PYRROLOPYRIMIDINE AMINES AS COMPLEMENT

INHIBITORS

RELATED APPLICATION

This application claims the benefit of priority to U.S. Provisional Patent Application serial number 63/004,799, filed April 3, 2020.

BACKGROUND OF THE INVENTION

The complement system is a branch of an organism’s immune system that enhances the ability of antibodies and phagocytic cells to destroy and remove foreign particles (eg., pathogens) from the organism. The complement system comprises a set of plasma proteins that act together to attack extracellular forms of pathogens and induce a series of inflammatory responses to help fight infection. Complement activation can occur through several pathways. For example, complement activation can occur spontaneously in response to certain pathogens or by antibody binding to a pathogen. When complement proteins are activated a cascade is triggered by which one complement protein induces the activation of the next protein in the sequence. The activation of a small number of complement proteins at the start of the pathway is hugely amplified by each successive enzymatic reaction, resulting in the rapid generation of a disproportionately large complement response. (Marrides, S. Pharmacological Reviews 1998, Vol. 50, pages 59-88). In healthy organisms there are regulatory mechanisms to prevent uncontrolled complement activation.

When activated, complement proteins can bind to a pathogen, opsonizing them for engulftnent by phagocytes bearing receptors for complement. Then, small fragments of some complement proteins act as chemoattractants to recruit more phagocytes to the site of complement activation, and also to activate these phagocytes. Next, the complement proteins create holes or pores in the invading organisms, leading to their destruction. While complement plays an important role in protecting the body from foreign organisms, it can also destroy healthy cells and tissue. The inappropriate activation of complement is implicated in a long list of disease pathologies (Morgan, B. EurJClin Invest 1994, Vol. 24, pages 219-228) affecting the immune, renal, cardiovascular, and neurological systems. Accordingly, there exists a need to develop further complement inhibitors, which have therapeutic potential in the treatment of numerous disorders. SUMMARY OF THE INVENTION

In certain aspects, the invention provides compounds having the structure of formula (I), and pharmaceutically acceptable salts thereof: wherein, independently for each occurrence: X is a bond or C(R ^X )2;

V is a bond, C(R ^Y ) ₂ , or -N(R ^b K

G is S or C(R ³ )z;

R ^a and R ^b are each independently H or (Ci-C6)alkyl;

R ¹ represents optionally substituted aryl, heteroaryl, alkyl, cycloalkyl, alkenyl, or cycloalkenyl;

R ² represents optionally substituted bicyclic or tricyclic heteroaryl;

R ³ is independently for each occurrence H, halogen, -CN, -Ntfc, -CH2NH2, (Ci- Ce)alkoxy or (Ci-Ce)alkyl; or two vicinal occurrences of R ³ taken together with the carbon atoms to which they are bonded form an optionally substituted fused (C3-C7)cycloalkyl or (Ce)aryl; or two geminal occurrences of R ³ taken together with the carbon atom to which they are bonded form an optionally substituted spiro (C.3-C7)cycloalkyl; or two hominal occurrences of R ³ taken together with the carbon atoms to which they are bonded form an optionally substituted bridged (C3-C7)cycloalkyl;

R ^x is independently for each occurrence H, (Ci-Ce)alkyl, or (C3-C7)cycloalkyl;

R ^Y is independently for each occurrence H, (Ci-Ce)alkyl, or (C3-C?)c>'cloalkyl; or an occurrence of R ^Y and a substituent on R ² taken together with the intervening atoms form a ring; optional substituents on R ¹ or R ² each independently represent halogen, -CN, -NO2, -OR ¹³ , -NR ¹³ R ¹⁴ , -C(0)R ¹³ , -C(0)0R ¹³ , -C(0)NR ¹³ R ¹⁴ , -0C(0)R ¹³ , -NR ¹³ C(0)R ¹⁴ , -0C(0)NR ¹³ R ¹⁴ , -0C(0)0R ¹³ , -NR ¹³ C(0)0R ¹⁴ , -NR ¹³ C(0)NR ^!3 R ¹⁴ , -0S(0)p(R ¹³ ), -SR ¹³ ,-NR ¹³ S(0)p(R ¹⁴ ), or optionally substituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkoxyalkyl, aryloxyalkyl, aralkyl, heteroaralkyl, heteroaryl, aryl, aryloxy, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, or (heterocycloalkyl)alkyl; or wherein two substituents on R ¹ or two substituents on R ² , taken together with the intervening atoms, form a ring;

R ¹³ and R ¹⁴ , independently for each occurrence, represent H or optionally substituted alkyl, haloalkyl, alkenyl, alkynyl, aryl, or heteroaiyl; and p is 0, 1, or 2.

In certain aspects, the invention provides a pharmaceutical composition, comprising a compound of the invention, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

In certain aspects, the invention provides methods of treating a disease or condition characterized by aberrant complement system activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound the invention, or a pharmaceutically acceptable salt thereof. In certain embodiments, the disease or condition characterized by aberrant complement system activity is an immunological disorder. In certain embodiments, the disease or condition characterized by aberrant complement system activity is a disease of the central nervous system. In certain embodiments, the disease or condition characterized by aberrant complement system activity is a neurodegenerative disease or neurological disease. In certain embodiments, the disease or condition characterized by aberrant complement system activity is a renal disease. In certain embodiments, the disease or condition characterized by aberrant complement system activity is a cardiovascular disease. In certain embodiments, the disease or condition characterized by aberrant complement system activity is a cardiometabolic disease. In certain embodiments, the disease or condition characterized by aberrant complement system activity is selected from the group consisting of paroxysmal noctural hemoglobinuria, atypical hemolytic membranoproliferative glomerulonephritis, dense-deposit disease, cold agglutinin disease, and catastrophic antiphospholipid syndrome. In certain other aspects, the disease or condition characterized by aberrant complement system activity is selected from the group consisting of adult respiratory distress syndrome, myocardial infarct, lung inflammation, sepsis, cardiopulmonary bypass, bums, asthma, restenosis, multiple organ dysfunction, Guillain-Barre syndrome, hemorrhagic shock, glomerulonephritis, systemic lupus erythematosus, rheumatoid arthritis, infertility, Alzheimer’s disease, multiple sclerosis, platelet storage, and hemodialysis. In certain other aspects, the disease or condition characterized by aberrant complement system activity is selected from the group consisting of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), warm autoimmune hemolytic anemia, IgA nephropathy, C3 glomerulonephritis, and focal segmental glomerulosclerosis. In further aspects, the disease or condition characterized by aberrant complement system activity is a hematological disorder. In further aspects, the disease or condition characterized by aberrant complement system activity is an ocular disorder or an eye disorder. In still further aspects, the disease or condition characterized by aberrant complement system activity is macular degeneration, age-related macular degeneration (AMD), wet AMD, geographic atrophy, macular edema, diabetic macular edema, choroidal neovascularization (CNV), uveitis, Behcet’s uveitis, proliferative diabetic retinopathy, non-proliferative diabetic retinopathy, glaucoma, hypertensive retinopathy, a comeal neovascularization disease, post-comeal transplant rejection, a comeal dystrophic disease, an autoimmune dry eye disease, Stevens-Johnson syndrome, Sjogren’s syndrome, an environmental dry eye disease, Fuchs’ endothelial dystrophy, retinal vein occlusion, or postoperative inflammation. In certain other aspects, the disease or condition characterized by aberrant complement system activity is selected from the group consisting of obesity, insulin resistance, diabetes, dyslipidemia, nephropathy, neuropathy, angioedema, e.g., hereditary angioedema or acquired angioedema, thrombotic microangiopathy, Parkinson’s disease, schizophrenia, periodontitis, Crohn’s disease, C3 glomerulopathy, membranous nephropathy, osteoarthritis, bullous pemphigoid, psoriasis, hidradenitis suppurativa, of ischemia/reperfusion injury, acute kidney injury, and organ transplantation, e.g., kidney transplant, systemic inflammatory response syndrome, septic shock, trauma, cancer, antibody-mediated rejection, Berger’s disease, delayed graft function, granulomatosis with polyangiitis, graft versus host disease, hematopoietic stem cell transplant-related thrombotic microangiopathy immune complex-mediated membranoproliferative glomerulonephritis immune-mediated necrotizing myopathy, idiopathic polypoidal choroidal vasculopathy, microscopic polyangitis, pyoderma gangrenosum, and Stargardt Disease 1.

DETAILED DESCRIPTION

Inhibitors of the complement system are useful in therapeutic methods and compositions suitable for use in treating disorders of the immune, renal, cardiovascular, and neurological systems. Provided herein are compounds of formula (I) and pharmaceutically acceptable salts thereof that are useful in treating or preventing a disease or condition characterized by aberrant activity of the complement system.

Definitions

The articles “a” and “an” are used herein to refer to one or to mote than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

The term ‘¾eteroatom” is art-recognized and refers to an atom of any element other than carbon or hydrogen. Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium, and alteratively oxygen, nitrogen or sulfur.

The term “alkyl” as used herein is a term of art and refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In certain embodiments, a straight-chain or branched-chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), and alteratively, about 20 or fewer, or 10 or fewer. In certain embodiments, the term “alkyl” refers to a C1-C10 alkyl group. In certain embodiments, the term “alkyl” refers to a Ci-Ce alkyl group, for example a Ci-Ce straight-chain alkyl group. In certain embodiments, the term “alkyl” refers to a C3-C12 branched-chain alkyl group. In certain embodiments, the term “alkyl” refers to a C3-C8 branched-chain alkyl group. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

The term “cycloalkyl” means mono- or bicyclic or bridged saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Certain cycloalkyls have from 5-12 carbon atoms in their ring structure, and may have 6-10 carbons in the ring structure. Preferably, cycloalkyl is (C C )cycloalk>'l which represents a monocyclic saturated carbocyclic ring having from 3 to 7 carbon atoms. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems include bridged monocyclic rings and fused bicyclic rings. Bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (/.<? ., a bridging group of the form -(Ctih)»-, where w is 1, 2, or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. Fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. The bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. Cycloalkyl groups are optionally substituted. In certain embodiments, the fused bicyclic cycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted.

The term “(cycloalkyl)alkyr’ as used herein refers to an alkyl group substituted with one or more cycloalkyl groups. An example of cycloalkylalkyl is cyclohexylmethyl group.

The term ‘¾eterocycloalkyl” as used herein refers to a radical of a non-aromatic ring system, including, but not limited to, monocyclic, bicyclic, and tricyclic rings, which can be completely saturated or which can contain one or more units of unsaturation, for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system, and having 3 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur. For purposes of exemplification, which should not be construed as limiting the scope of this invention, the following are examples of heterocyclic rings: aziridinyl, azirinyl, oxiranyl, thiiranyl, thiircnyl, dioxiranyl, diazirinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3- dithiolanyl, 1,3-dithianyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, azetyl, oxetanyl, oxetyl, thietanyl, thietyl, diazetidinyl, dioxetanyl, dioxetenyl, dithietanyl, dithietyl, dioxalanyl, oxazolyl, thiazolyl, triazinyl, isothiazolyl, isoxazolyl, azepines, azetidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxopiperidinyl oxopyrrolidinyl piperazinyl piperidinyl pyranyl pyrazolinyl pyrazolidinyl tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, trithianyl, and 2- azobicyclo[3.1.0]hexane. A heterocycloalkyl group is optionally substituted by one or more substituents as described below.

The term “(heterocycloalkyl)alkyl” as used herein refers to an alkyl group substituted with one or more heterocycloalkyl (i.e., heterocyclyl) groups.

The term “alkenyl” as used herein means a straight or branched chain hydrocarbon radical containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-metiiyl-2-propenyl, 3-butenyl, 4-pentenyl, 5- hexenyl, 2-heptenyl, 2-methyl- 1-heptenyl, and 3-decenyl. The unsaturated bond(s) of the alkenyl group can be located anywhere in the moiety and can have either the (Z) or the (E) configuration about the double bond(s).

The term “alkynyl” as used herein means a straight or branched chain hydrocarbon radical containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1- propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

The term “alkylene” is art-recognized, and as used herein pertains to a diradical obtained by removing two hydrogen atoms of an alkyl group, as defined above. In one embodiment an alkylene refers to a disubstituted alkane, i.e., an alkane substituted at two positions with substituents such as halogen, azide, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano, or the like. That is, in one embodiment, a “substituted alkyl” is an “alkylene”.

The term “amino’' is a term of art and as used herein refers to both imsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas: wherein Ra Rt> and Rc each independently represent a hydrogen an alkyl an complete a heterocycle having from 4 to 8 atoms in the ring structure; Rd represents an aryl, a heteroaiyl, a cycloalkyl, a cycloalkenyl, a heterocyclyl or a polycyclyl; and x is zero or an integer in the range of 1 to 8. In certain embodiments, only one of Ra or Rb may be a carbonyl, e.g., Ra, Rb, and the nitrogen together do not form an imide. In other embodiments, Ra and Rb (and optionally Rc) each independently represent a hydrogen, an alkyl, an alkenyl, or -(CI½)x-Rd. In certain embodiments, Ra and Rb are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaiyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, aryl alkyl, heteroarylalkyl, alkoxyalkyl, or haloalkyl, any of which may be further substituted (e.g., by halogen, alkyl, alkoxy, hydroxy, and so forth). In certain embodiments, the term “amino” refers to -NHz.

In certain embodiments, the term “alkylamino” refers to -NH(alkyl).

In certain embodiments, the term “dialkylamino” refers to -N(alkyl)z.

The term “amido”, as used herein, means -NHC(=0)-, wherein the amido group is bound to the parent molecular moiety through the nitrogen. Examples of amido include alkylamido such as Ο¾0(=0)Ν(Η)- and CH ₃ CH2C(=0)N(H)

The term “acyl” is a term of art and as used herein refers to any group or radical of the form RCO- where R is any organic group, e.g., alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl. Representative acyl groups include acetyl, benzoyl, and malonyl.

The term “aminoalkyl” as used herein refers to an alkyl group substituted with one or more one amino groups. In one embodiment, the term “aminoalkyl” refers to an aminomethyl group, i.e., -CH2NH2.

The term “aminoacyl” is a term of art and as used herein refers to an acyl group substituted with one or more amino groups.

The term “aminothionyl” as used herein refers to an analog of an aminoacyl in which the O ofRC(O)- has been replaced by sulfur, hence is of the form RC(S)-.

The term “phosphoryl” is a term of art and as used herein may in general be represented by the formula:

Q50

P

O IR59 wherein Q50 represents S or O, and R59 represents hydrogen, a lower alkyl or an aryl; for example, -P(0)(0Me)- or -P(0)(0H)2. When used to substitute, e.g., an alkyl, the phosphoryl group of the phosphorylalkyl may be represented by the general formulas: Q50 Q50

Q51 — p - o - Q51 — p— OR59

OR59 OR59 wherein Q50 and R59, each independently, are defined above, and Q51 represents O, S or N; for example, -0-P(0)(0H)0Me or -NH-P(0)(0H)2. When Q50 is S, the phosphoryl moiety is a “phosphorothioate.”

The term “aminophosphoryl” as used herein refers to a phosphoryl group substituted with at least one amino group, as defined herein; for example, -P(0)(0H)NMez.

The term “azide” or “azido”, as used herein, means an -Na group.

The term “carbonyl” as used herein refers to -C(=0)-.

The term ‘thiocarbonyV’ as used herein refers to -C(=S)-.

The term “alkylphosphoryl” as used herein refers to a phosphoryl group substituted with at least one alkyl group, as defined herein; for example, -P(0)(0H)Me.

The term “alkylthio” as used herein refers to alkyl-S-. The term “(alkylthio)alkyl” refers to an alkyl group substituted by an alkylthio group.

The term “carboxy”, as used herein, means a -CO2H group.

The term “ar>'l” is a term of art and as used herein refers to includes monocyclic, bicyclic and polycyclic aromatic hydrocarbon groups, for example, benzene, naphthalene, anthracene, and pyrene. Typically, an aryl group contains from 6-10 carbon ring atoms (i.e., (C«-Cio)aryl). The aromatic ring may be substituted at one or more ring positions with one or more substituents, such as halogen, azide, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano, or the Uke. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is an aromatic hydrocarbon, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. In certain embodiments, the term “aryl” refers to a phenyl group.

The term ‘beteroarvi” is a term of art and as used herein refers to a monocyclic, bicyclic, and polycyclic aromatic group having 3 to 12 total atoms including one or more heteroatoms such as nitrogen, oxygen, or sulfur in the ring structure. Exemplary heteroaryl i l d i d l l b (b) hi l b i id l l b f l b l l benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, indolinyl, indazolyl, isoindolinyl, isoxazolyl, isothiazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]p>'rimidinyl, pyrazolo[3,4-d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl, thiazolyl, thiophenyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl, thienyl, thiomorpholinyl, triazolyl or tropanyl, and the like. The “heteroaryl” may be substituted at one or more ring positions with one or more substituents such as halogen, azide, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano, or the like. The term “heteroaryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more atoms are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is an aromatic group having one or more heteroatoms in the ring structure, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Such heteroaryl groups may be connected to the rest of the molecule through either the aromatic group having one or more heteroatoms in the ring structure or the other cyclic group. For example, heteroaryl includes indole, which comprises a benzene ring and a pyrrole ring that are fused together. An indole substituent may be attached to a parent structure through either the benzene ring or through the pyrrole ring of the indole.

The term “aralkyl” or “arylalkyl” is a term of art and as used herein refers to an alkyl group substituted with an aryl group, wherein the moiety is appended to the parent molecule through the alkyl group.

The term ‘¾eteroaralkyl” or “heteroarylalkyl” is a term of art and as used herein refers to an alkyl group substituted with a heteroaryl group, appended to the parent molecular moiety through the alkyl group.

The term “alkoxy” as used herein means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

The term “alkoxyalkyl” refers to an alkyl group substituted by an alkoxy group.

The term “alkoxycarbonyl” means an alkoxy group as defined herein appended to herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxy carbonyl, and te/7-butoxy carbonyl .

The term “alkylcarbonyl”, as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl- 1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

The term “arylcarbonyl”, as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylcarbonyl include, but are not limited to, benzoyl and (2- pyridinyl)carbonyl .

The term “alkylcarbonyloxy” and “arylcarbonyloxy”, as used herein, means an alkylcarbonyl or arylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, elhylcarbonyloxy, and ter/-butylcarbonyloxy. Representative examples of arylcarbonyloxy include, but are not limited to phenylcarbonyloxy.

The term “alkenoxy” or “alkenoxyl” means an alkenyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkenoxyl include, but are not limited to, 2-propen- 1-oxyl (i.e., CH2=CH-CH2-0-) and vinyloxy (i.e., CHFCH-O-).

The term “aryloxy” as used herein means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

The term “heteroaryloxy” as used herein means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

The term “carbocyclyl” as used herein means a monocyclic or multicyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbon radical containing from 3 to 12 carbon atoms that is completely saturated or has one or more unsaturated bonds, and for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system (e.g., phenyl).

Examples of carbocyclyl groups include 1 -cyclopropyl, 1 -cyclobutyl, 2-cyclopentyl, 1- cyclopentenyl, 3-cyclohexyl, 1-cyclohexenyl and 2-cyclopentenylmethyl.

The term “cyano” is a term of art and as used herein refers to -CN.

The term “halo” is a term of art and as used herein refers to -F, -Cl, -Br, or -I.

The term “haloalkyl” as used herein refers to an alkyl group, as defined herein, wherein some or all of the hydrogens are replaced with halogen atoms The term ‘¾ydroxyalkyl”, as used herein, means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4- hydroxyheptyl.

The term “silyl”, as used herein, includes hydrocarbyl derivatives of the silyl (EbSi-) group (i.e., (hydrocarbyl)3Si-), wherein a hydrocarbyl groups are univalent groups formed by removing a hydrogen atom from a hydrocarbon, e.g., ethyl, phenyl. The hydrocarbyl groups can be combinations of differing groups which can be varied in order to provide a number of silyl groups, such as trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert- butyldimethylsilyl (TBS/TBDMS), triisopropylsilyl (TIPS), and [2- (trimethylsilyl)ethoxy]methyl (SEM).

The term “silyloxy”, as used herein, means a silyl group, as defined herein, is appended to the parent molecule through an oxygen atom.

Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, compounds of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and tram- isomers, (/?)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary', where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.

It will be understood that “substitution ^' " or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound e g which does not spontaneously undergo transformation such as by rearrangement, fragmentation, decomposition, cyclization, elimination, or other reaction.

The term “substituted” is also contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The permissible substituents may be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.

In certain embodiments, the optional substituents contemplated in this invention include halogen, azide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, hydroxyl, alkoxyl, amino, aminoalkyl, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether (e.g., -alkylene-0(alkyl)), alkylthio, sulfonyl, sulfonamido, ketone (e.g., - CO(alkyl)), aldehyde (-C(O)H), ester (e.g., -COO(alkyl)), haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, and cyano.

As used herein, the term “optionally substituted” or “substituted or unsubstituted” when it precedes a list of chemical moieties means that the list of chemical moieities that follow are each substituted or unsubstituted. For example, “substituted or unsubstituted aryl, heteroaryl, and cycloalkyl” or “optionally substituted aryl, heteroaryl, and cycloalkyl” means substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted cycloalkyl.

The term “vicinal” describes the positional relationship between two substituents, moieties, or functional groups each of which is bonded to one of two adjacent carbon atoms that are bonded to each other (i.e., the two substituents, moieties, or functional groups are in a 1,2-relationship). The methyl groups in 3,4-dimethylheptane are vicinal.

The term “geminal” describes the positional relationship between two substituents, moieties, or functional groups bonded to the same carbon atom (i.e., the two substituents, moieties, or functional groups are in a 1,1-relationship). The methyl groups in 3,3- dimethylheptane are geminal The term “hominal” describes the positional relationship between two substituents, moieties, or functional groups each of which is bonded to one of two carbon atoms that themselves are each bonded to a single carbon atom (i.e., the two substituents, moieties, or functional groups are in a 1,3-relationship). The methyl groups in 3,5-dimethylheptane are hominal.

The phrase “protecting group”, as used herein, means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2 ^nd ed.; Wiley: New York, 1991). Protected forms of the inventive compounds are included within the scope of this invention.

For purposes of the invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.

Other chemistry terms herein are used according to conventional usage in the art, as exemplified by The McGraw-Hill Dictionary of Chemical Terms (ed. Parker, S., 1985), McGraw-Hill, San Francisco, incorporated herein by reference). Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

The term “pharmaceutically acceptable salt” as used herein includes salts derived from inorganic or organic acids including, for example, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluoroacetic, trichloroacetic, naphthalene-2-sulfonic, and other acids. Pharmaceutically acceptable salt forms can include forms wherein the ratio of molecules comprising the salt is not 1:1. For example, the salt may comprise more than one inorganic or organic acid molecule per molecule of base, such as two hydrochloric acid molecules per molecule of compound of Formula I. As another example, the salt may comprise less than one inorganic or organic acid molecule per molecule of base, such as two molecules of compound of Formula I per molecule of tartaric acid.

The term “prodrug” as used herein refers to a compound that can be metabolized in vivo to provide a compound of formula I Thus prodrugs include compounds that can be a corresponding compound that can be metabolized in vivo to provide a compound of formula I. Such modifications are known in the art. For example, one or more hydroxyl groups or amine groups in a compound of formula I can be acylated with alkyl-C(=0)- groups or with residues from amino acids to provide a prodrug.

Prodrug forms of a compound beating various nitrogen-containing functional groups (amino, hydroxyamino, amide, etc.) may include the following types of derivatives, where each Rp group individually may be hydrogen, substituted or unsubstituted alkyl, aryl, alkenyl, a!kynyl, heterocycle, alksiarsi, aryl alkyl, ara!kenyl, aralkynyl, cycloalkyl or cycloalkenyl.

(a) Carboxamides, represented as NHC(0)Rp

(b) Carbamates, represented as — NHC(0)0Rp

(c) (Acyloxy)alkyl Carbamates, represented as NHC(0)0R0C(0)R _P

(d) Enamines, represented as NliCRi=<HC()zRp> or --NHCR(==CHCONRpRp)

(e) Schiff Bases, represented as N=€R _f ,Rp

(f) Mannich Bases (from carboximide compounds), represented as

RCONHCTfcNRpRp

Preparations of such prodrug derivatives are discussed in various literature sources (examples are: Alexander ct al., J. Med. Chem. 1988, 31, 318, Aligas-Martin et al., PCT W00041531, p. 30)

Prodrug forms of carboxyl-bearing compounds include esters ( — COaRm), where the Rm group corresponds to any alcohol whose release m the body through enzymatic or hydrolytic processes would be at pharmaceutically acceptable levels. Another prodrug derived from a carboxylic acid form of the disclosure may· be a quaternary salt type of structure described by Bodor et al., J. Med. Chem. 1980, 23, 469.

The terms “carrier' ^* and “pharmaceutically acceptable carrier” as used herein refer to a diluent, adjuvant, excipient, or vehicle with which a compound is administered or formulated for administration. Non-limiting examples of such pharmaceutically acceptable carriers include liquids, such as water, saline, and oils; and solids, such as gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating, flavoring, and coloring agents may be used. Other examples of suitable pharmaceutical carriers are described in Remington 's Pharmaceutical Sciences by E.W. Martin, herein incorporated by reference in its entirety.

The term “treat” as used herein means prevent, halt or slow the progression of, or eliminate a disease or condition in a subject In one embodiment “treat” means halt or slow “treat” means reduce at least one objective manifestation of a disease or condition in a subject.

The term “effective amount” as used herein refers to an amount that is sufficient to bring about a desired biological effect.

The term “therapeutically effective amount” as used herein refers to an amount that is sufficient to bring about a desired therapeutic effect.

The term “inhibit” as used herein means decrease by an objectively measurable amount or extent. In various embodiments “inhibit” means decrease by at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 95 percent compared to relevant control. In one embodiment “inhibit” means decrease 100 percent, i.e., halt or eliminate.

The term “subject” as used herein refers to a mammal. In various embodiments, a subject is a mouse, rat, rabbit, cat, dog, pig, sheep, horse, cow, or non-human primate. In one embodiment, a subject is a human.

