02-4.86 (m, 1H), 4.29 (s, 0.4H), 4.21 (s, 0.31H), 4.14 (s, 0.3H), 4.04-3.92 (m, 1H), 3.75-3.65 (m, 1H), 3.37-3.32 (m, 2H), 2.94- 2.80 (m, 6H), 1.79-1.70 (m, 0.53H), 1.69-1.63 (m, 0.6H), 1.63-1.58 (m, 0.6H), 1.36 (d, J = 7.6 Hz, 0.3H), 1.27-1.21 (m, 0.2H), 1.12 (d, J = 7.6 Hz, 0.3H), 1.08-0.81 (m, 6H). LC-MS (Method C): Rt = 0.455 min; MS (ESIpos): m/z = 532.2 [M+H] ⁺ . SFC: dr = 37: 44: 17. Preparation of CPD0277843 Procedure for preparation of methyl (2S)-2-(tert-butoxycarbonylamino)-3- [ethyl(methyl)amino]propanoate To a solution of methyl (2R)-2-(tert-butoxycarbonylamino)-3-iodo-propanoate (15.0 g, 45.6 mmol, 1.00 eq) in N,N-dimethylformamide (20.0 mL) were added potassium carbonate (12.6 g, 91.1 mmol, 2.00 eq) and N-methylethanamine (2.69 g, 45.6 mmol, 3.92 mL, 1.00 eq). After stirring at 20 °C for 16 h, the reaction mixture was diluted with water (120 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (120 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 20% Ethyl acetate/Petroleum ethergradient @ 80 mL/min) to afford methyl (2S)-2-(tert-butoxycarbonylamino)-3- [ethyl(methyl)amino]propanoate (8.00 g, 30.7 mmol, 67% yield) as yellow oil. LC-MS (Method C): R _t = 0.208 min; MS (ESIpos): m/z = 205.3 [M-55] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.01 (d, J = 7.6 Hz, 1H), 4.14-4.12 (m, 1H), 3.62 (s, 3H), 2.61-2.51 (m, 2H), 2.38 (q, J = 7.2 Hz, 2H), 2.16 (s, 3H), 1.38 (s, 9H), 0.94 (t, J = 7.2 Hz, 3H). Procedure for preparation of (2S)-2-(tert-butoxycarbonylamino)-3- [ethyl(methyl)amino]propanoic acid To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[ethyl(methyl)amino]prop anoate (8.00 g, 30.7 mmol, 1.00 eq) in methanol (15.0 mL) were added lithium hydroxide monohydrate (2.58 g, 61.5 mmol, 2.00 eq) and water (15.0 mL). After stirring at 20 °C for 16 h, hydrochloric acid (1M) was added to the reaction mixture to adjust pH to 6. The solution was concentrated under reduced pressure to give (2S)-2-(tert-butoxycarbonylamino)-3-[ethyl(methyl)amino]prop anoic acid (7.00 g, crude) as a white solid. LC-MS (Method Y): R _t = 0.512 min; MS (ESIpos): m/z = 247.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 6.45 (d, J = 7.2 Hz, 1H), 3.93 (q, J = 7.2 Hz, 1H), 2.99-2.82 (m, 4H), 2.54 (s, 3H), 1.36 (s, 9H), 1.09 (t, J = 7.2 Hz, 3H). Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3- [ethyl(methyl)amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3.1 .0]hexane-2-carboxylate To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-[ethyl(methyl)amino]prop anoic acid (7.00 g, 23.6 mmol, 83% purity, 1.00 eq) and methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylate (7.28 g, 35.4 mmol, 1.50 eq, hydrogen chloride) in dichloromethane (100 mL) were added diisopropylethylamine (6.10 g, 47.2 mmol, 8.22 mL, 2.00 eq) and 3-[chloro-(2-oxo-1,3-oxazolidin-3- yl)phosphoryl]-1,3-oxazolidin-2-one (9.01 g, 35.4 mmol, 1.50 eq). After stirring at 20 °C for 3 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (Instrument: 300 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.05% formic acid), eluent B: acetonitrile; gradient: 15 min 25% B; flow 90 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to afford methyl (1R,2S,5S)-3-[(2S)-2-(tert- butoxycarbonylamino)-3-[ethyl(methyl)amino]propanoyl]-6,6-di methyl-3-azabicyclo[3.1.0]hexane-2- carboxylate (3.80 g, 9.37 mmol, 40% yield, 98% purity) as yellow oil. LC-MS (Method Y): R _t = 1.020 min; MS (ESIpos): m/z = 398.5 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 5.76 (s, 1H), 4.60-4.35 (m, 1H), 4.31-4.03 (m, 2H), 3.96-3.82 (m, 1H), 3.82-3.54 (m, 4H), 2.96-2.56 (m, 4H), 2.51 (br. s, 3H), 1.65-1.51 (m, 1H), 1.50-1.25 (m, 9H), 1.16- 0.82 (m, 9H). Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3- [ethyl(methyl)amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3.1 .0]hexane-2-carboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3- [ethyl(methyl)amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3.1 .0]hexane-2-carboxylate (3.80 g, 9.56 mmol, 1.00 eq) in methanol (10.0 mL) were added lithium hydroxide monohydrate (1.20 g, 28.7 mmol, 3.00 eq) and water (10.0 mL). After stirring at 20 °C for 16 h, hydrogen chloride (1M) was added to the reaction mixture to adjust pH to 5. The solution was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (Instrument: 300 g Flash; Column: Welch Ultimate XB_C1820-40μm; eluent A: water (0.05% formic acid), eluent B: acetonitrile; gradient: 15 min 25% B; flow 110 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)-3-[(2S)- 2-(tert-butoxycarbonylamino)-3-[ethyl(methyl)amino]propanoyl ]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (800 mg, 1.98 mmol, 21% yield, 95% purity) as a white solid. LC-MS (Method Y): R _t = 1.006 min; MS (ESIpos): m/z = 384.1 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-amino-3-[ethyl(methyl)amino]propanoyl]- 6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid To a solution of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-[ethyl(met hyl)amino]propanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (800 mg, 2.09 mmol, 1.00 eq) in hydrogen- chloride (4M in ethyl acetate, 10.0 mL). After stirring at 20 °C for 2 h, the reaction mixture was concentrated under reduced pressure to give (1R,2S,5S)-3-[(2S)-2-amino-3- [ethyl(methyl)amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3.1 .0]hexane-2-carboxylic acid (600 mg, crude) as a white solid. LC-MS (Method C): R _t = 0.608 min; MS (ESIpos): m/z = 284.1 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-3-[ethyl(methyl)amino]-2-[(2,2,2- trifluoroacetyl)amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3 .1.0]hexane-2-carboxylic acid To a solution of (1R,2S,5S)-3-[(2S)-2-amino-3-[ethyl(methyl)amino]propanoyl]- 6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (600 mg, 1.88 mmol, 1.00 eq, hydrogen chloride) in methanol (10.0 mL) were added methyl 2,2,2-trifluoroacetate (721 mg, 5.63 mmol, 0.568 mL, 3.00 eq) and diisopropylethylamine (728 mg, 5.63 mmol, 3.00 eq). After stirring at 20 °C for 16 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (Instrument: 80 g Flash; Column: Welch Ultimate XB_C1820-40μm; eluent A: water (0.05% formic acid), eluent B: acetonitrile; gradient: 12 min 18% B; flow 90 mL/min; temperature: room temperature; Detector: UV 220/254 nm) to afford (1R,2S,5S)-3-[(2S)-3-[ethyl(methyl)amino]-2-[(2,2,2- trifluoroacetyl)amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3 .1.0]hexane-2-carboxylic acid (390 mg, 0.925 mmol, 49% yield, 90% purity) as a white solid. To a mixture of (1R,2S,5S)-3-[(2S)-3-[ethyl(methyl)amino]-2-[(2,2,2-trifluor oacetyl)amino]propanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (390 mg, 1.03 mmol, 1.00 eq) and 2-amino- 2-phthalazin-1-yl-acetamide (849 mg, 3.08 mmol, 3.00 eq, 2 hydrochloride) in dimethylacetamide (5.00 mL) were added 3-[chloro-(2-oxo-1,3-oxazolidin-3-yl)phosphoryl]-1,3-oxazoli din-2-one (785 mg, 3.08 mmol, 3.00 eq) and diisopropylethylamine (1.33 g, 10.3 mmol, 1.79 mL, 10.0 eq). After stirring at 20 °C for 16 h, the reaction mixture was quenched with water (30.0 mL), extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-HPLC (column: UniSil 3-100 C18 UItra (150*25mm*3 μm); mobile phase: [water(FA)-ACN]; B%: 13%-33%,7 min) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -3-[ethyl(methyl)amino]-2-[(2,2,2- trifluoroacetyl)amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3 .1.0]hexane-2-carboxamide (240 mg, 0.426 mmol, 41% yield) as a white solid. LC-MS (Method C): R _t = 0.491 min; MS (ESIpos): m/z = 564.3 [M+H] ⁺ . To a mixture of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -3-[ethyl(methyl)amino]-2- [(2,2,2-trifluoroacetyl)amino]propanoyl]-6,6-dimethyl-3-azab icyclo[3.1.0]hexane-2-carboxamide (130 mg, 0.231 mmol, 1.00 eq) in dichloromethane (5.00 mL) was added triethylamine (233 mg, 2.31 mmol, 0.321 mL, 10.0 eq) and trifluoroacetic anhydride (651 mg, 2.31 mmol, 0.381 mL, 10.0 eq). After stirring at 20 °C for 16 h, the reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: YMC Triart C18150*25mm*5 μm; mobile phase: [water(TFA)-ACN]; B%: 30%- 50%, 10 min) to give a residue. The residue was purified by prep-HPLC again (column: Phenomenex Synergi Polar-RP 100*25mm*4um; mobile phase: [water (TFA)-ACN]; B%: 21%-41%, 9 min) to give (1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]-3-[(2S)-3-[ethyl (methyl)amino]-2-[(2,2,2- trifluoroacetyl)amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3 .1.0]hexane-2-carboxamide (16.0 mg, 27.5 μmol, 12% yield) as a yellow solid. LC-MS (Method C): Rt = 0.521min; MS (ESIpos): m/z = 546.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.64 (s, 0.1H), 10.76 (s, 0.3H), 10.27-10.10 (m, 0.9H), 9.81-9.69 (m, 0.8H), 9.46-9.28 (m, 0.7H), 8.81-8.77 (m, 0.4H), 8.32-8.27 (m, 0.5H), 8.12-7.95 (m, 2H), 7.86-7.78 (m, 1H), 7.44-7.20 (m, 0.6H), 5.00-4.92 (m, 1H), 4.29-4.15 (m, 1H), 4.01-3.99 (m, 2H), 3.53-3.43 (m, 5H), 2.86-2.77 (m, 2H), 1.91-1.88 (m, 0.14H), 1.75-1.73 (m, 0.33H), 1.69-1.57 (m, 0.80H), 1.52-1.48 (m, 0.20H), 1.37-1.35 (m, 0.2H), 1.22-0.72 (m, 9H). Preparation of CPD0336667 (single diastereoisomer) and CPD0336668 (single diastereoisomer) Procedure for preparation of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(3-furyl)propanoate A mixture of zinc (11.9 g, 183 mmol, 3.01 eq) and iodine (1.54 g, 6.08 mmol, 0.100 eq) in N,N- dimethylformamide (100 mL) was stirred at 70 °C for 0.5 h. After cooling to 50 °C, a solution of methyl (2R)-2-(tert-butoxycarbonylamino)-3-iodo-propanoate (20.0 g, 60.7 mmol, 1.00 eq) in N,N- dimethylformamide (100 mL) was added. After stirring at this temperature for 0.5 h, a solution of 3- bromofuran (26.7 g, 182 mmol, 16.3 mL, 3.00 eq), tris(dibenzylideneacetone)dipalladium(0) (2.78 g, 3.04 mmol, 0.05 eq) and 2-di-tert-butylphosphino-2’,4’,6’-triisopropylbiphenyl (5.79 g, 12.1 mmol, 0.200 eq) in N,N-dimethylformamide (100 mL) were added to the freshly prepared zinc reagent, and the reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was poured into saturated sodium bicarbonate (1.00 L) and extracted with ethyl acetate (300 mL × 3). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 20: 1 to 2: 1) to give methyl (2S)-2-(tert-butoxycarbonylamino)- 3-(3-furyl)propanoate (11.0 g, 30.6 mmol, 50% yield, 75% purity) as brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.36 (t, J = 1.6 Hz, 1H), 7.25 (s, 1H), 6.21 (s, 1H), 5.04-5.03 (m, 1H), 4.61-4.44 (m, 1H), 3.74 (s, 3H), 3.02-2.84 (m, 2H), 1.44 (s, 9H). Procedure for preparation of methyl (2S)-2-(tert-butoxycarbonylamino)-3-tetrahydrofuran-3-yl- propanoate To a mixture of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(3-furyl)propanoate (2.00 g, 5.57 mmol, 75% purity, 1.00 eq) in methanol (50.0 mL) was added rhodium on carbon (400 mg, 5% purity) under nitrogen atmosphere. The mixture was degassed under vacuum and purged with hydrogen for 3 times. After stirring at 50 °C for 12 h under hydrogen atmosphere (50 psi), the reaction mixture was filtered and the filter cake was washed with methanol (200 mL). The filtrate was concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 10: 1 to 2: 1) to give methyl (2S)-2-(tert-butoxycarbonylamino)-3-tetrahydrofuran-3-yl- propanoate (1.20 g, 3.95 mmol, 70% yield, 90% purity) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.14-4.92 (m, 1H), 4.43-4.24 (m, 1H), 3.99-3.82 (m, 2H), 3.75 (s, 3H), 3.73-3.70 (m, 1H), 3.43-3.29 (m, 1H), 2.32-2.24 (m, 1H), 2.19-2.07 (m, 1H), 1.96-1.84 (m, 1H), 1.77- 1.66 (m, 1H), 1.56-1.50 (m, 1H), 1.45 (s, 9H). Procedure for preparation of (2S)-2-(tert-butoxycarbonylamino)-3-tetrahydrofuran-3-yl- propanoic acid To a mixture of methyl (2S)-2-(tert-butoxycarbonylamino)-3-tetrahydrofuran-3-yl-pro panoate (4.50 g, 13.1 mmol, 80% purity, 1.00 eq) in mixed solvent of methanol (30.0 mL) and water (30.0 mL) was added lithium hydroxide monohydrate (1.66 g, 39.5 mmol, 3.00 eq) at 20 °C. After stirring at 20 °C for 12 h, hydrochloric acid (1.00 M) was added to the reaction mixture to adjust pH 4~5 and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were concentrated under vacuum to give (2S)-2- (tert-butoxycarbonylamino)-3-tetrahydrofuran-3-yl-propanoic acid (3.50 g, crude) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.12-5.07 (m, 1H), 4.41-4.24 (m, 1H), 4.01-3.93 (m, 1H), 3.92-3.84 (m, 1H), 3.80-3.74 (m, 1H), 3.46-3.34 (m, 1H), 2.42-2.26 (m, 1H), 2.22-2.09 (m, 1H), 2.02-1.88 (m, 1H), 1.84-1.68 (m, 1H), 1.65-1.53 (m, 1H), 1.46 (s, 9H). Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3- tetrahydrofuran-3-yl-propanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxylate To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-tetrahydrofuran-3-yl-pro panoic acid (3.50 g, 13.5 mmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexaflu orophosphate (6.16 g, 16.2 mmol, 1.20 eq) and N,N-diisopropylethylamine (5.23 g, 40.4 mmol, 7.05 mL, 3.00 eq) in N,N- dimethylformamide (30.0 mL) was added methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxylate (2.77 g, 13.5 mmol, 1.00 eq, HCl). After stirring at 25°C for 12 h, the reaction mixture was poured into saturated ammonium chloride (100 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80g SepaFlash® Silica Flash Column, Eluent of 27~32% Ethyl acetate/Petroleum ether gradient @100mL/min) to give methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3- tetrahydrofuran-3-yl-propanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxylate (3.80 g, 7.87 mmol, 58% yield, 85% purity) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.35-4.88 (m, 1H), 4.45-4.33 (m, 1H), 4.08-3.67 (m, 7H), 3.62-3.22 (m, 2H), 2.40-2.05 (m, 2H), 1.77-1.50 (m, 5H), 1.48-1.36 (m, 9H), 1.11-1.03 (m, 3H), 0.99-0.88 (m, 3H). Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3- tetrahydrofuran-3-yl-propanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-tetrahydro furan-3-yl- propanoyl] -6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (2.00 g, 4.87 mmol, 1.00 eq) in mixed solvent of methanol (10.0 mL) and water (10.0 mL) was added lithium hydroxide monohydrate (817 mg, 19.4 mmol, 4.00 eq). After stirring at 25 °C for 12 h, hydrochloric acid (1 M) was added to the reaction mixture to adjust pH to 6~7 and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-tetrahydro furan-3-yl-propanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.80 g, 4.54 mmol, 93% yield, crude) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.49-5.13 (m, 1H), 4.08-4.01 (m, 1H), 3.98-3.70 (m, 4H), 3.64-3.50 (m, 1H), 3.46-3.30 (m, 1H), 2.40-2.11 (m, 2H), 1.77-1.50 (m, 5H), 1.47-1.37 (m, 9H), 1.11-1.04 (m, 3H), 0.98-0.90 (m, 3H). Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-amino-3-tetrahydrofuran-3-yl-propanoyl] -6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid A solution of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-tetrahydro furan-3-yl-propanoyl] -6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.80 g, 4.54 mmol, 1.00 eq) in hydrochloric acid (20.0 mL, 4M in dioxane) was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give (1R,2S,5S)-3-[(2S)-2-amino-3-tetrahydrofuran-3-yl-propanoyl] -6,6-dimethyl- 3-azabicyclo [3.1.0]hexane-2-carboxylic acid (1.50 g, 4.51 mmol, 99% yield, HCl) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.18 (s, 2H), 4.42 (s, 1H), 4.27-4.20 (m, 2H), 3.99-3.83 (m, 2H), 3.81- 3.72 (m, 1H), 3.58-3.32 (m, 2H), 2.23-1.96 (m, 3H), 1.88-1.73 (m, 1H), 1.66-1.54 (m, 3H), 1.09 (s, 3H), 0.96 (s, 3H). Procedure for preparation of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-tetrahydrofuran-3-yl-2-[(2 ,2,2- trifluoroacetyl)amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2 -carboxylic acid To a solution of (1R,2S,5S)-3-[(2S)-2-amino-3-tetrahydrofuran-3-yl-propanoyl] -6,6-dimethyl-3- azabicyclo [3.1.0]hexane-2-carboxylic acid (1.50 g, 4.51 mmol, 1.00 eq, HCl) and triethylamine (1.37 g, 13.5 mmol, 1.88 mL, 3.00 eq) in methanol (20.0 mL) was added methyl 2,2,2-trifluoroacetate (865 mg, 6.76 mmol, 1.50 eq). After stirring at 25°C for 12 h, hydrochloric acid (1M) was added to the reaction mixture to adjust pH to 4~5 and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 48~52% Ethyl acetate/Petroleum ether gradient @ 80 mL/min) to give (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-tetrahydrofuran-3-yl-2-[(2 ,2,2-trifluoroacetyl)amino]propanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (1.30 g, 3.31 mmol, 73% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.41-9.50 (m, 1H), 4.60-4.40 (m, 1H), 4.27-4.04 (m, 1H), 3.87-3.67 (m, 2H), 3.60-3.48 (m, 2H), 3.29-3.11 (m, 2H), 2.11-2.02 (m, 1H), 1.97-1.72 (m, 2H), 1.71-1.54 (m, 2H), 1.53-1.30 (m, 2H), 1.08-0.73 (m, 6H). Procedure for preparation of benzyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-tetrahydrofuran-3-yl-2- [(2,2,2-trifluoroacetyl)amino]propanoyl]-3-azabicyclo[3.1.0] hexane-2-carboxylate To a mixture of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-tetrahydrofuran-3-yl-2-[(2 ,2,2-trifluoroacetyl) amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.00 g, 2.55 mmol, 1.00 eq) and potassium carbonate (1.06 g, 7.65 mmol, 3.00 eq) in acetonitrile (20.0 mL) was added bromomethylbenzene (653 mg, 3.82 mmol, 1.50 eq) at 25 °C. After stirring at 25°C for 12 h, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 10~40% Ethyl acetate/Petroleum ether gradient @ 60 mL/min) to give benzyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3- tetrahydrofuran-3-yl-2-[(2,2,2-trifluoroacetyl)amino] propanoyl]-3-azabicyclo[3.1.0]hexane-2- carboxylate (1.00 g, 1.87 mmol, 73% yield, 90% purity) as colorless oil. LC-MS (Method C): R _t = 0.928 min; MS (ESIpos): m/z = 483.2 [ . Procedure for preparation of benzyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-tetrahydrofuran-3-yl-2- [(2,2,2-trifluoroacetyl)amino]propanoyl]-3-azabicyclo[3.1.0] hexane-2-carboxylate, benzyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-tetrahydrofuran-3-yl-2-[(2 ,2,2- trifluoroacetyl)amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2 -carboxylate Benzyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-tetrahydrofuran-3-yl-2-[(2 ,2,2-trifluoroacetyl)amino] propanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylate was purified by SFC (column: DAICEL CHIRALPAK AD-H (250mm*30 mm, 5 μm); mobile phase: [Neu-ETOH]; B%: 20%-20%,4.0 min) to give benzyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-tetrahydrofuran-3-yl-2-[(2 ,2,2- trifluoroacetyl)amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2 -carboxylate (240 mg, 0.472 mmol, 25% yield, 95% purity) and benzyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-tetrahydrofuran-3-yl-2-[(2 ,2,2- trifluoroacetyl)amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2 -carboxylate (600 mg, 1.18 mmol, 63% yield, 95% purity) as colorless oil. LC-MS (Method C): R _t = 0.934 min; MS (ESIpos): m/z = 483.2 [M+H] ⁺ . SFC: dr = 24: 76. LC-MS (Method C): R _t = 0.929 min; MS (ESIpos): m/z = 483.2 [ . SFC: dr = 22: 78. Procedure for preparation of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-tetrahydrofuran-3-yl-2-[(2 ,2,2- trifluoroacetyl)amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2 -carboxylic acid To a mixture of benzyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-tetrahydrofuran-3-yl-2-[(2 ,2,2-trifluoroacetyl) amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylate (240 mg, 0.472 mmol, 95% purity, 1.00 eq) in methanol (5.00 mL) was added palladium on carbon (30.0 mg, 0.472 mmol, 10% purity) under nitrogen atmosphere. The mixture was degassed under vacuum and purged with hydrogen for 3 times. After stirring at 25 °C for 12 h under hydrogen atmosphere (15 psi), the reaction mixture was filtered. The filter cake was washed with methanol (20.0 mL) and the filtrate was concentrated under vacuum to give (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-tetrahydrofuran-3-yl-2-[(2 ,2,2- trifluoroacetyl)amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2 -carboxylic acid (150 mg, crude) as colorless oil. LC-MS (Method L): R _t = 0.514 min; MS (ESIpos): m/z = 393.1 [M+H] ⁺ . To a mixture of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-tetrahydrofuran-3-yl-2-[(2 ,2,2-trifluoroacetyl) amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (150 mg, 0.382 mmol, 1.00 eq), 2- amino-2-phthalazin-1-yl-acetamide (91.2 mg, 0.382 mmol, 1.00 eq, HCl) and 4-methylmorpholine (116 mg, 1.15 mmol, 3.00 eq) in dichloromethane (5.00 mL) was added benzotriazol-1-yloxy- tris(dimethylamino)phosphanium;hexafluorophosphate (202 mg, 0.458 mmol, 1.20 eq). After stirred at 25°C for 12 h, the reaction mixture was poured into water (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 70~100% [Ethyl acetate/methanol = 10: 1]/ Petroleum ether gradient @ 30 mL/min) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-6,6-dim ethyl-3-[(2S)-3-tetrahydrofuran-3-yl-2- [(2,2,2-trifluoroacetyl)amino]propanoyl]-3-azabicyclo[3.1.0] hexane-2-carboxamide (160 mg, 250 μmol, 65% yield, 90% purity) as a yellow solid. LC-MS (Method C): R _t = 0.447 min; MS (ESIpos): m/z = 577.3 [M+H] ⁺ . Procedure for preparation of C dimethyl-3-[(2S)-3-tetrahydrofura azabicyclo[3.1.0]hexane-2-carbox A mixture of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-6,6-dim ethyl-3-[(2S)-3- tetrahydrofuran -3-yl-2-[(2,2,2-trifluoroacetyl)amino]propanoyl]-3-azabicycl o[3.1.0]hexane-2- carboxamide (160 mg, 0.249 mmol, 90% purity, 1.00 eq) and (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (178 mg, 0.749 mmol, 3.00 eq) in dichloromethane (3.00 mL) was stirred at 25 °C for 12 h. The reaction mixture was concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C18 75*30mm*3 μm; mobile phase: [water (FA)-ACN]; B%: 30%-60%, 7 min) to give (1R,2S,5S)-N- [cyano(phthalazin-1-yl)methyl]-6,6-dimethyl-3-[(2S)-3-tetrah ydrofuran-3-yl-2-[(2,2,2- trifluoroacetyl)amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2 -carboxamide (86.0 mg, 0.152 mmol, 61% yield, 99% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.55 (s, 0.17H), 10.66-10.44 (m, 0.15H), 10.25-9.60 (m, 1.55H), 9.20 (d, J=17.0 Hz, 0.35H), 8.83-8.73 (m, 0.41H), 8.40-8.22 (m, 0.49H), 8.20-8.03 (m, 1.42H), 8.01- 7.88 (m, 0.40H), 7.87-7.68 (m, 1.32H), 7.38-7.07 (m, 0.39H), 4.96-4.31 (m, 1.12H), 4.25-3.86 (m, 1.15H), 3.82-3.45 (m, 3.52H), 3.43-3.35 (m, 1H), 3.27-2.97 (m, 1.12H), 2.26-1.22 (m, 6.59H), 1.17-0.68 (m, 6H). LC-MS (Method C): R _t = 0.830 min; MS (ESIpos): m/z = 559.3 [M+H] ⁺ . HPLC (Method M): R _t = 1.896 min; HPLC purity: 99%. Procedure for preparation of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-tetrahydrofuran-3-yl-2-[(2 ,2,2- trifluoroacetyl)amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2 -carboxylic acid To a mixture of benzyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-tetrahydrofuran-3-yl-2-[(2 ,2,2-trifluoroacetyl) amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylate (600 mg, 1.18 mmol, 95% purity, 1.00 eq) in methanol (10.0 mL) was added palladium on carbon (60.0 mg, 0.472 mmol, 10% purity) under nitrogen atmosphere. The mixture was degassed under vacuum and purged with hydrogen for 3 times. After stirring at 25 °C for 12 h under hydrogen atmosphere (15 psi), the reaction mixture was filtered. The filter cake was washed with methanol (50.0 mL). The filtrate was concentrated under vacuum to give (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-tetrahydrofuran-3-yl-2-[(2 ,2,2-trifluoroacetyl)amino]propanoyl]- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (400 mg, crude) as colorless oil. LC-MS (Method L): R _t = 0.518 min; MS (ESIpos): m/z = 393.2 [M+H] ⁺ . Procedure for preparation of (1 3-[(2S)-3-tetrahydrofuran-3-yl-2 azabicyclo[3.1.0]hexane-2-carb To a mixture of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-tetrahydrofuran-3-yl-2-[(2 ,2,2-trifluoroacetyl)amino] propanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (350 mg, 0.892 mmol, 1.00 eq), 2-amino-2- phthalazin-1-yl-acetamide (212 mg, 0.892 mmol, 1.00 eq, HCl) and 4-methylmorpholine (270 mg, 2.68 mmol, 3.00 eq) in dichloromethane (10.0 mL) was added benzotriazol-1-yloxy- tris(dimethylamino)phosphanium;hexafluorophosphate (473 mg, 1.07 mmol, 1.20 eq). After stirring at 25 °C for 12 h, the reaction mixture was poured into water (30.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 70~100% [ethyl acetate/methanol=10:1]/ petroleum ether gradient @ 30 mL/min) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-6,6-dim ethyl-3-[(2S)-3-tetrahydrofuran-3-yl-2- [(2,2,2-trifluoroacetyl)amino]propanoyl]-3-azabicyclo[3.1.0] hexane-2-carboxamide (400 mg, 0.624 mmol, 70% yield, 90% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.08-9.61 (m, 2H), 9.49-8.88 (m, 1H), 8.55-7.89 (m, 4H), 7.66-7.24 (m, 2H), 6.49-6.20 (m, 1H), 4.75 (d, J = 18.8 Hz, 0.5H), 4.51 (s, 0.5H), 4.45-4.28 (m, 0.5H), 4.26-4.18 (m, 0.3H), 3.87-3.84 (m, 0.5H), 3.76-3.43 (m, 4H), 3.31-3.04 (m, 1.6H), 2.16-2.01 (m, 0.8H), 1.96-1.83 (m, 0.9H), 1.80-1.59 (m, 2.2H), 1.57-1.37 (m, 2.2H), 1.33-1.19 (m, 0.9H), 1.07-0.82 (m, 6H). LC-MS (Method C): R _t = 0.593 min; MS (ESIpos): m/z = 577.3 [M+H] ⁺ . A mixture of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-6,6-dim ethyl-3-[(2S)-3- tetrahydrofuran-3-yl-2-[(2,2,2-trifluoroacetyl)amino]propano yl]-3-azabicyclo[3.1.0]hexane-2- carboxamide (370 mg, 0.577 mmol, 90% purity, 1.00 eq) and (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (165 mg, 0.693 mmol, 1.20 eq) in dichloromethane (10.0 mL) was stirred at 25 °C for 12 h. The reaction mixture was concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: UniSil 3-100 C18 UItra (150*25mm*3 μm); mobile phase: [water(FA)-ACN]; B%: 38%-58%, 7 min) to give (1R,2S,5S)-N- [cyano(phthalazin-1-yl)methyl]-6,6-dimethyl-3-[(2S)-3-tetrah ydrofuran-3-yl-2- [(2,2,2- trifluoroacetyl)amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2 -carboxamide (190 mg, 0.330 mmol, 57% yield, 97% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.49 (s, 0.2H), 10.55 (s, 0.3H), 10.15-9.86 (m, 0.3H), 9.85-9.61 (m, 0.8H), 9.31-9.11 (m, 0.5H), 8.84-8.72 (m, 0.6H), 8.32-8.22 (m, 0.3H), 8.18-8.02 (m, 1.3H), 8.01-7.89 (m, 0.3H), 7.87-7.68 (m, 2H), 7.31-7.20 (m, 0.2H), 4.82-4.29 (m, 1.2H), 4.24-3.86 (m, 1.3H), 3.78-3.65 (m, 1.3H), 3.64-3.41 (m, 2.8H), 3.01 (t, J = 8.2 Hz, 0.2H), 2.20-1.31 (m, 7H), 1.14-0.73 (m, 6H). LC-MS (Method C): R _t = 0.829 min; MS (ESIpos): m/z = 559.3 [M+H] ⁺ . HPLC (Method M): R _t = 1.890 min; HPLC purity: 97%. To a solution of 4-aminopyridin-3-ol (4.50 g, 40.9 mmol, 1.00 eq) in acetone (45.0 mL) and water (22.0 mL) were added benzyl chloroformate (7.67 g, 45.0 mmol, 1.10 eq) and sodium bicarbonate (6.87 g, 81.7 mmol, 3.18 mL, 2.00 eq) at 0 °C. The mixture was allowed to up to 20 °C and stirred for 16 h. To the reaction mixture was added water (40.0 mL) and ethyl acetate (60.0 mL). A lot of solid precipitated out. The suspension was filtered under reduced pressure. The filter cake was collected and dried in vacuo to give benzyl N-(3-hydroxy-4-pyridyl) carbamate (6.61 g, 26.2 mmol, 64 % yield, 97% purity) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.15 (d, J = 5.6 Hz, 1H), 8.11-7.97 (m, 1H), 7.84-7.75 (m, 2H), 7.46- 7.32 (m, 5H), 5.24 (s, 2H). Procedure for preparation of dimethyl (2S,4S)-2-[[4-(benzyloxycarbonylamino)-3-pyridyl]oxy]-4- (tert-butoxycarbonylamino)pentanedioate To a solution of dimethyl (2S,4R)-2-(tert-butoxycarbonylamino)-4-hydroxy-pentanedioate (3.00 g, 10.3 mmol, 1.00 eq), benzyl N-(3-hydroxy-4-pyridyl)carbamate (2.52 g, 10.3 mmol, 1.00 eq) and triphenylphosphine (3.24 g, 12.4 mmol, 1.20 eq) in tetrahydrofuran (72.0 mL) was added diisopropyl azodicarboxylate (3.12 g, 15.5 mmol, 3.00 mL, 1.50 eq) dropwise at 0 °C under nitrogen atmosphere. The mixture was allowed to up to 20 °C and stirred for 15 h. Saturated ammonium chloride solution (40.0 mL) was added to the reaction mixture. The solution was extracted with ethyl acetate (60.0 mL ´ 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to get a residue. The residue was purified by flash silica gel chromatography (40.0 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ethergradient @ 80 mL/min) to give dimethyl (2S,4S)-2-[[4-(benzyloxycarbonylamino)-3-pyridyl]oxy]-4-(ter t- butoxycarbonylamino)pentanedioate (7.00 g, 4.06 mmol, 39% yield, 30% purity) as yellow oil. Procedure for preparation of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxo-1H- pyrido[3,4-b][1,4]oxazin-3-yl]propanoate To a solution of dimethyl (2S,4S)-2-[[4-(benzyloxycarbonylamino)-3-pyridyl]oxy]-4-(ter t- butoxycarbonylamino)pentanedioate (5.00 g, 9.66 mmol, 1.00 eq) in methanol (50.0 mL) was added palladium on activated charcoal (10.0 % palladium, contains 50.0 % water, 500 mg) at 25 °C. The reaction mixture was stirred at 25 °C for 14 h under hydrogen (15 Psi) atmosphere. The reaction mixture was filtered under reduced pressure through a pad of celite. The filtrate was concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 100: 1 then 0: 1) to give methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxo-1H-pyrido[3, 4- b][1,4]oxazin-3-yl]propanoate (1.40 g, 3.98 mmol, 41% yield) as a white solid. LC-MS (Method C): R _t = 0.492 min; MS (ESIpos): m/z = 352.1 [M+H] ⁺ . Procedure for preparation of tert-butyl N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-1H-pyrido[3,4- b][1,4]oxazin-3-yl]methyl]ethyl]carbamate A solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxo-1H-pyrido[3, 4-b][1,4]oxazin-3- yl]propanoate (1.40 g, 3.98 mmol, 1.00 eq) in ammonia (7.00 M in methanol, 35.0 mL, 61.5 eq) was stirred at 25 °C for 30 h. The combined reaction mixture was concentrated in vacuum to give a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate = 1: 0-0: 1) to give tert-butyl N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-1H-pyrido[3,4-b][1,4]ox azin-3- yl]methyl]ethyl]carbamate (1.00 g, 2.97 mmol, 75% yield) as a white solid. ¹ H NMR (400 MHz, CD3OD) δ = 8.24-8.19 (m, 1H), 8.08-8.06 (m, 1H), 6.93-6.90 (m, 1H), 4.74-4.72 (m, 1H), 4.45-4.43 (m, 1H), 2.51-2.19 (m, 2H), 1.43 (s, 9H). Procedure for preparation of (2S)-2-amino-3-[(3S)-2-oxo-1H-pyrido[3,4-b][1,4]oxazin-3- yl]propanamide A solution of tert-butyl N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-1H-pyrido[3,4-b][1,4]ox azin-3- yl]methyl]ethyl]carbamate (500 mg, 1.49 mmol, 1.00 eq) in hydrogen chloride (4.00 M in 1,4-dioxane, 10.0 mL) was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give (2S)-2-amino-3-[(3S)-2-oxo-1H-pyrido[3,4-b][1,4]oxazin-3-yl] propanamide (460 mg, 1.49 mmol, 100% yield, 2 hydrochloride) as a white solid. Procedure for preparation of (1R,2S,5S)-N-[2-amino-2-oxo-1-[[(3S)-2-oxo-1H-pyrido[3,4- b][1,4]oxazin-3-yl]methyl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2, 2,2-trifluoroacetyl)amino]butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (2S)-2-amino-3-[(3S)-2-oxo-1H-pyrido[3,4-b][1,4]oxazin-3-yl] propanamide (460 mg, 1.49 mmol, 1.00 eq, 2 hydrochloride) in N,N-dimethylformamide (10.0 mL) were added dropwise O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (848 mg, 2.23 mmol, 1.50 eq) and N,N-diisopropylethylamine (769 mg, 5.95 mmol, 1.04 mL, 4.00 eq) at 0 °C. After stirring at 0 °C for 10 min, (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0] hexane-2-carboxylic acid (650 mg, 1.78 mmol, 1.20 eq) was added into the reaction mixture at 0 °C. After stirring at 25 °C for 12 h, the reaction mixture was slowly added into water (100 mL) at 0 °C and extracted with ethyl acetate (50.0 mL ´ 3). The combined organic layers were washed with brine (150 mL), hydrochloric acid (40.0 mL, 0.5 M, in water) and saturated sodium bicarbonate solution (50.0 mL). The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (Methanol: Ethyl acetate = 0: 10 then 1: 9) to give (1R,2S,5S)-N-[2-amino-2-oxo-1-[[(3S)-2-oxo-1H- pyrido[3,4-b][1,4]oxazin-3-yl]methyl]ethyl]-3-[(2S)-3,3-dime thyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (800 mg, 1.37 mmol, 92% yield) as a white solid. LC-MS (Method C): R _t = 0.664 min; MS (ESIpos): m/z = 583.3 [M+H] ⁺ . Procedure for preparation of CPD0191304 (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxo-1H- pyrido[3,4-b][1,4]oxazin-3-yl]ethyl]-3-[(2S)-3,3-dimethyl-2- [(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide The reaction were performed for 4 batches in parallel: To a solution of (1R,2S,5S)-N-[2-amino-2-oxo-1- [[(3S)-2-oxo-1H-pyrido[3,4-b][1,4]oxazin-3-yl]methyl]ethyl]- 3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino] butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxami de (200 mg, 343 μmol, 1.00 eq) in dichloromethane (10.0 mL) was added Burgess reagent (245 mg, 1.03 mmol, 3.00 eq) at 25 °C. After stirring at 25 °C for 5 h, the reaction mixture of 4 batches were combined and added into saturated aqueous ammonium chloride (50.0 mL) at 0 °C. The mixture was extracted with dichloromethane (10.0 mL ´ 3). The combined organic layers were washed with brine (50.0 mL), saturated sodium bicarbonate solution (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 0: 10 then 3: 7) to give 370 mg of the crude product. The crude product was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um; mobile phase: [water(FA)-ACN];B%: 19%-49%,10min) to give 200 mg of crude product. (1R,2S,5S)-N- [(1S)-1-cyano-2-[(3S)-2-oxo-1H-pyrido[3,4-b][1,4]oxazin-3-yl ]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (150 mg, 266 μmol, 1.00 eq) was purified by SFC (column: REGIS(S,S)WHELK-O1(250mm*25mm,10 μm); mobile phase: [Neu-IPA];B%: 30%-30%,3.2 min) and concentrated in vacuo to give (1R,2S,5S)-N-[(1S)-1- cyano-2-[(3S)-2-oxo-1H-pyrido[3,4-b][1,4]oxazin-3-yl]ethyl]- 3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (60.9 mg, 108 μmol, 40% yield, 99% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.16-11.09 (m, 1 H), 9.34-9.31 (m, 1H), 9.10 (d, J = 8.4 Hz, 1H), 8.16-8.09 (m, 2H), 6.86 (d, J = 4.8 Hz, 1H), 5.19-5.14 (m, 1H), 4.66-4.63 (m, 1H), 4.34 (s, 1H), 4.12 (s, 1H), 3.91-3.87 (m, 1H), 3.68 (d, J = 10.4 Hz, 1H), 2.56-2.53 (m, 1H), 2.40-2.32 (m, 1H), 1.59-1.56 (m, 1H), 1.35 (d, J = 7.6 Hz, 1H), 1.04-0.68 (m, 15H). LC-MS (Method L): R _t = 0.450 min; MS (ESIpos): m/z = 565.3 [M+H] ⁺ . HPLC (Method K): R _t = 1.530 min. Preparation of CPD0191309 Procedure for preparation of 1-(tert-butyl) 2-methyl (2S,4S)-4-acetoxypyrrolidine-1,2- dicarboxylate To a solution of 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (20.0 g, 81.5 mmol, 1.00 eq), 4-dimethylaminopyridine (199 mg, 1.63 mmol, 0.02 eq) and pyridine (12.9 g, 163 mmol, 2.00 eq) in tetrahydrofuran (500 mL) was added acetic anhydride (12.5 g, 122 mmol, 1.50 eq) at 25 °C. After stirring at the same temperature for 1 h, the solution was diluted with mixed solvent of water (300 mL) and hydrochloric acid (300 mL, 1 M in water) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-(tert-butyl) 2-methyl (2S,4S)-4-acetoxypyrrolidine- 1,2-dicarboxylate (22.0 g, 76.6 mmol, 94% yield) as colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 5.18-5.02 (m, 1H), 4.42-4.29 (m, 1H), 3.70-3.63 (m, 3H), 3.64-3.56(m, 1H), 2.10-2.02 (m, 1H), 1.94 (s, 3H), 1.80-1.74(m, 1H), 1.46-1.32 (m, 9H). Procedure for preparation of 1-tert-butyl 2-methyl (2S,4S)-4-acetoxy-5-oxo-pyrrolidine-1,2- dicarboxylate To a solution of sodium periodate (32.8 g, 153 mmol, 2.00 eq) in water (150 mL) was added ruthenium (III) chloridetrihydrate (1.11 g, 5.36 mmol, 0.07 eq) at 0 °C. After stirring at 25 °C for 10 min, a solution of 1-tert-butyl 2-methyl (2S,4S)-4-acetoxypyrrolidine-1,2-dicarboxylate (22.0 g, 76.6 mmol, 1.00 eq) in acetonitrile (150 mL) was added dropwise into the above mixture. After stirring at 25 °C for 12 h, the reaction mixture was filtered, the filter cake was washed with saturated sodium sulfite aqueous solution (100 mL) and ethyl acetate (400 mL). The combined filtrate was extracted with ethyl acetate (300 mL × 2). The combined organic layers were washed with water (500 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 5: 1 to 3: 1) to give 1-(tert-butyl) 2-methyl (2S,4S)-4-acetoxy-5-oxopyrrolidine-1,2-dicarboxylate (5.50 g, 16.4 mmol, 22% yield, 90% purity) as colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 5.42 (t, J = 8.4 Hz, 1H), 4.55 (t, J = 8.4 Hz, 1H), 3.72 (s, 3H), 3.67- 3.64(m, 1H), 2.80-2.77 (m, 1H), 2.08 (s, 3H), 1.43 (s, 9H). LC-MS (Method C): R _t = 0.462 min; MS (ESIpos): m/z = 202.2 [M-100+H] ⁺ . Procedure for preparation of dimethyl (2S,4S)-2-(tert-butoxycarbonylamino)-4-hydroxy- pentanedioate To a solution of 1-(tert-butyl) 2-methyl (2S,4S)-4-acetoxy-5-oxopyrrolidine-1,2-dicarboxylate (8.30 g, 27.6 mmol, 1.00 eq) in methanol (100 mL) was added sodium bicarbonate (4.63 g, 55.1 mmol, 2.00 eq) at 25 °C. After stirring at 25 °C for 12 h, the reaction mixture was filtered. The filter cake was washed with ethyl acetate (200 mL). The combined filtrate was poured into saturated ammonium chloride aqueous solution (200 mL) and extracted with ethyl acetate (300 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 5: 1 to 3: 1) to give dimethyl (2S,4S)-2-(tert-butoxycarbonylamino)-4- hydroxy-pentanedioate (3.9 g, 12.1 mmol, 44% yield, 90% purity) as colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.27 (d, J = 8.2 Hz, 1H), 5.70 (d, J = 6.4 Hz, 1H), 4.23-4.15 (m, 1H), 4.08-3.95 (m, 1H), 3.65-3.59 (m, 6H), 1.99-1.79 (m, 2H), 1.38 (s, 9H). LC-MS (Method C): R _t = 0.426 min; MS (ESIpos): m/z = 192.1 [M-100+H] ⁺ . Procedure for preparation of dimethyl (2S, 4S)-2-((tert-butoxycarbonyl)amino)-4-((3-nitropyridin- 4-yl)oxy)pentanedioate To a solution of dimethyl (2S, 4S)-2-((tert-butoxycarbonyl)amino)-4-hydroxypentanedioate (3.90 g, 13.4 mmol, 1.00 eq) and 4-chloro-3-nitro-pyridine (2.76 g, 17.4 mmol, 1.30 eq) in N,N-dimethylformamide (100 mL) was added potassium carbonate (2.78 g, 20.1 mmol, 1.50 eq). After stirring at 75 °C for 2 h, the mixture was poured into water (30.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (100~200 mesh, Petroleum ether: Ethyl acetate = 1: 0 to 3: 7) to give dimethyl (2S, 4S)-2-((tert-butoxycarbonyl)amino)-4-((3-nitropyridin-4-yl)o xy)pentanedioate (2.70 g, 5.88 mmol, 44% yield, 90% purity) as light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.09 (s, 1H), 8.59 (d, J = 6.0 Hz, 1H), 6.81 (d, J = 5.6 Hz, 1H), 5.46-5.30 (m, 1H), 4.98 (dd, J = 10.4, 2.4 Hz, 1H), 4.73-4.60 (m, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 2.69-2.57 (m, 1H), 2.40-2.29 (m, 1H), 1.35 (s, 9H). LC-MS (Method C): R _t = 0.496 min; MS (ESIpos): m/z = 414.0 [M+H] ⁺ . Procedure for preparation of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-4-hydroxy-3-oxo- 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-2-yl)propanoate To a solution of dimethyl (2S, 4S)-2-((tert-butoxycarbonyl)amino)-4-((3-nitropyridin-4- yl)oxy)pentanedioate (2.70 g, 6.53 mmol, 1.00 eq) in methanol (50.0 mL) was added palladium on carbon (300 mg, 10% purity contained 50% water) at 25 °C. The suspension was degassed under vacuum and purged with hydrogen for 3 times. After stirring at 25 °C for 16 h under hydrogen (15 Psi) atmosphere, the mixture was filtered through a pad of celite. The filter cake was washed with methanol (20.0 mL × 3). The combined organic layers were concentrated to give methyl (S)-2-((tert- butoxycarbonyl)amino)-3-((S)-4-hydroxy-3-oxo-3,4-dihydro-2H- pyrido[4,3-b][1,4]oxazin-2- yl)propanoate (2.4 g, crude) as colorless oil. LC-MS (Method C): R _t = 0.363 min; MS (ESIpos): m/z = 368.1 [M+H] ⁺ . Procedure for preparation of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-3-oxo-3,4- dihydro-2H-pyrido[4,3-b][1,4]oxazin-2-yl)propanoate To a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-4-hydroxy-3-oxo-3, 4-dihydro-2H- pyrido [4,3-b][1,4]oxazin-2-yl)propanoate (2.40 g, 6.53 mmol, 1.00 eq) in mixed solvent of methanol (30.0 mL) and water (3.00 mL) was added sodium hydrosulfite (5.69 g, 32.7 mmol, 5.00 eq) at 20 °C. After stirring at 75 °C for 16 h, the mixture was filtered. The filter cake was washed with methanol (10.0 mL × 3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was partitioned between water (30.0 mL) and ethyl acetate (30.0 mL). The separated organic layers were concentrated to give methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-3-oxo-3,4- dihydro-2H-pyrido[4,3-b][1,4] oxazin-2-yl)propanoate (1.80 g, 5.12 mmol, 78% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.95 (s, 1H), 8.17-8.02 (m, 2H), 7.42 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 5.2 Hz, 1H), 4.73 (dd, J = 9.6, 3.2 Hz, 1H), 4.32-4.19 (m, 1H), 3.61 (s, 3H), 2.29-2.09 (m, 2H), 1.37 (s, 9H). LC-MS (Method C): R _t = 0.380 min; MS (ESIpos): m/z = 352.2 [M+H] ⁺ . Procedure for preparation of Compound 8 - tert-butyl ((S)-1-amino-1-oxo-3-((S)-3-oxo-3,4- dihydro-2H-pyrido[4,3-b][1,4]oxazin-2-yl)propan-2-yl)carbama te A mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-3-oxo-3,4-dihydro- 2H-pyrido[4,3-b] [1,4]oxazin-2-yl)propanoate (1.80 g, 5.12 mmol, 1.00 eq) and ammonia gas (7 M in methanol, 20.0 mL, 27.3 eq) was stirred at 25 °C for 64 h in sealed tube. The mixture was concentrated to give tert-butyl ((S)-1-amino-1-oxo-3-((S)-3-oxo-3,4-dihydro-2H-pyrido[4,3-b] [1,4]oxazin-2-yl)propan-2-yl)carbamate (1.60 g, 4.76 mmol, 92.9% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.91 (s, 1H), 8.17-8.01 (m, 2H), 7.34-7.17 (m, 1H), 7.13-6.77 (m, 3H), 4.84-4.58 (m, 1H), 4.24-3.97 (m, 1H), 2.30-1.95 (m, 2H), 1.36 (s, 9H). Procedure for preparation of tert-butyl ((S)-1-cyano-2-((S)-3-oxo-3,4-dihydro-2H-pyrido[4,3- b][1,4]oxazin-2-yl)ethyl)carbamate To a mixture of tert-butyl ((S)-1-amino-1-oxo-3-((S)-3-oxo-3,4-dihydro-2H-pyrido[4,3-b] [1,4] oxazin-2- yl)propan-2-yl)carbamate (1.60 g, 4.76 mmol, 1.00 eq) in pyridine (20.0 mL) was added trifluoroacetic anhydride (1.20 g, 5.71 mmol, 1.20 eq) at 0 °C. After stirring at 0 °C for 0.5 h, the mixture was poured into water (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~60% (Ethyl acetate: Methanol = 10/1)/ Petroleum ether gradient @ 60 mL/min) to give tert-butyl ((S)- 1-cyano-2-((S)-3-oxo-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin -2-yl)ethyl)carbamate (1.50 g, 4.71 mmol, 99% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.29 (s, 1H), 8.25 (d, J = 5.6 Hz, 1H), 8.17 (s, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.20 (d, J = 6.0 Hz, 1H), 4.99 (dd, J = 8.4, 4.0 Hz, 1H), 4.80-4.64 (m, 1H), 2.48-2.34 (m, 2H), 1.39 (s, 9H). LC-MS (Method C): R _t = 0.380 min; MS (ESIpos): m/z = 319.2 [M+H] ⁺ . A mixture of tert-butyl ((S)-1-cyano-2-((S)-3-oxo-3,4-dihydro-2H-pyrido[4,3-b][1,4]o xazin-2-yl)ethyl) carbamate (200 mg, 0.628 mmol, 1.00 eq) in mixed solvent of hydrochloric acid (4 M in dioxane, 5.00 mL, 31.8 eq) and acetonitrile (5.00 mL) was stirred at 0 °C for 0.5 h. The mixture was concentrated to give (S)-2-amino-3-((S)-3-oxo-3,4-dihydro-2H-pyrido[4,3-b][1,4]ox azin-2-yl)propanenitrile (160 mg, 0.628 mmol, hydrochloric acid salt) as a white solid. Procedure for preparation of CPD0191309 - (1R,2S,5S)-N-((S)-1-cyano-2-((S)-3-oxo-3,4-dihydro- 2H-pyrido[4,3-b][1,4]oxazin-2-yl)ethyl)-3-((S)-3,3-dimethyl- 2-(2,2,2-trifluoroacetamido)butanoyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of (S)-2-amino-3-((S)-3-oxo-3,4-dihydro-2H-pyrido[4,3-b][1,4]ox azin-2-yl)propanenitrile (160 mg, 0.628 mmol, 1.00 eq, hydrochloric acid salt) and (1R,2S,5S)-3-((S)-3,3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxylic acid (206 mg, 0.565 mmol, 0.900 eq) in N,N-dimethylformamide (3.00 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (358 mg, 0.942 mmol, 1.50 eq) and N,N- diisopropylethylamine (325 mg, 2.51 mmol, 4.00 eq) at 25 °C. After stirring at 25 °C for 16 h, the mixture was poured into water (15.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25 mm* 10 μm; mobile phase: [water (FA)-ACN]; B%: 20%-50%, 10 min) to give (1R,2S,5S)-N-((S)-1-cyano-2-((S)-3-oxo-3,4-dihydro- 2H-pyrido[4,3-b][1,4]oxazin-2-yl)ethyl)-3-((S)-3,3-dimethyl- 2-(2,2,2-trifluoroacetamido)butanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (95.2 mg, 0.155 mmol, 25% yield, 92% purity) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.25-11.19 (m, 0.2H), 11.16 (s, 0.8H), 9.34 (d, J = 8.8 Hz, 1H), 9.12 (d, J = 8.0 Hz, 0.8H), 9.09-9.04 (m, 0.2 H), 8.23-8.15 (m, 1H), 8.08-8.10 (m.1H), 7.24-7.10 (m, 0.2H), 7.04 (d, J = 5.6 Hz, 0.8H), 5.20-5.10 (m, 0.8H), 5.03-5.09 (m, 0.2H), 5.02-4.95 (m, 0.2H), 4.83-4.76 (m, 0.8H), 4.45-4.37 (m, 0.2H), 4.34 (d, J = 8.0 Hz, 0.8H), 4.20 (s, 0.2H), 4.13 (s, 0.8H), 3.92-3.85 (m, 1H), 3.71-3.66 (m, 1H), 2.46-2.36 (m, 2H), 1.63-1.48 (m, 1H), 1.39-1.31 (m, 1H), 1.06-0.76 (m, 15H). LC-MS (Method C): R _t = 0.459 min; MS (ESIpos): m/z = 565.3 [M+H] ⁺ . HPLC (Method K): R _t = 1.107 min; HPLC purity: 92%. SFC: dr = 78: 8: 13. Preparation of CPD0220199 Procedure for preparation of 7-hydroxyimidazo[1,2-a]pyrimidin-5(1H)-one A mixture of 1H-imidazol-2-amine; (5.00 g, 18.9 mmol, 1.00 eq, 1/2 sulfuric acid salt), dimethyl propanedioate (5.00 g, 37.8 mmol, 2.00 eq) and sodium methoxide (17.0 g, 94.6 mmol, 5.00 eq, 30% purity in methanol) in methanol (50.0 mL) was stirred at 75 °C for 16 h. After concentration, the residue was suspended into ethyl acetate (100 mL) and stirred at 15 °C for 0.5 h. After filtration, the filter cake was dried to give 7-hydroxyimidazo[1,2-a]pyrimidin-5(1H)-one (10.0 g, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.01 (d, J = 1.6 Hz, 1H), 6.63 (d, J = 1.6 Hz, 1H), 4.02 (s, 1H). Procedure for preparation of 5,7-dichloroimidazo[1,2-a]pyrimidine A mixture of 7-hydroxyimidazo[1,2-a]pyrimidin-5(1H)-one (9.00 g, 59.5 mmol, 1.00 eq) and phosphorus oxychloride (29.7 g, 194 mmol, 3.25 eq) was heated to 90 °C and stirred at this temperature for 3 h. The mixture was concentrated to remove phosphorus oxychloride to give a residue. The residue was diluted with ethyl acetate (100 mL) and water (100 mL), adjusted to pH = 7~8 with sodium bicarbonate solid and extracted with ethyl acetate (100 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 5,7-dichloroimidazo[1,2-a]pyrimidine (2.60 g, 13.8 mmol, 23% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.14 (d, J = 1.6 Hz, 1H), 7.95 (d, J = 1.6 Hz, 1H), 7.80 (s, 1H). Procedure for preparation of 7-chloroimidazo[1,2-a]pyrimidin-5(1H)-one A mixture of 5,7-dichloroimidazo[1,2-a]pyrimidine (2.60 g, 13.8 mmol, 1.00 eq) and sodium hydroxide (1 M in water, 41.5 mL, 3.00 eq) was stirred at100 °C for 0.5 h. Hydrochloric acid (1 M in water) was added to the mixture to adjust pH to 1~2 and extracted with ethyl acetate (100 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 7- chloroimidazo[1,2-a]pyrimidin-5(1H)-one 7 (600 mg, 3.54 mmol, 26% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 13.14 (s, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 5.91 (s, 1H). Procedure for preparation of 7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,2- a]pyrimidin-5(1H)-one To a mixture of 7-chloroimidazo[1,2-a]pyrimidin-5(1H)-one (540 mg, 3.18 mmol, 1.00 eq) and potassium carbonate (880 mg, 6.37 mmol, 2.00 eq) in N,N-dimethylformamide (10.0 mL) was added 2- (chloromethoxy)ethyl-trimethyl-silane (637 mg, 3.82 mmol, 1.20 eq) dropwise at 0 °C. After stirring at 25 °C for 2 h, the mixture was poured into water (50.0 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~27% Ethyl acetate/Petroleum ether gradient @ 45 mL/min) to give 7- chloro-1-((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,2-a]pyr imidin-5(1H)-one (750 mg, 2.50 mmol, 79% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.79 (d, J = 2.8 Hz, 1H), 7.74 (d, J = 2.8 Hz, 1H), 6.03 (s, 1H), 5.45 (s, 2H), 3.60 (t, J = 8.0 Hz, 2H), 0.875 (d, J = 8.0 Hz, 2H), -0.05 (s, 9H). Procedure for preparation of methyl 2-((diphenylmethylene)amino)-2-(5-oxo-1-((2- (trimethylsilyl)ethoxy)methyl)-1,5-dihydroimidazo[1,2-a]pyri midin-7-yl)acetate To a mixture of 7-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)imidazo[1,2-a]p yrimidin-5(1H)-one (700 mg, 2.33 mmol, 1.00 eq) and methyl 2-((diphenylmethylene)amino)acetate (710 mg, 2.80 mmol, 1.20 eq) in N,N-dimethylformamide (10.0 mL) were added potassium phosphate (1.49 g, 7.00 mmol, 3.00 eq) and [2-(2-aminophenyl)phenyl]-chloro-palladium;tritert-butylphos phane (59.8 mg, 0.117 mmol, 0.05 eq) at 15 °C. After stirring at 90 °C for 16 h under nitrogen atmosphere, the mixture was poured into water (50.0 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 60 mL/min) to give methyl 2-((diphenylmethylene)amino)-2-(5-oxo- 1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydroimidazo[1,2- a]pyrimidin-7-yl)acetate (650 mg, 1.26 mmol, 54% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.76-7.72 (m, 1H), 7.71-7.68 (m, 1H), 7.64-7.60 (m, 2H), 7.57-7.41(m, 6H), 7.24-7.14 (m, 2H), 6.11 (s, 1H), 5.39 (s, 2H), 5.00 (s, 1H), 3.63 (s, 3H), 3.58-3.51 (m, 2H), 0.85- 0.78 (m, 2H), -0.12 (s, 9H). Procedure for preparation of 2-((diphenylmethylene)amino)-2-(5-oxo-1-((2- (trimethylsilyl)ethoxy)methyl)-1,5-dihydroimidazo[1,2-a]pyri midin-7-yl)acetamide A mixture of methyl 2-((diphenylmethylene)amino)-2-(5-oxo-1-((2-(trimethylsilyl) ethoxy)methyl)-1,5- dihydroimidazo[1,2-a]pyrimidin-7-yl)acetate (650 mg, 1.26 mmol, 1.00 eq) in ammonia (7 M in methanol, 30 mL, 167 eq) was stirred at 15 °C for 16 h. The mixture was concentrated to give 2- ((diphenylmethylene) amino)-2-(5-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dih ydroimidazo[1,2- a]pyrimidin-7-yl)acetamide (600 mg, 1.20 mmol, crude) as yellow oil. Procedure for preparation of 2-amino-2-(5-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5- dihydroimidazo[1,2-a]pyrimidin-7-yl)acetamide A mixture of 2-((diphenylmethylene)amino)-2-(5-oxo-1-((2-(trimethylsilyl) ethoxy)methyl)-1,5- dihydroimidazo[1,2-a]pyrimidin-7-yl)acetamide (600 mg, 1.20 mmol, crude) in hydrochloric acid (1M in water, 5 mL, 4.18 eq) was stirred at 20 °C for 1 h. The mixture was washed with ethyl acetate (10.0 mL). The separated aqueous phase was adjusted to pH = 7~8 with saturated sodium bicarbonate solution and extracted with ethyl acetate (20.0 mL × 4). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 2-amino-2-(5-oxo-1-((2- (trimethylsilyl)ethoxy)methyl)-1,5-dihydroimidazo[1,2-a]pyri midin-7-yl)acetamide (350 mg, crude) as yellow oil. Procedure for preparation of (1R,2S,5S)-N-(2-amino-2-oxo-1-(5-oxo-1-((2- (trimethylsilyl)ethoxy)methyl)-1,5-dihydroimidazo[1,2-a]pyri midin-7-yl)ethyl)-3-((S)-3,3- dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2- carboxamide To a mixture of (1R,2S,5S)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)b utanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (291 mg, 0.800 mmol) and 2-amino-2-(5-oxo-1-((2- (trimethylsilyl)ethoxy)methyl)-1,5-dihydroimidazo[1,2-a]pyri midin-7-yl)acetamide (300 mg, crude) in N,N-dimethylformamide (10.0 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (507 mg, 1.33 mmol, 1.50 eq) and N,N-diisopropylethylamine (460 mg, 3.56 mmol, 4.00 eq) at 15 °C. After stirring at 15 °C for 16 h, the mixture was poured into water (50.0 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-(5-oxo-1-((2- (trimethylsilyl)ethoxy)methyl)-1,5-dihydroimidazo[1,2-a]pyri midin-7-yl)ethyl)-3-((S)-3,3-dimethyl-2- (2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicycl o[3.1.0]hexane-2-carboxamide (350 mg, 0.491 mmol, 55% yield, 96% purity) as a white solid. To a mixture of (1R,2S,5S)-N-(2-amino-2-oxo-1-(5-oxo-1-((2-(trimethylsilyl)e thoxy)methyl)-1,5- dihydroimidazo[1,2-a]pyrimidin-7-yl)ethyl)-3-((S)-3,3-dimeth yl-2-(2,2,2-trifluoroacetamido)butanoyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (330 mg, 0.483 mmol, 1.00 eq) in dichloromethane (10.0 mL) was added trifluoroacetic acid (5.00 mL) at 15 °C. After stirring at 15 °C for 16 h, the mixture was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~100% (Ethyl acetate ^ methanol=10:1)/Petroleum ether gradient @ 30 mL/min) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-(5- oxo-1,5-dihydroimidazo[1,2-a]pyrimidin-7-yl)ethyl)-3-((S)-3, 3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ] hexane-2-carboxamide (300 mg) as yellow oil. LC-MS (Method C): R _t = 0.500 min; MS (ESIpos): m/z = 554.3 Procedure fo a]pyrimidin-7 3-azabicyclo[ To a mixture of (1R,2S,5S)-N-(2-amino-2-oxo-1-(5-oxo-1,5-dihydroimidazo[1,2- a]pyrimidin-7-yl)ethyl)- 3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (200 mg, 0.361 mmol, 1.00 eq) and trimethylamine (219 mg, 2.17 mmol, 6.00 eq) in dichloromethane (10.0 mL) was added trifluoroacetic anhydride (379 mg, 1.81 mmol, 5.00 eq) at 25 °C. After stirring at 25 °C for 2 h, the mixture was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) and prep-HPLC(column: UniSil 3-100 C18 UItra (150*25mm*3μm); mobile phase: [water(FA)-ACN]; B%: 39%-59%, 7 min) to give (1R,2S,5S)-N- (cyano(5-oxo-1,5-dihydroimidazo[1,2-a]pyrimidin-7-yl)methyl) -3-((S)-3,3-dimethyl-2-(2,2,2- trifluoroacetamido) butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxami de (16.7 mg, 30.6 μmol, 8% yield, 98% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 13.11 (s, 1H), 9.57-9.35 (m, 2H), 7.72-7.55 (m, 2H), 6.08-5.92 (m, 2H), 4.45-4.39 (m, 1H), 4.29-4.38 (m, 1H), 3.98-3.62 (m, 2H), 1.63-1.53 (m, 1H), 1.41-1.21 (m, 1H), 1.08-0.79 (m, 15H). LC-MS (Method C): R _t = 0.793 min; MS (ESIpos): m/z = 536.3 [M+H] ⁺ . HPLC (Method K): R _t = 1.833 min; purity: 98%. Preparation of CPD0277856 Procedure for preparation of 2-[(3-bromo-2-pyridyl)oxymethoxy]ethyl-trimethyl-silane To a solution of 3-bromo-1H-pyridin-2-one (10.0 g, 57.5 mmol, 1.00 eq) in tetrahydrofuran (100 mL) was added sodium hydrogen (4.60 g, 115 mmol, 60% purity, 2.00 eq) in portions at 0 °C under N2 atmosphere. After stirring at 0 °C for 0.5 h, 2-(chloromethoxy)ethyl-trimethyl-silane (19.2 g, 115 mmol, 20.3 mL, 2.00 eq) was added dropwise at 0 °C. After warming to 20 °C, the reaction mixture was stirred for 15.5 h. The reaction mixture was quenched with saturated ammonium chloride solution (300 mL) at 0 °C under N ₂ atmosphere. The reaction mixture was extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate = 1: 1) to give 2-[(3-bromo-2-pyridyl)oxymethoxy]ethyl- trimethyl-silane (9.30 g, 30.6 mmol, 53% yield) as white oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.93 (dd, J = 7.2, 1.6, Hz, 1H), 7.76 (dd, J = 6.4, 1.6 Hz, 1H), 6.21 (t, J = 7.2 Hz, 1H), 5.32 (s, 2H), 3.60-3.56 (m, 2H), 0.89-0.85 (m, 2H), 0.04 (s, 9H). Procedure for preparation of methyl (2S)-3,3-dimethyl-2-[[2-(2-trimethylsilylethoxymethoxy)-3- pyridyl]amino]butanoate To a solution of 2-[(3-bromo-2-pyridyl)oxymethoxy]ethyl-trimethyl-silane (3.00 g, 9.86 mmol, 1.00 eq) in dioxane (30.0 mL) was added methyl (2S)-2-amino-3,3-dimethyl-butanoate (1.43 g, 9.86 mmol, 1.00 eq), tris(dibenzylideneacetone)dipalladium ⁽⁰⁾ (903 mg, 986 μmol, 0.100 eq), ditert-butyl-[2-[2,4,6- tri(propan-2-yl)phenyl]phenyl]phosphane (940 mg, 1.97 mmol, 0.200 eq) and cesium carbonate (19.3 g, 59.2 mmol, 6.00 eq) under N2 atmosphere. The mixture was heated to 100 °C and stirred for 16 h. The reaction mixture was partitioned between water (200 mL) and ethyl acetate (400 mL). The organic phase was separated, washed with brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 5: 1) and concentrated to give methyl (2S)-3,3- dimethyl-2-[[2-(2-trimethylsilylethoxymethoxy)-3-pyridyl]ami no]butanoate (700 mg, 1.90 mmol, 19% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 6.96 (dd, J = 7.2, 1.6 Hz, 1H), 6.31 (dd, J = 7.2, 1.6 Hz, 1H), 6.14 (t, J = 7.2 Hz, 1H), 5.36- 5.25 (m, 3H), 3.83 (d, J = 10.4 Hz, 1H), 3.63 (s, 3H), 3.55 (t, J = 8.0 Hz, 2H), 0.99 (s, 9H), 0.87 - 0.83 (m, 2H), 0.05 (m, 9H). Procedure for preparation of (2S)-3,3-dimethyl-2-[[2-(2 trimethylsilylethoxymethoxy)-3- pyridyl]amino]butanoic acid To a solution of methyl (2S)-3,3-dimethyl-2-[[2-(2-trimethylsilylethoxymethoxy)-3- pyridyl]amino]butanoate (700 mg, 1.90 mmol, 1.00 eq) in mixed solvent of methanol (10.0 mL) and water (2.00 mL) was added lithium hydroxide monohydrate (240 mg, 5.70 mmol, 3.00 eq). After stirring at 20 °C for 16 h, hydrochloride (1M, 15.0 mL) was added to the reaction mixture to adjust pH to 3. The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give (2S)-3,3-dimethyl-2-[[2-(2 trimethylsilylethoxymethoxy)-3-pyridyl]amino]butanoic acid (500 mg, 1.41 mmol, 74% yield) as a green oil without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 6.98 (d, J = 6.8 Hz, 1H), 6.35 (d, J = 6.8 Hz, 1H), 6.19-6.16 (m, 1H), 5.52-5.29 (m, 3H), 3.72 (d, J = 10.0 Hz, 1H), 3.60 (t, J = 8.0 Hz, 2H), 1.05 (s, 9H), 0.90 (t, J = 8.0 Hz, 2H), 0.00 (s, 9H). Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[[2-(2- trimethylsilylethoxymethoxy)-3-pyridyl]amino]butanoyl]-6,6- dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate To a solution of (2S)-3,3-dimethyl-2-[[2-(2-trimethylsilylethoxymethoxy)-3-py ridyl]amino]butanoic acid (400 mg, 1.13 mmol, 1.00 eq) in N,N-dimethylformamide (4.00 mL) were added methyl (1R,2S,5S)-6,6- dimethyl-3azabicyclo[3.1.0]hexane-2-carboxylate (511 mg, 2.48 mmol, 2.20 eq, hydrochloride), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-d imethylazanium;hexafluorophosphate (858 mg, 2.26 mmol, 2.00 eq) and N,N-diethylpropan-2-amine (1.02 g, 7.90 mmol, 1.38 mL, 7.00 eq). After stirring at 20 °C for 6 h, the reaction mixture was partitioned between water (50.0 mL) and ethyl acetate (100 mL). The organic phase was separated, washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 2: 1 to 1: 1) to give methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[[2-(2-trimethylsilylethox ymethoxy)-3- pyridyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxylate (500 mg, 989 μmol, 88% yield) as blue oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 6.97 (dd, J = 6.8, 1.2 Hz, 1H), 6.58-6.56 (m, 1H), 6.15 (t, J = 7.2 Hz, 1H), 5.41 (d, J = 10.8 Hz, 1H), 5.33-5.31 (m, 2H), 4.22 (s, 1H), 4.11-4.05 (m, 1.5H), 3.93-3.88 (m, 1.5H), 3.71 (s, 3H), 3.63-3.52 (m, 2H), 1.64-1.61 (m, 1H), 1.48-1.48 (m, 1H), 1.07-0.97 (m, 12.5H), 0.88 (t, J = 8.0 Hz, 2H), 0.76 (s, 2.5H), 0.08 (s, 9H). Procedure trimethylsilyle azabicyclo[3.1 To a mixture of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[[2-(2-trimethylsilylethox ymethoxy)-3- pyridyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexa ne-2-carboxylate (1.50 g, 2.97 mmol, 1.00 eq) in mixed solvent of methanol (20.0 mL) and water (5.00 mL) was added lithium hydroxide monohydrate (498 mg, 11.9 mmol, 4.00 eq). After stirring at 20 °C for 2 h, the reaction mixture was diluted with water (20.0 mL), concentrated to remove most of methanol. Hydrochloride (1M) was added to adjust pH 3~4. The solution was extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give (1R,2S,5S)-3-[(2S)-3,3- dimethyl-2-[[2-(2-trimethylsilylethoxymethoxy)-3-pyridyl]ami no]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (1.45 g, 2.95 mmol, 99% yield) as a black solid without further purification. LC-MS (Method C): R _t = 0.670 min; MS (ESIpos): m/z = 492.