Compounds

The present invention provides compounds having the structure of Formula (I), and pharmaceutically acceptable salts thereof: wherein, independently for each occurrence:

X is a bond or C(R ^X )J;

V is a bond, C(R ^Y ) ₂ , or -N(R ^b K G is S or C(R ³ )z;

R ^a and R ^b are each independently H or (Ci-Cejalkyl;

R ¹ represents optionally substituted aryl, heteroaiyl, alkyl, cycloalkyl, alkenyl, or cycloalkenyl;

R ² represents optionally substituted bicyclic or tricyclic heteroaryl; R ³ is independently for each occurrence H, halogen, -CN, -NHz, -CH2NH2, (Ci- Ce)alkoxy or (Ci-Ce)alkyl; or two vicinal occurrences of R ³ taken together with the carbon atoms to which they are bonded form an optionally substituted fused (C3-C7)cycloalkyl or (Ce)aiyl; or two geminal occurrences of R ³ taken together with the carbon atom to which they are bonded form an optionally substituted spiro (C3-C7)cycloalkyl; or two hominal occurrences of R ³ taken together with the carbon atoms to which they are bonded form an optionally substituted bridged (C3-C?)cycloalk>'l;

R ^x is independently for each occurrence H, (Ci-C6)alkyl, or (C3-C7)cycloalkyl;

R ^Y is independently for each occurrence H, (Ci-Ce)alkyl, or (C3-C7)cycloalkyl; or an occurrence of R ^Y and a substituent on R ² taken together with the intervening atoms form a ring; optional substituents on R ¹ or R ² each independently represent halogen, -CN, -NO2, -OR ¹³ , -NR ¹³ R ¹⁴ , -C(0)R ¹³ , -C(0)0R ¹³ , -C(0)NR ¹³ R ¹⁴ , -0C(0)R ¹³ , -NR ¹³ C(0)R ¹⁴ , -OC(0)NR ¹³ R ¹⁴ , -0C(0)0R ¹³ , -NR ¹³ C(0)0R ¹⁴ , -NR ¹³ C(0)NR ¹³ R ¹⁴ , -0S(0)p(R ¹³ ), -SR ¹³ , -NR ¹³ S(0)p(R ¹⁴ ), or optionally substituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkoxyalkyl, aryloxyalkyl, aralkyl, heteroaralkyl, heteroaryl, aryl, aryloxy, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, or (heterocycloalkyl)alkyl; or wherein two substituents on R ¹ or two substituents on R ² , taken together with the intervening atoms, form a ring;

R ¹³ and R ¹⁴ , independently for each occurrence, represent H or optionally substituted alkyl, haloalkyl, alkenyl, alkynyl, aryl, or heteroaryl; and p is 0, l, or 2.

In certain embodiments, Y represents C(R ^Y )2, preferably CHz.

In certain embodiments, X represents a bond. Alteratively, X may represent CH2. In certain embodiments, R ¹ represents optionally substituted aryl or heteroaryl. In some embodiments, R ¹ is optionally substituted heteroaryl. Exemplary embodiments of R ¹ include optionally substituted phenyl (e.g., 3-halophenyl, or 2,3-dihalophenyl), (C3- C6)cycloalkyl, alkenyl, pyridinyl (e.g., 6-halopyridin-2-yl), orpyrazinyl (e.g., 6-halopyrazin-

2-yl).

In certain embodiments, R ¹ is mono-, di-, ortri- substituted.

In certain embodiments, R ¹ represents optionally substituted pyridinyl, preferably optionally substituted 2-pyridinyl. For example, R ¹ may represent

In other embodiments, R ¹ represents optionally substituted phenyl. For example, R ¹ may represent

In certain embodiments, R ² represents *

Z ¹ represents N or CR ^1Z ; Z ² represents N or CR ^2Z ; Z ³ represents N or C;

Z ⁴ represents N or CR ^4Z ; Z ⁵ represents N or CR ^5Z ; Z ⁶ represents N or CR ^6Z ; Z ⁸ represents C;

Z ⁹ represents N or C; k is an integer from 1-4; m is an integer from 1-3; and each occurrence of R ^1Z , R ^2Z , R ^4Z , R ^5Z , R ^6Z , R ^7Z , R ^M independently represents H, halogen, -CN, -NO2, -OR ¹³ , -NR ¹³ R ¹⁴ , -C(0)R ¹³ , -C(0)0R ¹³ , -C(0)NR ¹³ R ¹⁴ , -0C(0)R ¹³ , -NR ^!3 C(0)R ¹⁴ , -0C(0)NR ¹³ R ¹⁴ , -0C(0)0R ¹³ , -NR ¹³ C(0)0R ¹⁴ , -NR ¹³ C(0)NR ¹³ R ¹⁴ , -0S(0)p(R ¹³ ), -SR ¹³ , -NR ¹³ S(0)p(R ¹⁴ ), or optionally substituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxy alkyl, alkoxy alkyl, cycloalkoxyalkyl, aryloxyalkyl, aralkyl, heteroaralkyl, heteroaiyl, aryl, aryloxy, cycloalkyl, (cycloalkyl)alkyl, heteroc>'cloalkyl, or (heterocycloalkyl)alkyl; or wherein an occurrence of R ^6Z and an occurrence of R ^7Z taken together with the intervening atoms form a ring; or wherein an occurrence of R ^Y and an occurrence of R ²² taken together with the intervening atoms form a ring.

In certain embodiments, Z ² , Z ³ , Z ⁴ , and Z ⁶ represent N.

In certain embodiments, Z ³ , Z ⁴ , and Z ⁶ represent N.

In certain embodiments, Z ⁹ , Z ⁴ , and Z ⁶ represent N.

In certain embodiments, Z ³ and Z ⁴ represent N.

In certain embodiments, Z ¹ , Z ³ , Z ⁴ , and Z ⁶ represent N.

In certain embodiments, R ² represents . For example, R ² may represent . In some embodiments, k is 2. In certain embodiments, R ² represents

R ^5Z

In certain embodiments, R ² represents R ^7Z R ^1Z

R ^2Z

In certain embodiments, R ² represents R ^7Z , for example

NH ₂

In certain embodiments, R ² represents

^R Y ^N N

In certain embodiments, R ² represents R ^{72 R1Z} , for example

NH ₂

In certain embodiments, R ^7Z represents -NR ¹³ R ¹⁴ , for example -NH2. In certain embodiments, R ^6Z represents -C(0)R ¹³ , -C(0)0R ¹³ , -C(0)NR ¹³ R ¹⁴ , or hydroxyalkyl.

In certain embodiments, R ^5Z represents alkyl, halo, or -NR ¹³ R ¹⁴ .

In certain embodiments, R ^1Z represents -CN, halo, haloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, -C(0)R ¹³ , -SR ¹³ , -NR ¹³ R ¹⁴ , -OR ¹³ , -C(0)0R ¹³ , -C(0)NR ¹³ R ¹⁴ , or -NR ¹³ C(0)R ¹⁴ .

In certain embodiments, each occurrence of R ^2A independently represents -CN, -NO2, halo, haloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted hydroxyalkyl, -C(0)NR ¹³ R ¹

In certain embodiments, G is C(R ³ )z.

In certain embodiments, the compound of the invention has the structure of formula

(la):

R ³ R ³ R ^a

R? ,R ¹

N-X

^R Ή

Y ⁰

R ² (la).

In certain embodiments, two vicinal occurrences of R ³ taken together with the carbon atoms to which they are bonded form an optionally substituted fused C3 -cycloalkyl.

In certain embodiments, at least one occurrence of R ³ is halo, preferably fluoro.

In certain embodiments, at least one occurrence of R ³ is methyl.

In certain embodiments, two vicinal occurrences of R ³ taken together with the carbon atoms to which they are bonded form an optionally substituted fused C3 -cycloalkyl and another occurrence of R ³ is methyl.

In certain embodiments, the compound of formula (I) is selected from the following table of compounds, and pharmaceutically acceptable salts thereof: 75d 24a

„ .^V'xy N ¾ l\

Λο °

NHCHg CA NH ₂ >~

76b 50f

0γΝ^γ1ν _α rS>

I* V ^N · ^{0 F} W Ό lT

NHCH ₃ fj NH¾ ₂ F

77b 157a

, V X ,»„,w

OH NH ₂

NH ₂

78a 158e

H

N N

^■ Cl r\ ⁰ F V bY ⁰ - ff V ⁿ * CH ₃ tr

- ^Γ Λ ^Ν m -

NH ₂ NH ₂

79a 32f

PY oY

“o tr w o o S V>N, A .N

NH _j

N¾

F

NH ₂

80a <7 43a

H

N N u VAT r\ ⁰ Λ m ^ ^IN N _v -'N

CO ₂ H 81a j·» i 35f

H r\J Cl w

F

N r.\, m / f NCn

NH ₂

NH ₂

82a 30f

VY ⁰ V r\ tr W Ό if i^ ^N V ^N '

NHCH _{3 f} N¾X_A

NH ₂

83d ¾ H N, Br 47g

N

N j o

O O'

0 COOCH3

N

N Π N¾ -h

NH ₂

H _j N

84a 48d

WC Br

^■V-N r

^N 'xjX? A

NH ₂

NH ₂ H ¾

85b 38e H ,Br

N ,N _;

PYY TT N' I

A O r S> ° m N r N *. I

NH ₂ NH ₂

OMe 86b o Slg

H

>A Cl H

Kl N N Br

A ^0N Ξ F N

O I m N. /

NH ₂ N

< N— ^ rs

NH ₂

87f 52f Br

A O v sV XVJ ^Br "W O

ΪΎ )

NH ₂ 0 NH¾ ₂ r

88f <¾· 54g ¾"V H _N .Br

H l|

N N

‘Cl N l\

A F

N , °

II N _¾ N A. /^

NH ₂ < rs

NH ₂

89b 44a H N Br

N . t r N

O

H ₂ N A r r

NH ₂

COzH

90d 29f l««· _/ H Br

N ,N.

N r VS>Y ⁰ VT O I

I

N A

Ώ 0 .

NH ₂ f N u >

NH ₂ 91a pu 22c and H Br

H Cl ,N.

>^ ^N 22d *. N

Cl N

F Me O

Y^o 4 rS> ⁰

.N.

N^XN^

NH ₂ f NXZn

NH ₂ Me

(+) and (-) isomer 96e H 17f

N 1 8

I :i _Y v ^Br rS) F n t}

"Vr

N ^{N •} N

NH ₂ » A

NHBoc

NH ₂

97b 18a

Ργγγ w /A

NL , _N if

NH ₂ r% NH ₂

NH ₂

98b 31f

Λv u5 -Cl W /A> irW N*_N f r *

NH ₂

N ,¾ o N=/

99b 60c ,Br

<7 H ,N.

N

A 5V ⁰ _X v N

O

F F °*s

_N trV/> y-N F .. „N

NH ₂ N

NH ₂

NH ₂

O

61 Br

100b a H

N ,N¾, fO H 'Ν' i

A T O o A

NH ₂ ΛΗ ₂ ^NH2

101b 129f

Ά j')V ⁰ -O

NH ₂ a .> ^;¾ y 102b 46g

^N<^ _Γ Λ,Τ ΧΎ” i TN> ⁰ —

C£ NH ₂ p COOC H _J CH _J

NH ₂

103b 62c H ,Br

N

> ui N r\ N o O I

.. .N

NH ₂ f N¾tP!

NH ₂ Γΐ

104a 63d

ΟγΝ^^ _α| o F ^■ o

N^XN^ 2 f N ^N ¾

NH x_n NH ₂

NH ₂

105b A 53d

VLK r\ ‘Cl o F N ¾ SV l

/ ^N ¾~-N Λ°

NH ₂

CF

NH _{2 3}

111b <? F

H 55a

A rv ° ST

^N iYV~N> N¾ N r.V / ³

NH ₂ <

N— ^ rs

NH ₂ 112b 172a

ΧΫΧ7 Br S \Ls l\ _* f

Γ θ N H

N H

Λ°

NH ₂

ΝΗ ₂ Q

CH ₃

119a 173a

<7 H

NU lV*

N H z?

Ο

^ ^N ¾r- ^N κι Λ °

NH ₂ « ΝΗ ₂ Γ

120c 161a

H

H

N N Ν ¾ l\

‘Cl

O O F Λ°

NH ₂ σ¾ CO ₂ H

NH ₂

121d 174g Br

H l| w - ‘Cl

N r\ ⁰ F F ₃

N; N.

N-/ r>

NH ₂ NH ₂

122c 175a

H , Br

N N.

H l| \

N

^N l\ if ‘Cl N ¾ r\ ⁰ F

N

N; N r.V J ³

N^XN^

NH ₂ r>

NH ₂ 123g 176a

I X !LAZ

N ¾ Ϊ

CO ,Ν Λ. °

X NH _j Γ : ΪΛ

N-/

NH ₂

118a 169f Br

Wxy W O

O'

¾ N. f

N

Ό

NH ₂

^HN x^

117d F. 177d NC.

N- tiW

„ r\ _> ^r

N ¾ l\ ύο y

NH _a

N. M Λ°

NH ₂

CF ₃

116b :i

^F t F- 178d NC^

H H _N .Br

^N T ^N N l\

N KT^O ^¾ o y

Λ

Γ ν ^Ν

*

NH ₂

CF ₃

115e Cl 162 Br

^F g 1 »···/ H

F- N N;

H

N N

N o y

A

NH ₂ /=» ,NH IOC n

\J ₂ NH ₂ 114f F Cl 163g H _N ,Br

\ F. s N l\

N O

O

Ό N. M rV",

N*. a f \

NH _j

NH ₂

113a 164a

H

N ¾ l\ r N XuCr Λ ⁰

/>

N f NXj^

NH ₂

NH ₂ OH

66b ;I.^ 165a

H

N N

^• Cl b ° F

/** N V-N K O ^N y O r ^N 'H N, yy*

N

HzN

NH ₂ 1 ,C<¾H

124b 170c Jt _h ,

^N ^■ _N S ' -V N

V-N

F* ^Cl N^J _^ r Ov O Vr

H ₂ N \

NH ₂

OH

68a 179d

H Br

N N.

N H l\

„ Λ ¾τ Λ iT ⁰

NH _2>

$ NH¾ ₂ > 132d 188g Br r H N _¾

¾; N

N

O I

Λ ^{0 F}

XO ° ..*S .N

NH ₂

N¾

NH ₂ NO ₂

133b F t 195e

H

N 1

N' 'Cl W o i¾ °*S .N

NHz >NH f NXn n ■OH

NH ₂

20a F

1 198a

H Br

<3 N ,N;

N·

N l\

■c ¾ \J N n o

F ;i

H _j 1 N N Λ F ⁰

NH ₂

134b 199a

P _Y « _^ QL _c , 4Π

N ¾ i\ rV ° ^F ir ^N V ^N ;

H

N Λ

NH ₂ V=e ⁰

8

& irVV.

CF ₃

NH ₂

135a ^F I 200a

H

N I

N ;i

N Ϊ

If 1

N Λ

NHa N¾ ⁰

N-/ rV ^Br

NH ₂ 138d 181a

F* H N: Br

N

N ¾ l\

Vt F l o A °

O

< N?j¾ZCn>

A V=N

NH ₂

NH ₂

139b F 182a

1 «··

¾

H N ¾ l\

N'Sy-N %

A i Cl

N F A° if

NH ₂ ^X — ^z

NH ₂ /

V.NH

125d F Cl 183a

\ F. H ,Br

N ,N.

H

N N ¾

N

O

“O Λ

N-/ ^N X-N ⁰ w

NH ₂ ^F 0 NH- ₂ 0

126f 207b

N· H b ° _-N _x , V\

Γ O O Br V-N N _x ^

N r*Y. U ^N - O ^'

H ₂ N

NH ₂ /

CF ₃

N

H

142d F 208d

H ,Br

N ,N.

H

N N \\ I

N Cl

A ° F A °

H ₃ C

Y Y ^N N

NH 143d F Cl 203a

F. <7 !L/V ^r

H N' y

N O

N

°*S

O .. .N

Ό f ^N in

N¾

N r¾*. juy :0

NH ₂

H ₂ N

NH ₂ /

O

144g :i 204a

F. <y H N

N _¾ Z ^Br

H l|

N N N I y

O r\ _° - ..S .N

H ₂ N o NH ₂ N¾

■O

NH ₂

HN

^X CH ₃

145a ^F t 184g

H Br

N ,N. rU^ N W l\ y

OyX^J N. " Λ Me ⁰

HN NH

T O a f \

NH ₂

CF ₃

235a F

1 185a l»··] H Br

N N.

N W l\

_^ y ,Ν /

O O

HN r F j W / Λ ⁰

Y NH

O OC f \

NH ₂

HN 146a Cl 186a

F. H N«

N _5j / ^Br

H l| N \\ \

^N T ^N

N r

N r\ ° V if o n

N¾

ΝΠ _2ο , OCH ₃ NH ₂

147a Cl 2 1

^F 06c t F.

H

N N H

N N

-,N , f b o

N V-N

N N O'"

H ₃ CO J H ₂ N \ o NH ₂ CF ₃

148d

^F 209b E t S

H

N N H

% N

‘Cl

O _/ N

Ό F Γ ^ V 4) d -X Br

N J jr w H ₂ N \

NH ₂

CF ₃

19a F 210d

1

N H

_/ N _x ll * ri P

O.> Y* _/ N _x O f * i/ 4) d D

T\' ^Br

N N f f

1 H ₂ 1

H _j N N

CF ₃

3b F 189g Br

1 Ό H

N N.

N

O rV ⁿ

/f b O e

N V-N

H ₂ N f NX_n

Me

NH ₂ 149b F

* 193a

H

ΥΎ ^Ν Cl N ¾ l\ r\ F

N ⁰ if rV

NH ₂ /"NH f N=t¾ n

Br

NH ₂

4b 190a

H ,B

N . r

<7 N.

N \\ l\

Ό

N. M Λ°

C N f*.T

NHH ₂ D NH ₂ C0 ₂ Et

5e 191a

H _, N Br

N .

, ,^ ^V Vy N W l\

N r.V /

03 f N

NH ₂ X_n

NH ₂ Me

ISOd F 192g

H w - Cl rS> ⁰ F le r N¾Cn

Me Br

NH ₂ NH ₂

69a F 196d

H ,Br

,N:

N

N ¾ l\ r ^N 'K W y

N _° v cs>¾¾ _f N ^N t_n

NH ₂ o

NH ₂

HN

" 70a 197c H N-. Br

N-V ^¾

N l\ V

0 r ^N 'H ° ..*S .N

N

NH ₂ N

NH ₂

H ₃ C-AJ

2d 214b

H .N: Br

N

Λ N T 0t l\ f ri f N ^N ¾xY _> CO ₂ H

NH ₂

NH ₂

71a 213d \

H

Crry- N H

Γ * /Λ d

N )fV r ^N 'K ^X N= ^{s/ Br}

N

H ₂ N \

NH ₂

CF ₃

72a 215g

H H Br

N N.

0¾r Br

N ¾ i\

NH, A ⁰

N

N"

NH ₂ /

9a 216g

1 III··; H Br

N N.

N H N i\ a N ^/ 6 ry A Me°

H ₂ N \ o NHc ₂

C<¾Me 151a 217a

O _y iUCjX vw r\ ^{0 F} le o NH ₂ f NX-Π

NH ₂ co ₂ Me

152d ^F 1 220a H N Br

N .

'·]

N' N

*u0 O \

'Cl

F

CH ₃ N. Λ irV M cozH

^N Y^N

NH ₂ az *

NH ₂ le 202a

H .N Br

N .

N ¾ Ϊ

Λ Λ ⁰ f N¾X_n

NH ₂ NO

NH _{2 2}

6e 205c t«*i H N; Br

N

N

O \

Λο

Λ flJ'

N

NH ₂ Me

NH ₂ ΓΛ

CH ₃

7b 222a

^F % H Br

N N.

Q^ N ¾ i o r

Ό Λ ⁰

N; N f XT^

N— N

NH ₂ Me NH ₂ CO ₂ H 21a F 236f Br

1 w

N H Ό r ^~ i. _A - V-N

Γ * N O O Br

N ty Q NH¾ ₂ I

H ₂ N 1

Me

73a 237a

V

H W Ό Cf

05 Q NH¾ ₂ ^Cl

NH ₂

74a 238g

H W o

_{N N} r<T¾y m CM NH _j ^v I

NH ₂

153a F 2

1 Cl 39a ,a

R

H 'Ν' i\ o y

^N TT ^N o=< 6 ,Na- ,N,

N. _ n r Ki N-V

NH ₂ ;i

OH

^NH = d=

27a

N

Λ

296a A n : Me r \ ^x

ΛΗ ₂ ^CF3 NH ₂

CF ₃ 25a E 240g

% s _^ Q F^· Vi¾f

Λ° N N

N. .

N _¾

<

N-/ n n /

O

NH ₂ ^:F 3 NH ₂ o

26a F

1 241g

Br

N-^ ^Ns ¾

N· H N ¾

VN n % N O O Br N J ty N¾ N r.V / f

H ₂ N 1 <

N-/ /

O

CF ₃ NH ₂

O

8b 242a

H Br

N N.

N W l\ w

Λ ⁰ N; N r.V /

N— ^ r> 2 NO

NH ₂

NH ₂

28a 243a

H Br Br

N N;

N ¾ l\ N l\

N¾ N Λ. > ° N; N r.V /

N-V n <

N-^ r>

CF

NH _{2 3} NH ₂ NO ₂

10b ,Br 244d

H ,N.

\ N

N i\ L o ¾ N Λ. ⁰ N r.x /!

N N:

«

N-/ r>

NH ₂ CH ₃ NH ₂ Ilf 245a

II· H Br

4 N.

<) N

N ¾ i N ¾ I

Λ

N ryVvv ⁰

N; N r.V / / ^ T\

N

NH ₂

CF ₃ NH ₂

12a 42a

H N; Br

>n N <

N ¾ i\ N ¾

Λ ⁰ N Λ. ⁰ i,¾ N

NH ₂

NH ₂

127d t? 16e Br

H

_N rixxy Ό

^CQ o PV-CFa

NH ₂

128a H .Br 36e H Br

Ό ,N. q N.

N N

N I N

A O O

N Λ.

O f N ^~ l_rV ^0Me

NH ₂

154e 39f H Br

N N;

N

O 6

^• O

N r. ° p fA-T>

NH ₂ } N¾

NH ₂ C0 ₂ Me 34e H ,Br 23f

Ό N N.

N \

O w

A

HZ *

NH ₂ NH ₂

Br

13b 40a

W¾T <7

N A\ \

Λ Λ ⁰

OC. *

NH ₂ NH ₂

C0 ₂ Me

14a E 156e t?

B H

H N r N

N . N

N

O r\ ⁰ XT

N Λ.

N¾ ^» _0γ ςχ> i N-/ rs H NH ₂

NH ₂ CF ₃

15a 45d 4>„.

^Ϊ ΓΛ Sv

'Π,Μ ^N¾ r N· H

N

.N /-i N

A N C Br

N*. i

H ¾

0¾ ₂ N

ΛΗ ₂ ^Cp 3 C0 ₂ Et

ISSf 41f

9YV

N rS> ° tT ^r W¾f

Ό

C0 ₂ Me

OH NH _Z fJ NH¾ ₂ > 228a 263c Η Br

<7 Ν Ν.

IL/V* Ν \

Ν ¾ Ο

Λ° A>

Ν. κι f ] Me cc Nc _s J f % f S

ΝΗ ₂

ΝΗ ₂ % /)

251f Ο Η 272c

Ν

Ο ^' Ν F W O

Λ ⁰ CL Λ°

¾ Λ¾Η ₂ ^cf =

CF

ΝΗ _{2 3}

233h 255c

Br ί\

ΝΗ f Ν¾

ΝΗ ₂

Ν— / _> .?

Ν r ^N J? ^~ S

Η,Ν

229c Ι«Ν Η Br 256a

\ Ν ,Ν.

Ν

Ο W r\e r\ e N-V^v, — L f Ν· Y-t f ΧΎ^ ΝΗζ ξ

Ν

NH _Z 230a 273c

N ¾ i\ 4V Br rV ₂ j · Xr

H N i f N ^N ¾t_n

,N

NH ₂ n¾

231g 257g l«»«J H , Br

N N.

N ¾ i\

Λ ⁰ Ό

N f N Me

L W NH ₂

OMe

CF ₃

246b F 258a

1

<1 IL/V*

N H N li \

^N

Γ ^ _x V N

N b o /Λί ⁰

N N Me

H ₂ N 1 N f -is

CF ₃ NH ₂

OMe

247d H ₃ CO 259d =*w

Ϊ

N H

N

N H _/ N _{x /} N _x Γ * N b o

Γ *) ^■ N ~ \) d Yy* N fV ^r

H ₂ N \

H ₂ N

CF ₃

CF ₃

248(1 H ₃ CO 260a =v i

N H

N H _/ N _s / _V Λ _'

Γ N O O *V

/HL *

Γ b o Yy- N

'N**'

N

H ₂ N 1

H ₂ N \

CF ₃

CF 232a 261d

H ,Br

N.

N

N ¾ ϊ N H

_/ N

CO ₂ H Γ ^■ ¾] iTi O |"V ^Br

.N. N ¹ *'

H ₂ N 1

N¾

CF ₃

NH ₂

234a WVN H , Br 262a

N N.

N

O

Λ Ό

N.

Γ θ ^ 0C f X

N¾

^N CF NH ₂

NH _{2 3}

N—

/

267c £ 264a

N H

N

_/ N _s N ft

Γ * N b o

N

^N - Λ Me ⁰

H ₂ N rr ^N

CF ₃ NH ₂

Π

^■ =N

268b 265a

H , Br

F <7 N N.

/ N ft t\ f \ N (

N _> J Xir ^*

H ₂ N Λ Me ⁰

CF ₃ o c

NH ₂

OH

269c 266b =*. i

N H

N H N

_/ N _{s /} N _s N b o

Γ *

N /Λ o- ^N ^ c, Γ *

N lQf ^B ’

1

1 H ₂ N

H ₂ N

CF ₃

CF ₃ H ,N. Br

N

W Cr N

0

N r.V / Me

280g 2

0 r> 88c rr f \

F NH ₂

NH ₂

H N. Br

H^ ^Br N

N ¾ l\ N H l\

281a

N r.V 289a 7 N r.V /

N. n f N ^N X_> i

N-/

F

NH ₂ NH ₂ Γ N

H Br

Ki N N.

N \

O

282a r\ e 290g N. f NW r NCr N ⁵ > ^®

Br

OH IMH ₂

NH ₂

H N Br

N

N ¾ i\ w

283g rV 291a N. M A Me f NX-Π a f %

‘N ⁵⁵¹ NH ₂

NH ₂ CF ₃

E

H N. Br

N

N I N t\ V

O A Ae'

301a A 302a if N^ ^¾ N Me _N

\> _Me

NH ₂ NH ₂

CF ₃ CF ₃

H ,N Br

N .

:n !J/ N

TXP A O

303a A 30 if ⁿ ^N Me 7c * NrOSJrA ^N . r\ f \>

NH ₂ ^n:

NH ₂

CF ₃

\ \ H N. Br

N

N ¾ N ¾ λ ^

A N

304a ° 305a A °

O NH ₂ X O NH ₂ X

CF ₃ CF ₃

¾ ¾ r H

N N; .Br

N ¾ L\

Svie

308c 309a A _* ⁰

/ N=Vs A

NH ₂ N NH ₂ A

NA

Me NA

Me H ,CI

N;

W¾ <7 N

N λ /v

325c f O N

L O N

326 Λ.

N Λ c . N. y

N _¾ / N:

< n¾

N-/ N-/ 2 r>

NH CF ₃ CF

NH _{2 3}

H Br

<1 ¾7 N N.

N ¾ N \

N O rV r^o

327c 328f

N. / /

N-V r\

NH ₂ CF ₃ NH ₂

H N. ,Br

N

N H w

329a Λ° 330f Λ

/

NH ₂ $ NH¾ ₂ /:

H Br 1

N N.

\ Ν-χ H

N ¾ l\

Br

331a Λο ° 336c o ^N _v sJL V

H ₂ N \

NH¾ ₂ v / o;

H .N ,CI

N . tuV

N ¾ N ¾ t\

337a *V 315a rV

< N"\Y ^s _l f N=X¾T

NH ₂ NH ₂ ^s _i r> H

N , Br

<7 N:

N ¾ Ϊ y N

O

Λ °

359c N'V-N Me 360 M A rr c f \ N rc _s J I f \

NH ₂ NH ₂ r?

H Br

¾"¾ N N.

N ¾ Ϊ y N L\ y

361a Νχ^Ν Λ o 0 Me 367g r N IS ΛL /

Ni _s

<

NH ₂ N-/ rv°

CF ₃

NH ₂ it* O H Br

N N.

H^ ^Br

N y N \ o y

368a N A ⁰ 369g r ff N _¾ N.N /

N j

W <

N-A n¾

NH ₂ CF ₃

CF ₃ NH ₂

H ,N ,Br

<7 N ,

N ft o y y

362f Λ% e 363a rV f NX-Π ( NW

CF ₃

NH ₂ NH ₂ ^N ^CF ₃

H N. ,Br m N

Me

364e r 364d

N.A / Nr.V / " f Nt-Ps f N¾tJp

CF CF

Pharmaceutical Compositions

The invention provides pharmaceutical compositions, each comprising one or more compounds of the invention, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises a plurality of compounds of the invention, which may include pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

In certain embodiments, a pharmaceutical composition of the invention further comprises at least one additional pharmaceutically active agent other than a compound of the invention. The at least one additional pharmaceutically active agent can be an agent useful in the treatment of a disease or condition characterized by aberrant complement system activity.

Pharmaceutical compositions of the invention can be prepared by combining one or more compounds of the invention with a pharmaceutically acceptable carrier and, optionally, one or more additional pharmaceutically active agents. Methods of Use

The present invention provides compounds, and pharmaceutically acceptable salts thereof, that are useful for treating or preventing a disease or condition characterized by aberrant complement system activity.

In certain aspects, the invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use as a medicament.

In certain aspects, the invention provides methods of treating or preventing a disease or condition characterized by aberrant complement system activity. The method includes the step of administering to a subject in need thereof a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, thereby treating or preventing the disease or condition characterized by aberrant complement system activity.

By reducing complement system activity in the subject, the disease or condition characterized by aberrant complement system activity is treated.

Alternatively, in certain aspects, the invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease or condition characterized by aberrant complement system activity.

Alternatively, in certain aspects, the invention provides tire use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in treatment of a disease or condition characterized by aberrant complement system activity.

As used herein, a “disease or condition characterized by aberrant complement system activity” refers to any disease or condition in which it is desirable to reduce complement system activity. For example, it may be desirable to reduce complement system activity in tire setting of inappropriate activation or hyperactivation of the complement system.

In certain embodiments, the disease or condition characterized by aberrant complement system activity is an immunological disorder.

In certain embodiments, the disease or condition characterized by aberrant complement system activity is a disease of the central nervous system.

In certain embodiments, the disease or condition characterized by aberrant complement system activity is a neurodegenerative disease or neurological disease.

In certain embodiments, the disease or condition characterized by aberrant complement system activity is a renal disease. In certain embodiments, the disease or condition characterized by aberrant complement system activity is a cardiovascular disease.

In certain embodiments, the disease or condition characterized by aberrant complement system activity is a cardiometabolic disease.

In certain embodiments, the disease or condition characterized by aberrant complement system activity is selected from the group consisting of paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, organ transplant rejection, myasthenia gravis, neuromyelitis optica, membranoproliferative glomerulonephritis, dense-deposit disease, cold agglutinin disease, and catastrophic antiphospholipid syndrome.

In certain embodiments, the disease or condition is paroxysmal nocturnal hemoglobinuria.

In certain embodiments, the disease or condition is atypical hemolytic uremic syndrome.

In certain embodiments, the disease or condition is organ transplant rejection.

In certain embodiments, the disease or condition is myasthenia gravis.

In certain embodiments, the disease or condition is neuromyelitis optica.

In certain embodiments, the disease or condition is membranoproliferative glomerulonephritis.

In certain embodiments, the disease or condition is dense-deposit disease.

In certain embodiments, the disease or condition is cold agglutinin disease.

In certain embodiments, the disease or condition is catastrophic antiphospholipid syndrome.

In other embodiments, the disease or condition characterized by aberrant complement system activity is adult respiratory distress syndrome, myocardial infarct, lung inflammation, hyperacute rejection (transplantation rejection), sepsis, cardiopulmonary bypass, bums, asthma, restenosis, multiple organ dysfunction syndrome, Guillain-Barre syndrome, hemorrhagic shock, paroxysmal nocturnal hemoglobinuria, glomerulonephritis, systemic lupus erythematosus, rheumatoid arthritis, infertility, Alzheimer’s disease, organ rejection (transplantation), myasthenia gravis, multiple sclerosis, platelet storage, or hemodialysis.

In other embodiments, the disease or condition characterized by aberrant complement system activity is selected from the group consisting of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), warm autoimmune hemolytic anemia, IgA nephropathy C3 glomerulonephritis and focal segmental glomerulosclerosis In certain embodiments, the disease or condition characterized by aberrant complement system activity is a hematological disorder.

In other embodiments, the disease or condition characterized by aberrant complement system activity is an ocular disorder or an eye disorder.

In certain embodiments, the disease or condition characterized by aberrant complement system activity is macular degeneration, age-related macular degeneration (AMD), wet AMD, geographic atrophy, macular edema, diabetic macular edema, choroidal neovascularization (CNV), uveitis, Behcet’s uveitis, proliferative diabetic retinopathy, nonproliferative diabetic retinopathy, glaucoma, hypertensive retinopathy, a corneal neovascularization disease, post-comeal transplant rejection, a comeal dystrophic disease, an autoimmune dry eye disease, Stevens-Johnson syndrome, Sjogren’s syndrome, an environmental dry eye disease, Fuchs’ endothelial dystrophy, retinal vein occlusion, or postoperative inflammation.

In certain embodiments, the disease or condition characterized by aberrant complement system activity is angioedema, e.g., hereditary angioedema or acquired angioedema.

In certain embodiments, the disease or condition characterized by aberrant complement system activity is obesity', insulin resistance, diabetes, dyslipidemia, nephropathy, or neuropathy.

In certain embodiments, the disease or condition characterized by aberrant complement system activity is selected from the group consisting of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), paroxysmal nocturnal hemoglobinuria, and thrombotic microangiopathy.

In certain embodiments, the disease or condition characterized by aberrant complement system activity is selected from the group consisting of Alzheimer’s disease, multiple sclerosis, neuromyelitis optica, generalized myasthenia gravis, Guillain-Barre syndrome, Parkinson’s disease, and schizophrenia.

In certain embodiments, the disease or condition characterized by aberrant complement system activity is periodontitis.

In certain embodiments, the disease or condition characterized by aberrant complement system activity is Crohn’s disease.

In certain embodiments, the disease or condition characterized by aberrant complement system activity is selected from the group consisting of asthma chronic In certain embodiments, the disease or condition characterized by aberrant complement system activity is atherosclerosis.

In certain embodiments, the disease or condition characterized by aberrant complement system activity is selected from the group consisting of age-related macular degeneration (AMD), uveitis, glaucoma, and wet AMD.

In certain embodiments, the disease or condition characterized by aberrant complement system activity is myocardial infarction.

In certain embodiments, the disease or condition characterized by aberrant complement system activity is selected from the group consisting of atypical hemolytic uremic syndrome, C3 glomerulopathy, lupus nephritis, IgA nephropathy, and membranous nephropathy.

In certain embodiments, the disease or condition characterized by aberrant complement system activity is selected from the group consisting of rheumatoid arthritis, osteoarthritis, bullous pemphigoid, psoriasis, hidradenitis suppurativa, and bums.

In certain embodiments, the disease or condition characterized by aberrant complement system activity is hemodialysis.

In certain embodiments, the disease or condition characterized by aberrant complement system activity is selected from the group consisting of ischemia/reperfusion injury, acute kidney injury, and organ transplantation, e.g., kidney transplant.

In certain embodiments, the disease or condition characterized by aberrant complement system activity is selected from the group consisting of systemic inflammatory response syndrome, sepsis, septic shock, trauma, systemic lupus erythematosus, hereditary angioedema, and cancer.

In certain embodiments, the disease or condition characterized by aberrant complement system activity is selected from the group consisting of antibody-mediated rejection, antiphospholipid syndrome, Berger’s disease, C3 glomerulonephritis, cold agglutinin disease, cardiopulmonary bypass, dense-deposit disease, delayed graft function, geographic atrophy, granulomatosis with polyangiitis, graft versus host disease, hematopoietic stem cell transplant-related thrombotic microangiopathy, immune complex- mediated membranoproliferative glomerulonephritis, immune-mediated necrotizing myopathy, idiopathic polypoidal choroidal vasculopathy, microscopic polyangitis, pyoderma gangrenosum, Stargardt Disease 1, and warm type autoimmune hemolytic anemia. Formulations, Routes of Administration, and Dosing

The compounds of the invention, and pharmaceutically acceptable salts thereof, can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient, in a variety of forms adapted to the chosen route of administration, e.g., orally or parenterally, by intravenous, intraperitoneal, intramuscular, topical, or subcutaneous routes. Additional routes of administration are also contemplated by the invention.

Thus, the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1 % of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2% to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.

The tablets, troches, pills, capsules, and the like may also contain the following diluents and carriers: binders such as gum tragacanth, acacia, com starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as com starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and tire like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices. The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water or physiologically acceptable aqueous solution, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by tiie use of surfactants. The prevention of the action of microoiganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation can include vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc clay microcrystalline glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.

Examples of useful dermatological compositions which can be used to deliver the compounds of the invention to the skin are known in the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392; incorporated herein by reference), Geria (U.S. Pat. No. 4,992,478; incorporated herein by reference), Smith et al. (U.S. Pat. No. 4,559,157; incorporated herein by reference), and Wortzman (U.S. Pat. No. 4,820,508; incorporated herein by reference).

Useful dosages of the compounds of the invention can be determined, at least initially, by comparing their in vitro activity and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known in the art; for example, see U.S. Pat. No. 4,938,949 (incorporated herein by reference).

The amount of the compound, or pharmaceutically acceptable salt thereof, required for use in treatment will vary not only with the particular compound or salt selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.

In general, however, a suitable dose will be in the range of from about 0.5 to about 100 mg/kg body weight of the recipient per day, e.g., from about 3 to about 90 mg/kg of body weight per day, from about 6 to about 75 mg per kilogram of body weight per day, from about of 10 to about 60 mg/kg of body weight per day, or from about 15 to about 50 mg/kg of body weight per day.

Compounds of the invention, or pharmaceutically acceptable salts thereof, can be conveniently formulated in unit dosage form; for example, containing 5 to 1000 mg, 10 to 750 mg, or 50 to 500 mg of active ingredient per unit dosage form. In one embodiment, the invention provides a composition comprising a compound of the invention or desired dose may conveniently be presented in a single dose or as divided doses to be administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.

Compounds of the invention, or pharmaceutically acceptable salts thereof, can also be administered in combination with other therapeutic agents, for example, other agents that are useful for treating or preventing ischemia, blood loss, or reperfusion injury. In certain embodiments, compounds of the invention, and pharmaceutically acceptable salts thereof, can also be administered in combination with one or more other therapeutic agents that are useful for treating or preventing an ocular disorder or eye disorder.

Other delivery- systems can include time-release, delayed release, or sustained release delivery systems such as are well-known in the art. Such systems can avoid repeated administrations of the active compound, increasing convenience to the subject and the physician. Many types of release delivery systems are available and known to those of ordinary skill in the art. Use of a long-term sustained release implant may be desirable. Long-term release, as used herein, means that the delivery system or is implant constructed and arranged to deliver therapeutic levels of the active ingredient for at least 30 days, and preferably 60 days.

In certain embodiments, a compound of the invention is formulated for intraocular administration, for example direct injection or insertion within or in association with an intraocular medical device. In certain embodiments, a compound of the invention is formulated as an ophthalmic solution. In certain embodiments, a compound of the invention can be administered via ocular delivery, for example, by local ocular administration, including topical, intravitreal, periocular, transscleral, retrobulbar, juxtascleral, suprachoroidal, or sub-tenon administration. A compound of the invention can be administered via ocular delivery either alone or in combination with one or more additional therapeutic agents.

The compounds of tire invention may be formulated for depositing into a medical device, which may include any of a variety of conventional grafts, stents, including stent grafts, catheters, balloons, baskets, or other device that can be deployed or permanently implanted within a body lumen. As a particular example, it would be desirable to have devices and methods which can deliver compounds of the invention to the region of a body which has been treated by interventional technique In exemplary embedment, a compound of the invention may be deposited within a medical device, such as a stent, and delivered to the treatment site for treatment of a portion of the body.

Stents have been used as delivery vehicles for therapeutic agents (i.e., drags). Intravascular stents are generally permanently implanted in coronary or peripheral vessels. Stent designs include those of U.S. Pat. No. 4,733,655 (Palmaz), U.S. Pat. No. 4,800,882 (Gianturco), or U.S. Pat. No. 4,886,062 (Wiktor). Such designs include both metal and polymeric stents, as well as self-expanding and balloon-expandable stents. Stents may also be used to deliver a drag at the site of contact with the vasculature, as disclosed in U.S. Pat. No. 5,102,417 (Palmaz), U.S. Pat. No. 5,419,760 (Narciso, Jr.), U.S. Pat. No. 5,429,634 (Narciso, Jr.), and in International Patent Application Nos. WO 91/12779 (Medtronic, Inc.) and WO 90/13332 (Cedars-Sanai Medical Center), for example.

The term “deposited” means that the compound is coated, adsorbed, placed, or otherwise incorporated into the device by methods known in the art. For example, the compound may be embedded and released from within (“matrix type”) or surrounded by and released through (“reservoir type”) polymer materials that coat or span the medical device.

In the latter example, the compound may be entrapped within the polymer materials or coupled to the polymer materials using one or more the techniques for generating such materials known in the art. In other formulations, the compound may be linked to the surface of the medical device without the need for a coating, for example by means of detachable bonds, and release with time or can be removed by active mechanical or chemical processes. In other formulations, the compound may be in a permanently immobilized form that presents the compound at the implantation site.

In certain embodiments, the compound may be incorporated with polymer compositions during the formation of biocompatible coatings for medical devices, such as stents. The coatings produced from these components are typically homogeneous and are useful for coating a number of devices designed for implantation.

The polymer may be either a biostable or a bioabsorbable polymer depending on the desired rate of release or the desired degree of polymer stability, but frequently a bioabsorbable polymer is preferred for this embodiment since, unlike a biostable polymer, it will not be present long after implantation to cause any adverse, chronic local response. Bioabsorbable polymers that could be used include, but are not limited to, poly(L-lactic acid), polycaprolactone polyglycolide (PGA) polyflactide-co-glycolide) (PLLA/PGA) polyanhydride, poly(glycolic acid), poly(D-lactic acid), poly(L-lactic acid), poly(D, L-lactic acid), poly(D, L-lactide) (PLA), poly (L-lactide) (PLLA), poly(glycolic acid-co-trimethylene carbonate) (PGA/PTMC), polyethylene oxide (PEO), polydioxanone (PDS), polyphosphoester, polyphosphoester urethane, poly(amino acids), cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate), copoly(ether-estens) (e.g., PEO/PLA), polyalkylene oxalates, polyphosphazenes and biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, cross linked or amphipathic block copolymers of hydrogels, and other suitable bioabsoibable poplymers known in the art. Also, biostable polymers with a relatively low chronic tissue response such as polyurethanes, silicones, and polyesters could be used, and other polymers could also be used if they can be dissolved and cured or polymerized on the medical device such as polyolefins, polyisobutylene and ethylene-alphaolefin copolymers; acrylic polymers and copolymers, vinyl halide polymers and copolymers, such as polyvinyl chloride; polyvinylpyrrolidone; polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidene halides, such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile, polyvinyl ketones; polyvinyl aromatics, such as polystyrene, polyvinyl esters, such as polyvinyl acetate; copolymers of vinyl monomers with each other and olefins, such as ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetate copolymers; pyran copolymer; polyhydroxy-propyl-methacrylamide- phenol; polyhydroxyethyl-aspartamide-phenol; polyethyleneoxide-polylysine substituted with palmitoyl residues; polyamides, such as Nylon 66 and polycaprolactam; alkyd resins, polycarbonates; polyoxymethylenes; polyimides; polyethers; epoxy resins, polyurethanes; rayon; rayon-triacetate; cellulose, cellulose acetate, cellulose butyrate; cellulose acetate butyrate; cellophane; cellulose nitrate; cellulose propionate; cellulose ethers; and carboxymethyl cellulose.

Polymers and semipermeable polymer matrices may be formed into shaped articles, such as valves, stents, tubing, prostheses and the like.

In certain embodiments of the invention, the compound of the invention is coupled to a polymer or semipermeable polymer matrix that is formed as a stent or stent-graft device.

Typically, polymers are applied to the surface of an implantable device by spin coating, dipping, or spraying. Additional methods known in the art can also be utilized for this purpose Methods of spraying include traditional methods as well as microdeposition implantable device using photo-patteming to place the polymer on only specific portions of the device. This coating of the device provides a uniform layer around the device which allows for improved diffusion of various analytes through the device coating.

In certain embodiments of the invention, the compound is formulated for release from the polymer coating into the environment in which the medical device is placed. Preferably, the compound is released in a controlled manner over an extended time frame (e.g., months) using at least one of several well-known techniques involving polymer carriers or layers to control elution. Some of these techniques are described in U.S. Patent Application 2004/0243225A1, the entire disclosure of which is incorporated herein in its entirety.

Moreover, as described for example in U.S. Pat. No. 6,770,729, which is incorporated herein in its entirety, the reagents and reaction conditions of the polymer compositions can be manipulated so that the release of the compound from the polymer coating can be controlled. For example, the diffusion coefficient of the one or more polymer coatings can be modulated to control tire release of the compound from the polymer coating. In a variation on this theme, the diffusion coefficient of the one or more polymer coatings can be controlled to modulate the ability of an analyte that is present in the environment in which the medical device is placed (e.g., an analyte that facilitates the breakdown or hydrolysis of some portion of the polymer) to access one or more components within the polymer composition (and for example, thereby modulate the release of the compound from the polymer coating). Yet another embodiment of the invention includes a device having a plurality of polymer coatings, each having a plurality of diffusion coefficients. In such embodiments of the invention, the release of the compound from the polymer coating can be modulated by the plurality of polymer coatings.

In yet another embodiment of the invention, the release of the compound from the polymer coating is controlled by modulating one or more of the properties of the polymer composition, such as the presence of one or more endogenous or exogenous compounds, or alternatively, the pH of the polymer composition. For example, certain polymer compositions can be designed to release a compound in response to a decrease in the pH of the polymer composition.

Kits

The invention also provides a kit, comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, packaging ri l d i i f d i i ri h d f h i i h pharmaceutically acceptable salt thereof and the other therapeutic agent or agents to a mammal to treat or prevent a disease or condition characterized by aberrant complement activity. In one embodiment, the mammal is a human.

It will be understood by one of ordinary skill in the relevant arts that other suitable modifications and adaptations to the compositions and methods described herein are readily apparent from the description of the invention contained herein in view of information known to the ordinarily skilled artisan, and may be made without departing from the scope of the invention or any embodiment thereof.

EXAMPLES

Having now described the present invention in detail, the same will be more clearly understood by reference to the following examples, which are included herewith for purposes of illustration only and are not intended to be limiting of the invention.

Scheme 1

C0 ₂ ¾u r CO ₂ H

Preparation of (lR,3S,5R)-2-(2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl )-N-(6-bromo- 3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamid e (le)

Step-1: Preparation of tert-butyl 2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetate (lb)

A mixture of 9H-pyrimido[4,5-b]indol-4-amine (la) (0.50 g, 2.71 mmol; CAS# 400754-64- 5), fcrt-butyl 2-bromoacetate (0.582 g, 2.99 mmol) and CS2CO3 (1.061 g, 3.26 mmol) in DMF (20 mL) was stirred at RT for 3 h diluted with H2O (30 mL) and extracted with EtOAc (30 filtered and concentrated under vacuum and purified by flash column chromatography [silica gel (24 g), eluting with MeOH in DCM from 0-3%] to provide /erf-butyl 2-(4-amino-9H- pyrimido[4,5-b]indol-9-yl)acetate (lb) (0.64 g, 79 % yield) as a yellow solid; Ή NMR (300 MHz, DMSO-ifc) δ 8.35 (d, J= 7.8 Hz, 1H), 8.29 (s, 1H), 7.55 (d,./= 8.1 Hz, 1H), 7.41 (dd, J = 8.3, 7.1 Hz, 1H), 7.35 - 7.18 (m, 3H), 5.12 (s, 2H), 1.41 (s, 9H).

Step-2: Preparation of 2-(4-amino-9H-pyrimido [4, 5 -b] indol-9-yl)acetic acid (lc)

A mixture of te/7-butyl 2-(4-amino-9H-pyiimido[4,5-b]indol-9-yl)acetate (lb) (0.63 g, 2.112 mmol) and 2,2,2-trifluoroacetic acid (12.12 mL, 31.7 mmol) in DCM (20 mL) was stirred at RT for 16 h and concentrated in vacuum to dryness to afford 2-(4-amino-9H-pyrimido[4,5- b]indol-9-yl)acetic acid (lc) (0.74 g, 99%) TFA salt as an orange slid; Ή NMR (300 MHz, DMSO-cfe) δ 8.55 (s, 1H), 8.49 (d, J= 7.8 Hz, 1H), 8.43 - 8.20 (m, 2H), 7.77 (d, J= 8.2 Hz, 1H), 7.58 - 7.48 (m, 1H), 7.42 (t, J= 7.6 Hz, 1H), 5.26 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) b -74.71.

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl )-N-(6- bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carb oxamide (le)

To a solution of 2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (lc) (50.7 mg, 0.142 mmol) TFA salt, ( lR,3S,5R)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1. OJhexane- 3-carboxamide (Id) HC1 salt [(43 mg, 0.129 mmol); prepared according to the procedure reported by Wiles, Jason A. et al., PCT Int. Appl. (2017), WO 2017035353 A1 20170302; incorporated by reference] and HATU (59.0 mg, 0.155 mmol) in DMF (5 mL) was added dropwise DIPEA (84 mg, 0.646 mmol) and stirred at RT for 16 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (20 mL x 2). The combined organics were washed with 0.5 M NaOH (25 mL), H2O (25 mL x 3), brine (25 mL), dried, filtered and concentrated in vacuum to dryness. The residue obtained was purified by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0-5%] to provide product as a pale oil, which was dissolved in MeOH (5 mL) and purified by reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-60%] to provide (lR,3S,5R)-2-(2-(4-amino-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (le) (48 mg, 71 % yield) HC1 salt as a white solid. Ή NMR (300 MHz, DMSO-ifc) δ 10.28 (s, 1H, DzO exchangeable), 8.83 - 8.59 (m, 3H, 2H DzO exchangeable), 8.54 (d, J = 7.9 Hz, 1H),

771 (d J = 8 2 Hz 1H) 762 (d J = 79 Hz 1H) 756 (t J = 78 Hz 1H) 745 (m 2H) 5 75 1H), 2.41 (m, 1H), 2.27 (m, 1H), 1.99 (s, 4H), 1.11 (m, 1H), 0.82 (m, 1H); MS (ES+): 520.0 (M+l); (ES-): 518.0 (M-l); Analysis calculated for C24Hz2BrN ₇ 02.1.1HC1.2.5H20: C, 47.60; H, 4.68; Cl, 6.44; N, 16.19; Found: C, 47.57; H, 4.60; Cl, 6.33; N, 16.19.

Scheme 2

Preparation of (lR,3S,5R)-2-(2-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)ac etyl)-N-(6- bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carb oxamide (2d)

Step-1: Preparation of tort-butyl 2-(4-aminopyrrolo[2, 1 -f) [ 1 ,2,4]triazin-7-y l)acetate (2b)

To a suspension of zinc (1.842 g, 28.2 mmol) (Note: Zinc dust was activated using aqueous 0.1 M HC1, followed by washing thoroughly with H2O, EtOH and Et20, and drying at 100 °C under vacuum before use) and TMSCI (0.179 mL, 1.408 mmol) in THF (5 mL) at 50 °C was added dropwise tort-butyl 2-bromoacetate (2.75 g, 14.08 mmol) in THF (5 mL) under an argon atmosphere. The mixture was heated at 50 °C for 30 min cooled to RT and was added via syringe to a suspension of 7-bromopyrrolo [ 1 ,2-f] [ 1 ,2,4]triazin-4-amine (2a) (1.00 g, 4.69 mmol; CAS # 937046-98-5), Pd ₂ (dba) ₃ (0.215 g, 0.235 mmol) and XPhos (0.224 g, 0.469 mmol) in THF (10 mL) at RT under an argon atmosphere and heated at 60 °C under argon for 16 h. The reaction mixture was cooled to RT diluted with EtOAc (30 mL), added solid NH*C1 (2 g) stirred at RT for 15-min and filtered to remove insoluble solids. The insoluble residue was washed with EtOAc (20 mL) and the filtrate was washed with saturated NHtCl (30 mL), H2O (30 mL), brine (30 mL), dried, filtered and concentrated in vacuum. The obtained residue was purified by flash column chromatography [SKfcgel (24 g), eluting with EtOAc in (2b) (0.65 g, 56 % yield) as a yellow solid; Ή NMR (300 MHz, DMSO-ifc) δ 7.82 (s, 1H), 7.66 (s, 2H), 6.83 (d, J = 4.3 Hz, 1H), 6.52 (d, J = 4.3 Hz, 1H), 3.84 (s, 2H), 1.40 (s, 9H); MS (ES+): 249 (M+l), (ES-): 247 (M-l).

Step-2: Preparation of 2-(4-aminopyrrolo[2, 1 -f] [ 1 ,2,4] triazin-7 -y l)acetic acid (2c)

Compound 2c was prepared according to the procedure reported in step-4 of scheme- 1, from tort-butyl 2-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)acetate (2b) (0.65 g, 2.62 mmol) using TFA (4.01 mL, 52 mmol) in DCM (20 mL) and stirring at RT for 16 h. The reaction mixture was concentrated in vacuum to afford 2-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)acetic acid (2c) (1.05 g) TFA salt as an orange solid; Ή NMR (300 MHz, DMSO -d ₆ ) δ 9.67 (dd, J = 5.7, 2.9 Hz, 1H), 9.11 (s, 1H), 8.18 (s, 1H), 7.37 (d, J = 4.6 Hz, 1H), 6.80 (d, J = 4.5 Hz, 1H), 3.96 (s, 2H). ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -74.71; MS (ES+): 193 (M+l), (ES-): 191 (M-l).