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.64-12.37 (m, 1H), 6.96 (d, J = 6.8 Hz, 1H), 6.55 (d, J = 6.0 Hz, 1H), 6.15 (t, J = 6.8 Hz, 1H), 5.42 (d, J = 11.2 Hz, 1H), 5.31 (s, 2H), 4.13-4.03 (m, 2H), 3.90-3.85 (m, 2H), 3.58 (t, J = 8.0 Hz, 2H), 1.61-1.58 (m, 1H), 1.45-1.44 (m, 1H), 1.07-0.95 (m, 12.5H), 0.89 (t, J = 6.0 Hz, 2H ), 0.74 (s, 2.5H), 0.00 (s, 9H). Procedure for preparation of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2-oxo-1H-pyridin-3- yl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylate To a mixture of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[[2-(2-trimethylsilylethox ymethoxy)-3- pyridyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexa ne-2-carboxylic acid (850 mg, 1.73 mmol, 1.00 eq) in methanol (5.00 mL) was added hydrochloride (12 M, 4.66 mL, 32.3 eq). After stirring at 20 °C for 14 h, the reaction mixture was heated to 50 °C, and stirred for 2 h. The reaction mixture was purified by reversed phase (instrument: 10 g Flash; Column: Welch Ultimate XB_C1820-40μm; eluent A: water (0.5% FA), eluent B: acetonitrile; gradient: 0-50 min 0-100% B; flow 55 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2-oxo- 1H-pyridin-3-yl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxylate (280 mg, 746 μmol, 43% yield) as a green solid. LC-MS (Method C): Rt = 0.550 min; MS (ESIpos): m/z = 376.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.46 (s, 1H), 6.62 (d, J = 6.0 Hz, 1H), 6.49 (d, J = 6.8 Hz, 1H), 6.03 (t, J = 7.2 Hz, 1H), 5.25 (d, J = 10.8 Hz, 1H), 4.17 (s, 1H), 4.00 (d, J = 11.2 Hz, 1H), 3.91-3.83 (m, 2H), 3.66 (s, 3H), 1.59-1.56 (1H), 1.42 (d, J = 7.2 Hz, 1H), 1.02-0.96 (m, 12.5H), 0.72 (s, 2.5H). Procedure for preparation of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2-oxo-1H-pyridin-3- yl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid To a mixture of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2-oxo-1H-pyridin-3-yl)am ino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (280 mg, 746 μmol, 1.00 eq) in mixed solvent of methanol (3.00 mL) and water (1.00 mL) was added lithium hydroxide monohydrate (125 mg, 2.98 mmol, 4.00 eq). After stirring at 20 °C for 16 h, the reaction mixture was quenched with hydrochloride (1M, 3.00 mL) to adjust pH to 3. The resulting precipitate was filtered and washed with water (10.0 ml). The filter cake was dried under reduced pressure to give (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2-oxo-1H- pyridin-3-yl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxylic acid (280 mg, crude) as a yellow solid without further purification. LC-MS (Method C): Rt = 0.538 min; MS (ESIpos): m/z = 362.1[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.47 (s, 1H), 6.62 (d, J = 6.4 Hz, 1H), 6.50-6.48 (m, 1H), 6.03 (t, J = 6.8 Hz, 1H), 4.08 (s, 1H), 4.03 - 3.95 (m, 3H), 1.56-1.52 (m, 1H), 1.41-1.35 (m, 1H), 1.02 - 0.97 (m, 12.5H), 0.71 (s, 2.5H). To a mixture of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2-oxo-1H-pyridin-3-yl)am ino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (280 mg, 775 μmol, 1.00 eq) and 2-amino-2- phthalazin-1-yl-acetamide (256 mg, 930 μmol, 1.20 eq, 2 hydrochloride) in dichloromethane (10.0 mL) was added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]- dimethylazanium;hexafluorophosphate (589 mg, 1.55 mmol, 2.00 eq) and N,N-diethylpropan-2-amine (501 mg, 3.87 mmol, 675 μL, 5.00 eq). After stirring at 20 °C for 16 h, the reaction mixture was concentrated to give a residue. The residue was purified by reversed phase (instrument: 10 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-50 min 0-100% B; flow 55 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -3,3-dimethyl-2-[(2-oxo-1H-pyridin-3- yl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (370 mg, 678 μmol, 88% yield) as a yellow solid. LC-MS (Method C): Rt = 0.738-0.788 min; MS (ESIpos): m/z = 546.3[M+H] ⁺ . To a mixture of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -3,3-dimethyl-2-[(2-oxo- 1H-pyridin-3-yl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (320 mg, 586 μmol, 1.00 eq) in dichloromethane (10.0 mL) was added burgess reagent (280 mg, 1.17 mmol, 2.00 eq). After stirring at 20 °C for 3 h, the reaction mixture was quenched with water (20.0 mL), extracted with dichloromethane (30.0 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by reversed phase (instrument: 10 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-50min 0-100% B; flow 55 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give a residue. The residue was purified by prep-HPLC again (FA condition; column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)- ACN]; B%: 36%-56%,10min) to give (1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]-3-[(2S)-3,3-dime thyl- 2-[(2-oxo-1H-pyridin-3-yl)amino]butanoyl]-6,6-dimethyl-3-aza bicyclo[3.1.0]hexane-2-carboxamide (10.0 mg, 19.0 μmol, 2% yield) as a yellow solid. LC-MS (Method C): Rt = 0.555 min; MS (ESIpos): m/z = 528.2[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.51-11.39 (m, 1H), 10.69 (s, 0.31H), 9.80-9.77 (m, 0.63H), 9.70- 9.67 (m, 0.14H), 9.45 (s, 0.32H), 8.79-8.76 (m, 0.36H), 8.29-8.22 (m, 0.60H), 8.15-8.02 (m, 1.25H), 7.98-7.89 (m, 0.54H), 7.86-7.77 (m, 1.19H), 7.32-7.22 (m, 0.42H), 6.66-6.56 (m, 1H), 6.51-6.43 (m, 1H), 6.05-5.97 (m, 1H), 5.31-5.17 (m, 1H), 4.65 (s, 0.20H), 4.23-4.20 (m, 0.50H), 4.10 (s, 0.20H), 4.03-3.95 (m, 1.50H), 3.94-3.74 (m, 1.50H), 1.71 (s, 0.40H), 1.70-1.62 (m, 0.75H), 1.58-1.56 (m, 0.74H), 1.42 (s, 0.20H), 1.32-1.23 (m, 0.53H), 1.07-0.92 (m, 12H), 0.87-0.84 (m, 1H), 0.80 (s, 1H), 0.70-0.65 (m, 1H). To a solution of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl -butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (5.00 g, 13.6 mmol, 1.00 eq) and 2-amino-2-phthalazin-1- yl-acetamide (3.40 g, 14.3 mmol, 1.05 eq, hydrochloric acid) in N,N-dimethylformamide (40.0 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexaflu orophosphate (6.19 g, 16.3 mmol, 1.20 eq) and N,N-diisopropylethylamine (7.02 g, 54.3 mmol, 4.00 eq). After stirring at 25 °C for 12 h, the reaction mixture was diluted with saturated ammonium chloride (40.0 mL) and extracted with ethyl acetate (40.0 mL × 3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~55% Ethyl acetate/ Petroleum ether; gradient @ 80.0 mL/min) to afford tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-[(2-amino-2-oxo-1-phthalazin-1-yl-et hyl)carbamoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]carb amate (6.35 g, 11.5 mmol, 85% yield) as a yellow solid. LC-MS (Method C): R _t = 0.597 min; MS (ESIpos): m/z = 553.4 Procedure for preparation of tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-[[cyano(phthalazin-1- yl)methyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 3-carbonyl]-2,2-dimethyl- propyl]carbamate To a solution of tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-[(2-amino-2-oxo-1-phthalazin-1-yl-et hyl)carbamoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimet hyl-propyl]carbamate (6.35 g, 11.5 mmol, 1.00 eq) in dichloromethane (40.0 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (4.11 g, 17.2 mmol, 1.50 eq). After stirring at 25 °C for 12 h, the reaction mixture was diluted with saturated sodium bicarbonate (40.0 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~42% Ethyl acetate/ Petroleum ether; gradient @ 55.0 mL/min) to afford tert-butyl N-[(1S)- 1-[(1R,2S,5S)-2-[[cyano(phthalazin-1-yl)methyl]carbamoyl]-6, 6-dimethyl-3-azabicyclo[3.1.0] hexane-3- carbonyl]-2,2-dimethyl-propyl]carbamate (3.94 g, 7.37 mmol, 64% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.72 (s, 0.5H), 9.85-9.75 (m, 0.7H), 9.67-9.64 (m, 0.2H), 9.43 (s, 0.5H), 8.83-8.74 (m, 0.5H), 8.35-8.23 (m, 0.5H), 8.06-7.97 (m, 0.4H), 7.93-7.72 (m,1.7H), 7.37-7.22 (m, 0.4H), 6.80-6.78 (m, 0.4H), 6.68-6.61 (m, 0.4H), 4.31-4.12 (m, 1H), 4.02-3.98 (m, 1H), 3.96-3.82 (m, 2H), 1.67-1.47(m, 2H), 1.46-1.26(m, 9H), 1.09-0.81(m, 15H). LC-MS (Method C): Rt = 0.660 min; MS (ESIpos): m/z = 535.4 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-N- [cyano(phthalazin-1-yl)methyl]-6,6-dimethyl-3-azabicyclo[3.1 .0]hexane-2-carboxamide To a solution of tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-[[cyano(phthalazin-1-yl)methyl]carba moyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl- propyl]carbamate (3.94 g, 7.37 mmol, 1.00 eq) in acetonitrile (15.0 mL) was added hydrochloric acid (4.00 mol/L in dioxane, 15.0 mL). After stirring at 0 °C for 2 h, the mixture was concentrated at 20 °C to give (1R,2S,5S)-3-[(2S)-2-amino-3,3- dimethyl-butanoyl]-N-[cyano(phthalazin-1-yl)methyl]-6,6-dime thyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (3.50 g, 6.90 mmol, 94% yield, 2 hydrochloric acid) as a yellow solid. LC-MS (Method C): R _t = 0.455 min; MS (ESIpos): m/z = 435.2 [M+H] ⁺ . To a solution of 3-methoxycyclobutanecarboxylic acid (53.9 mg, 414 μmol, 1.00 eq), O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (236 mg, 621 μmol, 1.50 eq) and N,N-diisopropylethylamine (214 mg, 1.66 mmol, 4.00 eq) in N,N-dimethylformamide (5.00 mL) was added (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-N-[cyano(p hthalazin-1-yl)methyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (209 mg, 414 μmol, 1.00 eq, 2 hydrochloric acid) at 0 °C. After stirring at 20 °C for 12 h, the mixture was poured into water (30.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 0 to 70: 30) and prep-HPLC (column: Phenomenex C1875*30 mm*3 μm; mobile phase: [water(FA)-ACN]; B%: 32%-62%, 7 min) to give (1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]-3-[(2S)-2-[(3-me thoxycyclobutanecarbonyl)amino]-3,3- dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (92.5 mg, 166 μmol, 40% yield, 98% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.70 (s, 0.4H), 9.82-9.70 (m, 0.8H), 9.65-9.54 (m, 0.2H), 9.42 (s, 0.4H), 8.79-8.74 (m, 0.4H), 8.29-8.23 (m, 0.5H), 8.12-8.03 (m, 1.2H), 8.02-7.95 (m, 0.5H), 7.91-7.71 (m, 2.7H), 7.35-7.25 (m, 0.5H), 4.39-4.29 (m, 1H), 4.26-4.10 (m, 1H), 3.96-3.81 (m, 2H), 3.79-3.61 (m, 1H), 3.12-3.05 (m, 3H), 2.79-2.62 (m, 1H), 2.30-2.11 (m, 2H), 1.96-1.72 (m, 2H), 1.66-1.56 (m, 1H), 1.54-1.28 (m, 1H), 1.09-1.01 (m, 3H), 1.00-0.87 (m, 9H), 0.82-0.74 (m, 3H). LCMS (Method C): R _t = 0.799 min; MS (ESIpos): m/z = 547.4 [M+H] ⁺ . HPLC (Method S): R _t = 1.964 min; purity: 98%. SFC: dr = 64: 36. To a mixture of (3S)-tetrahydrofuran-3-carboxylic acid (500 mg, 4.31 mmol, 1.00 eq) and methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimeth yl-3-azabicyclo[3.1.0]hexane-2- carboxylate (1.67 g, 4.74 mmol, 1.10 eq, 2hydrochlorine) in dichloromethane (5.00 mL) were added benzotriazol-1-yloxy(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (2.46 g, 4.74 mmol, 1.10 eq) and N-methylmorpholine (1.74 g, 17.2 mmol, 1.89 mL, 4.00 eq). After stirring at 25 °C for 16 h, the reaction mixture was partitioned between dichloromethane (20.0 mL) and water (20.0 mL). The organic phase was separated, washed with water (10.0 mL) and brine (10.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~75% Ethyl acetate/Petroleum ethergradient @30 mL/min) to give methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2- [[(3S)-tetrahydrofuran-3-carbonyl]amino]butanoyl]-6,6-dimeth yl-3-azabicyclo[3.1.0]hexane-2- carboxylate (1.30 g, 3.08 mmol, 71% yield, 90% purity) as colorless oil. LC-MS (Method C): R _t = 0.584 min and 0.600 min; MS (ESIpos): m/z = 381.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.05 (d, J = 9.2 Hz, 0.9H), 7.93 (d, J = 9.2 Hz, 0.1H), 4.56 (s, 0.1H), 4.42 (d, J = 9.2 Hz, 0.9H), 4.28 (d, J = 10.0 Hz, 0.1H), 4.20 (s, 0.9H), 3.87-3.75 (m, 3H), 3.70-3.60 (m, 5H), 3.48-3.44 (m, 1H), 3.18-3.08 (m, 1H), 1.98-1.82 (m, 1H), 1.53-1.48 (m, 1H), 1.43-1.40 (m, 1H), 1.08-0.95 (m, 11.4H), 0.86 (s, 1H), 0.84-0.79 (m, 2.7H). Procedure for preparation of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[[(3S)-tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxylic acid A mixture of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[[(3S)-tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxylate (1.30 g, 3.42 mmol, 1.00 eq) in mixed solvent of methanol (2.00 mL) and water (0.20 mL) was added lithium hydroxide monohydrate (430 mg, 10.3 mmol, 3.00 eq). After stirring at 25 °C for 6 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (20.0 mL), washed with ethyl acetate (20.0 mL × 2). Hydrochloric acid (1 M, 10.0 ml) was added to the aqueous phase to adjust pH 3~4. The aqueous phase was extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[[(3S)- tetrahydrofuran-3-carbonyl]amino]butanoyl]-6,6-dimethyl-3-az abicyclo[3.1.0]hexane-2-carboxylic acid (1.10 g, 2.85 mmol, 84% yield, 95% purity) as colorless oil. LC-MS (Method C): R _t = 0.531 min and 0.561 min; MS (ESIpos): m/z = 367.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.5 (br. s, 1H), 8.04 (d, J = 9.2 Hz, 1H), 4.43 (d, J = 9.2 Hz, 1H), 4.12 (s, 1H), 3.85-3.76 (m, 3H), 3.73-3.60 (m, 2H), 3.48-3.44 (m, 1H), 3.16-3.09 (m, 1H), 1.98-1.91 (m, 2H), 1.51-1.48 (m, 1H), 1.41-1.39 (m, 1H), 1.01 (s, 3H), 0.96 (m, 9H), 0.79 (m, 3H). Procedure for purification of tert-butyl N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4-benzoxazin- 2-yl]methyl]ethyl]carbamate A mixture of tert-butyl N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4-benzoxazin-2- yl]methyl]ethyl]carbamate (5.00 g, 14.9 mmol, 1.00 eq) in ethyl acetate (30.00 mL) was heated to 80 °C. After stirring for 10 min, methanol (10.0 mL) was added to the solution above. The mixture was kept at 80 °C and stirred for 10 min, the mixture got clear, and was cooled to 20 °C. The solution was concentrated under reduced pressure, the solid was appeared when concentration. The mixture was stirred at 20 °C, then ethyl acetate (30.0 mL) was added. After stirring at 20 °C for 15 h, the reaction mixture was filtered, the filter cake was washed with ethyl acetate (10.0 mL), dried under reduced pressure to give tert-butyl N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4-benzoxazin-2- yl]methyl]ethyl]carbamate (2.30 g, 6.52 mmol, 44% yield, 95% purity) as a white solid. LC-MS (Method C): R _t = 0.479 min; MS (ESIpos): m/z = 236.0 [M-99] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.70 (s, 1H), 7.24 (s, 1H), 7.06 (s, 1H), 7.11-6.88 (m, 5H), 4.45- 4.44 (m, 1H), 4.18-4.16 (m, 1H), 2.11-2.01 (m, 2H), 1.37 (s, 9H). SFC: de% = 89%. Procedure for preparation of (2S)-2-amino-3-[(2S)-3-oxo-4H-1,4-benzoxazin-2-yl]propanamid e A mixture of tert-butyl N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4-benzoxazin-2- yl]methyl]ethyl]carbamate (2.30 g, 6.86 mmol, 1.00 eq) in hydrogen chloride (4 M in ethyl acetate, 20.6 mL, 12.0 eq) was stirred at 25 °C for 4 h. The reaction mixture was filtered. The filter cake was washed with ethyl acetate (20.0 mL), dried under reduced pressure to give (2S)-2-amino-3-[(2S)-3-oxo-4H-1,4- benzoxazin-2-yl]propanamide (1.90 g, 6.17 mmol, 90% yield, 90% purity, 2hydrochlorine) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.88 (s, 1H), 8.39 (d, J = 3.2 Hz, 2H), 8.04 (s, 1H), 7.63 (s, 1H), 7.06-7.04 (m, 1H), 6.98-6.92 (m, 3H), 4.72 (dd, J = 10.0, 2.8 Hz, 1H), 4.05-3.96 (m, 1H), 2.47-2.42 (m, 1H), 2.25-2.17 (m, 1H). Procedure for preparation of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4- benzoxazin-2-yl]methyl]ethyl]-3-[(2S)-3,3-dimethyl-2-[[(3S)- tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[[(3S)-tetrahydrofuran-3-c arbonyl]amino]butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.10 g, 3.00 mmol, 1.00 eq) and (2S)-2- amino-3-[(2S)-3-oxo-4H-1,4-benzoxazin-2-yl]propanamide (925 mg, 3.00 mmol, 1.00 eq, 2hydrochlorine) in dichloromethane (4.00 mL) were added [dimethylamino(triazolo[4,5-b]pyridin-3- yloxy)methylene]-dimethyl-ammonium;hexafluorophosphate (1.71 g, 4.50 mmol, 1.50 eq) and N,N- diisopropylethylamine (1.94 g, 15.0 mmol, 2.61 mL, 5.00 eq). After stirring at 25 °C for 16 h, the reaction mixture was partitioned between dichloromethane (20.0 mL) and water (10.0 mL). The organic phase was separated, washed with brine (10.0 mL), dried over anhydrous sodium sulfate. filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0~60% Ethyl acetate/methanol ethergradient @ 60 mL/min) to give (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(2S)-3- oxo-4H-1,4-benzoxazin-2-yl]methyl]ethyl]-3-[(2S)-3,3-dimethy l-2-[[(3S)-tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxamide (1.30 g, 2.00 mmol, 67% yield, 90% purity) as a white solid. LC-MS (Method C): R _t = 0.835 min; MS (ESIpos): m/z = 584.3[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.63 (s, 1H), 8.31 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 9.2 Hz, 1H), 7.31 (m, 1H), 7.13 (m, 1H), 6.93-6.85 (m, 4H), 4.58-4.46 (m, 2H), 4.32 (d, J = 9.2 Hz, 1H), 4.19 (s, 1H), 3.81- 3.73 (m, 3H), 3.65- 3.59 (m, 2H), 3.43-3.39 (m, 1H), 3.10-3.06 (m, 1H), 2.24-2.21 (m, 1H), 2.14-2.10 (m, 1H), 1.92-1.88 (m, 2H), 1.47-1.42 (m, 2H), 1.00 (s, 3H), 0.8 (s, 3H), 0.72 (s, 9H). Procedure for preparation of CPD0329792 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-3-oxo-4H-1,4- benzoxazin-2-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-[[(3S)-tetrahy drofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxamide To a solution of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4-benzo xazin-2- yl]methyl]ethyl]-3-[(2S)-3,3-dimethyl-2-[[(3S)-tetrahydrofur an-3-carbonyl]amino]butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0] hexane-2-carboxamide (1.30 g, 2.23 mmol, 1.00 eq) in dichloromethane (4.00 mL) was added burgess reagent (1.06 g, 4.45 mmol, 2.00 eq) at 25 °C. After stirring for 16 h, the reaction mixture was partitioned between dichloromethane (30.0 mL) and water (20.0 mL). The organic phase was separated, washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*40mm* 15 μm; mobile phase: [water(FA)-ACN];B%: 33%- 63%,15min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-3-oxo-4H-1,4-benzoxazin-2 -yl]ethyl]-3-[(2S)- 3,3-dimethyl-2-[[(3S)-tetrahydrofuran-3-carbonyl]amino]butan oyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (580 mg, 1.00 mmol, 45% yield, 98% purity) as a white solid. LC-MS (Method C): R _t = 0.573 min; MS (ESIpos): m/z = 566.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.75 (s, 1H), 9.01 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 9.2 Hz, 1H), 6.95- 6.87 (m, 4H), 5.16-5.10 (m, 1H), 4.54 (dd, J = 10.4 Hz, 2.4 Hz, 1H), 4.29 (d, J = 8.8 Hz, 1H), 4.08 (s, 1H), 3.84-3.72 (m, 3H), 3.69-3.57 (m, 2H), 3.41-3.38 (m.1H), 3.09-3.05 (m, 1H), 2.54 (m, 1H), 2.31- 2.24 (m, 1H), 1.93-1.87 (m, 2H), 1.52 (dd, J= 7.6 Hz, 5.2 Hz, 1H), 1.29 (d, J= 7.61H), 1.01 (s, 3H), 0.80 (s, 3H), 0.73 (s, 9H). SFC: de% = 91%. To a mixture of (3R)-tetrahydrofuran-3-carboxylic acid (500 mg, 4.31 mmol, 1.00 eq) and 4- methylmorpholine (1.74 g, 17.2 mmol, 1.89 mL, 4.00 eq) in dichloromethane (5.00 mL) was added benzotriazol-1-yloxy(tripyrrolidin-1-yl)phosphonium;hexafluo rophosphate (3.36 g, 6.46 mmol, 1.5 eq). After stirring at 25 °C for 10 min, methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (2.06 g, 6.46 mmol, 1.50 eq, hydrogen chloride) was added. The mixture was stirred at 25 °C for 16 h and concentrated under vacuum to give a residue. The residue was diluted with water (30.0 mL), extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with hydrochloric acid (1M), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by reverse phase column (instrument: 80 g Flash; Column: Welch Ultimate XB_C1820-40μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-30 min 0-85% B; flow 45 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[[(3R)-tetrahydrofuran-3-c arbonyl]amino]butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.50 g, 3.94 mmol, 92% yield) as yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.26 (d, J = 9.6 Hz, 1H), 4.57 (d, J = 9.6 Hz, 1H), 4.46 (s, 1H), 3.98-3.90 (m, 4H), 3.89-3.81 (m, 2H), 3.76 (s, 3H), 2.97-2.85 (m, 1H), 2.19-2.07 (m, 2H), 1.56-1.46 (m, 2H), 1.08- 1.03 (m, 12H), 0.89 (s, 3H). Procedure for preparation of ((1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[[(3R)-tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxylic acid A mixture of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[[(3R)-tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxylate (1.00 g, 2.63 mmol, 1.00 eq) and lithium hydroxide (126 mg, 5.26 mmol, 2.00 eq) in mixed solvent of methanol (10.0 mL) and water (1.00 mL) was stirred at 25 °C for 16 h. The mixture was concentrated to give a residue. The residue was purified by reversed phase (instrument: 80 g Flash; Column: Welch Ultimate XB_C1820- 40 μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-10 min 0-60% B; flow 60 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2- [[(3R)-tetrahydrofuran-3-carbonyl]amino]butanoyl]-6,6-dimeth yl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (600 mg, 1.64 mmol, 62% yield) as yellow oil. Procedure for preparation of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4- benzoxazin-2-yl]methyl]ethyl]-3-[(2S)-3,3-dimethyl-2-[[(3R)- tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxamide A mixture of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[[(3R)-tetrahydrofuran-3-c arbonyl]amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (500 mg, 1.36 mmol, 1.00 eq), (2S)-2-amino-3- [(2S)-3-oxo-4H-1,4-benzoxazin-2-yl]propanamide (321 mg, 1.36 mmol, 1.00 eq), N,N- diisopropylethylamine (705 mg, 5.46 mmol, 0.950 mL, 4.00 eq) and [dimethylamino(triazolo[4,5- b]pyridin-3-yloxy)methylene]-dimethyl-ammonium;hexafluoropho sphate (778 mg, 2.05 mmol, 1.50 eq) in dichloromethane (5.00 mL) was stirred 25 °C for 16 h. The mixture was concentrated to give a residue. The residue was purified by reversed phase (instrument: 80 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-10 min 0-60% B; flow 85 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)-N-[(1S)-2- amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4-benzoxazin-2-yl]methyl]eth yl]-3-[(2S)-3,3-dimethyl-2-[[(3R)- tetrahydrofuran-3-carbonyl]amino]butanoyl]-6,6-dimethyl-3-az abicyclo[3.1.0]hexane-2-carboxamide (800 mg, 1.15 mmol, 84% yield, 84% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.62 (s, 1H), 8.30 (d, J = 8.6 Hz, 1H), 7.88 (d, J = 9.2 Hz, 1H), 7.30 (s, 1H), 7.13 (s, 1H), 6.96-6.81 (m, 4H), 4.60-4.53 (m, 1H), 4.52-4.46 (m, 1H), 4.30 (d, J = 9.2 Hz, 1H), 4.18 (s, 1H), 3.84-3.75 (m, 3H), 3.69-3.59 (m, 2H), 3.56-3.49 (m, 1H), 3.13-3.06 (m, 1H), 2.28-2.04 (m, 2H), 1.94-1.82 (m, 2H), 1.53-1.39 (m, 2H), 1.00 (s, 4H), 0.80 (s, 3H), 0.70 (s, 8H). Procedure for preparation of Compound CPD0329793 of (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-3- oxo-4H-1,4-benzoxazin-2-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-[[( 3R)-tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxamide A mixture of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(2S)-3-oxo-4H-1,4-benzo xazin-2-yl]methyl]ethyl]-3- [(2S)-3,3-dimethyl-2-[[(3R)-tetrahydrofuran-3-carbonyl]amino ]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0] hexane-2-carboxamide (500 mg, 856 umol, 1.00 eq) and methoxycarbonyl- (triethylammonio)sulfonyl-azanide (612 mg, 2.57 mmol, 3.00 eq) in dichloromethane (10.0 mL) was stirred at 25 °C for 4 h. The mixture was concentrated in vacuo and was purified by reversed phase reversed phase (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)- ACN];B%: 37%-57%, 9 min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-3-oxo-4H-1,4-benzoxazin-2 - yl]ethyl]-3-[(2S)-3,3-dimethyl-2-[[(3R)-tetrahydrofuran-3-ca rbonyl]amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (363 mg, 0.641 mmol, 75% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.75 (s, 1H), 9.02 (d, J = 8.4 Hz, 1H), 7.89 (br d, J = 8.8 Hz, 1H), 6.98-6.84 (m, 4H), 5.21-5.08 (m, 1H), 4.60-4.51 (m, 1H), 4.29 (d, J = 8.8 Hz, 1H), 4.10 (s, 1H), 3.86- 3.76 (m, 3H), 3.66-3.59 (m, 2H), 3.55-3.49 (m, 1H), 3.12-3.01 (m, 1H), 2.31-2.23 (m, 1H), 1.94-1.73 (m, 2H), 1.59-1.50 (m, 1H), 1.30 (d, J = 7.6 Hz, 1H), 1.01 (s, 3H), 0.81 (s, 3H), 0.71 (s, 9H). LC-MS (Method C): Rt = 0.521 min; MS (ESIpos): m/z = 565.3 [M+H] ⁺ . SFC: dr = 95: 4. Preparation of CPD0277829 Procedure for preparation of N-phenylpyridine-4-carboxamide To a solution of isonicotinic acid (100 g, 812 mmol, 1.00 eq) in tetrahydrofuran (1.50 L) was added 1,1- carbonyldiimidazole (160 g, 987 mmol, 1.21 eq) at 60 °C. After stirring at 60 °C for 2 h, aniline (100 g, 1.07 mol, 98.0 mL, 1.32 eq) was added into the reaction mixture at 60 °C. The mixture was stirred at 60 °C for 12 h. The combined reaction mixture was concentrated in vacuo to give a residue. The residue was triturated with water (2.00 L) at 25 °C for 15 min, followed by filtration. The filter cake was washed with water (1.00 L), and triturated with a solution of petroleum ether and methyl tert-butyl ether (v/v = 10/1, 2.00 L). The suspension was filtered under reduced pressure. The filter cake was dried to give N- phenylpyridine-4-carboxamide (150 g, 757 mmol, 93% yield) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.72 (d, J = 5.6 Hz, 2H), 7.88 (d, J = 6.0 Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.37 (t, J = 8.0 Hz, 2H), 7.18 (t, J = 7.6 Hz, 1H). Procedure for preparation of 3-hydroxy-2-phenyl-3H-pyrrolo[3,4-c]pyridin-1-one To a solution of N-phenylpyridine-4-carboxamide (150 g, 757 mmol, 1.00 eq) in tetrahydrofuran (1.50 L) was added dropwise N-butyllithium (2.50 M, 757 mL, 2.50 eq) at -70 °C under nitrogen atmosphere. The mixture was warmed to 0 °C and stirred for 0.5 h under nitrogen atmosphere. The reaction mixture was cooled to -70 °C, N,N-dimethyl formamide (277 g, 3.78 mol, 291 mL, 5.00 eq) was added dropwise under nitrogen. After stirring at -70 °C for 0.5 h, the reaction mixture was warmed to 0 °C and stirred for 1 h. The mixture was quenched with water (500 mL) at 0 °C. The organic layer was separated, and the aqueous layer was adjusted to pH = 8 with hydrogen chloride (2M). The resulting suspension was filtered under reduced pressure. The filter cake was washed with water (500 mL), and dried under vacuum to give 3-hydroxy-2-phenyl-3H-pyrrolo[3,4-c]pyridin-1-one (100 g, 442 mmol, 58% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.99 (s, 1H), 8.87 (d, J = 5.2 Hz, 1H), 7.78-7.75 (m, 3H), 7.48 (t, J = 5.2 Hz, 2H), 7.27 (t, J = 7.2 Hz, 2H), 7.07 (d, J = 9.6 Hz, 1H), 6.70 (d, J = 9.6 Hz, 1H). Procedure for preparation of pyrido[3,4-d]pyridazin-1-ol To a solution of 3-hydroxy-2-phenyl-3H-pyrrolo[3,4-c]pyridin-1-one (100 g, 442 mmol, 1.00 eq) in isopropanol (1.00 L) was added hydrazine hydrate (103 g, 2.02 mol, 100 mL, 98.0% purity, 4.56 eq) at 20 °C. After stirring at 100 °C for 16 h, the reaction mixture was evaporated under reduced pressure. The mixture was diluted with water (100 mL) and filtered under reduced pressure and filter cake was dried in vacuo to give pyrido[3,4-d]pyridazin-1-ol (57.0 g, 387 mmol, 88% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.94 (br. s, 1 H), 9.32 (d, J = 0.8 Hz, 1H), 8.97 (d, J = 5.6 Hz, 1H), 8.52 (s, 1H), 8.06 (d, J = 5.2 Hz, 1H). Procedure for preparation of 1-chloropyrido[3,4-d]pyridazine To a solution of pyrido[3,4-d]pyridazin-1-ol (5.00 g, 34.0 mmol, 1.00 eq) in toluene (100 mL) was added phosphorus oxychloride (52.1 g, 340 mmol, 31.6 mL, 10.0 eq) and N,N-diisopropylethylamine (13.2 g, 102 mmol, 17.8 mL, 3.00 eq) at 25 °C. The reaction mixture was stirred at 120 °C for 2 h. The reaction mixture was concentrated in vacuo to give a residue. The residue was diluted with ethyl acetate (50.0 mL) and added dropwise into ice-water (100 mL). The mixture was extracted with ethyl acetate (100 mL ´ 5). The combined organic layers were washed with saturated sodium bicarbonate solution (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1-chloropyrido[3,4- d]pyridazine (4.00 g, 24.2 mmol, 71.1% yield) as a yellow solid. LC-MS (Method C): R _t = 0.322 and 0.563 min; MS (ESIpos): m/z = 166.0 [M+H] ⁺ . Procedure for preparation of methyl 2-(benzhydrylideneamino)-2-pyrido[3,4-d]pyridazin-1-yl- acetate To a solution of methyl 2-(benzhydrylideneamino)acetate (4.59 g, 18.1 mmol, 1.50 eq) in acetonitrile (30.0 mL) was added cesium carbonate (5.90 g, 18.1 mmol, 1.50 eq) at 25 °C. After stirring at 25 °C for 10 min, 1-chloropyrido[3,4-d]pyridazine (2.00 g, 12.1 mmol, 1.00 eq) was added at 25 °C. The reaction mixture was stirred at 25 °C for 14 h and filtered under reduced pressure. The filter cake was washed with acetonitrile (20.0 mL). The filtrate was collected to give methyl 2-(benzhydrylideneamino)-2- pyrido[3,4-d]pyridazin-1-yl-acetate (4.62 g, crude, dissolved in acetonitrile (50.0 mL)) as brown liquid. LC-MS (Method C): R _t = 0.759 min; MS (ESIpos): m/z = 383.0 [M+H] ⁺ . Procedure for preparation of methyl 2-amino-2-pyrido[3,4-d]pyridazin-1-yl-acetate To a solution of methyl 2-(benzhydrylideneamino)-2-pyrido[3,4-d]pyridazin-1-yl-aceta te (4.62 g, 12.1 mmol, 1.00 eq) in acetonitrile (50.0 mL) was added hydrogen chloride (4.00 M in 1,4-dioxane, 15.0 mL, 4.97 eq) at 25 °C. The mixture was stirred at 25 °C for 20 min and concentrated in vacuo to give methyl 2-amino-2-pyrido[3,4-d]pyridazin-1-yl-acetate (2.64 g, crude) as a brown solid. Procedure for preparation of methyl 2-(tert-butoxycarbonylamino)-2-pyrido[3,4-d]pyridazin-1-yl- acetate To a solution of methyl 2-amino-2-pyrido[3,4-d]pyridazin-1-yl-acetate (2.64 g, 12.1 mmol, 1.00 eq) in methanol (50.0 mL) were added sodium carbonate (7.69 g, 72.6 mmol, 6.00 eq) and di-tert- butyldicarbonate (7.92 g, 36.3 mmol, 8.34 mL, 3.00 eq) at 25 °C. After stirring at 25 °C for 15 h, the reaction mixture was concentrated to give a residue. The residue was diluted with water (100 mL) and extracted with ethyl acetate (50.0 mL ´ 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 1: 1) to give methyl 2-(tert-butoxycarbonylamino)- 2-pyrido[3,4-d]pyridazin-1-yl-acetate (450 mg, 1.41 mmol, 12% yield) as a yellow solid. Procedure for preparation of tert-butyl N-(2-amino-2-oxo-1-pyrido[3,4-d]pyridazin-1-yl- ethyl)carbamate A mixture of methyl 2-(tert-butoxycarbonylamino)-2-pyrido[3,4-d]pyridazin-1-yl-a cetate (450 mg, 1.41 mmol, 1.00 eq) in ammonia (7.00 M in methanol, 15.0 mL, 74.3 eq) was stirred at 25 °C for 16 h. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 100: 1 then 0: 1) to give tert-butyl N-(2-amino-2-oxo- 1-pyrido[3,4-d]pyridazin-1-yl-ethyl)carbamate (230 mg, 758 μmol, 54% yield) as a brown solid. LC-MS (Method C): R _t = 0.575 min; MS (ESIpos): m/z = 304.1 Procedure for preparation of -amino-2-pyrido[3,4-d]pyridazin-1-yl-acetamide A solution of tert-butyl N-(2-amino-2-oxo-1-pyrido[3,4-d]pyridazin-1-yl-ethyl)carbama te (230 mg, 758 μmol, 1.00 eq) in hydrogen chloride (4.00 M in 1,4-dioxane, 10.0 mL, 52.8 eq) was stirred at 25 °C for 1 h. The mixture was concentrated in vacuo to give 2-amino-2-pyrido[3,4-d]pyridazin-1-yl-acetamide (209 mg, 758 μmol, 100% yield, 2 hydrochloride) as a yellow solid. To a solution of 2-amino-2-pyrido[3,4-d]pyridazin-1-yl-acetamide (209 mg, 756 μmol, 1.00 eq, 2 hydrochloride) in N,N-dimethyl formamide (10.0 mL) were added dropwise N.N-diisopropylethylamine (489 mg, 3.78 mmol, 659 μL, 5.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (575 mg, 1.51 mmol, 2.00 eq) at 0 °C. After stirring at 0 °C for 10 min, (1R,2S,5S)- 6,6-dimethyl-3-[(2S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amin o]butanoyl]-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (265 mg, 756 μmol, 1.00 eq) was added at 0 °C. After stirring at 25 °C for 12 h, the mixture was added into water (50.0 mL) at 0 °C. The solution was extracted with ethyl acetate (15.0 mL ´ 3). The combined organic layers were washed with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 1: 0 to 0: 1) to give (1R,2S,5S)- N-[(1S)-2-amino-2-oxo-1-pyrido[3,4-d]pyridazin-1-yl-ethyl]-6 ,6-dimethyl-3-[(2S)-3-methyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2- carboxamide (105 mg, 196 μmol, 26% yield) as a yellow solid. LC-MS (Method C): R _t = 0.730 min; MS (ESIpos): m/z = 536.2 [M+H] ⁺ . Procedure for preparation of CPD0277829 - (1R,2S,5S)-N-[(S)-cyano(pyrido[3,4-d]pyridazin-1- yl)methyl]-6,6-dimethyl-3-[(2S)-3-methyl-2-[(2,2,2-trifluoro acetyl)amino]butanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-pyrido[3,4-d]pyridazin-1- yl-ethyl]-6,6-dimethyl-3- [(2S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-3-a zabicyclo[3.1.0]hexane-2-carboxamide (105 mg, 196 μmol, 1.00 eq) in dichloromethane (10.0 mL) was added Burgess reagent (140 mg, 588 μmol, 3.00 eq) at 25 °C. After stirring at 25 °C for 12 h, the mixture was quenched with saturated sodium bicarbonate (50.0 mL) solution at 0 °C and extracted with dichloromethane (15.0 mL ´ 3). The combined organic layers were washed with dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate = 1: 2) followed by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN];B%: 36%-66%,10min) to give (1R,2S,5S)-N-[(S)-cyano(pyrido[3,4-d]pyridazin- 1-yl)methyl]-6,6-dimethyl-3-[(2S)-3-methyl-2-[(2,2,2-trifluo roacetyl)amino]butanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxamide (7.24 mg, 13.5 μmol, 7% yield, 96% purity) as a white solid. ¹ H NMR (400 MHz, CD3OD) δ = 8.96 (s, 1 H), 8.82 (d, J = 6.0 Hz, 1H), 8.70 (d, J = 5.6 Hz, 1H), 8.04 (s, 1H), 4.58 (s, 1H), 4.39 (s, 1H), 4.33 (d, J = 9.6 Hz, 1H), 4.04-4.03 (m, 2H), 2.29-2.20 (m, 1H), 1.75- 1.71 (m, 1H), 1.56 (d, J = 7.6 Hz, 1H), 1.13 (s, 3H), 1.02-0.97 (m, 1H). LC-MS (Method L): R _t = 0.562 min; MS (ESIpos): m/z = 518.1 [M+H] ⁺ . HPLC (Method K): R _t = 1.854 min and 1.910 min. Preparation of CPD0277830 Procedure for preparation of N-phenylpyridine-2-carboxamide To a solution of pyridine-2-carboxylic acid (20.0 g, 162 mmol, 1.10 eq), aniline (13.8 g, 148 mmol, 13.5 mL, 1.00 eq), N,N-4-dimethylaminopyridine (1.80 g, 14.8 mmol, 0.100 eq) in dichloromethane (200 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (31.1 g, 162 mmol, 1.10 eq). After stirring at 20 °C for 12 h, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate 300 mL (100 mL × 3). The combined organic layers were washed with brine (300 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate = 1: 0 to 10: 1) to give N-phenylpyridine-2-carboxamide (20.0 g, 101 mmol, 68% yield) as a brown solid. LCMS (Method D): R _t = 1.597 min; MS (ESIpos): m/z =199.1 [M+H] ⁺ . Procedure for preparation of 5-hydroxy-6-phenyl-5H-pyrrolo[3, 4-b]pyridin-7-one To a solution of N-phenylpyridine-2-carboxamide (10.0 g, 50.5 mmol, 1.00 eq) in tetrahydrofuran (100 mL) was added N-butyllithium (2.50 M, 50.5 mL, 2.50 eq) at -78 °C. After stirring at -78 °C for 0.5 h, the reaction mixture was allowed to rise to 0 °C and kept at 0 ° C for 0.1 h. The mixture was cooled to -78 °C and N,N-dimethylformamide (7.38 g, 101 mmol, 7.76 mL, 2.00 eq) was added. The reaction mixture was stirred at -78 °C for 1 h, warmed up to 0 °C and kept at 0 °C for 1.4 h. The reaction mixture was quenched with saturated ammonium chloride (100 mL) at 0 °C, and diluted with water (30.0 mL). The resulting suspension was filtered and the filter cake was concentrated under reduced pressure to give 5-hydroxy-6-phenyl-5H-pyrrolo[3,4-b]pyridin-7-one (5.75 g, 25.4 mmol, 25% yield) as a white solid. LCMS (Method D): R _t = 1.018 min; MS (ESIpos): m/z =227.0 [M+H] ⁺ . Procedure for preparation of pyrido[2, 3-d]pyridazin-8-ol To a solution of 5-hydroxy-6-phenyl-5H-pyrrolo[3, 4-b]pyridin-7-one (5.75 g, 25.4 mmol, 1.00 eq) in acetic acid (60.0 mL) was added hydrazine hydrate (2.18 g, 37.0 mmol, 2.12 mL, 85% purity, 1.46 eq). After stirred at 80 °C for 3 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with ethyl acetate at 20 ^o C for 0.5 h, followed by filtration to give pyrido[2, 3-d]pyridazin-8-ol (3.00 g, 20.4 mmol, 80% yield) as a white solid. LCMS (Method B): R _t = 0.778 min; MS (ESIpos): m/z =148.1 [M+H] ⁺ . Procedure for preparation of 8-chloropyrido[2, 3-d]pyridazine To a solution of pyrido[2, 3-d]pyridazin-8-ol (3.00 g, 20.4 mmol, 1.00 eq) in toluene (30.0 mL) were added diisopropylethylamine (5.27 g, 40.8 mmol, 7.10 mL, 2.00 eq) and phosphorus oxychloride (15.6 g, 102 mmol, 9.47 mL, 5.00 eq). After stirring at 100 °C for 3 h, saturated sodium bicarbonate was added to the reaction mixture to adjust pH = 7. The solution was diluted with water (50.0 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine (60.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8-chloropyrido[2, 3-d]pyridazine (823 mg, crude) as a black brown solid. LCMS (Method B): R _t = 1.063 min; MS (ESIpos): m/z = 166.1 [M+H] ⁺ . Procedure for preparation of methyl 2-(benzhydrylideneamino) -2-pyrido[2, 3-d]pyridazin-8-yl- acetate To a solution of 8-chloropyrido[2, 3-d]pyridazine (823 mg, 4.97 mmol, 1.00 eq) and methyl 2- (benzhydrylideneamino) acetate (1.13 g, 4.47 mmol, 0.900 eq) in N,N-dimethylformamide (15.0 mL) was added cesium carbonate (4.86 g, 14.9 mmol, 3.00 eq). After stirring at 25 °C for 12 h, the reaction mixture was diluted with water (30.0 mL) and extracted with ethyl acetate 90.0 mL (30.0 mL × 3). The combined organic layers were washed with brine (60.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give methyl 2-(benzhydrylideneamino)-2-pyrido[2, 3-d]pyridazin-8-yl-acetate (2.20 g, crude) as brown oil. LCMS (Method F): R _t =2.771 min; MS (ESIpos): m/z = 383.1 [M+H] ⁺ . Procedure for preparation of methyl 2-amino-2-pyrido[2, 3-d]pyridazin-8-yl-acetate To a solution of methyl 2-(benzhydrylideneamino)-2-pyrido[2, 3-d]pyridazin-8-yl-acetate (2.20 g, 5.75 mmol, 1.00 eq) in hydrochloride (4.00 M in methanol, 20.0 mL, 13.9 eq). After stirring at 25 °C for 1 h, the reaction mixture was concentrated in vacuo to give methyl 2-amino-2-pyrido[2, 3-d]pyridazin-8-yl- acetate (1.26 g, crude) as brown oil. LCMS (Method H): R _t = 1.334 min; MS (ESIpos): m/z = 219.1 [M+H] ⁺ . Procedure for preparation of methyl 2-(tert-butoxycarbonylamino) -2-pyrido[2, 3-d]pyridazin-8- yl-acetate To a solution of methyl 2-amino-2-pyrido[2, 3-d]pyridazin-8-yl-acetate (1.26 g, 5.77 mmol, 1.00 eq) in methyl alcohol (15.0 mL) was added triethylamine (1.17 g, 11.6 mmol, 1.61 mL, 2.00 eq). Tert-butyl (2- methylpropan-2-yl)oxycarbonyl carbonate (1.89 g, 8.66 mmol, 1.99 mL, 1.50 eq) was added and the mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate = 1: 0 to 1: 2) to give methyl 2-(tert-butoxycarbonylamino)-2-pyrido[2, 3-d]pyridazin-8-yl-acetate (732 mg, 2.30 mmol, 40% yield) as a yellow solid. LCMS (Method B): R _t = 2.448 min; MS (ESIpos): m/z = 319.1 [M+H] ⁺ . Procedure for preparation of tert-butyl N-(2-amino-2-oxo-1-pyrido[2, 3-d]pyridazin-8-yl-ethyl) carbamate A solution of methyl 2-(tert-butoxycarbonylamino)-2-pyrido[2, 3-d]pyridazin-8-yl-acetate (680 mg, 2.14 mmol, 1.00 eq) in ammonia (7.00 M in methanol, 20.0 mL, 65.5 eq) was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give tert-butyl N-(2-amino-2-oxo-1- pyrido[2, 3-d]pyridazin-8-yl-ethyl) carbamate (647 mg, crude) as brown oil. LCMS (Method B): R _t = 1.519 min; MS (ESIpos): m/z = 304.1 [M+H] ⁺ . Procedure for preparation of 2-amino-2-pyrido[2, 3-d]pyridazin-8-yl-acetamide To a solution of tert-butyl N-(2-amino-2-oxo-1-pyrido[2, 3-d]pyridazin-8-yl-ethyl) carbamate (647 mg, 2.13 mmol, 1.00 eq) in methanol (10.0 mL) was added hydrochloric acid(4.00 M in ethyl acetate, 10.0 mL, 18.8 eq). After stirring at 25 °C for 2 h, the reaction mixture was concentrated under reduced pressure to give 2-amino-2-pyrido[2, 3-d]pyridazin-8-yl-acetamide (433 mg, crude) as a yellow solid. A solution of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-[(2,2,2-trifluoro acetyl)amino]butanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (747 mg, 2.13 mmol, 1.00 eq) and O-(7-azabenzotriazol-1- yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (1.22 g, 3.20 mmol, 1.50 eq) in N,N- dimethylformamide (10.0 mL) was stirred at 25 °C for 0.5 h. Diisopropylethylamine (826 mg, 6.39 mmol, 1.11 mL, 3.00 eq) and 2-amino-2-pyrido[2,3-d]pyridazin-8-yl-acetamide (433 mg, 2.13 mmol, 1.00 eq) were added to the reaction mixture. After stirring at 25 °C for 11.5 h, the reaction mixture was purified by reversed phase HPLC (instrument: 80 g Flash; Column: Welch Ultimate XB_C ₁ 820-40 μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-50 min 0-100% B; flow 60 mL/min; temperature: room temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)-N-[(1S)-2-amino-2-oxo-1-pyrido[2,3- d]pyridazin-8-yl-ethyl]-6, 6-dimethyl-3-[(2S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino] butanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxamide (700 mg, 1.31 mmol, 61% yield) as a yellow solid. LCMS (Method D): R _t = 1.474 min; MS (ESIpos): m/z = 536.1 [M+H] ⁺ . To a solution of (1R, 2S, 5S) -N-[ (1S) -2-amino-2-oxo-1-pyrido[2, 3-d]pyridazin-8-yl-ethyl]-6, 6- dimethyl-3-[(2S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]bu tanoyl]-3-azabicyclo[3.1.0]hexane-2- carboxamide (650 mg, 1.21 mmol, 1.00 eq) in dichloromethane (7.00 mL) was added methoxycarbonyl- (triethylammonio) sulfonyl-azanide (1.45 g, 6.07 mmol, 5.00 eq). After stirring at 25 °C for 4 h, the reaction mixture was quenched with water (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine 120 mL (60.0 mL × 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Waters xbridge 150*25 mm 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 26%- 56%, 11 min) to give (1R,2S,5S)-N-[(S)-cyano(pyrido[2,3-d]pyridazin-8-yl)methyl]- 6,6-dimethyl-3-[(2S)- 3-methyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-3-azabicy clo[3.1.0]hexane-2-carboxamide (150 mg, 0.270 mmol, 22% yield, 93% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 10.67 (br. s, 1H), 9.93 (d, J = 7.6 Hz, 1H), 9.84-9.70 (m, 0.2H), 9.66- 9.58 (m, 0.2H), 9.49 (s, 1H), 9.40-9.34 (m, 0.3H), 8.87 (dd, J = 4.4, 1.6 Hz, 1H), 8.76-8.70 (m, 0.2H), 8.17-8.12 (m, 0.2H), 8.10 (dd, J = 8.0, 1.6 Hz, 1H), 8.00 (s, 1H), 7.77 (dd, J = 8.0, 4.4 Hz, 1H), 7.22- 7.13 (m, 0.2H), 4.34-4.31 (m, 0.2H), 4.30 (s, 1H), 4.14 (d, J = 8.4 Hz, 1H), 3.98-3.90 (m, 1H), 3.86 (d, J = 10.4 Hz, 1.6H), 2.24-2.11 (m, 1H), 1.64 (d, J = 5.2 Hz, 1H), 1.61-1.58 (m, 1H), 1.55-1.48 (m, 0.3H), 1.36 (d, J = 7.2 Hz, 0.2H), 1.28-1.20 (m, 0.5H), 1.07 (s, 3H), 0.98-0.94 (m, 1H), 0.93 - 0.88 (m, 10H), 0.82 (d, J = 6.8 Hz, 1H). LCMS (Method C): R _t = 1.481 min; MS (ESIpos): m/z = 518.3 [M+H] ⁺ . To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoic acid (6.00 g, 27.6 mmol, 1.00 eq) in dichloromethane (100 mL) was added bis(2-oxo-3-oxazolidinyl)phosphinic chloride (8.44 g, 33.1 mmol, 1.20 eq). After stirring at 20 °C for 0.5 h, N,N- diisopropylethylamine (10.7 g, 82.9 mmol, 14.4 mL, 3.00 eq) and methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (5.68 g, 27.6 mmol, 1.00 eq, hydrochloride) were added into the mixture. The mixture was stirred at 20 °C for 15.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ethergradient @ 90 mL/min) and concentrated to give methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-methyl-but anoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (6.80 g, 18.4 mmol, 67% yield) as a colorless oil. LCMS (Method L): Rt = 1.725 min; MS (ESIpos): m/z = 269.4 [M-99] ⁺ , 313.1 [M-55] ⁺ , 369.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.09-7.05 (m, 1H), 4.18 (s, 1H), 4.07-3.97 (m, 1H), 3.86-3.73 (m, 2H), 3.64 (s, 3H), 1.93-1.80 (m, 1H), 1.58-1.48 (m, 1H), 1.44-1.39 (m, 1H), 1.38-1.27 (m, 9H), 1.05-0.96 (m, 3H), 0.93-0.81 (m, 9H). Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-2-amino-3-methyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate A solution of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-methyl-but anoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylate (6.80 g, 18.5 mmol, 1.00 eq) in hydrochloride (4M in ethyl acetate, 50.0 mL) was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give methyl (1R,2S,5S)-3-[(2S)-2-amino-3-methyl-butanoyl]-6,6-dimethyl-3 - azabicyclo[3.1.0]hexane-2-carboxylate (5.30 g, crude) as a white solid. LC-MS (Method L): Rt = 0.786 min; MS (ESIpos): m/z = 269.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.33 (br. s, 2H), 4.25 (s, 1H), 3.94 (t, J = 4.8 Hz, 1H), 3.81-3.71 (m, 2H), 3.69-3.62 (m, 3H), 2.13 (dd, J = 12.4, 6.8 Hz, 1H), 1.58 (dd, J = 7.2, 4.8 Hz, 1H), 1.48 (d, J = 7.6 Hz, 1H), 1.06-0.99 (m, 6H), 0.91 (s, 6H). Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-2-[(3,3- difluorocyclobutanecarbonyl)amino]-3-methyl-butanoyl]-6,6-di methyl-3- azabicyclo[3.1.0]hexane-2-carboxylate To a solution of 3,3-difluorocyclobutanecarboxylic acid (2.03 g, 14.9 mmol, 1.00 eq) in dichloromethane (60.0 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (8.50 g, 22.4 mmol, 1.50 eq). After stirring at 20 °C for 0.5 h, methyl (1R,2S,5S)-3-[(2S)-2-amino-3- methyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-ca rboxylate (4.00 g, 14.9 mmol, 1.00 eq) and N,N- diisopropylethylamine (5.78 g, 44.7 mmol, 7.79 mL, 3.00 eq) were added into the mixture. The reaction mixture was stirred at 20 °C for 15.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~40% Ethyl acetate/Petroleum ethergradient @ 60 mL/min) and concentrated to give methyl (1R,2S,5S)-3-[(2S)-2-[(3,3- difluorocyclobutanecarbonyl)amino]-3-methyl-butanoyl]-6,6-di methyl-3-azabicyclo[3.1.0]hexane-2- carboxylate (4.16 g, 10.8 mmol, 72% yield) as a colorless solid. LC-MS (Method L): Rt = 1.556 min; MS (ESIpos): m/z = 387.5 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.34 (br. d, J = 8.4 Hz, 1H), 4.23-4.12 (m, 2H), 3.94 (d, J = 10.4 Hz, 1H), 3.79 (dd, J = 10.4, 5.2 Hz, 1H), 3.65 (s, 3H), 3.01-2.89 (m, 1H), 2.73-2.58 (m, 4H), 1.97-1.86 (m, 1H), 1.58-1.48 (m, 1H), 1.42 (d, J = 7.6 Hz, 1H), 1.01 (s, 3H), 0.94-0.80 (m, 9H). Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino ]-3- methyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-ca rboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino ]-3-methyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyla te (4.10 g, 10.6 mmol, 1.00 eq) in mixed solvent of water (15.0 mL) and methanol (15.0 mL) was added lithium hydroxide monohydrate (1.34 g, 31.8 mmol, 3.00 eq). After stirring at 20 °C for 2 h, the reaction mixture was concentrated under reduced pressure to remove most of the organic solvent. The resulting residue was purified by reversed phase (Instrument: 300 g Flash; Column: Welch Ultimate XB C1820-40μm; eluent A: water (0.05% FA), eluent B: acetonitrile; gradient: 0-20 min 0-65% B; flow 75 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino ]-3- methyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxylic acid (3.3 g, 8.86 mmol, 84% yield) as a light yellow solid. LC-MS (Method L): Rt = 1.654 min; MS (ESIpos): m/z = 373.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.88-12.46 (m, 1H), 8.35-8.29 (m, 1H), 4.22-4.13 (m, 1H), 4.12- 4.07 (m, 1H), 3.96-3.88 (m, 1H), 3.81-3.72 (m, 1H), 2.95 (dt, J = 8.4, 3.6 Hz, 1H), 2.74-2.58 (m, 4H), 2.01-1.86 (m, 1H), 1.51 (dd, J = 7.2, 5.6 Hz, 1H), 1.40 (d, J = 7.6 Hz, 1H), 1.03-0.99 (m, 3H), 0.91-0.87 (m, 3H), 0.87-0.84 (m, 3H), 0.83-0.79 (m, 3H). Procedure for preparation of [(3,3-difluorocyclobutanecarbon azabicyclo[3.1.0]hexane-2-carbo To a mixture of 2-amino-2-phthalazin-1-yl-acetamide (887 mg, 3.22 mmol, 1.20 eq, 2 hydrochloride) and (1R,2S,5S)-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino ]-3-methyl-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (1.00 g, 2.69 mmol, 1.00 eq) in dichloromethane (10.0 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (1.53 g, 4.03 mmol, 1.50 eq) and N,N-diisopropylethylamine (1.74 g, 13.4 mmol, 2.34 mL, 5.00 eq). After stirring at 20 °C for 16 h, the reaction mixture was diluted with dichloromethane (100 mL), washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 0 to 0: 1) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -2-[(3,3- difluorocyclobutanecarbonyl)amino]-3-methyl-butanoyl]-6,6-di methyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (1.9 g, crude) as yellow oil. LC-MS (Method C): Rt = 0.508 MS (ESIpos): m/z = 557.3[M+H] ⁺ . To a mixture of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -2-[(3,3- difluorocyclobutanecarbonyl)amino]-3-methyl-butanoyl]-6,6-di methyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (1.60 g, 2.87 mmol, 1.00 eq) in dichloromethane (15.0 mL) was added burgess reagent (2.06 g, 8.62 mmol, 3.00 eq). After stirring at 20 °C for 16 h, the reaction mixture was diluted with dichloromethane (50.0 mL), washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 0 to 1: 2) and concentrated to give a crude product (1.2 g, crude). The crude product (500 mg, crude) was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10 μm; mobile phase: [water (FA)-ACN]; B%: 40%-60%,10min) to give (1R,2S,5S)-N- [cyano(phthalazin-1-yl)methyl]-3-[(2S)-2-[(3,3-difluorocyclo butanecarbonyl)amino]-3-methyl-butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (180 mg, 334 μmol, 12% yield) as a yellow solid. LC-MS (Method C): Rt = 0.570 min; MS (ESIpos): m/z = 539.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.74 (s, 0.5H), 9.77-9.74 (m, 0.7H), 9.66 (d, J = 8.8 Hz, 0.2H), 9.44 (s, 0.5H), 8.79-8.77 (m, 0.5H), 8.46 (d, J = 8.0 Hz, 0.5H), 8.32-8.25 (m, 1H), 8.12-8.06 (m, 1.3H), 8.02- 7.98 (m, 0.5H), 7.94-7.91 (m, 0.3H), 7.86-7.76 (m, 1.6H), 7.31-7.27 (m, 0.4H), 4.28-4.22 (m, 1H), 4.18- 4.10 (m, 1H), 3.95-3.83 (m, 2H), 3.01-2.89 (m, 1H), 2.73-2.54 (m, 4H), 2.07-1.87 (m, 1H), 1.65-1.62 (m, 0.7H), 1.57-1.51 (m, 1H), 1.33-1.31 (m, 0.3H), 1.04-0.74 (m, 12H). Preparation of CPD0279192 Procedure for preparation of (1R,2S,5S)-N-[(1S)-2-amino-1-[[(2S)-6-fluoro-3-oxo-4H-1,4- benzoxazin-2-yl]methyl]-2-oxo-ethyl]-6,6-dimethyl-3-[(2S)-3- methyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2- carboxamide To a mixture of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-[(2,2,2-trifluoro acetyl)amino] butanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (300 mg, 0.770 mmol, 90% purity, 1.00 eq), (2S)-2-amino-3- [(2S)-6-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]propanamide (223 mg, 0.770 mmol, 1.00 eq, HCl) and N,N-diisopropylethylamine (298 mg, 2.31 mmol, 3.00 eq) in N,N-dimethylformamide (5.00 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexaflu orophosphate (351 mg, 0.924 mmol, 1.20 eq) at 25 °C. After stirring at 25°C for 12 h, the mixture was poured into water (30.0 mL) and extracted with ethyl acetate (15.0 mL × 3). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 60~100% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to give (1R,2S,5S)-N-[(1S)-2-amino-1-[[(2S)-6-fluoro-3-oxo-4H-1,4-be nzoxazin-2-yl]methyl]-2- oxo-ethyl]-6,6-dimethyl-3-[(2S)-3-methyl-2-[(2,2,2-trifluoro acetyl)amino]butanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxamide (400 mg, 0.614 mmol, 79% yield, 90% purity) as colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.74 (s, 1H), 9.75 (d, J = 7.6 Hz, 1H), 8.36 (d, J = 8.6 Hz, 1H), 7.32 (s, 1H), 7.12 (s, 1H), 6.93-6.85 (m, 1H), 6.79-6.64 (m, 2H), 4.58-4.43 (m, 2H), 4.21 (s, 1H), 4.07-4.03 (m, 1H), 3.87-3.76 (m, 2H), 2.23-2.04 (m, 2H), 1.89-1.74 (m, 1H), 1.53-1.41 (m, 2H), 1.01 (s, 3H), 0.85 (s, 3H), 0.79-0.74 (m, 6H). LC-MS (Method L): R _t = 0.547 min; MS (ESIpos): m/z = 586.2 [M+H] ⁺ . A mixture of (1R,2S,5S)-N-[(1S)-2-amino-1-[[(2S)-6-fluoro-3-oxo-4H-1,4-be nzoxazin-2-yl] methyl]-2- oxo-ethyl]-6,6-dimethyl-3-[(2S)-3-methyl-2-[(2,2,2-trifluoro acetyl)amino]butanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxamide (350 mg, 0.537 mmol, 90% purity, 1.00 eq) and methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (256 mg, 1.08 mmol, 2.00 eq) in dichloromethane (5.00 mL) was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuum and purified by prep-HPLC (column: Phenomenex C1875*30mm*3 μm; mobile phase: [water(FA)-ACN]; B%: 40%- 70%, 7 min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-6-fluoro-3-oxo-4H-1,4-ben zoxazin-2-yl] ethyl]- 6,6-dimethyl-3-[(2S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amin o]butanoyl]-3-azabicyclo[3.1.0]hexane-2- carboxamide (220 mg, 0.387 mmol, 71% yield, 99% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.87 (s, 1H), 9.80 (s, 1H), 9.05 (d, J = 8.2 Hz, 1H), 6.98-6.89 (m, 1H), 6.79-6.74 (m, 1H), 6.72-6.65 (m, 1H), 5.12-5.06 (m, 1H), 4.58-4.51 (m, 1H), 4.24-3.98 (m, 2H), 3.92-3.74 (m, 2H), 2.48-2.43 (m, 1H), 2.36-2.23 (m, 1H), 1.93-1.78 (m, 1H), 1.63-1.51 (m, 1H), 1.33 (d, J = 7.6 Hz, 1H), 1.02 (s, 3H), 0.85 (s, 3H), 0.81-0.76 (m, 6H). LC-MS (Method C): R _t = 0.898 min; MS (ESIpos): m/z = 568.3 [M+H] ⁺ . HPLC (Method M): R _t = 2.176 min; purity: 99%. SFC: de% = 82%. Preparation of CPD0279194 Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino ]-3- (3-pyridyl)propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane -2-carboxylate To a solution of 3,3-difluorocyclobutanecarboxylic acid (846 mg, 6.22 mmol, 1.00 eq) and methyl (1R,2S,5S)-3-[(2S)-2-amino-3-(3-pyridyl)propanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxylate (2.20 g, 6.22 mmol, 1.00 eq, hydrochloric acid) in N,N-dimethylformamide (20.0 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexaflu orophosphate (2.84 g, 7.46 mmol, 1.20 eq) and N,N-diisopropylethylamine (3.21 g, 24.9 mmol, 4.33 mL, 4.00 eq). After stirring at 25 °C for 16 h, the reaction mixture was diluted with saturated ammonium chloride (40.0 mL) and extracted with ethyl acetate (40.0 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash column chromatography (ISCO®;20 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether; gradient @45 mL/min) to afford methyl (1R,2S,5S)-3-[(2S)-2-[(3,3- difluorocyclobutanecarbonyl)amino]-3-(3-pyridyl)propanoyl]-6 ,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylate (2.43 g, 5.58 mmol, 90% yield) as yellow oil. LC-MS (Method C): R _t = 0.494 min; MS (ESIpos): m/z = 436.0 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino ]-3- (3-pyridyl)propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane -2-carboxylic acid To a mixture of methyl (1R,2S,5S)-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino ]-3-(3- pyridyl)propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylate (2.43 g, 5.58 mmol, 1.00 eq) in methanol (30.0 mL) was added a solution of lithium hydroxide (937 g, 22.3 mmol, 4.00 eq) in water (30.0 mL). After stirring at 20 °C for 12 h, the reaction mixture was adjusted to pH~7 with hydrochloric acid (1 M in water) and extracted with ethyl acetate (40.0 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed flash (Instrument: 80 g Flash; Column: Welch Ultimate XB_C1820-40μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-15 min 12-60% B; flow 85 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to afford (1R,2S,5S)-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino ]-3-(3-pyridyl)propanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (301 mg, 714 μmol, 13% yield) as a yellow gum. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.50-8.40 (m, 3H), 7.68-7.86 (m, 1H), 7.28-7.25 (m, 1H), 4.70-4.64 (m, 1H), 4.11 (s, 1H), 3.77-3.76 (m, 1H), 3.47-3.41 (m, 3H), 3.00-2.61 (m, 4H), 2.38-2.32 (m, 1H), 1.52-1.48 (m, 1H), 1.42-1.37 (m, 1H), 1.01(s, 3H), 0.84 (s, 3H). LC-MS (Method C): R _t = 0.497 min; MS (ESIpos): m/z = 422.0 Procedure for preparation of CPD0279194 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-6-fluoro-3-oxo- 4H-1,4-benzoxazin-2-yl]ethyl]-3-[(2S)-2-[(3,3-difluorocyclob utanecarbonyl) amino]-3-(3- pyridyl)propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide To a solution of (2S)-2-amino-3-[(2S)-6-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]p ropanenitrile (110 mg, 261 μmol, 1.00 eq) and (2S)-2-amino-3-[(2S)-6-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]p ropanenitrile (98.2 mg, 418 μmol, 1.60 eq) in dichloromethane (5.00 mL) were added benzotriazol-1- yloxy(tripyrrolidin-1-yl)phosphanium hexafluorophosphate (217 mg, 418 μmol, 1.60 eq) and N- methylmorpholine (105 mg, 1.04 mmol, 4.00 eq). After stirring at 25 °C for 16 h, the reaction mixture was diluted with saturated ammonium chloride (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 150*25mm*3 μm; mobile phase: [water(formic acid)- acetonitrile];B%: 21.0%-51.0%, 10 min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-6-fluoro-3-oxo-4H- 1,4-benzoxazin-2-yl]ethyl]-3-[(2S)-2-[(3,3-difluorocyclobuta necarbonyl) amino]-3-(3-pyridyl)propanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (99.1 mg, 152 μmol, 58% yield, 98% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.91 (s, 1H), 9.00 (d, J = 8.0 Hz, 1H), 8.60-8.50 (m, 3H), 7.99-7.92 (m, 1H), 7.63-7.59 (m, 1H), 6.97-6.92 (m, 1H), 6.75-6.65 (m, 2H), 5.08-5.02 (m, 1H), 4.75-4.64 (m, 1H), 4.63-4.58 (m, 1H), 4.11 (s, 1H), 3.86-3.71 (m, 3H), 3.62-3.52 (m, 1H), 2.86-2.78 (m, 2H), 2.64-2.59 (m, 2H), 2.58-2.54 (m, 2H), 2.31-2.28 (m, 1H), 1.55-1.52 (m, 1H), 1.34-1.32 (m, 1H), 1.02 (s, 3H), 0.84 (s, 1H). LC-MS (Method C): R _t = 0.532 min; MS (ESIpos): m/z = 639.4 [M+H] ⁺ . SFC: dr = 81: 8: 7. HPLC (Method S): R _t = 2.358 min; purity: 98%. To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoic acid (1.00 g, 4.60 mmol, 1 eq), ethyl (3S,3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole -3-carboxylate (1.11 g, 5.06 mmol, 1.1 eq, HCl salt) in N,N-dimethylformamide (20 mL) were added 1-hydroxybenzotriazole (933 mg, 6.90 mmol, 1.5 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (1.32 g, 6.90 mmol, 1.5 eq) and N,N-diisopropylethylamine (1.78 g, 13.8 mmol, 2.41 mL, 3 eq) at 25 °C. After stirring at 25°C for 16 hours, the mixture was diluted with water (80 mL), extracted with ethyl acetate (40 mL ´ 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give ethyl (3S,3aS,6aR)-2-[(2S)-2- (tert-butoxycarbonylamino)-3-methyl-butanoyl]-3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]pyrrole-3- carboxylate (1.76 g, crude) as colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ = 8.02 (s, 1H), 5.23 (d, J = 5.6 Hz, 1H), 4.38-4.32 (m, 1H), 4.28 (dd, J = 9.2, 6.0 Hz, 1H), 4.17-4.08 (m, 2H), 3.82 (dd, J = 10.4, 2.4 Hz, 1H), 3.73-3.63 (m, 1H), 2.82-2.71 (m, 1H), 2.70-2.61 (m, 1H), 2.02-1.78 (m, 4H), 1.61-1.49 (m, 2H), 1.49-1.37 (m, 12H), 1.02 (d, J = 6.4 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H). Procedure for preparation of ethyl (3S, 3aS, 6aR)-2-[(2S)-2-amino-3-methyl-butanoyl]-3, 3a, 4, 5, 6, 6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate To a solution of ethyl (3S,3aS,6aR)-2-[(2S)-2-(tert-butoxycarbonylamino)-3-methyl-b utanoyl]- 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylat e (1.76 g, 4.60 mmol, 1 eq) in dioxane (10 mL) was added hydrochloric acid (10 mL, 4M in dioxane) at 25 °C. After stirring at 25 °C for 16 hours, the mixture was concentrated under reduced pressure to give ethyl (3S,3aS,6aR)-2-[(2S)-2- amino-3-methyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopen ta[c]pyrrole-3-carboxylate (1.47 g, crude, HCl salt) as colorless gum. Procedure for preparation of ethyl (3S, 3aS, 6aR)-2-[(2S)-2-(2, 2-difluoropropanoylamino)-3- methyl-butanoyl]-3, 3a, 4, 5, 6, 6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate To a solution of ethyl (3S,3aS,6aR)-2-[(2S)-2-amino-3-methyl-butanoyl]-3,3a,4,5,6,6 a-hexahydro-1H- cyclopenta[c]pyrrole-3-carboxylate (0.50 g, 1.57 mmol, 1 eq, HCl salt) in N,N-dimethylformamide (10 mL) were added 2,2-difluoropropanoic acid (259 mg, 2.35 mmol, 1.5 eq), 1-(3-dimethylaminopropyl)-3- ethylcarbodiimidehydrochloride (601 mg, 3.14 mmol, 2 eq) and 1-hydroxybenzotriazole (424 mg, 3.14 mmol, 2 eq), trimethylamine (476 mg, 4.70 mmol, 0.655 mL, 3 eq) at 25 °C. After stirring at 25 °C for 16 hours, the mixture was diluted with water (50 mL), extracted with ethyl acetate (20 mL ´ 2). The combined layer was concentrated under reduced pressure to give a residue. The residue was purified by Combi-Flash (Petroleum ether: Ethyl acetate = 10: 1 to 5: 1) to give ethyl (3S,3aS,6aR)-2-[(2S)-2- (2,2-difluoropropanoylamino)-3-methyl-butanoyl]-3,3a,4,5,6,6 a-hexahydro-1H-cyclopenta[c]pyrrole-3- carboxylate (0.380 g, 1.01 mmol, 65% yield) as colorless gum. LC-MS (Method C): R _t = 0.960 min; MS (ESIpos): m/z = 375.3 [M+H] ⁺ _. Procedure for preparation of 3S,3aS,6aR)-2-[(2S)-2-(2,2-difluoropropanoylamino)-3-methyl- butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3- carboxylic acid To a mixture of ethyl (3S,3aS,6aR)-2-[(2S)-2-(2,2-difluoropropanoylamino)-3-methyl -butanoyl]- 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylat e (0.35 g, 0.935 mmol, 1 eq) in mixed solvent of ethanol (5 mL) and tetrahydrofuran (5 mL) was added a solution of lithium hydroxide water complex (78.5 mg, 1.87 mmol, 2 eq) in water (5.00 mL) at 25 °C. After stirring at 25 °C for 16 hours, the mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL). Hydrochloric acid (1M) was added to the aqueous phase to adjust pH~1. The solution was extracted with ethyl acetate (20 mL ´ 3). The combined organic layers were concentrated under reduced pressure to give (3S,3aS,6aR)-2- [(2S)-2-(2,2-difluoropropanoylamino)-3-methyl-butanoyl]-3,3a ,4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrole-3-carboxylic acid (200 mg, 0.577 mmol, 62% yield) as yellow oil. LC-MS (Method C): R _t = 0.623 min; MS (ESIpos): m/z = 347.2 [M+H] ⁺ _. Procedure for preparation of (3S,3aS,6aR)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-2-[(2 S)-2- (2,2-difluoropropanoylamino)-3-methyl-butanoyl]-3,3a,4,5,6,6 a-hexahydro-1H- cyclopenta[c]pyrrole-3-carboxamide To a mixture of (3S,3aS,6aR)-2-[(2S)-2-(2,2-difluoropropanoylamino)-3-methyl -butanoyl]- 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (0.100 g, 0.289 mmol, 1 eq) in N,N- dimethylformamide (2 mL) were added 2-amino-2-phthalazin-1-yl-acetamide (82.7 mg, 0.347 mmol, 1.2 eq, HCl salt), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (111 mg, 0.577 mmol, 2 eq), 1-hydroxybenzotriazole (78.0 mg, 0.577 mmol, 2 eq) and N,N-diisopropylethylamine (112 mg, 0.866 mmol, 0.15 mL, 3 eq) at 0 °C. After stirring at 25 °C for 16 hours, the mixture was diluted with water (20 mL), extracted with ethyl acetate (15 mL ´ 2). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative-HPLC (column: Boston Green ODS 150*30mm*5 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 23%-39%, 14min) to give (3S,3aS,6aR)-N-(2-amino-2- oxo-1-phthalazin-1-yl-ethyl)-2-[(2S)-2-(2,2-difluoropropanoy lamino)-3-methyl-butanoyl]-3,3a,4,5,6,6a- hexahydro-1H-cyclopenta [c]pyrrole-3-carboxamide (100 mg, 0.188 mmol, 65% yield) as a yellow solid. LC-MS (Method C): R _t = 0.844 min; MS (ESIpos): m/z = 531.3 [M+H] ⁺ . To a mixture of (3S,3aS,6aR)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-2-[(2 S)-2-(2,2- difluoropropanoylamino)-3-methyl-butanoyl]-3,3a,4,5,6,6a-hex ahydro-1H-cyclopenta[c]pyrrole-3- carboxamide (100 mg, 0.188 mmol, 1.00 eq) in dichloromethane (10 mL) was added Burgess reagent (67.4 mg, 0.283 mmol, 1.50 eq) in portions at 0 °C. After warming to 25 °C, and stirring at the same temperature for 16 h, additional Burgess reagent (45.0 mg, 0.189 mmol, 1.00 eq) was added to the above mixture and stirred at 25 °C for another 16 h. The mixture was quenched with saturated ammonium chloride (15.0 mL). The solution was extracted with dichloromethane (15.0 mL ´ 2). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by Combi-Flash (Dichloromethane: Methanol = 100: 1 to 10: 1) followed by preparative HPLC (column: Welch Xtimate C18150*25mm*5μm; mobile phase: [water (0.05% NH ₄ HCO ₃ )-ACN]; B%: 30%-60%, 11min) to give (3S,3aS,6aR)-N-[cyano(phthalazin-1-yl)methyl]-2-[(2S)-2-(2,2 - difluoropropanoylamino)-3-methyl-butanoyl]-3,3a,4,5,6,6a-hex ahydro-1H-cyclopenta[c]pyrrole-3- carboxamide (27.3 mg, 0.0520 mmol, 28% yield) as a yellow solid. LC-MS (Method L): R _t = 0.555 min; MS (ESIpos): m/z = 513.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.78 (s, 0.36H), 9.77 (d, J = 3.2 Hz, 0.4H), 9.72-9.58 (m, 0.4H), 9.42 (s, 0.4H), 8.95-8.61 (m, 1.3H), 8.30-8.22 (m, 0.4H), 8.13-8.05 (m, 1.0H), 8.03-7.89 (m, 0.7H), 7.86- 7.72 (m, 1.3H), 7.28 (d, J = 8.6 Hz, 0.4H), 4.39-4.01 (m, 2H), 3.93-3.63 (m, 2H), 2.76-2.68 (m, 1H), 2.27-1.20 (m, 11H), 1.15-0.70 (m, 6H). HPLC (Method M): R _t = 1.963 min; HPLC purity: 98%. SFC: dr = 67: 33. To a mixture of (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[(3,3- difluorocyclobutanecarbonyl)amino]propanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (400 mg, 1.04 mmol, 1.00 eq) and (2S)-2-amino-3-[(2S)-7-fluoro-3-oxo-4H-1,4-benzoxazin-2- yl]propanamide (339 mg, 1.04 mmol, 1.00 eq, 2 hydrochloride) in dichloromethane (5.00 mL) were added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]- dimethylazanium;hexafluorophosphate (593mg, 1.56 mmol, 1.50 eq) and N,N-diethylpropan-2-amine (672 mg, 5.20 mmol, 0.906 mL, 5.00 eq). After stirring at 20 °C for 4 h, the reaction mixture was diluted with dichloromethane (40.0 mL), washed with water (30.0 mL) and brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 5: 1 to 1: 5) to give (1R,2S,5S)-N-[(1S)- 2-amino-1-[[(2S)-7-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]methy l]-2-oxo-ethyl]-3-[(2S)-3-cyclopropyl-2- [(3,3-difluorocyclobutanecarbonyl) amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (510 mg, 0.823 mmol, 79% yield) as a white solid. LC-MS (Method C): Rt = 0.864 min; MS (ESIpos): m/z = 620.3 [M+H] ⁺ . Procedure for preparation of Compound CPD0279197 - (1R,2S,5S)-N-((S)-1-cyano-2-((S)-7- To a mixture of (1R,2S,5S)-N-[(1S)-2-amino-1-[[(2S)-7-fluoro-3-oxo-4H-1,4-be nzoxazin-2-yl]methyl]-2- oxo-ethyl]-3-[(2S)-3-cyclopropyl-2-[(3,3-difluorocyclobutane carbonyl)amino]propanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (460 mg, 0.742 mmol, 1.00 eq) in dichloromethane (10.0 mL) was added burgess reagent (531 mg, 2.23 mmol, 3.00 eq). After stirring at 20 °C for 16 h, the reaction mixture was diluted with dichloromethane (50.0 mL), washed with water (30.0 mL) and brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water (FA)- ACN];B%: 45%-65%,9 min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-7-fluoro-3-oxo-4H-1,4- benzoxazin-2-yl]ethyl]-3-[(2S)-3-cyclopropyl-2-[(3,3-difluor ocyclobutanecarbonyl)amino]propanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxamide (200 mg, 0.332 mmol, 45% yield) as a white solid. LC-MS (Method C): Rt = 0.897 min; MS (ESIpos): m/z = 602.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.82 (br. s, 1H), 8.94 (d, J = 8.0 Hz 1H), 8.28 (d, J = 7.8 Hz, 1H), 6.90-6.76 (m, 3H), 5.07-5.01 (m, 1H), 4.63-4.57 (m, 1H), 4.39-4.27 (m, 1H), 4.08 (s, 1H), 3.89-3.78 (m, 2H), 2.91-2.85 (m, 1H), 2.67-2.58 (m, 4H), 2.33-2.25 (m, 1H), 1.71-1.70 (m, 0.36H), 1.56-1.52 (m, 1.38H), 1.41-1.34 (m, 1.17H), 1.30 (d, J = 7.8 Hz, 1H), 1.13-1.06 (m, 1H), 1.01 (s, 3H), 0.88-0.84 (m, 3H), 0.70-0.64 (m, 1H), 0.40-0.32 (m, 2H), 0.067-0.033 (m, 1H), -0.034--0.066 (m, 1H). SFC: dr = 3: 93: 4. To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-hydroxy-3-methyl-butanoi c acid (1.60 g, 6.86 mmol, 1.00 eq), 4-methylmorpholine (1.73 g, 17.2 mmol, 1.89 mL, 2.50 eq) and (benzotriazol-1- yloxy)tripyrrolidinophosphonium,hexafluorophosphate (3.93 g, 7.55 mmol, 1.10 eq) in dichloromethane (40.0 mL) was added methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (1.55 g, 7.55 mmol, 1.10 eq, Hydrochloride) at 0 °C. After stirring at 25 °C for 12 h, the reaction mixture was quenched with water (20.0 mL), and extracted with dichloromethane (20.0 mL × 2). The combined extracts were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by flash column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 0: 1 to 1: 1) to give methyl (1R,2S,5S)-3-[(2S)- 2-(tert-butoxycarbonylamino)-3-hydroxy-3-methyl-butanoyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylate (800 mg, 2.08 mmol, 30% yield) as colorless oil. LC-MS (Method C): Rt = 0.668 min; MS (ESIpos): m/z = 258.2 [M-100+H] ^+. Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-hydroxy-3- methyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-ca rboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-hydroxy-3- methyl-butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (700 mg, 1.82 mmol, 1.00 eq) in mixed solvent of methanol (14.0 mL) and water (1.40 mL) was added lithium hydroxide hydrate (153 mg, 3.64 mmol, 2.00 eq). After stirring at 25 °C for 12 h, the solvent was removed under reduced pressure to give a residue. The residue was dissolved in water (30.0 mL). Hydrochloric acid (2M) was added to adjust pH~2. The separated aqueous phase was extracted with ethyl acetate (20.0 mL × 2). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-hydroxy-3- methyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxylic acid (700 mg, 1.27 mmol, 70% yield) as a white solid. LC-MS (Method C): Rt = 0.841 min; MS (ESIpos): m/z = 315.1 [M-56+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-amino-3-hydroxy-3-methyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid To a solution of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-hydroxy-3- methyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (700 mg, 1.89 mmol, 1.00 eq) in HCl/dioxane (4 M, 7.00 mL, 14.8 eq)was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuo at 50 °C to afford (1R,2S,5S)-3-[(2S)-2-amino-3-hydroxy-3-methyl-butanoyl]-6,6- dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (500 mg, 1.63 mmol, 86% yield, Hydrochloride) as white solid. LC-MS (Method C): Rt = 0.200 min; MS (ESIpos): m/z = 271.2 [M+H] ^+. Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-(2,2-difluoropropanoylamino)-3-hydroxy- 3- methyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-ca rboxylic acid To a solution of methyl 2,2-difluoropropanoate (734 mg, 5.92 mmol, 4.00 eq) in methanol (4.00 mL) were added triethylamine (449 mg, 4.44 mmol, 0.618 mL, 3.00 eq) and (1R,2S,5S)-3-[(2S)-2-amino-3- hydroxy-3-methyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]h exane-2-carboxylic acid (400 mg, 1.48 mmol, 1.00 eq). After stirring at 50 °C for 24 h, the reaction mixture was concentrated under reduced pressure at 50 °C to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 25%-55%,min) to afford (1R,2S,5S)- 3-[(2S)-2-(2,2-difluoropropanoylamino)-3-hydroxy-3-methyl-bu tanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (120 mg, 0.331 mmol, 22% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.79 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 4.44-4.39 (m, 1H), 4.13 (s, 1H), 3.93-3.87 (m, 1H), 3.76-3.69 (m, 1H), 1.75 (t, J = 19.6 Hz, 3H), 1.57-1.50 (m, 1H), 1.45-1.41 (m, 1H), 1.20 (s, 3H), 1.14 (s, 3H), 1.01 (s, 3H), 0.85 (s, 3H). Procedure for preparation of CPD0279198 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-6-fluoro-3-oxo- 4H-1,4-benzoxazin-2-yl]ethyl]-3-[(2S)-2-(2,2-difluoropropano ylamino)-3-hydroxy-3-methyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxami de To a solution of 1R,2S,5S)-3-[(2S)-2-(2,2-difluoropropanoylamino)-3-hydroxy-3 -methyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (90.0 mg, 248 umol, 1.00 eq), 4- methylmorpholine (75.4 mg, 0.745 mmol, 81.9 μL, 3.00 eq) and (benzotriazol-1- yloxy)tripyrrolidinophosphonium,hexafluorophosphate (142 mg, 0.273 mmol, 1.10 eq) in dichloromethane (2.00 mL) was added(2S)-2-amino-3-[(2S)-6-fluoro-3-oxo-4H-1,4-benzoxazin-2 - yl]propanenitrile (58.4 mg, 0.248 mmol, 1.00 eq). After stirring at 20 °C for 12 h, the reaction mixture was concentrated under reduced pressure at 50 °C to give a residue. The residue was purified by prep- TLC (SiO ₂ , Dichloromethane: Tetrahydrofuran = 5: 1) followed by prep-HPLC (column: Waters Xbridge 150*25mm* 5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 33%-63%,8min) to afford (1R,2S,5S)- N-[(1S)-1-cyano-2-[(2S)-6-fluoro-3-oxo-4H-1,4-benzoxazin-2-y l]ethyl]-3-[(2S)-2-(2,2- difluoropropanoylamino)-3-hydroxy-3-methyl-butanoyl]-6,6-dim ethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (38.6 mg, 63.3 μmol, 26% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.89 (s, 1H), 8.92 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 7.2 Hz, 1H), 6.98- 6.88 (m, 1H), 6.80-6.73 (m, 1H), 6.71-6.67 (m, 1H), 5.11-5.00 (m, 1H), 4.96 (s, 1H), 4.57-4.51 (m, 1H), 4.38 (d, J = 7.6 Hz, 1H), 4.17 (s, 1H), 3.99-3.91 (m, 1H), 3.70 (d, J = 10.8 Hz, 1H), 2.46-2.40 (m, 1H), 2.37-2.30 (m, 1H), 1.73 (t, J = 19.6 Hz, 3H), 1.50-1.45 (m, 1H), 1.36-1.30 (m, 1H), 1.08-1.05 (m, 5H), 1.04-1.01 (m, 1H), 1.00 (s, 3H), 0.87 (s, 3H). LC-MS (Method G): Rt = 0.926 min; MS (ESIpos): m/z = 580.2 [M+H] ⁺ . SFC: dr = 3: 93 :4. Preparation of CPD0279199 Procedure for preparation of methyl (2S)-2-(tert-butoxycarbonylamino)-3-hydroxy-3-methyl- butanoate To a mixture of (2S)-2-(tert-butoxycarbonylamino)-3-hydroxy-3-methyl-butanoi c acid (4.00 g, 17.1 mmol, 1.00 eq) in methanol (40.0 mL) was added dropwise diazomethyl(trimethyl)silane (2.00 M, 17.1 mL, 2.00 eq) at 0 °C. After stirring for 2 h, the mixture was concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography ((ISCO®; 80g SepaFlash® Silica Flash Column, Eluent of 40~60% Ethyl acetate/Petroleum ethergradient @ 80mL/min) to give methyl (2S)-2- (tert-butoxycarbonylamino)-3-hydroxy-3-methyl-butanoate (4.00 g, 12.9 mmol, 75% yield, 80% purity) as white oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 6.70 (d, J = 8.6 Hz, 1H), 4.69 (s, 1H), 3.94 (d, J = 8.6 Hz, 1H), 3.61 (s, 3H), 1.38 (s, 9H), 1.14 (s, 6H). Procedure for preparation of methyl (2S)-2-(tert-butoxycarbonylamino)-3-methoxy-3-methyl- butanoate A mixture of methyl (2S)-2-(tert-butoxycarbonylamino)-3-hydroxy-3-methyl-butanoa te (1 g, 4.04 mmol, 1 eq) and silver (Ϩ) oxide (1.87 g, 8.09 mmol, 2.00 eq) in iodomethane (20.0 mL) was stirred at 40 °C for 48 h. The reaction mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 5: 1) to give methyl (2S)-2-(tert-butoxycarbonylamino)-3-methoxy-3-methyl-butanoa te (277 mg, 1.06 mmol, 9% yield) as colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 5.34 (d, J = 8.4 Hz, 1H), 4.25 (d, J = 8.8 Hz, 1H), 3.73 (s, 3H), 3.20 (s, 3H), 1.43 (s, 9H), 1.24 (s, 6H). Procedure for preparation of (2S)-2-(tert-butoxycarbonylamino)-3-methoxy-3-methyl-butanoi c acid To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-methoxy-3-methyl-butanoa te (277 mg, 1.06 mmol, 1.00 eq) in methanol (4.00 mL) and water (1.00 mL) was added lithium hydroxide (133 mg, 3.18 mmol, 3.00 eq). After stirring at 25 °C for 2 h, the reaction mixture was diluted with water (20 mL). Hydrochloric acid (1M) was added to the reaction mixture to adjust pH~7. The aqueous phase was extracted with ethyl acetate (50.0 mL × 2). The combined organic layers were washed with brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give (2S)-2- (tert-butoxycarbonylamino)-3-methoxy-3-methyl-butanoic acid (170 mg, 0.680 mmol, 64% yield, 99% purity) as white oil. Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3- methoxy-3-methyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]h exane-2-carboxylate To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-methoxy-3-methyl-butanoi c acid (170 mg, 0.687 mmol, 1.00 eq) and methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (116 mg, 0.687 mmol, 1.00 eq) in dichloromethane (2.00 mL) were added N,N-diisopropylethylamine (355 mg, 2.75 mmol, 0.478 mL, 4.00 eq) and ammonium; hexafluorophosphate (392 mg, 1.03 mmol, 1.50 eq). After stirring at 25 °C for 16 h, the reaction mixture was concentrated to give a residue. The residue was purified by reversed phase (instrument: 40g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-10 min 0-60% B; flow 60 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give methyl (1R,2S,5S)-3-[(2S)-2-(tert- butoxycarbonylamino)-3-methoxy-3-methyl-butanoyl]-6,6-dimeth yl-3-azabicyclo[3.1.0]hexane-2- carboxylate (200 mg, 0.501 mmol, 73% yield) as a white solid LC-MS (Method C): Rt = 0.911 min; MS (ESIpos): m/z = 399.3 [M+H] ⁺ . Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-2-amino-3-methoxy-3-methyl-butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate A mixture of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-methoxy-3- methyl-butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (200 mg, 501 umol, 1.00 eq) and hydrochloric acid /1,4-dioxane (4.00 M, 4.00 mL, 31.8 eq) in 1,4-dioxane (4.00 mL) was stirred at 25°C for 3 h. The mixture was concentrated under reduced pressure to give methyl (1R,2S,5S)-3-[(2S)-2-amino-3- methoxy-3-methyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]h exane-2-carboxylate (110 mg, 0.239 mmol, 48% yield, 65% purity) as yellow oil. LC-MS (Method C): Rt = 0.451 min; MS (ESIpos): m/z = 299.2 [ . A mixture of 3,3-difluorocyclobutanecarboxylic acid (50.0 mg, 0.367 mmol, 1.00 eq), methyl (1R,2S,5S)- 3-[(2S)-2-amino-3-methoxy-3-methyl-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (109 mg, 0.367 mmol, 1.00 eq, hydrochloric acid), [dimethylamino(triazolo[4,5-b]pyridin-3- yloxy)methylene]-dimethyl-ammonium;hexafluorophosphate (209 mg, 0.551 mmol, 1.50 eq) and N,N- diisopropylethylamine (189 mg, 1.47 mmol, 0.255 mL, 4.00 eq) in dichloromethane (2.00 mL) was stirred at 25 °C for 16 h. The mixture was concentrated and purified by reversed phase (instrument: 40g Flash; Column: Welch Ultimate XB_C1820-40μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-10 min 60-80% B; flow 40 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give methyl (1R,2S,5S)-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino ]-3-methoxy-3- methyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxylate (80.0 mg, 0.180 mmol, 49% yield, 94% purity) as a yellow solid. LC-MS (Method C): Rt = 0.580 min; MS (ESIpos): m/z = 417.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino ]-3- methoxy-3-methyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]h exane-2-carboxylic acid A mixture of methyl (1R,2S,5S)-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino ]-3-methoxy-3- methyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-ca rboxylate (80.0 mg, 0.192 mmol, 1.00 eq) and lithium hydroxide (9.20 mg, 0.384 mmol, 2.00 eq) in mixed solvent of methanol (1.50 mL) and water (0.500 mL) was stirred at 25 °C for 16 h. Hydrochloric acid solution (1.00 M) was added to the mixture to adjust pH = 5 and diluted with water (50 mL). The aqueous phase was extracted with ethyl acetate (50.0 mL × 3). dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give (1R,2S,5S)-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino ]-3-methoxy-3-methyl-butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxylic acid (100 mg, 0.173 mmol, 90% yield, 70% purity) (100 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.25-8.02 (m, 1H), 4.67 (d, J = 8.6 Hz, 0.5H), 4.56 (s, 0.2H), 4.51 (d, J = 9.6 Hz, 0.3H), 4.10 (s, 0.5H), 3.92-3.75 (m, 1H), 3.48-3.38 (m, 2H), 3.11-3.03 (m, 3H), 2.79-2.52 (m, 4H), 1.55-1.45 (m, 1H), 1.42-1.34 (m, 1H), 1.25-1.11 (m, 5H), 1.08-0.95 (m, 5H), 0.83 (s, 2H). Procedure for preparation of Compound CPD0279199 of (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-6- fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]ethyl]-3-[(2S)-2-[(3,3-d ifluorocyclobutanecarbonyl)amino]- 3-methoxy-3-methyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-2-[(3,3-difluorocyclobutanecarbonyl)amino ]-3-methoxy-3-methyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyli c acid (100 mg, 0.248 mmol, 1.00 eq) and (2S)-2-amino-3-[(2S)-6-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]p ropanenitrile (58.4 mg, 0.248 mmol, 1.00 eq) in dichloromethane (2.00 mL) were added ammonium hexafluorophosphate (141 mg, 0.372 mmol, 1.50 eq) and N,N-diisopropylethylamine (96.3 mg, 0.745 mmol, 0.129 mL, 3.00 eq). After stirring at 25 °C for 16 h, the reaction mixture was concentrated to give a residue. The residue was purified by reversed phase (instrument: 40 g Flash; Column: Welch Ultimate XB_C1820-40μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-10 min 60-80% B; flow 40 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-6-fluoro-3-oxo-4H- 1,4-benzoxazin-2-yl]ethyl]-3-[(2S)-2-[(3,3-difluorocyclobuta necarbonyl)amino]-3-methoxy-3-methyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxamide (84.2 mg, 0.133 mmol, 54% yield, 99% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.88 (s, 1H), 9.11 (d, J = 7.2 Hz, 0.2H), 8.83 (d, J = 8.4 Hz, 0.8H), 8.11-8.01 (m, 1H), 7.07-6.87 (m, 1H), 6.81-6.64 (m, 2H), 5.20-5.08 (m, 0.8H), 4.83-4.74 (m, 0.2H), 4.61- 4.54 (m, 1H), 4.53-4.47 (m, 0.8H), 4.46-4.41 (m, 0.2H), 4.08 (s, 0.8H), 3.96-3.84 (m, 0.8H), 3.83-3.78 (m, 0.7H), 3.68-3.56 (m, 0.3H), 3.45-3.41 (m, 0.2H), 3.08-2.98 (m, 4H), 2.72-2.53 (m, 4H), 2.47-2.37 (m, 1H), 2.35-2.24 (m, 1H), 1.55-1.48 (m, 0.8H), 1.43-1.37 (m, 0.3H), 1.36-1.26 (m, 1H), 1.07 (s, 1H), 1.03-0.94 (m, 7H), 0.90 (s, 2H), 0.85 (s, 2H). LC-MS (Method C): Rt = 0.593 min; MS (ESIpos): m/z = 620.5 [M+H] ⁺ . SFC: dr = 82: 18. Preparation of CPD0279201 Procedure for preparation of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-6,6-dim ethyl- 3-[(2S)-3-(3-pyridyl)-2-[(2,2,2-trifluoroacetyl)amino]propan oyl]-3-azabicyclo[3.1.0]hexane-2- carboxamide To a mixture of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-(3-pyridyl)-2-[(2,2,2-trif luoroacetyl)amino]propanoyl]- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (300 mg, 0.751 mmol, 1.00 eq), benzotriazol-1- yloxy(tripyrrolidin-1-yl)phosphanium;hexafluorophosphate (508 mg, 0.977 mmol, 1.30 eq) and 4- methylmorpholine (304 mg, 3.00 mmol, 4.00 eq) in dichloromethane (5.00 mL) was added 2-amino-2- phthalazin-1-yl-acetamide (152 mg, 0.751 mmol, 1.00 eq). After stirring at 25 °C for 16 h, the mixture was diluted with saturated ammonium chloride (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 30~100% Ethyl acetate/Petroleum ether; gradient @ 30 mL/min) to give tert-butyl 4-[3-(1,3-diaminopyrrolo[3,2- f]quinazolin-7-yl)propyl]piperazine-1-carboxylate (460 mg, 1.08 mmol, 62% yield) as a yellow solid. LC-MS (Method C): R _t = 0.438 min; MS (ESIpos): m/z = 584.3 [M+H] ⁺ . Procedure for preparation of CPD0279201 - (1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]-6,6- dimethyl-3-[(2S)-3-(3-pyridyl)-2-[(2,2,2-trifluoroacetyl)ami no]propanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-6,6-dim ethyl-3-[(2S)-3-(3- pyridyl)-2-[(2,2,2-trifluoroacetyl)amino]propanoyl]-3-azabic yclo[3.1.0]hexane-2-carboxamide (340 mg, 0.583 mmol, 1.00 eq) in dichloromethane (2.00 mL) was added methoxycarbonyl- (triethylammonio)sulfonyl-azanide (139 mg, 0.583 mmol, 1.00 eq) at 0 °C. After stirring at 25 °C for 12 h, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: YMC Triart C18150*25mm*5 μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 18%-48%, 10 min) to give (1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]-6,6-dimethyl-3-[ (2S)-3-(3- pyridyl)-2-[(2,2,2-trifluoroacetyl)amino] propanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide (107 mg, 0.185 mmol, 32% yield, 98% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.71 (s, 0.4H), 10.15-10.10 (m, 0.5H), 9.90-10.00 (m, 0.4H), 9.65- 9.80 (m, 1H), 9.25 (s, 0.5H), 8.75-8.80 (m, 0.5H), 8.55-8.65 (m, 0.7H), 8.40-8.48 (m, 1.2H), 8.25-8.30 (m, 0.5H), 7.90-8.20 (m, 2H),7.65-7.85 (m, 2.6H), 7.25-7.35 (m, 1.4H), 4.69-4.75 (m, 1H), 4.19-4.26 (m, 2H), 3.80-3.95 (m, 1H), 3.65-3.70 (m, 1H), 3.10-3.15 (m, 1H), 2.90-3.05 (m, 1H),1.62-1.66 (m, 1H), 1.58-1.60 (m, 0.5H), 1.11-1.35 (m,0.5 H), 0.73-1.17 (m, 6H). LC-MS (Method C): R _t = 0.457 min; MS (ESIpos): m/z = 566.1 [M+H] ⁺ . HPLC (Method O): R _t = 1.543 min; purity: 98%. SFC: dr = 62: 38. Preparation of CPD0279317 Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-2-amino-3-methyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate To a solution of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-methyl-but anoyl] -6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (6.00 g, 16.3 mmol, 1.00 eq) in hydrochloric acid (4 M in dioxane, 60.0 mL) was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give methyl (1R,2S,5S)-3-[(2S)-2-amino-3-methyl-butanoyl]-6,6-dimethyl-3 - azabicyclo[3.1.0] hexane-2-carboxylate (5.40 g, 16.0 mmol, 98% yield, hydrochloride) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.25 (s, 3H), 7.30-7.06 (m, 2H), 4.27 (s, 1H), 3.96 (d, J =4.8 Hz, 1H), 3.80-3.70 (m, 2H), 3.67 (s, 3H), 2.18-2.08 (m, 1H), 1.59 (m, 1H), 1.49-1.47 (m, 1H), 1.07-0.99 (m, 6H), 0.98-0.90 (m, 6H). LC-MS (Method C): R _t = 0.433 min; MS (ESIpos): m/z = 269.2 [M+H] ⁺ . Procedure for preparation of methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-[(2- tetrahydropyran-4-ylacetyl)amino]butanoyl]-3-azabicyclo[3.1. 0]hexane-2-carboxylate To a solution of methyl (1R,2S,5S)-3-[(2S)-2-amino-3-methyl-butanoyl]-6,6-dimethyl-3 -azabicyclo [3.1.0]hexane-2-carboxylate (4.90 g, 16.1 mmol, 1.00 eq, hydrochloride), O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (7.95 g, 20.9 mmol, 1.30 eq) and N,N- diisopropylethylamine (8.31 g, 64.3 mmol, 11.2 mL, 4.00 eq) in N,N-dimethylformamide (50.0 mL) was added 2-tetrahydropyran-4-ylacetic acid (2.78 g, 19.3 mmol, 1.20 eq). After stirring at 25 °C for 12 h, the reaction mixture was poured into saturated ammonium chloride (100 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 33~48% Ethyl acetate/Petroleum ether; gradient @ 75 mL/min) to give methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3- methyl-2-[(2- tetrahydropyran-4-ylacetyl)amino]butanoyl]-3-azabicyclo[3.1. 0]hexane-2-carboxylate (6.00 g, 13.7 mmol, 85% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.12 (d, J = 8.8 Hz, 1H), 4.20-4.08 (m, 2H), 3.98-3.95 (m, 1H), 3.80- 3.76 (m, 3H), 3.64 (s, 3H), 3.28-3.19 (m, 2H), 2.04-2.02 (m, 2H), 1.95-1.78 (m, 2H), 1.56-1.32 (m, 5H), 1.12-1.11 (m, 1H), 1.00 (s, 3H), 0.92-0.81 (m, 9H). LC-MS (Method C): R _t = 0.493 min; MS (ESIpos): m/z = 395.3 [M+H] ⁺ . To a solution of methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-[(2-tetrahydropyr an-4-ylacetyl) amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylate (6.00 g, 15.2 mmol, 1.00 eq) in mixed solvent of methanol (20.0 mL) and water (20.0 mL) was added lithium hydroxide monohydrate (1.91 g, 45.6 mmol, 3.00 eq) at 0 °C. After stirring at 25 °C for 2 h, hydrochloric acid (1M in water) was added to the reaction mixture to adjust pH to 5~6, and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-[(2-tetrahydropyr an-4- ylacetyl)amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxy lic acid (5.50 g, 14.5 mmol, 95% yield) as yellow oil. LC-MS (Method C): R _t = 0.521 min; MS (ESIpos): m/z = 381.3 [M+H] ⁺ . Procedure for preparation of CPD0279317 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-6-fluoro-3-oxo- 4H-1,4-benzoxazin-2-yl]ethyl]-6,6-dimethyl-3-[(2S)-3-methyl- 2-[(2-tetrahydropyran-4- ylacetyl)amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxa mide To a solution of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-[(2-tetrahydropyr an-4-ylacetyl) amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (100 mg, 263 μmol, 1.00 eq), O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (120 mg, 315 μmol, 1.20 eq) and N,N-diisopropylethylamine (102 mg, 788 μmol, 137 μL, 3.00 eq) in N,N-dimethylformamide (1.00 mL) was added (2S)-2-amino-3-[(2S)-6-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]p ropanenitrile (61.8 mg, 263 μmol, 1.00 eq). After stirring at 25 °C for 12 h, the reaction mixture was poured into saturated ammonium chloride (2.00 mL) and extracted with ethyl acetate (1.00 mL × 5). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18150*25mm*10 μm; mobile phase: [water(FA)-ACN]; B%: 38%-68%, 9 min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)- 6-fluoro-3-oxo-4H -1,4-benzoxazin-2-yl]ethyl]-6,6-dimethyl-3-[(2S)-3-methyl-2- [(2-tetrahydropyran-4- ylacetyl)amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxa mide (27.5 mg, 44.0 μmol, 17% yield, 95% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.86 (s, 1H), 8.99 (d, J = 8.4 Hz, 1H), 8.13-7.99 (m, 1H), 6.92-6.88 (m, 1H), 6.80-6.71 (m, 1H), 6.68-6.65 (m, 1H), 5.10-5.04 (m, 1 H), 4.56-4.51 (m, 1 H), 4.15-4.06 (m, 1 H), 4.05-4.00 (m, 1 H), 3.92-3.85 (m, 1 H), 3.83-3.70 (m, 3 H), 3.23-3.15 (m, 2 H), 2.30-2.19 (m, 1 H), 2.04-1.94 (m, 2H), 1.86-1.70 (m, 1H), 1.69-1.57 (m, 1H), 1.54-1.48 (m, 1H), 1.47-1.35 (m, 2H), 1.30- 1.25 (m, 1H), 1.17-1.06 (m, 2H), 1.02-0.97 (m, 3H), 0.91-0.83 (m, 1H), 0.82-0.79 (m, 3H), 0.74 (d, J = 6.8 Hz, 3H), 0.68 (d, J = 6.8 Hz, 3H). LCMS (Method C): R _t = 0.538 min; MS (ESIpos): m/z = 598.2 [M+H] ⁺ . HPLC (Method S): R _t = 2.392 min; purity: 95%. SFC: dr = 78: 13: 9. To a mixture of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-methyl-but anoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (5.00 g, 13.6 mmol, 1.00 eq) in methanol (50.0 mL) was added a solution of lithium hydroxide monohydrate (2.28 g, 54.2 mmol, 4.00 eq) in water (50.0 mL). After stirring at 20 °C for 12 h, the reaction solution was adjusted pH~5 with hydrochloric acid (1 M in water) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrate to afford (1R,2S,5S)-3-[(2S)-2-(tert- butoxycarbonylamino)-3-methyl-butanoyl]-6,6-dimethyl-3-azabi cyclo[3.1.0]hexane-2-carboxylic acid (4.70 g, 13.3 mmol, 98% yield) as a white solid. LC-MS (Method C): R _t = 0.610 min; MS (ESIpos): m/z = 255.0 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-methyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyli c acid To a solution of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-methyl-but anoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (1.00 g, 2.82 mmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (1.29 g, 3.39 mmol, 1.20 eq) and N,N- diisopropylethylamine (1.46 g, 11.3 mmol, 4.00 eq) in dichloromethane (10.0 mL) was added 2-amino- 2-phthalazin-1-yl-acetamide (570 mg, 2.82 mmol, 1.00 eq). After stirring at 20 °C for 12 h, the reaction mixture was diluted with saturated ammonium chloride (50.0 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~90% Ethyl acetate/ Petroleum ether; gradient @ 40.0 mL/min) to afford ethyl tert- butyl N-[(1S)-1-[(1R,2S,5S)-2-[(2-amino-2-oxo-1-phthalazin-1-yl-et hyl)carbamoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-propyl]carbamat e (800 mg, 1.49 mmol, 53% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.67 (m, 1H), 9.30-8.85 (m, 1H), 8.28-7.97 (m, 4H), 7.61-7.43 (m, 2H), 7.15-6.90 (m, 1H), 6.35-6.23 (m, 1H), 4.50-4.29 (m, 1H), 4.00-3.92 (m, 1H), 3.85-3.72 (m, 2H), 1.53-1.45 (m, 1H), 1.39-1.29 (m, 10H), 0.96-0.80 (m, 12H). LC-MS (Method C): R _t = 0.582 min; MS (ESIpos): m/z = 539.1 [M+H] ⁺ . To a solution of tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-[(2-amino-2-oxo-1-phthalazin-1-yl-et hyl)carbamoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl- propyl]carbamate (750 mg, 1.39 mmol, 1.00 eq) in dichloromethane (10.0 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (498 mg, 2.09 mmol, 1.50 eq). After stirring at 25 °C for 12 h, the mixture was quenched with methanol (10.0 mL) and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12.0 g SepaFlash® Silica Flash Column, Eluent of 0~40% Ethyl acetate/Petroleum ether; gradient @45.0 mL/min) to afford tert-butyl N- [(1S)-1-[(1R,2S,5S)-2-[[cyano(phthalazin-1-yl)methyl]carbamo yl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-propyl]carbamat e (473 mg, 909 μmol, 65% yield) as a yellow solid. LC-MS (Method C): R _t = 0.638 min; MS (ESIpos): m/z = 521.1 Procedure for preparation of tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-[[cyano(phthalazin-1- yl)methyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 3-carbonyl]-2-methyl- propyl]carbamate To a solution of tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-[[cyano(phthalazin-1-yl)methyl]carba moyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-prop yl]carbamate (423 mg, 812 μmol, 1.00 eq) in acetonitrile (10.0 mL) was added hydrochloric acid (4 M in dioxane, 10.0 mL). After stirring at 0 °C for 2 h, the mixture was concentrated at 20 °C to give a residue. The residue was suspended into saturated sodium bicarbonate (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12.0 g SepaFlash® Silica Flash Column, Eluent of 0~7% Ethyl acetate/Petroleum ether; gradient @20.0 mL/min) to afford (1R,2S,5S)-3-[(2S)-2-amino-3-methyl-butanoyl]-N-[cyano(phtha lazin-1-yl)methyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (217 mg, 475 μmol, 58% yield, hydrochloride) as a yellow solid. LC-MS (Method C): Rt = 0.496 min; MS (ESIpos): m/z = 421.1 [M+H] ⁺ . Procedure for preparation of CPD0279318 - (1R,2S,5S)-3-[(2S)-2-amino-3-methyl-butanoyl]-N- [cyano(phthalazin-1-yl)methyl]-6,6-dimethyl-3-azabicyclo[3.1 .0]hexane-2-carboxamide To a solution of 2-tetrahydropyran-4-ylacetic acid (89.3 mg, 619 umol, 1.20 eq) and (1R,2S,5S)-3-[(2S)- 2-amino-3-methyl-butanoyl]-N-[cyano(phthalazin-1-yl)methyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide (217 mg, 516 μmol, 1.00 eq) in N,N-dimethylformamide (10.0 mL) were added O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (235 mg, 619 μmol, 1.20 eq) and N,N-diisopropylethylamine (267 mg, 2.06 mmol, 4.00 eq). After stirring at 25 °C for 12 h, the reaction mixture was diluted with saturated ammonium chloride (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18150*25mm*10 μm; mobile phase: [water(formic acid)- acetonitrile]; B%: 31%-61%, 10 min) to give (1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]-6,6-dimethyl-3-[ (2S)-3- methyl-2-[(2-tetrahydropyran-4-ylacetyl)amino]butanoyl]-3-az abicyclo[3.1.0]hexane-2-carboxamide (95.5 mg, 168 μmol, 33% yield, 96% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.75 (s, 0.4H), 9.86-9.65 (m, 1H), 9.44 (s, 0.5H), 8.79-8.77 (m, 0.5H), 8.29-8.24 (m, 1H), 8.11-7.76 (m, 4H), 7.31-7.27 (m, 0.4H), 4.27-4.01 (m, 2H), 3.99-3.94 (m, 1H), 3.91-3.87 (m, 1H), 3.81-3.75 (m, 2H), 3.28-3.23 (m, 2H), 2.08-1.98 (m, 3H), 1.87-1.83 (m, 1H), 1.64- 1.43 (m, 4H), 1.32-1.14 (m, 2H), 1.06-0.99 (m, 3H), 0.91-0.74 (m, 9H). LC-MS (Method C): R _t = 0.559 min; MS (ESIpos): m/z = 547.2 [M+H] ⁺ . SFC: dr = 19: 30: 32: 15. Preparation of CPD0279319 Procedure for preparation of methyl (1R,2S,5S)-6,6-dimethyl-3-(pyrimidin-5-yl-L-valyl)-3- azabicyclo[3.1.0]hexane-2-carboxylate To a mixture of (2S)-3-methyl-2-(pyrimidin-5-ylamino)butanoic acid (900 mg, 4.61 mmol, 1.00 eq) and methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (1.14 g, 5.53 mmol, 1.20 eq, hydrochloric acid salt) in dichloromethane (10.0 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (2.28 g, 5.99 mmol, 1.30 eq) and N,N-diisopropylethylamine (2.38 g, 18.4 mmol, 4.00 eq) at 25 °C. After stirring at 25 °C for 16 h, the mixture was poured into water (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were died over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~60% Ethyl acetate/Petroleum ether gradient @ 65 mL/min) to give methyl (1R,2S,5S)-6,6-dimethyl-3-(pyrimidin-5- yl-L-valyl)-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.50 g, 4.33 mmol, 94% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.37 (s, 1H), 8.20 (s, 2H), 6.07 (d, J = 9.6 Hz, 1H), 4.19 (s, 1H), 4.11 (dd, J = 9.6, 6.8 Hz, 1H), 3.89-3.78 (m, 2H), 3.64 (s, 3H), 2.12-2.03(m, 1H), 1.61-1.55 (m, 1H), 1.47- 1.36 (m, 1H), 1.04-0.97 (m, 6H), 0.92-0.97 (m, 3H), 0.83-0.76 (m, 3H). Procedure for preparation of (1R,2S,5S)-6,6-dimethyl-3-(pyrimidin-5-yl-L-valyl)-3- azabicyclo[3.1.0]hexane-2-carboxylic acid A mixture of methyl (1R,2S,5S)-6,6-dimethyl-3-(pyrimidin-5-yl-L-valyl)-3-azabicy clo[3.1.0]hexane-2- carboxylate (1.50 g, 4.33 mmol, 1.00 eq) and lithium hydroxide monohydrate (908 mg, 21.6 mmol, 5.00 eq) in mixed solvent of methanol (10.0 mL) and water (10.0 mL) was stirred at 25 °C for 16 h. Hydrochloric acid solution (1 M in water) was added to the mixture to adjust pH to 5~6 and extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% (Ethyl acetate: methanol)/Petroleum ether gradient @ 30 mL/min) to give (1R,2S,5S)-6,6-dimethyl-3-(pyrimidin-5-yl-L-valyl)-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (400 mg, 1.20 mmol, 28% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.69 (s, 1H), 8.36 (s, 1H), 8.21 (s, 2H), 6.06 (d, J = 10.0 Hz, 1H), 4.15-4.06 (m, 2H), 3.89-3.75 (m, 2H), 2.12-1.99 (m, 1H), 1.60-1.52 (m, 1H), 1.43-1.37 (m, 1H), 1.04- 0.90 (m, 9H), 0.80 (s, 3H). Procedure for preparation of CPD0279319 - (1R,2S,5S)-N-(cyano(1,6-naphthyridin-8-yl)methyl)- 6,6-dimethyl-3-(pyrimidin-5-yl-L-valyl)-3-azabicyclo[3.1.0]h exane-2-carboxamide To a mixture of (1R,2S,5S)-6,6-dimethyl-3-(pyrimidin-5-yl-L-valyl)-3-azabicy clo[3.1.0]hexane-2- carboxylic acid (350 mg, 1.05 mmol, 1.00 eq) and 2-amino-2-(1,6-naphthyridin-8-yl)acetonitrile (194 mg, 1.05 mmol, 1.00 eq) in N,N-dimethylformamide (5.00 mL) were added O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (480 mg, 1.26 mmol, 1.20 eq) and N,N- diisopropylethylamine (544 mg, 4.21 mmol, 4.00 eq) at 25 °C. After stirring at 25 °C for 16 h, the mixture was poured into water (50.0 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN];B%: 31%-51%,9min) and column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 1 to 0: 1) to give (1R,2S,5S)-N-(cyano(1,6-naphthyridin-8-yl)methyl)-6,6-dimeth yl-3- (pyrimidin-5-yl-L-valyl)-3-azabicyclo[3.1.0]hexane-2-carboxa mide (135 mg, 0.267 mmol, 25% yield, 98% purity) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.66-9.40 (m, 2H), 9.29-9.22 (m, 1H), 8.95-8.88 (m, 1H), 8.70 (dd, J = 8.4, 1.6 Hz, 1H), 8.39-8.31 (m, 1H), 8.25-8.14 (m, 2H), 7.89-7.78 (m, 1H), 6.90-6.76 (m, 1H), 6.12- 5.99 (m, 1H), 4.35-4.24 (m, 1H), 4.19-4.08 (m, 1H), 3.92-3.80 (m, 2H), 2.17-1.93 (m, 1H), 1.65-1.50 (m, 1H), 1.43-1.37 (m, 0.5H), 1.28-1.17 (m, 0.5H), 1.08-0.74 (m, 12H). LC-MS (Method C): R _t = 0.779 min; MS (ESIpos): m/z = 499.3 [M+H] ⁺ . SFC: dr = 4: 9: 46: 41. To a mixture of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-[(2-tetrahydropyr an-4- ylacetyl)amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxy lic acid (150 mg, 0.394 mmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexaflu orophosphate (180 mg, 0.473 mmol, 1.20 eq) and N,N-diisopropylethylamine (204 mg, 1.58 mmol, 4.00 eq) in N,N-dimethylformamide (5.00 mL) was added (2S)-2-amino-3-[(2S)-7-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]p ropanamide (99.8 mg, 0.394 mmol, 1.00 eq) at 25 °C. After stirring at 25 °C for 16 h, the mixture was diluted with saturated ammonium chloride (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~80% Ethyl acetate/Petroleum ether gradient @ 30 mL/min) to afford (1R,2S,5S)-N-[(1S)-2-amino-1-[[(2S)-7-fluoro- 3-oxo-4H-1,4-benzoxazin-2-yl]methyl]-2-oxo-ethyl]-6,6-dimeth yl-3-[(2S)-3-methyl-2-[(2- tetrahydropyran-4-ylacetyl)amino]butanoyl]-3-azabicyclo[3.1. 0]hexane-2-carboxamide (190 mg, 0.309 mmol, 78% yield) as a yellow solid. LC-MS (Method C): R _t = 0.489 min; MS (ESIpos): m/z = 616.4 [M+H] ⁺ . Procedure for preparation of CPD0279320 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-7-fluoro-3-oxo- 4H-1,4-benzoxazin-2-yl]ethyl]-6,6-dimethyl-3-[(2S)-3-methyl- 2-[(2-tetrahydropyran-4- ylacetyl)amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxa mide To a solution of (1R,2S,5S)-N-[(1S)-2-amino-1-[[(2S)-7-fluoro-3-oxo-4H-1,4-be nzoxazin-2-yl]methyl]-2- oxo-ethyl]-6,6-dimethyl-3-[(2S)-3-methyl-2-[(2-tetrahydropyr an-4-ylacetyl)amino]butanoyl]-3- azabicyclo [3.1.0]hexane-2-carboxamide (160 mg, 0.260 mmol, 1.00 eq) in dichloromethane (3.00 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (74.3 mg, 0.312 mmol, 1.20 eq) at 0 °C. After stirring at 25 °C for 2 h, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (Ethyl acetate) to afford (1R,2S,5S)-N-[(1S)-1-cyano-2- [(2S)-7-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]ethyl]-6,6-dimet hyl-3-[(2S)-3-methyl-2-[(2- tetrahydropyran-4-ylacetyl)amino]butanoyl]-3-azabicyclo[3.1. 0]hexane-2-carboxamide (36.9 mg, 58.9 μmol, 23% yield, 95% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.80 (s, 1H), 9.02 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 6.91- 6.82 (m, 2H), 6.79-6.76 (m, 1H), 5.14-5.08 (m, 1H), 4.61-4.58 (m, 1H), 4.08-4.02 (m, 2H), 3.94-3.85 (m, 1H), 3.83-3.75 (m, 3H), 3.28-3.17(m, 2H), 2.35-2.27 (m, 1H), 2.01-1.99 (m, 2H), 1.83-1.77 (m, 1H), 1.67-1.61 (m, 1H), 1.55-1.52 (m, 1H) 1.49-1.38 (m, 2H), 1.33-1.28 (m, 1H), 1.17-1.08 (m, 2H), 1.01 (s, 3H), 0.95-0.86 (m, 1H), 0.83 (s, 3H), 0.76-0.70 (m, 6H). LC-MS (Method C): R _t = 0.496 min; MS (ESIpos): m/z = 598.4 [M+H] ⁺ . HPLC (Method S): R _t = 1.858 min; purity: 95%. SFC: de% = 73%. Preparation of CPD0279321 Procedure for preparation of methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3- cyclopropylpropanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane -2-carboxylate To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propanoic acid (10.0 g, 43.6 mmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexaflu orophosphate (24.9 g, 65.4 mmol, 1.50 eq) and N,N-diisopropylethylamine (22.6 g, 175 mmol, 30.4 mL, 4.00 eq) in N,N- dimethylformamide (50.0 mL) was added methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxylate (9.42 g, 45.8 mmol, 1.05 eq, hydrochloric acid) at 0 °C. After stirring at 20 °C for 12 h, the mixture was poured into saturated ammonium chloride (50.0 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 0 to 4: 1) to give methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropy l-propanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (13.1 g, 33.7 mmol, 77% yield) as light yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.10 (d, J = 7.2 Hz, 1H), 4.23-4.11 (m, 2H), 3.97-3.92 (m, 1H), 3.81- 3.75 (m, 1H), 3.62 (s, 3H), 1.59-1.50 (m, 2H), 1.36-1.32 (m, 10H), 1.29-1.22 (m, 1H), 1.01 (s, 3H), 0.91 (s, 3H), 0.79-0.71 (m, 1H), 0.40-0.36 (m, 2H), 0.17-0.11 (m, 2H). LC-MS (Method C): R _t = 0.895 min; MS (ESIpos): m/z = 381.3 [M-Boc+H] ⁺ . Procedure for preparation of methyl (1R,2S,5S)-3-((S)-2-amino-3-cyclopropylpropanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate To a solution of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropy l-propanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (6.00 g, 15.8 mmol, 1.00 eq) in dioxane (5.00 mL) was added hydrochloric acid (4 M in dioxane, 60.0 mL) at 0 °C. After stirring at 20 °C for 2 h, the mixture was concentrated under reduced pressure to give methyl (1R,2S,5S)-3-[(2S)-2-amino-3-cyclopropyl- propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (5.90 g, 14.9 mmol, 94% yield, hydrochloric acid) as light yellow oil. LC-MS (Method C): R _t = 0.466 min; MS (ESIpos): m/z = 281.2 [M+H] ⁺ . Procedure for preparation of methyl (1R,2S,5S)-3-((S)-3-cyclopropyl-2-((S)-2- methoxypropanamido)propanoyl)-6,6-dimethyl-3-azabicyclo[3.1. 0]hexane-2-carboxylate To a solution of (2S)-2-methoxypropanoic acid (493 mg, 4.73 mmol, 1.00 eq), O-(7-azabenzotriazol-1- yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (2.70 g, 7.10 mmol, 1.50 eq) and N,N- diisopropylethylamine (2.45 g, 18.9 mmol, 3.30 mL, 4.00 eq) in N,N-dimethylformamide (15.0 mL) was added methyl (1R,2S,5S)-3-[(2S)-2-amino-3-cyclopropyl-propanoyl]-6,6-dime thyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (1.50 g, 4.73 mmol, 1.00 eq, hydrochloric acid) at 0 °C. After stirring at 20°C for 12 h, the reaction mixture was poured into water (30.0 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with saturated calcium chloride aqueous solution (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 0 to 7: 3) to give methyl (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[[(2S)- 2-methoxypropanoyl]amino]propanoyl]-6,6-dimethyl-3-azabicycl o[3.1.0] hexane-2-carboxylate (1.30 g, 3.19 mmol, 67% yield) as light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.18 (d, J = 8.4 Hz, 1H), 4.77-4.69 (m, 1H), 4.46 (s, 1H), 3.95-3.85 (m, 2H), 3.75 (s, 3H), 3.71 (d, J = 6.8 Hz, 1H), 3.38 (s, 3H), 1.83-1.76 (m, 1H), 1.56-1.48 (m, 2H), 1.47-1.43 (m, 1H), 1.37 (d, J =6.8 Hz, 3H), 1.06 (s, 3H), 0.97 (s, 3H), 0.90-0.74 (m, 1H), 0.60-0.41 (m, 2H), 0.23- 0.02 (m, 2H). LC-MS (Method C): R _t = 0.574 min; MS (ESIpos): m/z = 367.3 [ . Procedure for preparation of (1R,2S,5S)-3-((S)-3-cyclopropyl-2-((S)-2- methoxypropanamido)propanoyl)-6,6-dimethyl-3-azabicyclo[3.1. 0]hexane-2-carboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[[(2S)-2- methoxypropanoyl]amino]propanoyl]-6,6-dimethyl-3-azabicyclo[ 3.1.0]hexane-2-carboxylate (1.30 g, 3.55 mmol, 1.00 eq) in methanol (10.0 mL) was added lithium hydroxide monohydrate (744 mg, 17.7 mmol, 5.00 eq) in water (5.00 mL). After stirring at 20 °C for 12 h, the mixture was washed with ethyl acetate (30.0 mL). The aqueous phase was diluted with water (20.0 mL), adjusted pH to 3~4 with hydrochloric acid aqueous (1M) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[[(2S)-2-methoxypropanoyl ]amino]propanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (1.10 g, 2.25 mmol, 63% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.87 (d, J = 8.0 Hz, 1H), 4.53-4.45 (m, 1H), 4.11 (s, 1H), 3.82-3.75 (m, 2H), 3.72-3.64 (m, 1H), 3.21 (s, 3H), 1.63-1.56 (m, 1H), 1.55-1.51 (m, 1H), 1.46-1.38 (m, 2H), 1.17 (d, J = 7.6 Hz, 3H), 1.01 (s, 3H), 0.88 (s, 3H), 0.82-0.73 (m, 1H), 0.43-0.32 (m, 2H), 0.18-0.00 (m, 2H). LC-MS (Method C): R _t = 0.729 min; MS (ESIpos): m/z = 353.2 [M+H] ⁺ . To a solution of (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[[(2S)-2-methoxypropanoyl ]amino]propanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (300 mg, 851 μmol, 1.00 eq), O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (486 mg, 1.28 mmol, 1.50 eq) and N,N-diisopropylethylamine (440 mg, 3.40 mmol, 4.00 eq) in N,N-dimethylformamide (10.0 mL) was added 2-amino-2-phthalazin-1-yl-acetamide (172 mg, 851 μmol, 1.00 eq) at 0 °C. After stirring at 20 °C for 12 h, the mixture was poured into water (40.0 mL) and extracted with dichloromethane (30.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 0 to 3: 7) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl- ethyl)-3-[(2S)-3-cyclopropyl-2-[[(2S)-2-methoxypropanoyl]ami no]propanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (560 mg, 835 μmol, 98% yield) as light yellow oil. LC-MS (Method C): R _t = 0.521 min; MS (ESIpos): m/z = 537.4 [M+H] ⁺ . Procedure for preparation of CPD0279321 - (1R,2S,5S)-N-(cyano(phthalazin-1-yl)methyl)-3-((S)- 3-cyclopropyl-2-((S)-2-methoxypropanamido)propanoyl)-6,6-dim ethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -3-cyclopropyl-2-[[(2S)-2- methoxypropanoyl]amino]propanoyl]-6,6-dimethyl-3-azabicyclo[ 3.1.0]hexane-2-carboxamide. (300 mg, 559 μmol, 1.00 eq) in dichloromethane (5.00 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (200 mg, 839 μmol, 1.50 eq) at 0 °C. After stirring at 20 °C for 2 h, the mixture was poured into water (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 0 to 3: 7) followed by prep-HPLC (FA condition: column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 38%-68%, 10 min) to give (1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]-3-[(2S)- 3-cyclopropyl-2-[[(2S)-2-methoxypropanoyl]amino]propanoyl]-6 ,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide (26.3 mg, 49.2 μmol, 9% yield, 97% purity) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.67 (s, 0.4H), 9.79-9.54 (m, 0.5H), 9.69 (d, J = 8.0 Hz, 0.2 H), 9.57 (d, J = 8.0 Hz, 0.2 H), 9.31 (s, 0.4H), 8.80-8.75 (s, 0.4H), 8.30-8.23 (m, 0.5H), 8.12-8.05 (m, 1.2H), 8.03-7.91 (m, 1.2H), 7.86-7.80 (m, 1.2H), 7.80-7.76 (m, 0.5H), 7.24 (d, J = 8.4 Hz, 1H), 4.52-4.37 (m, 1H), 4.28-4.14 (m, 1H), 3.96-3.87 (m, 1H), 3.85-3.61 (m, 2H), 3.25-3.15 (m, 3H), 1.68-1.55 (m, 2H), 1.53-1.38 (m, 1H), 1.36-1.25 (m, 1H), 1.22-1.12 (m, 3H), 1.11-0.96 (m, 3H), 0.95-0.83 (m, 3H), 0.81- 0.52 (m, 1H), 0.47-0.17 (m, 2H), 0.14--0.13 (m, 2H). LC-MS (Method C): R _t = 0.524 min; MS (ESIpos): m/z = 519.3 [M+H] ⁺ . HPLC (Method S): R _t = 1.814 min; purity: 97%. SFC: dr = 64: 36. To a solution of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-(tetrahydrofuran- 3- carbonylamino)butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxyl ic acid (200 mg, 568 μmol, 1.00 eq), 2- amino-2-(1,6-naphthyridin-8-yl)acetonitrile (105 mg, 568 μmol, 1.00 eq) and diisopropylethylamine (220 mg, 1.70 mmol, 297 μL, 3.00 eq) in dichloromethane (2.00 mL) was added O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluronium hexafluorophosphate (237 mg, 624 μmol, 1.10 eq). After stirring at 25 °C for 12 h, the reaction mixture was concentrated in vacuum at 50 °C to give a residue. The residue was purified by prep-TLC (SiO ₂ , Dichloromethane: Tetrahydrofuran = 1: 1) followed by prep-HPLC (column: Waters Xbridge 150*25mm* 5 μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 28%-58%,8min) to afford (1R,2S,5S)-N-[cyano(1,6-naphthyridin-8-yl)methyl]-6,6-dimeth yl-3-[(2S)-3-methyl-2- (tetrahydrofuran-3-carbonylamino)butanoyl]-3-azabicyclo[3.1. 0]hexane-2-carboxamide (125 mg, 238 μmol, 42% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.56 (d, J = 7.6 Hz, 0.5H), 9.52 (d, J = 2.4 Hz, 1H), 9.42 (d, J = 7.6 Hz, 0.5H), 9.31-9.21 (m, 1H), 8.94 (d, J = 11.6 Hz, 1H), 8.71 (dd, J = 8.4, 1.6 Hz, 1H), 8.21 (dd, J = 11.6, 8.6 Hz, 1H), 7.85 (dd, J = 8.4, 4.0 Hz, 1H), 6.88 (d, J = 7.6 Hz, 0.5H), 6.82 (d, J = 7.6 Hz, 0.5H), 4.30 (dd, J = 16.4, 3.2 Hz, 1H), 4.14 (td, J = 16.4, 8.4 Hz, 1H), 3.92-3.74 (m, 3H), 3.72-3.60 (m, 2H), 3.58-3.53 (m, 0.5H), 3.50-3.43 (m, 0.5H), 3.06-2.93 (m, 1H), 1.98-1.80 (m, 3H), 1.60-1.44 (m, 1H), 1.39 (dd, J = 7.6, 2.0 Hz, 0.5H), 1.20 (dd, J = 7.6, 1.6 Hz, 0.5H), 1.07-1.03 (m, 1.5H), 0.95-0.92 (m, 1.5H), 0.85 (d, J = 6.8 Hz, 4H), 0.81 (d, J = 7.2 Hz, 3H), 0.78 (s, 1H), 0.77 (br. s, 1H). LC-MS (Method C): Rt = 0.620 min; MS (ESIpos): m/z = 519.2[M+H] ⁺ . SFC: dr = 18: 27: 32: 22. Preparation of CPD0279324 Procedure for preparation of methyl (1R, 2S, 5S)-3-[(2S)-2-(tertbutoxycarbonylamino)-3- cyclopropyl-propanoyl]-6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate To a mixture of (2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propanoic acid (500 mg, 2.18 mmol, 1 eq) and N,N-diisopropylethylamine (1.41g, 10.9 mmol, 1.90 mL, 5 eq) in N,N-dimethylformamide (5 mL) was added o-(7-azabenzotriazol-1-yl)-n,n,n,n-tetramethyluronium hexafluorophosphate (1.24 g, 3.27 mmol, 1.5 eq) at 0 °C. After stirring at the same temperature for 0.5 hour, methyl (1R, 2S, 5S)-6, 6- dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate (449 mg, 2.18 mmol, 1 eq, HCl) was added to the above mixture at 0 °C. The reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (30 mL ´ 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give a residue. The residue was purified by Combi-Flash (SiO ₂ , Petroleum ether: Ethyl acetate = 4: 1 to 7: 3) to give methyl (1R,2S,5S)-3-[(2S)-2-(tertbutoxycarbonylamino)-3-cyclopropyl -propanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (800 mg, 2.10 mmol, 96% yield) as a yellow gum. ¹ H NMR (400MHz, CDCl ₃ ) δ = 5.17 (d, J = 9.2 Hz, 1H), 4.50-4.40 (m, 2H), 3.99-3.84 (m, 2H), 3.73 (s, 3H), 1.83-1.67 (m, 2H), 1.55-1.47 (m, 1H), 1.40 (s, 9H), 1.38-1.32 (m, 1H), 1.05 (s, 3H), 0.95 (s, 3H), 0.87-0.77 (m, 1H), 0.43-0.52 (m, 2H), 0.05-0.17 (m, 2H). Procedure for preparation of methyl (1R, 2S, 5S)-3-[(2S)-2-amino-3-cyclopropyl-propanoyl]-6, 6- dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate A mixture of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropy l-propanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (800 mg, 2.10 mmol, 1 eq) in hydrochloric acid (4 M in dioxane, 10 mL) was stirred at 25 °C for 5 hours. The reaction mixture was concentrated to give methyl (1R,2S,5S)-3-[(2S)-2-amino-3-cyclopropyl-propanoyl]-6,6-dime thyl-3-azabicyclo[3.1.0]hexane- 2-carboxylate (660 mg, crude, HCl salt) as a yellow solid. NMR (400MHz, DMSO-d ₆ ) δ (ppm) = 8.44 (s, 3H), 4.26 (s, 1H), 4.05-4.16 (m, 1H), 3.71-3.84 (m, 2H), 3.66 (s, 3H), 1.64-1.76 (m, 1H), 1.53-1.63 (m, 2H), 1.48 (d, J = 7.2 Hz, 1H), 1.02 (s, 3H), 0.94 (s, 3H), 0.84-0.91 (m, 1H), 0.39-0.52 (m, 2H), 0.13-0.23 (m, 2H). Procedure for preparation of methyl (1R, 2S, 5S)-3-[(2S)-3-cyclopropyl-2-[(2-tetrahydropyran-4- ylacetyl)amino]propanoyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate To a mixture of 2-tetrahydropyran-4-ylacetic acid (300 mg, 2.08 mmol, 1 eq) and N,N- diisopropylethylamine (1.34 g, 10.4 mmol, 1.81 mL, 5 eq) in N,N-dimethylformamide (5 mL) was added o-(7-azabenzotriazol-1-yl)-n,n,n,n-tetramethyluronium hexafluorophosphate (1.19 g, 3.12 mmol, 1.5 eq) at 0 °C. After stirring for 0.5 hour, methyl (1R,2S,5S)-3-[(2S)-2-amino-3-cyclopropyl-propanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (659 mg, 2.08 mmol, 1 eq, HCl salt) was added to the above mixture at 0 °C. After stirring at 25 °C for 12 hours, the reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (50 mL ´ 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give a residue. The residue was purified by Combi-Flash (Petroleum ether: Ethyl acetate = 1: 4) to give methyl (1R,2S,5S)-3-[(2S)- 3-cyclopropyl-2-[(2-tetrahydropyran-4-ylacetyl)amino]propano yl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (800 mg, 1.73 mmol, 83% yield, 88% purity) as a yellow gum. LC-MS (Method C): R _t = 0.647 min; MS (ESIpos): m/z = 407.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[(2-tetrahydropyran-4- ylacetyl)amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]he xane-2-carboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[(2-tetrahydropyran-4- ylacetyl)amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]he xane-2-carboxylate (400 mg, 0.984 mmol, 1 eq) in tetrahydrofuran (5 mL) was added a solution of lithium hydroxide water complex (124 mg, 2.95 mmol, 3 eq) in water (5 mL) at 25 °C. After stirring at 25 °C for 16 hours, the mixture was diluted with water (10 mL) and adjusted to pH = 3 by hydrochloric acid (1M), and extracted with ethyl acetate (15 mL ´ 2). The combined organic layers were washed with brine (10 mL ´ 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-3- [(2S)-3-cyclopropyl-2-[(2-tetrahydropyran-4-ylacetyl)amino]p ropanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (320 mg, crude) as a yellow solid. To a solution of 2-amino-2-phthalazin-1-yl-acetamide (195 mg, 0.815 mmol, 1 eq, HCl), o-(7- azabenzotriazol-1-yl)-n,n,n,n-tetramethyluronium hexafluorophosphate (372 mg, 0.978 mmol, 1.2 eq) and N,N-diisopropylethylamine (316 mg, 2.45 mmol, 3 eq) in N,N-dimethylformamide (3 mL) was added (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[(2-tetrahydropyran-4-yla cetyl)amino]propanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0] hexane-2-carboxylic acid (320 mg, 0.815 mmol, 1 eq) at 0 °C. After stirring at 25 °C for 2 hours, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (15 mL ´ 3). The combined organic layers were washed with brine (20 mL ´ 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (DCM: Methanol = 100: 1 to 10: 1) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin- 1-yl-ethyl)-3-[(2S)-3-cyclopropyl-2-[(2-tetrahydropyran-4-yl acetyl)amino]propanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (140 mg, 0.243 mmol, 30% yield) as a white solid. LC-MS (Method C): R _t = 0.574 min; MS (ESIpos): m/z = 577.3 [M+H] ⁺ _. To a solution of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -3-cyclopropyl-2-[(2- tetrahydropyran-4-ylacetyl)amino]propanoyl]-6,6-dimethyl-3-a zabicyclo[3.1.0]hexane-2-carboxamide (120 mg, 0.208 mmol, 1.00 eq) in dichloromethane (6.00 mL) was added Burgess reagent (64.5 mg, 0.271 mmol, 1.30 eq) at 0 °C. After stirring at 25 °C for 2 h, additional Burgess reagent (100 mg, 0.416 mmol, 2.00 eq) was added to the mixture at 25 °C. The mixture was stirred at 25 °C for another 16 h. The solution was diluted with water (10.0 mL) and saturated ammonium chloride aqueous (10.0 mL), extracted with dichloromethane (10.0 mL ´ 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to give a residue. The residue was purified by preparative-HPLC (column: Boston Green ODS 150*30mm* 5μm; mobile phase: [water (0.225% FA)-ACN]; B%: 25%-55%, 14 min) to give an impure product (60 mg, 0.107 mmol, 52% yield) as a yellow solid. The impure product was purified again by preparative-HPLC (column: Boston Green ODS 150*30mm*5 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 25%- 55%,14 min) to give (1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]-3-[(2S)-3-cyclop ropyl-2-[(2- tetrahydropyran-4-ylacetyl)amino]propanoyl]-6,6-dimethyl-3-a zabicyclo[3.1.0]hexane-2-carboxamide (9.90 mg, 0.0168 mmol, 24% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.66 (s, 0.4H), 9.91-9.47 (m, 0.5H), 9.31 (s, 0.4H), 8.82-8.73 (m, 0.4H), 8.30-8.19 (m, 0.9H), 8.18-8.03 (m, 1.3H), 8.01-7.90 (m, 0.4H), 7.87-7.72 (m, 1.3H), 7.25-7.22 (m, 0.2H), 4.70-4.08 (m, 2H), 3.98-3.61 (m, 4H), 3.29-3.15 (m, 2H), 2.11-1.94 (m, 2H), 1.93-1.76 (m, 1H), 1.75-1.23 (m, 6H), 1.21-1.09 (m, 2H), 1.07-0.80 (m, 6H), 0.79-0.54 (m, 1H), 0.50-0.23 (m, 2H), 0.20-0.16 (m, 2H). LC-MS (Method L): R _t = 0.535 min; MS (ESIpos): m/z = 559.3 [M+H] ⁺ . HPLC (Method M): R _t = 1.876 min; HPLC purity: 95%. SFC: dr = 30: 38: 32. Preparation of CPD0279325 Procedure for preparation of (1R,2S,5S)-methyl 3-((S)-3-cyclopropyl-2-(2-(tetrahydro-2H-pyran- 4-yl)acetamido)propanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]he xane-2-carboxylate. To a solution of methyl (1R,2S,5S)-3-[(2S)-2-amino-3-cyclopropyl-propanoyl]-6,6-dime thyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (500 mg, 1.58 mmol, 1.00 eq, Hydrochloride) and N-ethyl-N- propan-2-ylpropan-2-amine (612 mg, 4.73 mmol, 0.825 mL, 3.00 eq) in dichloromethane (10.0 mL) were added 2-tetrahydropyran-4-ylacetic acid (250 mg, 1.74 mmol, 31.6 uL, 1.10 eq) and [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-d imethylazanium;hexafluorophosphate (600 mg, 1.58 mmol, 1.00 eq) at 25 °C. After stirring at 25 °C for 1 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 1 to 0: 1) to give methyl (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[(2- tetrahydropyran-4-ylacetyl)amino]propanoyl]-6,6-dimethyl-3-a zabicyclo[3.1.0]hexane-2-carboxylate (600 mg, 1.18 mmol, 75% yield, 80% purity) as yellow oil. Procedure for preparation of [(1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[(2-tetrahydropyran-4- ylacetyl)amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]he xane-2-carboxylic acid. To a solution of methyl (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[(2-tetrahydropyran-4- ylacetyl)amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]he xane-2-carboxylate (500 mg, 1.23 mmol, 1.00 eq) in methanol (10.0 mL) was added lithium hydroxide (155 mg, 3.69 mmol, 3.00 eq) at 25 °C. After stirring at 25 °C for 1 h, acetic acid was added to adjust pH~4 and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with water (50 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give [(1R,2S,5S)-3-[(2S)-3- cyclopropyl-2-[(2-tetrahydropyran-4-ylacetyl)amino]propanoyl ]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (500 mg, crude) as a white solid. Procedure for preparation of (1R,2S,5S)-N-((S)-1-amino-3-((S)-7-fluoro-3-oxo-3,4-dihydro- 2H- benzo[b][1,4]oxazin-2-yl)-1-oxopropan-2-yl)-3-((S)-3-cyclopr opyl-2-(2-(tetrahydro-2H-pyran-4- yl)acetamido)propanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexa ne-2-carboxamide. To a solution of (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[(2-tetrahydropyran-4-yla cetyl)amino]propanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (200 mg, 0.510 mmol, 1.00 eq) in N,N- dimethylformamide (2.00 mL) were added (2S)-2-amino-3-[(2S)-7-fluoro-3-oxo-4H-1,4-benzoxazin-2- yl]propanamide (148 mg, 0.510 mmol, 1.00 eq, Hydrochloride), [dimethylamino(triazolo[4,5-b]pyridin-3- yloxy)methylidene]-dimethylazanium;hexafluorophosphate (194 mg, 0.510 mmol, 1.00 eq) and N-ethyl- N-propan-2-ylpropan-2-amine (198 mg, 1.53 mmol, 0.266 mL, 3.00 eq) at 25 °C. After stirring at 25 °C for 1 h, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 1 to 0: 1, Petroleum ether: Ethyl acetate = 0: 1) to give (1R,2S,5S)-N-[(1S)-2-amino-1-[[(2S)-7-fluoro-3-oxo-4H-1,4-be nzoxazin-2-yl]methyl]-2- oxo-ethyl]-3-[(2S)-3-cyclopropyl-2-[(2-tetrahydropyran-4-yla cetyl)amino]propanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (300 mg, 0.430 mmol, 84% yield, 90% purity) as a white solid. Procedure for preparation of CPD0279325 - (1R, 2S, 5S)-N-[(1S)-1-cyano-2-[(2S)-7-fluoro-3-oxo- 4H-1,4-benzoxazin-2-yl]ethyl]-3-[(2S)-3-cyclopropyl-2-[(2-te trahydropyran-4- ylacetyl)amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]he xane-2-carboxamide To a solution of (1R,2S,5S)-N-[(1S)-2-amino-1-[[(2S)-7-fluoro-3-oxo-4H-1,4-be nzoxazin-2-yl]methyl]-2- oxo-ethyl]-3-[(2S)-3-cyclopropyl-2-[(2-tetrahydropyran-4-yla cetyl)amino]propanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (250 mg, 0.398 mmol, 1.00 eq) in dichloromethane (5.00 mL) was added methoxycarbonyl-(triethylammonio)sulfonyl-azanide (94.9 mg, 0.398 mmol, 1.00 eq) at 25 °C. After stirring at 25 °C for 1 h, the reaction mixture was concentrated under reduced pressure and purified by prep-HPLC [column: Phenomenex C1875*30mm*3 μm; mobile phase: [water (formic acid)- acetonitrile]; B%: 32%-62%, 7 min] to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-7-fluoro-3-oxo-4H-1,4- benzoxazin-2-yl]ethyl]-3-[(2S)-3-cyclopropyl-2-[(2-tetrahydr opyran-4-ylacetyl)amino]propanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (97.4 mg, 0.163 mmol, 41% yield, 99% purity) as a white solid. LC-MS (Method G): Rt = 0.844 min; MS (ESIpos): m/z = 610.