Step-3: Preparation of ( 1 R, 3 S,5 R)-2-(2-(4-aminopyrrolo [2, 1 -f] [ 1 ,2,4]triazin-7 -y l)acetyl)-N - (6-bromo-3-metfaylpyridin-2-yl)-2-azabicyclo[3.1.0] hexane-3 -carboxamide (2d)

Compound 2d was prepared according to the procedure reported in step-3 of scheme- 1 from TFA salt of 2-(4-aminopyrrolo[2,l-f|[l,2,4]triazin-7-yl)acetic acid (2c) (54.7 mg, 0.179 mmol) in DMF (5 mL) using HC1 salt of ( 1 R,3 S,5 R)-N -(6-bromo-3 -me thy lpyridin-2-y l)-2- azabicyclo[3.1.0]hexane-3-carboxamide (Id) (54 mg, 0.162 mmol), HATU (74.1 mg, 0.195 mmol), DIPEA (105 mg, 0.812 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g) eluting with MeOH in DCM from 0 - 5%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-60%]

( 1 R,3 S,5R)-2-(2-(4-aminopynolo[2, 1 -fj [ 1 ,2,4]triazin-7-yl)acetyl)-N-(6-bromo-3- methylpyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (2d) (20 mg, 26 % yield) as a white solid; Ή NMR (300 MHz, DMSO-i/s) δ 10.25 (s, 1H, D ₂ 0 exchangeable), 10.01 (s, 1H, DzO exchangeable), 9.21 (s, 1H, D2O exchangeable), 8.20 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 4.6 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 6.84 (d, J = 4.6 Hz, 1H), 4.38 (dd, J = 9.1, 5.2 Hz, 1H), 4.31 (d, J = 17.0 Hz, 1H), 4.17 (d, J = 17.0 Hz, 1H), 3.68 - 3.66 (m, 1H), 2.36 (m, 1H), 2.24 (m, 1H), 2.07 (s, 3H), 1.92 - 1.77 (m, 1H), 0.96 (m, 1H), 0.62 (m, 1H); MS (ES+): 470.0 (M+l), (ES-): 468.0 (M-l).

Scheme 3

Preparation of (2S,4R)- l-(2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-brom o-3- methylpyridin-2-yI)-4-fluoropyrrolidine-2-carboxamide (3b)

Compound 3b was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of2-(4-amino-9H-pytimido[4,5-b]indol-9-yl)acetic acid (lc) (150 mg, 0.421 mmol) in DMF (5 mL) using HC1 salt of (2S,4R)-N-(6-bromo-3-methylpyridin-2-yl)-4- fluoropyrrolidine-2-carboxamide (3a) [(143 mg, 0.421 mmol); prepared according to the procedure reported by Wiles, Jason A. et al., PCT Int. Appl. (2017), WO 2017035355 A1 20170302; incorporated by reference], HATU (192 mg, 0.505 mmol) DIPEA (272 mg, 2.105 mmol) and stirring at RT for 16 h. This gave after workup and purification by reverse-phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-60%] (2S,4R)-l-(2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N -(6- bromo-3-methylpyridin-2-yl)-4-fluoropyrrolidine-2-caiboxamid e (3b) (123 mg, 56 % yield) HC1 salt as a white solid; ¾i NMR (300 MHz, DMSO-dk) δ (a mixture of two retainers) 10.92 (s) and 10.48 (s) (2s, 1H, D2O exchangeable), 8.73 (s, 3H, D2O exchangeable), 8.62 (s, 1H), 8.53 (d, J= 7.8 Hz, 1H), 7.70 (d ,J= 8.0 Hz, 1H), 7.67 - 7.49 (m, 2H), 7.43 (t, J= 7.9 Hz, 2H), 5.67 (d, J= 4.0 Hz, 1H), 5.63 - 5.45 (m, 1H), 5.37 (d, J= 17.3 Hz, 1H), 4.57 (t, J= 9.4, 7.6 Hz, 1H), 4.48 - 4.23 (m, 1H), 4.20 - 3.95 (m, 1H), 2.79 - 2.49 (m, 4H), 2.32 - 2.05 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-tfc) δ -176.05, -176.37; MS (ES+): 526.0 (M+l), 524.0 (M- 1); Analysis calculated for C23H2iBrFN ₇ 02.HCl 2.75H20: C, 45.11; H, 4.53; Cl, 5.79; N, 16.01; Found: C, 45.12; H, 4.29; Cl, 5.71; N, 15.84.

Scheme 4

Preparation of (lR,3S,5R)-2-(2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl )-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4b)

Compound 4b was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-9H-pyrimido[4,5-bJindol-9-yl)acetic acid (lc) (150 mg, 0.421 mmol) in DMF (5 mL) using HC1 salt of ( 1 R,3 S,5R)-N-(6-bromopyridin-2-yI)-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (4a) [(134 mg, 0.421 mmol); prepared according to the procedure reported by Altmann, Eva et al., PCT Int. Appl. (2012), WO 2012093101 A1 20120712; incorporated by reference], HATU (192 mg, 0.505 mmol), DIPEA (272 mg, 2.105 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 5%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-60%] (lR,3S,5R)-2-(2-(4-amino-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1 ,0]hexane-3- carboxamide (4b) (110 mg, 52 % yield) HC1 salt as a white solid. Ή NMR (300 MHz, DMSO-ifc) δ 10.77 (s, 1H, D2O exchangeable), 8.63 (m, 3H, 2H DzO exchangeable), 8.53 (d, J = 7.9 Hz, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.76 - 7.66 (m, 2H), 7.58 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 5.78 (d, J = 17.4 Hz, 1H), 5.44 (d, J = 17.3 Hz, 1H), 4.43 (dd, J = 9.0, 5.5 Hz, 1H), 3.93 (m, 1H), 2.44 - 2.16 (m, 2H), 2.01 - 1.86 (m, 1H), 1.08 (m, 1H), 0.78 (m, 1H); MS (ES+) 506.0 (M+l); (ES-): 504.0 (M-l); Analysis calculated for: C23H2oBrN ₇ 02.HCl. 2.25Ι¾0: C, 47.36; H, 4.41; Cl, 6.08; N, 16.81; Found: C, 47.25; H,

4.18; Cl, 6.02; N, 16.70.

Scheme 5

Preparation of (2S,4R)- 1 -(2-(4-ammo-7H-py rrolo [2,3 -d] pyrimidin-7 -yl )acetyl)-N-(6- bromopyridin-2-yl)-4-fiuoropyrrolidine-2-carboxamide (5e)

Step-3: Preparation of tort-butyl 2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (5b)

Compound 5b was prepared according to the procedure reported in step-1 of scheme- 1, from 7H-pyrrolo[2,3-d]pyrimidin-4-amine (5a) (1.0 g, 7.45 mmol; CAS # 1500-85-2) in DMF (20 mL) using tort-butyl 2-bromoacetate (1.600 g, 8.20 mmol), CS2CO3 (2.91 g, 8.95 mmol) and stirring at RT for 3 h. This gave after workup and purification by flash column chromatography, [silica (24 g), eluting with 0-3% MeOH in DCM] tort-butyl 2-(4-amino-7H- pyrrolo[2,3-d]pyrimidin-7-yl)acetate (5b) (0.62 g, 34 % yield) as a yellow solid; 'HNMR (300 MHz, DMSO-cfe) δ 8.04 (s, 1H), 7.12 (d, J = 3.5 Hz, 1H), 6.99 (s, 2H), 6.54 (d, J = 3.5 Hz, 1H), 4.86 (s, 2H), 1.41 (s, 9H); MS (ES+): 249 (M+l).

Step-4: Preparation of 2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (5c)

Compound 5c was prepared according to the procedure reported in step-2 of scheme- 1, from tort-butyl 2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (5b) (0.62 g, 2.497 mmol) using TFA (19.11 mL, 49.9 mmol) in DCM (20 mL) and stirring at RT for 16 h. This gave after workup 2-(4-amino-7H-pyrrolo[2,3-d]pyrimidm-7-yl)acetic acid (5c) (1.42 g) TFA salt as an orange solid; ¾NMR (300 MHz, DMSO-ifc) δ 9.00 (s, 2H), 8.39 (s, 1H), 7.50 (d, J= 3.5 Hz, 1H), 6.93 (d, J= 3.5 Hz, 1H), 5.05 (s, 2H); MS (ES+): 193 (M+l); (ES-): 191 (M-l). Step-5: Preparation of (2S,4R)-l-(2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetyl )-N-(6- bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (5e)

Compound 5e was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-7H-pyrrolo[2,3-dJpyrimidin-7-yl)acetic acid (5c) (137 mg, 0.448 mmol) in DMF (5 mL) using TFA salt of (2S,4R)-N-(6-bromopyridin-2-yl)-4- fluoropyrrolidine-2-carboxamide (5d) [(150 mg, 0.373 mmol); prepared according to the procedure reported by Wiles, Jason A. et al., PCT Int. Appl. (2017), WO 2017035348 A1 20170302; incorporated by reference], HATU (170 mg, 0.448 mmol), DIPEA (241 mg, 1.865 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with 0 - 5% MeOH in DCM] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-60%] (2S,4R)-l-(2-(4-amino-7H-pyrrolo[2,3- d]pyrimidin-7-yl)acetyl)-N-(6-bromopyridin-2-yl)-4-fluoropyr rolidine-2-carboxamide (5e) (84 mg, 49% yield) as a white solid; Ή NMR (300 MHz, DMSO-de) δ (a mixture of two rotamers) 11.36 (s) and 11.03 (s) (2s, 1H, DzO exchangeable), 9.22 (s, 2H, D2O exchangeable), 8.36 (s, 1H), 8.01 (d,J= 8.2 Hz, 1H), 7.71 (t,J= 8.0 Hz, 1H), 7.40 (d,J= 3.5 Hz, 1H), 7.33 (d, J= 7.7 Hz, 1H), 6.93 (d, ./= 3.5 Hz, 1H), 5.66 - 5.39 (m, 1H), 5.33 (d ,J= 17.1 Hz, 1H), 5.18 (d, J= 17.1 Hz, 1H), 4.65 (t, J= 8.5 Hz, 1H), 4.26 - 4.06 (m, 1H), 3.89 (ddd, J= 38.2, 12.2, 3.0 Hz, 1H), 2.63 - 2.43 (m, 1H), 2.25 - 1.95 (m, 1H); ¹⁹ F NMR(282 MHz, DMSOnt/d) δ -175.70, -175.96; MS (ES+): 462.0 (M+l), 460.0 (M-l); Analysis calculated for Ci8H17BrFN7O2.HCl.2H2O: C, 40.43; H, 4.15; Cl, 6.63; N, 18.33; Found: C, 40.19; H, 3.86; Cl, 6.98; N, 17.96.

Scheme 6

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamid e (6e)

Step-1: Preparation of 6-methyl-9H-pyrimido[4,5-b]indol-4-amine (6b)

To a solution of triethyl orthoformate (47.7 mL, 450 mmol), AcOH (6.43 mL, 112 mmol) was added 2-amino-5-methyl- lH-indole-3-carbonitrile (6a) (3.85 g, 22.49 mmol) and NEUOAc (8.67 g, 112 mmol) in a 350-mL pressure vessel and heated at 100 °C under pressure for 16 h. The reaction mixture was diluted with H2O (20 mL) and stirred for 15 min. The mixture was then filtered and the solid was washed H2O and air dried to provide 6- methyl-9H-pjrimido[4,5-b]indol-4-amine (6b) (3.60 g, 81%) as a pale-yellow solid; Ή NMR (300 MHz, DMSO-tifc) δ 11.67 (s, 1H), 8.22 (s, 1H), 8.12 (s, 1H), 7.32 (d,J= 8.2 Hz, 1H), 7.17 (dd,J= 8.3, 1.5 Hz, 1H), 7.07 (s, 2H), 2.45 (s, 3H); MS (ES+): 1.99 (M+l), (ES-): 197 (M-l).

Step-2: Preparation of terf-butyl 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetate

(6c)

Compound 6c was prepared according to the procedure reported in step-1 of scheme- 1, from 6-methyl-9H-pyrimido[4,5-b]indol-4-amine (6b) (2.00 g, 10.09 mmol; CAS # 1242140-67-5) in DMF (20 mL) using tert-butyl 2-bromoacetate (2.362 g, 12.11 mmol), CszCOs (6.57 g,

20.18 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (20 g), eluting with MeOH in DCM from 0-3%] tert- butyl yellow solid; Ή NMR (300 MHz, DMSO-tfc) δ 8.26 (s, 1H), 8.18 (s, 1H), 7.42 (d,J= 8.3 Hz, 1H), 7.29 - 7.15 (m, 3H), 5.08 (s, 2H), 2.47 (s, 3H), 1.40 (s, 9H); MS (ES+): 313 (M+l), (ES-): 311 (M-l).

Step-3: Preparation of 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (6d) Compound 6d was prepared according to the procedure reported in step-2 of scheme- 1, from te/7-butyl 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (6c) (0.220 g, 0.704 mmol) using TFA (8.03 mg, 7.04) in DCM (10 mL) and stirring at RT for 16 h. This gave after workup 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (6d) (300 mg) TFA salt as a purple solid; Ή NMR (300 MHz, DMSO-i/e) δ 8.54 (d, J = 1.1 Hz, 1H), 8.48 - 8.26 (m, 3H), 7.67 (d, J= 8.4 Hz, 1H), 7.38 (d, J= 8.6 Hz, 1H), 5.24 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-i/e) δ -74.24; MS (ES+): 257 (M+l), (ES-): 255 (M-l).

Step-4: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yI)-2-azabicycIo[3.1.0]hexane -3-carboxamide (6e)

Compound 6e was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-vi)acetic acid (6d) (50 mg, 0.135 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.OJhexane-3-carboxamide (4a) (43 mg, 0.135 mmol), HATH (61.6 mg, 0.162 mmol), DIPEA (87 mg, 0.675 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with 0 - 5% MeOH in DCM] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-60%] (lR,3S,5R)-2-(2-(4- amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bro mopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (6e) (48 mg, 68 % yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-flfc) δ 10.76 (s, 1H, D ₂ 0 exchangeable), 8.88 (s, 2H, D2O exchangeable), 8.68 (s, 1H), 8.40 (s, 1H), 8.01 (d, J= 8.1 Hz, 1H), 7.71 (t ,J= 8.0 Hz, 1H), 7.63 (d, J= 8.4 Hz, 1H), 7.42 (dd, ./= 8.3, 1.6 Hz, 1H), 7.32 (d, J= 7.7 Hz, 1H), 5.76 (d, J= 17.3 Hz, 1H), 5.41 (d ,J= 17.1 Hz, 1H), 4.42 (dd, J= 9.0, 5.5 Hz, 1H), 3.92 (m, 1H), 2.34 (m, 1H), 2.21 (m, 1H), 1.92 (m, 1H), 1.07 (m, 1H), 0.77 (m, 1H); MS (ES+): 520.0 (M+l); (ES-): 518.0 (M-l); Analysis calculated for C24H22BrN702.1.25HC1.2.75H20: C, 46.83; H, 4.71; Cl, 7.20; N, 15.93; Found: C, 46.68; H, 4.62; Cl, 7.26; N, 15.75.

Scheme 7

Preparation of (2S,4R)-l-(2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl) acetyl)-N-(3- chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (7b)

Compound 7b was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-methyl-9H-pyrimido|4,5-b]indol-9-yl)acetic acid (6d) (50 mg, 0.135 mmol) in DMF (5 mL) using TFA salt of (2S,4R)-N-(3-chloro-2-fluorobenzyl)-4- fluoropyrrohdine-2-carboxamide (7a) [(52.5 mg, 0.135 mmol); prepared according to the procedure reported in Wiles, Jason A. et al., PCT Int. Appl. (2017), WO 2017035349 A1 20170302; incorporated by reference], HATU (61.6 mg, 0.162 mmol) DIPEA (0.118 mL, 0.675 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 5%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-60%] (2S,4R)-l-(2-(4-amino-6- methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(3-chloro-2-fl uorobenzyl)-4- fhxoropyrrohdine-2-carboxamide (7b) (30 mg, 43 % yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-tifc) δ (a mixture of two rotamers) 9.12 (s) and 8.73 - 8.47 (m)(s and m,

4H, 2H exchangeable), 8.37 (s, 1H), 7.60 (d, 7= 8.4 Hz, 1H), 7.46 - 7.35 (m, 1H), 7.35 - 7.25 (m, 1H), 7.14 (td, 7= 8.8, 8.4, 3.0 Hz, 1H), 6.86 (t ,7= 7.9 Hz, 1H), 5.65 - 5.49 (m, 1H), 5.46 - 5.37 (m, 1H), 5.32 (d, 7= 17.3 Hz, 1H), 4.51 - 4.13 (m, 4H), 4.00 (ddd, 7= 37.1, 12.7, 3.1 Hz, 1H), 2.45 (s, 4H), 2.25 - 1.90 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-cfc) δ -121.26, - 121.77, -176.26, -176.48; MS (ES+): 513.0 (M+l), 511.0 (M-l); Analysis calculated for C25H23ClF2N6O2.HCl.2H2O: C, 51.29; H, 4.82; Cl, 12.11; N, 14.36; Found: C, 51.22; H, 4.90; Cl, 12.01; N, 14.43.

Scheme 8

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N- (6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-c arboxamide (8b)

Compound 8b was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (6d) (50 mg, 0.135 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-5- methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) [(44.9 mg, 0.135 mmol); prepared according to the procedure reported by Wiles, Jason A. et al., PCT Int. Appl. (2017), WO 2017035353 Al 20170302], HATU (61.6 mg, 0.162 mmol), DIPEA (87 mg, 0.675 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with 0 - 5% MeOH in DCM] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-60%] (lR,3S,5R)-2-(2-(4-amino-6-methyl-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5- methyl-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (8b) (40 mg, 55 % yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfe) δ 10.76 (s, 1H, D ₂ 0 exchangeable), 8.57 (s, 1H), 8.47 (s, 2H, DzO exchangeable), 8.33 (s, 1H), 8.01 (d, J= 8.2 Hz, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.37 (d,J= 8.4 Hz, 1H), 7.31 (d, J= 7.7 Hz, 1H), 5.68 (d, J= 17.3 Hz, 1H), 5.34 (d, J= 17.2 Hz, 1H), 4.36 (dd, J= 9.0, 5.9 Hz, 1H), 3.71 - 3.66 (m, 1H), 2.59 - 2.39 (m, 4H), 1.97 (dd, J= 13.2, 5.8 Hz, 1H), 1.30 (s, 3H), 1.05 - 0.96 (m, 1H), 0.96 - 0.88 (m, 1H); MS (ES+) 534.0 (M+l), 532.0 (M-l).

Scheme 9

Preparation of (lR,3S,5R)-2-(2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl )-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (9a)

Compound 9a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (lc) (50 mg, 0.14 mmol) in DMF (1.5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-5-methyl-2- azabicyclo[3.1.0]hexane-3-caiboxamide (8a) (46.7 mg, 0.14 mmol), HATU (80 mg, 0.211 mmol), DIPEA (0.122 mL, 0.702 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0-100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl )-N-(6-bromopyridin-2-yl)-5- methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (9a) (49 mg, 67% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-tfc) δ 10.78 (s, 1H, DzO exchangeable), 8.77 (s, 2H, DzO exchangeable), 8.66 (s, 1H), 8.54 (d, J= 7.9 Hz, 1H), 8.01 (d, J= 8.2 Hz, 1H), 7.75 - 7.67 (m, 2H), 7.61 - 7.55 (m, 1H), 7.45 (t, J= 7.5 Hz, 1H), 7.32 (d, J= 7.7 Hz, 1H), 5.75 (d, J= 17.4 Hz, 1H), 5.39 (d,J= 17.3 Hz, 1H), 4.38 (dd, J= 9.1, 5.9 Hz, 1H), 3.71 (dd, .7= 5.5, 2.4 Hz, 1H), 2.49 - 2.41 (m, 1H), 1.99 (dd, J= 13.3, 5.9 Hz, 1H), 1.31 (s, 3H), 1.02 (t, J= 5.4 Hz, 1H), 0.94 (dd, J= 5.4, 2.4 Hz, 1H); MS (ES+): 520.0 (M+l), 542.0 (M+Na); (ES-): 518.0 (M-l); Analysis calculated for Cz4HzzBrN ₇ 0z.1 ,75(HzO).1.25(HC1): C, 48.25; H, 4.51; Cl, 7.42; N, 16.41; Found: C, 48.06; H, 4.27; Cl, 7.28; N, 16.27.

Scheme 10

' CH

ΝΗ _{Ζ 3}

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9- yl)acetyI)-N- (6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]h exane-3-carboxamide (10b)

Compound 10b was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (6d) (50 mg, 0.135 mmol) in DMF (2 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromo-3- methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (10a) [(46.7 mg, 0.14 mmol); prepared according to the procedure reported by Wiles, Jason A. et al., PCT Int. Appl. (2018), WO 2018160889 Al 20180907; incorporated by reference], HATU (80 mg, 0.211 mmol), DIPEA (0.122 mL, 0.702 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0-100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-ammo-6-methyl-9H-pyrimido[4,5-b]indo]-9-y l)acetyl)-N-(6- bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexa ne-3-carboxamide (10b) (49 mg, 67% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO^fe) δ 10.29 (s, 1H,

D2O exchangeable), 8.72 - 8.51 (m, 3H, 2H D2O exchangeable), 8.37 (s, 1H), 7.71 - 7.53 (m, 2H), 7.45 (d, J= 7.9 Hz, 1H), 7.38 (d, ./= 8.5 Hz, 1H), 5.67 (d, J= 17.4 Hz, 1H), 5.38 (d, J= 17.3 Hz, 1H), 4.36 (dd, 9.2, 5.2 Hz, 1H), 3.66 (dd, J= 5.6, 2.4 Hz, 1H), 2.61 - 2.52 (m, 4H), 2.05 (d, J= 5.4 Hz, 1H), 2.01 (s, 3H), 1.33 (s, 3H), 1.14 - 0.91 (m, 2H); MS (ES+): 548.0 (M+l), 569.9 (M+Na); (ES-): 546.0 (M-l); Analysis calculated for C26H26BrN ₇ 02.3H20.1 .15HC1: C, 48.46; H, 5.19; Cl, 6.33; N, 15.21; Found: C, 48.64; H, 5.03; Cl, 6.07; N, 15.02.

Scheme 11 CF ₃ H

O- CO ₂ H H ₂ N ^• NH

NC CN HC(OMe) ₃ , NH4OAC N 6.. li Br^CO _j feu

I

° -b - AcOH H \ CS2C03

Cut, NC ₂ N K2CO3

CF ₃ CF ₃

11a 11b 11c l

HN·

,Br

/— C0 ₂ H NH

/— C(¾'Bu Γ V- N ¾ l\

N N. °

10a _→ 0 Br >

Nf V-N. _ _ TFA f f H ₂ N \ HATU, DIPEA Λ °

N.

H ₂ N \ N¾

CF ₃ <

CF ₃ N-/ rs

C

11d 11e F

NHa ₃ 11f

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5 -b]indol-9- yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabi cyclo[3.1 ,0]hexane-3- carboxamide (Ilf)

Step-1: Preparation of 2-amino-5 -(trifluoromethyl)- 1 H-indole-3 -carbonitrile (lib)

A mixture of 2,2,2-trifluoro-N-(2-iodo-4-(trifluoromethyl)phenyl)acetamid e (11a) (4.00 g, 10.44 mmol), malononitrile (0.828 g, 12.53 mmol), L-proline (0.240 g, 2.089 mmol), Cui (0.199 g, 1.044 mmol), and K2CO3 (2.89 g, 20.89 mmol) were suspended in a 1:1 mixture of DMSO (20 mL) and HzO (20 mL) and stirred at 60 °C for 16 h under an argon atmosphere. The reaction mixture was diluted with saturated NH4CI (30 mL) and extracted with EtOAc (30 mL x 3). The combined organics were washed with HzO (30 mL x 4), brine (30 mL), dried, filtered and concentrated in vacuum. The residue obtained was purified by flash column chromatography [SiOzgel (40 g), eluting with EtOAc in hexane from 0-50%] to provide 2-amino-5 -(trifluoromethyl)- 1 H-indole-3 -carbonitrile (lib) (1.24 g, 53 % yield) as an orange solid; Ή NMR (300 MHz, DMSO-ifc) δ 11.14 (s, 1H), 7.37 (d, J = l .7 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 7.22 (dd, J = 8.4, 1.8 Hz, 1H), 7.12 (s, 2H). ^!9 F NMR (282 MHz, DMSO-cfc) δ -58.93; MS (ES+): 226 (M+l); (ES-): 224 (M-l).

Step-2: Preparation of 6-(trifluoromethy l)-9H-pyrimido [4,5 -b] indol-4-amine (11c)

Compound 11c was prepared according to the procedure reported in step-1 of scheme-6, from 2-amino-5-(trifluoromethyl)-lH-indole-3-carbonitrile (lib) (1.24 g, 5.51 mmol) using trimethyl orthoformate (18.12 mL, 165 mmol), AcOH (1.575 mL, 27.5 mmol) and NH*OAc MeOH in DCM from 0-5%] 6-(trifluoromethyl)-9H-pyTimido[4,5-b]indol-4-amine (11c) (1.13 g, 4.48 mmol) as apale yellow solid; Ή NMR (300 MHz, DMSO-^e) δ 12.25 (s, 1H), 8.78 (s, 1H), 8.31 (s, 1H), 7.66 (dd, J = 8.4, 1.7 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.46 (s, 2H). ¹⁹ FNMR (282 MHz, DMSO-<fc) δ -58.13; MS (ES+): 253 (M+l); (ES-): 251 (M-l). Step-3: Preparation of tert-butyl 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9- yl)acetate (lid)

Compound lid was prepared according to the procedure reported in step-1 of scheme- 1, from 6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-4-amine (11c) (0.75 g, 2.97 mmol) in DMF (20 mL) using terf-butyl 2-bromoacetate (0.580 g, 2.97 mmol), CS2CO3 (1.163 g, 3.57 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH in DCM from 0-3%] /erf-butyl 2-(4- amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)aceta te (lid) (0.89 g, 82% yield) as a pale orange solid; >H NMR (300 MHz, DMSCM _> ) δ 8.83 (s, 1H), 8.36 (s, 1H), 7.84 - 7.70 (m, 2H), 7.60 (s, 2H), 5.21 (s, 2H), 1.41 (s, 9H).

Step-4: Preparation of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (lie)

Compound lie was prepared according to the procedure reported in step-2 of scheme- 1, from te/f-butyl 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl) acetate (lid) (0.89 g, 2.429 mmol) using TFA (4.43 g, 38.9 mmol) in DCM (7 mL) and stirring at RT for 16 h. This gave after workup 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (lie) (1.26 g) TFA salt as an orange solid; Ή NMR (300 MHz, DMSO-afe) δ 8.96 (s, 1H), 8.57 (s, 1H), 8.43 (s, 2H), 7.96 (d, J = 8.6 Hz, 1H), 7.84 (dd, J = 8.6, 1.7 Hz, 1H), 5.31 (s, 2H). ¹⁹ F NMR (282 MHz, DMSOncfe) δ -58.51, -74.65; MS (ES+): 311 (M+l); (ES-): 309 (M-l).