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.82 (s, 1H), 9.01-8.84 (m, 1H), 8.11-8.00 (m, 1H), 6.92-6.81(m, 2H), 6.79-6.73 (m, 1H), 5.09-4.97 (m, 1H), 4.66-4.53 (m, 1H), 4.44-4.30 (m, 1H), 4.15-4.02 (m, 1H), 3.87-3.81 (m, 2H), 3.80-3.72 (m, 2H), 3.27-3.16 (m, 2H), 2.31-2.24 (m, 1H), 2.02-1.92 (m, 2H), 1.86- 1.73 (m, 1H), 1.57-1.51 (m, 1H), 1.49-1.40 (m, 2H), 1.39-1.31 (m, 1H), 1.29 (d, J = 7.6 Hz, 1H), 1.16- 1.03 (m, 3H), 1.02-0.99 (m, 3H), 0.88-0.85 (m, 3H), 0.72-0.60 (m, 1H), 0.40-0.27 (m, 2H), 0.1--0.01 (m, 1H), -0.03--0.09 (m, 1H). Preparation of CPD0279327 Procedure for preparation of (2S)-3-methyl-2-(pyrimidin-5-ylamino)butanoic acid A mixture of 5-bromopyrimidine (20.7 g, 130 mmol, 2.00 eq), (2S)-2-amino-3-methyl-butanoic acid (10.0 g, 65.1 mmol, 1.00 eq, hydrochloric acid), iodocopper (1.24 g, 6.51 mmol, 0.100 eq) and potassium carbonate (26.9 g, 195 mmol, 3.00 eq) in methylsulfinylmethane (100 mL) was degassed and purged with nitrogen for 3 times. After stirring at 100 °C for 16 h under nitrogen atmosphere, the reaction mixture was partitioned between water (200 mL) and ethyl acetate (400 mL). The aqueous solution was filtered and adjusted to pH~6 with hydrochloric acid (1M). The solution was lyophilized to give a residue. The residue was diluted with mixed solvent of methanol and dichloromethane (v/v =10/1, 500 mL) and stirred at 25 °C for 30 min. The suspension was filtered and the filtrate was concentrated to give (2S)-3-methyl- 2-(pyrimidin-5-ylamino)butanoic acid (10.0 g, 51.2 mmol, 79% yield, contained DMSO) as a green oil. Procedure for preparation of methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-(pyrimidin-5- ylamino)butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylate A mixture of (2S)-3-methyl-2-(pyrimidin-5-ylamino)butanoic acid (1.50 g, 7.68 mmol, 1.00 eq), methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (1.95 g, 9.48 mmol, 1.23 eq, hydrogen chloride), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dim ethyl- ammonium;hexafluorophosphate (5.84 g, 15.4 mmol, 2.00 eq) and N,N-diisopropylethylamine (2.98 g, 23.0 mmol, 4.02 mL, 3.00 eq) in dichloromethane (20.0 mL) was stirred 25 °C for 16 h. The mixture was concentrated to give a residue. The residue was purified by reversed phase (instrument: 120 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-10 min 0-60% B; flow 85 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-(pyrimidin-5-ylam ino)butanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxylate (420 mg, 1.18 mmol, 15% yield, 97% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.39-8.33 (m, 1H), 8.23-8.17 (m, 2H), 6.10-6.03 (m, 1H), 4.19 (s, 1H), 4.16-4.07 (m, 1H), 3.91-3.79 (m, 2H), 3.64 (s, 3H), 2.18-1.89 (m, 1H), 1.66-1.52 (m, 1H), 1.42 (d, J = 7.6 Hz, 1H), 1.03-0.98 (m, 6H), 0.95 (d, J = 6.8 Hz, 3H), 0.81 (s, 3H). Procedure for preparation of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-(pyrimidin-5- ylamino)butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid A mixture of methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-(pyrimidin-5-ylam ino)butanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxylate (300 mg, 0.866 mmol, 1.00 eq) and lithium hydroxide (104 mg, 4.33 mmol, 5.00 eq) in mixed solvent of methanol (3.00 mL) and water (0.200 mL) was stirred 25 °C for 16 h. The mixture was concentrated to give a residue. The residue was purified by reversed phase (instrument: 120 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-10 min 0-60% B; flow 85 ml/min; temperature: room temperature; Detector: UV 220/254 nm)] to give (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-(pyrimidin-5-ylam ino)butanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (220 mg, 0.490 mmol, 57% yield, 74% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.66 (br. s, 1H), 8.39-8.33 (m, 1H), 8.23-8.18 (m, 2H), 6.12-5.97 (m, 1H), 4.18-4.05 (m, 2H), 3.91-3.75 (m, 2H), 2.15-2.08 (m, 1H), 1.64-1.50 (m, 1H), 1.45-1.38 (m, 1H), 1.03-0.99 (m, 6H), 0.96-0.91 (m, 3H), 0.80 (s, 3H). Procedure for preparation of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-6,6-dim ethyl- 3-[(2S)-3-methyl-2-(pyrimidin-5-ylamino)butanoyl]-3-azabicyc lo[3.1.0]hexane-2-carboxamide A mixture of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-(pyrimidin-5-ylam ino)butanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (60.0 mg, 0.181 mmol, 1.00 eq), 2-amino-2-phthalazin-1-yl- acetamide (36.5 mg, 0.153 mmol, 1.00 eq, hydrochloric acid), N,N-diisopropylethylamine (69.9 mg, 0.541 mmol, 94.3 μL, 3.00 eq) and [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dim ethyl- ammonium;hexafluorophosphate (102 mg, 0.270 mmol, 1.50 eq) in dichloromethane (1.00 mL) was stirred 25 °C for 16 h. The mixture was concentrated to give a residue. The residue was purified by reversed phase (instrument: 40 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-10 min 0-60% B; flow 60 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)- 6,6-dimethyl-3-[(2S)-3-methyl-2-(pyrimidin-5-ylamino)butanoy l]-3-azabicyclo[3.1.0]hexane-2- carboxamide (40.0 mg, 7.40 μmol, 17% yield) as a yellow solid. A mixture of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-6,6-dim ethyl-3-[(2S)-3-methyl-2- (pyrimidin-5-ylamino)butanoyl]-3-azabicyclo[3.1.0]hexane-2-c arboxamide (80.0 mg, 0.155 mmol, 1.00 eq) and methoxycarbonyl-(triethylammonio)sulfonyl-azanide (110 mg, 0.464 mmol, 3.00 eq) in dichloromethane (1.00 mL) was stirred 25 °C for 4 h. The mixture was concentrated to give a residue. The residue was purified by reversed phase (ccolumn: Phenomenex Synergi Polar-RP 100*25mm*4 μm; mobile phase: [water(TFA)-ACN];B%: 33%-63%,9min) to give (1R,2S,5S)-N-[cyano(phthalazin-1- yl)methyl]-6,6-dimethyl-3-[(2S)-3-methyl-2-(pyrimidin-5-ylam ino)butanoyl]-3-azabicyclo[3.1.0]hexane- 2-carboxamide as a yellow solid. LC-MS (Method C): Rt = 0.478 min; MS (ESIpos): m/z = 499.3[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.68 (s, 0.3H), 9.77 (s, 0.53H), 9.76 (br. s, 0.16H), 9.67 (d, J = 8.8 Hz, 0.23H), 9.41 (s, 0.4H), 8.85-8.71 (m, 0.5H), 8.51-8.34 (m, 1H), 8.33-8.15 (m, 2.5H), 8.14-8.04 (m, 1.4H), 8.03-7.92 (m, 0.9H), 7.87-7.80 (m, 0.8H), 7.79-0.74 (m, 0.4H), 7.31-7.25 (m, 0.4H), 6.39-5.90 (m, 0.6H), 4.26 (s, 0.5H), 4.20 (s, 0.2H), 4.14 (s, 0.3H), 4.13-4.08 (m, 0.9H), 4.07-4.04 (m, 0.2H), 3.97- 3.83 (m, 2H), 2.16-2.04 (m, 1H), 1.83-1.60 (m, 1H), 1.60-1.54 (m, 0.65H), 1.30 (d, J = 7.6 Hz, 0.3H), 1.08-0.93 (m, 8H), 0.90-0.84 (m, 3H), 0.78-0.74 (m, 1H). Preparation of CPD0279328 Procedure for preparation of (S)-3-cyclopropyl-2-(pyrimidin-5-ylamino)propanoic acid To a mixture of (2S)-2-amino-3-cyclopropyl-propanoic acid (5.00 g, 38.7 mmol, 1.00 eq) and 5- bromopyrimidine (9.23 g, 58.0 mmol, 1.50 eq) in (methylsulfinyl)methane (50.0 mL) were added potassium carbonate (16.0 g, 116 mmol, 3.00 eq), copper(I) iodide (737 mg, 3.87 mmol, 0.10 eq) under nitrogen atmosphere. After stirring at 100 °C for 16 h under nitrogen atmosphere, the reaction mixture was quenched with water (150 mL) at 25 °C, and extracted with ethyl acetate (200 mL). Hydrogen chloride (1M) was added to adjust pH~2 and extracted with ethyl acetate (200 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with dichloromethane (30.0 mL) at 25 °C for 30 min, and filtered. The filter cake was dried under reduced pressure to afford (2S)-3-cyclopropyl-2- (pyrimidin-5-ylamino)propanoic acid (3.50 g, 13.5 mmol, 35% yield, 80% purity) as a brown solid. LC-MS (Method A): R _t = 0.345 min, MS (ESIpos): m/z = 208.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 13.15-12.33 (m, 1H), 8.74-8.09 (m, 2H), 6.41 (br. s, 1H), 4.09 (br. s, 1H), 1.77-1.58 (m, 2H), 0.91-0.77 (m, 1H), 0.46-0.34 (m, 2H), 0.21-0.04 (m, 2H). Procedure for preparation of methyl (1R,2S,5S)-3-((S)-3-cyclopropyl-2-(pyrimidin-5- ylamino)propanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylate To a solution of (2S)-3-cyclopropyl-2-(pyrimidin-5-ylamino)propanoic acid (2.50 g, 12.0 mmol, 1.00 eq), methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (2.98 g, 14.4 mmol, 1.20 eq, hydrogen chloride) in dichloromethane (30.0 mL) were added diisopropylethylamine (6.24 g, 48.2 mmol, 8.41 mL, 4.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (6.88 g, 18.1 mmol, 1.50 eq). After stirring at 25 °C for 16 h, the reaction mixture was quenched with water (30 mL) at 25 °C, extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate = 1: 0 to 1: 1) to give methyl (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-(pyrimidin-5-ylamino)prop anoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylate (2.90 g, 8.09 mmol, 67% yield, 90% purity) as a red solid. LC-MS (Method C): R _t = 1.255 min, MS (ESIpos): m/z = 359.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.45-8.34 (m, 1H), 8.12 (s, 2H), 6.28 (d, J = 9.2 Hz, 1H), 4.40-4.30 (m, 1H), 4.19 (s, 1H), 3.94 (d, J = 10.8 Hz, 1H), 3.83-3.78 (m, 1H), 3.63 (s, 3H), 1.63-1.48 (m, 3H), 1.42 z, 1H), 1.02 (s, 3H), 0.89 (s, 4H), 0.49-0.28 (m, 2H), 0.27-0.08 (m, 2H). 89. Procedure for preparation of (1R,2S,5S)-3-((S)-3-cyclopropyl-2-(pyrimidin-5-ylamino)propa noyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-(pyrimidin-5-ylamino)prop anoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.00 g, 2.79 mmol, 1.00 eq) in mixed solvent of methyl alcohol (10.0 mL) and water (2.00 mL) was added lithium hydroxide (234 mg, 5.58 mmol, 2.00 eq). After stirring at 25 °C for 4 h, the reaction mixture was diluted with water (20.0 mL) and washed with ethyl acetate (10.0 mL). Hydrogen chloride (1M) was added to aqueous phase to adjusted pH~2 and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-3-[(2S)-3- cyclopropyl-2-(pyrimidin-5-ylamino)propanoyl]-6,6-dimethyl-3 -azabicyclo[3.1.0]hexane-2-carboxylic acid (600 mg, 1.74 mmol, 62% yield, 90% purity) as a yellow solid. LC-MS (Method C): R _t = 1.431 min, MS (ESIpos): m/z = 345.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.50-8.34 (m, 1H), 8.23-8.05 (m, 2H), 4.38-4.30 (m, 1H), 4.11 (s, 1H), 3.93 (d, J = 10.8 Hz, 1H), 3.79-3.76 (m, 1H), 1.64-1.43 (m, 3H), 1.40 (d, J = 7.6 Hz, 1H), 1.02 (s, 3H), 0.95-0.77 (m, 4H), 0.47-0.33 (m, 2H), 0.26-0.03 (m, 2H). SFC: dr = 21: 78. To a solution of (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-(pyrimidin-5-ylamino)prop anoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (1.00 g, 2.90 mmol, 1.00 eq), 2-amino-2-phthalazin-1-yl- acetamide (1.04 g, 4.36 mmol, 1.50 eq, hydrogen chloride) in dichloromethane (15.0 mL) and N,N- dimethylformamide (5.00 mL) were added diisopropylethylamine (1.50 g, 11.6 mmol, 2.02 mL, 4.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (1.66 g, 4.36 mmol, 1.50 eq). After stirring at 25 °C for 16 h, the reaction mixture was quenched with water (20 mL) at 20 °C, and extracted with dichloromethane (20.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was reversed phase (instrument: 80 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.05% FA), eluent B: acetonitrile; gradient: 0-20min 0-50% B; flow 55 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl- ethyl)-3-[(2S)-3-cyclopropyl-2-(pyrimidin-5-ylamino)propanoy l]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (600 mg, 1.14 mmol, 39% yield, 85% purity) as a yellow solid. LC-MS (Method C): R _t = 1.312 min, MS (ESIpos): m/z = 529.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.69 - 9.56 (m, 1H), 9.27-8.83 (m, 1H), 8.40-8.34 (m, 1H), 8.32-8.25 (m, 1H), 8.24-8.16 (m, 1H), 8.13-8.02 (m, 3H), 7.98-7.82 (m, 1H), 7.66-7.22 (m, 2H), 6.51-5.76 (m, 2H), 4.52-4.22 (m, 2H), 3.99-3.77 (m, 2H), 1.62-1.44 (m, 3H), 1.23-1.16 (m, 1H), 1.08-1.02 (m, 1H), 0.98- 0.77 (m, 6H), 0.61-0.35 (m, 2H), 0.28-0.06 (m, 2H). Procedure for preparation of Compound CPD0279328 - (1R,2S,5S)-N-(cyano(phthalazin-1- yl)methyl)-3-((S)-3-cyclopropyl-2-(pyrimidin-5-ylamino)propa noyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -3-cyclopropyl-2- (pyrimidin-5-ylamino)propanoyl]-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2-carboxamide (600 mg, 1.14 mmol, 1.00 eq) in dichloromethane (7.00 mL) were added 2,2,2-trifluoroacetic anhydride (715 mg, 3.41 mmol, 0.473 mL, 3.00 eq) and triethylamine (344 mg, 3.41 mmol, 0.479 mL, 3 eq). After stirring at 25 °C for 1 h, the reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (20.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 1 to 0: 1) followed by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(formic acid)- acetonitrile];B%: 25%- 55%,8min) to give (1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]-3-[(2S)-3-cyclop ropyl-2-(pyrimidin-5- ylamino)propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (35 mg, 68.6 μmol, 6% yield) as a yellow solid. LC-MS (Method C): R _t = 1.286 min, MS (ESIpos): m/z = 511.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.62 (s, 0.3H), 9.74 (S, 0.4H), 9.71-9.67 (d, J = 8.2 Hz, 0.2H), 9.62 (d, J = 8.6 Hz, 0.2H), 9.32 (s, 0.39H), 8.82-8.71 (m, 0.4H), 8.39 (s, 0.3H), 0.37 (s, 0.2H), 8.35 (s, 0.2H), 8.39-8.34 (m, 1H), 8.31-8.18 (m, 1H), 8.15 (s, 1H), 8.12-8.05 (m, 2H), 8.01-7.92 (m, 1H), 7.85-7.73 (m, 1H), 7.24 (dd., J = 8.4, 4.4 Hz, 1H), 6.37 (d, J = 9.2 Hz, 0.4H), 6.29-6.21 (m, 0.5H), 4.41-4.27 (m, 1H), 4.26 (s, 0.4H), 4.20 (s, 0.24H), 4.16 (s, 0.2H), 3.99-3.85 (m, 1.6H), 3.71-3.46 (m, 0.5H), 1.74-1.48 (m, 3H), 1.47-1.21 (m, 1H), 1.12-0.74 (m, 7H), 0.53-0.32 (m, 2H), 0.30-0.00 (m, 2H). SFC: dr = 34: 33: 31. Preparation of CPD0279329 Procedure for preparation of Methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3- cyclopropyl-propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan e-2-carboxylate To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propanoic acid (4.90 g, 21.4 mmol, 1.00 eq) and methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (4.84 g, 23.5 mmol, 1.10 eq, Hydrochloride) in methylene chloride (60 mL) were added 3-[chloro-(2-oxo-1,3- oxazolidin-3-yl)phosphoryl]-1,3-oxazolidin-2-one (5.71 g, 22.4 mmol, 1.05 eq) and N-ethyl-N-propan-2- ylpropan-2-amine (8.29 g, 64.1 mmol, 3.00 eq) at 25 °C. After stirring at 25 °C for 15 h, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 10: 1 to 5: 1) to give methyl (1R,2S,5S)-3-[(2S)-2-(tert- butoxycarbonylamino)-3-cyclopropyl-propanoyl]-6,6-dimethyl-3 -azabicyclo[3.1.0]hexane-2-carboxylate (8.00 g, 18.9 mmol, 88% yield, 90% purity) as yellow oil. Procedure for preparation of Methyl (1R, 2S, 5S)-3-[(2S)-2-amino-3-cyclopropyl-propanoyl]-6, 6- dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate. A mixture of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropy l-propanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (7.90 g, 20.8 mmol, 1.00 eq) in hydrogen chloride (4 M in ethyl acetate, 100 mL, 19.3 eq) was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give methyl (1R,2S,5S)-3-[(2S)-2-amino-3-cyclopropyl-propanoyl]-6, 6- dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxylate (7 g, crude, Hydrochloride) as a yellow solid. Procedure for preparation of methyl (1R,2S,5S)-3-((S)-2-(cyclopropanecarboxamido)-3- cyclopropylpropanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane -2-carboxylate To a solution of methyl (1R,2S,5S)-3-[(2S)-2-amino-3-cyclopropyl-propanoyl]-6,6-dime thyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (1.00 g, 3.16 mmol, 1.00 eq, Hydrogen chloride) and N-ethyl-N- propan-2-ylpropan-2-amine (1.22 g, 9.47 mmol, 1.65 mL, 3.00 eq) in methylene chloride (20.0 mL) was added cyclopropanecarbonyl chloride (363 mg, 3.47 mmol, 0.316 mL, 1.10 eq) at 25 °C. After stirring at 25 °C for 1 h, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 5: 1 to 1: 1) to give methyl (1R,2S,5S)-3-[(2S)- 2-(cyclopropanecarbonylamino)-3-cyclopropyl-propanoyl]-6,6-d imethyl-3-azabicyclo[3.1.0]hexane-2- carboxylate (1.00 g, 2.87 mmol, 91% yield) as yellow oil. Procedure for preparation of (1R, 2S, 5S)-3-((S)-2-(cyclopropanecarboxamido)-3- cyclopropylpropanoyl)-6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-2-(cyclopropanecarbonylamino)-3-cycloprop yl-propanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (500 mg, 1.43 mmol, 1.00 eq) in methanol (10.0 mL) was added lithium hydroxide (4.00 M, 1.08 mL, 3.00 eq) at 25 °C. After stirring at 25 °C for 1 h, hydrogen chloride (1M) was added to adjust pH to 4. The solution was extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with water (100 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give [(1R,2S,5S)-3-[(2S)-2- (cyclopropanecarbonylamino)-3-cyclopropyl-propanoyl]-6,6-dim ethyl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (500 mg, crude) as yellow oil. To a solution of (1R,2S,5S)-3-[(2S)-2-(cyclopropanecarbonylamino)-3-cycloprop yl-propanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (250 mg, 0.748 mmol, 1.00 eq) and 2-amino-2- phthalazin-1-yl-acetamide (214 mg, 0.897 mmol, 1.20 eq, Hydrogen chloride) in methylene chloride (10 mL) were added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]- dimethylazanium;hexafluorophosphate (284 mg, 0.747 mmol, 1.00 eq) and N-ethyl-N-propan-2- ylpropan-2-amine (290 mg, 2.24 mmol, 0.391 mL, 3.00 eq) at 25 °C. After stirring at 25 °C for 1 h, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 1 to 0: 1) to give (1R, 2S, 5S)-N-(2-amino-2-oxo-1-phthalazin- 1-yl-ethyl)-3-[(2S)-2-(cyclopropanecarbonylamino)-3-cyclopro pyl-propanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (300 mg, 0.463 mmol, 62% yield, 80% purity) as a yellow solid. To a solution of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -2- (cyclopropanecarbonylamino)-3-cyclopropyl-propanoyl]-6,6-dim ethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (300 mg, 0.579 mmol, 1.00 eq) in methylene chloride (10.0 mL) was added methoxycarbonyl-(triethylammonio)sulfonyl-azanide (137 mg, 0.578 mmol, 1.00 eq) at 25 °C. After stirring at 25 °C for 1 h, the reaction mixture was concentrated under reduced pressure and purified by prep-HPLC [column: Phenomenex C18 75*30mm*3 μm; mobile phase: [water(Formic acid)- acetonitrile];B%: 38%-68%,7min]and column: Waters Xbridge 150*25mm* 5 μm; mobile phase: [water(Carbonic acid hydrogen ammonia)- acetonitrile]; B%: 33%-63%,8min, column: Phenomenex C1875*30mm*3 μm; mobile phase: [water(FA)-ACN]; B%: 35%-65%, 7min] to give (1R,2S,5S)-N- [cyano(phthalazin-1-yl)methyl]-3-[(2S)-2-(cyclopropanecarbon ylamino)-3-cyclopropyl-propanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (42.0 mg, 79.7 μmol, 14% yield, 95% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.67 (s, 0.5H), 9.79-9.74 (m, 0.4H), 9.68-9.64 (m, 0.2H), 9.55-9.50 (m, 0.2H), 9.32 (m, 0.6H), 8.80-8.73 (m, 0.6H), 8.49-8.43 (m, 0.6H), 8.33-8.25 (m, 1H), 8.12-8.04 (m, 1H), 8.02-7.91 (m, 0.6H), 7.86-7.76 (m, 2H), 7.28-7.17 (m, 0.3H), 4.45-4.37 (m, 1H), 4.26-4.15 (m, 1H), 3.93-3.72 (m, 2H), 1.71-1.48 (m, 3.6H), 1.44-1.24 (m, 1.31H), 1.14-1.00 (m, 3H), 0.96-0.88 (m, 2H), 0.85-0.73 (m, 2H), 0.70-0.50 (m, 4H), 0.50-0.25 (m, 2H), 0.22-0.18 (m, 0.3H), 0.15-0.08 (m, 1H), 0.05- -0.03 (m, 0.8H), -0.05--0.15 (m, 0.2H). To a solution of ethyl (1R,2S,5S)-3-[(2S)-2-amino-3-cyclopropyl-propanoyl]-6,6-dime thyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (300 mg, 0.947 mmol, 1.00 eq, Hydrogen chloride) and (2S)-2- methoxypropanoic acid (108 mg, 1.04 mmol, 1.10 eq) in dichloromethane (3.00 mL) were added diisopropylethylamine (367 mg, 2.84 mmol, 0.495 mL, 3.00 eq) and O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluronium hexafluorophosphate (432 mg, 1.14 mmol, 1.20 eq). After stirring at 25 °C for 12 h, the reaction mixture was concentrated under vacuum to give a residue. The residue was purified by flash column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 10: 1 to 4: 1) to afford methyl (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[[(2S)-2-methoxypropanoyl ]amino]propanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylate (350 mg, 0.783 mmol, 83% yield) as colorless oil. LC-MS (Method C): Rt = 0.693 min; MS (ESIpos): m/z = 367.2 [M+H] ^+. Procedure for preparation of (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[[(2S)-2- methoxypropanoyl]amino]propanoyl]-6,6-dimethyl-3-azabicyclo[ 3.1.0]hexane-2-carboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[[(2S)-2- methoxypropanoyl]amino]propanoyl]-6,6-dimethyl-3-azabicyclo[ 3.1.0]hexane-2-carboxylate (350 mg, 955 μmol, 1.00 eq) in mixed solvent of methanol (4.00 mL) and water (0.40 mL) was added lithium hydroxide hydrate (80.2 mg, 1.91 mmol, 2.00 eq). After stirring at 25 °C for 12 h, the solvent was removed under reduced pressure to give a residue. The residue was dissolved with water (20.0 mL). Hydrochloric acid (2M) was added to adjust to pH~2 at 25 °C. The aqueous phase was extracted with ethyl acetate (10.0 mL × 2). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford (1R,2S,5S)-3-[(2S)-3- cyclopropyl-2-[[(2S)-2-methoxypropanoyl]amino]propanoyl]-6,6 -dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (300 mg, 0.851 mmol, 89% yield) as colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.62 (br. s, 1H), 7.85 (d, J = 7.6 Hz, 1H), 4.49 (q, J = 7.2 Hz, 1H), 4.11 (s, 1H), 3.79 (d, J = 2.0 Hz, 2H), 3.72-3.65 (m, 1H), 3.25 (s, 1H), 3.21 (s, 3H), 1.63-1.50 (m, 2H), 1.47-1.37 (m, 2H), 1.17 (d, J = 6.8 Hz, 3H), 1.02 (s, 3H), 0.88 (s, 3H), 0.81-0.71 (m, 1H), 0.44-0.32 (m, 2H), 0.18- 0.11 (m, 1H), 0.09-0.00 (m, 1H). To a solution of (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[[(2S)-2-methoxypropanoyl ]amino]propanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (150 mg, 0.426 mmol, 1.00 eq) and 2-amino-2- (1,6-naphthyridin-8-yl)acetonitrile (78.40 mg, 0.426 mmol, 1.00 eq) in dichloromethane (2.00 mL) were added diisopropylethylamine (165 mg, 1.28 mmol, 0.222 mL, 3.00 eq) and O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluronium hexafluorophosphate (178 mg, 0.468 mmol 1.10 eq). After stirring at 20 °C for 2 h, the reaction mixture was concentrated at 50 °C to give a residue. The residue was purified by prep-TLC (SiO ₂ , Dichloromethane: Tetrahydrofuran = 1: 1) and prep-HPLC (column: Phenomenex luna C18150*25 mm* 10um;mobile phase: [water(FA)-ACN];B%: 33%-53%,9min) to afford (1R,2S,5S)- N-[cyano(1,6-naphthyridin-8-yl)methyl]-3-[(2S)-3-cyclopropyl -2-[[(2S)-2- methoxypropanoyl]amino]propanoyl]-6,6-dimethyl-3-azabicyclo[ 3.1.0]hexane-2-carboxamide (60.5 mg, 0.112 mmol, 26% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.48 (d, J = 7.8 Hz, 0.5H), 9.45 (d, J = 0.6 Hz, 1H), 9.36 (d, J = 7.8 Hz, 0.59.22-9.16 (m, 1H), 8.85 (d, J = 14.8 Hz, 1H), 8.64 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 7.8 Hz, 0.5H), 7.81-7.73 (m, 1.5H), 6.81 (d, J = 7.8 Hz, 0.5H), 6.74 (d, J = 7.8 Hz, 0.5H), 4.47-4.33 (m, 1H), 4.26 (s, 0.5H), 4.21 (s, 0.5H), 3.83-3.76 (m, 1H), 3.74-3.69 (m, 1H), 3.65-3.56 (m, 1H), 3.14 (d, J = 9.8 Hz, 3H), To a solution of 2-tetrahydropyran-4-ylacetic acid (751 mg, 5.21 mmol, 1.10 eq), benzotriazol-1- yloxy(tripyrrolidin-1-yl)phosphanium hexafluorophosphate (2.96 g, 5.68 mmol, 1.20 eq) and 4- methylmorpholine (1.92 g, 18.9 mmol, 2.08 mL, 4.00 eq) in dichloromethane (15.0 mL) was added methyl (1R,2S,5S)-3-[(2S)-2-amino-3-cyclopropyl-propanoyl]-6,6-dime thyl-3-azabicyclo[3.1.0]hexane- 2-carboxylate (1.50 g, 4.73 mmol, 1.00 eq, hydrochloric acid) at 0 °C. After stirring at 20 °C for 12 h, the mixture was poured into water (30.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers werewashed with saturated calcium chloride aquesous solution (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether : Ethyl acetate = 1: 0 to 3: 7) to give methyl (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[(2-tetrahydropyran-4- ylacetyl)amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]he xane-2-carboxylate (736 mg, 1.65 mmol, 35% yield) as light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.18 (d, J = 8.4 Hz, 1H), 4.81-4.72 (m, 1H), 4.45 (s, 1H), 3.98-3.84 (m, 4H), 3.76 (s, 3H), 3.44-3.34 (m, 2H), 2.13-2.08 (m, 2H), 2.07-2.05 (m, 2H), 1.82-1.73 (m, 1H), 1.49-1.44 (m, 2H), 1.34-1.25 (m, 4H), 1.07 (s, 3H), 0.95 (s, 3H), 0.86-0.77 (m, 1H), 0.56-0.45 (m, 2H), 0.19-0.05 (m, 2H). LC-MS (Method C): R _t = 0.527 min; MS (ESIpos): m/z = 407.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-((S)-3-cyclopropyl-2-(2-(tetrahydro-2H-pyran-4- yl)acetamido)propanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexa ne-2-carboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[(2-tetrahydropyran-4- ylacetyl)amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]he xane-2-carboxylate (736 mg, 1.81 mmol, 1.00 eq) in methanol (10.0 mL) was added a solution of lithium hydroxide monohydrate (380 mg, 9.05 mmol, 5.00 eq) in water (5.00 mL). After stirring at 20 °C for 12 h, the mixture was poured into water (20.0 mL) and washed with ethyl acetate (20.0 mL × 2). The aqueous phase was adjusted pH to 4~5 with hydrochloric acid (1M) and extracted with (dichloromethane/ isopropanol, v/v = 5/ 1, 20.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[(2-tetrahydropyran-4- ylacetyl)amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]he xane-2-carboxylic acid (540 mg, 1.24 mmol, 68% yield) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.12 (d, J = 7.2 Hz, 1H), 4.44 (q, J = 7.2 Hz, 1H), 4.08 (s, 1H), 3.90- 3.83 (m, 1H), 3.82-3.73 (m, 3H), 3.27-3.18 (m, 2H), 2.05-1.97 (m, 2H), 1.88-1.77 (m, 1H), 1.62-1.54 (m, 1H), 1.54-1.44 (m, 3H), 1.41-1.36 (m, 1H), 1.31-1.22 (m, 1H), 1.19-1.10 (m, 2H), 1.01 (s, 3H), 0.87 (s, 3H), 0.82-0.73 (m, 1H), 0.44-0.32 (m, 2H), 0.17-0.01 (m, 2H). LC-MS (Method C): R _t = 0.533 min; MS (ESIpos): m/z = 393.2 [M+H] ⁺ . Procedure for preparation of CPD0279332 (1R,2S,5S)-N-((S)-1-cyano-2-((S)-6-fluoro-3-oxo-3,4- dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-3-((S)-3-cyclopro pyl-2-(2-(tetrahydro-2H-pyran-4- yl)acetamido)propanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexa ne-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[(2-tetrahydropyran-4-yla cetyl)amino]propanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (150 mg, 382 μmol, 1.00 eq), O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (218 mg, 573 μmol, 1.50 eq) and N,N-diisopropylethylamine (198 mg, 1.53 mmol, 4.00 eq) in N,N-dimethylformamide (5.00 mL) was added (2S)-2-amino-3-[(2S)-6-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]p ropanenitrile (89.9 mg, 382 μmol, 1.00 eq) at 0 °C. After stirring at 20 °C for 12 h, the mixture was poured into water (30.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with saturated calcium chloride aqueous solution (20.0 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC ( FA condition:column: Phenomenex C1875*30mm*3 μm; mobile phase: [water (FA)-ACN]; B%: 32%-62%, 7 min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-6-fluoro-3-oxo-4H-1,4-ben zoxazin-2-yl]ethyl]-3- [(2S)-3-cyclopropyl-2-[(2-tetrahydropyran-4-ylacetyl)amino] propanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (83.6 mg, 132 μmol, 34% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.88 (s, 1H), 8.92 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 7.6 Hz, 1H), 6.95- 6.89 (m, 1H), 6.81-6.65 (m, 2H), 5.07-4.99 (m, 1H), 4.57-4.54 (m, 1H), 4.39-4.32 (m, 1H), 4.08 (s, 1H), 3.87-3.80 (m, 2H), 3.79-3.73 (m, 2H), 3.26-3.16 (m, 2H), 2.48-2.43 (m, 1H), 2.32-2.23 (m, 1H), 2.00- 1.95 (m, 2H), 1.87-1.75 (m, 1H), 1.56-1.51 (m, 1H), 1.50-1.40 (m, 2H), 1.36-1.26 (m, 2H), 1.14-1.11 (m, 1H), 1.10-1.03 (m, 2H), 1.01 (s, 3H), 0.87 (s, 3H), 0.71-0.60 (m, 1H), 0.40-0.27 (m, 2H), 0.10-0.09 (m, 2H). Special LCMS (Method P): R _t = 13.080 min; MS (ESIpos): m/z = 610.3 [M+H] ⁺ . HPLC (Method S): R _t = 2.017 min; purity: 96%. SFC: dr = 94: 6. To a solution of 2-tetrahydrofuran-3-ylacetic acid (500 mg, 3.84 mmol, 1.00 eq), 4-methylmorpholine (1.55 g, 15.4 mmol, 1.69 mL, 4.00 eq) and (benzotriazol-1- yloxy)tripyrrolidinophosphonium,hexafluorophosphate (2.20 g, 4.22 mmol, 1.1 eq) in dichloromethane (15.0 mL) was added methyl (1R,2S,5S)-3-[(2S)-2-amino-3-methyl-butanoyl]-6,6-dimethyl-3 - azabicyclo[3.1.0]hexane-2-carboxylate (1.57 g, 4.61 mmol, 1.20 eq, 2hydrochloride). After stirring at 25 °C for 12 h, the reaction mixture was concentrated under vacuum to give a residue. The residue was purified by flash column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 0: 1 to 1: 1) to afford methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-[(2-tetrahydrofur an-3-ylacetyl)amino]butanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxylate (1.40 g, 3.68 mmol, 95.8% yield) as colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.23-8.13 (m, 1H), 4.17 (s, 1H), 4.13 (t, J = 9.2 Hz, 1H), 3.97 (d, J = 10.4 Hz, 1H), 3.78 (dd, J = 10.4, 5.2 Hz, 1H), 3.72-3.66 (m, 2H), 3.65 (s, 3H), 3.63 - 3.55 (m, 1H), 3.25- 3.17 (m, 1H), 2.41 (qd, J = 13.6, 6.8 Hz, 1H), 2.24-2.09 (m, 2H), 1.97-1.82 (m, 2H), 1.53 (dd, J = 7.2, 5.2 Hz, 1H), 1.50-1.36 (m, 2H), 1.01 (s, 3H), 0.90 (s, 1H), 0.89-0.87 (m, 3H), 0.86 (d, J = 1.2 Hz, 1.5H), 0.84 (d, J = 1.2 Hz, 3H), 0.79-0.74 (m, 0.5H). Procedure for preparation of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-[(2-tetrahydrofur an-3- ylacetyl)amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxy lic acid To a solution of methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-[(2-tetrahydrofur an-3- ylacetyl)amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxy late (1.40 g, 3.68 mmol, 1.00 eq) in mixed solvent of methanol (15.0 mL) and water (1.50 mL) was added lithium hydroxide hydrate (8.82 mg, 7.36 mmol, 2.00 eq). After stirring at 25 °C for 12 h, the solvent was removed under reduced pressure to give a residue. The residue was diluted with water (50.0 mL). Hydrochloric acid (2M) was added to above solution to adjust pH = 2 at 25 °C. The solution was extracted with ethyl acetate (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-[(2-tetrahydrofur an-3-ylacetyl)amino]butanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (1.20 g, 3.27 mmol, 89% yield) as a white solid. LC-MS (Method C): Rt = 0.590 min; MS (ESIpos): m/z = 367.2 [M+H] ⁺ . To a solution of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-[(2-tetrahydrofur an-3- ylacetyl)amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxy lic acid (400 mg, 1.09 mmol, 1.00 eq) and 2-amino-2-(1,6-naphthyridin-8-yl)acetonitrile (200 mg, 1.09 mmol, 0.950 eq) in dichloromethane (5.00 mL) were added diisopropylethylamine (423 mg, 3.27 mmol, 570 μL, 3.00 eq) and O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (456 mg, 1.20 mmol, 1.10 eq). After stirring at 20 °C for 12 h, the reaction mixture was concentrated in vacuum at 50 °C to give a residue. The residue was purified by prep-TLC (SiO ₂ , Dichloromethane: Tetrahydrofuran = 1: 2) followed by prep-HPLC (column: Welch Ultimate XB-CN 250*50*10 μm; mobile phase: [Hexane-EtOH (0.1% NH3.H2O)];B%: 15%-55%,15min) to afford 1R,2S,5S)-N-[cyano(1,6-naphthyridin-8-yl)methyl]- 6,6-dimethyl-3-[(2S)-3-methyl-2-[(2-tetrahydrofuran-3-ylacet yl)amino]butanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxamide (70.0 mg, 131 μmol, 12% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.56 (d, J = 7.6 Hz, 0.5H), 9.52 (d, J = 1.6 Hz, 1H), 9.43 (d, J = 8.0 Hz, 0.5H), 9.26 (td, J = 4.4, 2.0 Hz, 1H), 8.94 (d, J = 12.4 Hz, 1H), 8.71 (dd, J = 8.4, 1.6 Hz, 1H), 8.20- 8.07 (m, 1H), 7.85 (dd, J = 8.0, 4.4 Hz, 1H), 6.90-6.80 (m, 1H), 4.30 (d, J = 16.4 Hz, 1H), 4.19-4.04 (m, 1H), 3.92 (dd, J = 10.2, 3.2 Hz, 1H), 3.85-3.77 (m, 1H), 3.73-3.63 (m, 2H), 3.62-3.54 (m, 1H), 3.25-3.15 (m, 1H), 2.41 (dd, J = 14.0, 6.8 Hz, 1H), 2.24-2.09 (m, 2H), 1.96-1.79 (m, 2H), 1.57-1.36 (m, 3H), 1.24- 1.18 (m, 1H), 1.04 (s, 1.5H), 0.95 (s, 1.5H), 0.86 (br. s, 3H), 0.84 (br. s, 1H), 0.82 (br s, 2H), 0.80-0.75 (m, 2H). LC-MS (Method C): Rt = 0.628 min; MS (ESIpos): m/z = 555.3 [M+Na] ⁺ . SFC: dr = 20: 18: 29: 33. Preparation of CPD0330359 Procedure for preparation of methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2- (tetrahydrofuran-3-carbonylamino)butanoyl]-3-azabicyclo[3.1. 0]hexane-2-carboxylate To a mixture of tetrahydrofuran-3-carboxylic acid (500 mg, 4.31 mmol, 413 μL, 1.00 eq) in dichloromethane (10.0 mL) were added N-methylmorpholine (2.18 g, 21.5 mmol, 2.37 mL, 5.00 eq) and benzotriazol-1-yloxy(tripyrrolidin-1-yl)phosphanium;hexafluo rophosphate (2.69 g, 5.17 mmol, 1.20 eq). After stirring at 20 °C for 1 h, methyl (1R,2S,5S)-3-[(2S)-2-amino-3-methyl-butanoyl]-6,6-dimethyl-3 - azabicyclo[3.1.0]hexane-2-carboxylate (1.76 g, 5.17 mmol, 1.20 eq, 2 hydrochloride) was added. The mixture was stirred at 20 °C for 15 h. The reaction mixture was diluted with dichloromethane (50.0 mL), washed with brine (40.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~60% Ethyl acetate/Petroleum ethergradient @ 50 mL/min) and concentrated to give methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-(tetrahydrofuran- 3- carbonylamino)butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (1.20 g, 3.27 mmol, 76% yield) as colorless oil. LC-MS (Method C): R _t = 0.571 min; MS (ESIpos): m/z = 367.2 [M+1] ⁺ . 1H NMR (400 MHz, CDCl ₃ ) δ = 8.31 (d, J = 8.4 Hz, 1H), 4.25-4.12 (m, 2H), 4.00 (t, J = 9.2 Hz, 1H), 3.91-3.81 (m, 2H), 3.03-3.52 (m, 6H), 3.07-3.03 (m, 1H), 2.04-1.92 (m, 3H), 1.60-1.54 (m, 1H), 1.48 (dd, J = 7.2, 0.8 Hz, 1H), 1.09 (s, 3H), 0.98-0.82 (m, 9H). Procedure for preparation of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-(tetrahydrofuran- 3- carbonylamino)butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxyl ic acid To a mixture of methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-(tetrahydrofuran- 3- carbonylamino)butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (1.10 g, 3.00 mmol, 1.00 eq) in mixed solvent of methanol (8.00 mL) and water (2.00 mL) was added lithium hydroxide monohydrate (252 mg, 6.00 mmol, 2.00 eq). After stirring at 20 °C for 16 h, the reaction mixture was concentrated to give a residue. The residue was diluted with water (40.0 mL). Hydrochloride solution (1 M) was added to the solution to adjust pH to 3. The solution was extracted with ethyl acetate (40.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-(tetrahydrofuran- 3-carbonylamino)butanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (1.00 g, 2.84 mmol, 95% yield) as colorless oil. LC-MS (Method C): R _t = 0.430 and 0.450 min; MS (ESIpos): m/z = 353.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.51-11.42 (m, 1H), 8.23 (d, J = 8.8 Hz, 1H), 4.18-4.09 (m, 2H), 3.90 (t, J = 8.8 Hz, 1H), 3.82-3.68 (m, 2H), 3.67-3.62 (m, 2H), 3.62-3.46 (m, 1H), 3.09-2.99 (m, 1H), 1.96-1.86 (m, 3H), 1.52-1.48 (m, 1H), 1.39 (dd, J = 7.6, 1.2, Hz, 1H), 1.01 (s, 3H), 0.93-0.75 (m, 9H). Procedure for preparation of CPD0330359 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-6-fluoro-3-oxo- 4H-1,4-benzoxazin-2-yl]ethyl]-6,6-dimethyl-3-[(2S)-3-methyl- 2-(tetrahydrofuran-3- carbonylamino)butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxam ide To a mixture of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-(tetrahydrofuran- 3- carbonylamino)butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxyl ic acid (135 mg, 383 μmol, 1.20 eq) and (2S)-2-amino-3-[(2S)-6-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]p ropanenitrile (75.0 mg, 319 μmol, 1.00 eq) in dichloromethane (4.00 mL) were added [dimethylamino(triazolo[4,5-b]pyridin-3- yloxy)methylidene]-dimethylazanium;hexafluorophosphate (182 mg, 478 μmol, 1.50 eq) and N,N- diethylpropan-2-amine (206 mg, 1.59 mmol, 278 μL, 5.00 eq). After stirring at 20 °C for 16 h, the reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water (FA)-ACN]; B%: 33%-63%, 9 min) and lyophilized to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-6-fluoro-3-oxo-4H-1,4-ben zoxazin-2-yl]ethyl]- 6,6-dimethyl-3-[(2S)-3-methyl-2-(tetrahydrofuran-3-carbonyla mino)butanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxamide (90 mg, 158.00 umol, 50% yield) as a white solid. LC-MS (Method C): R _t = 0.842 min; MS (ESIpos): m/z = 570.3 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ = 10.88 (s, 1H), 9.00 (d, J = 8.0 Hz, 1H), 8.17 (d, J = 7.6 Hz, 1H), 6.94-6.90 (m, 1H), 6.77 (dt, J = 8.8, 2.8, Hz, 1H), 6.69 (dd, J = 8.8, 3.2 Hz, 1H), 5.12-5.07 (m, 1H), 4.57 (dd, J = 10.0, 2.0 Hz, 1H), 4.10-4.03 (m, 2H), 3.87-3.74 (m, 2.5H), 3.69-3.59 (m, 2H), 3.54 (t, J = 7.6 Hz, 0.5H), 3.43 (t, J = 7.6 Hz, 1H), 3.01-2.95 (m, 1H), 2.48-2.45 (m, 1H), 2.33-2.26 (m, 1H), 1.94-1.79 (m, 2H), 1.71-1.66 (m, 1H), 1.53 (t, J = 5.6 Hz, 1H), 1.31-1.29 (m, 1H), 1.01 (s, 3H), 0.84-0.70 (m, 9H). SFC: dr = 47: 53. Preparation of CPD0330365 Procedure for preparation of (2S)-2-amino-3-[(2S)-3-oxo-4H-pyrido[4,3-b][1,4]oxazin-2- yl]propanenitrile To a mixture of tert-butyl N-[(1S)-1-cyano-2-[(2S)-3-oxo-4H-pyrido[4,3-b][1,4]oxazin-2- yl]ethyl]carbamate (200 mg, 628 umol, 1.00 eq) in acetonitrile (2.00 mL) was added hydrochloride/dioxane (4 M, 2.00 mL) at 0 °C, then the mixture was stirred at 0 °C for 0.5 h. The reaction mixture was concentrated to give (2S)-2-amino-3-[(2S)-3-oxo-4H-pyrido[4,3-b][1,4]oxazin-2- yl]propanenitrile (130 mg, 596 μmol, 95% yield) as an off-white solid. Procedure for preparation of CPD0330365 - (2S)-2-amino-3-[(2S)-3-oxo-4H-pyrido[4,3- b][1,4]oxazin-2-yl]propanenitrile To a mixture of (2S)-2-amino-3-[(2S)-3-oxo-4H-pyrido[4,3-b][1,4]oxazin-2-yl] propanenitrile (130 mg, 596 umol, 1.00 eq) and (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-(tetrahydrofuran- 3- carbonylamino)butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxyl ic acid (210 mg, 596 μmol, 1.00 eq) in N,N-dimethylformamide (2.00 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N’,N’- tetramethyluronium hexafluorophosphate (340 mg, 894 μmol, 1.50 eq) and N,N-diisopropylethylamine (385 mg, 2.98 mmol, 519 μL, 5.00 eq). The mixture was stirred at 20 °C for 3 h and purified by prep- HPLC (neutral condition, column: Waters Xbridge 150*25mm* 5 μm; mobile phase: [water (NH ₄ HCO ₃ )- ACN]; B%: 18%-48%, 9min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-3-oxo-4H-pyrido[4,3- b][1,4]oxazin-2-yl]ethyl]-6,6-dimethyl-3-[(2S)-3-methyl-2-(t etrahydrofuran-3-carbonylamino)butanoyl]- 3-azabicyclo[3.1.0]hexane-2-carboxamide (150 mg, 271 μmol, 46% yield) as a white solid. LC-MS (Method C): R _t = 0.398 min; MS (ESIpos): m/z = 553.5 [M+1] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.07 (s, 1H), 9.08 (d, J = 8.4 Hz, 1H), 8.26-8.23 (m, 1H), 8.21-8.14 (m, 2H), 7.00 (d, J = 5.6 Hz, 1H), 5.19-5.13 (m, 1H), 4.84 (dd, J = 10.0, 2.8 Hz, 1H), 4.24-4.15 (m, 1H), 4.11 (t, J = 8.8 Hz, 1H), 3.92-3.80 (m, 3H), 3.77-3.65 (m, 2H), 3.62-3.58 (m, 0.5H), 3.51-3.47 (m, 0.5H), 3.06-3.01 (m, 1H), 2.62-2.61 (m, 1H), 2.49-2.38 (m, 1H), 2.00-1.85 (m, 2H), 1.77-1.72 (m, 1H), 1.60 (br t, J = 5.6 Hz, 1H), 1.37 (dd, J = 7.6, 1.6, Hz 1H), 1.07 (s, 3H), 0.90 (d, J = 6.8 Hz, 3H), 0.83-0.75 (m, 6H). SFC: dr = 46: 53. To a solution of 3,5-dibromopyridine-4-carbaldehyde (40.0 g, 151 mmol, 1.00 eq), potassium hydride;trifluoro(vinyl)boron (24.3 g, 181 mmol, 1.20 eq) and cesium carbonate (103 g, 317 mmol, 2.10 eq) in mixed solvent of water (100 mL) and 1,2-dimethoxyethane (400 mL) was added [1,1- bis(diphenylphosphino)ferrocene]dichloropall,adium(II) (11.1 g, 15.1 mmol, 0.100 eq) at 20 °C under nitrogen atmosphere. After stirring at 50 °C for 14 h under nitrogen atmosphere, O- methylhydroxylamine;hydrochloride (56.8 g, 680 mmol, 4.50 eq) was added into the reaction mixture. The reaction mixture was stirred at 50 °C for 5 h. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (500 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 1:0 to 7:1) to give 1-(3-bromo-5-vinyl-4- pyridyl)-N-methoxy-methanimine (12.0 g, 49.8 mmol, 33% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.68 (s, 1H), 8.65 (s, 1H), 8.34 (s, 1H), 7.21-7.14 (dd, J = 17.2, 10.8 Hz, 1H), 5.75 (dd, J = 17.6, 0.8 Hz, 1H), 5.43 (dd, J = 11.2, 0.8 Hz, 1H), 4.05 (s, 3H). Procedure for preparation of 4-bromo-2,6-naphthyridine A mixture of 1-(3-bromo-5-vinyl-4-pyridyl)-N-methoxy-methanimine (12.0 g, 49.8 mmol, 1.00 eq) in diphenyl ether (120 mL) was stirred at 180 °C for 2 h. The mixture was cooled to 20 °C and diluted with hydrochloric acid (100 mL, 1.00 moL/L, in water). The mixture was extracted with mixed solvent of petroleum ether and ethyl acetate (v/v = 10/1, 200 mL × 3). Saturated sodium bicarbonate was added to adjust pH to 9-10. The mixture was extracted with ethyl acetate (500 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 0: 1 to 1: 1) to give 4-bromo-2,6-naphthyridine (4.10 g, 19.6 mmol, 39% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.50 (s, 1H), 9.45 (s, 1H), 8.92 (s, 1H), 8.87 (d, J = 5.6 Hz, 1H), 8.10 (d, J = 5.6 Hz, 1H). Procedure for preparation of methyl 2-(benzhydrylideneamino)-2-(2,6-naphthyridin-4-yl)acetate 20 batches reactions were run in parallel. To a solution of 4-bromo-2,6-naphthyridine (200 mg, 957 μmol, 1.00 eq), methyl 2-(benzhydrylideneamino)acetate (485 mg, 1.91 mmol, 2.00 eq) and potassium phosphate (610 mg, 2.87 mmol, 3.00 eq) in N,N-dimethylformamide (5.00 mL) was added chloro[(tri- tert-butylphosphine)-2-(2-aminobiphenyl)] palladium(II) (25.0 mg, 48.8 umol, 5.1 x 10 ^-2 eq) at 20 °C under nitrogen atmosphere. The reaction mixture was stirred at 90 °C for 16 h under nitrogen atmosphere. The 20 batches of the reaction mixtures were combined and added dropwise into water (400 mL) at 0 °C. The mixture was extracted with ethyl acetate (500 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 1:0 then 1:1) to give methyl 2-(benzhydrylideneamino)-2-(2,6-naphthyridin-4-yl)acetate (4.50 g, 11.8 mmol, 62% yield) as brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.99 (s, 1H), 9.26 (s, 1H), 8.75 (d, J = 5.6 Hz, 1H), 8.45 (s, 1H), 7.78 (dd, J = 5.6, 0.8 Hz, 1H), 7.72-7.70 (m, 2H), 7.54-7.48 (m, 3H), 7.42-7.38 (m, 1H), 7.34-7.30 (m, 2H), 7.13 (d, J = 3.6 Hz, 2H), 5.69 (s, 1H), 3.69 (s, 3H). Procedure for preparation of 2-(benzhydrylideneamino)-2-(2,6-naphthyridin-4-yl)acetamide. A mixture of methyl 2-(benzhydrylideneamino)-2-(2,6-naphthyridin-4-yl)acetate (2.40 g, 6.29 mmol, 1.00 eq) and ammonia (7.00 M in methanol, 50.0 mL, 55.6 eq) was stirred at 25 °C for 15 h. The mixture was concentrated under reduced pressure to give a residue. The residue was triturated with a mixed solvent of petroleum ether and ethyl acetate (v/v = 5/1, 60.0 mL) at 25 °C for 3 h. The suspension was filtered under reduced pressure. The filter cake was collected and dried to give 2- (benzhydrylideneamino)-2-(2,6-naphthyridin-4-yl)acetamide (1.60 g, 3.89 mmol, 62% yield, 89% purity) as a white solid. LC-MS (Method C): R _t = 0.734 min; MS (ESIpos): m/z = 377.1 [M+H] ⁺ . Procedure for preparation of 2-amino-2-(2,6-naphthyridin-4-yl)acetamide To a solution of 2-(benzhydrylideneamino)-2-(2,6-naphthyridin-4-yl)acetamide (1.60 g, 4.37 mmol, 1.00 eq) in mixed solvent of dichloromethane (10.0 mL) and methanol (5.00 mL) was added dropwise hydrochloric acid (1.00 M in water, 18.0 mL, 4.12 eq) at 25 °C. After stirring at 25 °C for 30 min, the mixture was diluted with water (20.0 mL) and washed with dichloromethane (50.0 mL × 3). The aqueous phase was concentrated under vacuum to give 2-amino-2-(2,6-naphthyridin-4-yl)acetamide (1.04 g, 4.36 mmol, 100% yield, hydrochloride) as a brown solid. To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(tetrahydrofuran-3-carbony lamino)butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (2.08 g, 5.66 mmol, 1.30 eq) in N,N- dimethylformamide (10.0 mL) were added dropwise O-(7-Azabenzotriazol-1-yl)-N,N,N’,N’- tetramethyluronium hexafluorophosphate (3.32 g, 8.73 mmol, 2.00 eq) and N,N-diisopropylethylamine (1.69 g, 13.1 mmol, 2.28 mL, 3.00 eq) at 0 °C. After stirring at 0 °C for 10 min, 2-amino-2-(2,6- naphthyridin-4-yl)acetamide (1.04 g, 4.36 mmol, 1.00 eq, hydrochloride) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure to give residue. The residue was purified by reversed phase (instrument: 330 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (neutral),eluent B: acetonitrile; gradient: 0-30 min 0-60% B; flow 100 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)-N-[2-amino-1-(2,6-naphthyridin-4-yl)-2-oxo-ethyl] -3-[(2S)-3,3-dimethyl-2-(tetrahydrofuran- 3-carbonylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxamide (2.07 g, 3.74 mmol, 86% yield, 99% purity) as a brown solid. LC-MS (Method C): R _t = 0.742 min and 0.758 min; MS (ESIpos): m/z = 551.2 [M+H] ⁺ . To a solution of (1R,2S,5S)-N-[2-amino-1-(2,6-naphthyridin-4-yl)-2-oxo-ethyl] -3-[(2S)-3,3-dimethyl-2- (tetrahydrofuran-3-carbonylamino)butanoyl]-6,6-dimethyl-3-az abicyclo[3.1.0]hexane-2-carboxamide (1.00 g, 1.82 mmol, 1.00 eq) in dichloromethane (10.0 mL) was added Burgess reagent (1.73 g, 7.26 mmol, 4.00 eq). After stirring at 25 °C for 12 h, the reaction mixture was quenched with saturated sodium bicarbonate (15.0 mL). The mixture was extracted with dichloromethane (10.0 mL × 3). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 10: 1 to 1: 1) to give a residue. The residue was further purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water (FA)-ACN];B%: 26%-56%,10min) to give (1R,2S,5S)-N-[cyano(2,6-naphthyridin-4-yl)methyl]-3-[(2S)- 3,3-dimethyl-2-(tetrahydrofuran-3-carbonylamino)butanoyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (208 mg, 382 μmol, 21% yield, 97% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.64 (d, J = 7.6 Hz, 0.5H), 9.54-9.51 (m, 2.2H), 8.87 (d, J = 7.2 Hz, 0.9H), 8.84-8.82 (m, 0.8H), 8.12 (t, J = 4.8 Hz, 0.9H), 7.98-7.91 (m, 0.9H), 7.09 (t, J = 7.2 Hz, 0.8H), 4.35-4.30 (m, 1H), 4.20-4.17 (m, 1H), 3.89-3.73 (m, 3H), 3.72-3.59 (m, 2H), 3.56-3.51 (m, 0.5H), 3.46- 3.37 (m, 0.6H), 3.12-3.06 (m, 1H), 1.96-1.77 (m, 2H), 1.58-1.50 (m, 1H), 1.32-1.29 (m, 0.5H), 1.12-1.10 (m, 0.5H), 1.02-0.77 (m, 15H). LC-MS (Method C): R _t = 0.730 min; MS (ESIpos): m/z = 533.3 [M+H] ⁺ . HPLC (Method K): R _t = 1.821 min, purity: 98%. To a solution of (3R)-tetrahydrofuran-3-carboxylic acid (391 mg, 3.37 mmol, 1.10 eq), O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (1.40 g, 3.67 mmol, 1.20 eq) and diisopropylethylamine (1.19 g, 9.18 mmol, 1.60 mL, 3.00 eq) in dichloromethane (10.0 mL) was added methyl (1R,2S,5S)-3-[(2S)-2-amino-4,4-difluoro-butanoyl]-6,6-dimeth yl-3- azabicyclo[3.1.0]hexane-2-carboxylate (1.00 g, 3.06 mmol, 1.00 eq, Hydrogen chloride). After stirring at 25 °C for 12 h, the reaction mixture was concentrated under vacuum to give a residue. The residue was purified by flash column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 100: 1 to 10: 1) to afford methyl (1R,2S,5S)-3-[(2S)-4,4-difluoro-2-[[(3R)-tetrahydrofuran-3-c arbonyl]amino]butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (800 mg, 2.06 mmol, 67% yield) as colorless oil. LC-MS (Method C): Rt = 0.820 min; MS (ESIpos): m/z = 389.1 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-4,4-difluoro-2-[[(3R)-tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-4,4-difluoro-2-[[(3R)-tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxylate (729 mg, 1.88 mmol, 1.00 eq) in mixed solvent of tetrahydrofuran (20.0 mL) and water (4.00 mL) was added lithium hydroxide hydrate (158 mg, 3.75 mmol, 2.00 eq). After stirring at 25 °C for 12 h, the solvent was removed under reduced pressure to give a residue. The residue was dissolved with water (20.0 mL). Hydrochloric acid (2M) was added to the mixture was basified by slowly adding 2 N at 25 °C degrees to pH = 2. The separated aqueous phase was extracted with ethyl acetate (10.0 mL × 2). The combined extracts were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford (1R,2S,5S)-3-[(2S)-4,4-difluoro-2-[[(3R)-tetrahydrofuran-3-c arbonyl]amino]butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (600 mg, 1.52 mmol, 81% yield) as colorless oil. LC-MS (Method C): Rt = 0.727 min; MS (ESIpos): m/z = 375.1 [M+H] ⁺ . Procedure for preparation of CPD0330375- (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-6-fluoro-3-oxo- 4H-1,4-benzoxazin-2-yl]ethyl]-3-[(2S)-4,4-difluoro-2-[[(3R)- tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-4,4-difluoro-2-[[(3R)-tetrahydrofuran-3-c arbonyl]amino]butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (140 mg, 374 μmol, 1.10 eq) and (2S)-2- amino-3-[(2S)-6-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]propanen itrile (80.0 mg, 340 μmol, 1.00 eq) in dichloromethane (4.00 mL) were added diisopropylethylamine (132 mg, 1.02 mmol, 177 μL, 3.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (155 mg, 408 mmol, 1.20 eq). After stirring at 20 °C for 2 h, the reaction mixture was concentrated under vacuum at 50 °C to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN];B%: 30%-60%,10min) to afford (1R,2S,5S)-N-[(1S)-1-cyano-2- [(2S)-6-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]ethyl]-3-[(2S)-4 ,4-difluoro-2-[[(3R)-tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxamide (75.6 mg, 135 μmol, 40% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.96-10.84 (m, 1H), 9.28 (d, J = 8.0 Hz, 0.2H), 8.96-8.84 (m, 0.6H), 8.60-8.52 (m, 0.5H), 8.52-8.40 (m, 0.5H), 7.04-6.92 (m, 1H), 6.84-6.64 (m, 2H), 6.12-6.00 (m, 0.3H), 5.96-5.88 (m, 0.4H), 5.84-5.72 (m, 0.2H), 5.12-4.88 (m, 1H), 4.72-4.60 (m, 1H), 4.60-4.48 (m, 1H), 4.32- 4.20 (m, 0.2H), 4.16-4.12 (m, 0.3H), 4.08 (s, 0.5H), 3.92-3.76 (m, 2H), 3.72-3.60 (m, 3H), 3.56-3.44 (m, 1H), 3.04-2.84 (m, 1H), 2.48-2.36 (m, 1H), 2.32-2.16 (m, 1H), 2.12-2.04 (m, 1H), 2.00-1.80 (m, 3H), 1.56-1.44 (m, 1H), 1.44-1.36 (m, 0.5H), 1.32 (d, J = 7.6 Hz, 0.5H), 1.12-1.04 (m, 0.5H), 1.00 (q, J = 2.4 Hz, 3H), 0.88-0.84 (m, 2H), 0.84-0.80 (m, 0.6H). LC-MS (Method C): Rt = 0.823 min; MS (ESIpos): m/z = 592.2 [M+H] ⁺ . To a mixture of (3S)-tetrahydrofuran-3-carboxylic acid (1.00 g, 8.61 mmol, 1.00 eq) and 3-[chloro-(2- oxooxazolidin-3-yl)phosphoryl]oxazolidin-2-one (3.29 g, 12.9 mmol, 1.50 eq) in dichloromethane (10.0 mL) was added N-ethyl-N-isopropyl-propan-2-amine (3.34 g, 25.8 mmol, 4.50 mL, 3.00 eq). After stirring at 25 °C for 10 min, methyl (1R,2S,5S)-3-[(2S)-2-amino-3-cyclopropyl-propanoyl]-6,6-dime thyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (3.00 g, 9.47 mmol, 1.10 eq, hydrochloride) was added. After stirring at 25 °C for 16 h, the reaction mixture was concentrated to give a residue. The residue was purified by reversed phase (instrument: 80 g Flash; Column: Welch Ultimate XB_C1820-40μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-25 min 0-75% B; flow 55 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give methyl (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[[(3S)- tetrahydrofuran-3-carbonyl]amino]propanoyl]-6,6-dimethyl-3-a zabicyclo[3.1.0]hexane-2-carboxylate (1.5 g, 3.96 mmol, 46% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.26 (d, J = 7.6 Hz, 1H), 4.49-4.40 (m, 1H), 4.17 (s, 1H), 3.91-3.75 (m, 3H), 3.73-3.57 (m, 6H), 3.55-3.46 (M, 1H), 3.00-2.90 (m, 1H), 2.01-1.85 (m, 2H), 1.68-1.50 (m, 2H), 1.44-1.36 (m, 1H), 1.33-1.21 (m, 1H), 1.01 (s, 3H), 0.93-0.85 (m, 3H), 0.82-0.69 (m, 1H), 0.49-0.32 (m, 2H), 0.20-0.00 (m, 2H). Procedure for preparation of (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[[(3S)-tetrahydrofuran-3- carbonyl]amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]he xane-2-carboxylic acid To a mixture of methyl (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[[(3S)-tetrahydrofuran-3- carbonyl]amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]he xane-2-carboxylate (1.00 g, 2.64 mmol, 1.00 eq) in methanol (10.0 mL) was added a solution of lithium hydroxide monohydrate (222 mg, 5.28 mmol, 2.00 eq) in water (2.00 mL). After stirring at 25 °C for 16 h, the reaction mixture was concentrated to give a residue. The residue was diluted with water (20.0 mL). Hydrochloric acid (1M) was added to adjust pH~2. The solution was extracted with ethyl acetate (20 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give (1R,2S,5S)- 3-[(2S)-3-cyclopropyl-2-[[(3S)-tetrahydrofuran-3-carbonyl]am ino]propanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (900 mg, 2.47 mmol, 93% yield) as light yellow oil. To a mixture of (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[[(3S)-tetrahydrofuran-3- carbonyl]amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]he xane-2-carboxylic acid (500 mg, 1.37 mmol, 1.00 eq), 3-[chloro-(2-oxooxazolidin-3-yl)phosphoryl]oxazolidin-2-one (524 mg, 2.06 mmol, 1.50 eq) in dichloromethane (5.00 mL) was added N-ethyl-N-isopropyl-propan-2-amine (709 mg, 5.49 mmol, 956 uL, 4.00 eq). The mixture was stirred at 25 °C for 10 min, then 2-amino-2-phthalazin-1-yl-acetamide (425.69 mg, 1.78 mmol, 1.3 eq, Hydrochloride) was added. The mixture was stirred at 25 °C for 16 h and concentrated in vacuo, diluted with water (30.0 mL), and extracted with Ethyl acetate (30 mL × 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reversed phase column (instrument: 80g Flash; Column: Welch Ultimate XB_C1820-40μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-25 min 0-80% B; flow 55 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)-N-(2-amino- 2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S)-3-cyclopropyl-2-[[(3S )-tetrahydrofuran-3- carbonyl]amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]he xane-2-carboxamide (450 mg, 820 umol, 60% yield) as a yellow solid. LC-MS (Method C): Rt = 0.789 min; MS (ESIpos): m/z = 549.3 [M+H] ⁺ . Procedure for preparation of Compound CPD0330436- (1R,2S,5S)-N-[cyano(phthalazin-1- yl)methyl]-3-[(2S)-3-cyclopropyl-2-[[(3S)-tetrahydrofuran-3- carbonyl]amino]propanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -3-cyclopropyl-2-[[(3S)- tetrahydrofuran-3-carbonyl]amino]propanoyl]-6,6-dimethyl-3-a zabicyclo[3.1.0]hexane-2-carboxamide (150 mg, 0.273 mmol, 1.00 eq) in dichloromethane (3.00 mL) was added burgess reagent (195 mg, 0.820 mmol, 3.00 eq). After stirring at 25 °C for 3 h, the mixture was quenched with water (20.0 mL) and extracted with dichloromethane (20 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep- HPLC (column: YMC Triart C18 150*25mm*5 μm; mobile phase: [water(FA)-ACN];B%: 33%- 63%,8.5min), followed by lyophilization to give (1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]-3-[(2S)-3- cyclopropyl-2-[[(3S)-tetrahydrofuran-3-carbonyl]amino]propan oyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (38.6 mg, 70.5 μmol, 26% yield, 97% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.55 (s, 0.3H), 9.66 (d, J = 1.6 Hz, 0.4H), 9.56 (d, J = 8.6 Hz, 0.2H), 9.44 (d, J = 8.6 Hz, 0.2H), 9.21 (s, 0.35H), 8.66 (d, J = 8.6 Hz, 0.4H), 8.31-8.21 (m, 0.5H), 8.20-8.06 (m, 1H), 8.02-7.92 (m, 1H), 7.91-7.78 (m, 0.6H), 7.76-7.62 (m, 1H), 7.19-7.06 (m, 0.5H), 4.51 (s, 0.1H), 4.38-4.27 (m, 0.8H), 4.27-4.19 (m, 0.3H), 4.13 (s, 0.4H), 4.08 (m, 0.2H), 4.04 (m, 0.2H), 3.83-3.66 (m, 2H), 3.65-3.46 (m, 3H), 3.45-3.34 (m, 1H), 2.95-2.71 (m, 1H), 1.90-1.75 (m, 2H), 1.63-1.36 (m, 2H), 1.33-1.10 (m, 1.5H), 1.05-0.97 (m, 0.5H), 0.97-0.88 (m, 2H), 0.86-0.78 (m, 2H), 0.76-0.67 (m, 2H), 0.66- 0.42 (m, 1H), 0.39-0.13 (m, 2H), 0.12--0.25 (m, 2H). LC-MS (Method C): Rt = 0.762 min; MS (ESIpos): m/z = 531.3 [M+H] ⁺ . SFC: dr = 31: 43: 24. Preparation of CPD0330437 Procedure for preparation of Compound CPD0330437 - (1R,2S,5S)-N-[cyano(1,6-naphthyridin-8- yl)methyl]-3-[(2S)-3-cyclopropyl-2-[[(3R)-tetrahydrofuran-3- carbonyl]amino]propanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[[(3R)-tetrahydrofuran-3- carbonyl]amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]he xane-2-carboxylic acid (600 mg, 1.65 mmol, 1.00 eq) in dichloromethane (12 mL) was added bis(2-oxo-3-oxazolidinyl)phosphinic chloride (629 mg, 2.47 mmol, 1.5 eq). After stirring at 20 °C for 0.5 h, N,N- diisopropylethylamine (638 mg, 4.94 mmol, 0.860 mL, 3.00 eq) and 2-amino-2-(1,6-naphthyridin-8-yl)acetonitrile (303 mg, 1.65 mmol, 1.00 eq) were added to the mixture above. After stirring at 20 °C for 15.5 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C18250*50mm*10 μm; mobile phase: water (ammonium hydrogen carbonate)- acetonitrile]; B%: 19%-49%,8min) to give (1R,2S,5S)-N-[cyano(1,6-naphthyridin-8-yl)methyl]-3-[(2S)-3- cyclopropyl-2-[[(3R)-tetrahydrofuran-3-carbonyl]amino]propan oyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (244 mg, 0.460 mmol, 28% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.56 (d, J = 8.0 Hz, 0.5H), 9.51 (s, 1H), 9.42 (d, J = 8.0 Hz, 0.5H), 9.30-9.20 (m, 1H), 8.93 (s, 0.5H), 8.89 (s, 0.5H), 8.73-8.64 (m, 1H), 8.33-8.16 (m, 1H), 7.89-7.79 (m, 1H), 6.89 (d, J = 8.0 Hz, 0.5H), 6.81 (d, J = 8.0 Hz, 0.5H), 4.51-4.36 (m, 1H), 4.32 (s, 0.5H), 4.26 (s, 0.5H), 3.91-3.75 (m, 3H), 3.72-3.52 (m, 3H), 3.01-2.87 (m, 1H), 1.97-1.82 (m, 2H), 1.65-1.46 (m, 2H), 1.43-1.27 (m, 1H), 1.26-1.17 (m, 1H), 1.08-0.83 (m, 6H), 0.81-0.64 (m, 1H), 0.44-0.24 (m, 2H), 0.22-- 0.10 (m, 2H). LC-MS (Method L): Rt = 1.722 min; MS (ESIpos): m/z = 531.4 [M+1] ⁺ . To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-phenyl-propanoic acid (6.00 g, 22.6 mmol, 1.00 eq) in dichloromethane (80.0 mL) was added dropwise bis(2-oxo-3-oxazolidinyl)phosphinic chloride (8.64 g, 33.9 mmol, 1.50 eq) at 20 °C. After stirring at this temperature for 30 min, methyl (1R,2S,5S)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (3.83 g, 22.6 mmol, 1.00 eq) and diisopropylethylamine (8.77 g, 67.9 mmol, 11.8 mL, 3.00 eq) were added dropwise at 20 °C. The resulting mixture was stirred at 20 °C for 15.5 h. The reaction mixture was diluted with water (30.0 mL) and extracted with dichloromethane 90 mL (30.0 mL × 3). The combined organic layers were washed with brine (60.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ethergradient @ 80 mL/min) to give methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-phenyl-pro panoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (7.40 g, 17.8 mmol, 79% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.31-7.17 (m, 6H), 4.34-4.24 (m, 1H), 4.19 (s, 1H), 3.87 (d, J = 10.4 Hz, 1H), 3.71-3.60 (m, 4H), 2.91-2.78 (m, 1H), 2.77-2.67 (m, 1H), 1.57-1.50 (m, 1H), 1.43-1.38 (m, 3H), 1.32-1.26 (m, 9H), 1.26-1.24 (m, 1H), 1.01 (s, 3H). LCMS (Method C): R _t = 0.486 min; MS (ESIpos): m/z =417.3 [M+H] ⁺ . Procedure dimethyl-3 A solution of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-phenyl-pro panoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (3.30 g, 7.92 mmol, 1.00 eq) in hydrogen chloride/ethyl acetate (30.0 mL) was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give methyl (1R,2S,5S)-3-[(2S)-2-amino-3-phenyl-propanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylate (2.2 g, crude) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.46 (s, 3H), 7.44-7.21 (m, 5H), 4.31 (s, 1H), 4.21 (s, 1H), 3.74-3.64 (m, 3H), 3.25-3.15 (m, 1H), 3.13-2.91 (m, 2H), 1.51-1.40 (m, 2H), 1.08-0.80 (m, 6H). Procedure for preparation of methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-phenyl-2-[[(3R)- tetrahydrofuran-3-carbonyl]amino]propanoyl]-3-azabicyclo[3.1 .0]hexane-2-carboxylate To a solution of methyl (1R,2S,5S)-3-[(2S)-2-amino-3-phenyl-propanoyl]-6,6-dimethyl- 3- azabicyclo[3.1.0]hexane-2-carboxylate (1.00 g, 3.16 mmol, 1.00 eq) in dichloromethane (20.0 mL) was added dropwise bis(2-oxo-3-oxazolidinyl)phosphinic chloride (1.21 g, 4.74 mmol, 1.50 eq) at 20 °C. After stirring at this temperature for 30 min, (3R)-tetrahydrofuran-3-carboxylic acid (367 mg, 3.16 mmol, 1.00 eq) and diisopropylethylamine (1.23 g, 9.48 mmol, 1.65 mL, 3.00 eq) were added dropwise at 20 °C. The resulting mixture was stirred at 20 °C for 15.5 h. The reaction mixture was diluted with water (30.0 mL) and extracted with dichloromethane (30 mL × 3). The combined organic layers were washed with brine 120 mL (60 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~70% Ethyl acetate/Petroleum ethergradient @ 60 mL/min) to give methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-phenyl-2-[[(3R)-tetrahydro furan-3- carbonyl]amino]propanoyl]-3-azabicyclo[3.1.0] hexane-2-carboxylate (1.10 g, 2.65 mmol, 84% yield) as a colorless oil. LCMS (Method C): R _t = 0.401 min; MS (ESIpos): m/z = 415.7 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-phenyl-2-[[(3R)-tetrahydro furan- 3-carbonyl]amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2-carb oxylic acid To a solution of methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-phenyl-2-[[(3R)-tetrahydro furan-3- carbonyl]amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2-carbox ylate (1.10 g, 2.65 mmol, 1.00 eq) in methyl alcohol (5.00 mL) and water (5.00 mL) was added lithium hydroxide (334 mg, 7.96 mmol, 3.00 eq). After stirring at 20 °C for 16 h, the reaction mixture was concentrated under reduced pressure to remove methyl alcohol. The residue was neutralized with hydrogen chloride (1M) until pH ~ 1. The solution was extracted with ethyl acetate 60.0 mL (30.0 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-phenyl-2-[[(3R)-tetrahydro furan-3-carbonyl]amino]propanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (1.05 g, 2.57 mmol, 97% yield, 98% purity) as colorless oil. LCMS (Method C): R _t = 0.338 min, 0.365 min; MS (ESIpos): m/z = 401.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-6,6-dim ethyl- 3-[(2S)-3-phenyl-2-[[(3R)-tetrahydrofuran-3-carbonyl]amino]p ropanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-phenyl-2-[[(3R)-tetrahydro furan-3- carbonyl]amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2-carbox ylic acid (950 mg, 2.37 mmol, 1.00 eq) in dichloromethane (2.00 mL) was added dropwise bis(2-oxo-3-oxazolidinyl)phosphinic chloride (906 mg, 3.56 mmol, 1.50 eq) at 20 °C. After stirring at this temperature for 30 min, 2-amino-2-phthalazin-1- yl-acetamide (576 mg, 2.85 mmol, 1.20 eq) and diisopropylethylamine (920 mg, 7.12 mmol, 1.24 mL, 3.00 eq) were added dropwise at 20 °C. The resulting mixture was stirred at 20 °C for 15.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (Instrument: 80 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.05% FA), eluent B: acetonitrile; gradient: 0-10 min 0-30% B; flow 75 ml/min; temperature: room temperature; Detector: UV 220/254 nm) and lyophilized to give (1R,2S,5S)-N-(2-amino-2-oxo-1- phthalazin-1-yl-ethyl)-6,6-dimethyl-3-[(2S)-3-phenyl-2-[[(3R )-tetrahydrofuran-3- carbonyl]amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2-carbox amide (740 mg, 1.27 mmol, 54% yield) as a light yellow solid. LCMS (Method C): R _t = 1.692 min; MS (ESIpos): m/z = 585.3 [ . Procedure for preparation of CPD03300438 (1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]-6,6- dimethyl-3-[(2S)-3-phenyl-2-[[(3R)-tetrahydrofuran-3-carbony l]amino]propanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-[2-amino-1-(3-fluoro-4-oxo-pyrido[1,2-a]pyrimid in-2-yl)-2-oxo-ethyl]-3- [(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl] -6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (270 mg, 0.045 mmol, 1.00 eq) in dichloromethane (2.00 mL) was added methoxycarbonyl-(triethylammonio)sulfonyl-azanide (442 mg, 1.85 mmol, 4.00 eq). The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 32%- 62%,58min) to give (1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]-6,6-dimethyl-3-[ (2S)-3-phenyl-2- [[(3R)-tetrahydrofuran-3-carbonyl]amino] propanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide (30.0 mg, 51.3 μmol, 4% yield, 97% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.65 (s,0.4H), 9.87-9.74 (m, 0.4H), 9.66 (d, J = 8.4 Hz, 0.2H), 9.57 (d, J = 8.4 Hz, 0.2H), 9.23 (s, 0.4H), 8.83-8.77 (m, 0.4H), 8.50 (d, J = 8.0 Hz, 0.4H), 8.35-8.23 (m, 1H), 8.13-8.07 (m, 1H), 8.06-7.95 (m, 1H), 7.90-7.75 (m, 1H), 7.33-7.10 (m, 5H), 4.66-4.47 (m, 1H), 4.33- 4.16 (m, 1H), 3.53 (d, J = 5.6 Hz, 5H), 3.26-3.15 (m, 1H), 3.03-2.60 (m, 3H), 1.93-1.77 (m, 2H), 1.65- 1.50 (m, 1.H), 1.32 (d, J = 7.6 Hz, 0.3H), 1.15 (d, J = 7.6 Hz, 0.3H), 0.88 (d, J = 2.8 Hz, 6H), 0.69-0.61 (m, 0.2H). LCMS (Method D): R _t = 2.055 min; MS (ESIpos): m/z = 567.2 [M+H] ⁺ . Preparation of CPD0330439 Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-amino-3-phenyl-propanoyl]-6,6-dimethyl- 3- azabicyclo[3.1.0]hexane-2-carboxylate A solution of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-phenyl-pro panoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (2.70 g, 6.48 mmol, 1.00 eq) in hydrogen chloride (4 M in 1,4-dioxane, 30.0 mL, 18.5 eq) was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuum to give methyl (1R,2S,5S)-3-[(2S)-2-amino-3-phenyl-propanoyl]-6,6-dimethyl- 3- azabicyclo[3.1.0]hexane-2-carboxylate (2.52 g, 6.47 mmol, 100% yield, 2HCl) as a white solid. Procedure for preparation of methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-phenyl-2-[[(3S)- tetrahydrofuran-3-carbonyl]amino]propanoyl]-3-azabicyclo[3.1 .0]hexane-2-carboxylate To a solution of (3S)-tetrahydrofuran-3-carboxylic acid (650 mg, 5.60 mmol, 1.00 eq) in dichloromethane (30.0 mL) were added bis(2-oxo-3-oxazolidinyl)phosphinicchloride (2.85 g, 11.2 mmol, 2.00 eq) and N,N-diisopropylethylamine (2.17 g, 16.8 mmol, 2.93 mL, 3.00 eq) at 0 °C. After stirring at 0 °C for 10 min, methyl (1R,2S,5S)-3-[(2S)-2-amino-3-phenyl-propanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane- 2-carboxylate (2.52 g, 6.47 mmol, 1.16 eq, 2HCl) was added at 0 °C. The resulting mixture was stirred at 25 °C for 12 h and concentrated in vacuum to give a residue. The residue was purified by reversed phase (instrument: 80 g Flash; Column: Welch Ultimate XB_C1820-40μm; eluent A: water (0.1% HCl), eluent B: acetonitrile; gradient: 0-40 min 0-90% B; flow 60 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-phenyl-2-[[(3S)- tetrahydrofuran-3-carbonyl]amino]propanoyl]-3-azabicyclo[3.1 .0]hexane-2-carboxylate (1.70 g, 4.10 mmol, 73% yield) as a yellow solid. LC-MS (Method C): Rt = 0.772 min; MS (ESIpos): m/z = 415.1 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-phenyl-2-[[(3S)-tetrahydro furan- 3-carbonyl]amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2-carb oxylic acid To a solution of methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-phenyl-2-[[(3S)-tetrahydro furan-3- carbonyl]amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2-carbox ylate (1.70 g, 4.10 mmol, 1.00 eq) in methanol (20.0 mL) was added dropwise a solution of lithium hydroxide monohydrate (516 mg, 12.3 mmol, 3.00 eq) at 25 °C. After stirring at 25 °C for 12 h, the reaction mixture was concentrated in vacuum to give a residue. The residue was purified by reversed phase (instrument: 80 g Flash; Column: Welch Ultimate XB_C1820-40μm; eluent A: water (0.05% HCl), eluent B: acetonitrile; gradient: 0-50 min 0- 90% B; flow 60 ml/min; temperature: room temperature; Detector: UV 220/254 nm) and lyophilized to give (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-phenyl-2-[[(3S)-tetrahydro furan-3-carbonyl]amino]propanoyl]- 3-azabicyclo[3.1.0] hexane-2-carboxylic acid (1.30 g, 3.25 mmol, 79% yield) as a yellow solid. LC-MS (Method C): Rt = 0.715 min 0.744 min; MS (ESIpos): m/z = 401.1 [M+H] ⁺ . Procedure for preparation of 3-[(2S)-3-phenyl-2-[[(3S)-tetra azabicyclo[3.1.0]hexane-2-ca To a solution of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-phenyl-2-[[(3S)-tetrahydro furan-3- carbonyl]amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2-carbox ylic acid (350 mg, 0.874 mmol, 1.00 eq) in dichloromethane (10.0 mL) were added bis(2-oxo-3-oxazolidinyl)phosphinicchloride (445 mg, 1.75 mmol, 2.00 eq) and N,N-diisopropylethylamine (904 mg, 6.99 mmol, 1.22 mL, 8.00 eq) at 0 °C. After stirring at 0 °C for 10 min, 2-amino-2-phthalazin-1-yl-acetamide (481 mg, 1.75 mmol, 2.00 eq, 2HCl) was added into the reaction mixture at 0 °C. After stirring at 25 °C for 12 h, the reaction mixture was concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 1: 0 to 0:1) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl- ethyl)-6,6-dimethyl-3-[(2S)-3-phenyl-2-[[(3S)-tetrahydrofura n-3-carbonyl]amino]propanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxamide (430 mg, 0.736 mmol, 84% yield) as a yellow solid. LC-MS (Method C): R _t = 0.821 min; MS (ESIpos): m/z = 585.3 [M+H] ⁺ . Procedure for preparation of dimethyl-3-[(2S)-3-phenyl-2-[[(3S) azabicyclo[3.1.0]hexane-2-carbox To a solution of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-6,6-dim ethyl-3-[(2S)-3-phenyl-2- [[(3S)-tetrahydrofuran-3-carbonyl]amino]propanoyl]-3-azabicy clo[3.1.0]hexane-2-carboxamide (430 mg, 0.735 mmol, 1.00 eq) in dichloromethane (15.0 mL) was added Burgess reagent (526 mg, 2.21 mmol, 3.00 eq) at 25 °C for 1 h. The mixture was added into saturated sodium bicarbonate solution (50.0 mL) at 0 °C. The mixture was extracted with dichloromethane (10.0 mL × 3). The mixture was washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 10: 0 to 0: 10) to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25 mm* 10 μm; mobile phase: [water(FA)-ACN];B%: 36%-56%,10 min) to give (1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]-6,6-dimethyl-3-[ (2S)-3-phenyl-2-[[(3S)- tetrahydrofuran-3-carbonyl]amino]propanoyl]-3-azabicyclo[3.1 .0] hexane-2-carboxamide (29.0 mg, 50.7 μmol, 7% yield, 99% purity) as a white powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.66 (s, 0.3H), 9.81-9.76 (m, 0.5H), 9.68-9.57 (m, 0.3H), 9.23 (s, 0.4H), 8.81-8.79 (m, 0.4H), 8.51 (d, J = 8.4 Hz, 0.4H), 8.34-8.25 (m, 0.9H), 8.11-8.07 (m, 1H), 8.05- 7.96 (m, 0.7H), 7.86-7.82 (m, 0.8H), 7.81-7.78 (m, 0.5H), 7.31-7.22 (m, 3.8H), 7.19-7.14 (m, 1.2H), 4.64-4.48 (m, 1H), 4.22-4.16 (m, 1H), 3.91-3.68 (m, 3H), 3.64-3.41 (m, 3H), 3.04-2.73 (m, 2H), 2.55- 2.52 (m, 1H), 1.88-1.76 (m, 1H), 1.72-1.52 (m, 2.4H), 1.32-1.14 (m, 0.6H), 1.09-0.80 (m, 6H). LC-MS (Method C): R _t = 0.768 min; MS (ESIpos): m/z = 567.5 [M+H] ⁺ . HPLC (Method K): R _t = 1.850 min. Preparation of CPD0330440 Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3- cyclopropyl-propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan e-2-carboxylate To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propanoic acid (5.00 g, 21.8 mmol, 1.00 eq) in dichloromethane (50.0 mL) was added bis(2-oxo-3-oxazolidinyl)phosphinic chloride (6.66 g, 26.2 mmol, 1.20 eq) and stirred at 20 °C for 0.5 h, then N,N- diisopropylethylamine (8.46 g, 65.4 mmol, 11.4 mL, 3.00 eq) and methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (3.69 g, 21.8 mmol, 1.00 eq) were added and stirred at 20 °C for 15.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~30 % Ethyl acetate/Petroleum ethergradient @ 60 mL/min) to give methyl (1R,2S,5S)-3-[(2S)-2-(tert- butoxycarbonylamino)-3-cyclopropyl-propanoyl]-6,6-dimethyl-3 -azabicyclo[3.1.0] hexane-2- carboxylate (7.00 g, 18.4 mmol, 84% yield) as colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.12-7.03 (m, 1H), 4.19 (s, 1H), 4.16 (d, J = 7.6 Hz, 1H), 3.95 (d, J = 10.4 Hz, 1H), 3.78 (dd, J = 10.0, 5.6 Hz, 1H), 3.63 (s, 3H), 1.60-1.49 (m, 2H), 1.42-1.38 (m, 1H), 1.37- 1.29 (m, 9H), 1.29-1.20 (m, 1H), 1.04-0.87 (m, 6H), 0.82-0.72 (m, 1H), 0.34 (br. s, 1H), 0.19-0.09 (m, 1H), 0.08--0.04 (m, 1H). LCMS (Method L): Rt = 1.599 min; MS (ESIpos): m/z = 281.3 [M-99] ⁺ , 325.3[M-55] ⁺ . Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-2-amino-3-cyclopropyl-propanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate To a solution of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropy l-propanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (7.00 g, 18.4 mmol, 1.00 eq) in hydrogen chloride (50.0 mL), then the mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give methyl (1R,2S,5S)-3-[(2S)-2-amino-3-cyclopropyl-propanoyl]-6,6-dime thyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (5.37 g, crude) as a white solid. LC-MS (Method L): Rt = 1.165 min; MS (ESIpos): m/z = 281.1 [M+1] ⁺ . Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[[(3R)-tetrahydrofuran-3- carbonyl]amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]he xane-2-carboxylate To a solution of (3R)-tetrahydrofuran-3-carboxylic acid (1.24 g, 10.7 mmol, 1.00 eq) in dichloromethane (50 mL) was added bis(2-oxo-3-oxazolidinyl)phosphinic chloride (4.09 g, 16.1 mmol, 1.50 eq). After stirring at 20 °C for 0.5 h, methyl (1R,2S,5S)-3-[(2S)-2-amino-3-cyclopropyl-propanoyl]-6,6-dime thyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (3.00 g, 10.7 mmol, 1.00 eq) and N,N- diisopropylethylamine (4.15 g, 32.10 mmol, 5.59 mL, 3.00 eq) were added into the mixture. The solution was stirred at 20 °C for 15.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~70% Ethyl acetate/Petroleum ethergradient @ 60 mL/min) to give methyl (1R,2S,5S)-3- [(2S)-3-cyclopropyl-2-[[(3R)-tetrahydrofuran-3-carbonyl]amin o]propanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (2.45 g, 6.47 mmol, 60% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.29-8.20 (m, 1H), 4.51-4.38 (m, 1H), 4.22-4.16 (m, 1H), 3.92-3.85 (m, 1H), 3.84-3.77 (m, 2H), 3.72-3.65 (m, 2H), 3.64 (s, 3H), 3.59-3.49 (m, 1H), 3.01-2.86 (m, 1H), 1.98- 1.83 (m, 2H), 1.67-1.58 (m, 1H), 1.57-1.51 (m, 1H), 1.45-1.37 (m, 1H), 1.32-1.22 (m, 1H), 1.04-0.99 (m, 3H), 0.92-0.86 (m, 3H), 0.81-0.70 (m, 1H), 0.46-0.34 (m, 2H), 0.20-0.11 (m, 1H), 0.09-0.02 (m, 1H). LC-MS (Method L): Rt = 1.328 min; MS (ESIpos): m/z = 379.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[[(3R)-tetrahydrofuran-3- carbonyl]amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]he xane-2-carboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[[(3R)-tetrahydrofuran-3- carbonyl]amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]he xane-2-carboxylate (2.45 g, 6.47 mmol, 1.00 eq) in mixed solvent of methyl alcohol (10.0 mL) and water (10.0 mL) were added lithium hydroxide (815 mg, 19.4 mmol, 3.00 eq). After stirring at 20 °C for 2 h, hydrochloric acid (1M) was added to the reaction mixture to adjust pH~5. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase column (Instrument: 300 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.05% formic acid), eluent B: acetonitrile; gradient: 0-15 min 0-55% B; flow 75 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[[(3R)-tetrahydrofuran-3- carbonyl]amino]propanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (2.10 g, 5.53 mmol, 86% yield, 96% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.88-12.27 (m, 1H), 8.32-8.17 (m, 1H), 4.50-4.39 (m, 1H), 4.13- 4.08 (m, 1H), 3.89-3.74 (m, 3H), 3.72-3.61 (m, 2H), 3.59-3.52 (m, 1H), 3.00-2.89 (m, 1H), 1.98-1.85 (m, 2H), 1.65-1.55 (m, 1H), 1.55-1.47 (m, 1H), 1.43-1.36 (m, 1H), 1.34-1.22 (m, 1H), 1.07-0.98 (m, 3H), 0.94-0.85 (m, 3H), 0.84-0.71 (m, 1H), 0.45-0.32 (m, 2H), 0.21-0.11 (m, 1H), 0.09-0.01 (m, 1H). LC-MS (Method L): Rt = 1.520 min; MS (ESIpos): m/z = 365.1 [M+H] ⁺ . To a solution of (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[[(3R)-tetrahydrofuran-3- carbonyl]amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]he xane-2-carboxylic acid (800 mg, 2.20 mmol, 1.00 eq) in dichloromethane (10.0 mL) were added bis(2-oxo-3-oxazolidinyl)phosphinic chloride (838 mg, 3.29 mmol, 1.50 eq). After stirring at 20 °C for 0.5 h, 2-amino-2-phthalazin-1-yl-acetamide (444 mg, 2.20 mmol, 1.00 eq) and N,N- diisopropylethylamine (851 mg, 6.59 mmol, 1.15 mL, 3.00 eq) were added into the mixture and stirred at 20 °C for 15.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (Instrument: 300 g Flash; Column: Welch Ultimate XB_C1820-40μm; eluent A: water (0.05% formic acid), eluent B: acetonitrile; gradient: 0-15 min 0-50% B; flow 75 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -3-cyclopropyl-2- [[(3R)-tetrahydrofuran-3-carbonyl]amino]propanoyl]-6,6-dimet hyl-3-azabicyclo [3.1.0]hexane-2- carboxamide (1.10 g, 2.00 mmol, 91% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.79-9.66 (m, 1H), 9.21-9.13 (m, 1H), 8.95-8.86 (m, 1H), 8.38-8.30 (m, 1H), 8.29-8.16 (m, 1H), 8.15-8.00 (m, 1H), 7.97-7.78 (m, 1H), 7.61-7.27 (m, 1H), 6.35-6.24 (m, 1H), 5.91-5.72 (m, 1H), 4.49-4.36 (m, 2H), 4.34-4.24 (m, 1H), 4.13-4.05 (m, 1H), 3.89-3.73 (m, 3H), 3.72- 3.59 (m, 2H), 3.59-3.50 (m, 1H), 3.04-2.87 (m, 1H), 1.99-1.80 (m, 2H), 1.65-1.54 (m, 1H), 1.54-1.45 (m, 1H), 1.42-1.34 (m, 1H), 1.34-1.14 (m, 2H), 1.07-0.97 (m, 3H), 0.97-0.92 (m, 1H), 0.91-0.84 (m, 3H), 0.81-0.69 (m, 1H), 0.45-0.29 (m, 2H), 0.17-0.10 (m, 1H), 0.08--0.03 (m, 1H). LC-MS (Method L): Rt = 1.672 min; MS (ESIpos): m/z = 547.1 [M+H] ⁺ . Procedure for preparation of Compound CPD0330440- (1R,2S,5S)-N-[cyano(phthalazin-1- yl)methyl]-3-[(2S)-3-cyclopropyl-2-[[(3R)-tetrahydrofuran-3- carbonyl]amino]propanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-N-(2-amino-2-oxo-1-phthalazin-1-yl-ethyl)-3-[(2S) -3-cyclopropyl-2-[[(3R)- tetrahydrofuran-3-carbonyl]amino]propanoyl]-6,6-dimethyl-3-a zabicyclo[3.1.0]hexane-2-carboxamide (250 mg, 0.456 mmol, 1.00 eq) in dichloromethane (2 mL) was added methoxycarbonyl- (triethylammonio)sulfonyl-azanide (217 mg, 0.911 mmol, 2.00 eq).After stirring at 20 °C for 4 h, the reaction mixture was diluted with water (5 mL) and extracted with dichloromethane (10 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water (formic acid)-ACN]; B%: 22%-52%,10 min) to give (1R,2S,5S)-N-[cyano(phthalazin-1-yl)methyl]-3-[(2S)-3-cyclop ropyl-2-[[(3R)-tetrahydrofuran-3- carbonyl]amino]propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]he xane-2-carboxamide (60 mg, 0.113 mmol, 25% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.73-10.62 (m, 0.4H), 9.81-9.72 (m, 0.4H), 9.71-9.65 (m, 0.2H), 9.62-9.51 (m, 0.2H), 9.39-9.28 (m, 0.4H), 8.83-8.72 (m, 0.4H), 8.38 (d, J = 7.2 Hz, 0.4H), 8.33-8.18 (m, 1H), 8.15-8.04 (m, 1H), 8.03-7.71 (m, 2H), 7.30-7.21 (m, 1H), 4.50-4.27 (m, 1H), 4.25-4.06 (m, 1H), 3.73 (d, J = 6.8 Hz, 3H), 3.70-3.50 (m, 3H), 3.04-2.86 (m, 1H), 2.04-1.76 (m, 2H), 1.74-1.59 (m, 1H), 1.58-1.44 (m, 1H), 1.42-1.23 (m, 1H), 1.14-0.79 (m, 7H), 0.77-0.53 (m, 1H), 0.47-0.22 (m, 2H), 0.19-- 0.21 (m, 2H). LC-MS (Method L): Rt = 1.676 min; MS (ESIpos): m/z = 531.1 [M+H] ⁺ . To a solution of 2-amino-2-(1,6-naphthyridin-8-yl)acetonitrile (75.8 mg, 412 μmol, 1.00 eq) and (1R,2S,5S)-3-[(2S)-3-cyclopropyl-2-[[(3S)-tetrahydrofuran-3- carbonyl]amino]propanoyl]-6,6-dimethyl- 3-azabicyclo [3.1.0]hexane-2-carboxylic acid (150 mg, 412, 1.00 eq) in dichloromethane (4.00 mL) were added diisopropylethylamine (160 mg, 1.23 mmol, 215 μL, 3.00 eq) and O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluronium hexafluorophosphate (172 mg, 452 μmol, 1.10 eq). After stirring at 20 °C for 16 h, the reaction mixture was concentrated in vacuo at 50 °C to give a residue. The residue was purified by prep-TLC (SiO ₂ , Dichloromethane: Tetrahydrofuran = 1: 2) and prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water (FA)-ACN]; B%: 30%-50%,9min) to afford (1R,2S,5S)-N-[(S)-cyano(1,6-naphthyridin-8-yl)methyl]-3-[(2S )-3-cyclopropyl-2-[[(3S)- tetrahydrofuran-3-carbonyl]amino] propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxam ide (52.2 mg, 94.3 μmol, 23% yield) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.47 (d, J = 7.8 Hz, 0.5H), 9.44 (s, 1H), 9.33 (d, J = 8.0 Hz, 0.5H), 9.22-9.15 (m, 1H), 8.84 (d, J = 17.2 Hz, 1H), 8.63 (d, J = 8.0 Hz, 1H), 8.22-8.11 (m, 1H), 7.81-7.74 (m, 1H), 6.81 (d, J = 8.0 Hz, 0.5H), 6.74 (d, J = 7.8 Hz, 0.6H), 4.41-4.30 (m, 1H), 4.24 (s, 0.5H), 4.18 (s, 0.5H), 3.81-3.67 (m, 3H), 3.64-3.52 (m, 2H), 3.46-3.39 (m, 1H), 2.94-2.82 (m, 1H), 1.91-1.81 (m, 2H), 1.58-1.40 (m, 2H), 1.32-1.13 (m, 2H), 0.97 (s, 1.5H), 0.89 (s, 1.5H), 0.83 (s, 1.5H), 0.79 (s, 1.5H), 0.75- 0.58 (m, 1H), 0.35-0.20 (m, 2H), 0.10--0.12 (m, 2H). LC-MS (Method C): Rt = 0.811 min; MS (ESIpos): m/z = 531.3 [M+H] ⁺ . SFC: dr = 52: 48. Preparation of CPD0336665 Procedure for preparation of methyl (1R, 2S, 5S)-3-((S)-2-amino-4-hydroxy-3,3- dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-c arboxylate To a solution of methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-4-hydroxy-3 ,3- dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-c arboxylate (700 mg, 1.76 mmol, 1.00 eq) in dioxane (2.00 mL) was added hydrochloric acid (4 M in dioxane, 4.39 mL, 10.0 eq) at 0 °C. After stirring at 20 °C for 1 h, the mixture was concentrated under vacuum to give methyl (1R,2S,5S)-3-((S)- 2-amino-4-hydroxy-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabi cyclo[3.1.0]hexane-2-carboxylate (680 mg, crude, hydrochloric acid salt) as light yellow gum. Procedure for preparation of methyl (1R, 2S, 5S)-3-((S)-4-hydroxy-3,3-dimethyl-2-((S)- tetrahydrofuran-3-carboxamido)butanoyl)-6,6-dimethyl-3-azabi cyclo[3.1.0]hexane-2- carboxylate To a solution of (S)-tetrahydrofuran-3-carboxylic acid (62.4 mg, 538 μmol, 1.00 eq), O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (307 mg, 806 μmol, 1.50 eq) and N,N-diisopropylethylamine (278 mg, 2.15 mmol, 4.00 eq) in N,N-dimethylformamide (5.00 mL) were added methyl (1R,2S,5S)-3-((S)-2-amino-4-hydroxy-3,3-dimethylbutanoyl)-6, 6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (180 mg, 538 μmol, 1.00 eq, hydrochlorate) at 0 °C. After stirring at 20 °C for 2 h, the mixture was poured into water (20.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were washed with brine (20.0 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 0 to 1: 1) to give methyl (1R,2S,5S)-3-((S)-4-hydroxy-3,3-dimethyl-2-((S)-tetrahydrofu ran-3-carboxamido)butanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (170 mg, 364 μmol, 68% yield, 85% purity) as light yellow oil. LC-MS (Method C): R _t = 0.440 min; MS (ESIpos): m/z = 397.1 Procedure for preparation of (1R, 2S, 5S)-3-((S)-4-hydroxy-3, 3-dimethyl-2-((S)-tetrahydrofuran- 3-carboxamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexa ne-2-carboxylic acid To a solution of methyl (1R,2S,5S)-3-((S)-4-hydroxy-3,3-dimethyl-2-((S)-tetrahydrofu ran-3- carboxamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane -2-carboxylate (150 mg, 378 μmol, 1.00 eq) in tetrahydrofuran (2.00 mL) was added a solution of lithium hydroxide monohydrate (31.8 mg, 757 μmol, 2.00 eq) in water (1.00 mL) at 0 °C. After stirring at 20 °C for 3 h, the mixture was poured into water (20.0 mL) and washed with ethyl acetate (30.0 mL × 2). Hydrochloric acid (1M) was added to the aqueous phase to adjust pH to 5, and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (20.0 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-3-((S)-4-hydroxy-3,3-dimethyl-2-((S)-tetrahydrofu ran-3- carboxamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane -2-carboxylic acid (120 mg, 314 μmol, 83% yield) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.05 (d, J = 8.8 Hz, 1H), 4.61-4.56 (m, 1H), 4.09 (s, 1H), 3.86-3.59 (m, 6H), 3.49-3.42 (m, 1H), 3.22-3.06 (m, 3H), 1.95-1.88 (m, 3H), 1.51-1.46 (m, 1H), 1.40-1.36 (m, 1H), 0.99 (s, 3H), 0.92 (s, 3H), 0.87 (s, 3H), 0.79 (s, 3H). LC-MS (Method C): R _t = 0.410 min; MS (ESIpos): m/z = 383.1 [M+H] ⁺ To a solution of (1R,2S,5S)-3-((S)-4-hydroxy-3,3-dimethyl-2-((S)-tetrahydrofu ran-3- carboxamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane -2-carboxylic acid (100 mg, 262 μmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexaflu orophosphate (149 mg, 392 μmol, 1.50 eq), N,N-diisopropylethylamine (101 mg, 784 μmol, 3.00 eq) in N,N-dimethylformamide (2.00 mL) was added (S)-2-amino-3-((S)-6-fluoro-3-oxo-3,4-dihydro-2H-benzo[b][1, 4]oxazin-2- yl)propanenitrile (61.5 mg, 262 μmol, 1.00 eq) at 0 °C. After stirring at 20 °C for 2 h, the mixture was poured into water (20.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were washed with brine (20.0 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition: column: Phenomenex luna C18150*25 mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 35%-65%, 7 min) to give (1R,2S,5S)-N-((S)-1-cyano-2-((S)-6-fluoro-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-2- yl)ethyl)-3-((S)-4-hydroxy-3,3-dimethyl-2-((S)-tetrahydrofur an-3-carboxamido)butanoyl)-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxamide (50.8 mg, 81.4 μmol, 31% yield, 96% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.94-10.85 (m, 1H), 8.98-8.89 (m, 1H), 8.04-8.00 (m, 0.2H), 7.96- 7.90 m, 0.8H), 7.06-6.99 (m, 0.2H), 6.94-6.88 (m, 0.8H), 6.82-6.63 (m, 2H), 5.19-4.99 (m, 1H), 4.85- 4.63 (m, 1H), 4.60-4.47 (m, 2H), 4.16 (s, 0.2H), 4.07 (s, 0.8H), 3.93-3.55 (m, 6H), 3.48-3.42 (m, 1H), 3.14-2.93 (m, 3H), 2.32-2.22 (m, 1H), 1.97-1.87 (m, 2H), 1.52-1.45 (m, 1H), 1.35-1.27 (m, 1H), 0.99 (s, 3H), 0.92 (s, 0.6H), 0.85 (s, 0.6H), 0.80 (s, 3H), 0.71 (s, 2.4H), 0.65 (s, 2.4H). LC-MS (Method C): R _t = 0.467 min; MS (ESIpos): m/z = 600.02 [M+H] ⁺ . HPLC (Method S): R _t = 1.285min; purity: 97%. SFC: dr = 81: 19. A mixture of (3R)-tetrahydrofuran-3-carboxylic acid (114 mg, 0.985 mmol, 1.10 eq), O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (511 mg, 1.34 mmol, 1.50 eq) and N,N-diisopropylethylamine (463 mg, 3.58 mmol, 4.00 eq) in N,N-dimethylformamide (5.00 mL) was stirred at 25 °C for 0.5 h, and then methyl (1R,2S,5S)-3-[(2S)-2-amino-4-hydroxy-3,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyla te (300 mg, 0.895 mmol, 1.00 eq, HCl) was added. After stirring at 25 °C for 11.5 h, the reaction mixture was poured into water (20.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 1 to 0: 1) to give methyl (1R,2S,5S)-3-[(2S)-4-hydroxy-3,3-dimethyl-2-[[(3R)- tetrahydrofuran-3-carbonyl]amino]butanoyl]-6,6-dimethyl-3-az abicyclo[3.1.0]hexane-2-carboxylate (300 mg, 0.529 mmol, 59% yield, 70% purity) as colorless gum. LC-MS (Method M): R _t = 0.445 min; MS (ESIpos): m/z = 397.4 [M+H] ⁺ . Procedure tetrahydro carboxylic To a solution of methyl (1R,2S,5S)-3-[(2S)-4-hydroxy-3,3-dimethyl-2-[[(3R)-tetrahydr ofuran-3-carbonyl] amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-car boxylate (300 mg, 0.529 mmol, 70% purity, 1.00 eq) in tetrahydrofuran (3.00 mL) was added a solution of lithium hydroxide monohydrate (66.6 mg, 1.59 mmol, 3.00 eq) in water (1.50 mL) at 0 °C. After stirring at 25 °C for 2 h, the mixture was poured into water (20.0 mL) and extracted with ethyl acetate (10.0 mL). The aqueous phase was adjusted pH to 4-5 with hydrochloric acid (1M) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were concentrated under vacuum to give (1R,2S,5S)-3-[(2S)-4-hydroxy-3,3- dimethyl-2-[[(3R)-tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (210 mg, crude) as colorless oil. LC-MS (Method M): R _t = 0.398 min; MS (ESIpos): m/z = 383.3 [M+H] ⁺ . Procedure for preparation of CPD0336666 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-6-fluoro-3-oxo- 4H-1,4-benzoxazin-2-yl]ethyl]-3-[(2S)-4-hydroxy-3,3-dimethyl -2-[[(3R)-tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-4-hydroxy-3,3-dimethyl-2-[[(3R)-tetrahydr ofuran-3-carbonyl] amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-car boxylic acid (210 mg, 0.549 mmol, 1.00 eq) in N,N-dimethylformamide (2.00 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (313 mg, 0.823 mmol, 1.50 eq) and N,N- diisopropylethylamine (283 mg, 2.20 mmol, 4.00 eq). After stirring at 25 °C for 0.5 h, (2S)-2-amino-3- [(2S)-6-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]propanenitrile (129 mg, 0.549 mmol, 1.00 eq) was added. After addition, the resulting mixture was stirred at 25°C for 11.5 h. The reaction mixture was poured into water (10.0 mL) and extracted with ethyl acetate (5.00 mL × 3). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water (FA)-ACN]; B%: 30%-60%, 9 min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-6-fluoro-3-oxo-4H-1,4-ben zoxazin-2-yl]ethyl]-3-[(2S)-4- hydroxy-3,3-dimethyl-2-[[(3R)-tetrahydrofuran-3-carbonyl]ami no]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (26.0 mg, 43.0 μmol, 8% yield, 99% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.93 (s, 0.3H), 10.87 (s, 0.6H), 8.99-8.89 (m, 0.9H), 8.06-7.97 (m, 0.3H), 7.96-7.87 (m, 0.7H), 7.06-6.98 (m, 0.3H), 6.92-6.89 (m, 0.7H), 6.84-6.62 (m, 2H), 5.20-5.08 (m, 0.7H), 5.07-4.99 (m, 0.3H), 4.88-4.63 (m, 1H), 4.59-4.43 (m, 2H), 4.17 (s, 0.3H), 4.08 (s, 0.7H), 3.96- 3.85 (m, 1H), 3.84-3.73 (m, 2H), 3.71-3.50 (m, 3H), 3.47-3.38 (m, 1H), 3.16-3.00 (m, 2H), 2.96-2.94 (m, 1H), 2.32-2.18 (m, 1H), 1.97-1.72 (m, 1H), 1.56-1.43 (m, 1H), 1.35-1.33 (m, 0.3H), 1.31-1.28 (m, 0.7H), 0.99 (s, 3H), 0.91 (s, 1H), 0.84 (s, 1H), 0.82(s, 3H), 0.71(s, 2H),0.64 (s, 2H). LCMS M th d M R = 0458 i MS ESI / = 6003 M+H ⁺ To a mixture of (2S)-2-(tert-butoxycarbonylamino)-4,4-difluoro-butanoic acid (1.50 g, 6.27 mmol, 1.00 eq), diisopropylethylamine (2.43 g, 18.8 mmol, 3.28 mL, 3.00 eq) in dichloromethane (20.0 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (3.58 g, 9.41 mmol, 1.50 eq). After stirring at 25 °C for 10 min, methyl (1R,2S,5S)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (1.42 g, 6.90 mmol, 1.10 eq, hydrogen chloride) was added. After stirring at 25 °C for 16 h, the reaction mixture was concentrated under vacuum and diluted with water (30.0 mL). The solution was extracted with ethyl acetate (30.0 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~60% Ethyl acetate/Petroleum ether gradient @ 55 mL/min) to give methyl (1R,2S,5S)-3- [(2S)-2-(tert-butoxycarbonylamino)-4,4-difluoro-butanoyl]-6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylate (2.00 g, 5.12 mmol, 82% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.61-7.25 (m, 1H), 6.21-5.74 (m, 1H), 4.40-4.24 (m, 1H), 4.20 (s, 0.7H), 4.12 (s, 0.3H), 3.94-3.82 (m, 1H), 3.77-3.73 (m, 0.4H), 3.72 (s, 0.6H), 3.69 (s, 0.2H), 3.66 (s, 2H), 3.61 (s, 0.7H), 3.56-3.43 (m, 1H), 2.19-2.02 (m, 2H), 1.65-1.53 (m, 1H), 1.46-1.41 (m, 1H), 1.39- 1.34 (m, 10H), 1.01 (s, 4H), 0.94-0.82 (m, 4H). To a solution of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-4,4-difluoro -butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (2.00 g, 5.12 mmol, 1.00 eq) in 1,4-dioxane (15.0 mL) was added hydrogen chloride/1,4-dioxane (4 M, 15.0 mL, 11.7 eq). After stirring at 25 °C for 4 h, the mixture was concentrated under vacuum to give methyl (1R,2S,5S)-3-[(2S)-2-amino-4,4-difluoro- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyla te (2.00 g, 4.41 mmol, 86% yield, 72% purity, hydrogen chloride) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 6.56-6.17 (m, 1H), 4.35-4.23 (m, 2H), 4.16-4.05 (m, 1H), 4.02-3.84 (m, 1H), 3.78-3.71 (m, 2H), 3.69-3.64 (m, 3H), 3.40-3.31 (m, 3H), 2.46-2.21 (m, 2H), 1.69-1.58 (m, 1H), 1.55-1.45 (m, 1H), 1.04-1.01 (m, 3H), 0.96-0.93 (m, 2H), 0.91-0.88 (m, 2H). Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-4,4-difluoro-2-[[(3S)-tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxylate To a solution of (3S)-tetrahydrofuran-3-carboxylic acid (255 mg, 2.20 mmol, 1.00 eq) and methyl (1R,2S,5S)-3-[(2S)-2-amino-4,4-difluoro-butanoyl]-6,6-dimeth yl-3-azabicyclo[3.1.0]hexane-2- carboxylate (1.00 g, 2.20 mmol, 72% purity, 1.00 eq, hydrogen chloride) in dichloromethane (10.0 mL) were added N,N-diisopropylethylamine (854 mg, 6.61 mmol, 1.15 mL, 3.00 eq) and O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (1.26 g, 3.31 mmol, 1.50 eq). After stirring at 25 °C for 16 h, the mixture was concentrated to give a residue. The residue was purified by reversed phase (Instrument: 80 g Flash; Column: Welch Ultimate XB_C1820-40μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-15 min 40-60% B; flow 85 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give methyl (1R,2S,5S)-3-[(2S)-4,4-difluoro-2-[[(3S)- tetrahydrofuran-3-carbonyl]amino]butanoyl]-6,6-dimethyl-3-az abicyclo[3.1.0]hexane-2-carboxylate (550 mg, 1.42 mmol, 64% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.73-8.29 (m, 1H), 6.26-5.76 (m, 1H), 4.84-4.74 (m, 0.23H), 4.68- 4.55 (m, 0.58H), 4.40-4.32 (m, 0.19H), 4.22-4.12 (m, 1H), 3.89-3.44 (m, 9H), 3.03-2.84 (m, 1H), 2.25- 2.05 (m, 2H), 1.98-1.81 (m, 2H), 1.67-1.51 (m, 1H), 1.49-1.39 (m, 1H), 1.32-1.22 (m, 0.5H), 1.16-1.11 (m, 0.5H), 1.01 (s, 3H), 0.93-0.78 (m, 3H). Procedure for preparation of (1R,2S,5S)-3-[(2S)-4,4-difluoro-2-[[(3S)-tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-4,4-difluoro-2-[[(3S)-tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxylate (500 mg, 1.29 mmol, 1.00 eq) in terahydrofuran (10.0 mL) and water (2.00 mL) was added lithium hydroxide (61.6 mg, 2.57 mmol, 2.00 eq). After stirring at 25 °C for 2 h, hydrochloric acid (1M) was added to the reaction mixture to adjust pH~6. The solution was extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give (1R,2S,5S)-3-[(2S)-4,4-difluoro-2-[[(3S)-tetrahydrofuran-3-c arbonyl]amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (480 mg, 1.28 mmol, 99% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.96-12.42 (m, 1H), 8.72-8.17 (m, 1H), 6.33-5.68 (m, 1H), 4.85- 4.76 (m, 0.2H), 4.74 (s, 0.2H), 4.67-4.56 (m, 0.58H), 4.50-4.38 (m, 0.23H), 4.12 (s, 0.54H), 4.07 (s, 0.21H), 3.88-3.42 (m, 6H), 3.04-2.83 (m, 1H), 2.26-2.05 (m, 2H), 1.99-1.93 (m, 2H), 1.57-1.51 (m, 0.7H), 1.41-1.38 (m, 0.3H), 1.32-1.24 (m, 0.5H), 1.16-1.11 (m, 0.5H), 1.02 (s, 3H), 0.93-0.79 (m, 3H). Procedure for preparation of Compound CPD0338199 of (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-6- fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]ethyl]-3-[(2S)-4,4-diflu oro-2-[[(3S)-tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-4,4-difluoro-2-[[(3S)-tetrahydrofuran-3-c arbonyl]amino]butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (127 mg, 340 μmol, 1.00 eq) and (2S)-2- amino-3-[(2S)-6-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]propanen itrile (80.0 mg, 340 μmol, 1.00 eq) in dichloromethane (2.00 mL) were added N,N-diisopropylethylamine (175 mg, 1.36 mmol, 236 μL, 4.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (155 mg, 408 μmol, 1.20 eq). After stirring at 25 °C for 16 h, the mixture was concentrated to give a residue. The residue was purified by reversed phase (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water (FA)- acetonitrile]; B%: 30%-60%,10 min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-6- fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]ethyl]-3-[(2S)-4,4-diflu oro-2-[[(3S)-tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxamide (43.4 mg, 84.5 μmol, 25% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.00-10.84 (m, 1H), 8.98-8.83 (m, 1H), 8.62-8.37 (m, 1H), 7.06- 6.89 (m, 1H), 6.83-6.65 (m, 2H), 6.25-5.73 (m, 1H), 5.13-4.93 (m, 1H), 4.78-4.44 (m, 2H), 4.18-4.03 (m, 1H), 3.85-3.73 (m, 2H), 3.73-3.58 (m, 3H), 3.56-3.38 (m, 1H), 3.02-2.84 (m, 1H), 2.36-2.25 (m, 1H), 2.04-1.86 (m, 3H), 1.60-1.48 (m, 1H), 1.44-1.27 (m, 1H), 1.11-0.96 (m, 3H), 0.92-0.78 (m, 3H). LC-MS (Method C): Rt = 0.621 min; MS (ESIpos): m/z = 592.2 [M+H] ⁺ . SFC: dr = 26: 48: 10: 15. Preparation of CPD0338200 Procedure for preparation of CPD0338200- (1R,2S,5S)-N-[cyano(1,6-naphthyridin-8-yl)methyl]-3- [(2S)-2-[(2-hydroxy-2-methyl-propanoyl)amino]-3,3-dimethyl-b utanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-4,4-difluoro-2-[[(3R)-tetrahydrofuran-3-c arbonyl]amino]butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (151 mg, 403 μmol, 1.10 eq) and (2S)-2- amino-3-[(2S)-3-oxo-4H-pyrido[4,3-b][1,4]oxazin-2-yl]propane nitrile (80.0 mg, 367 μmol, 1.10 eq) in dichloromethane (4.00 mL) were added diisopropylethylamine (142 mg, 1.10 mmol, 192 μL, 3.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (167 mg, 440 μmol, 1.20 eq). After stirring at 20 °C for 2 h, the reaction mixture was concentrated under vacuum at 50 °C to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 5%-35%,10min) to afford (1R,2S,5S)-N-[(1S)-1-cyano-2- [(2S)-3-oxo-4H-pyrido[4,3-b][1,4]oxazin-2-yl]ethyl]-3-[(2S)- 4,4-difluoro-2-[[(3R)-tetrahydrofuran-3- carbonyl]amino] butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxami de (34.6 mg, 60.5 μmol, 17% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.16-11.04 (m, 1H), 8.92 (d, J = 8.0 Hz, 0..8H), 8.60-8.52 (m, 0.2H), 8.52-8.36 (m, 1H), 8.16-8.04 (m, 2H), 7.16-6.92 (m, 1H), 6.16-5.76 (m, 1H), 5.08-4.96 (m, 1H), 4.80 (dd, J = 9.6, 3.2 Hz, 1H), 4.64-4.52 (m, 1H), 4.14-4.04 (m, 1H), 3.92-3.76 (m, 2H), 3.72-3.56 (m, 4H), 2.96-2.84 (m, 1H), 2.44-2.36 (m, 1H), 2.04-1.84 (m, 4H), 1.56 (dd, J = 7.6, 5.2 Hz, 1H), 1.32 (d, J = 7.6 Hz, 1H), 1.24 (s, 1H), 1.04-0.96 (m, 3H), 0.88-0.84 (m, 2.7H), 0.80 (s, 0.3H). LC-MS (Method C): Rt = 0.685 min; MS (ESIpos): m/z = 575.2 [M+H] ⁺ . To a solution of (1R,2S,5S)-3-[(2S)-4,4-difluoro-2-[[(3S)-tetrahydrofuran-3-c arbonyl]amino]butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (137 mg, 458 μmol, 1.00 eq) and (2S)-2- amino-3-[(2S)-3-oxo-4H-pyrido[4,3-b][1,4]oxazin-2-yl]propane nitrile (80.0 mg, 458 μmol, 1.00 eq) in dichloromethane (2.00 mL) were added N,N-diisopropylethylamine (236 mg, 1.83 mmol, 319 μL, 4.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (209 mg, 549 μmol, 1.20 eq). After stirring at 25 °C for 16 h, the mixture was concentrated under vacuum to give a residue. The residue was purified by reversed phase (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water (FA)-acetonitrile]; B%: 5%-35%,10 min) to give (1R,2S,5S)-N-[(1S)-1-cyano- 2-[(2S)-3-oxo-4H-pyrido[4,3-b][1,4]oxazin-2-yl]ethyl]-3-[(2S )-4,4-difluoro-2-[[(3S)-tetrahydrofuran-3- carbonyl]amino] butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxami de (24.4 mg, 69.6 μmol, 15% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.21-11.07 (m, 1H), 8.92 (d, J = 8.0 Hz, 1H), 8.66-8.32 (m, 1H), 8.23-8.04 (m, 2H), 7.21-6.93 (m, 1H), 6.24-5.74 (m, 1H), 5.11-4.89 (m, 1.4H), 4.87-4.80 (m, 0.7H), 4.65- 4.51 (m, 1H), 4.16-4.01 (m, 1H), 3.85-3.74 (m, 2H), 3.70-3.58 (m, 3H), 3.53-3.48 (m, 1H), 3.05-2.81 (m, 2H), 2.43-2.35 (m, 1H), 2.02-1.86 (m, 3H), 1.58-1.51 (m, 0.7H), 1.50-1.45 (m, 0.3H), 1.42-1.39 (m, 0.2H), 1.25-1.27 (m, 0.8H), 1.04-0.98 (m, 3H), 0.89-0.82 (m, 3H). LC-MS (Method C): Rt = 0.518 min; MS (ESIpos): m/z =575.2 [ . SFC: dr = 82: 6: 12. Preparation of CPD0330473 Procedure for preparation of methyl (1R,2S,5S)-3-((S)-2-(2-cyanoacetamido)-3,3- dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-c arboxylate To a solution of methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimeth yl-3- azabicyclo[3.1.0]hexane-2-carboxylate (4.00 g, 12.5 mmol, 1.00 eq, hydrogen chloride) and 2- cyanoacetic acid (1.17 g, 13.8 mmol, 1.10 eq) in dichloromethane (40.0 mL) were added 4- methylmorpholine (5.08 g, 50.2 mmol, 5.52 mL, 4.00 eq) and benzotriazol-1-yloxy(tripyrrolidin-1- yl)phosphonium;hexafluorophosphate (7.18 g, 13.8 mmol, 1.10 eq). After stirring at 25 °C for 16 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate = 1: 0 to 1: 1) to give methyl (1R,2S,5S)-3- [(2S)-2-[(2-cyanoacetyl)amino]-3,3-dimethyl-butanoyl]-6,6-di methyl-3-azabicyclo[3.1.0]hexane-2- carboxylate (1.00 g, 2.86 mmol, 23% yield) as yellow oil. LC-MS (Method C): R _t = 0.793 min, MS (ESIpos): m/z = 350.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.39 (d, J = 8.4 Hz, 1H), 4.34 (d, J = 8.4 Hz, 1H), 4.20 (s, 1H), 3.90- 3.77 (m, 2H), 3.72 (d, J = 8.4 Hz, 2H), 3.68-3.63 (m, 3H), 1.59-1.49 (m, 1H), 1.44 (d, J = 7.6 Hz, 1H), 1.05-0.93 (m, 12H), 0.87-0.83 (m, 4H). Procedure for preparation of (1R,2S,5S)-3-((S)-2-(2-cyanoacetamido)-3,3-dimethylbutanoyl) -6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-2-[(2-cyanoacetyl)amino]-3,3-dimethyl-but anoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.70 g, 4.87 mmol, 1.00 eq) in mixed solvent of methyl alcohol (10.0 mL) and water (2.00 mL) was added lithium hydroxide (306 mg, 7.30 mmol, 1.50 eq). After stirring at 25 °C for 2 h, the reaction mixture was quenched with water (20.0 mL) at 25 °C. Hydrogen chloride (1M) was added to adjust pH 2~3. The mixture was extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate = 1: 1 to 0: 1) to give (1R,2S,5S)-3-[(2S)-2-[(2- cyanoacetyl)amino]-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-aza bicyclo[3.1.0] hexane-2-carboxylic acid (1.00 g, 2.98 mmol, 61% yield) as yellow oil. LC-MS (Method C): R _t = 0.496 min, MS (ESIpos): m/z = 336.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.53 (d, J = 6.4 Hz, 1H), 8.53-8.10 (m, 1H), 4.45-4.31 (m, 1H), 4.12 (s, 1H), 3.86-3.74 (m, 2H), 3.71 (d, J = 8.4 Hz, 1H), 3.59-3.54 (m, 1H), 3.43-3.27 (m, 3H), 1.55-1.48 (m, 1H), 1.45 - 1.37 (m, 1H), 1.05-0.90 (m, 12H), 0.88-0.80 (m, 4H). To a solution of (1R,2S,5S)-3-[(2S)-2-[(2-cyanoacetyl)amino]-3,3-dimethyl-but anoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (200 mg, 0.596 mmol, 1.00 eq) and 2-amino-2-(1,6- naphthyridin-8-yl)acetonitrile (109 mg, 0.596 mmol, 1.00 eq) in dichloromethane (2.00 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (249 mg, 0.655 mmol, 1.10 eq) and diisopropylethylamine (231 mg, 1.79 mmol, 0.311 mL, 3.00 eq). After stirring at 25 °C for 16 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate = 0: 1) followed by prep-SFC (column: DAICEL CHIRALCEL OJ (250mm × 30mm,10 μm); mobile phase: [0.1% ammonia ethanol]; B%: 15%- 15%,5.3min) to give (1R,2S,5S)-3-[(2S)-2-[(2-cyanoacetyl)amino]-3,3-dimethyl-but anoyl]-N- [cyano(1,6-naphthyridin-8-yl)methyl]-6,6-dimethyl-3-azabicyc lo[3.1.0]hexane-2-carboxamide (70.0 mg, 0.132 mmol, 22% yield, 95% purity) as a white solid. LC-MS (Method C): R _t = 0.466 min, MS (ESIpos): m/z = 502.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.59 (d, J = 7.6 Hz, 0.5H), 9.52 (s, 0.5H), 9.50 (s, 0.5H), 9.43 (d, J = 7.6 Hz, 0.5H), 9.26 (td, J = 4.4, 2.0 Hz, 1H), 8.96 (s, 0.5H), 8.93 (s, 0.5H), 8.71 (t, J = 2.0 Hz, 0.5H), 8.69 (t, J = 2.0 Hz, 0.5H), 8.36 (d, J = 8.4 Hz, 0.5H), 8.31 (d, J = 8.4 Hz, 0.5H), 7.84 (dd., J = 8.4, 4.4 Hz, 1H), 6.85 (d, J = 7.6 Hz, 0.5H), 6.81 (d, J = 7.6 Hz, 0.5H), 4.40-4.23 (m, 2H), 3.90-3.82 (m, 1H), 3.81-3.63 (m, 3H), 1.59-1.48 (m, 1H), 1.43 (d, J = 7.6 Hz, 0.5H), 1.22 (br. d, J = 7.6 Hz, 0.5H), 1.07- 0.79 (m, 15H). SFC: dr = 48:45. Preparation of CPD0330476 Procedure for preparation of methyl (1R,2S,5S)-3-((S)-2-(1-hydroxycyclopropane-1- carboxamido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxylate Thionyl chloride (16.4 g, 137 mmol, 10.0 mL, 21.9 eq) was added to 1-hydroxycyclopropanecarboxylic acid (640 mg, 6.27 mmol, 1.00 eq) followed by N,N-dimethylformamide (0.10 mL). The mixture was heated to 80 °C and stirred for 1 h. The mixture was concentrated under vacuum and added to a solution of methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimeth yl-3-azabicyclo[3.1.0]hexane- 2-carboxylate (2.00 g, 6.27 mmol, 1.00 eq, hydrochloride) and N-ethyl-N-propan-2-ylpropan-2-amine (3.24 g, 25.0 mmol, 4.37 mL, 4.00 eq) in dichloromethane (20.0 mL). After stirring at 20 °C for 1 h, the reaction mixture was poured into water (50.0 mL). The solution was extracted with dichloromethane (50.0 mL × 3). The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford methyl (1R,2S,5S)-3-[(2S)-2-[(1-hydroxycyclopropanecarbonyl)amino]- 3,3-dimethyl-butanoyl]- 6,6-dimethyl-3- azabicyclo[3.1.0] hexane-2-carboxylate (2.90 g, crude) as yellow oil. LCMS (Method A): Rt = 0.923 min; MS (ESIpos): m/z = 367.2 [M+1] ⁺ . Procedure for preparation of (1R,2S,5S)-3-((S)-2-(1-hydroxycyclopropane-1-carboxamido)-3, 3- dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-c arboxylic acid A mixture of methyl (1R,2S,5S)-3-((S)-2-(1-hydroxycyclopropane-1-carboxamido)-3, 3- dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-c arboxylate (2.00 g, 5.46 mmol, 1.00 eq), lithium hydroxide (458 mg, 10.9 mmol, 2.00 eq) in mixed solvent of tetrahydrofuran (10.0 mL), water (8.00 mL) and methanol (8.00 mL) was stirred at 20 °C for 1 h. The mixture was concentrated, and diluted with water (30.0 mL). Hydrochloric acid (1M) was added to adjust pH to 2. The solution was extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated to afford a residue. The residue was purified by reversed-phase column (instrument: 30 g Flash; Column: Sfar C1830 g D Duo 30μm; eluent A: water (0.1% Formic acid), eluent B: acetonitrile; gradient: 0-30min 0-100% B; flow 50 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to afford the (1R,2S,5S)-3-((S)-2-(1-hydroxycyclopropane-1- carboxamido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxylic acid (820 mg, 2.17 mmol, 40% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.96-12.47 (m, 1H), 7.32 (d, J = 9.6 Hz, 1H), 6.52 (s, 1H), 4.41 (d, J = 9.6 Hz, 1H), 4.15 (s, 1H), 3.88-3.76 (m, 2H), 1.52 (dd, J = 7.6, 4.8 Hz, 1H), 1.42 (d, J = 7.6 Hz, 1H), 1.07-0.96 (m, 13H), 0.95-0.84 (m, 4H), 0.84-0.77 (m, 3H). LC-MS (Method A): Rt = 0.597 min; MS (ESIpos): m/z = 353.1 [M+1] ⁺ . Procedure for preparation of Compound CPD0330476 - (1R,2S,5S)-N-(cyano(1,6-naphthyridin-8- yl)methyl)-3-((S)-2-(1-hydroxycyclopropane-1-carboxamido)-3, 3-dimethylbutanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide A mixture of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2- (oxazole-5-carbonylamino)butanoyl]-6,6-dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxylic acid (350 mg, 0.96 mmol, 1.00 eq), 2-amino-2-(1,6-naphthyridin-8-yl)acetonitrile (177 mg, 0.960 mmol, 1.00 eq), N-ethyl-N-propan-2-ylpropan-2-amine (373 mg, 2.89 mmol, 0.500 mL, 3.00 eq) and 3-[chloro-(2-oxo- 1,3-oxazolidin-3-yl)phosphoryl]-1,3-oxazolidin-2-one (490 mg, 1.93 mmol, 2.00 eq) in dichloromethane (20.0 mL) was stirred at 20 °C for 12 h. The mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: YMC Triart C18150*25mm*5 μm; mobile phase: [water (FA)- ACN]; B%: 37%-67%,8.5min) to afford (1R,2S,5S)-N-(cyano(1,6-naphthyridin-8-yl)methyl)-3-((S)-2-( 1- hydroxycyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-6,6 -dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide (240 mg, 0.460 mmol, 41% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.60 (d, J = 7.6 Hz, 0.5H), 9.52 (s, 0.5H), 9.51 (s, 0.5H), 9.45 (d, J = 7.6 Hz,0.5H), 9.26 (dt, J = 4.0, 1.6 Hz, 1H), 8.96 (s, 0.5H), 8.93 (s, 0.5H), 8.72 (d, J = 1.6 Hz, 0.5H), 8.70 (d, J = 1.6 Hz, 0.5H), 7.89-7.78 (m, 1H), 7.32 (d, J = 9.6 Hz, 0.5H), 7.26 (d, J = 9.6 Hz, 0.5H), 6.85 (d, J = 7.6 Hz, 0.5H), 6.81 (d, J = 7.6 Hz, 0.5H), 6.52 (s, 0.5H), 6.49 (s, 0.5H), 4.43-4.30 (m, 2H), 3.91- 3.83 (m, 1H), 3.80-3.73 (m, 1H), 1.59-1.46 (m, 1H), 1.43 (d, J = 7.6 Hz, 0.5H), 1.22 (d, J = 7.6 Hz, 0.5H), 1.08 - 0.99 (m, 3H), 0.98-0.88 (m, 7H), 0.87-0.76 (m, 9H). LC-MS (Method A): Rt = 0.916 min; MS (ESIpos): m/z = 519.3 [M+1] ⁺ . SFC: dr = 52: 48. A mixture of oxazole-5-carboxylic acid (532 mg, 4.70 mmol, 1.00 eq) and methyl (1R,2S,5S)-3-[(2S)-2- amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxylate (1.50 g, 4.70 mmol, 1.00 eq, hydrochloride), 3-[chloro-(2-oxo-1,3-oxazolidin-3-yl)phosphoryl]-1,3-oxazoli din-2-one (2.40 g, 9.41 mmol, 2.00 eq) and N-ethyl-N-propan-2-ylpropan-2-amine (2.43 g, 18.8 mmol, 3.28 mL, 4.00 eq) in N,N-dimethylformamide (15.0 mL) was stirred at 20 °C for 4 h. The reaction mixture was poured into water, extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, concentrated to afford a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 10: 1 to 5: 1) to afford methyl (1R,2S,5S)-3- ((S)-3,3-dimethyl-2-(oxazole-5-carboxamido)butanoyl)-6,6-dim ethyl-3-azabicyclo[3.1.0]hexane-2- carboxylate (1.20 g, 3.12 mmol, 66% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.90 (s, 1H), 7.72-7.65 (m, 1H), 6.86 (d, J = 9.6 Hz, 1H), 4.71 (d, J = 9.6 Hz, 1H), 4.45 (s, 1H), 3.99-3.88 (m, 2H), 3.78-3.74 (m, 3H), 1.55-1.43 (m, 2H), 1.13-0.83 (m, 15H). LCMS (Method A): Rt = 0.949 min; MS (ESIpos): m/z = 378.1 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-((S)-3,3-dimethyl-2-(oxazole-5- carboxamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane -2-carboxylic acid A mixture of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(oxazole-5-carbonylamino)b utanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.10 g, 2.91 mmol, 1.00 eq), lithium hydroxide (244 mg, 5.83 mmol, 2.00 eq) in mixed solvent of tetrahydrofuran (8.00 mL), water (8.00 mL) and methanol (4.00 mL) was stirred at 20 °C for 1 h. The mixture was concentrated under vacuum, and diluted with water (20.0 mL). Hydrochloric acid (1M) was added to adjust pH ~ 2. The solution was extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated to give a residue. The residue was purified by reversed phase column (instrument: 30 g Flash; Column: Sfar C1860 g D Duo 30μm; eluent A: water (0.1% Formic acid), eluent B: acetonitrile; gradient: 0-30min 0-100% B; flow 60 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to afford (1R,2S,5S)-3-((S)-3,3-dimethyl-2-(oxazole-5-carboxamido)buta noyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (550 mg, 1.41 mmol, 48% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.70 (br. s, 1H), 8.58-8.49 (m, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.03- 7.97 (m, 1H), 4.57 (d, J = 8.8 Hz, 1H), 4.15 (s, 1H), 3.90-3.79 (m, 2H), 1.54 (dd, J = 7.2, 4.4 Hz, 1H), 1.42 (d, J = 7.4 Hz, 1H), 1.05-0.97 (m, 12H), 0.82 (s, 3H). LC-MS (Method A): Rt = 0.858 min; MS (ESIpos): m/z = 364.1 [M+H] ⁺ . Procedure for preparation of Compound CPD0330477 N-((S)-1-((1R,2S,5S)-2-((cyano(1,6- naphthyridin-8-yl)methyl)carbamoyl)-6,6-dimethyl-3-azabicycl o[3.1.0]hexan-3-yl)-3,3-dimethyl- 1-oxobutan-2-yl)oxazole-5-carboxamide A mixture of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(oxazole-5- carbonylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexa ne-2-carboxylic acid (350 mg, 0.96 mmol, 1.00 eq), 2-amino-2-(1,6-naphthyridin-8-yl)acetonitrile (177 mg, 0.960 mmol, 1.00 eq), N-ethyl- N-propan-2-ylpropan-2-amine (373 mg, 2.89 mmol, 0.500 mL, 3.00 eq) and 3-[chloro-(2-oxo-1,3- oxazolidin-3-yl)phosphoryl]-1,3-oxazolidin-2-one (490 mg, 1.93 mmol, 2.00 eq) in dichloromethane (20.0 mL) was stirred at 20 °C for 12 h. The mixture was concentrated to afford a residue. The residue was purified by prep-HPLC (column: YMC Triart C18150*25mm*5 μm; mobile phase: [water(FA)-ACN]; B%: 36%-66%, 8.5min) to afford N-((S)-1-((1R,2S,5S)-2-((cyano(1,6-naphthyridin-8- yl)methyl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3 -yl)-3,3-dimethyl-1-oxobutan-2- yl)oxazole-5-carboxamide (140 mg, 0.260 mol, 27% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.59 (d, J = 7.6 Hz, 0.5H), 9.50 (d, J = 3.6 Hz, 1H), 9.43 (d, J = 7.6 Hz, 0.5H), 9.25 (td, J = 4.0, 2.0 Hz, 1H), 8.95 (s, 0.5H), 8.92 (s, 0.5H), 8.70 (d, J = 1.2 Hz, 0.5H), 8.69 (d, J = 1.2 Hz, 0.5H), 8.53 (s, 0.5H), 8.51 (s, 0.5H), 8.16 (d, J = 8.4 Hz, 0.5H), 8.12 (d, J = 8.4 Hz, 0.5H), 8.00 (s, 0.5H), 7.98 (s, 0.5H), 7.85 (dd, J = 4.4, 1.2 Hz, 0.5H), 7.83 (dd, J = 4.4, 1.2 Hz, 0.5H), 6.85 (d, J = 7.6 Hz, 0.5H), 6.81 (d, J = 7.6 Hz, 0.5H), 4.51 (dd, J = 13.6, 8.8 Hz, 1H), 4.36 (s, 0.5H), 4.31 (s, 0.5H), 3.95-3.84 (m, 1H), 3.79 (dd, J = 10.4, 5.6 Hz, 1H), 1.59-1.48 (m, 1H), 1.42 (d, J = 7.6 Hz, 0.5H), 1.22 (d, J = 7.6 Hz, 0.5H), 1.06-0.92 (m, 8H), 0.89 (s, 4H), 0.82 (d, J = 14.8 Hz, 3H). LC-MS (Method A): Rt = 0.926 min; MS (ESIpos): m/z = 530.4 [M+H] ⁺ . SFC: dr = 53: 44. g, 4.51 mmol, 1.20 eq, hydrochloride) in dichloromethane (20.0 mL) were added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-d imethylazanium;hexafluorophosphate (2.14 g, 5.63 mmol, 1.50 eq) and N-ethyl-N-propan-2-ylpropan-2-amine (1.94 g, 15.0 mmol, 2.62 mL, 4.00 eq). After stirring at 20 °C for 16 h, the reaction mixture was diluted with dichloromethane (50.0 mL), washed with water (50.0 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® Silica Flash Column, Eluent of 0~35% Ethyl acetate/Petroleum ethergradient @ 50 mL/min) and concentrated to give methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-(2- pyridyl) propanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (820 mg, 1.96 mmol, 52.3% yield) as black brown oil. LC-MS (Method L): Rt = 0.481 min; MS (ESIpos): m/z = 418.2 [M+H] ⁺ . Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-2-amino-3-(2-pyridyl)propanoyl]-6,6- dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate A mixture of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-(2-pyridyl )propanoyl] -6,6- dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (800 mg, 1.92 mmol, 1.00 eq) in hydrochloride/dioxane (4.00 M, 10.0 mL, 20.9 eq) was stirred at 20 °C for 1 h. The reaction mixture was concentrated to give methyl (1R,2S,5S)-3-[(2S)-2-amino-3-(2-pyridyl)propanoyl]-6,6-dimet hyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (800 mg, crude) as a brown oil. LC-MS (Method L): Rt = 0.580-0.661 min; MS (ESIpos): m/z = 318.1 [M+H] ⁺ . Procedure for preparation of methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-(2-pyridyl)-2-[(2- tetrahydrofuran-3- ylacetyl)amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2-carbox ylate To a mixture of methyl (1R,2S,5S)-3-[(2S)-2-amino-3-(2-pyridyl)propanoyl]-6,6-dimet hyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (800 mg, 2.05 mmol, 1.00 eq, 2hydrochloride) and 2- (tetrahydrofuran-3-yl)acetic acid (293 mg, 2.25 mmol, 1.10 eq) in dichloromethane (10.0 mL) were added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]- dimethylazanium;hexafluorophosphate (1.17 g, 3.07 mmol, 1.50 eq) and N-ethyl-N-propan-2-ylpropan- 2-amine (1.32 g, 10.3 mmol, 1.79 mL, 5.00 eq). After stirring at 20 °C for 16 h, the reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 0 to 1: 0) to give methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-(2-pyridyl)-2-[(2- tetrahydrofuran-3-ylacetyl)amino]propanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxylate (600 mg, 1.40 mmol, 68% yield) as a yellow solid. LC-MS (Method L): Rt = 0.689 min; MS (ESIpos): m/z = 430.2 [M+H] ⁺ . Procedure for preparation of methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-(2-pyridyl)-2-[(2- tetrahydrofuran-3- ylacetyl)amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2-carbox ylate To a mixture of methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-(2-pyridyl)-2-[(2-tetrahyd rofuran-3- ylacetyl)amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2-carbox ylate (600 mg, 1.40 mmol, 1.00 eq) in mixed solvent of methanol (5.00 mL) and water (1.00 mL) was added lithium hydroxide monohydrate (117 mg, 2.80 mmol, 2.00 eq). After stirring at 20 °C for 16 h, the reaction mixture was concentrated. HCl (1M) was added to the solution to adjust pH to 3. The solution was extracted with ethyl acetate (40.0 mL ´ 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-(2-pyridyl)-2-[(2-tetrahyd rofuran-3- ylacetyl)amino]propanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (480 mg, 1.16 mmol, 83% yield) as a yellow solid. LC-MS (Method L): Rt = 0.422 min; MS (ESIpos): m/z = 416.2 [M+H] ⁺ . Procedure for preparation of CPD0330478 - (1R,2S,5S)-N-[cyano(1,6-naphthyridin-8-yl) methyl]- 6,6-dimethyl-3-[(2S)-3-(2-pyridyl)-2-[(2-tetrahydrofuran-3-y lacetyl)amino]propanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-(2-pyridyl)-2-[(2-tetrahyd rofuran-3-ylacetyl) amino]propanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (100 mg, 240 μmol, 1.00 eq) and 2- amino-2-(1,6-naphthyridin-8- yl)acetonitrile (53.2 mg, 289 μmol, 1.20 eq) in dichloromethane (3.00 mL) were added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-d imethylazanium hexafluorophosphate (137 mg, 361 μmol, 1.50 eq) and N-ethyl-N-propan-2-ylpropan-2-amine (93.3 mg, 722 μmol, 126 μL, 3.00 eq). After stirring at 20 °C for 4 h, the reaction mixture was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient, then ethyl acetate/methanol = 1:1, 50 mL/min) followed by prep-HPLC (column: Waters Xbridge C18150*50 mm* 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 22%-52%, 9 min) to give (1R,2S,5S)-N-[cyano(1,6-naphthyridin- 8-yl)methyl]-6,6-dimethyl-3-[(2S)-3-(2-pyridyl)-2-[(2- tetrahydrofuran-3-ylacetyl)amino]propanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxamide (20.0 mg, 34.0 μmol, 14% yield) as a yellow solid. LC-MS (Method L): Rt = 0.430 min; MS (ESIpos): m/z = 582.