Step-5: Preparation of (lR,3S,5R)-2-(2-(4-ammo-6-(trifluoromethyl)-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-meth yl-2-azabicyclo[3.1.0]hexane- 3-carboxamide (Ilf)

Compound Ilf was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (lie) (50 mg, 0.118 mmol) in DMF (2 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromo-3- methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0Jhexane-3-car boxamide (10a) (40.9 mg, for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH in DCM from 0 - 5%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5 - b]indol-9-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-meth yl-2-azabicyclo[3.1 ,0]hexane- 3-carboxamide (Ilf) (55 mg, 77% yield) HC1 salt as a white solid; *H NMR (300 MHz, DMSO-tife) δ 10.29 (s, 1H, DzO exchangeable), 8.99 (s, 1H), 8.59 (m, 3H, 2H D2O exchangeable), 7.84 (d, J= 2.1 Hz, 2H), 7.62 (d, ./= 8.0 Hz, 1H), 7.45 (d, J= 7.9 Hz, 1H), 5.73 (d ,J= 17.4 Hz, 1H), 5.45 (d, J= 17.3 Hz, 1H), 4.36 (dd, J= 9.2, 5.2 Hz, 1H), 3.67 (dd, J= 5.4, 2.5 Hz, 1H), 2.60 - 2.54 (m, 1H), 2.09 - 2.02 (m, 1H), 2.00 (s, 3H), 1.34 (s, 3H),

1.06 (t, ./= 5.3 Hz, 1H), 0.99 (dd, J= 5.4, 2.4 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO-ifc) δ - 58.51; MS (ES+): 602.0 (M+l), 623.9 (M+Na); (ES-): 600.0 (M-l); Analysis calculated for C26H23BrF3N ₇ 02.2.5H20.1HCl: C, 45.66; H, 4.27; Cl, 5.18; N, 14.34; Found: C, 45.66; H, 4.02; Cl, 5.29; N, 14.26.

Scheme 12

Preparation of (lR,3S,5R)-2-(2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl )-N-(6-bromo- 3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-c arboxamide (12a)

Compound 12a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (lc) (50 mg, 0.14 mmol) in DMF (2 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2- azabicyclo[3.1.0]hexane-3-caiboxamide (10a) (48.7 mg, 0.14 mmol), HATU (80 mg, 0.211 mmol), DIPEA (0.122 mL, 0.702 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography (lR,3S,5R)-2-(2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl )-N-(6-bromo-3- methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.OJhexane-3-car boxamide (12a) (47 mg, 63 % yield) as a white solid; Ή NMR (300 MHz, DMSO-ois) δ 10.31 (s, 1H, DzO exchangeable), 8.77 (s, 2H, DzO exchangeable), 8.66 (s, 1H), 8.55 (d, ./= 7.9 Hz, 1H), 7.71 (d, J= 8.2 Hz, 1H), 7.62 (d ,J= 8.0 Hz, 1H), 7.56 (t, J= 7.7 Hz, 1H), 7.45 (dd, J= 7.9, 6.0 Hz, 2H), 5.72 (d, J= 17.3 Hz, 1H), 5.42 (d, J= 17.3 Hz, 1H), 4.37 (dd,J= 9.2, 5.3 Hz, 1H), 3.68 (dd, J= 5.6,

2.4 Hz, 1H), 2.61 - 2.52 (m, 1H), 2.09 - 2.01 (m, 1H), 2.00 (s, 3H), 1.34 (s, 3H), 1.06 (t, J=

5.4 Hz, 1H), 0.99 (dd, J= 5.3, 2.4 Hz, 1H). MS (ES+): 534.0 (M+l), 556.0 (M+Na); (ES-): 532.0 (M-l); Analysis calculated for CzsHztBrNvOz^.SHzO.1.1HC1: C, 48.47; H, 4.90; Cl, 6.29; N, 15.83; Found: C, 48.70; H, 4.84; Cl, 6.26; N, 15.63.

Scheme 13

Preparation of (S)-l-(2-(4-amino-9H-pyrirnido[4,5-b]indol-9-yl)acetyl)-N-(6 -brornopyridin- 2-yl)pyrrolidine-2 -carboxamide (13b)

Compound 13b was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (lc) (50 mg, 0.14 mmol) in DMF (2 mL) using TFA salt of (S)-N-(6-bromopyridin-2-yl)pyrrolidine-2- carboxamide (13a) [(53.9 mg, 0.140 mmol); Wiles, Jason A. et al., PCT Int. Appl. (2017), WO 2017035353 Al 20170302], HATU (80 mg, 0.211 mmol), DIPEA (0.122 mL, 0.702 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-60%] (S)-l-(2-(4-amino-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridm-2-yl)pyrrolidine-2-car boxamide (13b) (42 mg, 61% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO -ck) 5 11.23 and 10.80 (2s, 1H D2O exchangeable), 8.63 - 8.50 (m, 3H, 2H D2O exchangeable), 8.45 (d, J= 7.9 Hz, 1H), 8 11 d 793 (2d J 8 1 H 1H) 764 ( J 82 H 2H) 755 744 ( 1H) 740 731 (m, 1H), 7.24 (d, J= 7.7 Hz, 1H), 5.45 - 5.28 (m, 2H), 4.46 (dd, J= 8.3, 4.3 Hz, 1H), 3.80 (tt, J= 9.7, 5.3 Hz, 2H), 2.23 - 1.76 (m, 4H); MS (ES+): 494.0 (M+l); (ES-): 492.0 (M-l); Analysis calculated for C22H2oBrN ₇ ()2.2.75H2().1HC1: C, 45.53; H, 4.60; Cl, 6.11; N, 16.89; Found: C, 45.78; H, 4.22; Cl, 6.37; N, 16.65.

Scheme 14

Preparation of (2S,4R)- l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-4-fluoropyrrolid ine-2-carboxamide (14a)

Compound 14a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (lie) (50 mg, 0.118 mmol) in DMF (2 mL) using HC1 salt of (2S,4R)-N-(6-bromo-3- methylpyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (3a) (39.9 mg, 0.118 mmol), HATU (67.2 mg, 0.177 mmol), DIPEA (0.103 mL, 0.589 mmol) and stirring at RT for 16 h. This gave after woikup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-60%] (2S,4R)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b] indol-9-yl)acetyl)-N- (6-bromo-3-methylpyridin-2-yl)-4-fluoropyrrolidine-2-carboxa mide (14a) (40mg, 57% yield) HC1 salt as a white solid; ¾i NMR (300 MHz, DMSO-dk) δ (a mixture of two rotamers)10.89 and 10.46 (2s, 1H, D2O exchangeable), 8.96 (s, 1H), 8.55 (s, 1H), 8.44 (s, 2H, D2O exchangeable), 7.90 - 7.69 (m, 2H), 7.59 (d, J= 8.0 Hz, 1H), 7.42 (d ,J= 8.0 Hz, 1H), 5.76 - 5.33 (m, 3H), 4.57 (t, J= 8.6 Hz, 1H), 4.33 (dd,J = 21.8, 12.7 Hz, 1H), 4.18 - 3.95 (m, 1H), 2.73 (s, 1H), 2.30 - 2.11 (m, 1H), 1.93 (s, 3H); ¹⁹ F NMR (282 MHz, DMSCM,) δ -58.47, - 58.75, -176.20; MS (ES+): 594.0 (M+l); (ES-): 592.0 (M-l); Analysis calculated for C24H2oBrF4N ₇ 02.1.75ΗίΟ.1HC1: C, 43.52; H, 3.73; Cl, 5.35; N, 14.80; Found: C, 43.54; H, Scheme 15

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(trifIuoromethyl)-9H-pyrimido[4,5 -b]indol-9- yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yI)-2-azabicyclo[3.1 .0]hexane-3-carboxamide

(15a)

Compound 15a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (lie) (50 mg, 0.118 mmol) in DMF (2 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromo-3- methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (Id) (39.2 mg, 0.118 mmol), HATU (67.2 mg, 0.177 mmol), DIPEA (0.103 mL, 0.589 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] ( 1 R,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b ]indol- 9-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3 .1 ,0]hexane-3-carboxamide (15a) (47 mg, 68% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-tife) δ 10.27 (s, 1H, D.O exchangeable), 9.00 (s, 1H), 8.70 - 8.54 (m, 3H, 2H D.O exchangeable), 7.93 - 7.80 (m, 2H), 7.62 (d,J= 8.0 Hz, 1H), 7.45 (d, J= 7.9 Hz, 1H), 5.78 (d,J= 17.4 Hz, 1H), 5.51 (d, J= 17.3 Hz, 1H), 4.38 (dd, J= 9.2, 5.1 Hz, 1H), 3.90 (td, J= 6.3, 5.4, 2.3 Hz, 1H), 2.46 - 2.18 (m, 2H), 2.03 - 1.86 (m, 4H), 1.11 (dt,J= 9.4, 5.3 Hz, 1H), 0.83 (dt,J= 7.1, 3.4 Hz, 1H); ¹⁹ FNMR (282 MHz, DMSO-tik) δ -58.52; MS (ES+): 587.9 (M+l); (ES-): 586.0 (M-l); Analysis calculated for CzsHziBrFsNzOz HCl.1 ,75HzO: C, 45.75; H, 3.92; Cl, 5.40; N, 14.94; Found: C, 45.96; H, 3.65; Cl, 4.95; N, 14.71.

Scheme 16

Preparation of (lR,3S,5R)-2-(2-(4-ammo-7-(trifluoromethy])-9H-pyrimido[4,5- b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (16c)

Step-1: Preparation of 7 -(trifluoromethyl)-9H-pyri mi do [4,5 -b] indol-4-amine (16b)

Compound 16b was prepared according to the procedure reported in step-1 of scheme-6, from 2-amino-6-(trifluoromethyl)-lH-indole-3-carbonitrile (16a) (1.95 g, 8.66 mmol; CAS # 1242140-69-7) using trimethyl orthoformate (18.95 mL, 173 mmol), AcOH (2.476 mL, 43.3 mmol) and NH*OAc (3.34 g, 43.3 mmol). This gave after woikup 7-(trifluoromethyl)-9H- pyrimido[4,5-b]indol-4-amine (16b) (2.08 g, 77% yield) acetic acid salt as a pale yellow solid; Ή NMR (300 MHz, DMSO-tfc) δ 12.20 (s, 1H), 11.98 (s, 1H), 8.52 (d, J= 8.3 Hz, 1H), 8.31 (s, 1H), 7.76 - 7.65 (m, 1H), 7.58 - 7.47 (m, 1H), 7.43 (s, 2H), 1.91 (s, 3H); MS (ES+): 253.10 (M+l).

Step-2: Preparation of tort-butyl 2-(4-amino-7-(trifluorome1hyl)-9H-pyrimido[4,5-b]indol-9- yl)acetate (16c)

Compound 16c was prepared according to the procedure reported in step-1 of scheme- 1 , from 7-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-4-amine (16b) (2 g, 7.93 mmol) in DMF (50 mL) using CszCOz (3.10 g, 9.52 mmol). This gave after workup and purification by flash column chromatography [silica gel (40 g), eluting with EtOAc in Hexane from 0-100%] tert- butyl 2-(4-amino-7-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl) acetate (16c) (0.93 g, 32% yield) as a pale yellow solid; Ή NMR (300 MHz, DMSO -ck) δ 8.57 (d, J= 8.2 Hz, 1H), 8.36 (s, 1H), 8.06 (d ,7 = 1.5 Hz, 1H), 7.65 - 7.51 (m, 3H), 5.25 (s, 2H), 1.40 (s, 9H); MS (ES+): 367.10 (M+l).

Step-3 : Preparation of 2-(4-amino-7-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (16d)

Compound 16d was prepared according to the procedure reported in step-2 of scheme- 1, from tert-butyl 2-(4-amino-7-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl) acetate (16c) (0.92 g, 2.51 mmol) using TFA (14.41 mL, 37.7 mmol; 20% TFA in DCM) and stirring at RT for 16 h. This gave after workup 2-(4-ammo-7-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9- yl)acetic acid (16d) (0.9 g, 84% yield) TFA salt as a white solid; Ή NMR (300 MHz, DMSO-tfc) δ 8.64 (d, 7= 8.3 Hz, 1H), 8.47 (s, 1H), 8.21 (s, 1H), 8.02 (s, 2H), 7.67 (d, 7= 8.3 Hz, 1H), 5.31 (s, 2H); MS (ES+): 311.00 (M+l).

Step-4: Preparation of (lR,3S,5R)-2-(2-(4-amino-7-(trifluoromethyl)-9H-pyrimido[4,5 - b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1.0]hexane-3-carboxamide

(16e)

Compound 16e was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-7-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (16d) (75 mg, 0.177 mmol) in DMF (2 mL) using HC1 salt of ( 1 R,3 S,5R)-N-(6-bromopytidin-2-yl)- 2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (70.0 mg, 0.177 mmol), HATU (101 mg, 0.265 mmol), DIPEA (0.154 mL, 0.884 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-7-(trifluoromethyl)-9H-pyrimido[4,5 -b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (16e) (62 mg, 61% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfe) δ 10.76 (s, 1H, D _z O exchangeable), 8.73 (d, 7= 8.1 Hz, 3H, 2H D2O exchangeable), 8.65 (s, 1H), 8.17 (s, 1H), 8.00 (d, 7= 8.1 Hz, 1H), 7.77 - 7.61 (m, 2H), 7.30 (d, 7= 7.7 Hz, 1H), 5.87 (d, 7= 17.4 Hz, 1H), 5.51 (d, 7= 17.3 Hz, 1H), 4.42 (dd, 7= 9.0, 5.5 Hz, 1H), 3.91 (ddd, 7= 7.4, 5.4, 2.3 Hz, 1H), 2.41 - 2.13 (m, 2H), 1.92 (t, 7= 6.4 Hz, 1H), 1.09 (dt, 7= 8.7, 5.5 Hz, 1H), 0.77 (td, 7= 5.2, 2.3 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -59.33; MS (ES+): 574.0 (M+l); (ES-): 572.0 (M-l); Analysis calculated for C24Hi9BrF3N ₇ 02.1.5H20.1HCI: C, 45.19; H, 3.63; Cl, Scheme 17

.0,

H ₂ N H

N ^• NH

HC(OMe) ₃ , NH ₄ OAC ^A °r Cp 2Cr NH ₂

Br ί C Pd ₂ (dba) ₃ . XPhos

NC r\ ^• AcOH s ₂ C0 ₃ Br H ₂ N Br

NH CS2CO3

17a 17b 17c

Q Η-γ. Br

HO Br

— x H N— /

LH ^N V— X H Ό

LiOH >y HATU, DIPEA

X NHBoc

NH ₂

NH ₂

17e NH ₂

17d 17f

Preparation of te/7-butyl (4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl) -2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]i ndol-7-yl)carbamate (17f)

Step-1: Preparation of 7-bromo-9H-pyrimido[4,5-b]indol-4-amine (17b)

Compound 17b was prepared according to the procedure reported in step-1 of scheme-6, from 2-am ino-6-bromo- 1 H-indole-3 -carbonitrile (17a) (2 g, 8.47 mmol; CAS # 1427028-36- 1) using trimethyl orthoformate (18.54 mL, 169 mmol), AcOH (2.423 mL, 42.4 mmol) and NHtOAc (3.27 g, 42.4 mmol). This gave after workup 7-bromo-9H-pyrimido[4,5-b]indol-4- amine (17b) (2.29 g, 84% yield) as a pale yellow solid; Ή NMR (300 MHz, DMSO-ifc) δ 11.97 (s, 2H), 8.27 (t, ./= 4.2 Hz, 2H), 7.58 (d, J= 1.8 Hz, 1H), 7.36 (dd, J= 8.4, 1.8 Hz, 1H), 7.26 (s, 2H), 1.92 (s, 3H).

Step-2: Preparation of /erf-butyl 2-(4-amino-7-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate

(17c)

Compound 17c was prepared according to the procedure reported in step-2 of scheme- 16, from 7-bromo-9H-pyrimido[4,5-b]indol-4-amine (17b) (2.2 g, 6.81 mmol) in DMF (75 mL) using terf-butyl 2-bromoacetate (1.056 mL, 7.15 mmol), CS2CO3 (4.88 g, 14.98 mmol) and stirring at RT for 15 h. Additional tert-butyl 2-bromoacetate (1.006 mL, 6.81 mmol) and K2CO3 (0.941 g, 6.81 mmol) were needed for completion of reaction. This gave after workup and purification by flash column chromatography [silica gel (40 g), eluting with EtOAc in hexane from 0-100%] tert-butyl 2-(4-amino-7-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (17c) (1.25 g, 49% yield) as a pale yellow solid; Ή NMR (300 MHz, DMSO-i/e) δ 8.31 (t, J = 4.2 Hz, 2H), 7.91 (d ,J= 1.7 Hz, 1H), 7.46 - 7.36 (m, 3H), 5.14 (s, 2H), 1.41 (s, 9H).

Step-3: Preparation of tort-butyl 2-(4-amino-7-((teit-butoxycaibonyl)amino)-9H- pyrimido[4,5-b]indol-9-yl)acetate (17d)

To a degassed solution of tort-butyl 2-(4-amino-7-bromo-9H-pyrimido [4,5 -b] indol-9- yl)acetate (17c) (200 mg, 0.530 mmol) in toluene (10 mL) was added XPhos (50.5 mg, 0.106 mmol), t-butyl carbamate (93 mg, 0.795 mmol), Pd2(dba)3 (48.5 mg, 0.053 mmol) and cesium carbonate (173 mg, 0.530 mmol), filled with nitrogen and heated at 90 °C for 16 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (50 mL), brine (50 mL), dried and concentrated in vacuum. The obtained residue was purified by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0-50%] to give tort-butyl 2-(4-amino-7-(tert-butoxycarbonylamino)-9H-pyrimido[4,5-b]in dol-9- yl)acetate (17d) (92mg, 42% yield) as a yellow solid; MS (ES+): 414.20 (M+l).

Step-4: Preparation of 2-(4-amino-7-((tort-butoxycarbonyl)amino)-9H-pj'rimido[4,5-b ]indol- 9-yl)acetic acid (17e)

To a stirred solution of tort-butyl 2-(4-amino-7-(tort-butoxycarbonylamino)-9H- pyrimido[4,5-b]indol-9-yl)acetatc (17d) (90 mg, 0.218 mmol) in THF/MeOH (4 mL; ratio 1:1) was added lithium hydroxide hydrate (1.088 mL, 1.088 mmol) and stirred at RT for 15 h. The reaction mixture was concentrated in vacuo, diluted with water (1 mL), acidified to pH 5-7 using 1M HC1 and concentrated to dryness to afford 2-(4-amino-7-((tort- butoxycarbonyl)amino)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (17e) (67 mg, 86 % yield); Ή NMR (300 MHz, DMSO-i/e) δ 9.71 (s, 1H), 8.63 - 8.45 (m, 4H), 8.38 (d, ./= 8.6 Hz, 1H), 7.95 (s, 1H), 7.36 (dd ,J= 8.7, 1.8 Hz, 1H), 5.19 (s, 2H), 1.51 (s, 9H); MS (ES+): 358.10 (M+l); (ES-): 356.10 (M-l).

Step-5: Preparation of tort-butyl (4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2- yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H- pyrimido[4,5-b]indol-7- yl)carbamate (I7f)

Compound 17f was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-7-((tert-butoxycarbonyl)amino)-9H-pyrimido[4,5-b] indol-9-yl)acetic acid (17e) (60mg, 0.168 mmol) in DMF (1 mL) using TFA salt of (lR,3S,5R)-N-(6- bromopyridin 2 yl) 2 azabicyclo[3 1 0]hexane 3 carboxamide (4a) (665 mg 0 168 mmol) HATU (96 mg, 0.252 mmol) DIPEA (0.146 mL, 0.839 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] tort-butyl 4-amino-9-(2-((lR,3S,5R)-3-(6- bromopyridin-2-ylcarbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2 -oxoethyl)-9H-pyrimido[4,5- b]indol-7-ylcarbamate (17f) (48mg, 46% yield). 10 mg of this compound was purified by reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] to yield tort-butyl 4-amino-9-(2-((lR,3S,5R)-3-(6- bromopyridin-2-ylcarbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2 -oxoethyl)-9H-pyrimido[4,5- b]indol-7-ylcarbamate (17f) (6 mg) HC1 salt as a white solid; Ή NMR (300 MHz, MeOD-cfc) δ 8.46 (s, 1H), 8.19 (d, J= 8.7 Hz, 1H), 8.05 (d, J= 8.2 Hz, 1H), 8.00 (d, J= 1.8 Hz, 1H), 7.60 (t, J= 8.0 Hz, 1H), 7.35 (dd, J= 8.7, 1.9 Hz, 1H), 7.24 (dd, J= 7.8, 0.7 Hz, 1H), 5.74 (d, J= 17.2 Hz, 1H), 5.53 (d, J= 17.1 Hz, 1H), 4.56 (t, 7.1 Hz, 1H), 3.89 (ddd ,J= 7.4, 5.4,

2.4 Hz, 1H), 2.46 (dd, J= 7.9, 3.6 Hz, 2H), 2.04 (d, J= 6.4 Hz, 1H), 1.56 (s, 9H), 1.24 (dt, J = 8.6, 5.5 Hz, 1H), 1.00 (dt, J= 7.6, 3.7 Hz, 1H). MS (ES+): 621.2 (M+l); (ES-): 619.1 (M-

1).

Scheme 18

ΝΗ ₂ NH ₂

17f 18a

Preparation of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2-(2-(4,7-diamino-9H-pyri mido[4, 5- b]indol-9-yl)acetyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (18a)

Compound 18a was prepared according to the procedure reported in step-3 of scheme- 1, from tort-butyl (4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl) -2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyiimido[4,5-b]i ndol-7-yl)carbamate (17f) (35mg, 0.056 mmol) in DCM (1 mL) using 2,2,2-trifluoroacetic acid (0.087 mL, 1.126 mmol) and stirring at RT for 16 h. This gave after workup and purification twice by reverse phase column chromatography [C18 column (50 g) eluting with ACN in water (containing 0 1% HCl) from 0-100%] (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2-(2-(4,7-diamino-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-2-azabicyclo[3.1.0]hexane- 3-carboxamide (17 mg, 58% yield) (18a) HCl salt as a white solid. Ή NMR (300 MHz, DMSO-^fc) δ 10.74 (s, 1H, DzO exchangeable), 8.45 (s, 1H), 8.29 (s, 2H, DzO exchangeable), 8.18 (d,./= 8.6 Hz, 1H), 7.95 (d, 8.2 Hz, 1H), 7.64 (t, J= 7.9 Hz, 1H), 7.25 (d ,J= 7.7 Hz, 1H), 6.81 (d, J= 7.0 Hz,

2H), 5.58 (d, J= 17.4 Hz, 1H), 5.22 (d,J= 17.4 Hz, 1H), 4.36 (dd, J = 9.0, 5.4 Hz, 1H), 3.89 - 3.76 (m, 1H), 2.34 - 2.06 (m, 2H), 1.85 (d ,J= 7.7 Hz, 1H), 1.10 - 0.92 (m, 1H), 0.68 (d, J = 5.9 Hz, 1H). MS (ES+): 521.1 (M+l); (ES-): 519.1 (M-l).

Scheme 19

Preparation of (2S,4R)-l-(2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N -(6- bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (19a)

Compound 19a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (lc) (150 mg, 0.421 mmol) in DMF (5 mL) using TFA salt of (2S,4R)-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2- carboxamide (5d) (169 mg, 0.421 mmol), HATH (192 mg, 0.505 mmol), DIPEA (272 mg, 2.105 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 5%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)-l-(2-(4-amino-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-4- fluoropyrrolidine-2- carboxamide (19a) (62 mg, 61% yield) HC1 salt as a white solid; ^! H NMR (300 MHz, DMSO-flfe) δ (a mixture of two rotamers) 11.37 (s) and 10.98 (s) (2s, 1H, D20 exchangeable),, 8.80 - 8.56 (m, 3H, 2H D20 exchangeable), 8.51 (d, J= 7.9 Hz, 1H), 7.98 (d, J= 8.1 Hz, 1H), 7.75 - 7.63 (m, 2H), 7.55 (t, J= 7.7 Hz, 1H), 7.50 - 7.37 (m, 1H), 7.31 4.71 - 4.57 (m, 1H), 4.43 - 4.21 (m, 1H), 4.18 - 3.96 (m, 1H), 2.74 - 2.50 (m, 1H), 2.29 - 2.02 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-flk) δ -175.73, -176.14; MS (ES+): 512.0 (M+l), (ES-): 510.0 (M-l); Analysis calculated for C22H19BrFN7O2.HCL2.5H2O: C, 44.50; H, 4.24; Cl, 5.97; N, 16.51; Found: C, 44.36; H, 4.10; Cl, 5.76; N, 16.25.

Scheme 20

Preparation of (2S,4R)- l-(2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(3-chlo ro-2- fluorobenzyl)-4-fluoropynolidine-2-carboxamide (20a)

Compound 20a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (lc) (200 mg, 0.561 mmol) in DMF (10 mL) using TFA salt of (2S,4R)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine- 2-carboxamide (7a) (218 mg, 0.561 mmol), HATU (256 mg, 0.674 mmol), DIPEA (0.490 mL, 2.81 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse-phase column chromatography [C-18 column, 100 g, eluting with 0.1% aqueous HC1 in H2O and MeCN from 0-100%] (2S,4R)-l-(2-(4-amino-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(3-chloro-2-fluorobenzyl )-4-fluoropyrrolidine-2- carboxamide (20a) (121 mg, 43% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-flfe) (a mixture of two rotamers) δ 9.15 (t, J= 5.8 Hz) and 8.79 - 8.64 (m, 3H, D2O exchangeable), 8.61 (d, ./= 3.0 Hz, 1H), 8.59 - 8.50 (m, 1H), 7.74 (d, J= 8.1 Hz, 1H), 7.58 - 7.34 (m, 4H), 7.21 - 7.11 (m, 1H), 6.92 - 6.79 (m, 1H), 5.72 - 5.53 (m, 1H), 5.54 - 4.76 (m, 2H), 4.56 - 4.14 (m, 4H), 4.14 - 3.92 (m, 1H), 2.62 - 2.40 (m, 1H), 2.22 - 1.95 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-tfo) δ -121.24, -121.76, -176.25, -176.47; MS (ES+): 499/501 (M+l).

Preparation of (2S,4R)- l-(2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)- N-(6- bromopyridm-2-yl)-4-fluoropyrrolidine-2-carboxamide (21a)

Compound 21a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (6d) (50 mg, 0.135 mmol) in DMF (5 mL) using TFA salt of (2S,4R)-N-(6-bromopyridin-2-yl)-4- fluoropyrrohdine-2-carboxamide (5d) (54.3 mg, 0.135 mmol), HATU (61.6 mg, 0.162 mmol), DIPEA (87 mg, 0.675 mmol) and stirring at RT for 16 h. This gave after woikup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0-5%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)-1- (2-(4-amino-6-methyl-9H-pyrimido [4, 5 -b] indol-9-yl)acety 1)-N -(6-bromopyridin-2-y 1) -4- fluoropyrrohdine-2-carboxamide (21a) (35 mg, 49% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-d!s) δ (a mixture of retainers) 11.35 (s) and 10.97 (s, 1H, D2O exchangeable), 8.76 - 8.52 (m, 3H, 2H DzO exchangeable), 8.35 (s, 1H), 7.98 (d, J= 8.2 Hz, 1H), 7.69 (t, .7= 7.9 Hz, 1H), 7.60 (d, J= 8.4 Hz, 1H), 7.38 (d, J= 8.5 Hz, 1H), 7.31 (d, J= 7.7 Hz, 1H), 5.71 - 5.25 (m, 3H), 4.62 (t, J= 8.5 Hz, 1H), 4.37 - 4.23 (m, 1H), 4.16 - 3.96 (m, 1H), 2.66 - 2.43 (m, 4H), 2.30 - 1.95 (m, 1H); ¹⁹ F NMR (282 MHz, DMSOncfc) δ - 175.73, -176.15; MS (ES+): 526.0 (M+l), (ES-): 524.0 (M-l); Analysis calculated for C23H2iBrFN ₇ 02.1.1HC1.2.25H20: C, 45.51; H, 4.42; Cl, 6.42; N, 16.15; Found: C, 45.21; H, 4.47; Cl, 6.40; N, 15.88.