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.90-9.52 (m, 2H), 9.28-9.27 (m, 1H), 8.94-8.89 (m, 1H), 8.73-8.70 (m, 1H), 8.70-8.51 (m, 1H), 8.50-7.86 (m, 1H), 7.87-7.84 (m, 1H), 7.83-7.22 (m, 1H), 7.23-7.18 (m, 2H), 6.94-6.82 (m, 1H), 5.02-4.84 (m, 1H), 4.32-3.86 (m, 1H), 3.85-3.83 (m, 1H), 3.61-3.53 (m, 3.5H), 3.15- 2.50 (m, 3.5H), 2.35-2.25 (m, 1H), 2.07-2.04 (m, 2H), 1.85-1.65 (m, 1H), 1.60-1.50 (m, 1H), 1.40-1.20 (m, 2H), 1.05-0.95 (m, 3H), 0.85-0.75 (m, 2H), 0.95-0.60 (m, 1H). SFC: dr = 23: 40: 15: 22. Preparation of CPD0330479 Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-(4- pyridyl)propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylate A mixture of (2S)-2-(tert-butoxycarbonylamino)-3-(4-pyridyl)propanoic acid (5.00 g, 18.8 mmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexaflu orophosphate (9.28 g, 24.4 mmol, 1.30 eq) and N,N-diisopropylethylamine (7.28 g, 56.3 mmol, 9.81 mL, 3.00 eq) in N,N- dimethylformamide (50.0 mL) was stirred at 25 °C for 0.5 h. Methyl (1R,2S,5S)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (4.25 g, 20.6 mmol, 1.10 eq, HCl) was added to the reaction mixture above. After stirring at 25°C for 11.5 h, the reaction mixture was poured into water (300 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 30~50% [Ethyl acetate: Methanol = 10:1]/Petroleum ether gradient @ 80 mL/min) to give methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-(4- pyridyl)propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylate (6.00 g, 12.2 mmol, 65% yield, 85% purity) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.46-8.44 (m, 2H), 7.35-7.28 (m, 3H), 4.42-4.33 (m, 1H), 4.18 (s, 1H), 3.89 (d, J = 10.4 Hz, 1H), 3.73-3.69 (m, 1H), 3.62 (s, 3H), 2.85 (d, J = 5.4 Hz, 1H), 2.80-2.74 (m, 1H), 1.56-1.50 (m, 1H), 1.40 (d, J = 7.4 Hz, 1H), 1.32-1.26 (m, 9H), 1.01 (s, 3H), 0.89 (s, 3H). LC-MS (Method C): R _t = 0.802 min; MS (ESIpos): m/z = 418.3 [M+H] ⁺ . Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-2-amino-3-(4-pyridyl)propanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate To a solation of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-(4-pyridyl ) propanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (6.00 g, 12.2 mmol, 85% purity, 1.00 eq) in dioxane (20.0 mL) was added hydrochloric acid (4.00 M in dioxane, 20.0 mL, 6.55 eq). After stirring at 25 °C for 1 h, the reaction mixture was concentrated under vacuum to give methyl (1R,2S,5S)-3-[(2S)-2-amino- 3-(4-pyridyl)propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexa ne-2-carboxylate (5.00 g, crude, 2HCl) as a brown solid. LC-MS (Method C): R _t = 0.276 min; MS (ESIpos): m/z = 318.3 [M+H] ⁺ . Procedure for preparation of methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-(4-pyridyl)-2-[[2- [tetrahydrofuran-3-yl]acetyl]amino]propanoyl]-3-azabicyclo[3 .1.0]hexane-2-carboxylate A mixture of 2-[tetrahydrofuran-3-yl]acetic acid (166 mg, 1.28 mmol, 1.00 eq), O-(7-azabenzotriazol-1- yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (730 mg, 1.92 mmol, 1.50 eq) and N,N- diisopropylethylamine (662 mg, 5.12 mmol, 4.00 eq) in N,N-dimethylformamide (10.0 mL) was stirred at 25 °C for 0.5 h. Methyl (1R,2S,5S)-3-[(2S)-2-amino-3-(4-pyridyl)propanoyl] -6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (500 mg, 1.28 mmol, 1.00 eq, 2HCl) was added to the reaction mixture above. After stirring at 25 °C for 11.5 h, the reaction mixture was poured into water (60.0 mL) and extracted with mixed solvent of dichloromethane and methanol (v/v = 10/1; 20.0 mL × 5). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 50~80% [Ethyl acetate: Methanol = 10: 1]/Petroleum ether gradient @ 50 mL/min) to give methyl (1R,2S,5S)- 6,6-dimethyl-3-[(2S)-3-(4-pyridyl)-2-[[2-[(3R)-tetrahydrofur an-3-yl]acetyl]amino]propanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxylate (700 mg, 1.14 mmol, 89% yield, 70% purity) as colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.51-8.38 (m, 3H), 7.38-7.26 (m, 2H), 4.85-4.68 (m, 1H), 4.17 (s, 1H), 3.87-3.72 (m, 2H), 3.63 (s, 3H), 3.58-3.49 (m, 2H), 3.22-3.03 (m, 3H), 2.98-2.93 (m, 1H), 2.81-2.75 (m, 1H), 2.36-2.23 (m, 1H), 2.15-2.02 (m, 2H), 1.84-1.68 (m, 1H), 1.54-1.51 (m, 1H), 1.42 (d, J = 7.2 Hz, 1H), 1.05-0.97 (m, 3H), 0.86 (s, 3H). LC-MS (Method L): R _t = 0.439 min; MS (ESIpos): m/z = 430.4 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-(4-pyridyl)-2-[[2-[tetrahy drofuran- 3-yl]acetyl]amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2-car boxylic acid A mixture of methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-(4-pyridyl)-2-[[2-[(3R)-te trahydrofuran-3-yl] acetyl]amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxyl ate (700 mg, 1.14 mmol, 70% purity, 1.00 eq) and lithium hydroxide (81.9 mg, 3.42 mmol, 3.00 eq) in mixed solvent of methanol (5.00 mL) and water (5.00 mL) was stirred at 25 °C for 12 h. The reaction mixture was poured into water (20.0 mL) and washed with ethyl acetate (10.0 mL × 2). Hydrochloric acid (1 M) was added to the aqueous phase to adjust pH ~7. The solution was extracted with mixed solvent of dichloromethane and isopropanol (v/v = 3/1; 10.0 mL × 8). The combined organic layers were concentrated under vacuum to give (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-(4-pyridyl)-2-[[2-[(3R)-te trahydrofuran-3- yl]acetyl]amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2-carbo xylic acid (300 mg, crude) as colorless oil. LC-MS (Method L): R _t = 0.369, 0.386 min; MS (ESIpos): m/z = 416.2 [M+H] ⁺ . Procedure for preparation of CPD0330479 (1R,2S,5S)-N-[cyano(1,6-naphthyridin-8-yl)methyl]- 6,6-dimethyl-3-[(2S)-3-(4-pyridyl)-2-[[2-[(tetrahydrofuran-3 -yl]acetyl]amino]propanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxamide A mixture of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-(4-pyridyl)-2-[[2-[tetrahy drofuran-3-yl]acetyl]amino] propanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (150 mg, 0.361 mmol, 1.00 eq), O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (205 mg, 0.541 mmol, 1.50 eq) and N,N-diisopropylethylamine (139 mg, 1.08 mmol, 3.00 eq) in N,N-dimethylformamide (1.00 mL) was stirred at 25 °C for 0.5 h.2-Amino-2-(1,6-naphthyridin-8-yl)acetonitrile (73.1 mg, 0.397 mmol, 1.10 eq) was added to the reaction mixture above. After stirring at 25 °C for 11.5 h, the reaction mixture was purified by prep-HPLC (column: YMC Triart C18150*25mm*5 μm; mobile phase: [water(FA)-ACN]; B%: 16%-46%, 8.5 min) to give (1R,2S,5S)-N-[cyano(1,6-naphthyridin-8-yl)methyl]-6,6-dimeth yl-3-[(2S)-3- (4-pyridyl) -2-[[2-[tetrahydrofuran-3-yl]acetyl]amino]propanoyl]-3-azabi cyclo[3.1.0]hexane-2- carboxamide (110 mg, 0.178 mmol, 49% yield, 93% purity) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.62 (d, J = 7.8 Hz, 0.5H), 9.54 (s, 1H), 9.48 (d, J = 7.8 Hz, 0.5H), 9.29-9.26 (m, 1H), 8.94 (s, 0.5H), 8.90 (s, 0.5H), 8.80 (s, 0.5H), 8.78 (s, 0.5H), 8.74-8.72 (m, 0.5H), 8.72-8.71 (m, 0.5H), 8.70 (s, 0.5H), 8.69 (s, 0.5H), 8.52-8.39 (m, 1H), 7.92 (s, 0.5H), 7.90 (s, 0.5H), 7.89-7.84 (m, 1H), 7.84-7.81 (m, 1H), 6.86 (d, J = 7.6 Hz, 1H), 6.81 (d, J = 7.6 Hz, 1H), 4.94-4.86 (m, 0.5H), 4.85-4.77 (m, 0.5H), 4.31 (s, 0.5H), 4.27 (s, 0.5H), 3.90-3.79 (m, 2H), 3.65-3.56 (m, 3H), 3.27- 3.23 (m, 0.6H), 3.17-3.10 (m, 1H), 3.07-3.03 (m, 1H), 3.01-2.95 (m, 0.5H), 2.38-2.26 (m, 1H), 2.18-2.01 (m, 2H), 1.88-1.71 (m, 1H), 1.59-1.46 (m, 1H), 1.41-1.31 (m, 1H), 1.31-1.21 (m, 1H), 1.03 (s, 1.5H), 0.96 (s, 1.5H), 0.87 (s, 1.5H), 0.84 (s, 1.5H). LC-MS (Method C): R _t = 0.703 min; MS (ESIpos): m/z = 582.3 [M+H] ⁺ . HPLC (Method M): R _t = 1.303 min; purity: 94%. SFC: dr = 48: 52. To a mixture of 1,4-dioxane-2-carboxylic acid (300 mg, 2.27 mmol, 1.00 eq) in dichloromethane (5.00 mL) were added 3-[chloro-(2-oxooxazolidin-3-yl)phosphoryl]oxazolidin-2-one (867 mg, 3.41 mmol, 1.50 eq) and N,N-diisopropylethylamine (1.17 g, 9.08 mmol, 1.58 mL, 4.00 eq). After stirring at 25 °C for 10 min, methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimeth yl-3- azabicyclo[3.1.0]hexane-2-carboxylate (868 mg, 2.72 mmol, 1.20 eq, hydrochloride) was added. After stirring at 25 °C for 16 h, the reaction mixture was concentrated under vacuum to give a residue. The residue was purified by reversed phase (instrument: 40 g Flash; Column: Welch Ultimate XB_C1820- 40 μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-15 min 0-80% B; flow 40 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give methyl (1R,2S,5S)-3-[(2S)-2-(1,4- dioxane-2-carbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl -3-azabicyclo[3.1.0]hexane-2- carboxylate (600 mg, 1.51 mmol, 67% yield) as yellow oil. Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-(1,4-dioxane-2-carbonylamino)-3,3-dimet hyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyli c acid A mixture of methyl (1R,2S,5S)-3-[(2S)-2-(1,4-dioxane-2-carbonylamino)-3,3-dimet hyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.00 g, 2.52 mmol, 1.00 eq) and lithium hydroxide (181 mg, 7.57 mmol, 3.00 eq) in mixed solvent of methanol (10.0 mL) and water (2.00 mL) was stirred at 25 °C for 4 h. The mixture was concentrated, and diluted with water (10.0 mL). Hydrochloric acid (1M) was added to adjust pH~6. The solution was extracted with ethyl acetate (15.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give (1R,2S,5S)-3-[(2S)-2-(1,4-dioxane-2-carbonylamino)-3,3-dimet hyl-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (900 mg, 1.67 mmol, 66% yield, 71% purity) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.73 (m, 1H), 7.31-7.17 (m, 1H), 4.43-4.37 (m, 1H), 4.18-4.14 (m, 0.5H), 4.14-4.11 (m, 1H), 4.10-4.06 (m, 1H), 3.86-3.78 (m, 3H), 3.69-3.59 (m, 2H), 3.57-3.42 (m, 2H), 3.29-3.20 (m, 1H), 1.57-1.49 (m, 1H), 1.47-1.39 (m, 1H), 1.01 (s, 3H), 0.96-0.92 (m, 8H), 0.87-0.83 (m, 1H), 0.80-0.78 (m, 2H). Procedure for preparation of Compound CPD0330480 (1R,2S,5S)-N-[cyano(1,6-naphthyridin-8- yl)methyl]-3-[(2S)-2-(1,4-dioxane-2-carbonylamino)-3,3-dimet hyl-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide A mixture of (1R,2S,5S)-3-[(2S)-2-(1,4-dioxane-2-carbonylamino)-3,3-dimet hyl-butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (200 mg, 522 umol, 1.00 eq), 2-amino-2-(1,6-naphthyridin- 8-yl)acetonitrile (96.3 mg, 522 μmol, 1.00 eq), N,N-diisopropylethylamine (270 mg, 2.09 mmol, 364 μL, 4.00 eq) and ammonium;hexafluorophosphate (298 mg, 784 μmol, 1.50 eq) in dichloromethane (5.00 mL) was stirred at 25 °C for 16 h. The mixture was concentrated to give a residue. The residue was purified by column chromatography (column: Welch Ultimate XB-SiOH 250*50*10 μm; mobile phase: [Hexane-EtOH];B%: 5%-45%,15 min) followed by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10 μm; mobile phase: [water (FA)-ACN]; B%: 36%-66%,10 min) to give (1R,2S,5S)-N- [cyano(1,6-naphthyridin-8-yl)methyl]-3-[(2S)-2-(1,4-dioxane- 2-carbonylamino)-3,3-dimethyl-butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (38.7 mg, 51.9 μmol, 10% yield, 95% purity) as yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.66-9.58 (m, 0.5H), 9.54-9.50 (m, 1H), 9.48-9.42 (m, 0.5H), 9.28- 9.24 (m, 1H), 9.02-8.87 (m, 1H), 8.78-8.60 (m, 1H), 7.90-9.80 (m, 1H), 7.32-7.13 (m, 1H), 6.92-6.77 (m, 1H), 4.46-4.28 (m, 2H), 4.20-4.04 (m, 1H), 3.94-3.77 (m, 3H), 3.76-3.58 (m, 3H), 3.57-3.42 (m, 1H), 3.28-3.18 (m, 1H), 1.61-1.47 (m, 1H), 1.43 (d, J = 7.6 Hz, 0.5H), 1.25-1.20 (m, 0.5H), 1.04 (s, 1H), 1.01- 0.86 (m, 7H), 0.86-0.75 (m, 7H). LC-MS (Method C): Rt = 0.558 min; MS (ESIpos): m/z =549.4 [M+H] ⁺ . SFC: dr = 33: 22: 20: 23. A mixture of 3-hydroxycyclobutanecarboxylic acid (500 mg, 4.31 mmol, 1.00 eq), methyl (1R,2S,5S)-3- [(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyc lo[3.1.0]hexane-2-carboxylate (1.46 g, 4.58 mmol, 1.06 eq, hydrochloride), 3-[chloro-(2-oxooxazolidin-3-yl)phosphoryl]oxazolidin-2-one (2.46 g, 6.46 mmol, 1.50 eq) and N,N-diisopropylethylamine (2.23 g, 17.2 mmol, 3.00 mL, 4.00 eq) in dichloromethane (10.0 mL) was stirred at 25 °C for 16 h. The mixture was concentrated to give a residue. The residue was purified by reversed phase (instrument: 120 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.1% FA), eluent B: acetonitrile; gradient: 0-10 min 60-80% B; flow 80 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give methyl (1R,2S,5S)-3- [(2S)-2-[(3-hydroxycyclobutanecarbonyl)amino]-3,3-dimethyl-b utanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (1.00 g, 1.60 mmol, 37% yield, 61% purity) as a yellow solid. LC-MS (Method C): Rt = 0.540 min; MS (ESIpos): m/z =381.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-[(3-hydroxycyclobutanecarbonyl)amino]-3 ,3- dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid A mixture of methyl (1R,2S,5S)-3-[(2S)-2-[(3-hydroxycyclobutanecarbonyl)amino]-3 ,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyla te (1.00 g, 2.63 mmol, 1.00 eq) and lithium hydroxide (125 mg, 5.26 mmol, 2.00 eq) in mixed solvent of methanol (10.0 mL) and water (2.00 mL) was stirred at 25 °C for 4 h. The mixture was concentrated, and diluted with water (50.0 mL). Hydrochloric acid (1M) was added to adjust pH~6. The solution was extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum to give (1R,2S,5S)-3-[(2S)-2-[(3-hydroxycyclobutanecarbonyl)amino]-3 ,3- dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (900 mg, 2.46 mmol, 93% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.23 (br s, 1H), 7.77 (br d, J = 9.2 Hz, 1H), 5.37-4.73 (m, 1H), 4.39 (d, J = 9.2 Hz, 1H), 4.10 (s, 1H), 3.93-3.83 (m, 2H), 3.82-3.75 (m, 1H), 2.28-2.13 (m, 2H), 2.02-1.96 (m, 1H), 1.86-1.79 (m, 1H), 1.54-1.45 (m, 1H), 1.39 (d, J = 7.6 Hz, 1H), 1.00 (s, 3H), 0.92 (s, 9H), 0.80 (s, 3H). Procedure for preparation of Compound CPD0330481 (1R,2S,5S)-N-[cyano(1,6-naphthyridin-8- yl)methyl]-3-[(2S)-2-[(3-hydroxycyclobutanecarbonyl)amino]-3 ,3-dimethyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide A mixture of (1R,2S,5S)-3-[(2S)-2-[(3-hydroxycyclobutanecarbonyl)amino]-3 ,3-dimethyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (200 mg, 545 μmol, 1.00 eq), 2-amino-2-(1,6- naphthyridin-8-yl)acetonitrile (100 mg, 545 μmol, 1.00 eq), ammonium;hexafluorophosphate (311 mg, 818 μmol, 1.50 eq) and N,N-diisopropylethylamine (282 mg, 2.18 mmol, 380 μL, 4.00 eq) in dichloromethane (1.00 mL) was stirred at 25 °C for 16 h. The mixture was concentrated under vacuum to give a residue. The residue was purified by flash column chromatography (column: Welch Ultimate XB-SiOH 250*50*10 μm; mobile phase: [ethyl acetate: methanol];B%: 1%-15%,10min) followed by prep-HPLC (column: UniSil 3-100 C18 UItra (150*25mm*3 μm); mobile phase: [water(FA)-ACN];B%: 29%-49%,7min) to give (1R,2S,5S)-N-[cyano(1,6-naphthyridin-8-yl)methyl]-3-[(2S)-2- [(3- hydroxycyclobutanecarbonyl)amino]-3,3-dimethyl-butanoyl]-6,6 -dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (65.0 mg, 114 μmol, 21% yield, 95% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.57-9.44 (m, 1.5H), 9.42-9.32 (m, 0.5H), 9.30-9.21 (m, 1H), 8.97- 8.91 (m, 1H), 8.77-8.65 (m, 1H), 7.87-7.82 (m, 1H), 7.78-7.65 (m, 1H), 6.89-6.75 (m, 1H), 5.13-4.96 (m, 1H), 4.41-4.23 (m, 2H), 3.95-3.76 (m, 3H), 2.26-2.09 (m, 2H), 1.98-1.77 (m, 2H), 1.57-1.46 (m, 1H), 1.41 (d, J = 7.6 Hz, 0.5H), 1.21 (d, J = 7.6 Hz, 0.5H), 1.04 (s, 1H), 0.97-0.86 (m, 6H), 0.85-0.73 (m, 8H). LC-MS (Method C): Rt = 0.442 min; MS (ESIpos): m/z =533.3 [M+H] ⁺ . SFC: dr = 60: 40. To a solution of (1R,2S,5S)-3-((S)-2-(1,4-dioxane-2-carboxamido)-3,3-dimethyl butanoyl)-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (100 mg, 261 μmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (149 mg, 392 umol, 1.50 eq), N,N- diisopropylethylamine (101 mg, 784 μmol, 3.00 eq) in N,N-dimethylformamide (3.00 mL) was added (S)-2-amino-3-((S)-6-fluoro-3-oxo-3,4-dihydro-2H-benzo[b][1, 4]oxazin-2-yl)propanenitrile (61.5 mg, 261 μmol, 1.00 eq). After stirring at 25 °C for 2 h, the mixture was poured into water (20.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic phase was washed with brine (20.0 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: YMC-Actus Triart C18 150*30mm*7 μm; mobile phase: [water(FA)-ACN]; B%: 43%-73%, 10 min) to give (1R,2S,5S)-3-((S)-2- (1,4-dioxane-2-carboxamido)-3,3-dimethylbutanoyl)-N-((S)-1-c yano-2-((S)-6-fluoro-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-2-yl)ethyl)-6,6-dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxamide (45.9 mg, 75.9 μmol, 29% yield, 99% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.87 (s, 1H), 9.16-9.00 (m, 1H), 7.21-7.09 (m, 1H), 6.93-6.86 (m, 1H), 6.80-6.71 (m, 1H), 6.70-6.64 (m, 1H), 5.20-5.03 (m, 1H), 4.55-4.43 (m, 1H), 4.34-4.25 (m, 1H), 4.16-4.00 (m, 2H), 3.89-3.57 (m, 7H), 3.52-3.47 (m, 1H), 3.22-3.17 (m, 1H), 2.32-2.24 (m, 1H), 1.58- 1.51 (m, 1H), 1.39-1.28 (m, 1H), 1.05-0.97 (m, 3H), 0.95-0.71 (m, 12H). LC-MS (Method C): R _t = 0.539 min; MS (ESIpos): m/z = 600.02 [M+H] ⁺ . HPLC (Method S): R _t = 1.547 min; purity: 99%. SFC: dr = 47: 53. To a solution of methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimeth yl-3- azabicyclo[3.1.0]hexane-2-carboxylate (4.00 g, 12.6 mmol, 1.00 eq, hydrochlorate) and 2-cyanoacetic acid (1.07 g, 12.6 mmol, 1.00 eq) in dichloromethane (80.0 mL) were added benzotriazol-1- yloxy(tripyrrolidin-1-yl)phosphanium hexafluorophosphate (7.83 g, 15.1 mmol, 1.20 eq) and N- methylmorpholine (5.08 g, 50.2 mmol, 4.00 eq). After stirring at 25 °C for 12 h, the mixture was diluted with saturated ammonium chloride (80.0 mL), and extracted with ethyl acetate (80.0 mL × 3). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~32% Ethyl acetate/Petroleum ether gradient @ 100 mL/min) to afford methyl (1R,2S,5S)-3-[(2S)-2-[(2- cyanoacetyl)amino]-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-aza bicyclo[3.1.0] hexane-2-carboxylate (1.60 g, 4.58 mmol, 37% yield) as colorless gum. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.37 (d, J = 8.8 Hz, 1H), 4.34 (d, J = 8.8 Hz, 1H), 4.20 (s, 1H), 3.86- 3.77 (m, 2H), 3.71 (d, J = 8.8 Hz, 2H), 3.66 (s, 3H), 1.56-1.51 (m, 1H), 1.43 (d, J = 7.2 Hz, 1H), 1.01- 0.95 (m, 11H), 0.88-0.83 (m, 4H). LC-MS (Method C): R _t = 0.512 min; MS (ESIpos): m/z = 350.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-[(2-cyanoacetyl)amino]-3,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyli c acid To a mixture of methyl (1R,2S,5S)-3-[(2S)-2-[(2-cyanoacetyl)amino]-3,3-dimethyl-but anoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (700 mg, 2.00 mmol, 1.00 eq) in water (8.00 mL) was added a solution of lithium hydroxide monohydrate (252 mg, 6.01 mmol, 3.00 eq) in tetrahydrofuran (8.0 mL) at 0 °C. After stirring at 0 °C for 2 h, the reaction mixture was diluted with water (20.0 mL), adjusted pH~5 with hydrochloric acid (1.00 M) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrate to afford (1R,2S,5S)-3-[(2S)-2-[(2-cyanoacetyl)amino]-3,3-dimethyl-but anoyl]-6,6- dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxylic acid (439 mg, 1.31 mmol, 65% yield) as a light yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.37 (d, J = 8.8 Hz, 1H), 4.34 (d, J = 8.8 Hz, 1H), 4.12 (s, 1H), 3.83-3.76 (m, 2H), 3.72-3.65(m, 2H), 1.53-1.50(m, 1H),1.42-1.40(m, 1H), 1.01-0.96 (m, 12H), 0.87-0.84 (m, 3H). LC-MS (Method C): R _t = 0.440 min; MS (ESIpos): m/z = 336.2 [M+H] ⁺ . To a solution of (1R,2S,5S)-3-[(2S)-2-[(2-cyanoacetyl)amino]-3,3-dimethyl-but anoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (150 mg, 447 μmol, 1.00 eq) and (2S)-2-amino-3-[(2S)-6- fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]propanenitrile (145.80 mg, 537 μmol, 1.20 eq, hydrochlorate) in N,N-dimethylformamide (10.0 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (204 mg, 537 μmol, 1.20 eq) and N,N-diisopropylethylamine (231 mg, 1.79 mmol, 4.00 eq). After stirring at 25 °C for 16 h, the reaction mixture was diluted with saturated ammonium chloride (20.0 mL) and extracted with ethyl acetate (10.0 mL × 5). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18150*25mm*10 μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 38.0%-68.0%, 10 min).to give (1R,2S,5S)-3-[(2S)-2-[(2-cyanoacetyl)amino]-3,3-dimethyl-but anoyl]-N-[(1S)-1-cyano-2-[(2S)-6- fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]ethyl]-6,6-dimethyl-3-az abicyclo[3.1.0]hexane-2-carboxamide (81.1 mg, 145 μmol, 32% yield, 99% purity) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.17-9.14 (m, 0.2H), 8.72-8.59 (m, 0.6H), 8.07 (d, J = 8.0 Hz, 0.2H), 7.63 (d, J = 8.0 Hz, 0.8H), 7.05-6.92 (m, 2H), 6.77-6.56 (m, 2H), 5.36-5.31 (m, 1H), 4.74-4.71 (m, 0.2H), 4.58-4.54 (m, 0.8H), 4.51-4.46 (m, 1H), 4.33 (s, 1H), 3.99-3.86 (m, 2H), 3.44-3.27 (m, 2H), 2.72-2.61 (m, 1H), 2.45-2.38, (m, 1H), 1.57-1.54 (m, 1H), 1.37-1.25 (m, 1H), 1.10-0.87 (m, 15H). LC-MS (Method S): R _t = 2.276 min; MS (ESIpos): m/z = 553.3 [M+H] ⁺ . SFC: dr = 75: 25. To a solution of methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimeth yl-3- azabicyclo[3.1.0]hexane-2-carboxylate (1.00 g, 3.14 mmol, 1.00 eq, hydrochloric acid) and N-ethyl-N- propan-2-ylpropan-2-amine (1.22 g, 9.41 mmol, 1.64 mL, 3.00 eq) in dichloromethane (20.0 mL) was added ethanesulfonyl chloride (403 mg, 3.14 mmol, 297 uL, 1.00 eq) at 0 °C. After stirring at 25 °C for 1 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate = 10: 1 to 5: 1 then Petroleum ether: Ethyl acetate = 5: 1) to give methyl (1R,2S,5S)-3-[(2S)-2-(ethylsulfonylamino)-3,3-dimethyl-butan oyl]- 6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate (800 mg, 2.01 mmol, 64% yield, 94% purity) as yellow oil. Procedure for preparation of (1R, 2S, 5S)-3-((R)-2-(ethylsulfonamido)-3, 3-dimethylbutanoyl)-6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-2-(ethylsulfonylamino)-3,3-dimethyl-butan oyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylate (200 mg, 534 umol, 1.00 eq) in mixed solvent of methanol (2.00 mL) and water (1.00 mL) was added lithium hydroxide (38.4 mg, 1.60 mmol, 140 μL, 3.00 eq) at 0 °C. After stirring at 25 °C for 1 h, the mixture was diluted with water (20.0 mL). Hydrochloric acid (1M) was added to adjust pH~4. The solution was extracted with ethyl acetate (20 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-3-[(2S)-2-(ethylsulfonylamino)-3,3-dimethyl-butan oyl]-6, 6-dimethyl-3- azabicyclo [3.1.0] hexane-2-carboxylic acid (200 mg, crude) as yellow oil. Procedure for preparation of CPD0330485 - (1R, 2S, 5S)-N-[cyano(1,6-naphthyridin-8-yl)methyl]- 3-[2-(ethylsulfonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethy l-3-azabicyclo[3.1.0]hexane-2- carboxamide To a solution of (1R,2S,5S)-3-[2-(ethylsulfonylamino)-3,3-dimethyl-butanoyl]- 6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (100 mg, 277 μmol, 1.00 eq) and [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-d imethylazanium;hexafluorophosphate (116 mg, 305 μmol, 1.10 eq) in dichloromethane (2.00 mL) were added 2-amino-2-(1,6-naphthyridin-8- yl)acetonitrile (91.8 mg, 416 μmol, 1.50 eq, hydrochloric acid) and N-ethyl-N-propan-2-ylpropan-2- amine (108 mg, 832 μmol, 145 μL, 3.00 eq) at 25 °C. After stirring at 25 °C for 15 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC [column: Waters Xbridge C18 150*50mm* 10 μm; mobile phase: [water (ammonium hydrogen carbonate)-acetonitrile]; B%: 32%-62%, 9min] to give (1R,2S,5S)-N-[cyano(1,6-naphthyridin-8- yl)methyl]-3-[2-(ethylsulfonylamino)-3,3-dimethyl-butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (33.6 mg, 63.8 μmol, 23% yield, 99% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.74-9.39 (m, 2H), 9.35-9.13 (m, 1H), 9.02-8.84 (m, 1H), 8.76-8.51 (m, 1H), 8.00-7.70 (m, 1H), 7.08-6.63 (m, 2H), 4.45-4.27 (m, 1H), 3.87-3.63 (m, 3H), 3.01-2.85 (m, 2H), 1.59-1.40 (m, 2H), 1.20-0.74 (m, 20H). LC-MS (Method C): Rt = 0.90 min; MS (ESIpos): m/z = 527.2 [M+H] ⁺ . Preparation of CPD0330487 Procedure for preparation of CPD0330487 -(1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-6-fluoro-3-oxo- 4H-1,4-benzoxazin-2-yl]ethyl]-6,6-dimethyl-3-[(2S)-3-(2-pyri dyl)-2-[[2-[tetrahydrofuran-3- yl]acetyl]amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2-carbo xamide To a mixture of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-(2-pyridyl)-2-[(2-tetrahyd rofuran-3- ylacetyl)amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2-carbox ylic acid (150 mg, 361 μmol, 1.00 eq) and (2S)-2-amino-3-[(2S)-6-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]p ropanenitrile (84.9 mg, 361 μmol, 1.00 eq) in dichloromethane (5.00 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N’,N’- tetramethyluronium hexafluorophosphate (206 mg, 542 μmol, 1.50 eq) and N,N-diisopropylethylamine (233 mg, 1.81 mmol, 314 μL, 5.00 eq). After stirring at 20 °C for 3 h, the reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 25%-55%,9 min) to give (1R,2S,5S)-N- [(1S)-1-cyano-2-[(2S)-6-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl] ethyl]-6,6-dimethyl-3-[(2S)-3-(2-pyridyl)- 2-[[2-[tetrahydrofuran-3-yl]acetyl] amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide (18.0 mg, 28.5 μmol, 8% yield) as a white solid. LCMS (Method C): Rt = 0.425 min; MS (ESIpos): m/z = 633.4[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.89 (s, 1H), 8.89 (d, J = 8.4 Hz, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.25 (t, J = 6.8 Hz, 1H), 7.67 (t, J = 7.2 Hz, 1H), 7.21 (t, J = 5.2 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 6.84 (m, 1H), 6.72-6.63 (m, 2H), 5.09-4.93 (m, 1H), 4.76 (m, 1H), 4.57 (dd, J = 10.0, 2.8 Hz, 1H), 4.09 (s, 1H), 3.85-3.79 (m, 2H), 3.61-3.48 (m, 4H), 3.14-3.07 (m, 1H), 3.04-2.97 (m, 1H), 2.89-2.79 (m, 1H), 2.69- 2.58 (m, 1H), 2.31-2.17 (m, 1H), 2.04-1.99 (m, 2H), 1.77-1.71 (m, 1H), 1.54-1.52 (m, 1H), 1.31 (d, J = 7.6 Hz, 2H), 1.06-0.94 (m, 3H), 0.85 (s, 3H). Preparation of CPD0330489 Procedure for preparation of CPD0330489 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-6-fluoro-3-oxo- 4H-1,4-benzoxazin-2-yl]ethyl]-6,6-dimethyl-3-[(2S)-3-(4-pyri dyl)-2-[[2-[tetrahydrofuran-3- yl]acetyl]amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2-carbo xamide A mixture of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-(4-pyridyl)-2-[[2-[tetrahy drofuran-3-yl] acetyl]amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxyl ic acid (80.0 mg, 0.192 mmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexaflu orophosphate (109 mg, 0.288 mmol, 1.50 eq) and N,N-diisopropylethylamine (74.6 mg, 0.577 mmol, 3.00 eq) in N,N-dimethyl formamide (1.00 mL) was stirred at 25 °C. After stirring for 0.5 h, (2S)-2-amino-3-[(2S)-6-fluoro-3-oxo-4H-1,4- benzoxazin-2-yl] propanenitrile (49.8 mg, 0.211 mmol, 1.10 eq) was added. After stirring at 25 °C for 11.5 h, the reaction mixture was poured into water (10.0 mL) and extracted with ethyl acetate (5.00 mL × 3). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: YMC Triart C18150*25mm*5 μm; mobile phase: [water(FA)-ACN]; B%: 20%-50%, 8.5 min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-6-fluoro-3-oxo-4H-1,4-ben zoxazin-2- yl]ethyl]-6,6-dimethyl-3- [(2S)-3-(4-pyridyl)-2-[[2-[tetrahydrofuran-3-yl]acetyl]amino ]propanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxamide (30.8 mg, 0.0459 mmol, 23% yield, 94% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.01-10.79 (m, 1H), 9.00 (d, J = 7.8 Hz, 1H), 8.84-8.67 (m, 2H), 8.49-8.32 (m, 1H), 7.90-7.69 (m, 2H), 7.03-6.86 (m, 1H), 6.80-6.59 (m, 2H), 5.11-4.91 (m, 1H), 4.79- 4.67 (m, 1H), 4.62-4.59 (m, 1H), 4.19-4.05 (m, 1H), 3.88-3.81 (m, 1H), 3.76 (d, J = 10.8 Hz, 1H), 3.64- 3.60 (m, 1H), 3.56-3.53 (m, 2H), 3.14-3.09 (m, 1H), 3.04-3.00 (m, 1H), 2.95-2.89 (m, 1H), 2.79-2.73 (m, 1H), 2.33-2.27 (m, 2H), 2.13-2.02 (m, 2H), 1.81-1.71 (m, 1H), 1.58-1.47 (m, 1H), 1.38-1.22 (m, 2H), 1.00 (s, 3H), 0.84 (s, 3H). LC-MS (Method L): R _t = 0.451 min; MS (ESIpos): m/z = 633.2 [M+H] ⁺ . HPLC (Method M): R _t = 1.453 min; HPLC purity: 94%. SFC: dr = 47: 46. To a solution of (1R,2S,5S)-3-((S)-2-(ethylsulfonamido)-3,3-dimethylbutanoyl) -6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (100 mg, 261 μmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (123 mg, 325 μmol, 1.30 eq), N,N- diisopropylethylamine (96.8 mg, 749 μmol, 3.00 eq) in N,N-dimethylformamide (3.00 mL) was added (S)-2-amino-3-((S)-6-fluoro-3-oxo-3,4-dihydro-2H-benzo[b][1, 4]oxazin-2-yl)propanenitrile (58.7 mg, 250 μmol, 1.00 eq). After stirring at 20 °C for 2 h, the mixture was poured into saturated ammonium chloride solution (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition: column: Phenomenex Luna C18150*25 mm*10 μm; mobile phase: [water(FA)-ACN]; B%: 40%-70%, 10 min) to give (1R,2S,5S)-N-((S)-1-cyano-2-((S)-6-fluoro-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-2- yl)ethyl)-3-((S)-2-(ethylsulfonamido)-3,3-dimethylbutanoyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (65.0 mg, 111 μmol, 45% yield, 99% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.86 (s, 1H), 9.13 (d, J = 8.4 Hz, 1H), 6.96-6.85 (m, 2H), 6.79-6.72 (m, 1H), 6.69-6.3 (m, 1H), 5.19-5.11 (m, 1H), 4.53-4.45 (m, 1H), 4.12 (s, 1H), 3.85-3.77 (m, 1H), 3.73- 3.59 (m, 2H), 2.95-2.83 (m, 2H), 2.48-2.44 (m, 1H), 2.34-2.22 (m, 1H), 1.60-1.52 (m, 1H), 1.35-1.29 (m, 1H), 1.15-1.08 (m, 3H), 1.02 (s, 3H), 0.89 (s, 3H), 0.74 (s, 9H). LC-MS (Method C): R _t = 0.821 min; MS (ESIpos): m/z = 578.3 [M+H] ⁺ . HPLC (Method S): R _t = 2.114 min; purity: 99% SFC: dr = 2: 94: 4. To a solution of (1R,2S,5S)-3-((S)-3,3-dimethyl-2-(oxazole-5-carboxamido)buta noyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (90.0 mg, 248 μmol, 1.00 eq), O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (122 mg, 322 μmol, 1.30 eq), N,N- diisopropylethylamine (96.0 mg, 743 μmol, 129 μL, 3.00 eq) in N,N-dimethylformamide (3.00 mL) was added (S)-2-amino-3-((S)-6-fluoro-3-oxo-3,4-dihydro-2H-benzo[b][1, 4]oxazin-2-yl)propanenitrile (61.2 mg, 260 μmol, 1.05 eq). After stirring at 20 °C for 2 h, the mixture was poured into saturated ammonium chloride (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition: column: Phenomenex luna C18150*25 mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 37%-67%, 10 min) to give N-((S)-1-((1R,2S,5S)-2-(((S)-1-cyano-2-((S)-6-fluoro-3-oxo-3 ,4-dihydro-2H-benzo[b][1,4]oxazin-2- yl)ethyl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3- yl)-3,3-dimethyl-1-oxobutan-2-yl)oxazole- 5-carboxamide (65.0 mg, 111 μmol, 45% yield, 99% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.87 (s, 1H), 9.06 (d, J = 8.4 Hz, 1H), 8.51 (s, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.98 (s, 1H), 6.95-6.87 (m, 1H), 6.80-6.73 (m, 1H), 6.70-6.65 (m, 1H), 5.19-5.10 (m, 1H), 4.55- 4.44 (m, 2H), 4.10 (s, 1H), 3.95-3.85 (m, 1H), 3.80-3.74 (m, 1H), 2.47-2.44 (m, 1H), 2.32-2.25 (m, 1H), 1.60-1.52 (m, 1H), 1.37-1.29 (m, 1H), 1.01 (s, 3H), 0.90-0.75 (m, 12H). LC-MS (Method R): R _t = 1.951 min; MS (ESIpos): m/z = 581.3 [M+H] ⁺ . SFC: dr = 94: 6. To a solution of 2-hydroxy-2-methyl-propanoic acid (203 mg, 1.95 mmol, 1.10 eq), methyl (1R,2S,5S)- 3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabic yclo[3.1.0]hexane-2-carboxylate (500 mg, 1.77 mmol, 1.00 eq) and diisopropylethylamine (915 mg, 7.08 mmol, 1.23 mL, 4.00 eq) in dichloromethane (10.0 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (808 mg, 2.12 mmol, 1.20 eq). After stirring at 20 °C for 2 h, the reaction mixture was concentrated under vacuum to give a residue. The residue was purified by flash column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 5: 1 to 0: 1) to afford methyl (1R,2S,5S)-3- [(2S)-2-[(2-hydroxy-2-methyl-propanoyl)amino]-3,3-dimethyl-b utanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (600 mg, 1.41 mmol, 80% yield) as colorless oil. LC-MS (Method C): Rt = 0.820 min; MS (ESIpos): m/z = 369.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-[(2-hydroxy-2-methyl-propanoyl)amino]-3 ,3- dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-2-[(2-hydroxy-2-methyl-propanoyl)amino]-3 ,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyla te (500 mg, 1.36 mmol, 1.00 eq) in mixed solvent of methanol (6.00 mL) and water (0.60 mL) was added lithium hydroxide hydrate (114 mg, 2.71 mmol, 2.00 eq). After stirring at 25 °C for 1 h, the solvent was removed under reduced pressure and the residue was dissolved with water (10.0 mL). Hydrochloric acid (2M) was added to the mixture at 25 °C to adjust pH~2. The aqueous phase was extracted with ethyl acetate (5.00 mL × 2). The combined extracts were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford (1R,2S,5S)-3-[(2S)-2-[(2-hydroxy-2-methyl-propanoyl)amino]-3 ,3- dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (350 mg, 987 umol, 73% yield) as a white solid. LC-MS (Method C): Rt = 0.765 min; MS (ESIpos): m/z = 355.2 [M+H] ⁺ . To a solution of (1R,2S,5S)-3-[(2S)-2-[(2-hydroxy-2-methyl-propanoyl)amino]-3 ,3-dimethyl-butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (350 mg, 987 umol, 1.00 eq) and 2-amino-2- (1,6-naphthyridin-8-yl)acetonitrile (200 mg, 1.09 mmol, 1.10 eq) in dichloromethane (7.00 mL) were added diisopropylethylamine (383 mg, 2.96 mmol, 516 μL, 3.00 eq) and O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluronium hexafluorophosphate (451 mg, 1.18 mmol, 1.20 eq). After stirring at 20 °C for 2 h, the reaction mixture was concentrated under vacuum at 50 °C to give a residue. The residue was purified by flash column chromatography (Dichloromethane: Tetrahydrofuran = 1: 1) followed by prep-HPLC (column: Waters Xbridge C18150*50mm* 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 26%-56%,10 min) to afford (1R,2S,5S)-N-[cyano(1,6-naphthyridin-8-yl)methyl]-3-[(2S)-2- [(2- hydroxy-2-methyl-propanoyl)amino]-3,3-dimethyl-butanoyl]-6,6 -dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (216 mg, 418 μmol, 42% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.56 (d, J = 7.6 Hz, 0.5H), 9.52 (d, J = 2.8 Hz, 1H), 9.44 (d, J = 7.6 Hz, 0.5H), 9.32-9.20 (m, 1H), 8.96 (d, J = 10.0 Hz, 1H), 8.79-8.71 (m, 1H), 7.89-7.77 (m, 1H), 7.36-7.20 (m, 1H), 6.88-6.82 (m, 1H), 5.68 (d, J = 8.0 Hz, 1H), 4.36 (s, 1H), 4.32 (t, J = 7.6 Hz, 1H), 3.92-3.84 (m, 1H), 3.80-3.72 (m, 1H), 1.57-1.48 (m, 1H), 1.43 (d, J = 7.6 Hz, 0.5H), 1.25 (d, J = 6.4 Hz, 3H), 1.22 (d, J = 7.6 Hz, 0.5H), 1.15 (d, J = 4.4 Hz, 3H), 1.04 (s, 1.5H), 0.94 (s, 1.5H), 0.92 (s, 4.5H), 0.81 (s, 4.5H), 0.78 (d, J = 12.6 Hz, 3H). LC-MS (Method C): Rt = 0.797 min; MS (ESIpos): m/z = 521.2 [M+H] ⁺ . Preparation of CPD0337534 Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(oxetane-3- carbonylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexa ne-2-carboxylate To a solution of oxetane-3-carboxylic acid (160 mg, 1.57 mmol, 1.00 eq), O-(benzotriazol-1-yl)-N,N,N,N- tetramethyluronium,tetrafluoroborate (604 mg, 1.88 mmol, 1.20 eq) and diisopropylethylamine (811 mg, 6.27 mmol, 1.09 mL, 4.00 eq) in tetrahydrofuran (10.0 mL) was added methyl (1R,2S,5S)-3-[(2S)-2- amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2-carboxylate (500 mg, 1.57 mmol, 1.00 eq, Hydrochloride). After stirring at 20 °C for 2 h, the reaction mixture was concentrated under vacuum to give a residue. The residue was purified by flash column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 5: 1 to 0: 1) to afford methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2- (oxetane-3-carbonylamino)butanoyl]-6,6-dimethyl-3-azabicyclo [3.1.0]hexane-2-carboxylate (200 mg, 524 μmol, 33% yield) as colorless solid. LC-MS (Method C): Rt = 0.647 min; MS (ESIpos): m/z = 367.2 [ Procedure for preparation of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(oxetane-3- carbonylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexa ne-2-carboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(oxetane-3-carbonylamino)b utanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (200 mg, 546 μmol, 1.00 eq) in mixed solvent of methanol (2.00 mL) and water (0.20 mL) was added lithium hydroxide hydrate (45.80 mg, 1.09 mmol, 2.00 eq). After stirring at 25 °C for 2 h, the solvent was concentrated under reduced pressure to give a residue. The residue was diluted with water (10.0 mL). Hydrochloric acid (2M) was added to adjust pH = 2 at 25 °C. The separated aqueous phase was extracted with ethyl acetate (5.00 mL × 2). The combined extracts were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(oxetane-3- carbonylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexa ne-2-carboxylic acid (200 mg, 437 μmol, 80% yield) as a yellow solid. LC-MS (Method C): Rt = 0.579 min; MS (ESIpos): m/z = 353.2 [M+H] ⁺ . To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(oxetane-3-carbonylamino)b utanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (200 mg, 567 umol, 1.00 eq) and 2-amino-2-(1,6- naphthyridin-8-yl)acetonitrile (105 mg, 567 μmol, 1.00 eq) in dichloromethane (5.00 mL) was added diisopropylethylamine (293 mg, 2.27 mmol, 395 μL, 4.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluronium hexafluorophosphate (259 mg, 681 μmol 1.20 eq). After stirring at 25 °C for 2 h, the reaction mixture was concentrated under vacuum at 50 °C to give a residue. The residue was purified by flash column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 1 to 0: 1) and prep-HPLC (column: Waters xbridge 150*25mm 10 μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 27%-57%,10 min) to afford (1R,2S,5S)-N-[cyano(1,6-naphthyridin-8-yl)methyl]-3-[(2S)-3, 3-dimethyl-2-(oxetane-3- carbonylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexa ne-2-carboxamide (100 mg, 193 μmol, 34% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.53 (d, J = 8.0 Hz, 0.5H), 9.51 (d, J = 5.2 Hz, 1H), 9.40 (d, J = 7.6 Hz, 0.5H), 9.27-9.22 (m, 1H), 8.94 (d, J = 9.8 Hz, 1H), 8.74-8.67 (m, 1H), 7.95 (dd, J = 17.6, 8.8 Hz, 1H), 7.84 (dd, J = 8.4, 4.4 Hz, 1H), 6.83 (dd, J = 19.0, 7.8 Hz, 1H), 4.64-4.52 (m, 3H), 4.47-4.35 (m, 2H), 4.32 (d, J = 20.0 Hz, 1H), 3.93-3.80 (m, 3H), 1.58-1.47 (m, 1H), 1.42 (d, J = 7.6 Hz, 0.5H), 1.21 (d, J = 7.6 Hz, 0.5H), 1.06-1.02 (m, 1.5H), 0.96 (s, 1.5H), 0.91 (s, 4.5H), 0.83 (d, J = 13.6 Hz, 3H), 0.80 (s, 4.5H). LC-MS (Method C): Rt = 0.790 min; MS (ESIpos): m/z = 519.2 [M+H] ⁺ . SFC: dr = 52:48. Preparation of CPD0337535 Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(1-methyl-2-oxo- piperidine-4-carbonyl)amino]butanoyl]-6,6-dimethyl-3-azabicy clo[3.1.0]hexane-2-carboxylate To a mixture of 1-methyl-2-oxo-piperidine-4-carboxylic acid (300 mg, 1.91 mmol, 1.00 eq), N,N- diisopropylethylamine (740 mg, 5.73 mmol, 997 μL, 3.00 eq) in dichloromethane (2.00 mL) was added 3-[chloro-(2-oxooxazolidin-3-yl)phosphoryl]oxazolidin-2-one (728 mg, 2.86 mmol, 1.50 eq) at 25 °C. After stirring for 10 min, methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimeth yl-3- azabicyclo[3.1.0]hexane-2-carboxylate (608 mg, 1.91 mmol, 1.00 eq, hydrochloride) was added. The mixture was stirred at 25 °C for 16 h. The mixture was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ethergradient @ 80 mL/min).to give methyl (1R,2S,5S)-3-[(2S)-3,3- dimethyl-2-[(1-methyl-2-oxo-piperidine-4-carbonyl)amino]buta noyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (700 mg, 1.66 mmol, 87% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.11-7.95 (m, 1H), 4.47-4.34 (m, 1H), 4.21-4.17 (m, 1H), 3.92-3.77 (m, 2H), 3.65 (s, 3H), 3.25-3.16 (m, 2H), 2.90-2.82 (m, 1H), 2.78-2.74 (m, 3H), 2.27-2.16 (m, 2H), 1.92- 1.84 (m, 1H), 1.81-1.70 (m, 1H), 1.57-1.48 (m, 1H), 1.42 (d, J = 7.6 Hz, 1H), 1.00 (s, 3H), 0.97 (s, 2H), 0.95 (s, 8H), 0.81-0.79 (m, 2H). Procedure for preparation of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(1-methyl-2-oxo-piperidin e-4- carbonyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(1-methyl-2-oxo-piperidin e-4- carbonyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxylate (300 mg, 711 μmol, 1.00 eq) in mixed solvent of methanol (5.00 mL) and water (1.00 mL) was added lithium hydroxide (59.7 mg, 1.42 mmol, 2.00 eq). After stirring at 25 °C for 4 h, the reaction mixture was diluted with water (10.0 mL) and adjusted pH to 2-3 by hydrochloric acid (1M). The solution was extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(1-methyl-2-oxo- piperidine-4-carbonyl)amino]butanoyl]-6,6-dimethyl-3-azabicy clo[3.1.0]hexane-2-carboxylic acid (280 mg, crude) as yellow oil. Procedure for preparation of Compound CPD0337535 - (1R,2S,5S)-N-[cyano(1,6-naphthyridin-8- yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(1-methyl-2-oxo-piperidin e-4-carbonyl)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(1-methyl-2-oxo-piperidin e-4- carbonyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxylic acid (280 mg, 687 μmol, 1.00 eq), 2-amino-2-(1,6-naphthyridin-8-yl)acetonitrile (126 mg, 687 μmol, 1.00 eq) in dichloromethane (4.00 mL) was added N,N-diisopropylethylamine (355 mg, 2.75 mmol, 478 μL, 4.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (313 mg, 824 μmol, 1.2 eq). After stirring at 25 °C for 16 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate = 1: 1 to 0: 1) followed by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)- acetonitrile]; B%: 26%-56%,10 min) to give (1R,2S,5S)-N-[cyano(1,6- naphthyridin-8-yl)methyl]-3-[(2S)-3,3-dimethyl-2-[(1-methyl- 2-oxo-piperidine-4- carbonyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxamide (50.0 mg, 81.0 μmol, 12% yield, 93% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.55-9.49 (m, 1.5H), 9.40 (d, J = 7.6 Hz, 1H), 9.28-9.23 (m, 1H), 8.94 (d, J = 10.4 Hz, 1H), 8.73-8.66 (m, 1H), 7.93 (dd, J = 16.4, 8.8 Hz, 1H), 7.88-7.80 (m, 1H), 6.85 (d, J = 7.6 Hz, 0.5H), 6.81 (d, J = 7.6 Hz, 0.5H), 4.35 (s, 0.76H), 4.33 (d, J = 4.0 Hz, 0.50H), 4.30 (s, 0.66H), 3.87-3.78 (m, 2H), 3.23-3.11 (m, 2.5H), 2.91-2.79 (m, 1.5H), 2.79-2.73 (m, 3H), 2.27-2.18 (m, 2H), 1.82- 1.61 (m, 2H), 1.571.46 (m, 1H), 1.41 (d, J = 7.6 Hz, 0.50H), 1.21 (d, J = 7.6 Hz, 0.50H), 1.04 (s, 1H), 0.99-0.87 (m, 7H), 0.86-0.78 (m, 7H). LC-MS (Method C): Rt = 0.546 min; MS (ESIpos): m/z =574.4 [M+H] ⁺ . SFC: dr = 41: 37: 4: 5. A mixture of 2,2-difluoroacetic acid (300 mg, 3.12 mmol, 196 μL, 1.00 eq), 3-[chloro-(2-oxooxazolidin- 3-yl)phosphoryl]oxazolidin-2-one (1.19 g, 4.69 mmol, 1.50 eq), N,N-diisopropylethylamine (1.61 g, 12.5 mmol, 2.18 mL, 4.00 eq) and methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimeth yl- 3-azabicyclo[3.1.0]hexane-2-carboxylate (996 mg, 3.12 mmol, 1.00 eq, hydrochloride) in dichloromethane (10.0 mL) was stirred at 25 °C for 16 h. The mixture was concentrated to give a residue. The residue was purified by flash column chromatography (ISCO ®; 40 g Sepa Flash® Silica Flash Column, Eluent of 40~60% Ethyl acetate/Petroleum ether gradient @ 50 mL/min).to give methyl (1R,2S,5S)-3-[(2S)-2-[(2,2-difluoroacetyl)amino]-3,3-dimethy l-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (600 mg, 1.66 mmol, 53% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.87 (d, J = 8.8 Hz, 1H), 6.28 (t, J = 52 Hz, 1H), 4.41 (d, J = 8.8 Hz, 1H), 4.22 (s, 1H), 3.91-3.83 (m, 1H), 3.82-3.74 (m, 1H), 3.71-3.59 (m, 3H), 1.59-1.50 (m, 1H), 1.48-1.40 (m, 1H), 1.03-0.94 (m, 11H), 0.90-0.81 (m, 4H). Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-[(2,2-difluoroacetyl)amino]-3,3-dimethy l- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyli c acid To a solution of methyl (1R,2S,5S)-3-[(2S)-2-[(2,2-difluoroacetyl)amino]-3,3-dimethy l-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (500 mg, 1.39 mmol, 1.00 eq) in mixed solvent of methanol (5.00 mL) and water (1.00 mL) was added lithium hydroxide (66.4 mg, 2.77 mmol, 2.00 eq). After stirring at 25 °C for 4 h, hydrochloric acid (1M) was added to the mixture to adjust pH = 2-3. The aqueous phase was extracted with ethyl acetate (20.0 mL × 3).The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give (1R,2S,5S)-3-[(2S)-2- [(2,2-difluoroacetyl)amino]-3,3-dimethyl-butanoyl]-6,6-dimet hyl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (400 mg, crude) as yellow oil. LC-MS (Method C): Rt = 0.574 min; MS (ESIpos): m/z =347.2 [M+H] ⁺ . Procedure for preparation of Compound CPD0337536 - (1R,2S,5S)-N-[cyano(1,6-naphthyridin-8- yl)methyl]-3-[(2S)-2-[(2,2-difluoroacetyl)amino]-3,3-dimethy l-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide To a solution of (1R,2S,5S)-3-[(2S)-2-[(2,2-difluoroacetyl)amino]-3,3-dimethy l-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (200 mg, 577 μmol, 1.00 eq) in dichloromethane (5.00 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (263 mg, 692 μmol, 1.20 eq). After stirring at 25 °C for 16 h, the mixture was concentrated to give a residue. The residue was purified by flash column chromatography ((ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 40~60% Ethyl acetate/Petroleum ether gradient @ 50 mL/min) followed by prep-HPLC (column: Waters xbridge 150*25mm 10 μm; mobile phase: [water (ammonium hydrogen carbonate)- acetonitrile]; B%: 32%-62%,10 min) to give (1R,2S,5S)-N-[cyano(1,6-naphthyridin-8-yl)methyl]-3-[(2S)- 2-[(2,2-difluoroacetyl)amino]-3,3-dimethyl-butanoyl]-6,6-dim ethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (130 mg, 253 μmol, 44% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.60 (d, J = 8.0 Hz, 0.5H), 9.51 (d, J = 4.4 Hz, 1H), 9.45 (d, J = 7.6 Hz, 0.5H), 9.28-9.24 (m, 1H), 8.95 (d, J = 10.4 Hz, 1H), 8.81 (dd, J = 16.4, 8.8 Hz, 1H), 8.73-8.68 (m, 1H), 7.85 (dd, J = 8.0, 4.4 Hz, 1H), 6.85 (d, J = 7.6 Hz, 0.5H), 6.81 (d, J = 7.8 Hz, 0.5H), 6.45-6.12 (m, 1H), 4.42-4.30 (m, 2H), 3.92-3.84 (m, 1H), 3.77-3.71 (m, 1H), 1.61-1.48 (m, 1H), 1.43 (d, J = 7.6 Hz, 0.5H), 1.22 (d, J = 7.6 Hz, 0.5H), 1.05 (s, 1H), 1.00-0.94 (m, 6H), 0.90-0.79 (m, 8H). LC-MS (Method C): Rt = 0.599 min; MS (ESIpos): m/z =513.3 [M+H] ⁺ . SFC: dr = 51: 48. Preparation of CPD0337537 Procedure for preparation of methyl (1R,2S,5S)-3-((S)-2-((methoxycarbonyl)amino)-3,3- dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-c arboxylate To a solution of methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimeth yl-3- azabicyclo[3.1.0]hexane-2-carboxylate (500 mg, 1.57 mmol, 1.00 eq, hydrogen chloride), diisopropylethylamine (608 mg, 4.70 mmol, 0.819 mL, 3.00 eq) in dichloromethane (5.00 mL) was added a solution of methyl carbonochloridate (570 mg, 6.03 mmol, 0.467 mL, 3.85 eq) in dichloromethane (1.00 mL) at 0 °C. After stirring at 25 °C for 0.5 h, the reaction mixture was quenched with saturated ammonium chloride (20.0 mL), and extracted with dichloromethane (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give methyl (1R,2S,5S)-3-[(2S)-2- (methoxycarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3 -azabicyclo[3.1.0]hexane-2- carboxylate (550 mg, crude) as white oil. LC-MS (Method C): R _t = 0.773 min, MS (ESIpos): m/z = 341.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.20 (d, J = 8.6 Hz, 1H), 4.20 (s, 1H), 4.05 (br d, J = 8.6 Hz, 1H), 3.85-3.79 (m, 2H), 3.65 (s, 3H), 3.51 (s, 3H), 1.57-1.51 (m, 1H), 1.42 (d, J = 7.6 Hz, 1H), 1.02-1.00 (m, 3H), 0.95 (s, 9H), 0.88-0.85 (m, 3H). Procedure for preparation of (1R,2S,5S)-3-((S)-2-((methoxycarbonyl)amino)-3,3- dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-c arboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-2-(methoxycarbonylamino)-3,3-dimethyl-but anoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (500 mg, 1.47 mmol, 1.00 eq) in mixed solvent of tetrahydrofuran (2.00 mL), water (1.00 mL) and methyl alcohol (2.00 mL) was added lithium hydrate (92.4 mg, 2.20 mmol, 1.50 eq). After stirring at 25 °C for 2 h, the reaction mixture was diluted with water (15.0 mL) and adjusted pH to 2~3 by hydrogen chloride (1M). The solution was extracted with ethyl acetate (15.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed phase column (instrument: 80 g Flash; Column: Welch Ultimate XB_C1820-40μm; eluent A: water (0.05% formic acid), eluent B: acetonitrile; gradient: 0-50min 0-50% B; flow 55 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)-3-[(2S)-2-(methoxycarbonylamino)- 3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxylic acid (280 mg, 0.857 mmol, 58% yield) as a white solid. LC-MS (Method C): R _t = 0.719 min, MS (ESIpos): m/z = 327.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.15 (d, J = 8.4 Hz, 1H), 4.12 (s, 1H), 4.05 (d, J = 8.8 Hz, 1H), 3.82- 3.82 (m, 2H), 3.51 (s, 3H), 1.50 (s, 1H), 1.40 (d, J = 7.6 Hz, 1H), 1.02 (s, 3H), 0.95 (s, 9H), 0.86 (s, 3H). Procedure for preparation of Compound CPD0337537 - methyl ((2S)-1-((1R,2S,5S)-2-((cyano(1,6- naphthyridin-8-yl)methyl)carbamoyl)-6,6-dimethyl-3-azabicycl o[3.1.0]hexan-3-yl)-3,3-dimethyl- 1-oxobutan-2-yl)carbamate To a solution of (1R,2S,5S)-3-[(2S)-2-(methoxycarbonylamino)-3,3-dimethyl-but anoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (230 mg, 0.704 mmol, 1.00 eq) in dichloromethane (3.00 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (401 mg, 1.06 mmol, 1.50 eq) and diisopropylethylamine (364 mg, 2.82 mmol, 0.490 mL, 4.00 eq). After stirring at 25 °C for 16 h, the reaction mixture was quenched with water (10.0 mL) at 25 °C. The solution was extracted with dichloromethane (10.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate = 1: 1 to 0: 1) and prep-HPLC (column: Phenomenex luna C18150 × 25mm 10 μm; mobile phase: [water(formic acid)-acetonitrile]; B%: 34%-64%,10 min) to give methyl N-[(1S)-1-[(1R,2S,5S)-2-[[cyano(1,6-naphthyridin-8- yl)methyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 3-carbonyl]-2,2-dimethyl- propyl]carbamate (210 mg, 0.422 mmol, 59% yield, 99% purity) as a yellow solid. LC-MS (Method C): R _t = 0.760 min, MS (ESIpos): m/z = 493.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.56 (d, J = 7.6 Hz, 0.5H), 9.51 (d, J = 5.2 Hz, 1H), 9.41 (d, J = 7.6 Hz, 0.5H), 9.25 (dd., J = 4.4, 1.6 Hz, 1H), 8.94 (d, J = 10.4 Hz, 1H), 8.73-8.66 (m, 1H), 7.84 (dd., J = 8.4, 4.4 Hz, 1H), 7.12 (dd., J = 19.6, 8.4 Hz, 1H), 6.83 (dd., J = 16.4, 7.6 Hz, 1H), 4.34 (d, J = 19.6 Hz, 1H), 4.02 (dd., J = 17.2, 8.4 Hz, 1H), 3.89-3.76 (m, 2H), 3.50 (d, J = 4.4 Hz, 3H), 1.59-1.47 (m, 1H), 1.41 (d, J = 7.6 Hz, 0.5H), 1.21 (d, J = 7.6 Hz, 0.5H), 1.09-0.98 (m, 2H), 0.98-0.78 (m, 13H). SFC: dr = 49: 46. Preparation of CPD0337538 Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-2-(3-hydroxypropanoylamino)-3,3- dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylate To a solution of 3-hydroxypropanoic acid (638 mg, 2.12 mmol, 30% purity, 1.20 eq), diisopropylethylamine (811 mg, 6.27 mmol, 1.09 mL, 4.00 eq) and methyl (1R,2S,5S)-3-[(2S)-2-amino- 3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan e-2-carboxylate (500 mg, 1.77 mmol, 1.00 eq) in dimethyl formamide (5.00 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluronium hexafluorophosphate (1.01 g, 2.66 mmol, 1.50 eq). After stirring at 25 °C for 16 h, the reaction mixture was concentrated under vacuum to give a residue. The residue was purified by flash column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 5: 1 to 1: 1) to afford methyl (1R,2S,5S)-3-[(2S)-2-(3-hydroxypropanoylamino)-3,3-dimethyl- butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (300 mg, 846 umol, 12% yield) as a yellow solid. LC-MS (Method C): Rt = 0.783 min; MS (ESIpos): m/z = 355.3 [ ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-2-(3-hydroxypropanoylamino)-3,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyli c acid To a solution of methyl (1R,2S,5S)-3-[(2S)-2-(3-hydroxypropanoylamino)-3,3-dimethyl- butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (300 mg, 846 μmol,1.00 eq) in mixed solvent of methanol (5.00 mL) and water (0.500 mL) was added lithium hydroxide hydrate (71.0 mg, 1.69 mmol, 2.00 eq). After stirring at 25 °C for 2 h, the reaction mixture was concentrated to give a residue. The residue was dissolved with water (10.0 mL). Hydrochloric acid (2M) was added to the mixture to adjust pH = 2 at 25 °C. The aqueous phase was extracted with ethyl acetate (5.00 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford (1R,2S,5S)-3-[(2S)-2-(3-hydroxypropanoylamino)-3,3-dimethyl- butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (250 mg, 441 μmol, 52% yield) as a white solid. LC-MS (Method C): Rt = 0.710 min; MS (ESIpos): m/z = 341.1 [M+H] ⁺ . To a solution of (1R,2S,5S)-3-[(2S)-2-(3-hydroxypropanoylamino)-3,3-dimethyl- butanoyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxylic acid (200 mg, 588 μmol, 1.00 eq) and 2-amino-2-(1,6- naphthyridin-8-yl)acetonitrile (119 mg, 646 μmol, 1.10 eq) in dichloromethane (4.00 mL) were added diisopropylethylamine (228 mg, 1.76 mmol, 307 μL, 3.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluronium hexafluorophosphate (246 mg, 646 μmol, 1.10 eq). After stirring at 20 °C for 12 h, the reaction mixture was concentrated under vacuum at 50 °C to give a residue. The residue was purified by flash column chromatography (SiO ₂ , Dichloromethane: Tetrahydrofuran = 1: 1) followed by prep-HPLC (column: Waters Xbridge 150*25mm* 5 μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN];B%: 24%-54%, 9 min) to afford (1R,2S,5S)-N-[cyano(1,6-naphthyridin-8-yl)methyl]-3-[(2S)-2- (3- hydroxypropanoylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3 -azabicyclo[3.1.0]hexane-2- carboxamide (19.0 mg, 36.7 μmol, 8% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.52 (d, J = 8.0 Hz, 0.5H), 9.52 (d, J = 3.6 Hz, 1H), 9.40 (d, J = 8.0 Hz, 0.5H), 9.28 (td, J = 2.0, 4.2 Hz, 1H), 8.96 (d, J = 11.6 Hz, 1H), 8.72 (d, J = 8.4 Hz, 1H), 7.88-7.76 (m, 2H), 6.85 (d, J = 7.6 Hz, 0.5H), 6.81 (d, J = 7.6 Hz, 0.5H), 4.60-4.52 (m, 1H), 4.36-4.28 (m, 2H), 3.88-3.76 (m, 2H), 3.60-3.48 (m, 2H), 2.40-2.24 (m, 2H), 1.56-1.44 (m, 1H), 1.40 (d, J = 7.6 Hz, 0.5H), 1.20 (d, J = 7.6 Hz, 0.5H), 1.08-1.04 (m, 1.5H), 0.96 (s, 1.5H), 0.92 (s, 4.5H), 0.84 (s, 1.5H), 0.83-0.78 (m, 6H). LC-MS (Method C): Rt = 0.776 min; MS (ESIpos): m/z = 507.3 [M+H] ⁺ . SFC: dr = 56: 44. Preparation of CPD0337539 Procedure for preparation of methyl (1R,2S,5S)-3-((S)-3,3-dimethyl-2-propionamidobutanoyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate To a mixture of methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimeth yl-3- azabicyclo[3.1.0]hexane-2-carboxylate (1.50 g, 4.70 mmol, 1.00 eq, hydrogen chloride), diisopropylethylamine (2.43 g, 18.8 mmol, 3.28 mL, 4.00 eq) in dichloromethane (15.0 mL) was added propanoyl chloride (1.09 g, 11.7 mmol, 1.09 mL, 2.50 eq) at 0 °C. After stirring at 25 °C for 2 h, the mixture was quenched with water (20 mL), concentrated under reduced pressure to remove dichloromethane. The solution was extracted with ethyl acetate (20 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(propanoylamino)butanoyl]- 6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (1.40 g, 4.14 mmol, 88% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.84 (d, J = 8.8 Hz, 1H), 4.37 (d, J = 8.8 Hz, 1H), 4.19 (s, 1H), 3.93- 3.77 (m, 2H), 3.65 (s, 3H), 2.19-2.08 (m, 2H), 1.54-1.49 (m, 1H), 1.41 (d, J = 7.6 Hz, 1H), 1.15-1.09 (m, 3H), 0.96-0.93 (m, 12H), 0.87-0.80 (m, 4H). LC-MS (Method C): R _t = 0.790 min, MS (ESIpos): m/z = 339.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-((S)-3,3-dimethyl-2-propionamidobutanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid To a solution of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(propanoylamino)butanoyl]- 6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (500 mg, 1.48 mmol, 1.00 eq) in mixed solvent of methanol (2.00 mL), tetrahydrofuran (2.00 mL) and water (1.00 mL) was added lithium hydroxide (92.9 mg, 2.22 mmol, 1.50 eq). After stirring at 25 °C for 2 h, the reaction mixture was diluted with water (10.0 mL) and adjusted to pH 2-3 by hydrogen chloride (1M). The solution was extracted with ethyl acetate (10 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed phase column (instrument: 80 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.05% formic acid), eluent B: acetonitrile; gradient: 0-50min 0-30% B; flow 55 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(propanoylamino)butanoyl]- 6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (100 mg, 0.308 mmol, 20% yield) as a gray solid. LC-MS (Method C): R _t = 0.708 min, MS (ESIpos): m/z = 325.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.82 (d, J = 9.2 Hz, 1H), 4.39 (d, J = 9.2 Hz, 1H), 4.11 (s, 1H), 3.90- 3.75 (m, 2H), 2.24-2.06 (m, 2H), 1.49 (dd., J = 7.6, 5.2 Hz, 1H), 1.39 (d, J = 7.6 Hz, 1H), 1.01 (s, 3H), 0.97-0.93 (m, 12H), 0.82 (s, 3H). To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(propanoylamino)butanoyl]- 6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (352 mg, 1.09 mmol, 1.00 eq) in dichloromethane (5.00 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (619 mg, 1.63 mmol, 1.50 eq) and diisopropylethylamine (561 mg, 4.34 mmol, 0.756 mL, 4.00 eq). After stirring at 25 °C for 16 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate = 1: 1 to 0: 1) followed by prep-HPLC (column: Waters xbridge 150 × 25mm 10 μm; mobile phase: [water(ammonium hydrogen carbonate)-acetonitrile]; B%: 30%-57%, 9 min) to give (1R,2S,5S)-N-[cyano(1,6-naphthyridin-8- yl)methyl]-3-[(2S)-3,3-dimethyl-2-(propanoylamino)butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxamide (290 mg, 0.591 mmol, 54% yield) as an off-white solid. LC-MS (Method C): R _t = 0.572 min, MS (ESIpos): m/z = 491.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.53 (d, J = 7.6 Hz, 0.5H), 9.51 (d, J = 4.2 Hz, 1H), 9.38 (d, J = 7.6 Hz, 0.5H), 9.28-9.23 (m, 1H), 8.94 (d, J = 11.2 Hz, 1H), 8.70 (td, J = 8.4, 1.6 Hz, 1H), 7.84 (dd., J = 8.4, 4.4 Hz, 1H), 7.78 (dd., J = 18.4, 9.2 Hz, 1H), 6.83 (dd., J = 19.2, 7.6 Hz, 1H), 4.35 (t, J = 4.4 Hz, 1H), 4.32-4.28 (m, 1H), 3.83 (s, 2H), 2.24-2.03 (m, 2H), 1.56-1.46 (m, 1H), 1.41 (d, J = 7.6 Hz, 0.5H), 1.21 (d, J = 7.6 Hz, 0.5H), 1.03 (s, 1.5H), 0.98-0.89 (m, 9H), 0.84-0.76 (m, 7.5H). SFC: dr = 51: 48. To a solution of methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimeth yl-3- azabicyclo[3.1.0]hexane-2-carboxylate (600 mg, 1.88 mmol, 1.00 eq, hydrochloride) and 2-(oxetan-3- yl)acetic acid (240 mg, 2.07 mmol, 1.10 eq) in dichloromethane (10.0 mL) were added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-d imethylazanium;hexafluorophosphate (787 mg, 2.07 mmol, 1.10 eq) and N-ethyl-N-propan-2-ylpropan-2-amine (973 mg, 7.53 mmol, 1.31 mL, 4.00 eq) at 25 °C. After stirring at 25 °C for 1 h, the reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate (60.0 mL). The organic layer was washed with water (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[[2-(oxetan-3-yl)acetyl]am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (600 mg, crude) as yellow oil. LC-MS (Method C): Rt = 0.757min, MS (ESIpos): m/z = 381.2[M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-((S)-3,3-dimethyl-2-(2-(oxetan-3- yl)acetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan e-2-carboxylic acid. To a solution of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[[2-(oxetan-3-yl)acetyl]am ino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (600 mg, 1.58 mmol, 1.00 eq) in methanol (10.0 mL) was added lithium hydroxide (2 M, 2.37 mL, 3.00 eq) at 25 °C. After stirring at 25 °C for 1 h, hydrochloric acid (1 M) was added to the mixture to adjust pH 2-3, extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were washed with water 20.0 mL (10.