Scheme 22

22c (-)-isomer 22d (+>isomer

Preparation of (lR,3S,5R)-2-((-)-2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indo l-9- yl)propanoyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (22c) and (lR,3S,5R)-2-((+)-2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indo l-9-yl)propanoyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (22d)

Step-1: Preparation of ter/-butyl 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9- yl)propanoate (22a)

Compound 22a was prepared according to the procedure reported in step- 1 of scheme- 1, from 6-methyl-9H-pyrimido[4,5-b]indol-4-amine (6b) (200 mg, 1.009 mmol) in DMF (10 mL) using (R)-tert-butyl 2-bromopropanoate (253 mg, 1.211 mmol; CAS # 54631-38-8), CszCOz (657 mg, 2.018 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0-3%] a mixture of two enantiomers of /erf-butyl 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9- yl)propanoate (22a) (250 mg, 76% yield) as a pale yellow solid; Ή NMR (300 MHz, DMSO- d ₆ ) δ 8.26 (d, J = 6.0 Hz, 1H), 8.23 - 8.15 (m, 1H), 7.40 (dd, J = 7.4, 3.1 Hz, 1H), 7.30 - 7.07 (m, 3H), 5.81 - 5.63 (m, 1H), 2.46 (s, 3H), 1.66 (d, J = 7.1 Hz, 3H), 1.30 (d, J = 5.7 Hz, 9H); MS (ES+): 327 (M+l). Step-2: Preparation of 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)propanoic acid (22b)

Compound 22b was prepared according to the procedure reported in step-2 of scheme- 1, from tert- butyl 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)propanoate (22a) (250 mg, 0.766 mmol) in DCM (20 mL) using TFA (0.879 mL, 11.49 mmol) and stirring at RT for 16 h. This gave after workup a mixture of two enantiomers of 2-(4-amino-6-methyl-9H- pyrimido[4,5-b]indol-9-yl)propanoic acid (22b) (304 mg) TFA salt as a white solid; Ή NMR (300 MHz, DMSCM,) δ 8.55 (s, 1H), 8.49 - 8.36 (m, 2H), 8.36 (s, 1H), 7.62 (d, J= 8.5 Hz, 1H), 7.37 (dd, J= 8.6, 1.6 Hz, 1H), 5.86 (q, J= 7.1 Hz, 1H), 1.75 (d, J= 7.2 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-tifc) δ -74.15; MS (ES+): 271 (M+l), (ES-): 269 (M-l).

Step-3: Preparation of (lR,3S,5R)-2-((-)-2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indo l-9- yl)propanoyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (22c) and (lR,3S,5R)-2-((+)-2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indo l-9-yl)propanoyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (22d)

Compounds 22c and 22d were prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)propanoic acid (22b) (50 mg, 0.130 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (41.5 mg, 0.130 mmol), HATU (59.4 mg, 0.156 mmol), DIPEA (84 mg, 0.651 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) flora 0-100%].

1. (lR,3S,5R)-2-((-)-2-(4-amino-6-me1hyl-9H-pyrimido[4,5-b]indo l-9-yl)propanoyl)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamid e (22c) (17 mgs, 25%) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO -de) δ 10.80 (s, 1H, DzO exchangeable), 8.64 (s, 1H), 8.62 - 8.50 (m, 2H, DzO exchangeable), 8.40 (s, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.76 (t, J = 7.9 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.37 (dd, J = 7.9, 2.6 Hz, 2H), 6.28 (q, J = 6.8 Hz, 1H), 4.27 (t, J = 7.2 Hz, 1H), 3.27 - 3.24 (m, 1H), 2.04 - 1.95 (m, 2H), 1.61 (m, 3H), 1.57 - 1.47 (m, 1H), -0.36 (m, 1H), -1.03 (m, 1H); MS (ES+): 534/536 (M+l), (ES-): 532/534 (M-l); Chiral HPLC: AD-H column 245 nm, 30 mins run time (Temp 40 °C). R _t = 10.54 (peak-1 (22c), 98.0742 %); R _t = 19.473 (peak-2; (22d) 1.388%) 97.4084% ee; Optical rotation [a] _D = -224 (c = 0.1, MeOH)

2. (lR,3S,5R)-2-((+)-2-(4-amino-6-methyl-9H-pyrimido[4,5-b]indo l-9-yl)propanoyl)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamid e (22d) (22 mgs,

32%) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO -de) δ 10.64 (s, 1H, DzO exchangeable), 8.62 (s, 1H), 8.59 - 8.46 (m, 2H, D2O exchangeable), 8.36 (s, 1H),

7.92 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H), 6.22 (q, J = 7.0 Hz, 1H), 4.53 (dd, J = 9.1, 5.6 Hz, 1H), 3.06 - 2.96 (m, 1H), 2.30 - 2.17 (m, 1H), 2.07 (m, 1H), 1.68 (m, 4H), 0.88 (m, 1H), 0.77 (m, 1H); MS (ES+): 534/536 (M+l), (ES-): 532/534 (M-l); Chiral HPLC: AD-H column 80/20 [(0.1% DEA in n-Hexane in 0.1% DEA in ethanol)] 1.0 mL/min UV detection 245 nm, 30 mins ran time (Temp 40 °C); R _t = 10.54 (peak-1 (22c) 0 %); R, = 19.427 (peak-2; (22d) 100%) >99.99% ee; Optical rotation [a]n = +92.632 (c = 0.095, MeOH).

Scheme 23

NH ₂

23e 23f Preparation of (lR,3S,5R)-2-(2-(4-amino-7-methyl-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamid e (23f)

Step-1: Preparation of 2-amino-6-methyl- 1 H-indole-3 -carbonitrile (23b)

Compound 23b was prepared according to the procedure reported in step-1 of scheme- 11, from 2,2,2-trifhioro-N-(2-iodo-5-methylphenyl)acetamide (23a) (7.03 g, 21.36 mmol) in DMSO (20 mL) using malononitrile (1.694 g, 26.6 mmol), L-proline (0.492 g, 4.27 mmol), Cul (0.407 g, 2.136 mmol), K2CO3 (5.91 g, 42.7 mmol) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification [SiOzgel (40 g), eluting with EtOAc in hexane from 0-40%] 2-amino-6-methyl- 1 H-indole-3 -carbonitrile (23b) (2.65 g, 73% yield) as an brown solid; Ή NMR (300 MHz, DMSO-cfc) δ 10.58 (s, 1H), 7.00 (d, J= 7.8 Hz, 1H), 6.93 (s, 1H), 6.78 (dd, J= 8.3, 1.5 Hz, 1H), 6.63 (s, 2H), 2.31 (s, 3H); MS (ES+): 172 (M+l); (ES-): 170 (M-l).

Step-2: Preparation of 7-methy l-9H-py rimido [4,5 -b] indol-4-amine (23c)

Compound 23c was prepared according to the procedure reported in step-1 of scheme-6, from 2-amino-6-methy 1- 1 H-indole-3 -carbonitrile (23b) (2.65 g, 15.48 mmol) using triethyl orthoformate (51.5 mL, 310 mmol), AcOH (4.43 mL, 77 mmol) and NEUOAc (5.97 g, 77 mmol). This gave after workup and purification [SiOzgel (24 g), eluting with MeOH in DCM from 0-5%] 7-methyl-9H-pyrimido[4,5-b]indol-4-amine (23c) (1.45 g) as a brown yellow solid; TLNMR^OO MHz, DMSO-cfe) δ 11.70 (s, 1H), 8.21 (s, 1H), 8.16 (d, J = 7.9 Hz, 1H), 7.23 (s, 1H), 7.15 - 6.96 (m, 3H), 2.45 (s, 3H); MS (ES+): 199 (M+l); (ES-): 197 (M-l).

Step-3: Preparation of tort-butyl 2-(4-amino-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (23d)

Compound 23d was prepared according to the procedure reported in step-1 of scheme- 1, from 7-me1hyl-9H-pyrimido[4,5-b]indol-4-amine (23c) (1.45 g, 7.31 mmol) in DMF (25 mL) using tort-butyl 2-bromoacetate (1.427 g, 7.31 mmol) C.S2CO3 (2.86 g, 8.78 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH in DCM from 0-3%] tort-butyl 2-(4- amino-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (23d) (0.84 g, 37% yield) as a pale yellow solid; ^l HNMR (300 MHz, DMSO-tifc) δ 8.26 (s, 1H), 8.22 (d, ./= 8.0 Hz, 1H), 7.36 (s, 1H), 7.19 (s, 2H), 7.14 - 7.06 (m, 1H), 5.07 (s, 2H), 2.48 (s, 3H), 1.41 (s, 9H); MS (ES+): Step-4: Preparation of 2-(4-amino-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (23e)

Compound 23e was prepared according to the procedure reported in step-2 of scheme- 1, from tort-butyl 2-(4-amino-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (23d) (0.84 g, 2.69 mmol) using TFA (6.13 g, 53.8 mmol) in DCM (20 mL) and stirring at RT for 16 h. This gave after workup 2-(4-amino-7 -methy l-9H-pyrimido [4,5 -b] indol-9-y l)acetic acid (23e) (1.01 g) TFA salt as a yellow solid; Ή NMR (300 MHz, DMSO-i/e) δ 8.51 (s, 1H), 8.36 (d, J= 8.0 Hz, 1H), 8.24 (s, 2H), 7.59 (s, 1H), 7.26 (d, 1H), 5.21 (s, 2H), 2.49 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-cfe) δ -74.09; MS (ES+): 257 (M+l), (ES-): 255 (M-l).

Step-5: Preparation of ( lR,3S,5R)-2-(2-(4-amino-7-methyl-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (23f) Compound 23f was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (23e) (50 mg, 0.135 mmol) in DMF (5 mL) using HC1 salt of ( lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (4a) (43.0 mg, 0.135 mmol), HATU (61.6 mg, 0.162 mmol), DIPEA (87 mg, 0.675 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-7-methyl-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (23f) (44 mg, 63% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfe) δ 10.76 (s, 1H, D2O exchangeable), 8.57 (s, 1H), 8.44 (s, 2H, DzO exchangeable), 8.37 (d, J= 8.1 Hz, 1H), 8.01 (d ,J= 8.2 Hz, 1H), 7.70 (t ,J= 8.0 Hz, 1H), 7.51 (s, 1H), 7.32 (d, J= 7.7 Hz, 1H), 7.29 - 7.23 (m, 1H), 5.71 (d, J = 17.3 Hz, 1H), 5.38 (d, J= 17.3 Hz, 1H), 4.42 (dd, J= 9.1, 5.6 Hz, 1H), 3.96 - 3.87 (m, 1H), 2.49 (s, 3H), 2.40 - 2.27 (m, 1H), 2.27 - 2.11 (m, 1H), 2.00 - 1.85 (m, 1H), 1.12 - 1.02 (m, 1H), 0.82 - 0.73 (m, 1H); MS (ES+): 520.0 (M+l), 518.0 (M-l); Analysis calculated for C24H22BrN ₇ 02.1.2HC1.2.5H20: C, 47.32; H, 4.67; Cl, 6.98; N, 16.10; Found: C, 47.10; H, 4.59; Cl, 6.75; N, 15.97.

Scheme 24

Preparation of (lR,3S,5R)-2-(2-(4-amino-7-methyl-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N- (6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-c arboxamide (24a)

Compound 24a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (23e) (50 mg, 0.135 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-5- methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (44.9 mg, 0.135 mmol), HATU (61.6 mg, 0.162 mmol), DIPEA (87 mg, 0.675 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-7-methyl-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N- (6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-c arboxamide (24a) (36 mg, 50% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-i/e) δ 10.77 (s, 1H, D ₂ 0 exchangeable), 8.61 (s, 3H, 2HDzO exchangeable), 8.39 (d,J= 8.1 Hz, 1H), 8.01 (d ,J= 8.2 Hz, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.52 (s, 1H), 7.31 (d, J= 7.7 Hz, 1H), 7.26 (d, J= 8.9 Hz, 1H), 5.68 (d,./= 17.3 Hz, 1H), 5.34 (d, J= 17.3 Hz, 1H), 4.37 (dd, J= 9.1, 5.9 Hz, 1H), 3.69 (dd, «7= 5.5, 2.4 Hz, 1H), 2.55 - 2.41 (m, 4H), 1.98 (dd,J= 13.2, 5.9 Hz, 1H), 1.31 (s, 3H), 1.08 - 0.97 (m, 1H), 0.97 - 0.89 (m, 1H); MS (ES+) 534.0 (M+l), 532.0 (M-l); Analysis calculated for C25H24BrN702.HC1.2.25H20: C, 49.11; H, 4.86; Cl, 5.80; N, 16.04; Found: C, 48.98; H, 4.79; Cl, 6.02; N, 15.90.

Scheme 25

Preparation of (2S,4R)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b] indol-9- yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2 -carboxamide (25a)

Compound 25a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (lie) (50 mg, 0.118 mmol) in DMF (10 mL) using TFA salt of (2S,4R)-N-(3-chloro-2- fluorobenzyl)-4-fluoropynolidine-2-carboxamide (7a) (45.8 mg, 0.118 mmol), HATU (53.8 mg, 0.141 mmol), DIPEA (0.103 mL, 0.589 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 5%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b] indol-9- yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2 -carboxamide (25a) (28 mg,

42% yield) HC1 salt as a white solid; ^! H NMR (300 MHz, DMSO-ifc) δ (a mixture of two rotamers) 8.98 (d, J= 3.6 Hz, 1H), 8.71 - 8.52 (m, 4H, 2H DzO exchangeable), 7.88 (d, J= 8.6 Hz, 1H), 7.75 (dd, J= 8.7, 1.7 Hz, 1H), 7.45 - 7.31 (m, 1H), 7.17 - 7.08 (m, 1H), 6.80 (t, J= 7.9 Hz, 1H), 5.64 (d, J= 17.4 Hz, 1H), 5.43 (d, J = 4.0 Hz, 1H), 4.54 - 4.26 (m, 3H), 4.23 (d, J= 5.8 Hz, 1H), 4.19 - 4.05 (m, 1H), 3.96 (dd, J= 12.3, 2.9 Hz, 1H), 2.62 - 2.41 (m, 1H), 2.23 - 1.91 (m, 1H); ¹⁹ FNMR(282 MHz, DMSO) δ -58.53, -121.26, -121.72, -176.26, - 176.42; MS (ES+): 567.0 (M+l), (ES-): 565.0 (M-l). Scheme 26

Preparation of (2S,4R)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b] indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-car boxamide (26a)

Compound 26a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (lie) (50 mg, 0.118 mmol) in DMF (5 mL) using TFA salt of (2S,4R)-N-(6-bromopyridin-2-yl)-4- fluoropyrrolidine-2-carboxamide (5d) (47.4 mg, 0.118 mmol), HATU (53.8 mg, 0.141 mmol), DIPEA (76 mg, 0.589 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 5%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)-1- (2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl )acetyl)-N-(6-bromopyridin-2- yl)-4-fluoropyrrohdine-2-carboxamide (26a) (33 mg, 48% yield) HC1 salt as a white solid; *H NMR (300 MHz, DMSO-tfc) δ 10.97 (s, 1H, DzO exchangeable), 8.95 (s, 1H), 8.64 - 8.38 (m, 3H, 2H D2O exchangeable), 7.98 (d, J = 8.2 Hz, 1H), 7.84 (dd, J= 8.4, 5.0 Hz, 2H), 7.68 (t,J= 8.0 Hz, 1H), 7.31 (d, 7 = 7.7 Hz, 1H), 5.71 - 5.57 (m, 1H), 5.51 - 5.39 (m, 1H), 4.62 (dd, J= 9.7, 7.5 Hz, 1H), 4.32 (dd,J= 22.1, 12.6 Hz, 1H), 4.18 - 4.08 (m, 1H), 4.01 (dd,J= 12.8, 3.0 Hz, 1H), 2.68 - 2.33 (m, 1H), 2.30 - 1.97 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-i/c) δ -58.51, -175.70; MS (ES+): 580.0 (M+l), (ES-): 578.0 (M-l); Analysis calculated for C23Hi8BrF4N7O2.HCL2.5H2O: C, 41.74; H, 3.66; Cl, 5.36; N, 14.81; Found: C, 41.66; H,

3.49; Cl, 5.10; N, 14.74.

Scheme 27

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5 -b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (27a)

Compound 27a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (lie) (50 mg, 0.118 mmol) in DMF (10 mL) using HC1 salt of ( 1R,3 S,5R)-N-(6-bromopyridin-2- jd)-2-azabicyclo[3.1.0]hexane-3-caiboxamide (4a) (37.5 mg, 0.118 mmol), HATU (53.8 mg, 0.141 mmol), DIPEA (76 mg, 0.589 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 5%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0- 100%] ( 1 R,3 S,5R)-2-(2-(4-ammo-6-(trifluoromethyl)-9H-pyrimido[4,5-b]ind ol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (27a) (42 mg, 62% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-de) δ 10.75 (s, 1H, DzO exchangeable), 8.96 (s, 1H), 8.59 (s, 1H), 8.52 (s, 2H, DzO exchangeable), 8.00 (d, J= 8.2 Hz, 1H), 7.85 (s, 2H), 7.70 (t, J= 8.0 Hz, 1H), 7.31 (d, J= 7.7 Hz, 1H), 5.80 (d, J= 17.4 Hz, 1H), 5.46 (d 17.3 Hz, 1H), 4.41 (dd, J= 9.1, 5.5 Hz, 1H), 3.95 - 3.88 (m, 1H), 2.40 - 2.28 (m, 1H), 2.28 - 2.13 (m, 1H), 1.99 - 1.82 (m, 1H), 1.14 - 1.00 (m, 1H), 0.81 - 0.74 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-de) δ -58.47; MS (ES+): 574.0 (M+l); (ES-): 572.0 (M-l); Analysis calculated for Cz4H19BrF3N7Oz.HCl.2HzO: C, 44.56; H, 3.74; Br, 12.35; Cl, 5.48; N, 15.16; Found: C, 44.27; H, 3.69; Cl, 5.59; N, 14.75.

Scheme 28

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5 -b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-caiboxamide

(28a)

Compound 28a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (lie) (50 mg, 0.118 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)- 5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (8a) (39.2 mg, 0.118 mmol), HATU (53.8 mg, 0.141 mmol), DIPEA (76 mg, 0.589 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0- 100%] ( 1 R,3 S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]in dol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (28a) (50 mg, 72% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-tfc) δ 10.76 (s, 1H, DzO exchangeable), 8.96 (s, 1H), 8.71 - 8.43 (m, 3H, 2H DzO exchangeable), 8.01 (d, J= 8.2 Hz, 1H), 7.91 - 7.80 (m, 2H), 7.69 (t, J= 8.0 Hz, 1H), 7.31 (d, J= 7.7 Hz, 1H), 5.76 (d ,J= 17.4 Hz, 1H), 5.41 (d,J= 17.3 Hz, 1H), 4.36 (dd, .7= 9.1, 6.0 Hz, 1H), 3.69 (dd, J= 5.5, 2.4 Hz, 1H), 2.52 - 2.39 (m, 1H), 1.98 (dd, J= 13.2, 5.9 Hz, 1H), 1.31 (s, 3H), 1.07 - 0.98 (m, 1H), 0.98 - 0.87 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-i/e) δ -58.53; MS (ES+): 588.0 (M+l), (ES-): 586.0 (M-l); Analysis calculated for CzsHziBrFaNzOz.1. lHCl.1 75HzO: C, 45.49; H, 3.91; Cl, 5.91; N, 14.86; Found: C, 45.32; H, 3.90; Cl, 5.87; N, 14.62.

Scheme 29

Preparation of (lR,3S,5R)-2-(2-(4-amino-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]p yrimidin-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo|3.1.0]hexane -3-carboxamide (29f)

Step-1: Preparation of 2-amino-lH-pyrrolo[2,3-c]pyridine-3-carbonitrile (29b)

To NaH (2.55 g, 63.7 mmol) cooled to 0 °C was added portion-wise a solution of malononitrile (4.21 g, 63.7 mmol) in THF (40 mL). The resulting cloudy mixture was stirred at 0 °C for 1 h, followed by slow addition of 4-chloro-3-nitropyridine (29a) (5.00 g, 31.5 mmol) in THF (10 mL). The mixture was then heated at 60 °C under argon for 3 h. The cooled mixture was quenched with HzO (30 mL) and extracted with EtOAc (50 mL x 5). The combined organic extract was washed with HzO (50 mL x 2), brine (50 mL), dried over anhydrous NazSO-t, filtered and concentrated to provide 2-(3-nitropyridin-4-yl)malononitrile (8.77 g) as an orange-red solid, which was used as such in the next reaction; MS (ES+) 189 (M+l), (ES-) 187 (M-l). To 2-(3-nitropyridin-4-yl)malononitrile (4.40 g, 23.39 mmol) suspended in DMF (20 mL) at rt was added a solution NaHCOz (9.82 g, 117 mmol) in HzO (20 mL) followed by solid NazSzO* (12.22 g, 70.2 mmol). The resulting mixture was stirred at rt for 16 h and filtered. The filtrate was extracted with EtOAc (50 mL x 4). The combined organic extract was washed with HzO (30 mL x 4) brine (30 mL), dried, filtered and concentrated in vacuum. The residue obtained was purified by flash column chromatography (SiOz, 40 g, eluting with 0-20% DMA-80 in DCM) to provide 2-amino- 1 H-pyrrolo[2,3- c]pyridine-3-carbonitrile (29b) (0.673 g, 18 % yield) as a beige solid. Ή NMR (300 MHz, DMSO-tfc) δ 8.30 (s, 1H), 8.03 (d, J = 5.3 Hz, 1H), 7.27 (s, 2H), 7.14 (d, J = 5.3 Hz, 1H); MS (ES+): 159 (M+l), (ES-): 157 (M-l). To a suspension of 2-amino-lH-pyrrolo[2,3-c]pyridine-3-carbonitrile (29b) (0.46 g, 2.91 mmol) in EtOH (10 mL) in a pressure vessel was added formamidine acetate (2.422 g, 23.27 mmol). The cloudy pale-yellow mixture was heated at 80 °C for 16 h, during which the cloudy mixture turned to a clear solution, and then a precipitate formed. The resulting cloudy pale-yellow mixture was hot-filtered. The filtered cake was washed thoroughly with boiling EtOH to provide the product 9H-pyrido [4’,3 ¹ : 4,5 ]pyrrolo [2,3 -d Jpyrimidin-4-amine (29c) (0.35 g, 65.0 % yield) as a pale-yellow solid. Ή NMR (300 MHz, DMSO-Jc) δ 12.15 (s, 1H), 8.78 (s, 1H), 8.38 (d, J = 5.3 Hz, 1H), 8.34 (s, 1H), 8.31 (d, J = 5.4 Hz, 1H), 7.49 (s, 2H); MS (ES+): 186 (M+l), (ES-): 184 (M-l).

Step-3: Preparation of tort-butyl 2-(4-amino-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-9- yl)acetate (29d)

Compound 29d was prepared according to the procedure reported in step-1 of scheme- 1, from 9H-pyrido[4',3':4,5]pynolo[2,3-d]pyrimidin-4-amme (29c) (0.35 g, 1.890 mmol) in DMF (25 mL) using tort-butyl 2-bromoacetate (0.369 g, 1.890 mmol), CS2CO3 (1.232 g, 3.78 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH in DCM from 0-7%] tort-butyl 2-(4- amino-9H-pyrido[4 ^, ,3 ^, :4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetate (29d) (0.27 g, 48% yield) as a pale yellow solid; Ή NMR (300 MHz, DMSO-i/e) δ 8.94 (s, 1H), 8.45 (d, 7= 5.3 Hz, 1H), 8.39 (s, 1H), 8.38 - 8.34 (m, 1H), 7.66 (s, 2H), 5.22 (s, 2H), 1.41 (s, 9H); MS (ES+): 300 (M+l), (ES-1): 298 (M-l).

Step-4: Preparation of 2-(4-amino-9H-pyrido[4 ^, ,3 ^, :4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetic acid (29e)

Compound 29e was prepared according to the procedure reported in step-2 of scheme- 1, from tort-butyl 2-(4-amino-9H-pyrido[4',3 ^, :4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetate (29d) (270 mg, 0.902 mmol) in DCM (10 mL) using TFA (1029 mg, 9.02 mmol) and stirring at RT for 16 h. This gave after workup 2-(4-amino-9H-pyrido[4',3 ^, :4,5]pyrrolo[2,3-d]pyrimidin-9- yl)acetic acid (29e) (0.53 g) TFA salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 9.51 (s, 1H), 8.96 (d, J= 6.2 Hz, 1H), 8.78 (d, J= 6.2 Hz, 1H), 8.56 (s, 1H), 5.35 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-flfe) δ -74.66.; MS (ES+): 244 (M+l), (ES-): 242 (M-l).

Step-5: Preparation of (lR,3S,5R)-2-(2-(4-amino-9H-pyrido[4 ^, ,3':4,5]pyTrolo[2,3- d]pyrimidm-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo [3.1 0]hexane-3-carboxamide

(290 Compound 29f was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of2-(4-amino-9H-pyrido[4 ^, ,3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetic acid (29e)

(50 mg, 0.140 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)- 2-azabicyclo[3.1 ,0]hexane-3-carboxamide (4a) (70.0 mg, 0.177 mmol), HATU (63.9 mg, 0.168 mmol), DIPEA (90 mg, 0.7 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-9H-pyrido[4 ^, ,3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (29f) (57 mg, 80 % yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.80 (s, 1H), 9.53 (s, 1H), 9.13 (d, J = 6.3 Hz, 1H), 8.94 (s, 2H), 8.80 (d, J= 6.3 Hz, 1H), 8.69 (s, 1H), 8.00 (d,J= 8.1 Hz, 1H), 7.70 (t, J= 7.9 Hz, 1H), 7.31 (d, J= 7.7 Hz, 1H), 5.96 (d, J= 17.4 Hz, 1H), 5.53 (d, J= 17.3 Hz, 1H), 4.47 - 4.44 (m, 1H), 3.91 - 3.86 (m, 1H), 2.40 - 2.29 (m, 1H), 2.29 - 2.13 (m, 1H), 2.00 - 1.85 (m, 1H), 1.16 - 1.00 (m, 1H), 0.98 - 0.80 (m, 1H); MS (ES+): 507/509 (M+l), (ES-): 505/507 (M-l).