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[[2- (oxetan-3-yl)acetyl]amino]butanoyl]-6,6-dimethyl-3-azabicycl o[3.1.0]hexane-2-carboxylic acid (300 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.95-7.74 (m, 1H), 4.62-4.53 (m, 2H), 4.44-4.37 (m, 1H), 4.30-4.15 (m, 2H), 4.00-3.91 (m, 1H), 3.76-3.64 (m, 2H), 3.22-3.07 (m, 1H), 2.61-2.52 (m, 2H), 1.35-1.30 (m, 1H), 1.25-1.14 (m, 1H), 0.97-0.90 (m, 12H), 0.86-0.81 (m, 2H), 0.77-0.65 (m, 3H). To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[[2-(oxetan-3-yl)acetyl]am ino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (300 mg, 819 μmol, 1.00 eq) and 2-amino-2-(1,6- naphthyridin-8-yl)acetonitrile (217 mg, 982 μmol, 1.20 eq) in dichloromethane (5.00 mL) were added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-d imethylazanium;hexafluorophosphate (373 mg, 982 μmol, 1.20 eq) and N-ethyl-N-propan-2-ylpropan-2-amine (317 mg, 2.46 mmol, 428 μL, 3.00 eq) at 25 °C. After stirring at 25 °C for 1 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC Waters Xbridge 150*25mm*5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 28%-58%,10 min and column: UniSil 3-100 C18 UItra (150*25mm*3 μm); mobile phase: [water (FA)-ACN]; B%: 38%-58%,7 min to give (1R,2S,5S)-N-[(S)- cyano(1,6-naphthyridin-8-yl)methyl]-3-[(2S)-3,3-dimethyl-2-[ [2-(oxetan-3-yl)acetyl]amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0] hexane-2-carboxamide (208 mg, 469 μmol, 99% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.57-9.48 (m, 1.5H), 9.43-9.36 (m, 0.5H), 9.29-9.21 (m, 1H), 8.96- 8.90 (m, 1H), 8.74-8.67 (m, 1H), 8.02-7.92 (m, 1H), 7.82-7.82 (m, 1H), 7.88-7.81 (m, 1H), 6.92-6.75 (m, 1H), 4.62-4.52 (m, 2H), 4.38-4.13 (m, 4H), 3.88-3.75 (m, 2H), 3.20-3.05 (m, 1H), 2.61-2.53 (m, 2H), 1.55-1.45 (m, 1H), 1.44-1.38 (m, 0.5H), 1.24-1.17 (m, 0.5H), 1.08-0.99 (m, 2H), 0.97-0.89 (m, 6H), 0.83- 0.71 (m, 7H). LC-MS (Method C): Rt = 0.731min, MS (ESIpos): m/z = 533.2[M+H] ⁺ . SFC: dr = 51:44: 3: 2. Preparation of CPD0337541 Procedure for preparation of methyl (1R,2S,5S)-3-((S)-2-(1-acetylazetidine-3-carboxamido)-3,3- dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-c arboxylate To a solution of 1-acetylazetidine-3-carboxylic acid (1.00 g, 6.99 mmol, 1.00 eq), methyl (1R,2S,5S)-3- [(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyc lo[3.1.0]hexane-2-carboxylate (1.97 g, 6.99 mmol, 1.00 eq, hydrochloride) in dichloromethane (10.0 mL) were added bis(2-oxo-3- oxazolidinyl)phosphinicchloride (2.13 g, 8.38 mmol, 1.20 eq) and diisopropylethylamine (2.71 g, 20.9 mmol, 3.65 mL, 3.00 eq). After stirring at 25 °C for 16 h, the reaction mixture was quenched with water (15.0 mL) at 25°C. The solution was extracted with ethyl acetate (15.0 mL × 3). The combined organic layers were washed with brine (15.0 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Ethyl acetate: Methanol = 1: 0 to 10: 1) to give methyl (1R,2S,5S)-3-[(2S)-2-[(1- acetylazetidine-3-carbonyl)amino]-3,3-dimethyl-butanoyl]-6,6 -dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylate (1.50 g, 3.68 mmol, 52% yield) as a white solid. LC-MS (Method C): R _t = 0.559 min, MS (ESIpos): m/z = 408.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.16 (dd., J = 8.8, 4.8 Hz, 1H), 4.42 (dd., J =8.8, 2.8 Hz, 1H), 4.20 (s, 1H), 4.18-4.13 (m, 1H), 4.08-4.03 (m, 1H), 3.96 (br. s, 4H), 3.67-3.62 (m, 3H), 3.49-3.43 (m, 1H), 1.71 (d, J = 2.4 Hz, 3H), 1.57-1.49 (m, 1H), 1.42 (d, J = 7.6 Hz, 1H), 1.02-0.94 (m, 11H), 0.87-0.79 (m, 4H). Procedure for preparation of (1R,2S,5S)-3-((S)-2-(1-acetylazetidine-3-carboxamido)-3,3- dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-c arboxylic acid A mixture of methyl (1R,2S,5S)-3-[(2S)-2-[(1-acetylazetidine-3-carbonyl)amino]-3 ,3-dimethyl-butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.00 g, 2.45 mmol, 1.00 eq) and lithium hydroxide (88.1 mg, 3.68 mmol, 1.50 eq) in mixed solvent of methanol (8.00 mL) and water (2.00 mL) was stirred at 25 °C for 16 h. The reaction mixture was diluted with water (20.0 mL). Hydrochloric acid (1M) was added to adjust pH 2-3. The solution was extracted with ethyl acetate (15.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (instrument: 80 g Flash; Column: Welch Ultimate XB_C1820-40 μm; eluent A: water (0.05% formic acid), eluent B: acetonitrile; gradient: 0-50min 0-30% B; flow 55 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to give (1R,2S,5S)-3-[(2S)-2-[(1-acetylazetidine-3-carbonyl)amino]-3 ,3-dimethyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (700 mg, 1.51 mmol, 61% yield, 85% purity) as a white solid. LC-MS (Method C): R _t = 0.669 min, MS (ESIpos): m/z = 394.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.14 (dd., J = 9.2, 4.4 Hz, 1H), 4.47-4.39 (m, 1H), 4.17 (dt, J = 8.4, 4.8 Hz, 1H), 4.12 (s, 1H), 4.05 (dd., J = 8.0, 6.0 Hz, 0.5H), 3.96-3.88 (m, 1H), 3.88-3.82 (m, 2H), 3.75 To a solution of (1R,2S,5S)-3-[(2S)-2-[(1-acetylazetidine-3-carbonyl)amino]-3 ,3-dimethyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (427 mg, 1.09 mmol, 1.00 eq) and 2-amino-2- (1,6-naphthyridin-8-yl)acetonitrile (200 mg, 1.09 mmol, 1.00 eq) in dichloromethane (5.00 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (619 mg, 1.63 mmol, 1.50 eq) and diisopropylethylamine (421 mg, 3.26 mmol, 0.567 mL, 3.00 eq). After stirring at 25 °C for 16 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Ethyl acetate: Methanol = 1: 0 to 4: 1) followed by prep-HPLC (column: Waters xbridge 150 × 25 mm 10 μm; mobile phase: [water (ammonium hydrogen carbonate)-acetonitrile]; B%: 25%-45%,10 min) to give (1R,2S,5S)-3-[(2S)-2-[(1-acetylazetidine-3- carbonyl)amino]-3,3-dimethyl-butanoyl]-N-[cy2ano(1,6-naphthy ridin-8-yl)methyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (200 mg, 0.375 mmol, 34% yield) as an off-white solid. LC-MS (Method C): R _t = 0.712 min, MS (ESIpos): m/z = 560.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.55 (m, 0.5H), 9.51 (d, J = 5.0 Hz, 1H), 9.44-9.37 (m, 0.5H), 9.28- 9.21 (m, 1H), 8.95 (d, J = 10.4 Hz, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.16-8.05 (m, 1H), 7.84 (dd., J = 8.4, 4.4 Hz, 1H), 6.86 (d, J = 7.6 Hz, 0.5H), 6.81 (d, J = 7.6 Hz, 0.5H), 4.42-4.29 (m, 2H), 4.23-4.12 (m, 1H), 4.09-4.02 (m, 0.5H), 3.93 (m, 0.5H), 3.91-3.80 (m, 3H), 3.78-3.71 (m, 0.5H), 3.63 (m, 0.5H), 3.52-3.41 (m, 1H), 1.75-1.68 (m, 3H), 1.58-1.46 (m, 1H), 1.44-1.40 (m, 0.5H), 1.24-1.19 (m, 0.5H), 1.04 (s, 1H), 0.96-0.88 (m, 6H), 0.87-0.77 (m, 8H). SFC: dr = 52: 47. Preparation of CPD0330488 Procedure for preparation of dimethyl (2S,4S)-2-((tert-butoxycarbonyl)amino)-4-(4,5-difluoro-2- nitrophenoxy)pentanedioate To a mixture of dimethyl (2S,4R)-2-((tert-butoxycarbonyl)amino)-4-hydroxypentanedioat e (1.00 g, 3.43 mmol, 1.00 eq), 4,5-difluoro-2-nitro-phenol (661 mg, 3.78 mmol, 1.10 eq) and triphenylphosphine (1.35 g, 5.15 mmol, 1.50 eq) in tetrahydrofuran (20.0 mL) was added diisopropyl azodicarboxylate (1.04 g, 5.15 mmol, 1.50 eq) at 0 °C. After stirring at 25 °C for 16 h, the mixture was poured into water (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were died over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate/Petroleum ether gradient @ 50 mL/min) to give dimethyl (2S,4S)-2-((tert- butoxycarbonyl)amino)-4-(4,5-difluoro-2-nitrophenoxy)pentane dioate (2.50 g, 2.90 mmol, 85% yield, 52% purity) as light yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.26 (t, J = 9.2 Hz, 1H), 7.68-7.58 (m, 1H), 7.36 (d, J = 9.2 Hz, 1H), 5.05-5.01 (m, 1H), 4.36-4.24 (m, 1H), 3.69 (s, 3H), 3.64 (s, 3H), 2.35-2.27 (m, 2H), 1.26 (s, 9H). Procedure for preparation of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-6,7-difluoro-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate To a solution of dimethyl (2S,4S)-2-((tert-butoxycarbonyl)amino)-4-(4,5-difluoro-2- nitrophenoxy)pentanedioate (2.50 g, 2.90 mmol, 52% purity, 1.00 eq) in methanol (30.0 mL) was added palladium on carbon (0.250 g, 10% purity contained 50% water) at 25 °C. The suspension was degassed under vacuum and purged with hydrogen for 3 times. After stirring at 25 °C for 16 h under hydrogen (15 psi) atmosphere, the mixture was filtered through a pad of celite. The filter cake was washed with methanol (2.00 mL × 3). The combined organic layers were concentrated to give methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-6,7-difluoro-3-oxo -3,4-dihydro-2H-benzo[b][1,4]oxazin-2- yl)propanoate (2.20 g, 2.85 mmol, 98% yield, 50% purity) as light yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.80 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.14 (dd, J = 10.8, 7.6 Hz, 1H), 6.88 (dd, J = 10.8, 7.6 Hz, 1H), 4.57-4.51 (m, 1H), 4.34-4.19 (m, 1H), 3.62 (s, 3H), 2.26-2.04 (m, 2H), 1.37 (s, 9H). Procedure for preparation of tert-butyl ((S)-1-amino-3-((S)-6,7-difluoro-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)-1-oxopropan-2-yl)carbamate A mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-6,7-difluoro-3-oxo -3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)propanoate (1.10 g, 2.85 mmol, 1.00 eq) and ammonium (7 M in methanol, 20.0 mL) was stirred at 25 °C for 34 h. The mixture was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~80% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give tert-butyl ((S)-1-amino-3-((S)- 6,7-difluoro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)- 1-oxopropan-2-yl)carbamate (500 mg, 1.35 mmol, 47% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.79 (s, 1H), 7.30-7.21 (m, 1H), 7.13-7.04 (m, 2H), 7.00 (d, J = 8.8 Hz, 1H), 6.90-6.85 (m, 1H), 4.55-4.45 (m, 1H), 4.20-4.07 (m, 1H), 2.08-2.01 (m, 2H), 1.37 (s, 9H). To a mixture of tert-butyl ((S)-1-amino-3-((S)-6,7-difluoro-3-oxo-3,4-dihydro-2H-benzo[ b][1,4]oxazin-2- yl)-1-oxopropan-2-yl)carbamate (400 mg, 1.08 mmol, 1.00 eq) in dichloromethane (5.00 mL) and dimethyl formamide (1.00 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (385 mg, 1.62 mmol, 1.50 eq) at 0 °C. After stirring at 25 °C for 16 h, the mixture was poured into water (10.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~40% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give tert-butyl ((S)-1-cyano-2-((S)-6,7-difluoro-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)carbamate (450 mg, 1.27 mmol, 95% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.89 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.17-7.07 (m, 1H), 6.93-6.82 (m, 1H), 4.79-4.58 (m, 2H), 2.44-2.18 (m, 2H), 1.40 (s, 9H). Procedure for preparation of (S)-2-amino-3-((S)-6,7-difluoro-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)propanenitrile A mixture of tert-butyl ((S)-1-cyano-2-((S)-6,7-difluoro-3-oxo-3,4-dihydro-2H-benzo[ b][1,4]oxazin-2- yl)ethyl)carbamate (200 mg, 0.566 mmol, 1.00 eq) and hydrochloric acid (4 M in dioxane, 5.00 mL) in acetonitrile (5.00 mL) was stirred at 0 °C for 2 h. The mixture was concentrated to give (S)-2-amino-3- ((S)-6,7-difluoro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2 -yl)propanenitrile (160 mg, hydrochloric acid salt) as yellow oil. Procedure for preparation of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[[(3R)-tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxylate To a solution of (3R)-tetrahydrofuran-3-carboxylic acid (364 mg, 3.14 mmol, 1.00 eq) and methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimeth yl-3-azabicyclo[3.1.0]hexane-2- carboxylate (1.00 g, 3.14 mmol, 1.00 eq, hydrochloric acid) in dichloromethane (10.0 mL) were added benzotriazol-1-yloxy(tripyrrolidin-1-yl)phosphanium hexafluorophosphate (1.96 g, 3.76 mmol, 1.20 eq) and N-methylmorpholine (1.27 g, 12.6 mmol, 1.38 mL, 4.00 eq). After stirring at 25 °C for 12 h, the mixture was diluted with saturated ammonium chloride solution (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®;20.0 g SepaFlash® Silica Flash Column, Eluent of 0~40% Ethyl acetate/Petroleum ether; gradient @45.0 mL/min) to afford methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2- [[(3R)-tetrahydrofuran-3-carbonyl]amino]butanoyl]-6,6-dimeth yl-3-azabicyclo[3.1.0]hexane-2- carboxylate (757 mg, 1.99 mmol, 63% yield) as a colorless gum. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.05 (d, J = 8.8 Hz, 1H), 4.41 (d, J = 8.8 Hz, 1H), 4.20 (s, 1H), 3.89- 3.80 (m, 3H), 3.67-3.62 (m, 5H), 3.58-3.54 (m, 1H), 3.18-3.10 (m, 1H), 1.92-1.81 (m, 2H), 1.57-1.49 (m, 1H), 1.43-4.14 (m, 1H), 1.01 (s, 3H), 0.95 (s, 9H), 0.85-0.82 (m, 3H). LC-MS (Method C): R _t = 0.576 min; MS (ESIpos): m/z = 381.3 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[[(3R)-tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxylic acid To a mixture of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[[(3R)-tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxylate (757 mg, 1.99 mmol, 1.00 eq) in methanol (6.00 mL) was added a solution of lithium hydroxide monohydrate (250 mg, 5.97 mmol, 3.00 eq) in water (6.00 mL). After stirring at 20 °C for 2 h, the reaction mixture was diluted with water (30.0 mL), adjusted pH~5 with hydrochloric acid (1.00 M) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrate to give (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[[(3R)-tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxylic acid (635 mg, 1.73 mmol, 87% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.04 (d, J = 9.2 Hz, 1H), 4.42(d, J = 9.2 Hz, 1H), 4.12 (s, 1H), 3.87- 3.78 (m, 3H), 3.70-3.63 (m, 2H), 3.60-3.51 (m, 1H), 3.16-3.09 (m, 1H), 1.93-1.82 (m, 2H), 1.54-1.47 (m, 1H), 1.44-1.37 (m, 1H), 1.01(s, 3H), 0.95 (s, 9H), 0.81 (s, 3H). LC-MS (Method C): R _t = 0.526 min; MS (ESIpos): m/z = 367.3 [M+H] ⁺ . Procedure for preparation of CPD0330488 - (1R,2S,5S)-N-((S)-1-cyano-2-((S)-6,7-difluoro-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-3-((S)-3,3-di methyl-2-((R)-tetrahydrofuran-3- carboxamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane -2-carboxamide To a mixture of (S)-2-amino-3-((S)-6,7-difluoro-3-oxo-3,4-dihydro-2H-benzo[b ][1,4]oxazin-2- yl)propanenitrile (160 mg, 0.552 mmol, hydrochloric acid salt, 1.00 eq) and (1R,2S,5S)-3-((S)-3,3- dimethyl-2-((R)-tetrahydrofuran-3-carboxamido)butanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid (202 mg, 0.552 mmol, 1.00 eq) in N,N-dimethylformamide (3.00 mL) were added O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (315 mg, 0.828 mmol, 1.50 eq) and N,N-diisopropylethylamine (285 mg, 2.21 mmol, 4.00 eq) at 25 °C. After stirring at 25 °C for 16 h, the mixture was poured into water (15.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 35%-65%, 10 min) to give (1R,2S,5S)-N-((S)-1-cyano-2-((S)-6,7- difluoro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl )-3-((S)-3,3-dimethyl-2-((R)- tetrahydrofuran-3-carboxamido)butanoyl)-6,6-dimethyl-3-azabi cyclo[3.1.0]hexane-2-carboxamide (127 mg, 0.205 mmol, 37% yield, 97% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.92 (s, 0.2H), 10.87 (s, 0.8H), 9.06 (d, J = 8.4 Hz, 0.8H), 8.96 (d, J = 8.4 Hz, 0.2H), 7.99 (d, J = 8.8 Hz, 0.2H), 7.92 (d, J = 8.8 Hz, 0.8H), 7.26-7.17(m, 0.2H), 7.04-6.97 (m, 0.8H), 6.94-6.82 (m, 1H), 5.22-5.02 (m, 0.8H), 5.08-4.99 (m, 0.2H), 4.78-4.67(m,0.2H), 4.58-4.49 (m, 0.8H), 4.41-4.35 (m, 0.2H), 4.33-4.27 (m, 0.8H), 4.18(s, 0.2H), 4.07 (s, 0.8H), 3.90-3.76 (m, 3H), 3.71-3.49 (m, 3H), 3.01-3.16 (m, 1H), 2.33-2.19 (m, 1H), 1.97-1.73 (m, 2H), 1.59-1.12 (m, 3H), 1.05- 0.67 (m, 15H). LC-MS (Method C): R _t = 0.512 min; MS (ESIpos): m/z = 602.3 [M+H] ⁺ . HPLC (Method S): R _t = 1.516 min; purity: 95%. SFC: dr = 81: 19. Preparation of CPD0336661 Procedure for preparation of O1-tert-butyl O2-methyl (2S,4R)-4-acetoxy-5-oxo-pyrrolidine-1,2- dicarboxylate To a solution of sodium periodate (44.6 g, 208 mmol, 2.00 eq) in water (200 mL) was added ruthenium trichloride (2.17 g, 10.4 mmol, 0.100 eq) at 0 °C. After stirring at 25 °C for 0.2 h, a solution of O1-tert- butyl O2-methyl (2S,4R)-4-acetoxypyrrolidine-1,2-dicarboxylate (30.0 g, 104 mmol, 1.00 eq) in acetonitrile (200 mL) was added dropwise to the above mixture. After stirring at 25 °C for 11.8 h, the mixture was filtered and the filter cake was washed with ethyl acetate (500 mL). The filtrate was poured into saturated sodium sulfite aqueous (500 mL) and extracted with ethyl acetate (300 mL × 2). The combined organic layers were washed with water (500 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 5: 1 to 3: 1) to give O1-tert- butyl O2-methyl (2S,4R)-4-acetoxy-5-oxo-pyrrolidine-1,2-dicarboxylate (20.0 g, 63.1 mmol, 60% yield, 95% purity) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 5.40-5.31 (m, 1H), 4.73-4.68 (m, 1H), 3.74 (s, 3H), 2.55-2.51 (m, 1H), 2.41-2.36 (m, 1H), 2.10 (s, 3H), 1.42 (s, 9H). Procedure for preparation of dimethyl (2R,4S)-2-acetoxy-4-(tert- butoxycarbonylamino)pentanedioate A mixture of O1-tert-butyl O2-methyl (2S,4R)-4-acetoxy-5-oxo-pyrrolidine-1,2-dicarboxylate (20.0 g, 66.3 mmol, 1.00 eq) and sodium bicarbonate (1.67 g, 19.9 mmol, 0.300 eq) in methanol (200 mL) was stirred at 25 °C for 2 h. After filtration, the filtrate was concentrated under vacuum to give a residue. The residue was diluted with ethyl acetate (500 mL), washed with saturated ammonium chloride (100 mL) and brine (100 mL). The organic layer was concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 5: 1 to 4: 1) to give dimethyl (2R,4S)-2-acetoxy-4-(tert-butoxycarbonylamino)pentanedioate (15.0 g, 42.7 mmol, 64% yield, 95% purity) as colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.40 (d, J = 8.4 Hz, 0.9H), 7.12-6.93 (m, 0.1H), 5.04-5.01 (m, 1H), 4.30-4.13 (m, 1H), 3.65 (s, 3H), 3.63 (s, 3H), 2.27-2.19 (m, 1H), 2.18-2.09 (m, 1H), 2.06 (s, 3H), 1.38 (s, 9H). Procedure for preparation of dimethyl (2R,4S)-2-acetoxy-4-[tert- butoxycarbonyl(methyl)amino]pentanedioate To a solution of dimethyl (2R,4S)-2-acetoxy-4-(tert-butoxycarbonylamino)pentanedioate (1.00 g, 3.00 mmol, 1.00 eq) in N,N-dimethylformamide (5.00 mL) were added iodomethane (4.26 g, 30.0 mmol, 10.0 eq) and silver oxide (1.39 g, 6.00 mmol, 2.00 eq) at 0 °C. After stirring at 25 °C for 12 h, the reaction mixture was filtered. The filtrate was poured into water (300 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 0 to 1: 4) to give dimethyl (2R,4S)- 2-acetoxy-4-[tert-butoxycarbonyl(methyl)amino]pentanedioate (7.00 g, crude) as yellow oil. Procedure for preparation of dimethyl (2S,4R)-2-[tert-butoxycarbonyl(methyl)amino]-4-hydroxy- pentanedioate A mixture of dimethyl (2R,4S)-2-acetoxy-4-[tert-butoxycarbonyl(methyl)amino]pentan edioate (7.00 g, 20.1 mmol, 1.00 eq) and sodium bicarbonate (3.39 g, 40.3 mmol, 2.00 eq) in methanol (50.0 mL) was stirred at 25 °C for 12 h. After filtration, the filtrate was adjusted pH to 7 with saturated ammonium chloride and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 0 to 1: 1) to give dimethyl (2S,4R)-2-[tert-butoxycarbonyl(methyl)amino]-4-hydroxy- pentanedioate (900 mg, 2.36 mmol, 11% yield, 80% purity) as yellow oil. Procedure for preparation of dimethyl (2S,4S)-2-[tert-butoxycarbonyl(methyl)amino]-4-(4-fluoro- 2-nitro-phenoxy)pentanedioate To a solution of dimethyl (2S,4R)-2-[tert-butoxycarbonyl(methyl)amino]-4-hydroxy-penta nedioate (900 mg, 2.36 mmol, 80% purity, 1.00 eq), 4-fluoro-2-nitro-phenol (407 mg, 2.59 mmol, 1.10 eq) and triphenylphosphine (804 mg, 3.07 mmol, 1.30 eq) in tetrahydrofuran (10.0 mL) was added diisopropyl azodicarboxylate (619 mg, 3.07 mmol, 1.30 eq) at 0 °C. After stirring at 25 °C for 12 h, the mixture was poured into water (50.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 0 to 81: 19) to give dimethyl (2S,4S)-2-[tert- butoxycarbonyl(methyl)amino] -4-(4-fluoro-2-nitro-phenoxy)pentanedioate (1.80 g, 2.03 mmol, 85% yield, 50% purity) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.10-7.79 (m, 1H), 7.65-7.44 (m, 1H), 7.41-7.22 (m, 1H), 5.47-5.29 (m, 0.4H), 5.04-5.03 (m, 0.3H), 4.94-4.84 (0.3H), 4.60-4.40 (m, 0.5H), 4.26-4.16 (m, 0.3H), 3.72-3.59 (m, 6H), 2.76-2.70 (m, 3H), 2.64-2.57 (m, 1H), 2.45-2.35 (m, 1H), 1.51-1.21 (m, 9H). LC-MS (Method M): R _t = 0.577 min; MS (ESIpos): m/z = 345.2 [M-Boc+H] ⁺ . To a mixture of dimethyl (2S,4S)-2-[tert-butoxycarbonyl(methyl)amino]-4-(4-fluoro-2-n itro-phenoxy) pentanedioate (1.80 g, 2.03 mmol, 50% purity, 1.00 eq) in methanol (20.0 mL) was added palladium on carbon (200 mg, 10% purity) under nitrogen atmosphere. The mixture was degassed under vacuum and purged with hydrogen for 3 times. After stirring at 25 °C for 2 h under hydrogen (15 psi) atmosphere, the reaction mixture was filtered. The filtrate was concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 20~60% Ethyl acetate/Petroleum ether gradient @ 60 mL/min) to give methyl (2S)-2-[tert- butoxycarbonyl(methyl)amino]-3-[(2S)-6-fluoro-3-oxo-4H-1,4-b enzoxazin-2-yl]propanoate (1.40 g, 1.83 mmol, 90% yield, 50% purity) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.11-10.50 (m, 1H), 7.08-6.87 (m, 1H), 6.82-6.62 (m, 2H), 4.74- 4.64 (m, 1H), 4.61-4.34 (m, 1H), 3.72-3.58 (m, 3H), 2.89-2.78 (m, 2H), 2.75 (s, 1H), 2.47-2.35 (m, 1H), 2.29-2.15 (m, 1H), 1.37-1.32 (m, 6H), 1.24 (s, 3H). LC-MS (Method M): R _t = 0.529 min; MS (ESIpos): m/z = 283.2 [M-Boc+H] ⁺ . Procedure for preparation of tert-butyl N-[(1S)-2-amino-1-[[(2S)-6-fluoro-3-oxo-4H-1,4- benzoxazin-2-yl]methyl]-2-oxo-ethyl]-N-methyl-carbamate Methyl (2S)-2-[tert-butoxycarbonyl(methyl)amino]-3-[(2S)-6-fluoro-3 -oxo-4H-1,4-benzoxazin-2-yl] propanoate (1.40 g, 1.83 mmol, 50% purity, 1.00 eq) in ammonia (7 M in methanol, 20.0 mL) was stirred at 25 °C for 16 h. After concentration, the residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 50~100% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give tert-butyl N-[(1S)-2-amino-1-[[(2S)-6-fluoro -3-oxo-4H-1,4-benzoxazin- 2-yl]methyl]-2-oxo-ethyl]-N-methyl-carbamate (450 mg, 1.16 mmol, 63% yield, 95% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.04-10.58 (m, 1H), 7.30 (s, 1H), 7.21-7.06 (m, 1H), 7.00-6.86 (m, 1H), 6.84-6.55 (m, 2H), 4.82-4.68 (m, 0.4H), 4.66-4.42 (m, 1H), 4.33-4.28 (m, 0.6H), 2.79-2.67 (m, 3H), 2.49-2.41 (m, 1H), 2.30-2.15 (m, 1H), 1.48-1.25 (m, 9H). LC-MS (Method M): R _t = 0.452 min; MS (ESIpos): m/z = 268.1 [M-Boc+H] ⁺ . Procedure for preparation of tert-butyl N-[(1S)-1-cyano-2-[(2S)-6-fluoro-3-oxo-4H-1,4- benzoxazin-2-yl]ethyl]-N-methyl-carbamate A mixture of tert-butyl N-[(1S)-2-amino-1-[[(2S)-6-fluoro-3-oxo-4H-1,4-benzoxazin-2- yl] methyl]-2-oxo- ethyl]-N-methyl-carbamae (450 mg, 1.16 mmol, 95% purity, 1.00 eq) and (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (554 mg, 2.33 mmol, 2.00 eq) in dichloromethane (5.00 mL) was stirred at 20 °C for 2 h. The reaction mixture was poured into water (30.0 mL) and extracted with ethyl acetate (15.0 mL × 3). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 20~50% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give tert-butyl N-[(1S)-1-cyano-2-[(2S)-6-fluoro-3- oxo-4H-1,4-benzoxazin-2-yl] ethyl]-N-methyl-carbamate (400 mg, 1.03 mmol, 88% yield, 90% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.08-10.63 (m, 1H), 7.03-6.89 (m, 1H), 6.80-6.74 (m, 1H), 6.73- 6.63 (m, 1H), 5.60-5.12 (m, 1H), 4.85-4.43 (m, 1H), 2.91-2.78 (m, 3H), 2.57-2.52 (m, 1H), 2.38-2.29 (m, 1H), 1.46-1.28 (m, 9H). LC-MS (Method M): R _t = 0.535 min; MS (ESIpos): m/z = 372.3 [M+Na] ⁺ . Procedure for preparation of (2S)-3-[(2S)-6-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]-2- (methylamino)propanamide A mixture of tert-butyl N-[(1S)-1-cyano-2-[(2S)-6-fluoro-3-oxo-4H-1,4-benzoxazin-2-y l] ethyl]-N-methyl- carbamate (350 mg, 0.901 mmol, 90% purity, 1.00 eq) in acetonitrile (20.0 mL) was added hydrochloric acid (4 M in dioxane, 10.0 mL) at 0 °C. After stirring at 0 °C for 0.2 h, the reaction mixture was concentrated under vacuum to give (2S)-3-[(2S)-6-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]-2- (methylamino) propanamide (280 mg, crude) as a yellow solid. LC-MS (Method M): R _t = 0.302 min; MS (ESIpos): m/z = 268.3 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[(1S)-2-amino-1-[[(2S)-6-fluoro-3-oxo-4H-1,4- benzoxazin-2-yl]methyl]-2-oxo-ethyl]-N,6,6-trimethyl-3-[(2S) -3-methyl-2-[[(3S)-tetrahydrofuran- 3-carbonyl]amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2-carbo xamide A mixture of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-[[(3S)-tetrahydro furan -3-carbonyl]amino] butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (178 mg, 0.507 mmol, 1.10 eq), O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (262 mg, 0.691 mmol, 1.50 eq) and N,N-diisopropylethylamine (238 mg, 1.84 mmol, 4.00 eq) in N,N-dimethylformamide (2.00 mL) was stirred at 0 °C for 0.5 h, followed by addition of (2S)-3-[(2S)-6-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl] -2- (methylamino) propanamide (140 mg, 0.460 mmol, 1.00 eq, hydrochlorate). After stirring at 25 °C for 11.5 h, the reaction mixture was poured into water (15.0 mL) and extracted with ethyl acetate (5.00 mL × 3). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 60~80% [Ethyl acetate/Methanol = 10/1]/Petroleum ether gradient @ 40 mL/min) to give (1R,2S,5S)- N-[(1S)-2-amino-1-[[(2S)-6-fluoro-3-oxo-4H-1,4-benzoxazin-2- yl]methyl]-2-oxo-ethyl]-N,6,6-trimethyl- 3-[(2S)-3-methyl-2-[[(3S)-tetrahydrofuran-3-carbonyl]amino]b utanoyl]-3-azabicyclo[3.1.0]hexane-2- carboxamide (170 mg, 0.183 mmol, 39% yield, 65% purity) as yellow gum. LC-MS (Method M): R _t = 0.450 min; MS (ESIpos): m/z = 602.4 [M+H] ⁺ . Procedure for preparation of methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-[[(3S)- tetrahydrofuran-3-carbonyl]amino]butanoyl]-3-azabicyclo[3.1. 0]hexane-2-carboxylate To a solution of methyl (1R,2S,5S)-3-[(2S)-2-amino-3-methyl-butanoyl]-6,6-dimethyl-3 -azabicyclo [3.1.0]hexane-2-carboxylate (788 mg, 2.58 mmol, 1.00 eq,, hydrochlorate) and (3S)-tetrahydrofuran-3- carboxylic acid (300 mg, 2.58 mmol, 1 eq) in N,N-dimethylformamide (20.0 mL) were added O-(7- azabenzotriazol-1-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (1.18 g, 3.10 mmol, 1.20 eq) and N,N-diisopropyl ethylamine (1.34 g, 10.3 mmol, 4.00 eq). After stirring at 25 °C for 16 h, the mixture was diluted with saturated ammonium chloride aqueous (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 1) to afford methyl (1R,2S,5S)-6,6-dimethyl- 3-[(2S)-3-methyl-2-[[(3S)-tetrahydrofuran-3-carbonyl]amino]b utanoyl]-3- azabicyclo[3.1.0]hexane-2- carboxylate (639 mg, 1.74 mmol, 67% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.25 (d, J = 8.4 Hz, 1H), 4.18-4.14 (m, 2H), 3.94-3.91 (m, 1H), 3.80- 3.75 (m, 2H),3.72-3.68 (m, 1H), 3.65 (s, 3H), 3.63-3.60 (m, 1H), 3.50-3.45 (m, 1H), 3.03-2.95 (m, 1H), 1.97-1.89 (m, 3H), 1.54-1.49 (m, 1H), 1.41 (d, J = 7.2 Hz, 1H), 1.00 (s, 3H), 0.92-0.82 (m, 9H). LC-MS (Method C): Rt = 0.471 min; MS (ESIpos): m/z = 367.2 [M+H] ⁺ . Procedure for preparation of methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-[[(3S)- tetrahydrofuran-3-carbonyl]amino]butanoyl]-3-azabicyclo[3.1. 0]hexane-2-carboxylate To a mixture of methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-[[(3S) -tetrahydrofuran-3- carbonyl]amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxy late (639 mg, 1.74 mmol, 1.00 eq) in methanol (6.00 mL) was added a solution of lithium hydroxide monohydrate (220 mg, 5.23 mmol, 3.00 eq) in water (6.00 mL). After stirring at 20 °C for 12 h, the reaction mixture was diluted with water (30.0 mL). Hydrochloric acid (1M in water) was added to adjust pH~5 and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrate to afford (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-[[(3S)- tetrahydrofuran-3-carbonyl]amino]butanoyl]-3-azabicyclo[3.1. 0]hexane-2-carboxylic acid (600 mg, 1.70 mmol, 98% yield) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.23 (d, J = 8.4 Hz, 1H), 4.18-4.14 (t, J = 8.4 Hz, 1H), 4.10 (s, 1H), 3.89 (d, J = 10.4 Hz, 1H), 3.80-3.72 (m, 2H), 3.70-3.60 (m, 2H), 3.49-3.44 (m, 1H), 3.05-2.95 (m, 1H), 1.98-1.88 (m, 3H), 1.51-1.47 (m, 1H), 1.39 (d, J = 7.6 Hz, 1H), 1.00 (s, 3H), 0.91-0.81 (m, 9H). LC-MS (Method C): R _t = 0.417 min; MS (ESIpos): m/z = 353.2 [M+H] ⁺ . Procedure for preparation of CPD0336661 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-6-fluoro-3-oxo- 4H-1,4-benzoxazin-2-yl]ethyl]-N,6,6-trimethyl-3-[(2S)-3-meth yl-2-[[(3S)-tetrahydrofuran-3- carbonyl]amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxa mide A mixture of (1R,2S,5S)-N-[(1S)-2-amino-1-[[(2S)-6-fluoro-3-oxo-4H-1,4-be nzoxazin-2-yl] methyl]-2- oxo-ethyl]-N,6,6-trimethyl-3-[(2S)-3-methyl-2-[[(3S)-tetrahy drofuran-3-carbonyl]amino]butanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxamide (150 mg, 0.162 mmol, 1.00 eq) and (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (77.2 mg, 0.324 mmol, 2.00 eq) in dichloromethane (2.00 mL) was stirred at 25 °C for 1 h. The reaction mixture was poured into water (10.0 mL) and extracted with ethyl acetate (5.00 mL × 3). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 40%-70%, 7 min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-6-fluoro-3-oxo-4H-1,4-ben zoxazin-2-yl]ethyl]-N,6,6-trimethyl- 3-[(2S)-3-methyl-2-[[(3S)-tetrahydrofuran-3-carbonyl]amino]b utanoyl]-3-azabicyclo[3.1.0]hexane-2- carboxamide (30.1 mg, 0.047 mmol, 29% yield, 92% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.11-10.75 (m, 1H), 8.45-7.91 (m, 1H), 7.07-6.87 (m, 1H), 6.86- 6.73 (m, 1H), 6.69-6.67 (m, 1H), 5.82-5.60 (m, 1H), 4.52-4.41 (m, 1H), 4.23-4.04 (m, 1H), 3.97-3.84 (m, 1H), 3.83-3.71 (m, 2H), 3.71-3.57 (m, 2H), 3.46 (t, J = 7.2 Hz, 1H), 3.38 (s, 1H), 3.26-3.12 (m, 3H), 3.00-2.93 (m, 1H), 2.62-2.56 (m, 1H), 2.32-2.17 (m, 1H), 2.03-1.88 (m, 2H), 1.77-1.62 (m, 1H), 1.60- 1.44 (m, 1H), 1.35 (d, J = 7.6 Hz, 1H), 1.10-0.96 (m, 3H), 0.87 (s, 4H), 0.83-0.65 (m, 5H). LC-MS (Method M): R _t = 0.502 min; MS (ESIpos): m/z = 584.4 [M+H] ⁺ . HPLC (Method O): R _t = 1.782 min; purity: 93%. SFC:dr = 2: 9: 5: 81. To a solution of methyl (1R,2S,5S)-3-[(2S)-2-amino-3-methyl-butanoyl]-6,6-dimethyl -3- azabicyclo[3.1.0]hexane-2-carboxylate (787 mg, 2.58 mmol, 1.00 eq, hydrochlorate) and (3R)- tetrahydrofuran-3-carboxylic acid (300 mg, 2.58 mmol, 1.00 eq) in N,N-dimethylformamide (20.0 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexaflu orophosphate (1.18 g, 3.10 mmol, 1.20 eq) and N,N-diisopropylethylamine (1.34 g, 10.3 mmol, 4.00 eq). After stirring at 25 °C for 16 h, the mixture was diluted with saturated ammonium chloride (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 3: 1) to afford methyl (1R,2S,5S)-6,6- dimethyl-3-[(2S)-3-methyl-2-[[(3R)-tetrahydrofuran-3-carbony l]amino]butanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxylate (753 mg, 2.05 mmol, 80 % yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.24 (d, J = 8.8 Hz, 1H), 4.21-4.13 (m, 2H), 3.96-3.91 (m, 1H), 3.84- 3.75 (m, 2H),3.70-3.68 (m, 1H), 3.65 (s, 3H), 3.64-3.61 (m, 1H), 3.57-3.53 (m, 1H), 3.02-2.95 (m, 1H), 1.96-1.83 (m, 3H), 1.54-1.51 (m, 1H), 1.42 (d, J = 6.4 Hz, 1H), 1.01 (s, 3H), 0.92-0.82 (m, 9H). LC-MS (Method C): R _t = 0.471 min; MS (ESIpos): m/z = 367.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-6,6-dimethyl-3- [(2S)-3-methyl-2-[[(3R)-tetrahydrofuran- 3-carbonyl]amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2-carbo xylic acid To a mixture of methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-[[(3R)-tetrahydro furan -3- carbonyl]amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxy late (753 mg, 2.05 mmol, 1.00 eq) in methanol (6.00 mL) was added a solution of lithium hydroxide monohydrate (259 mg, 6.16 mmol, 3.00 eq) in water (6.00 mL). After stirring at 20 °C for 12 h, the reaction mixture was diluted with water (30.0 mL). Hydrochloric acid (1M in water) was added to adjust pH~5 and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrate to afford (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-[[(3R)- tetrahydrofuran-3-carbonyl] amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (509 mg, 1.44 mmol, 70% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.22 (d, J = 8.4 Hz, 1H), 4.18-4.13 (t, J = 8.0 Hz, 1H), 4.10 (s, 1H), 3.94-3.89 (m, 1H), 3.84-3.74 (m, 2H), 3.70-3.60 (m, 2H), 3.57-3.53 (m, 1H), 3.02-2.95 (m, 1H), 1.94- 1.82 (m, 3H), 1.52-1.47 (m, 1H), 1.39 (d, J = 7.6 Hz, 1H), 1.01 (s, 3H), 0.91-0.79 (m, 9H). LC-MS (Method C): R _t = 0.416 min; MS (ESIpos): m/z = 353.3 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-N-[(1S)-2-amino-1-[[(2S)-6-fluoro-3-oxo-4H-1,4- benzoxazin-2-yl]methyl]-2-oxo-ethyl]-N,6,6-trimethyl-3-[(2S) -3-methyl-2-[[(3R)-tetrahydrofuran- 3-carbonyl]amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2-carbo xamide A mixture of (1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-methyl-2-[[(3R)-tetrahydro furan-3-carbonyl]amino] butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (178 mg, 0.507 mmol, 1.10 eq), O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (263 mg, 0.691 mmol, 1.50 eq) and N,N-diisopropylethylamine (238 mg, 1.84 mmol, 4.00 eq) in N,N-dimethylformamide (2.00 mL) was stirred at 0 °C for 0.5 h, followed by addition of (2S)-3-[(2S)-6-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]-2- (methylamino)propanamide (140 mg, 0.460 mmol, 1.00 eq, hydrochlorate). After stirring at 25 °C for 11.5 h, the reaction mixture was poured into water (15.0 mL) and extracted with ethyl acetate (5.00 mL × 3). The combined organic layers were concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 60~80% [Ethyl acetate/Methanol = 10/1]/Petroleum ether gradient @ 40 mL/min) to give (1R,2S,5S)- N-[(1S)-2-amino-1-[[(2S)-6-fluoro-3-oxo-4H-1,4-benzoxazin-2- yl]methyl]-2-oxo-ethyl]-N,6,6-trimethyl- 3-[(2S)-3-methyl-2-[[(3R)-tetrahydrofuran-3-carbonyl]amino]b utanoyl]-3-azabicyclo[3.1.0]hexane-2- carboxamide (100 mg, 0.132 mmol, 28% yield, 80% purity) as yellow gum. LC-MS (Method M): R _t = 0.454 min; MS (ESIpos): m/z = 602.3 [M+H] ⁺ . Procedure for preparation of CPD0336662 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-6-fluoro-3-oxo- 4H-1,4-benzoxazin-2-yl]ethyl]-N,6,6-trimethyl-3-[(2S)-3-meth yl-2-[[(3R)-tetrahydrofuran-3- carbonyl]amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxa mide A mixture of (1R,2S,5S)-N-[(1S)-2-amino-1-[[(2S)-6-fluoro-3-oxo-4H-1,4 -benzoxazin-2-yl] methyl]-2- oxo-ethyl]-N,6,6-trimethyl-3-[(2S)-3-methyl-2-[[(3R)-tetrahy drofuran-3-carbonyl]amino]butanoyl]-3- azabicyclo[3.1.0]hexane-2-carboxamide (100 mg, 0.132 mmol, 1.00 eq) and Burgess reagent (63.3 mg, 0.265 mmol, 2.00 eq) in dichloromethane (2.00 mL) was stirred at 25 °C for 1 h. The reaction mixture was poured into water (10.0 mL) and extracted with ethyl acetate (5.00 mL × 3). The combined organic layers were concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water (FA)-ACN]; B%: 40%-70%, 7 min) to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-6-fluoro-3-oxo-4H-1,4-ben zoxazin-2-yl]ethyl]-N,6,6- trimethyl- 3-[(2S)-3-methyl-2-[[(3R)-tetrahydrofuran-3-carbonyl]amino]b utanoyl]-3-azabicyclo[3.1.0]hexane-2- carboxamide (9.69 mg, 0.014 mmol, 11% yield, 89% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.97-10.82 (m, 1H), 8.27-8.04 (m, 1H), 6.99-6.89 (m, 1H), 6.78- 6.73 (m, 1H), 6.72-6.64 (m, 1H), 5.73-5.69 (m, 1H), 4.52-4.39 (m, 1H), 4.22-4.02 (m, 1H), 3.98-3.86 (m, 1H), 3.85-3.72 (m, 2H), 3.68-3.58 (m, 2H), 3.54-3.48 (m, 1H), 3.37 (s, 1H), 3.23-3.13 (m, 3H), 3.03-2.92 (m, 1H), 2.63-2.60 (m, 1H), 2.31-2.21 (m, 1H), 1.93-1.81 (m, 2H), 1.72-1.61 (m, 1H), 1.57-1.49 (m, 1H), 1.39-1.29 (m, 1H), 1.06-0.96 (m, 3H), 0.93-0.84 (m, 4H), 0.82-0.67 (m, 5H). LC-MS (Method M): R _t = 0.501 min; MS (ESIpos): m/z = 584.4 [M+H] ⁺ . HPLC (Method O): R _t = 1.759 min; purity: 89%. SFC:dr = 17: 83. Diisopropyl azodicarboxylate (1.36 g, 6.72 mmol, 1.40 eq) was added into a solution of 5-chloro-2- nitrophenol (1.00 g, 5.76 mmol, 1.20 eq), dimethyl (2S,4R)-2-((tert-butoxycarbonyl)amino)-4- hydroxypentanedioate (1.40 g, 4.80 mmol, 1.00 eq) and triphenylphosphine (1.76 g, 6.72 mmol, 1.40 eq) in dichloromethane (15.0 mL) at 0 °C. After stirring at 25 °C for 12 h, the reaction mixture was poured into water (30.0 mL) and extracted with dichloromethane (10.0 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate/Petroleum ether gradient @ 50 mL/min) to give dimethyl (2S, 4S)-2- ((tert-butoxycarbonyl)amino)-4-(5-chloro-2-nitrophenoxy)pent anedioate (3.20 g, 4.65 mmol, 97% yield, 65% purity) as light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.89 (d, J = 8.8 Hz, 1H), 7.13-7.04 (m, 1H), 6.95 (s, 1H), 4.88 (dd, J = 10.0, 2.8 Hz, 1H), 3.88-3.71 (m, 6H), 3.22 (s, 1H), 2.52-2.70 (m, 1H), 2.44-2.30 (m, 1H), 1.38 (s, 9H). LC-MS (Method C): R _t = 0.604 min; MS (ESIpos): m/z = 347.1 [M-Boc+H] ⁺ . Procedure for preparation of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-7-chloro-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate A mixture of dimethyl (2S, 4S)-2-((tert-butoxycarbonyl)amino)-4-(5-chloro-2- nitrophenoxy)pentanedioate (2.40 g, 3.49 mmol, 65% purity, 1.00 eq) and sodium hydrosulfite (6.08 g, 34.9 mmol, 10.0 eq) in mixed solvent of water (30.0 mL) and methanol (30.0 mL) was stirred at 60 °C for 12 h. The reaction was poured into water (50.0 mL) and extracted with ethyl acetate (50.0 mL × 2). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~45% Ethyl acetate/Petroleum ether gradient @ 60 mL/min) to give methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-7-chloro-3-oxo-3,4 -dihydro-2H-benzo[b][1,4]oxazin-2- yl)propanoate (0.240 g, 0.617 mmol, 17.7% yield, 99% purity) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.45 (s, 1H), 7.06 (s, 1H), 6.96 (dd, J = 8.4, 2.0 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 5.28 (d, J = 8.8 Hz, 1H), 4.70-4.64 (m, 2H), 3.77 (s, 3H), 2.46-2.28 (m, 2H), 1.45 (s, 9H). LC-MS (Method C): R _t = 0.537 min; MS (ESIpos): m/z = 407.1 [M+Na] ⁺ . Procedure for preparation of tert-butyl ((S)-1-amino-3-((S)-7-chloro-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)-1-oxopropan-2-yl)carbamate A mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-7-chloro-3-oxo-3,4 -dihydro-2H- benzo[b][1,4]oxazin-2-yl)propanoate (0.240 g, 0.624 mmol, 1.00 eq) in ammonium (7 M in methanol, 10 mL) was stirred at 20 °C for 36 h. The reaction mixture was concentrated to give tert-butyl ((S)-1- amino-3-((S)-7-chloro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxaz in-2-yl)-1-oxopropan-2-yl)carbamate (0.220 g, 0.595 mmol, 95% yield) as a light yellow solid. The crude product was used for next step directly without further purification. LC-MS (Method C): R _t = 0.460 min; MS (ESIpos): m/z = 392.0 [M+Na] ⁺ . Procedure for preparation of tert-butyl ((S)-2-((S)-7-chloro-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)-1-cyanoethyl)carbamate To a mixture of tert-butyl ((S)-1-amino-3-((S)-7-chloro-3-oxo-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-2-yl)- 1-oxopropan-2-yl)carbamate (220 mg, 0.595 mmol, 1.00 eq) in mixed solvent of dichloromethane (3.00 mL) and N,N-dimethyl formamide (1.00 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (213 mg, 0.892 mmol, 1.50 eq) at 0 °C. After stirring at 25 °C for 16 h, the mixture was poured into water (10.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ether gradient @ 15 mL/min) to give tert-butyl ((S)-2-((S)-7-chloro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazi n-2-yl)-1- cyanoethyl)carbamate (200 mg, 0.569 mmol, 96% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.93 (s, 1H), 7.85 (d, J = 7.6 Hz, 1H), 6.98-7.10 (m, 2H), 6.89 (d, J = 8.4 Hz, 1H), 4.80-4.60 (m, 2H), 2.43-2.20 (m, 2H), 1.40 (s, 9H). Procedure for preparation of (S)-2-amino-3-((S)-7-chloro-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)propanenitrile A mixture of tert-butyl ((S)-2-((S)-7-chloro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazi n-2-yl)-1- cyanoethyl)carbamate (200 mg, 0.569 mmmol, 1.00 eq) and hydrochloric acid (4 M in dioxane, 5.00 mL) in acetonitrile (5.00 mL) was stirred at 0 °C for 0.5 h. The mixture was concentrated to give (S)-2- amino-3-((S)-7-chloro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxaz in-2-yl)propanenitrile (160 mg, 0.555 mmol, 98% yield, hydrochloric acid salt) as a yellow solid. The crude product was used for next step directly without purification. Procedure for preparation of CPD0336702 - (1R,2S,5S)-N-((S)-2-((S)-7-chloro-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-2-yl)-1-cyanoethyl)-6,6-dimethyl-3-(( 2-(tetrahydro-2H-pyran-4-yl)acetyl)- L-valyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide To a mixture of (S)-2-amino-3-((S)-7-chloro-3-oxo-3,4-dihydro-2H-benzo[b][1, 4]oxazin-2- yl)propanenitrile (160 mg, 0.555 mmol, 1.00 eq, hydrochloric acid salt) and (1R,2S,5S)-6,6-dimethyl-3- ((2-(tetrahydro-2H-pyran-4-yl)acetyl)-L-valyl)-3-azabicyclo[ 3.1.0]hexane-2-carboxylic acid (211 mg, 0.555 mmol, 1.00 eq) in N,N-dimethylformamide (3.00 mL) were added O-(7-azabenzotriazol-1-yl)- N,N,N,N-tetramethyluroniumhexafluorophosphate (317 mg, 0.833 mmol, 1.50 eq) and N,N- diisopropylethylamine (287 mg, 2.22 mmol, 4.00 eq) at 25 °C. After stirring at 25 °C for 16 h, the mixture was poured into water (15.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-HPLC (column: YMC-Actus Triart C18150*30mm*7 μm; mobile phase: [water (FA)-ACN]; B%: 35%-65%, 10 min) to give (1R,2S,5S)-N-((S)-2-((S)-7-chloro-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-2-yl)-1-cyanoethyl)-6,6-dimethyl-3-(( 2-(tetrahydro-2H-pyran-4-yl)acetyl)-L- valyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (120 mg, 0.192 mol, 35% yield, 99% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.90 (s, 1H), 9.02 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.04 (dd, J = 8.4, 2.4 Hz, 1H), 6.93 (d, J = 2.4 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 5.19-5.06 (m, 1H), 4.60 (dd, J = 10.4, 2.8 Hz, 1H), 4.09-3.97 (m, 2H), 3.95-3.86 (m, 1H), 3.83-3.73 (m, 3H), 3.24-3.17 (m, 2H), 2.33- 2.25 (m, 1H), 2.05-1.94 (m, 2H), 1.85-1.73 (m, 1H), 1.63-1.37 (m, 4H), 1.32-1.27 (m, 1H), 1.16-1.06 (m, 2H), 1.01 (s, 3H), 0.92-0.84 (m, 1H), 0.82 (s, 3H), 0.77-0.63 (m, 6H). LC-MS (Method C): R _t = 0.511 min; MS (ESIpos): m/z = 614.4 [M+H] ⁺ . HPLC (Method K): R _t = 1.456 min; HPLC purity: 99%. SFC: dr = 93: 6. To a solution of (3S)-tetrahydrofuran-3-carboxylic acid (681 mg, 5.87 mmol, 1.10 eq) and methyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimeth yl-3-azabicyclo[3.1.0]hexane-2- carboxylate (1.70 g, 5.33 mmol, 1.00 eq, hydrochlorate) in dichloromethane (30.0 mL) were added benzotriazol-1-yloxy(tripyrrolidin-1-yl)phosphanium hexafluorophosphate (3.33 g, 6.40 mmol, 1.20 eq) and N-methylmorpholine (2.16 g, 21.3 mmol, 4.00 eq). After stirring at 25 °C for 12 h, the mixture was diluted with saturated ammonium chloride aqueous (40.0 mL) and extracted with ethyl acetate (40.0 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate= 4/ 1) to afford methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[[(3S)- tetrahydrofuran-3-carbonyl]amino]butanoyl]-6,6-dimethyl-3-az abicyclo[3.1.0]hexane-2-carboxylate (1.39 g, 3.65 mmol, 69% yield) as colorless gum. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.04 (d, J = 9.2 Hz, 1H), 4.41 (d, J = 9.2 Hz, 1H), 4.19 (s, 1H), 3.86- 3.75 (m, 3H), 3.69-3.61 (m, 5H), 3.47-3.44 (m, 1H), 3.15-3.08 (m, 1H), 1.95-1.90 (m, 2H), 1.53-1.48 (m, 1H), 1.42-1.40 (m, 1H), 1.00 (s, 3H), 0.95 (s, 9H), 0.79 (s, 3H). LC-MS (Method C): R _t = 0.494 min; MS (ESIpos): m/z = 381.2 [M+H] ⁺ . Procedure for preparation of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[[(3S)-tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxylic acid To a mixture of methyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[[(3S)-tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxylate (1.39 g, 3.65 mmol, 1.00 eq) in methanol (10.0 mL) was added a solution of lithium hydroxide monohydrate (613 mg, 14.6 mmol, 4.00 eq) in water (10.0 mL). After stirring at 20 °C for 2 h, the reaction mixture was diluted with water (25.0 mL), adjusted pH~5 with hydrochloric acid (1.00 mol/L) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrate to afford (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[[(3S)-tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxylic acid (928 mg, 2.53 mmol, 69% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.6 (s, 1H), 8.03 (d, J = 9.2 Hz, 1H), 4.42 (d, J = 9.2 Hz, 1H), 4.10 (s, 1H), 3.84-3.75 (m, 3H), 3.72-3.60 (m, 2H), 3.47-3.44 (m, 1H), 3.16-3.08 (m, 1H), 1.97-1.87 (m, 2H), 1.50-1.47 (m, 1H), 1.40-1.38 (m, 1H), 1.00 (s, 3H), 0.95 (s, 9H), 0.78 (s, 3H) LC-MS (Method C): R _t = 0.436 min; MS (ESIpos): m/z = 367.1 Procedure for preparation of CPD0337634 - (1R,2S,5S)-N-((S)-1-cyano-2-((S)-6,7-difluoro-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-3-((S)-3,3-di methyl-2-((S)-tetrahydrofuran-3- carboxamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane -2-carboxamide To a mixture of (S)-2-amino-3-((S)-6,7-difluoro-3-oxo-3,4-dihydro-2H-benzo[b ][1,4]oxazin-2- yl)propanenitrile (160 mg, 0.552 mmol, hydrochlorate, 1.00 eq) and (1R,2S,5S)-3-((S)-3,3-dimethyl-2- ((S)-tetrahydrofuran-3-carboxamido)butanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (182 mg, 0.497 mmol, 0.900 eq) in N,N-dimethylformamide (3.00 mL) were added O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (315 mg, 0.828 mmol, 1.50 eq) and N,N-diisopropylethylamine (285 mg, 2.21 mmol, 4.00 eq) at 25 °C. After stirring at 25 °C for 16 h, the mixture was poured into water (15.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-HPLC(column: Phenomenex Luna C18150*25mm*10 μm; mobile phase: [water(FA)-ACN]; B%: 40%-70%, 10 min) to give (1R,2S,5S)-N-((S)-1-cyano-2-((S)-6,7- difluoro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl )-3-((S)-3,3-dimethyl-2-((R)- tetrahydrofuran-3-carboxamido)butanoyl)-6,6-dimethyl-3-azabi cyclo[3.1.0]hexane-2-carboxamide (117.57 mg, 192 μmol, 35% yield, 98% purity) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.86 (s, 1H), 9.04 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.00 (dd, J = 10.8, 7.2 Hz, 1H), 6.86 (dd, J = 10.8, 8.0 Hz, 1H), 5.21-5.08 (m, 1H), 4.58-4.46 (m, 1H), 4.36- 4.25 (m, 1H), 4.05 (s, 1H), 3.88-3.55 (m, 5H), 3.43-3.34 (m, 1H), 3.14-2.98 (m, 1H), 2.33-2.23 (m, 1H), 1.98-1.85 (m, 2H), 1.56-1.30 (m, 3H), 1.33-1.28 (m, 1H), 1.06-0.66 (m, 15H). LC-MS (Method C): R _t = 0.524 min; MS (ESIpos): m/z = 602.2 [M+H] ⁺ . HPLC (Method K): R _t = 1.526 min; HPLC purity: 99%. SFC: dr: 82: 7: 9. To a solution of dimethyl (2S, 4R)-2-(tert-butoxycarbonylamino)-4-hydroxy-pentanedioate (1.50 g, 5.15 mmol, 1.00 eq), 2-fluoro-6-nitro-phenol (971 mg, 6.18 mmol, 1.20 eq), diethyl (E)-diazene-1,2- dicarboxylate (1.35 g, 7.72 mmol, 1.50 eq) in toluene (40.0 mL) was added tributylphosphane (1.56 g, 7.72 mmol, 1.50 eq) at 0 °C. After stirring at 40 °C for 16 h, the mixture was diluted with saturated ammonium chloride (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 3/1) to give dimethyl (2S, 4S)-2-(tert- butoxycarbonylamino)-4-(2-fluoro-6-nitro-phenoxy)pentanedioa te (2.08 g, 4.45 mmol, 86% yield, 92% purity) as brown oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.79-7.74 (m, 1H), 7.68-7.59 (m, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.35- 7.25 (m, 1H), 5.10-4.94 (m, 1H), 4.40-4.28 (m, 1H), 3.65 (s, 3H), 3.62 (s, 3H), 2.33-2.14 (m, 2H), 1.39- 1.28 (m, 9H). LC-MS (Method C): R _t = 0.820 min; MS (ESIpos): m/z = 331.3 [M-Boc+H] ⁺ Procedure for preparation of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(2S)-8-fluoro-3-oxo- 4H-1,4-benzoxazin-2-yl]propanoate To a solution of dimethyl (2S,4S)-2-(tert-butoxycarbonylamino)-4-(2-fluoro-6-nitro- phenoxy)pentanedioate (2.08 g, 4.83 mmol, 1.00 eq) in methanol (20.0 mL) was added palladium on carbon (50.0 mg, 10% purity) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen for 3 times. After stirring at at 20 °C for 16 h under hydrogen (15 psi), the reaction mixture was filtered. The filtrate was concentrated to afford methyl (2S)-2-(tert- butoxycarbonylamino)-3-[(2S)-8-fluoro-3-oxo-4H-1,4-benzoxazi n-2-yl]propanoate (1.78 g, 4.83 mmol, crude) as brown gum. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.0 (s, 1H), 7.45-7.40 (m, 1H), 7.00-6.87 (m, 2H), 6.74-6.72 (m, 1H), 4.65-4.62 (m, 1H), 3.67-3.63 (m, 1H), 4.30-4.18 (m, 1H), 3.61 (s, 3H), 2.21-2.12 (m, 2H), 1.37 (s, 9H). LC-MS (Method C): R _t = 0.510 min; MS (ESIpos): m/z = 269.0 [M-Boc+H] ⁺ . Procedure for preparation of tert-butyl N-[(1S)-2-amino-1-[[(2S)-8-fluoro-3-oxo-4H-1,4- benzoxazin-2-yl]methyl]-2-oxo-ethyl]carbamate A mixture of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(2S)-8-fluoro-3-oxo-4H- 1,4-benzoxazin-2- yl]propanoate (1.78 g, 4.83 mmol, 1.00 eq) in ammonium (7 M in methanol, 30.0 mL) was stirred at 20 °C for 36 h. The reaction mixture was concentrated, triturated with ethyl acetate (40 mL). The resulting suspension was filtered. The filter cake was dried to afford tert-butyl N-[(1S)-2-amino-1-[[(2S)-8-fluoro- 3-oxo-4H-1,4-benzoxazin-2-yl]methyl]-2-oxo-ethyl]carbamate (950 mg, 2.69 mmol, 56% yield) as a gray solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.88 (s, 1H), 7.26 (s, 1H), 7.07 (s, 1H), 7.00-6.87 (m, 3H), 6.72 (d, J = 7.6 Hz, 1H), 4.59-4.55 (m, 1H), 4.18-4.09 (m, 1H), 2.12-2.08 (m, 2H), 1.37 (s, 9H). LC-MS (Method C): R _t = 0.433 min; MS (ESIpos): m/z = 353.2 Procedure for preparation of tert-butyl N-[(1S)-1-cyano-2-[(2S)-8-fluoro-3-oxo-4H-1,4- benzoxazin-2-yl]ethyl]carbamate To a solution of tert-butyl N-[(1S)-2-amino-1-[[(2S)-8-fluoro-3-oxo-4H-1,4-benzoxazin-2- yl]methyl]-2- oxo-ethyl]carbamate (950 mg, 2.69 mmol, 1.00 eq) in N,N-dimethylformamide (20.0 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (1.92 g, 8.07 mmol, 3.00 eq). After stirring at 25 °C for 24 h, the mixture was diluted with saturated ammonium chloride (40.0 mL) and extracted with ethyl acetate (40.0 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 4: 1) to afford tert-butyl N-[(1S)-1- cyano-2-[(2S)-8-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]ethyl]ca rbamate (793 mg, 2.36 mmol, 88% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.01 (s, 1H), 7.90-7.83 (m, 1H), 7.00-6.88 (m, 2H), 6.73 (d, J = 7.6 Hz, 1H), 4.76-4.64 (m, 2H), 2.46-2.43 (m, 1H), 2.37-2.34 (m, 1H), 1.40 (m, 9H). LC-MS (Method C): R _t = 0.508 min; MS (ESIpos): m/z = 336.1 [M+H] ⁺ . Procedure for preparation of (2S)-2-amino-3-[(2S)-8-fluoro-3-oxo-4H-1,4-benzoxazin-2- yl]propanenitrile To a mixture of tert-butyl N-[(1S)-1-cyano-2-[(2S)-8-fluoro-3-oxo-4H-1,4-benzoxazin-2- yl]ethyl]carbamate (478 mg, 1.43 mmol, 1.00 eq) in acetonitrile (10 mL) was added hydrochloric acid (4.00 M in dioxane, 10.0 mL) at 0 °C. After stirring at 0 °C for 2 h, the mixture was concentrated to afford (2S)-2-amino-3-[(2S)-8-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]p ropanenitrile (382 mg, 1.41 mmol, 99% yield, hydrochlorate) as yellow gum. LC-MS (Method C): R _t = 0.311 min; MS (ESIpos): m/z = 236.1 [M+H] ⁺ . Procedure for preparation of CPD0337635 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-8-fluoro-3-oxo- 4H-1,4-benzoxazin-2-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-[[(3R)- tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxamide To a solution of (2S)-2-amino-3-[(2S)-8-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]p ropanenitrile (133 mg, 491 μmol, 1.20 eq, hydrochlorate) and (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[[(3R)-tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxylic acid (150 mg, 409 μmol, 1.00 eq) in N,N-dimethylformamide (10.0 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (187 mg, 491 μmol, 1.20 eq) and N,N-diisopropylethylamine (212 mg, 1.64 mmol, 4.00 eq). After stirring at 25 °C for 16 h, the reaction mixture was diluted with saturated ammonium chloride solution (15.0 mL) and extracted with ethyl acetate (15.0 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18150*25mm*10 μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 35%-65%, 10 min).to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-8-fluoro-3-oxo-4H-1,4-ben zoxazin- 2-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-[[(3R)-tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (62.9 mg, 106 μmol, 26% yield, 98% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.05 (s, 0.2H), 10.97 (s, 0.8H), 9.06 (d, J = 8.4 Hz, 0.8H), 8.99 (d, J = 8.4 Hz, 0.2H), 8.00 (d, J = 9.2 Hz, 0.2H), 7.91 (d, J = 9.2 Hz, 0.8H), 6.96-6.85 (m, 2H), 6.75-6.68 (m, 1H), 5.16-5.10 (m, 0.8H), 5.04-4.98 (m, 0.2H), 4.82-4.78 (m, 0.2H), 4.66-4.59 (m, 0.8H), 4.40-4.35 (m, 0.2H), 4.30-4.28 (m, 0.8H), 4.17 (s, 0.2H), 4.08 (s, 0.8H) 3.86-3.75 (m, 3H), 3.67-3.50 (m, 3H), 3.14- 3.05 (m, 1H), 2.63-2.56 (m, 1H), 2.41-2.35 (m, 1H), 1.93-1.75 (m, 2H), 1.55-1.47 (m, 1H), 1.37-1.31 (m, 1H), 1.04-0.82 (m, 9H), 0.91 (s, 6H). LC-MS (Method C): R _t = 0.496 min; MS (ESIpos): m/z = 584.3 [M+H] ⁺ . HPLC (Method S): R _t = 1.415 min; purity: 99%. SFC: dr = 20: 80. Preparation of CPD0337636 Procedure for preparation of CPD0337636 - (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-8-fluoro-3-oxo- 4H-1,4-benzoxazin-2-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-[[(3S)- tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxamide To a solution of (2S)-2-amino-3-[(2S)-8-fluoro-3-oxo-4H-1,4-benzoxazin-2-yl]p ropanenitrile (74.1 mg, 273 μmol, 1.00 eq, hydrochlorate) and (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[[(3S)-tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex ane-2-carboxylic acid (100 mg, 273 μmol, 1.00 eq) in N,N-dimethylformamide (5 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluroniumhexafluorophosphate (125 mg, 327 μmol, 1.20 eq) and N,N-diisopropylethylamine (141 mg, 1.09 mmol, 4.00 eq). After stirring at 25 °C for 16 h, the reaction mixture was diluted with saturated ammonium chloride (20.0 mL) and extracted with ethyl acetate (10.0 mL × 5). The combined organic layers was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18150*25mm*10 μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 38%-68%, 10 min).to give (1R,2S,5S)-N-[(1S)-1-cyano-2-[(2S)-8-fluoro-3-oxo-4H-1,4-ben zoxazin- 2-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-[[(3S)-tetrahydrofuran-3- carbonyl]amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (26.0 mg, 44.0 μmol, 16% yield, 99% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.03 (m, 0.2H), 10.96 (s, 0.7H), 9.04 (d, J = 8.4 Hz, 0.7H), 8.98 (d, J = 8.4 Hz, 0.2H), 7.99 (d, J = 8.8 Hz, 0.2H), 7.90 (d, J = 8.8 Hz, 0.7H), 6.98-6.84 (m, 2H), 6.75-6.73 (m, 0.2H), 6.69 (d, J = 7.6 Hz, 0.7H), 5.16-5.10 (m, 0.7H), 5.04-4.98 (m, 0.2H), 4.83-4.73 (m, 0.3H), 4.64-4.61 (m, 0.7H), 4.39-4.37 (m, 0.2H), 4.30 (d, J = 9.2 Hz, 0.7H), 4.17 (s, 0.2H), 4.07 (s, 0.7H), 3.86- 3.73 (m, 3H), 3.68-3.44 (m, 3H), 3.16-3.04 (m, 1H), 2.65-2.58 (m, 1H), 2.40-2.33 (m, 1H), 1.97-1.88 (m, 2H), 1.55-1.46 (m, 1H), 1.36-1.30 (m, 1H), 1.03-0.80 (m, 9H), 0.71 (s, 6H). LC-MS (Method C): Rt = 0.508 min; MS (ESIpos): m/z = 584.4 [M+H] ⁺ . HPLC (Method S): Rt = 1.452 min; purity: 99% SFC: dr = 70: 23: 6. To a mixture of dimethyl (2S,4R)-2-((tert-butoxycarbonyl)amino)-4-hydroxypentanedioat e (1.40 g, 4.81 mmol, 1.00 eq), 2-chloro-6-nitrophenol (918 mg, 5.29 mmol, 1.10 eq) and triphenylphosphine (1.89 g, 7.21 mmol, 1.50 eq) in tetrahydrofuran (30.0 mL) was added diethylazodicarboxylate (1.26 g, 7.21 mmol, 1.50 eq) at 0 °C. After stirring at 25 °C for 16 h, the mixture was poured into water (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were died over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~20% ethyl acetate/ petroleum ether gradient @ 60 mL/min) to give dimethyl (2S,4S)-2-((tert-butoxycarbonyl)amino)-4-(2- chloro-6-nitrophenoxy)pentanedioate (2.20 g, 3.94 mmol, 82% yield, 80% purity) as light yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.90 (dd, J = 8.0, 1.6 Hz, 1H), 7.84 (dd, J = 8.0, 1.6 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 5.06 (dd, J = 9.2, 3.6 Hz, 1H), 4.39-4.31 (m, 1H), 3.66 (s.3H), 3.56 (s, 3H), 2.33-2.19 (m, 2H), 1.38 (s, 9H). To a solution of dimethyl (2S,4S)-2-((tert-butoxycarbonyl)amino)-4-(2-chloro-6- nitrophenoxy)pentanedioate (2.00 g, 4.48 mmol, 1.00 eq) in mixed solvent of methanol (20.0 mL) and water (2.00 mL) was added sodium hydrosulfite (7.79 g, 44.7 mmol, 10.0 eq) at 20 °C. After stirring at 70 °C for 16 h, the mixture was cooled to ambient temperature and filtered. The filter cake was washed with methanol (5.00 mL × 2). The combined organic layers were concentrated to give a residue. The residue was diluted with water (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~30% ethyl acetate/ petroleum ether gradient @ 60 mL/min) to give methyl (S)-2- ((tert-butoxycarbonyl)amino)-3-((S)-8-chloro-3-oxo-3,4-dihyd ro-2H-benzo[b][1,4]oxazin-2- yl)propanoate (450 mg, 1.17 mmol, 26.1% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.94 (s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.11-7.04 (m, 1H), 6.98 (t, J = 8.0 Hz, 1H), 6.89-6.83 (m, 1H), 4.64 (dd, J = 10.4, 2.8 Hz, 1H), 4.40-4.28 (m, 1H), 3.61 (s, 3H), 2.25- 2.02 (m, 2H), 1.38 (s, 9H). Procedure for preparation of tert-butyl ((S)-1-amino-3-((S)-8-chloro-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)-1-oxopropan-2-yl)carbamate A mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-8-chloro-3-oxo-3,4 -dihydro-2H- benzo[b][1,4]oxazin-2-yl)propanoate (450 mg, 1.17 mmol, 1.00 eq) in ammonium (7 M in methanol, 20 mL) was stirred at 25 °C for 48 h in sealed tube. The mixture was concentrated to give tert-butyl ((S)-1- amino-3-((S)-8-chloro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxaz in-2-yl)-1-oxopropan-2-yl)carbamate (400 mg, 1.08 mmol, 92.5% yield) as yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.93-10.49 (m, 1H), 7.30-6.62 (m, 6H), 4.70-4.54 (m, 1H), 4.28- 4.15 (m, 1H), 2.20-1.94 (m, 2H), 1.37 (s, 9H). Procedure for preparation of tert-butyl ((S)-2-((S)-8-chloro-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)-1-cyanoethyl)carbamate To a mixture of tert-butyl ((S)-1-amino-3-((S)-8-chloro-3-oxo-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-2-yl)- 1-oxopropan-2-yl)carbamate (400 mg, 1.08 mmol, 1.00 eq) in mixed solvent of dichloromethane (4.00 mL) and N,N-dimethyl formamide (1.00 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (387 mg, 1.62 mmol, 1.50 eq) at 0 °C. After stirring at 20 °C for 16 h, the mixture was poured into water (15.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~40% ethyl acetate/ petroleum ether gradient @ 30 mL/min) to give tert-butyl ((S)-2-((S)-8-chloro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazi n-2-yl)-1- cyanoethyl)carbamate (400 mg, crude) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.00 (s, 1H), 7.84 (d, J = 7.2 Hz, 1H), 7.7.07 (dd, J = 8.0, 1.6 Hz, 1H), 6.98 (t, J = 8.0 Hz, 1H), 6.86 (dd, J = 8.0, 1.6 Hz, 1H), 4.79-4.62 (m, 2H), 2.46-2.43 (m, 1H), 2.36- 2.28 (m, 1H), 1.40 (s, 9H). Procedure for preparation of (S)-2-amino-3-((S)-8-chloro-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)propanenitrile To a mixture of tert-butyl ((S)-2-((S)-8-chloro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazi n-2-yl)-1- cyanoethyl)carbamate (200 mg, 0.567 mmol, 1.00 eq) in acetonitrile (5.00 mL) was added hydrochloric acid (4 M in dioxane, 5 mL) at 0 °C. After stirring at 0 °C for 0.5 h, the mixture was concentrated to give (S)-2-amino-3-((S)-8-chloro-3-oxo-3,4-dihydro-2H-benzo[b][1, 4]oxazin-2-yl)propanenitrile (160 mg, 0.555 mmol, 98% yield, hydrochloric acid salt) as a yellow solid. Procedure for preparation of CPD0337769 - (1R,2S,5S)-N-((S)-2-((S)-8-chloro-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-2-yl)-1-cyanoethyl)-3-((S)-3,3-dimeth yl-2-((S)-tetrahydrofuran-3- carboxamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane -2-carboxamide To a mixture of (S)-2-amino-3-((S)-8-chloro-3-oxo-3,4-dihydro-2H-benzo[b][1, 4]oxazin-2- yl)propanenitrile (160 mg, 0.555 mmol, 1.00 eq, hydrochlorate) and (1R,2S,5S)-3-((S)-3,3-dimethyl-2- ((S)-tetrahydrofuran-3-carboxamido)butanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (183 mg, 0.500 mmol, 0.900 eq) in N,N-dimethylformamide (3.00 mL) were added O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (317 mg, 0.833 mmol, 1.50 eq) and N,N-diisopropylethylamine (287 mg, 2.22 mmol, 4.00 eq) at 25 °C. After stirring at 25 °C for 16 h, the mixture was poured into water (15.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water(FA)-ACN]; B%: 35%-65%, 10 min) to give (1R,2S,5S)-N-((S)-2-((S)-8-chloro-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-1-cyanoethyl)-3 -((S)-3,3-dimethyl-2-((S)- tetrahydrofuran-3-carboxamido)butanoyl)-6,6-dimethyl-3-azabi cyclo[3.1.0]hexane-2-carboxamide (60.0 mg, 98.8 μmol, 18% yield, 98% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.05-11.00 (m, 0.1H), 10.97 (s, 0.5H), 9.04 (d, J = 8.4 Hz, 0.8H), 9.02-8.98 (m, 0.2H), 8.04-7.98 (m, 0.2H), 7.91 (d, J = 8.8 Hz, 0.8H), 7.11-7.02 (m, 1H), 7.02-6.91 (m, 1H), 6.90-6.78 (m, 1H), 5.21-5.11 (m, 0.8H), 5.04-4.95 (m, 0.2H), 4.86-4.76 (m, 0.2H), 4.69-4.61 (m, 0.8H), 4.44-4.34 (m, 0.2H), 4.29 (d, J = 9.2 Hz, 0.8H), 4.18-4.13 (m, 0.2H), 4.08 (s, 0.8H), 3.89-3.54 (m, 5H), 3.43-3.36 (m, 1H), 3.13-3.00 (m, 1H), 2.62-2.55 (m, 1H), 2.41-2.34 (m, 1H), 1.99-1.83 (m, 2H), 1.58-1.44 (m, 1H), 1.38-1.28 (m, 1H), 1.05-0.61 (m, 15H). LC-MS (Method C): R _t = 0.516 min; MS (ESIpos): m/z = 600.3 [M+H] ⁺ . HPLC (Method K): R _t = 1.525 min; HPLC purity: 99%. SFC: dr = 4: 13: 82. Procedure for preparation of CPD0337770 - (1R,2S,5S)-N-((S)-2-((S)-8-chloro-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-2-yl)-1-cyanoethyl)-3-((S)-3,3-dimeth yl-2-((R)-tetrahydrofuran-3- carboxamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane -2-carboxamide To a mixture of (S)-2-amino-3-((S)-8-chloro-3-oxo-3,4-dihydro-2H-benzo[b][1, 4]oxazin-2- yl)propanenitrile (160 mg, 0.555 mmol, 1.00 eq, hydrochlorate) and (1R,2S,5S)-3-((S)-3,3-dimethyl-2- ((R)-tetrahydrofuran-3-carboxamido)butanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (183 mg, 0.500 mmol, 0.900 eq) in N,N-dimethylformamide (3.00 mL) were added O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (317 mg, 0.833 mmol, 1.50 eq) and N,N-diisopropylethylamine (287 mg, 2.22 mmol, 4.00 eq) at 25 °C. After stirring at 25 °C for 16 h, the mixture was poured into water (15.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water (FA)-ACN];B%: 35%-65%,10min) to give (1R,2S,5S)-N-((S)-2-((S)-8-chloro-3- oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-1-cyanoethyl)-3 -((S)-3,3-dimethyl-2-((R)- tetrahydrofuran-3-carboxamido)butanoyl)-6,6-dimethyl-3-azabi cyclo[3.1.0]hexane-2-carboxamide (33.9 mg, 55.9 μmol, 10 % yield, 99% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.05-11.00 (m, 0.1H), 10.97 (s, 0.5H), 9.04 (d, J = 8.0 Hz, 0.8H), 9.02-8.97 (m, 0.2H), 8.02-7.97 (m, 0.2H), 7.90 (d, J = 9.2 Hz, 0.8H), 7.11-7.02 (m, 1H), 7.01-6.91 (m, 1H), 6.90-6.79 (m, 1H), 5.22-5.11 (m, 0.8H), 5.07-4.95 (m, 0.2H), 4.86-4.77 (m, 0.2H), 4.68-4.61 (m, 0.8H), 4.44-4.34 (m, 0.2H), 4.28 (d, J = 9.2 Hz, 0.8H), 4.18-4.14 (m, 0.2H), 4.09 (s, 0.8H), 3.90-3.71 (m, 3H), 3.70-3.47 (m, 1H), 3.13-3.00 (m, 1H), 2.64-2.58 (m, 1H), 2.41-2.35 (m, 1H), 1.95-1.72 (m, 2H), 1.58-1.45 (m, 1H), 1.37-1.28 (m, 1H), 1.06-0.61 (m, 15H). LC-MS (Method C): R _t = 0.510 min; MS (ESIpos): m/z = 600.3 [M+H] ⁺ . HPLC (Method K): R _t = 1.511 min; HPLC purity: 99%. SFC: dr = 6: 13: 80. To a solution of dimethyl (2S,4R)-2-((tert-butoxycarbonyl)amino)-4-hydroxypentanedioat e (1.40 g, 4.81 mmol, 1.00 eq), 4-chloro-2-nitrophenol (918 mg, 5.29 mmol, 1.10 eq) and triphenylphosphane (1.89 g, 7.21 mmol, 1.50 eq) in tetrahydrofuran (30.0 mL) was added diethyl azodicarboxylate (1.26 g, 7.21 mmol, 1.31 mL, 1.50 eq) at 0 °C. After stirring at 20 °C for 12 h, the mixture was poured into water (30.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 0 to 4: 1) to give dimethyl (2S, 4S)-2-((tert-butoxycarbonyl)amino)-4-(4-chloro-2- nitrophenoxy)pentanedioate (2.10 g, crude) as a light yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.90 (d, J = 2.4 Hz, 1H), 7.45 (dd, J = 8.8, 2.4 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 5.48-5.28 (m, 1H), 4.90-4.83 (m, 1H), 4.74-4.58 (m, 1H), 3.77 (s, 3H), 3.35 (s,3H), 2.65-2.50 (m, 1H), 2.41-2.29 (m, 1H), 1.39 (s, 9H). LC-MS (Method C): R _t = 0.580 min; MS (ESIpos): m/z = 347.0 [M-Boc+H] ⁺ . Procedure for preparation of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-6-chloro-3-oxo- 3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate To a solution of dimethyl (2S,4S)-2-((tert-butoxycarbonyl)amino)-4-(4-chloro-2- nitrophenoxy)pentanedioate (1.20 g, 2.69 mmol, 1.00 eq) in mixed solvent of methanol (10.0 mL) and water (3.00 mL) was added sodium hydrosulfite (4.68 g, 26.9 mmol, 10.0 eq). After stirring at 75 °C for 12 h, the reaction mixture was filtered. The filtrate was poured into water (100 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 0 to 1: 4) to give methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-6-chloro-3-oxo-3,4 -dihydro-2H- benzo[b][1,4]oxazin-2-yl)propanoate (300 mg, 702 μmol, 26% yield) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.85 (s, 1H), 8.67-8.56 (m, 1H), 7.47-7.36 (m, 1H), 7.01-6.94 (m, 2H), 6.92-6.88 (m, 1H), 4.60-4.50 (m, 1H), 4.32-4.20 (m, 1H), 3.61 (s, 3H), 2.21-2.06 (m, 2H), 1.37 (s, 9H). LC-MS (Method C): R _t = 0.537 min; MS (ESIpos): m/z = 285.0 [M-Boc+H] ⁺ . Procedure for preparation of tert-butyl ((S)-1-amino-3-((S)-6-chloro-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)-1-oxopropan-2-yl)carbamate To a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-6-chloro-3-oxo-3,4 -dihydro-2H- benzo[b][1,4]oxazin-2-yl)propanoate (500 mg, 1.30 mmol, 1.00 eq) in methanol (2.00 mL) was added ammonium (7 M in methanol, 20.0 mL, 108 eq). After stirring the mixture at 20 °C for 16 h, the mixture was concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (SiO ₂ , Petroleum ether: (Ethyl acetate: Methanol = 10: 1) = 1: 0 to 30: 1) to give tert- butyl N-[(1S)-2-amino-1-[[(2S)-6-chloro-3-oxo-4H-1,4-benzoxazin-2- yl]methyl]-2-oxo-ethyl]carbamate (290 mg, 745 μmol, 57% yield) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.82 (s, 1H), 7.24 (s, 1H), 7.06 (s, 1H), 7.03-6.87 (m, 4H), 4.58- 4.44 (m, 1H), 4.24-4.10 (m, 1H), 2.10-2.03 (m, 2H), 1.37 (s, 9H). LC-MS (Method C): R _t = 0.470 min; MS (ESIpos): m/z = 270.0 [M-Boc+H] ⁺ . Procedure for preparation of tert-butyl ((S)-2-((S)-6-chloro-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)-1-cyanoethyl)carbamate To a solution of tert-butyl ((S)-1-amino-3-((S)-6-chloro-3-oxo-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-2-yl)- 1-oxopropan-2-yl)carbamate (290 mg, 784 μmol, 1.00 eq) in mixed solvent of dichloromethane (5.00 mL) and N,N-dimethylformamide (2.00 mL) was added (methoxycarbonyl)[(triethylazaniumyl)sulfonyl]azanide (280 mg, 1.18 mmol, 1.50 eq). After stirring at 20 °C for 2 h, the mixture was poured into water (20.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1: 0 to 1: 1) to give tert- butyl ((S)-2-((S)-6-chloro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazi n-2-yl)-1-cyanoethyl)carbamate (250 mg, 640 μmol, 82% yield) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.93 (s, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.04-6.94 (m, 2H), 6.91-6.89 (m, 1H), 4.78-4.60 (m, 2H), 2.42-2.24 (m, 2H), 1.40 (s, 9H). LC-MS (Method C): R _t = 0.539 min; MS (ESIpos): m/z = 352.0 [M+H] ⁺ . Procedure for preparation of (S)-2-amino-3-((S)-6-chloro-3-oxo-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)propanenitrile To a solution of tert-butyl ((S)-2-((S)-6-chloro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazi n-2-yl)-1- cyanoethyl)carbamate (250 mg, 711 μmol, 1.00 eq) in acetonitrile (2.00 mL) was added hydrochloric acid (4 M in dioxane, 5.00 mL) at 0 °C. After stirring at 0 °C for 0.5 h, the mixture was concentrated under vacuum to give (S)-2-amino-3-((S)-6-chloro-3-oxo-3,4-dihydro-2H-benzo[b][1, 4]oxazin-2- yl)propanenitrile (230 mg, crude, hydrochloric acid salt) as a yellow solid. Procedure for preparation of CPD0337844 - (1R,2S,5S)-N-((S)-2-((S)-6-chloro-3-oxo-3,4-dihydro- 2H-benzo[b][1,4]oxazin-2-yl)-1-cyanoethyl)-3-((S)-3,3-dimeth yl-2-((R)-tetrahydrofuran-3- carboxamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane -2-carboxamide To a solution of (1R,2S,5S)-3-((S)-3,3-dimethyl-2-((R)-tetrahydrofuran-3-carb oxamido)butanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (153 mg, 417 μmol, 1.20 eq), O-(7- azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluoroph osphate (198 mg, 521 μmol, 1.50 eq) and N,N-diisopropylethylamine (179 mg, 1.39 mmol, 242 μL, 4.00 eq) in N,N-dimethylformamide (1.00 mL) was added (S)-2-amino-3-((S)-6-chloro-3-oxo-3,4-dihydro-2H-benzo[b][1, 4]oxazin-2- yl)propanenitrile (100 mg, 347 μmol, 1.00 eq, hydrochlorate) at 0 °C. After stirring at 20 °C for 12 h, the mixture was poured into water (20.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition;column: Phenomenex luna C18150*25mm* 10 μm; mobile phase: [water (FA)-ACN];B%: 45%-75%, 7 min) to give (1R,2S,5S)-N-((S)-2-((S)-6-chloro-3-oxo-3,4-dihydro-2H-benzo [b][1,4]oxazin- 2-yl)-1-cyanoethyl)-3-((S)-3,3-dimethyl-2-((R)-tetrahydrofur an-3-carboxamido)butanoyl)-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carboxamide (97.0 mg, 162 μmol, 47% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.88 (s, 1H), 9.03 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 9.2 Hz, 1H), 7.02- 6.94 (m, 1H), 6.92-6.86 (m, 2H), 5.19-5.09 (m, 1H), 4.55 (dd, J = 10.8, 2.4 Hz, 1H), 4.30 (d, J = 9.2 Hz, 1H), 4.07 (s, 1H), 3.88-3.74 (m, 3H), 3.70-3.48 (m, 3H), 3.13-3.01 (m, 1H), 2.47-2.40(m, 1H), 2.32-2.25 (m, 1H), 1.94-1.73 (m, 2H), 1.56-1.49 (m, 1H), 1.36-1.27 (m, 1H), 1.01 (s, 3H), 0.81 (s, 3H), 0.71 (s, 9H). LC-MS (Method C): R _t = 0.521 min; MS (ESIpos): m/z = 600.4 [M+H] ⁺ . HPLC (Method S): R _t = 1.570 min; purity: 97%. SFC: dr = 94: 2: 4. Preparation of CPD0337845 Procedure for preparation of CPD0337845 - (1R,2S,5S)-N-[(1S)-2-[(2S)-6-chloro-3-oxo-4H-1,4- benzoxazin-2-yl]-1-cyano-ethyl]-3-[(2S)-3,3-dimethyl-2-(tetr ahydrofuran-3- carbonylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexa ne-2-carboxamide A mixture of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-(tetrahydrofuran-3-carbony lamino)butanoyl] -6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (150 mg, 0.409 mmol, 1.00 eq), (2R)-2-amino-3- [(2S)-6-chloro-3-oxo-4H-1,4-benzoxazin-2-yl]propanenitrile (117 mg, 0.409 mmol, 1.00 eq, hydrochloric acid), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexaflu orophosphate (233 mg, 0.614 mmol, 1.50 eq) and N,N-diisopropylethylamine (52.9 mg, 0.409 mmol, 1.00 eq) in N,N- dimethylformamide (3.00 mL) was stirred at 25°C for 12 h. The reaction mixture was poured into water (15.0 mL) and extracted with ethyl acetate (8.00 mL × 3). The combined organic layers were concentrated under vacuum to give a residue. This residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5 μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 38%-68%, 9 min) to give (1R,2S,5S)-N-[(1S)-2-[(2S)-6-chloro-3-oxo-4H-1,4-benzoxazin- 2-yl]-1-cyano-ethyl]-3-[(2S)-3,3- dimethyl-2-(tetrahydrofuran-3-carbonylamino)butanoyl]-6,6-di methyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (28.0 mg, 0.0450 mmol, 11% yield, 96% purity) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.88 (s, 1H), 9.03 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.03- 6.93 (m, 1H), 6.92-6.81 (m, 2H), 5.24-5.03 (m, 1H), 4.58-4.52 (m, 1H), 4.30 (d, J = 9.2 Hz, 1H), 4.06 (s, 1H), 3.88-3.71 (m, 3H), 3.71-3.54 (m, 3H), 3.10-3.04 (m, 1H), 2.40-2.35(m, 1H), 2.30-2.25 (m, 1H), 1.95-1.84 (m, 2H), 1.57-1.46 (m, 1H), 1.37-1.27 (m, 1H), 1.08-0.91 (m, 4H), 0.85-0.60 (m, 11H). LC-MS (Method M): R _t = 0.524 min; MS (ESIpos): m/z = 600.4 [M+H] ⁺ . HPLC (Method P): R _t = 1.590 min; purity: 97%. SFC:dr = 88: 7: 5. Example 2 – Surface Plasmon Resonance (SPR) affinity experiments Cytiva Biacore S200 and T200 machines were used for all SPR experiments. Data were collected at a constant temperature of 20°C. Mpro-10His was captured on an NTA chip using standard protocols in running buffer: 20 mM Hepes (pH 7.5), 150 mM NaCl, 50 μM EDTA, 0.05% (v/v) Tween 20 and either 1 or 3% (v/v) DMSO at 2000, 5000 or 8500 RU. The compounds were screened at concentrations ranging from 23 nM to 50 μM adjusted appropriately for each compound, injecting from the lowest to highest concentrations. Scrubber 2 (Biologic software) was used to process and analyse SPR data. Kinetics were fitted using a 1:1 binding model with local Rmax for each concentration where required. Data for the inhibitors were referenced to those for a blank surface and blank injections to normalize for non-specific binding and drift. A DMSO calibration was run to remove excluded volume effect of binding responses between reference and target surface (see results Table 2 below). Example 3 – Inhibition Activity against SARS-CoV-2 Mpro Evaluation of the activity of test compounds against SARS-CoV-2 Mpro in the enzymatic assay. Compounds are assayed at 10 concentrations, in duplicate for the IC50 determination. The C-His6- tagged COVID-19 Mpro (NC_045512) was cloned, expressed in E. coli and purified by WuXi. The substrate of Dabcyl- KTSAVLQǁSGFRKM -(Edans) was synthesized. The assay buffer contains 20 mM of Tris-HCl (pH 7.3), 100 mM of NaCl, 1 mM of EDTA, 5mM of TCEP and 0.1%BSA. The final concentrations of the Mpro protein and substrate are 25 nM and 25 μM, respectively, in the Mpro enzymatic assay. 10 Doses: Compounds are 3-fold serially diluted for 10 doses and added to an assay plate (384w format) using ECHO, in duplicate wells. 25 μL of 30 nM of Mpro protein is added to an assay plate containing compounds using a Multidrop. The compounds and Mpro protein are pre-incubated at room temperature 30min. Then 5 μL of 150 μM of substrate is added to an assay plate using a Multidrop. The final concentrations of Mpro and substrate are 25 nM and 25 μM respectively. For 100% inhibition control (HPE, hundred percent effect), no enzyme and compound are added. For no inhibition control (ZPE, zero percent effect), no compound is added. The final DMSO concentration is 1%. Each activity testing point has a relevant background control to normalize the fluorescence interference of compound. After 60 min incubation at 30°C, the fluorescence signal (RFU) is detected using a microplate reader M2e (SpectraMax) at Ex/Em=340nm/490nm. The inhibition activity is calculated using the formula below, IC50 values were calculated using the Inhibition% data. Inhibition data for compounds of the disclosure are shown in Table 2 below. IC50 values of compounds are calculated with the GraphPad Prism software using the nonlinear regression model of log(inhibitor) vs. response -- Variable slope (four parameters). Example 4 – Mpro Inhibition and Binding Measurements The concentrations are given in ranges, wherein A refers to an IC50 value against SARS-CoV-2 Mpro or and SPR Kd value of below 1,000 nM, B refers to an IC50 value between 1,000 and 10,000 nM, and C refers to an IC50 value of above 10,000 nM.

Table 2: Mpro biochemical data for exemplary compounds of the disclosure Example 5 – Broad-spectrum Activity In the below table IC50 values in the same concentration ranges as provided for Table 2 are provided against various viruses for a selection of compounds according to the disclosure. The results demonstrate the surprising potential broad spectrum coronavirus activity of compounds according to this disclosure. Table 3: Mpro biochemical data for exemplary compounds of the disclosure against a range of viral targets. CLAUSES Alternative expressions of the inventive concept are set out in each of the following numbered clauses: A1. A method of treating or preventing a viral infection in a subject in need thereof, comprising administering to the subject an effective amount of the compound of Formula (I) including any diastereomers and enantiomers, or a pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof: (I), wherein R ¹ is monocyclic or bicyclic cycloalkyl, aryl, heteroaryl or combinations thereof, any of which may have one more or substituents, typically R ¹ may be a five or six membered cycloalkyl or heteroaryl, optionally having one or more substituents, wherein any such monocyclic or bicyclic cycloalkyl, aryl, heteroaryl or combination thereof may be directly connected to the remaining compound (I) or connected via an alkyl linker such as -CH2- or -CH2(CH2)-; R ^1’ is nitrile (CN); R ^1a is absent, hydrogen, deuterium or C _1-6 alkyl; R ² is hydrogen or R ² and R ⁶ taken together with the nitrogen and carbon atoms to which they are attached form a pyrrolidine or piperidine ring, which is optionally substituted with one to four R ^2a ; R ^2a at each occurrence may be independently selected from the group consisting of fluoro, hydroxy, C ₁ -C ₆ alkyl optionally substituted with one to three fluoro, and C ₁ -C ₆ alkoxy optionally substituted with one to three fluoro; or two R ^2a groups when attached to adjacent carbons and taken together with the carbons to which they are attached form a fused C ₃ -C ₆ cycloalkyl which is optionally substituted with one to four R ^2b ; or two R ^2a groups when attached to the same carbon and taken together with the carbon to which they are attached form a spiro C ₃ -C ₆ cycloalkyl which is optionally substituted with one to four R ^2b ; R ^2b at each occurrence is optionally independently selected from fluoro, hydroxy, C ₁ -C ₃ alkyl optionally independently substituted with one to three fluoro or hydroxy, and C ₁ -C ₃ alkoxy optionally independently substituted with one to three fluoro or hydroxy; R ³ is selected from the group consisting of C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, (C ₁ -C ₆ alkoxy)-C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, aryl, heteroaryl optionally fused with a 5- or 6-membered heteroaryl or phenyl, (C ₃ - C ₁₂ cycloalkyl)-C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkoxy, (C ₃ -C ₁₂ cycloalkoxy)-C ₁ -C ₆ alkyl, 4- to 12-membered heterocycloalkyl which is optionally fused with a 5- to 6-membered heteroaryl or phenyl and wherein said heterocycloalkyl comprises one to four heteroatoms independently selected from N, O and S(O)n; (4- to 12-membered heterocycloalkyl)-C ₁ -C ₆ alkyl wherein said heterocycloalkyl moiety comprises one to four heteroatoms independently selected from N, O and S(O)n; C ₆ -C ₁₀ aryl optionally fused with a C4-C ₆ cycloalkyl or a 4- to 7-membered heterocycloalkyl; (C ₆ -C ₁₀ aryl)-C ₁ -C ₆ alkyl; 5- to 10-membered heteroaryl comprising one to five heteroatoms independently selected from N, O and S, which is optionally fused with a C ₅ -C ₆ cycloalkyl; (5- to 10-membered heteroaryl)-C ₁ -C ₆ alkyl wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S; (C ₆ - C ₁₀ aryl)-(5- to 10-membered heteroaryl)- wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S, (5- to 10-membered heteroaryloxy)-C ₁ -C ₆ alkyl wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S; (5- to 6-membered heteroaryl)-(5- to 6-membered heteroaryl)- wherein each heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; (4- to 7-membered heterocycloalkyl)-(5- to 6-membered heteroaryl)- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n and the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; (5- to 6-membered heteroaryl)-(4- to 7-membered heterocycloalkyl)- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n and the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; wherein each R ³ group is optionally substituted with one to five R ⁴ ; and n at each occurrence is independently selected from 0, 1 and 2; R ⁴ at each occurrence is independently selected from the group consisting of oxo, halo, hydroxy, cyano, phenyl, benzyl, amino, (C ₁ -C ₆ alkyl)amino optionally substituted with one to five fluoro, di(C ₁ -C ₆ alkyl)amino optionally substituted with one to ten fluoro, C ₁ -C ₆ alkyl optionally substituted with one to five fluoro, (5- to 6-membered heteroaryl)amino- wherein the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; (4- to 7-membered heterocycloalkyl)amino- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n; C ₁ -C ₆ alkoxy optionally substituted with one to five fluoro; C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl optionally substituted with one to five fluoro; C ₃ -C ₆ cycloalkyl optionally substituted with one to three fluoro or C ₁ -C ₃ alkyl; C ₁ -C ₆ alkyl-C(O)NH- optionally substituted with one to five fluoro; C ₁ -C ₆ alkyl-OC(O)NH- optionally substituted with one to five fluoro or with one R ⁵ ; C ₁ - C ₆ alkyl-NHC(O)NH- optionally substituted with one to five fluoro or with one R ⁵ ; C ₁ -C ₆ alkyl-S(O)2NH- optionally substituted with one to five fluoro or with one R ⁵ ; C ₁ -C ₆ alkyl-C(O)- optionally substituted with one to five fluoro or with one R ⁵ ; C ₁ -C ₆ alkyl-S(O)n- optionally substituted with one to five fluoro or with one R ⁵ ; and n at each occurrence is independently selected from 0, 1 and 2; R ⁵ is selected from phenyl, phenoxy, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkoxy, 4- to 7- membered heterocycloalkyl wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n, or a 5- or 6-membered heteroaryl wherein the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; wherein each R ⁵ is optionally independently substituted with one to three halo, C ₁ -C ₃ alkyl and C ₁ -C ₃ alkoxy; and n at each occurrence is independently selected from 0, 1 and 2. A2. The method of Clause A1, wherein the viral infection is coronavirus. A3. The method of Clause A1 or Clause A2, wherein the viral infection is SARS, MERS, SARS- CoV-2 (COVID-19). A4. The method of any of Clauses A1 to A3, wherein the compound is an inhibitor of the virus- encoded protease M ^pro . A5. The method of any of Clauses A1 to A4, wherein the compound is administered orally, topically, by inhalation, by intranasal administration, or systemically by intravenous, intraperitoneal, subcutaneous, or intramuscular injection. A6. The method of any of Clauses A1 to A5, wherein the method comprises administering the compound according to formula (I) in combination with one or more additional therapeutic agent. A7. The method of any of Clauses A1 to A6, wherein the compound according to Formula (I) and the one or more additional therapeutic agent are administered simultaneously, sequentially or separately. A8. The methods of Clause A6 or Clause A7, wherein the one or more additional therapeutic agent is selected from at least one additional antiviral agent, at least one IL-1 inhibitor or combinations thereof. A9. The method of Clause A8, wherein the at least one additional antiviral agent is selected from an inhibitor of viral RNA-dependent RNA polymerase, an inhibitor of virus-encoded protease that affects processing of a viral RNA-dependent RNA polymerase, an inhibitor of coronavirus binding or release from infected cells, an inhibitor of virus binding to a specific cell surface receptor, an inhibitor of receptor- induced conformational changes in virus spike glycoprotein that are associated with virus entry, or combinations thereof. A10. The method of any of Clauses A1 to A9, wherein the compound of Formula (I) is defined according to this disclosure, including any embodiment disclosed herein or any of the appended claims. A11. The method of any of Clauses A1 to A10, wherein the compound of Formula (I) is a compound of Table 1A, 1B and/or 1C. A12. A pharmaceutical composition comprising: a compound of Formula (I) including any diastereomers and enantiomers thereof or a pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof: wherein R ¹ is monocyclic or bicyclic cycloalkyl, aryl, heteroaryl or combinations thereof, any of which may have one more or substituents, typically R ¹ may be a five or six membered cycloalkyl or heteroaryl, optionally having one or more substituents, wherein any such monocyclic or bicyclic cycloalkyl, aryl, heteroaryl or combination thereof may be directly connected to the remaining compound (I) or connected via an alkyl linker such as -CH ₂ - or -CH ₂ (CH ₂ )-; R ^1’ is nitrile (CN); R ^1a may be absent, hydrogen, deuterium or C _1-6 alkyl; R ² is hydrogen or R ² and R ⁶ taken together with the nitrogen and carbon atoms to which they are attached form a pyrrolidine or piperidine ring, which is optionally substituted with one to four R ^2a ; R ^2a at each occurrence may be independently selected from the group consisting of fluoro, hydroxy, C ₁ - C ₆ alkyl optionally substituted with one to three fluoro, and C ₁ -C ₆ alkoxy optionally substituted with one to three fluoro; or two R ^2a groups when attached to adjacent carbons and taken together with the carbons to which they are attached form a fused C ₃ -C ₆ cycloalkyl which is optionally substituted with one to four R ^2b ; or two R ^2a groups when attached to the same carbon and taken together with the carbon to which they are attached form a spiro C ₃ -C ₆ cycloalkyl which is optionally substituted with one to four R ^2b ; R ^2b at each occurrence is optionally independently selected from fluoro, hydroxy, C ₁ -C ₃ alkyl optionally independently substituted with one to three fluoro or hydroxy, and C ₁ -C ₃ alkoxy optionally independently substituted with one to three fluoro or hydroxy; R ³ is selected from the group consisting of C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, (C ₁ -C ₆ alkoxy)-C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, aryl, heteroaryl optionally fused with a 5- or 6-membered heteroaryl or phenyl, (C ₃ - C ₁₂ cycloalkyl)-C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkoxy, (C ₃ -C ₁₂ cycloalkoxy)-C ₁ -C ₆ alkyl, 4- to 12-membered heterocycloalkyl which is optionally fused with a 5- to 6-membered heteroaryl or phenyl and wherein said heterocycloalkyl comprises one to four heteroatoms independently selected from N, O and S(O)n; (4- to 12-membered heterocycloalkyl)-C ₁ -C ₆ alkyl wherein said heterocycloalkyl moiety comprises one to four heteroatoms independently selected from N, O and S(O)n; C ₆ -C ₁₀ aryl optionally fused with a C ₄ -C ₆ cycloalkyl or a 4- to 7-membered heterocycloalkyl; (C ₆ -C ₁₀ aryl)-C ₁ -C ₆ alkyl; 5- to 10-membered heteroaryl comprising one to five heteroatoms independently selected from N, O and S, which is optionally fused with a C ₅ -C ₆ cycloalkyl; (5- to 10-membered heteroaryl)-C ₁ -C ₆ alkyl wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S; (C ₆ - C ₁₀ aryl)-(5- to 10-membered heteroaryl)- wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S; (5- to 10-membered heteroaryloxy)-C ₁ -C ₆ alkyl wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S; (5- to 6-membered heteroaryl)-(5- to 6-membered heteroaryl)- wherein each heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; (4- to 7-membered heterocycloalkyl)-(5- to 6-membered heteroaryl)- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n and the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; (5- to 6-membered heteroaryl)-(4- to 7-membered heterocycloalkyl)- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n and the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; wherein each R ³ group is optionally substituted with one to five R ⁴ ; and n at each occurrence is independently selected from 0, 1 and 2; R ⁴ at each occurrence may be independently selected from the group consisting of oxo, halo, hydroxy, cyano, phenyl, benzyl, amino, (C ₁ -C ₆ alkyl)amino optionally substituted with one to five fluoro, di(C ₁ -C ₆ alkyl)amino optionally substituted with one to ten fluoro; C ₁ -C ₆ alkyl optionally substituted with one to five fluoro; (5- to 6-membered heteroaryl)amino- wherein the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; (4- to 7-membered heterocycloalkyl)amino- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n; C ₁ -C ₆ alkoxy optionally substituted with one to five fluoro; C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl optionally substituted with one to five fluoro; C ₃ -C ₆ cycloalkyl optionally substituted with one to three fluoro or C ₁ -C ₃ alkyl; C ₁ -C ₆ alkyl-C(O)NH- optionally substituted with one to five fluoro; C ₁ -C ₆ alkyl-OC(O)NH- optionally substituted with one to five fluoro or with one R ⁵ ; C ₁ - C ₆ alkyl-NHC(O)NH- optionally substituted with one to five fluoro or with one R ⁵ ; C ₁ -C ₆ alkyl-S(O)2NH- optionally substituted with one to five fluoro or with one R ⁵ ; C ₁ -C ₆ alkyl-C(O)- optionally substituted with one to five fluoro or with one R ⁵ ; C ₁ -C ₆ alkyl-S(O)n- optionally substituted with one to five fluoro or with one R ⁵ ; and n at each occurrence is independently selected from 0, 1 and 2; R ⁵ is selected from phenyl, phenoxy, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkoxy, 4- to 7- membered heterocycloalkyl wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n; or a 5- or 6-membered heteroaryl wherein the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; wherein each R ⁵ is optionally independently substituted with one to three halo, C ₁ -C ₃ alkyl and C ₁ -C ₃ alkoxy; and n at each occurrence is independently selected from 0, 1 and 2. A13. The pharmaceutical composition of Clause A12, wherein, R ¹ is selected from the following monocyclic or bicyclic cycloalkyl, aryl, heteroaryl structures: pyridine, δ-lactam, -γ-lactam, cyclohexyl, cyclopentyl, δ-lactone, cyclobutyl optionally fused to phenyl, pyrazole, thiazole, triazole, pyridine, cyclopentandiene; and optionally substituted with C ₁ -C ₃ alkyl, wherein said C ₁ -C ₃ alkyl optionally carries one to four heteroatoms independently selected from N, O and S. A14. The pharmaceutical composition of Clause A12 or Clause A13, wherein, R ¹ is selected any one of the following structures:

A15. The pharmaceutical composition of any of Clauses A12 to A14, wherein R ¹ is isoquinoline, quinoline, CH2-δ-lactam, CH2-γ-lactam or CH2-pyridine. A16. The pharmaceutical composition of any of Clauses A12 to A15, wherein R ³ is selected from any one of the following structures:

A17. The pharmaceutical composition of any of Clauses A12 to A16, wherein, R ³ is selected from one of the following structures: A18. The pharmaceutical composition of any of Clauses A12 to A17, wherein, R ⁶ and R ² together with the nitrogen and carbon respectively to which they attach, form one of the following structures: A19. The pharmaceutical composition of any of Clauses A12 to A18, wherein, R ⁶ and R ² together with the nitrogen and carbon to which they are attached may form one of the following structures: A20. The pharmaceutical composition of any of Clauses A12 to A19, wherein R ^1a is hydrogen or methyl. A21. The pharmaceutical composition of any of Clauses A12 to A20, wherein, the compound of formula (I) has the following structures: wherein R ¹ is selected from the group consisting of: monocyclic or bicyclic cycloalkyl, aryl, heteroaryl or combinations thereof. A22. The pharmaceutical composition of any of Clauses A12 to A20, wherein, the compound of formula (I) has the following structures: wherein R ¹ is selected from the group consisting of: monocyclic or bicyclic cycloalkyl, aryl, heteroaryl or combinations thereof. A23. The pharmaceutical composition according to any of Clauses A12 to A22, wherein the compound is a compound of Table 1. A24. The pharmaceutical composition of any of Clauses A12 to A23, for use in the treatment or prevention of a viral infection. A25. The pharmaceutical composition for use according to Clause A24, wherein the viral infection is coronavirus. A26. The pharmaceutical composition for use according to Clause A24 or Clause A25, wherein the viral infection is selected from the group consisting of: SARS, MERS, SARS-CoV-2 (COVID-19) or combinations thereof. A27. The pharmaceutical composition for use according to any of Clauses A24 to A26, wherein the use is in a method comprising administering the pharmaceutical composition comprising a compound according to Formula (I) in combination with one or more additional therapeutic agent. Still further expressions of the inventive concept are set out in each of the following numbered clauses: B1. A compound of Formula (I) including any diastereomers and enantiomers thereof or a pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof: (I), wherein R ¹ is monocyclic or bicyclic cycloalkyl, aryl, heteroaryl or combinations thereof, any of which may have one more or substituents, typically R ¹ may be a five or six membered cycloalkyl or heteroaryl, optionally having one or more substituents, wherein any such monocyclic or bicyclic cycloalkyl, aryl, heteroaryl or combination thereof may be directly connected to the remaining compound (I) or connected via an alkyl linker such as -CH ₂ - or -CH ₂ (CH ₂ )-; R ^1’ is nitrile (CN); R ^1a is absent, hydrogen, deuterium or C _1-6 alkyl; R ² is hydrogen or R ² and R ⁶ taken together with the nitrogen and carbon atoms to which they are attached form a pyrrolidine or piperidine ring, which is optionally substituted with one to four R ^2a ; R ^2a at each occurrence may be independently selected from the group consisting of fluoro, hydroxy, C ₁ -C ₆ alkyl optionally substituted with one to three fluoro, and C ₁ -C ₆ alkoxy optionally substituted with one to three fluoro; or two R ^2a groups when attached to adjacent carbons and taken together with the carbons to which they are attached form a fused C ₃ -C ₆ cycloalkyl which is optionally substituted with one to four R ^2b ; or two R ^2a groups when attached to the same carbon and taken together with the carbon to which they are attached form a spiro C ₃ -C ₆ cycloalkyl which is optionally substituted with one to four R ^2b ; R ^2b at each occurrence is optionally independently selected from fluoro, hydroxy, C ₁ -C ₃ alkyl optionally independently substituted with one to three fluoro or hydroxy, and C ₁ -C ₃ alkoxy optionally independently substituted with one to three fluoro or hydroxy; R ³ is selected from the group consisting of C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, (C ₁ -C ₆ alkoxy)-C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, aryl, heteroaryl optionally fused with a 5- or 6-membered heteroaryl or phenyl, (C ₃ - C ₁₂ cycloalkyl)-C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkoxy, (C ₃ -C ₁₂ cycloalkoxy)-C ₁ -C ₆ alkyl, 4- to 12-membered heterocycloalkyl which is optionally fused with a 5- to 6-membered heteroaryl or phenyl and wherein said heterocycloalkyl comprises one to four heteroatoms independently selected from N, O and S(O)n; (4- to 12-membered heterocycloalkyl)-C ₁ -C ₆ alkyl wherein said heterocycloalkyl moiety comprises one to four heteroatoms independently selected from N, O and S(O)n; C ₆ -C ₁₀ aryl optionally fused with a C ₄ -C ₆ cycloalkyl or a 4- to 7-membered heterocycloalkyl; (C ₆ -C ₁₀ aryl)-C ₁ -C ₆ alkyl; 5- to 10-membered heteroaryl comprising one to five heteroatoms independently selected from N, O and S, which is optionally fused with a C ₅ -C ₆ cycloalkyl; (5- to 10-membered heteroaryl)-C ₁ -C ₆ alkyl wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S; (C ₆ - C ₁₀ aryl)-(5- to 10-membered heteroaryl)- wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S, (5- to 10-membered heteroaryloxy)-C ₁ -C ₆ alkyl wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S; (5- to 6-membered heteroaryl)-(5- to 6-membered heteroaryl)- wherein each heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; (4- to 7-membered heterocycloalkyl)-(5- to 6-membered heteroaryl)- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n and the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; (5- to 6-membered heteroaryl)-(4- to 7-membered heterocycloalkyl)- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n and the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; wherein each R ³ group is optionally substituted with one to five R ⁴ ; and n at each occurrence is independently selected from 0, 1 and 2; R ⁴ at each occurrence is independently selected from the group consisting of oxo, halo, hydroxy, cyano, phenyl, benzyl, amino, (C ₁ -C ₆ alkyl)amino optionally substituted with one to five fluoro, di(C ₁ -C ₆ alkyl)amino optionally substituted with one to ten fluoro, C ₁ -C ₆ alkyl optionally substituted with one to five fluoro, (5- to 6-membered heteroaryl)amino- wherein the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; (4- to 7-membered heterocycloalkyl)amino- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n; C ₁ -C ₆ alkoxy optionally substituted with one to five fluoro; C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl optionally substituted with one to five fluoro; C ₃ -C ₆ cycloalkyl optionally substituted with one to three fluoro or C ₁ -C ₃ alkyl; C ₁ -C ₆ alkyl-C(O)NH- optionally substituted with one to five fluoro; C ₁ -C ₆ alkyl-OC(O)NH- optionally substituted with one to five fluoro or with one R ⁵ ; C ₁ - C ₆ alkyl-NHC(O)NH- optionally substituted with one to five fluoro or with one R ⁵ ; C ₁ -C ₆ alkyl-S(O)2NH- optionally substituted with one to five fluoro or with one R ⁵ ; C ₁ -C ₆ alkyl-C(O)- optionally substituted with one to five fluoro or with one R ⁵ ; C ₁ -C ₆ alkyl-S(O)n- optionally substituted with one to five fluoro or with one R ⁵ ; and n at each occurrence is independently selected from 0, 1 and 2; R ⁵ is selected from phenyl, phenoxy, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkoxy, 4- to 7- membered heterocycloalkyl wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n, or a 5- or 6-membered heteroaryl wherein the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; wherein each R ⁵ is optionally independently substituted with one to three halo, C ₁ -C ₃ alkyl and C ₁ -C ₃ alkoxy; and n at each occurrence is independently selected from 0, 1 and 2. B2. The compound of Clause B1, wherein, R ¹ is selected from the following monocyclic or bicyclic cycloalkyl, aryl, heteroaryl structures: pyridine, δ-lactam, γ-lactam, cyclohexyl, cyclopentyl, δ-lactone, cyclobutyl optionally fused to phenyl, pyrazole, thiazole, triazole, pyridine, cyclopentandiene; and wherein said R ¹ is optionally substituted with C ₁ -C ₃ alkyl which optionally carries one to four heteroatoms independently selected from N, O and S. B3. The compound of Clause B1 or Clause B2, wherein, R ¹ is selected any one of the following structures: structures: B4. The compound of any of Clauses B1 to B3, wherein R ¹ is isoquinoline, quinoline, CH2-δ-lactam, CH2-γ-lactam or CH2-pyridine. B5. The compound of any of Clauses B1 to B4, wherein R ³ is selected from any one of the following structures: B6. The compound of any of Clauses B1 to B5, wherein, R ³ is selected from one of the following structures: B7. The compound of any of Clauses B1 to B6, wherein, R ⁶ and R ² together with the nitrogen and carbon respectively to which they attach, form one of the following structures: B8. The compound of any of Clauses B1 to B7, wherein, R ⁶ and R ² together with the nitrogen and carbon to which they are attached may form one of the following structures: B9. The compound of any of Clauses B1 to B8, wherein R ^1a is hydrogen or methyl. B10. The compound of Clauses B1 to B9, wherein, the compound of formula (I) has the following structure: (II), wherein R ¹ is selected from the group consisting of: monocyclic or bicyclic cycloalkyl, aryl, heteroaryl or combinations thereof. B11. The compound of Clauses B1 to B9, wherein, the compound of formula (I) has the following structures: wherein R ¹ is selected from the group consisting of: monocyclic or bicyclic cycloalkyl, aryl, heteroaryl or combinations thereof. B12. A compound of any of Clauses B1 to B11, wherein the compound is selected from a compound in Table 1A, 1B or 1C. B13. The compound of any of Clauses B1 to B12 for use in the treatment of a viral infection. B14. The compound for use according to Clause B13, wherein the viral infection is coronavirus. B15. The compound for use according to Clause B13 or Clause B14, wherein the virus is selected from the group consisting of: SARS, MERS, SARS-CoV-2 (COVID-19) or combinations thereof. B16. The compound for use according to any of Clauses B13 to B15, wherein the compound is an inhibitor of the virus-encoded protease M ^pro . B17. The compound for use according to any of Clauses B13 to B16, wherein the use is in a method comprising administering the compound orally, topically, by inhalation, by intranasal administration, or systemically by intravenous, intraperitoneal, subcutaneous, or intramuscular injection. B18. The compound for use according to any of Clauses B13 to B17, wherein the use is in a method comprising administering the compound according to formula (I) in combination with one or more additional therapeutic agent. B19. The compound for use according to Clause B18, wherein the one or more additional therapeutic agent is selected from at least one additional antiviral agent. B20. The compound for use according to Clause B19, wherein the at least one additional antiviral agent is selected from an inhibitor of viral RNA-dependent RNA polymerase, an inhibitor of virus- encoded protease that affects processing of a viral RNA-dependent RNA polymerase, an inhibitor of coronavirus binding or release from infected cells, an inhibitor of virus binding to a specific cell surface receptor, an inhibitor of receptor-induced conformational changes in virus spike glycoprotein that are associated with virus entry, or combinations thereof. B21. The compound for use according to any of Clauses B18 to B20, wherein the administering comprising administering the compound according to formula (I), simultaneously, sequentially or separately from the one or more additional therapeutic agent. B22. A pharmaceutical composition comprising: a compound of Formula (I) including any diastereomers and enantiomers thereof or a pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof: wherein R ¹ is monocyclic or bicyclic cycloalkyl, aryl, heteroaryl or combinations thereof, any of which may have one more or substituents, typically R ¹ may be a five or six membered cycloalkyl or heteroaryl, optionally having one or more substituents, wherein any such monocyclic or bicyclic cycloalkyl, aryl, heteroaryl or combination thereof may be directly connected to the remaining compound (I) or connected via an alkyl linker such as -CH2- or -CH2(CH2)-; R ^1’ is nitrile (CN); R ^1a may be absent, hydrogen, deuterium or C _1-6 alkyl; R ² is hydrogen or R ² and R ⁶ taken together with the nitrogen and carbon atoms to which they are attached form a pyrrolidine or piperidine ring, which is optionally substituted with one to four R ^2a ; R ^2a at each occurrence may be independently selected from the group consisting of fluoro, hydroxy, C ₁ - C ₆ alkyl optionally substituted with one to three fluoro, and C ₁ -C ₆ alkoxy optionally substituted with one to three fluoro; or two R ^2a groups when attached to adjacent carbons and taken together with the carbons to which they are attached form a fused C ₃ -C ₆ cycloalkyl which is optionally substituted with one to four R ^2b ; or two R ^2a groups when attached to the same carbon and taken together with the carbon to which they are attached form a spiro C ₃ -C ₆ cycloalkyl which is optionally substituted with one to four R ^2b ; R ^2b at each occurrence is optionally independently selected from fluoro, hydroxy, C ₁ -C ₃ alkyl optionally independently substituted with one to three fluoro or hydroxy, and C ₁ -C ₃ alkoxy optionally independently substituted with one to three fluoro or hydroxy; R ³ is selected from the group consisting of C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, (C ₁ -C ₆ alkoxy)-C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, aryl, heteroaryl optionally fused with a 5- or 6-membered heteroaryl or phenyl, (C ₃ - C ₁₂ cycloalkyl)-C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkoxy, (C ₃ -C ₁₂ cycloalkoxy)-C ₁ -C ₆ alkyl, 4- to 12-membered heterocycloalkyl which is optionally fused with a 5- to 6-membered heteroaryl or phenyl and wherein said heterocycloalkyl comprises one to four heteroatoms independently selected from N, O and S(O)n; (4- to 12-membered heterocycloalkyl)-C ₁ -C ₆ alkyl wherein said heterocycloalkyl moiety comprises one to four heteroatoms independently selected from N, O and S(O)n; C ₆ -C ₁₀ aryl optionally fused with a C ₄ -C ₆ cycloalkyl or a 4- to 7-membered heterocycloalkyl; (C ₆ -C ₁₀ aryl)-C ₁ -C ₆ alkyl; 5- to 10-membered heteroaryl comprising one to five heteroatoms independently selected from N, O and S, which is optionally fused with a C ₅ -C ₆ cycloalkyl; (5- to 10-membered heteroaryl)-C ₁ -C ₆ alkyl wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S; (C ₆ - C ₁₀ aryl)-(5- to 10-membered heteroaryl)- wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S; (5- to 10-membered heteroaryloxy)-C ₁ -C ₆ alkyl wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S; (5- to 6-membered heteroaryl)-(5- to 6-membered heteroaryl)- wherein each heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; (4- to 7-membered heterocycloalkyl)-(5- to 6-membered heteroaryl)- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n and the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; (5- to 6-membered heteroaryl)-(4- to 7-membered heterocycloalkyl)- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n and the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; wherein each R ³ group is optionally substituted with one to five R ⁴ ; and n at each occurrence is independently selected from 0, 1 and 2; R ⁴ at each occurrence may be independently selected from the group consisting of oxo, halo, hydroxy, cyano, phenyl, benzyl, amino, (C ₁ -C ₆ alkyl)amino optionally substituted with one to five fluoro, di(C ₁ -C ₆ alkyl)amino optionally substituted with one to ten fluoro; C ₁ -C ₆ alkyl optionally substituted with one to five fluoro; (5- to 6-membered heteroaryl)amino- wherein the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; (4- to 7-membered heterocycloalkyl)amino- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n; C ₁ -C ₆ alkoxy optionally substituted with one to five fluoro; C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl optionally substituted with one to five fluoro; C ₃ -C ₆ cycloalkyl optionally substituted with one to three fluoro or C ₁ -C ₃ alkyl; C ₁ -C ₆ alkyl-C(O)NH- optionally substituted with one to five fluoro; C ₁ -C ₆ alkyl-OC(O)NH- optionally substituted with one to five fluoro or with one R ⁵ ; C ₁ - C ₆ alkyl-NHC(O)NH- optionally substituted with one to five fluoro or with one R ⁵ ; C ₁ -C ₆ alkyl-S(O)2NH- optionally substituted with one to five fluoro or with one R ⁵ ; C ₁ -C ₆ alkyl-C(O)- optionally substituted with one to five fluoro or with one R ⁵ ; C ₁ -C ₆ alkyl-S(O)n- optionally substituted with one to five fluoro or with one R ⁵ ; and n at each occurrence is independently selected from 0, 1 and 2; R ⁵ is selected from phenyl, phenoxy, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkoxy, 4- to 7- membered heterocycloalkyl wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n; or a 5- or 6-membered heteroaryl wherein the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; wherein each R ⁵ is optionally independently substituted with one to three halo, C ₁ -C ₃ alkyl and C ₁ -C ₃ alkoxy; and n at each occurrence is independently selected from 0, 1 and 2. B23. The pharmaceutical composition of Clause B22, wherein the compound is defined according to any of Clauses B2 to B12. B24. The pharmaceutical composition of Clause B22 or Clause B23, for use in the treatment or prevention of a viral infection. B25. The pharmaceutical composition for use according to Clause B23, wherein the use is defined according to any of Clauses B13 to B21. C ₁ . A method of treating, preventing or alleviating a viral infection in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of Formula (I) including any diastereomers and enantiomers, or a pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof: (I), wherein R ¹ is monocyclic or bicyclic cycloalkyl, heterocycloalkyl, aryl, heteroaryl or combinations thereof, any of which may have one more or substituents, wherein any such monocyclic or bicyclic cycloalkyl, aryl, heteroaryl or combination thereof may be directly connected to the remaining compound (I) or connected via a C ₁ -C ₃ alkylene linker, wherein the alkylene linker may optionally be substituted with one to three R ⁹ ; R ^1’ is nitrile (CN); R ^1a is absent, hydrogen, deuterium or C ₁ -6 alkyl; R ² is hydrogen; R ⁶ is selected from the group consisting of C ₁ -C ₆ alkyl which is optionally substituted with a cyano or with one to five fluoro; C2-C ₆ alkynyl; and (C ₃ -C ₆ cycloalkyl)-C ₁ -C ₃ alkyl which is optionally substituted with one or two substituents selected from trifluoromethyl and C ₁ -C ₃ alkyl, wherein the C ₁ - C ₃ alkyl is optionally substituted with one to five fluoro; or R ² and R ⁶ taken together with the nitrogen and carbon atoms to which they are attached form a pyrrolidine or piperidine ring, which is optionally substituted with one to four R ^2a ; R ^2a at each occurrence may be independently selected from the group consisting of fluoro, hydroxy, C ₁ -C ₆ alkyl optionally substituted with one to three fluoro, and C ₁ -C ₆ alkoxy optionally substituted with one to three fluoro; or two R ^2a groups when attached to adjacent carbon atoms and taken together with the carbon atoms to which they are attached form a C ₃ -C ₆ cycloalkyl which is optionally substituted with one to four R ^2b ; or two R ^2a groups when attached to the same carbon and taken together with the carbon to which they are attached form a C ₃ -C ₆ cycloalkyl which is optionally substituted with one to four R ^2b ; R ^2b at each occurrence is optionally independently selected from fluoro, hydroxy, C ₁ -C ₃ alkyl optionally independently substituted with one to three fluoro or hydroxy, and C ₁ -C ₃ alkoxy optionally independently substituted with one to three fluoro or hydroxy, or two R ^2b groups when attached to the same carbon and taken together with the carbon to which they are attached form a C ₃ -C ₆ cycloalkyl which is optionally substituted with one to four R ⁹ ; R ³ is selected from the group consisting of straight or branched C ₁ -C ₈ alkyl, straight or branched C ₁ -C ₈ alkoxy, straight or branched (C ₁ -C ₆ alkoxy)-C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, aryl, heteroaryl optionally fused with a 5- or 6-membered heteroaryl or phenyl, (C ₃ -C ₁₂ cycloalkyl)-C ₁ -C ₆ alkyl, C ₃ - C ₁₂ cycloalkoxy, (C ₃ -C ₁₂ cycloalkoxy)-C ₁ -C ₆ alkyl, 4- to 12-membered heterocycloalkyl which is optionally fused with a 5- to 6-membered heteroaryl or phenyl and wherein said heterocycloalkyl comprises one to four heteroatoms independently selected from N, O and S(O)n; (4- to 12-membered heterocycloalkyl)-C ₁ -C ₆ alkyl wherein said heterocycloalkyl moiety comprises one to four heteroatoms independently selected from N, O and S(O)n; C ₆ -C ₁₀ aryl optionally fused with a C ₄ -C ₆ cycloalkyl or a 4- to 7-membered heterocycloalkyl; (C ₆ -C ₁₀ aryl)-C ₁ -C ₆ alkyl; 5- to 10-membered heteroaryl comprising one to five heteroatoms independently selected from N, O and S, which is optionally fused with a C5- C ₆ cycloalkyl; (5- to 10-membered heteroaryl)-C ₁ -C ₆ alkyl wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S; (C ₆ -C ₁₀ aryl)-(5- to 10-membered heteroaryl)- wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S, (5- to 10-membered heteroaryloxy)-C ₁ -C ₆ alkyl wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S; (5- to 6-membered heteroaryl)-(5- to 6-membered heteroaryl)- wherein each heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; (4- to 7-membered heterocycloalkyl)-(5- to 6- membered heteroaryl)- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n and the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; (5- to 6-membered heteroaryl)-(4- to 7- membered heterocycloalkyl)- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n and the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; wherein each R ³ group is optionally substituted with one to five R ⁴ ; and n at each occurrence is independently selected from 0, 1 and 2; R ⁴ at each occurrence is independently selected from the group consisting of oxo, halo, hydroxy, cyano, phenyl, benzyl, amino, (C ₁ -C ₆ alkyl)amino optionally substituted with one to five fluoro or with one to three R ⁹ , di(C ₁ -C ₆ alkyl)amino optionally substituted with one to ten fluoro or with one to three R ⁹ , C ₁ -C ₆ alkyl optionally substituted with one to five fluoro or with one to three R ⁹ , (5- to 6- membered heteroaryl)amino- wherein the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S and wherein the heteroaryl is optionally substituted with one to three R ⁹ ; (4- to 7-membered heterocycloalkyl)amino- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n and wherein the heterocycloalkyl is optionally substituted with one to three R ⁹ ; C ₁ -C ₆ alkoxy optionally substituted with one to five fluoro or with one to three R ⁹ ; C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl optionally substituted with one to five fluoro or with one to three R ⁹ ; C ₃ -C ₆ cycloalkyl optionally substituted with one to three fluoro or C ₁ -C ₃ alkyl or R ⁵ ; C ₃ - C ₆ cycloalkyl-C(O)NH- optionally substituted with one to five fluoro or R ⁵ ; 4- to 7-membered heterocycloalkyl-C(O)NH- optionally substituted with one to five fluoro or R ⁵ and wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n; 5- to 6-membered heteroaryl)-C(O)NH- optionally substituted with one to five fluoro or R ⁵ and wherein the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; C ₁ -C ₆ alkyl-C(O)NH- optionally substituted with one to five fluoro or R ⁹ ; C ₁ -C ₆ alkyl-OC(O)NH- optionally substituted with one to five fluoro or R ⁵ ; C ₁ -C ₆ alkyl-NHC(O)NH- optionally substituted with one to five fluoro or R ⁵ ; C ₁ -C ₆ alkyl-S(O)2NH- optionally substituted with one to five fluoro or R ⁵ ; C ₁ - C ₆ alkyl-C(O)- optionally substituted with one to five fluoro or R ⁵ ; C ₁ -C ₆ alkyl-S(O)n- optionally substituted with one to five fluoro or R ⁵ ; and n at each occurrence is independently selected from 0, 1 and 2; R ⁵ is selected from C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, phenyl, phenoxy, C ₃ -C ₆ cycloalkyl, C ₃ - C ₆ cycloalkoxy, 4- to 7- membered heterocycloalkyl wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O)n, or a 5- or 6-membered heteroaryl wherein the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; wherein each R ⁵ is optionally independently substituted with one to three R ⁹ ; and n at each occurrence is independently selected from 0, 1 and 2; R ⁹ is selected from the group consisting of deuterium, oxo, halo, hydroxy, cyano, amino, C ₁ -C ₃ alkyl optionally independently substituted with one to three fluoro or hydroxy, and C ₁ -C ₃ alkyoxy optionally independently substituted with one to three fluoro or hydroxy, and C ₁ -C ₃ alkoxy optionally independently substituted with one to three fluoro or hydroxy; with the proviso that the compound is not a compound selected from: CPD0077063, CPD0084200, CPD0084205, CPD0084207, CPD0084208, CPD0084209, CPD0084210, CPD0084211, CPD0084212, CPD0084215, CPD0084216, CPD0084217, CPD0084221, CPD0084228, CPD0084231, CPD0084235, CPD0084242, CPD0084248, CPD0084249, CPD0084250, CPD0084252, CPD0084253, CPD0084254, CPD0084301, CPD0084531, CPD0084769, CPD0186407, CPD0186408, CPD0186409, CPD0186410, CPD0186412, CPD0186526, CPD0186529, CPD0186530, CPD0187053, CPD0187106, CPD0187107, CPD0187510, CPD0188058, CPD188059 and CPD0188163. C2. The method of Clause C ₁ , wherein the compound of Formula (I) is defined according to any of the appended claims (e.g. Claims 2 to 88 as set out below), or according to any aspect or embodiment of the present disclosure. C ₃ . The method of Clause C ₁ of Claims C2, wherein the viral infection is coronavirus. C4. The method of any of Clauses C ₁ to C ₃ , wherein the viral infection is caused by a virus selected form the group consisting: SARS, MERS, 229E, OC43, HKU1, NL63 and SARS-CoV-2 (COVID-19) or combinations or two, three, four or more thereof. C5. The method of any of Clauses C ₁ to C4, wherein the viral infection is caused by SARS-CoV-2 (COVID-19) or a variant thereof. C ₆ . The method of any of Clauses C ₁ to C5, wherein the compound is an inhibitor of the virus- encoded protease M ^pro . C ₆ . The method of any of Clauses C ₁ to C ₆ , wherein the method comprising administering the compound orally, topically, by inhalation, by intranasal administration, by intracerebroventricular, or systemically by intravenous, intraperitoneal, subcutaneous, or intramuscular injection. C7. The method of any of Clauses C ₁ to C ₆ , wherein the method comprising administering the compound according to formula (I) in combination with one or more additional therapeutic agent. C8. The method of Clause C7, wherein the one or more additional therapeutic agent is selected from at least one additional antiviral agent, at least one IL-1 inhibitor or combinations thereof. C9. The method of Clause C8, wherein the at least one additional antiviral agent is selected from an inhibitor of viral RNA-dependent RNA polymerase, an inhibitor of virus-encoded protease that affects processing of a viral RNA-dependent RNA polymerase, an inhibitor of coronavirus binding or release from infected cells, an inhibitor of virus binding to a specific cell surface receptor, an inhibitor of receptor- induced conformational changes in virus spike glycoprotein that are associated with virus entry, an inhibitor of a viral encoded helicase, an inhibitor of a methyl transferase, or combinations thereof. C ₁ 0. The method of any of Clauses C ₁ to C9, wherein the administering comprising administering the compound according to formula (I), simultaneously, sequentially or separately from the one or more additional therapeutic agent. C ₁ 1. The method of any of Clauses C ₁ to C ₁ 0, wherein the compound of Formula (I) is a compound of Table 1A, 1B and/or 1C. Many modifications may be made to the above examples without departing from the scope of the present invention as defined in the accompanying claims.