Scheme 30

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-9H-pyrimido[4,5-b]indol-9- yl)acetyI)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (30f)

Step-1: Preparation of 2-amino-7-methyl- lH-indole-3-caibonitrile (30b) Compound 30b was prepared according to the procedure reported in step-1 of scheme- 11, from N-(2-bromo-6-methylphenyl)-2,2,2-trifluoroacetamide (30a) (7.45 g, 26.4 mmol; CAS # 2007409-96-1) in DMSO (20 mL) using malononitrile (2.094 g, 31.7 mmol), L-proline (0.608 g, 5.28 mmol), Cul (0.503 g, 2.64 mmol), a solution of K2CO3 (7.30 g, 52.80 mmol) in water (20 mL) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification [SiChgel (40 g), eluting with EtOAc in hexane from 0-40%] 2- amino-7-methyl-lH-indole-3-carbonitrile (30b) (2.35 g, 52% yield) as a brown solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.73 (s, 1H), 6.97 (d, J= 7.6 Hz, 1H), 6.88 (t, J= 7.5 Hz, 1H), 6.73 (d, 7.3 Hz, 1H), 6.49 (s, 2H), 2.33 (s, 3H); MS (ES+): 172 (M+l); (ES-): 170

(M-l).

Step-2: Preparation of 8-methyl-9H-pyrimido[4,5-b]indol-4-amine (30c)

Compound 30c was prepared according to the procedure reported in step-1 of scheme-6, from 2-amino-7-meth\i- 1 H-indole-3-carbonitrile (30b) (4.28 g, 25 mmol) using trimethyl orthoformate (26.5 g, 250 mmol), AcOH (4.50 g, 75 mmol) and NHtOAc (5.78 g, 75 mmol). This gave after workup 8-methyl-9H-pyrimido[4,5-b]indol-4-amine (30c) (4.24 g, 86% yield) as a pale-yellow solid; ¾NMR (300 MHz, DMSO-afe) δ 11.81 (s, 1H), 8.26 (s, 1H), 8.10 (dd, J = 7.4, 1.8 Hz, 1H), 7.21 - 7.02 (m, 4H), 2.54 (s, 3H). MS (ES+): 199 (M+l).

Step-3: Preparation of tort-butyl 2-(4-amino-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (30d)

Compound 30d was prepared according to the procedure reported in step-1 of scheme- 1, from 8-methyl-9H-pyiimido[4,5-b]indol-4-amine (30c) (3.07 g, 15.49 mmol) in DMF (20 mL) using tort-butyl 2-bromoacetate (3.02 g, 15.49 mmol) CS2CO3 (6.06 g, 18.59 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH in DCM from 0-3%] tort-butyl 2-(4- amino-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (30d) (3.52 g, 73% yield) as a pale yellow solid; ΉΝΜΚ (300 MHz, DMSO-tife) δ 8.29 (s, 1H), 8.19 (dd, ./= 5.8, 3.4 Hz, 1H), 7.26 (s, 2H), 7.17 (d,J= 2.6 Hz, 1H), 7.15 (s, 1H), 5.34 (s, 2H), 2.64 (s, 3H), 1.43 (s, 9H); MS (ES+): 313 (M+l); (ES-): 311 (M-l).

Step-4: Preparation of 2-(4-anuno-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (30e)

Compound 30e was prepared according to the procedure reported in step-2 of scheme- 1 , from mmol) using TFA (438 mg , 3.84 mmol) in DCM (5 mL) and stirring at RT for 16 h. This gave after workup 2-(4-amino-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (30e) (0.190 g) TFA salt as a yellow solid; Ή NMR (300 MHz, DMSO-tfe) δ 8.87 - 8.66 (m, 2H), 8.64 (s, 1H), 8.36 (dd, J= 5.8, 3.4 Hz, 1H), 7.40 - 7.25 (m, 2H), 5.47 (s, 2H), 2.70 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-cfe) δ -74.60; MS (ES+): 257 (M+l), (ES-): 255 (M-l).

Step-5: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (30f)

Compound 30f was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-9H-pyrimido[4,5-b]indol-9-vi)acetic acid (30e) (50 mg, 0.135 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0Jhexane-3-carboxamide (4a) (43.0 mg, 0.135 mmol), HATU (61.6 mg, 0.162 mmol) DIPEA (87 mg, 0.675 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 4%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%]

( 1 R, 3 S ,5R)-2-(2-(4-amino-8-methyl -9H-pyri mi do [4,5 -b] ί ndol-9-yl)acety 1 )-N-(6- bromopyiidin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (300 (44 mg, 63% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfc) 5 10.82 (s, 1H, DzO exchangeable), 8.82 - 8.54 (m, 3H, 2H DzO exchangeable), 8.42 - 8.28 (m, 1H), 8.00 (d, J= 8.2 Hz, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.38 - 7.24 (m, 3H), 5.93 (d,J= 18.0 Hz, 1H), 5.65 (d,J= 17.9 Hz, 1H), 4.42 (dd, J= 9.0, 5.7 Hz, 1H), 3.96 - 3.90 (m, 1H), 2.71 (s, 3H), 2.43 - 2.28 (m, 1H), 2.25 - 2.12 (m, 1H), 1.99 - 1.83 (m, 1H), 1.14 - 0.99 (m, 1H), 0.74 - 0.59 (m, 1H); MS (ES+):

520.0 (M+l), (ES-): 518.0 (M-l); Analysis calculated for Cz4HzzBrN70z.l.lHC1.2.5Hz0: C, 47.60; H, 4.68; Cl, 6.44; N, 16.19; Found: C, 47.64; H, 4.48; Cl, 6.39; N, 16.14.

Scheme 31

Preparation of (lR,3S,5R)-2-(2-(4-ammo-9H-pyrido[2 ^, ,3':4,5]pyrrolo[2,3-d]pyrimidin-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (31f)

Step-1: Preparation of 2-amino-lH-pyrrolo[3,2-b]pyridine-3-carbonitrile (31b)

NaH (1.990 g, 49.8 mmol) was added portion-wise to a cold solution of malononitrile (3.29 g, 49.8 mmol) in THF (40 mL) at 0 °C. The resulting cloudy mixture was stirred at 0 °C for 1 h, followed by slow addition of 2-bromo-3-nitropyridine (31a) (5.00 g, 24.63 mmol) in THF (10 mL). The mixture was then heated at 60 °C under argon for 3 h. The cooled mixture was quenched with H2O (30 mL) and extracted with EtOAc (50 mL x 5). The combined organic extract was washed with H2O (50 mL x 2), brine (50 mL), dried, filtered and concentrated to provide 2-(3-nitropyridin-2-yl)malononitrile (8.62 g) as an orange-red solid, which was used as such in the next reaction; MS (ES+): 189 (M+l), (ES-): 187 (M-l). A suspension of 2-(3- nitropyridin-2-yl)malononitrile (4.315 g, 22.93 mmol) zinc (7.50 g, 115 mmol) in acetic acid (27.5 g, 459 mmol) was heated at 60 °C for 2 h and filtered hot. The filtered cake was washed thoroughly with boiling EtOH. The filtrate was concentrated to dryness. The concentrate was suspended in H2O (50 mL), neutralized with 3 M aqueous NaOH until pH 7, and then extracted with EtOAc (50 mL x 3). The combined extract was washed with H2O (30 mL x 2), brine (30 mL), dried, filtered and concentrated in vacuum. The residue obtained was purified by flash column chromatography (S1O2, 40 g, eluting with 0-20% DMA-80 in DCM) to provide 2-amino-lH-pyrrolo[3,2-b]pyridine-3-carbonitrile (31b) (320 mg, 9 % yield) as beige solid; Ή NMR (300 MHz, DMSO-ae) δ 10.82 (s, 1H), 8.04 (dd, J = 5.0, 1.4 Hz, 1H), 7.36 (dd, J = 7.8, 1.4 Hz, 1H), 7.16 (s, 2H), 6.86 (dd, J = 7.8, 4.9 Hz, 1H); MS (ES+): 159 (M+l), (ES-): 157 (M-l).

Step-2: Preparation of 9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (31c)

Compound 31c was prepared according to the procedure reported in step-1 of scheme-6, from 2-amino-lH-pyrrolo[3,2-b]pyridine-3-carbonitrile (31b) (0.31 g, 1.960 mmol) using trimethyl orthoformate (4.16 g, 39.2 mmol), AcOH (0.589 g, 9.80 mmol) and NH+OAc (0.755 g, 9.80 mmol). This gave after workup and purification [silica gel (12 g), eluting with DMA-80 in DCM from 0-30%] 9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (31c) (100 mg, 28% yield) as a pale-yellow solid; Ή NMR (300 MHz, DMSO-cfc) δ 12.02 (d, J = 2.0 Hz, 1H),

8.49 (dd, J = 4.8, 1.4 Hz, 1H), 8.34 (s, 1H), 7.83 (dd, J = 8.1, 1.4 Hz, 1H), 7.37 (dd, J = 8.2, 4.8 Hz, 1H); MS (ES+): 186 (M+l), (ES-): 184 (M-l).

Step-3: Preparation of ten-butyl 2-(4-ammo-9H-pyrido[2 ^l ,3 ^, :4,5]pyrrolo[2,3-d]pyrimidin-9- yl)acetate (31d)

Compound 31 d was prepared according to the procedure reported in step-2 of scheme- 16, 9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (31c) (80 mg, 0.432 mmol) in DMF (2.5 mL) using ten-butyl 2-bromoacetate (0.077 mL, 0.518 mmol), CS2CO3 (282 mg, 0.864 mmol) and stirring at RT for 1.5 h under nitrogen atmosphere and quenching by adding water. The solid separated was filtered and dried to give ten-butyl 2-(4-amino-9H- pyrido[2',3':4,5]pyiTolo[2,3-d]pyrimidin-9-y])acetate (31d) (109 mg, 84 % yield) as a pale yellow solid; Ή NMR (300 MHz, DMSO-de) δ 8.54 (dd, J= 4.9, 1.3 Hz, 1H), 8.39 (s, 1H), 8.04 (dd, J= 8.3, 1.3 Hz, 1H), 7.43 (dd,J= 8.2, 4.8 Hz, 1H), 5.17 (s, 2H), 1.40 (s, 9H); MS (ES+): 300.1 (M+l).

Step-4: Preparation of 2-(4-amino-9H-pyrido[2 ^, ,3 ^, :4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetic acid (31e)

Compound 31e was prepared according to the procedure reported in step-2 of scheme- 1, from ten-butyl 2-(4-amino-9H-pyrido[2',3 ^, :4,5]pyrrolo[2,3-dJpyrimidin-9-yl)acetate (31d) (80 mg, 0.267 mmol) using 20% TFA in DCM (1534 pL, 4.01 mmol) and stirring at RT for 16 h.

This gave after workup 2-(4-amino-9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl) acetic acid (31e) (64 mg, 98% yield) TFA salt as a yellow solid; Ή NMR (300 MHz, DMSO-c/e) δ 8.65 (dd, J = 4.9, 1.3 Hz, 1H), 8.55 (s, 1H), 8.25 (d, J= 8.3 Hz, 1H), 7.56 (dd, J= 8.3, 4.9 Step-5: Preparation of (lR,3S,5R)-2-(2-(4-amino-9H-pyrido[2 ^, ,3 ^, :4,5]pyrrolo[2,3- d]pyrimidin-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicycl o[3.1 ,0]hexane-3-carboxamide

(31f)

Compound 31f was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl) acetic acid (31e)

(60 mg, 0.247 mmol) in DMF (2 mL) using TFA salt of (lR,3S,5R)-N-(6-bromopyiidin-2- yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (98.0 mg, 0.247 mmol), HATU (141 mg, 0.370 mmol), DIPEA (0.215 mL, 1.233 mmol) and stirring at RT for 1 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-9H-pyrido[2 ^, ,3 ^, :4,5]pyrrolo[2,3-d]pyrimidm-9-yl)acetyl)- N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxam ide (31f) (79 mg, 63% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-dk) δ 10.77 (s, 1H, D ₂ 0 exchangeable), 8.97 (s, 1H, D2O exchangeable), 8.75 - 8.64 (m, 2H), 8.31 (d, J = 8.4 Hz, 1H), 8.00 (d, J=

8.2 Hz, 1H), 7.75 - 7.61 (m, 2H), 7.31 (d, J= 7.7 Hz, 1H), 5.84 (d, J= 17.4 Hz, 1H), 5.47 (d, J= 17.3 Hz, 1H), 4.45 - 4.37 (m, 1H), 3.89 (ddd, J= 7.5, 5.4, 2.4 Hz, 1H), 2.40 - 2.13 (m, 2H), 1.99 - 1.82 (m, 1H), 1.07 (dt, J= 8.7, 5.4 Hz, 1H), 0.80 (td, J= 5.2, 2.3 Hz, 1H); MS (ES+): 507.1 (M+l); (ES-): 505.0 (M-l); Analysis calculated for CiiHigBrNsCb 1.75H20.1.2HC1: C, 45.35; H, 4.10; Cl, 7.30; N, 19.23; Found: C, 45.38; H, 4.02; Cl, 7.16;

N, 18.95.

Scheme 32

NH ₂ ^F H ₂ N

32d 32e 32f

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-fluoro-9H-pyrimido[4,5-b]mdol-9-y l)acetyl)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (32f)

Step-1: Preparation of 2 -amino-5 -fluoro- 1 H-indole-3 -carbonitrile (32b)

Compound 32b was prepared according to the procedure reported in step-1 of scheme- 11 , from 2,2,2-trifluoro-N-(4-fluoro-2-iodophenyl)acetamide (32a) (7.03 g, 21.1 mmol; CAS # 784183-55-7) in DMSO (30 mL) using malononitrile (1.673 g, 25.3 mmol), L-proline (0.486 g, 4.22 mmol), Cul (0.402 g, 2.110 mmol), K2CO3 (5.83 g, 42.2 mmol) and heating at 60 °C for 15 h under an argon atmosphere. This gave after workup and purification [S1O2 gel (80 g), eluting with EtOAc in hexane from 0-50%] 2-amino-5 -fluoro- 1 H-indole-3 -carbonitrile (32b) (2.657 g, 72% yield) as a brown solid; MS (ES+): 176.05 (M+l).

Step-2: Preparation of 6-fluoro-9H-pyrimido[4,5-b]indol-4-amine (32c)

Compound 32c was prepared according to the procedure reported in step-2 of scheme-29, from 2-amino-5-fluoro- lH-indole-3-carbonitrile (32b) (1.2 g, 6.85 mmol) in ethanol (30 mL) using formamidine acetate (5.76 g, 54.8 mmol) and refluxing for 40 h. This gave after workup 6-fluoro-9H-pyrimido[4,5-b]indol-4-amine (32c) as a brown solid (2.706 g) which was used as such in the next step; MS (ES+): 203.00 (M+l).

Step-3: Preparation of fert-butyl 2-(4-amino-6-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetate (32d) Compound 32d was prepared according to the procedure reported in step-1 of scheme- 1, from 6-fluoro-9H-pyrimido[4,5-b]indol-4-amine (32c) (346 mg, 1.71 mmol) in DMF (10 mL) using terr-butyl 2-bromoacetate (0.252 mL, 1.71 mmol), cesium carbonate (1.337 g) and stirring at RT for 47 h. This gave after workup and purification by flash column chromatography [silica gel (40 g), eluting with hexanes/10% methanol in ethyl acetate (1:0 to 1:1)] fer/-butyl 2-(4-amino-6-fluoro-9H-pyrimido [4,5 -b] indol-9-yl)acetate (32d) (160 mg, 30% yield) as a light yellow solid; 1H NMR (300 MHz, DMSO-ifc) δ 8.32 - 8.22 (m, 2H), 7.57 (dd, J= 8.9, 4.5 Hz, 1H), 7.38 (s, 2H), 7.26 (td, J= 9.2, 2.5 Hz, 1H), 5.12 (s, 2H), 1.39 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-cfc) δ -122.42; MS (ES+): 317.10 (M+l).

Step-4: Preparation of 2-(4-amino-6-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (32e)

Compound 32e was prepared according to the procedure reported in step-2 of scheme- 1, from te/t-butyl 2-(4-amino-6-fluoro-9H-pyri mido [4,5 -b] i ndol-9-y l)acetate (32d) (140 mg, 0.443 mmol) in DCM (10 mL) using TFA. The reaction mixture was concentrated to dryness to afford 2-(4-amino-6-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (32e) which used as such for the next step; MS (ES+): 261.10 (M+l); (ES-): 259.00 (M-l).

Step-5: Preparation of (lR,3S,5R)-2-(2-(4-ammo-6-fluoro-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (32f)

Compound 32f was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (32e) (0.443 mmol, from above step-4) in DMF (15 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (141.0 mg, 0.443 mmol), HATH (337 mg, 0.886 mmol) DIPEA (0.386 mL, 2.215 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 5%] followed by treating of product obtained with acetonitrile (2 mL) and 50 mM aq. HC1 (8 mL) and lyophilization (lR,3S,5R)-2-(2-(4- amino-6-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bro mopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (32f) (53 mg, 23% yield) HC1 salt as a light brown solid; Ή NMR (300 MHz, DMSO-ifc) 5 10.76 (s, 1H, DzO exchangeable), 8.73 (s, 2H, DzO exchangeable), 8.63 (s, 1H), 8.47 (dd, J= 9.8, 2.5 Hz, 1H), 8.00 (d, J= 8.1 Hz, 1H), 7.79 - 7.65 (m, 2H), 7.45 (td, J= 9.2, 2.5 Hz, 1H), 7.32 (d, J= 7.7 Hz, 1H), 5.78 (d, J= 17.4 Hz, 1H), 5.43 (d, J= 17.3 Hz, 1H), 4.41 (dd, J= 9.0, 5.5 Hz, 1H), 4.02 - 3.82 (m, 1H), 2.41 - MHz, DMSO-cfe) δ -119.89; MS (ES+): 524.10 & 526.10 (M+l); MS (ES-): 522.00 & 524.00 (M-l); Analysis calculated for C23Hi9BrFN ₇ 02.1.2HC1.2.75H20: C, 44.73; H, 4.19; N, 15.87; Cl, 6.89; Found: C, 44.84; H, 4.13; N, 15.51; Cl, 6.81.

Scheme 33

Preparation of (lR,3S,5R)-2-(2-(4-amino-7-fluoro-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamid e (33e)

Step-1: Preparation of 7-fluoro-9H-pyrimido[4,5-b]indol-4-amine (33b)

Compound 33b was prepared according to the procedure reported in step-2 of scheme-29, from 2-amino-6-fluoro-lH-indole-3-cafbonitrile (33a) (1.2 g, 6.85 mmol; CAS # 378236-80- 7) in ethanol (30 mL) using formamidine acetate (5.76 g, 54.8 mmol) and refluxing for 20 h. This gave after workup 7-fluoro-9H-pyrimido[4,5-b]indol-4-amine (33b) as a brown solid (2.62 g) which was used as such in the next step; Ή NMR (300 MHz, DMSO-ifc) δ 8.29 (dd, J= 8.7, 5.4 Hz, 1H), 8.23 (s, 1H), 7.78 (s, 1H), 7.22 (dd, J= 9.7, 2.4 Hz, 1H), 7.10 - 7.01 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-tVe) δ -116.72; MS (ES+): 203.10 (M+l).

Step-2: Preparation of te/7-butyl 2-(4-amino-7-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetate

(33c)

Compound 33c was prepared according to the procedure reported in step-1 of scheme- 1, from 7 fl 9H i id [45 b]i d l 4 i (33b) (346 1 71 l) i DMF (10 L) using tert- butyl 2-bromoacetate (0.252 mL, 1.71 mmol), cesium carbonate (1.337 g) and stirring at RT for 46 h. This gave after workup and purification by flash column chromatography [silica gel (40 g), eluting with hexanes/10% methanol in ethyl acetate (1:0 to 1:1)] fcrf-butyl 2-(4-amino-7-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetate (33c) (151 mg, 28% yield) as a light yellow solid; 1H NMR (300 MHz, DMSO-J6) δ 8.35 (dd,J= 8.7, 5.4 Hz, 1H), 8.28 (s, 1H), 7.53 (dd, J= 10.2, 2.4 Hz, 1H), 7.31 (s, 2H), 7.17 - 7.04 (m, 1H), 5.11 (s, 2H), 1.40 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-i/e) δ -116.10; MS (ES+): 317.20 (M+l). Step-3: Preparation of 2-(4-amino-7-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (33d) Compound 33d was prepared according to the procedure reported in step-2 of scheme- 1, from terf-butyl 2-(4-amino-7-fluoro-9H-pyri mi do [4,5 -b] i ndol-9-yl)acetate (33c) (145 mg, 0.458 mmol) in DCM (10 mL) using TFA. This gave after workup 2-(4-amino-7-fluoro-9H- pyrimido[4,5-b]indol-9-yl)acetic acid (33d) which was used as such in next step; MS (ES+): 261.10 (M+l); (ES-): 259.00 (M-l).

Step-4: Preparation of(lR,3S,5R)-2-(2-(4-amino-7-fluoro-9H-pyrimido[4,5-b]indol- 9- yl)acetyl)-N -(6-bromopyridin-2-yl)-2-azabicyclo [3.1.0Jhexane-3-carboxamide (33e)

Compound 33e was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-7-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (33d) (119 mg, 0.458 mmol) in DMF (15 mL) using HC1 salt of ( lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (4a) (146.0 mg, 0.458 mmol), HATU (348 mg,

0.916 mmol), DIPEA (0.399 mL, 2.29 mmol) and stirring at RT for 16 h. This gave after workup and purification by reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] followed by purification using flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 5%], dissolving the product in acetonitrile (3 mL) and 0.1% aq. HC1 (20 mL) followed by lyophilization (lR,3S,5R)-2-(2-(4-amino-7-fluoro-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (33e) (31 mg, 13% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-i/e) δ 10.77 (s, 1H, DzO exchangeable), 8.76 - 8.66 (m, 3H, DzO exchangeable), 8.63 (s, 1H), 8.56 (dd, J= 8.8, 5.2 Hz, 1H), 8.00 (d, J= 8.2 Hz, 1H), 7.75 - 7.63 (m, 2H), 7.37 - 7.25 (m, 2H), 5.76 (d,J= 17.4 Hz, 1H), 5.40 (d, J= 17.3 Hz, 1H), 4.42 (dd, 9.1, 5.5 Hz, 1H), 3.95 - 3.84 (m, 1H), 2.42 - 2.12 (m, 2H), 2.02 - 1.76 (m, 1H), 1.12 - 0.99 (m, 1H), 0.89 - 0.75 (m, 1H); ¹⁹ FNMR(282 MHz, DMSO- i/e) δ -113 65; MS (ES+): 524 10 & 526 10 (M+l); MS (ES-): 522 10 & 52400 (M-l); Analysis calculated for CzsHigBrFNvCh.1. IHCI.2.OH2O: C, 46.00; H, 4.05; Cl, 6.49; N, 16.33; Found: C, 46.28; H, 4.10; Cl, 6.44; N, 15.96.

Scheme 34

NH ₂

Br

34d 34e

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-bromo-9H-pyrimido[4,5-bJindol-9-y l)acetyl)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (34e)

Step-1: Preparation of 6-bromo-9H-pyrimido[4,5-b]indol-4-amine (34b)

Compound 34b was prepared according to the procedure reported in step-1 of scheme-6, from 2-amino-5-bromo-lH-indole-3-carbonitrile (34a) (2.20 g, 9.32 mmol; CAS # 1242140- 64-2) using triethyl orthoformate (31.0 mL, 186 mmol), AcOH (2.66 mL, 46.6 mmol) and NtfcOAc (3.59 g, 46.6 mmol). This gave after woik up 6-bromo-9H-pyrimido[4,5-b]indol-4- amine (34b) (1.58 g, 64% yield) as a pale yellow solid; Ή NMR (300 MHz, DMSO-i/e) δ 11.99 (s, 1H), 8.58 (d, J= 1.9 Hz, 1H), 8.26 (s, 1H), 7.48 (dd, J= 8.6, 1.8 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 7.30 (s, 2H); MS (ES+): 263/265 (M+l).

Step-2: Preparation of tert- ^butyl 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate

(34c)

Compound 34c was prepared according to the procedure reported in step-1 of scheme- 1, from 6-bromo-9H-pyrimido[4,5-b]indol-4-amine (34b) (1.58 g, 6.01 mmol) in DMF (20 mL) using RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH in DCM from 0-3%] tert- butyl 2-(4-amino-6-bromo-9H- pyrimido[4,5-b]indol-9-yl)acetate (34c) (2.265 g, 72% yield) as a pale orange solid; ‘HNMR (300 MHz, DMSO-ifc) δ 8.64 (s, 1H), 8.31 (s, 1H), 7.56 (s, 2H), 7.44 (s, 2H), 5.13 (s, 2H), 1.40 (s, 9H); MS (ES+): 377/379 (M+l), (ES-): 375/377 (M-l).

Step-3: Preparation of 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (34d)

Compound 34d was prepared according to the procedure reported in step-2 of scheme- 1, from terf-butyl 2-(4-amino-6-bromo-9H-pyri mi do [4,5 -b] i ndol-9-yl)acetate (34c) (0.300 g, 0.795 mmol) in DCM (10 mL) using TFA (0.907 g, 7.95 mmol) and stirring at RT for 16 h. This gave after workup 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (34d) (0.387 g) TFA salt as a yellow solid; ‘HNMR (300 MHz, DMSO-cfc) 58.79 (s, 1H), 8.70 - 8.44 (m, 3H), 7.77 (d, J= 8.8 Hz, 1H), 7.69 (dd, J= 8.7, 1.8 Hz, 1H), 5.26 (s, 2H); MS (ES+): 321/323 (M+l), (ES-): 319/321 (M-l).

Step-4: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N -(6-bromopyridin-2-y l)-2-azabicyclo [3.1.0 Jhexane-3 -carboxamide (34e)

Compound 34e was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (34d) (50 mg, 0.115 mmol) in DMF (5 mL) using HC1 salt of ( lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (4a) (36.6 mg, 0.115 mmol), HATU (52.4 mg, 0.138 mmol) DIPEA (74.3 mg, 0.575 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 5%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%]

( 1 R,3 S, 5 R)-2-(2-(4-amino-6-bromo-9H-pyrimido [4,5 -b] indol-9-yl)acetyl)-N -(6- bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (34e) (26 mg, 39% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfe) δ 10.75 (s, 1H, D2O exchangeable), 8.76 (d, J= 3.1 Hz, 1H), 8.54 (d, J= 5.2 Hz, 1H), 8.38 (s, 2H, DzO exchangeable), 8.00 (d, J= 8.1 Hz, 1H), 7.75 - 7.58 (m, 3H), 7.32 (d, J= 7.7 Hz, 1H), 5.73 (dd, J= 17.7, 1.8 Hz, 1H), 5.39 (d,J= 17.4 Hz, 1H), 4.40 (dd, J= 9.2, 5.5 Hz, 1H), 3.94 - 3.86 (m, 1H), 2.38 - 2.26 (m, 1H), 2.26 - 2.15 (m, 1H), 1.96 - 1.84 (m, 1H), 1.13 - 0.97 (m, 1H), 0.81 - 0.72 (m, 1H); MS (ES+) 584.0 (M+l); (ES-): 582.0 (M-l); Analysis calculated for C23Hi9BnN702 HC1 225H20: C 41 71; H 3 73; Cl 5 35; N 1481; Found: C 41 55; H Scheme 35

NH ₂ 35f

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-bromo-9H-pyrimido[4,5-b]indol-9-y l)acetyl)-N- (6-bromopyridin-2-yI)-2-azabicyclo[3.1.0]hexane-3-carboxamid e (35f)

Step-1: Preparation of 2-amino-7 -bromo- 1 H-i ndole-3 -carbon itrile (35b)

Compound 35b was prepared according to the procedure reported in step-1 of scheme- 11, from N-(2,6-dibromophenyl)-2,2,2-trifluoroacetamide (35a) (7.79 g, 22.45 mmol; CAS # 340034-49-3) in DMSO (20 mL) using malononitrile (1.780 g, 26.9 mmol), L-proline (0.517 g, 4.49 mmol), Cul (0.428 g, 2.245 mmol), K2CO3 (6.21 g, 44.9 mmol) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification [SiOzgel (40 g), eluting with EtOAc in hexane from 0-40%] 2-amino-7-bromo-lH-indole-3-carbonitrile (35b) (4.18 g, 18% yield) as a pale orange solid; >HNMR(300 MHz, DMSO-de) δ 10.91 (s, 1H), 7.15 (dd, J = 7.7, 1.0 Hz, 1H), 7.11 (dd, J = 7.9, 0.9 Hz, 1H), 6.93 (t, J = 7.8 Hz, 1H), 6.69 (s, 2H); MS (ES+): 236 ; (ES-): 234 (M-l).

Step-2: Preparation of 8-bromo-9H-pyrimido[4,5-b]indol-4-amine (35c)

Compound 35c was prepared according to the procedure reported in step-1 of scheme-6, from orthoformate (37.6 mg, 354 mmol), AcOH (5.06 mL, 89 mmol) and NH*OAc (6.82 g, 89 mmol). This gave after workup 8-bromo-9H-pyrimido[4,5 -b] indol-4-amine (35c) as a pale- yellow solid residue was used as such for the next step; Ή NMR (300 MHz, DMSO-ifc) δ 11.97 (s, 1H), 8.32 (d, J= 7.9 Hz, 2H), 7.56 (d, J= 7.8 Hz, 1H), 7.30 (s, 2H), 7.17 (t, J= 7.8 Hz, 1H).

Step-3: Preparation of /erf-butyl 2-(4-amino-8-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (35d)

Compound 35d was prepared according to the procedure reported in step-1 of scheme- 1, from 8-bromo-9H-pyrimido[4,5-b]indol-4-amine (35c) (4.11 g, 15.62 mmol) in DMF (20 mL) using fe/7-butyl 2-bromoacetate (3.05 g, 15.62 mmol) CS2CO3 (6.62 g, 20.31mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH in DCM from 0-3%] terf-butyl 2-(4- amino-8-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (35d) (4.11 g, 88% yield) as a pale orange solid; Ή NMR (300 MHz, DMSO-ifc) δ 8.39 (d, J= 7.8 Hz, 1H), 8.34 (s, 1H), 7.59 (d, J= 7.8 Hz, 1H), 7.48 (s, 2H), 7.21 (t, J= 7.8 Hz, 1H), 5.44 (s, 2H), 1.43 (s, 9H).

Step-4: Preparation of 2-(4-ammo-8-bromo-9H-pyrimido[4,5-b]indol-9-yl)acctic acid (35e)

Compound 35e was prepared according to the procedure reported in step-2 of scheme- 1, from tezf-butyl 2-(4-amino-8-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (35d) (0.250 g, 0.663 mmol) using TFA (1.511 g, 13.25 mmol) in DCM (20 mL) and stirring at RT for 16 h. This gave after workup 2-(4-amino-8-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (35e) (0.356 g) TFA salt as a yellow solid; Ή NMR (300 MHz, DMSO-ifc) δ 8.57 (s, 1H), 8.51 (d, J= 7.9 Hz, 1H), 8.49 - 8.24 (m, 2H), 7.72 (d, J= 7.8 Hz, 1H), 7.32 (t, ./= 7.9 Hz, 1H), 5.54 (s, 2H).

Step-5: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-bromo-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (35f)

Compound 35f was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (35e) (50 mg,

0.115 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.OJhexane-3-carboxamide (4a) (36.6 mg, 0.115 mmol), HATU (52.4 mg, 0.138 mmol), DIPEA (74.3 mg, 0.575 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-8-bromo-9H-pyrimido[4,5-b]indol-9-y l)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (35f) (38 mg, 57% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-i/e) δ 10.76 (s, 1H, D2O exchangeable), 8.59 (s, 1H), 8.55 - 8.32 (m, 3H, 2H DzO exchangeable), 8.00 (d 8.2 Hz, 1H), 7.70 (t, J= 7.4 Hz, 2H), 7.30 (dt, J= 7.9, 4.0 Hz, 2H), 5.98 (d, J = 17.7 Hz, 1H), 5.84 - 5.72 (m, 1H), 4.41 (dd, J= 9.0, 5.7 Hz, 1H), 3.91 - 3.87 (m, 1H), 2.40 - 2.25 (m, 1H), 2.25 - 2.15 (m, 1H), 2.00 - 1.84 (m, 1H), 1.12 - 0.99 (m, 1H), 0.81 - 0.69 (m, 1H); MS (ES+): 584.0 (M+l), (ES-): 582.0 (M-l); Analysis calculated for C23H19Br2N7O2.HCl.2H2O: C, 42.00; H, 3.68; Cl, 5.39; N, 14.91; Found: C, 41.98; H, 3.61; Cl, 5.08; N, 14.77.

Scheme 36

Preparation of (lR,3S,5R)-2-(2-(4-ammo-7-methoxy-9H-pyrimido[4,5-b]indol-9- yl)acetyl)- N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (36e)

Step-1: Preparation of 7-metfaoxy-9H-pyrimido[4,5-b]indol-4-amine (36b)

Compound 36b was prepared according to the procedure reported in step-1 of scheme-6, from 2-amino-6-methoxy- lH-indole-3-carbonitrile (36a) (2.50 g, 13.35 mmol; CAS # 1016680-93-5) using triethyl orthoformate (44.4 mL, 267 mmol), AcOH (3.82 mL, 66.8 mmol) and NH*OAc (5.15 g, 66.8 mmol). This gave after work up 7-methoxy-9H- pyrimido[4,5-b]indol-4-amine (36b) (0.89 g, 31% yield) as a brown yellow solid; *H NMR (300 MHz, DMSO-ifc) δ 11.70 (s, 1H), 8.17 (d, J= 9.9 Hz, 2H), 7.01 (s, 2H), 6.93 (d, J= 2.3 Hz 1H) 6 82 (dd 1H) 3 83 (s 3H) Step-2: Preparation of te/7-butyl 2-(4-amino-7-methoxy-9H-pyrimido[4,5-b]indol-9- yl)acetate (36c)

Compound 36c was prepared according to the procedure reported in step-1 of scheme- 1, from 7-methoxy-9H-pyrimido[4,5-b]indol-4-amine (36b) (0.89 g, 4.15 mmol) in DMF (20 mL) using tert-butyl 2-bromoacetate (0.81 g, 4.15 mmol) and CszCOs (1.624 g, 4.99 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH in DCM from 0-3%] tert-butyl 2-(4- amino-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetate (36c) (0.83 g, 61% yield) as a pale yellow solid; ΉΝΜΚ (300 MHz, DMSO-tife) δ 8.22 (d, ./= 7.5 Hz, 2H), 7.22 - 7.07 (m, 3H), 6.89 (dd, J= 8.6, 2.3 Hz, 1H), 5.10 (s, 2H), 3.85 (s, 3H), 1.41 (s, 9H).

Step-3: Preparation of 2-(4-amino-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (36d)

Compound 36d was prepared according to the procedure reported in step-2 of scheme- 1, from tert- butyl 2-(4-amino-7 -methoxy-9H-py rimido [4,5 -b] indol-9-y l)acetate (36c) (0.83 g, 2.53 mmol) in DMF (20 mL) using TFA (5.76 g, 50.6 mmol) and stirring at RT for 16 h. The reaction mixture was concentrated in vacuum to afford 2-(4-amino-7-methoxy-9H- pyrimido[4,5-b]indol-9-yl)acetic acid (36d) (1.18 g) TFA salt as a yellow solid; ^l HNMR (300 MHz, DMSO-tik) δ 8.61 (s, 2H), 8.59 (s, 1H), 8.41 (d,J= 8.8 Hz, 1H), 7.46 (d,J= 2.3 Hz, 1H), 7.07 (dd, J= 8.8, 2.2 Hz, 1H), 5.28 (s, 2H), 3.89 (s, 3H).

Step-4: Preparation of ( 1 R,3S,5R)-2-(2-(4-amino-7-methoxy-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N -(6-bromopyridin-2-y l)-2-azabicyclo [3.1.0]hexane-3 -carboxamide (36e)

Compound 36e was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (36d) (50 mg, 0.129 mmol) in DMF (5 mL) using HC1 salt of ( lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (4a) (41.2 mg, 0.129 mmol), HATU (59.1 mg, 0.155 mmol), DIPEA (84 mg, 0.647 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-7-methoxy-9H-pyrimido[4,5-b]indol-9 -yl)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (36e) (52 mg, 75% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifo) δ 10.67 (s, 1H, DzO exchangeable), 7.64 (t, J = 8.0 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 7.19 (d, J = 2.2 Hz, 1H), 6.97 (dd, J = 8.7, 2.2 Hz, 1H), 5.64 (d, J = 17.3 Hz, 1H), 5.35 (d, J = 17.2 Hz, 1H), 4.40 - 4.29 (m, 1H), 3.88 - 3.80 (m, 4H), 2.34 - 2.23 (m, 1H), 2.23 - 2.10 (m, 1H), 1.92 - 1.80 (m, 1H), 1.06 - 0.95 (m, 1H), 0.74 - 0.64 (m, 1H); MS (ES+): 536.0 (M+l), (ES-): 534.0 (M-l); Analysis calculated for C24H22BrN ₇ 03.1 2HC1.2.25H20: C, 46.44; H, 4.50; Cl, 6.85; N, 15.80; Found: C, 46.47; H, 4.50; Cl, 6.46; N, 15.867.

Scheme 37

36d NH ₂ 37a

Preparation of (lR,3S,5R)-2-(2-(4-amino-7-methoxy-9H-pyrimido[4,5-b]indol-9 -yl)acetyl)- N-(6-bromopyridin-2-yI)-5-methyl-2-azabicyclo[3.1.0]hexane-3 -carboxamide (37a)

Compound 37a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (36d) (100 mg, 0.259 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-5- methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (8a) (86 mg, 0.259 mmol), HATU (118 mg, 0.311 mmol), DIPEA (167 mg, 1.294 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-7-methoxy-9H-pyrimido[4,5-b]indol-9 -yl)acetyl)- N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3 -carboxamide (37a) (85 mg, 60% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-de) 5 10.73 (s, 1H, D2O exchangeable), 8.55 (s, 1H), 8.46 (s, 2H, D2O exchangeable), 8.39 (d, J= 8.8 Hz, 1H), 8.01 (d, J= 8.2 Hz, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.32 (d, ./= 7.7 Hz, 1H), 7.26 (d, J= 2.3 Hz,

1H), 7.04 (dd,J= 8.7, 2.3 Hz, 1H), 5.67 (d, J= 17.3 Hz, 1H), 5.37 (d, J= 17.3 Hz, 1H), 4.37 (dd, J= 9.2, 5.9 Hz, 1H), 3.87 (s, 3H), 3.69 (dd, J= 5.5, 2.3 Hz, 1H), 2.54 - 2.47 (m, 1H), 1.99 (dd, J= 13.2, 5.9 Hz, 1H), 1.31 (s, 3H), 1.07 - 0.97 (m, 1H), 0.96 - 0.83 (m, 1H); MS (ES+): 550.0 (M+l); (ES-): 548.0 (M-l).

Scheme 38

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-methoxy-9H-pyrimido[4,5-b]indol-9 -yl)acetyl)- N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxam ide (38e)

Step-1: Preparation of 6-methoxy-9H-pyrimido[4,5-b]indol-4-amine (38b)

Compound 38b was prepared according to the procedure reported in step-1 of scheme-6, from 2-amino-5 -methoxy- 1 H-indole-3 -carbonitri le (38a) (3.10 g, 16.56 mmol; CAS # 1304143-87-0) using trimethyl orthoformate (35.1 g, 331 mmol), AcOH (4.74 mL, 83 mmol) and NH4OAC (6.38 g, 83 mmol). This gave after work up 6-methoxy-9H-pyrimido[4,5- b]indol-4-amine (38b) (2.78 g, 78% yield) as a pale yellow solid; NMR (300 MHz, DMSO-dis) δ 11.62 (s, 1H), 8.20 (s, 1H), 7.85 (d, J= 2.4 Hz, 1H), 7.32 (d, J= 8.7 Hz, 1H), 7.17 (s, 2H), 6.96 (dd, J= 8.7, 2.4 Hz, 1H), 3.85 (s, 3H). MS (ES+): 215 (M+l), (ES-): 213 (M-l).

Step-2: Preparation of fe/7-butyl 2-(4-amino-6-methoxy-9H-pyrimido[4,5-b]indol-9- yl)acetate (38c)

Compound 38c was prepared according to the procedure reported in step-1 of scheme- 1, from 6-methoxy-9H-pyrimido[4,5-b]indol-4-amine (38b) (0.59 g, 2.75 mmol) in DMF (25 mL) i te f b t l 2 b t t (0537 275 l) C CO (1 077 3 30 l) d stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH in DCM from 0-3%] tert- butyl 2-(4- amino-6-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetate (38c) (0.56 g, 62% yield) as a pale yellow solid; ^! HNMR (300 MHz, DMSO-ifc) δ 8.25 (s, 1H), 7.91 (d, J= 2.4 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.31 (s, 2H), 7.02 (dd, J= 8.8, 2.4 Hz, 1H), 5.07 (s, 2H), 3.87 (s, 3H),

1.40 (s, 9H).; MS (ES+): 329 (M+l), (ES-): 327 (M-l).

Step-3: Preparation of 2-(4-amino-6-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (38d)

Compound 38d was prepared according to the procedure reported in step-2 of scheme- 1, from fm-butyl 2-(4-amino-6-methoxy-9H-pyiimido[4,5-b]indol-9-yl)acetate (38c) (0.56 g, 1.705 mmol) in DCM (20 mL) using TFA (1.945 g, 17.05 mmol) and stirring at RT for 16 h. This gave after workup 2-(4-amino-6-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (38d) (0.68 g,) TFA salt as a yellow solid; Ή NMR (300 MHz, DMSO-ifc) δ 8.69 - 8.44 (m, 3H), 8.05 (d, J= 2.4 Hz, 1H), 7.70 (d, .7= 9.0 Hz, 1H), 7.17 (dd, J= 8.9, 2.4 Hz, lH), 5.23 (s, 2H), 3.89 (s, 3H). ¹⁹ F NMR (282 MHz, DMSO-cfc) δ -74.16; MS (ES+): 273 (M+l), (ES-): 271 (M-l).

Step-4: Preparation of ( 1 R, 3 S ,5 R)-2-(2-(4-amino-6-methoxy-9H-pyri mi do [4,5 -b] i ndol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (38e)

Compound 38e was prepared according to the procedure reported in step-3 of scheme- 1 , from TFA salt of 2-(4-amino-6-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (38d) (50 mg, 0.129 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (4a) (41.2 mg, 0.0.129 mmol), HATU (59.1 mg, 0.155 mmol), DIPEA (84 mg, 0.647 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C 18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0- 100%] ( 1 R,3 S,5R)-2-(2-(4-amino-6-methoxy-9H-pyrimido[4,5-b]indol-9-yl)a cetyl)- N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxam ide (38e) (41 mg, 59% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-flfe) δ 10.75 (s, 1H), 8.81 (s, 2H), 8.60 (s, 1H), 8.07 (s, 1H), 7.99 (d, J= 8.1 Hz, 1H), 7.69 (t, J= 8.0 Hz, 1H), 7.61 (d, J= 9.0 Hz, 1H), 7.31 (d, J= 7.7 Hz, 1H), 7.18 (d, J= 8.9 Hz, 1H), 5.71 (d, .7= 17.3 Hz, lH), 5.39 (d, J= 17.2 Hz, 1H), 4.40 (dd, J= 9.0, 5.5 Hz, 1H), 3.90 - 3.86 (m, 4H), 2.40 - 2.27 (m, 1H), 227 - 2 13 (m 1H) 1 98 - 1 83 (m 1H) 1 12 - 1 00 (m 1H) 0 84 - 070 (m 1H); MS C24H22BrN703.HC1.2.75H20: C, 46.31; H, 4.62; Cl, 5.70; N, 15.75; Found: C, 46.48; H, 4.40; Cl, 5.45; N, 15.18.

Scheme 39

39f

Preparation of methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoe1hyl)-9H-pyrimido[4,5-b]i ndole-6-carboxylate (39f)

Step-1: Preparation of methyl 2-amino-3-cyano- lH-indole-5-carboxylate (39b)

Compound 39b was prepared according to the procedure reported in step-1 of scheme- 11, from methyl 3-iodo-4-(2,2,2-trifluoroacetamido)benzoate (39a) (6.61 g, 17.72 mmol; CAS # 848485-43-8) in DMSO (20 mL) using malononitrile (1.405 g, 21.26 mmol), L-prohne (0.408 g, 3.54 mmol), Cul (0.337 g, 1.772 mmol), K2CO3 (4.90 g, 35.4 mmol) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification [S1O2 gel (40 g), eluting with EtOAc in hexane from 0-40%] methyl 2-amino-3-cyano-lH-indole-5- cafboxylate (39b) (2.94 g, 77% yield) as a brown solid; Ή NMR (300 MHz, DMSO-^e) δ 11 12 (s 1H) 773 (d J= 1 6 Hz 1H) 758 (dd J= 82 1 7 Hz 1H) 722 (d J= 83 Hz Step-2: Preparation of methyl 4-amino-9H-pyrimido[4,5-b]indole-6-carboxylate (39c)

Compound 39c was prepared according to the procedure reported in step-1 of scheme-6, from methyl 2-amino-3-cyano- lH-indole-5 -carboxylate (39b) (2.94 g, 13.66 mmol) using trimethyl orthoformate (29.0 g, 273 mmol), AcOH (3.91 mL, 68.3 mmol) and NHtOAc (5.27 g, 68.3 mmol). The pale-yellow solid residue obtained after workup was used as such for the next step; ^! HNMR (300 MHz, DMSO-e/e) δ 12.25 (s, 1H), 8.95 (s, 1H), 8.30 (s, 1H), 7.99 (dd, J= 8.5, 1.6 Hz, 1H), 7.52 (d, J= 8.5 Hz, 1H), 7.42 (s, 2H), 3.89 (s, 3H).

Step-3: Preparation of methyl 4-amino-9-( 2-(te/7-butoxy)-2-oxoethyl )-9H-py rimido [4,5 - b]indole-6-carboxylate (39d)

Compound 39d was prepared according to the procedure reported in step-1 of scheme- 1, from methyl 4-amino-9H-pyrimido[4,5-b]indole-6-carboxylate (39c) (2.68 g, 11.06 mmol) in DMF (20 mL) using tert-butyl 2-bromoacetate (2.158 g, 11.06 mmol), CS2CO3 (4.33 g, 13.28 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH in DCM from 0-3%] methyl 4-amino- 9-(2-(terf-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-6-ca rboxylate (39d) (2.50 g, 63% yield) as a pale orange solid; Ή NMR (300 MHz, DMSO-i/e) δ 9.00 (d, J= 1.6 Hz, 1H), 8.34 (s, 1H), 8.04 (dd, J= 8.6, 1.6 Hz, 1H), 7.69 (d, J= 8.6 Hz, 1H), 7.54 (s, 2H), 5.18 (s, 2H), 3.91 (s, 3H), 1.40 (s, 9H).

Step-4: Preparation of 2-(4-amino-6-(methoxycarbonyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (39e)

Compound 39e was prepared according to the procedure reported in step-2 of scheme- 1, from methyl 4-amino-9-(2-(ftrr-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-b]ind ole-6-carboxylate (39d) (2.50 g, 7.02 mmol) using TFA (16 g, 140 mmol) in DCM (20 mL) and stirring at RT for 16 h. This gave after workup 2-(4-amino-6-(methoxycarbonyl)-9H-pyrimido[4,5-b]indol- 9-yl)acetic acid (39e) (3.70 g) TFA salt as a yellow solid; Ή NMR (300 MHz, DMSO-cfe) δ 9.16 (d, .7= 1.6 Hz, 1H), 8.65 (s, 2H), 8.60 (s, 1H), 8.13 (dd,J= 8.6, 1.6 Hz, 1H), 7.89 (d, .7= 8.7 Hz, 1H), 5.31 (s, 2H), 3.93 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-i/e) δ -74.65.

Step-5: Preparation of methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2- yl)carbamoyl)-2-azabic>'clo[3.1.0]hexan-2-yl)-2-oxoethyl) -9H-pyrimido[4,5-b]indole-6- carboxylate (39f)

Compound 39f was prepared according to the procedure reported in step-3 of scheme- 1, from (50 mg, 0.121 mmol) in DMF (5 mL) using HC1 salt of ( 1R,3 S,5R)-N-(6-bromopyridin-2-yl)- 2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (38.5 mg, 0.121 mmol), HATU (55.1 mg, 0.145 mmol), DIPEA (78 mg, 0.603 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]i ndole-6-carboxylate (39f) (53 mg, 78% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-i/e) δ 10.76 (s, 1H,

DzO exchangeable), 9.13 (s, 1H), 8.59 (s, 1H), 8.54 (s, 2H, DzO exchangeable), 8.12 (dd, J= 8.7, 1.6 Hz, 1H), 8.00 (d, .7= 8.1 Hz, 1H), 7.77 (d, .7= 8.8 Hz, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.31 (d, .7= 7.7 Hz, 1H), 5.79 (d, J= 17.4 Hz, 1H), 5.44 (d, J= 17.4 Hz, 1H), 4.41 (dd,J= 8.9, 5.5 Hz, 1H), 3.92 (s, 4H), 2.38 - 2.28 (m, 1H), 2.28 - 2.14 (m, 1H), 1.99 - 1.84 (m, 1H), 1.14 - 0.97 (m, 1H), 0.84 - 0.74 (m, 1H); MS (ES+): 564.0 (M+l), (ES-): 562.0 (M-l); Analysis calculated for Cz5HzzBrN ₇ 04.HC1.2.75Hz0: C, 46.17; H, 4.42; Cl, 5.45; N, 15.08; Found: C, 46.19; H, 4.27; Cl, 5.68; N, 14.87.

Scheme 40

40a

Preparation of methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 5- methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimid o[4,5-bJindole-6-carboxylate

(40a)

Compound 40a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-(methoxycarbonyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (39e) (100 mg, 0.241 mmol) in DMF (5 mL) using HC1 salt of ( 1 R,3 S,5R)-N-(6-bromopyridin-2- yl) 5 methyl 2 azabicyclo[3 1 0]hexane 3 carboxamide (8a) (80 mg 0241 mmol) HATU (110 mg, 0.290 mmol), DIPEA (156 mg, 1.207 mmol) and stirring at RT for 16 h. This gave after woikup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 5- methyl-2-azabicyclo[3.1 0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-6-carboxy late (40a) (53 mg, 78% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-tife) δ 10.77 (s, 1H, DzO exchangeable), 9.14 (s, 1H), 8.79 - 8.52 (m, 3H, 2H D2O exchangeable), 8.13 (dd, J= 8.7, 1.6 Hz, 1H), 8.00 (d, 8.2 Hz, 1H), 7.78 (d, J= 8.7 Hz, 1H), 7.69 (t, 8.0

Hz, 1H), 7.31 (d, J= 7.7 Hz, 1H), 5.75 (d, J= 17.3 Hz, 1H), 5.39 (d, J= 17.3 Hz, 1H), 4.37 (dd, J= 9.0, 5.9 Hz, 1H), 3.92 (s, 3H), 3.69 (dd, J= 5.7, 2.4 Hz, 1H), 2.56 - 2.42 (m, 1H), 1.98 (dd, J= 13.2, 5.9 Hz, 1H), 1.31 (s, 3H), 1.05 - 0.97 (m, 1H), 0.97 - 0.90 (m, 1H); MS (ES+): 578.0 (M+l), (ES-): 576.0 (M-l); Analysis calculated for

C26H24BrN704.HC1.2.25H20: C, 47.65; H, 4.54; Cl, 5.41; N, 14.96; Found: C, 47.54; H, 4.50; Cl, 5.29; N, 14.92.

Scheme 41

41f

Preparation of methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 2- Step-1: Preparation of methyl 2-amino-3 -cyano- lH-indole-6-carboxy late (41b)

Compound 41b was prepared according to the procedure reported in step-1 of scheme- 11 , from methyl 4-iodo-3-(2,2,2-trifluoroacetamido)benzoate (41a) (6.73 g, 18.04 mmol; CAS # 494799-11-0) in DMSO (20 mL) and using malononitrile (1.430 g, 21.65 mmol), L-proline (0.415 g, 3.61 mmol), Cul (0.344 g, 1.804 mmol), K2CO3 (4.99 g, 36.1 mmol) and heating at 60 °C for 16 h under an aigon atmosphere. This gave after workup and purification [S1O2 gel (40 g), eluting with EtOAc in hexane from 0-50%] methyl 2-amino-3-cyano- lH-indole-6- carboxylate (41b) (1.32 g, 34% yield) as a brown solid; Ή NMR (300 MHz, DMSO-cfc) δ 10.96 (s, 1H), 7.74 (d, J= 1.5 Hz, 1H), 7.63 (dd,J= 8.2, 1.5 Hz, 1H), 7.26 - 7.12 (m, 3H), 3.81 (s, 3H); MS (ES+): 216 (M+l), (ES-): 214 (M-l).

Step-2: Preparation of methyl 4-amino-9H-pyrimido[4,5-b]indole-7-carboxylate (41c)

Compound 41c was prepared according to the procedure reported in step-1 of scheme-6, from methyl 2-amino-3 -cyano- 1 H-indole-6-carboxy late (41b) (1.32 g, 6.13 mmol) using trimethyl orthoformate (13.02 g, 123 mmol), AcOH (1.754 mL, 30.7 mmol) andNHtOAc (2.364 g, 30.7 mmol). This gave after workup methyl 4-amino-9H-pyrimido[4,5-b]indole-7- carboxylate (41c) (0.83 g, 56 % yield) as a pale-yellow solid. Ή NMR (300 MHz, DMSO-cfe) δ 12.14 (s, 1H), 8.43 (d, J = 8.3 Hz, 1H), 8.30 (s, 1H), 8.03 (d, J = 1.4 Hz, 1H), 7.82 (dd, J = 8.3, 1.5 Hz, 1H), 7.41 (s, 2H), 3.90 (s, 3H); MS (ES+): 243 (M+l), (ES-): 241 (M-l).

Step-3: Preparation of methyl 4-amino-9-(2-(tert-butoxy)-2-oxoethyl)-9H-pyrimido[4,5- b]indole-7-carboxylate (41d)

Compound 41 d was prepared according to the procedure reported in step-1 of scheme- 1, from methyl 4-amino-9H-pyrimido[4,5-b]indole-7-carbox>'late (41c) (0.83 g, 3.43 mmol) in DMF (20 mL) using tert-butyl 2-bromoacetate (0.668 g, 3.43 mmol), CS2CO3 (1.340 g, 4.11 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH in DCM from 0-3%] methyl 4-amino- 9-(2-(tert-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-7-ca iboxylate (41d) (0.67 g, 55% yield) as a pale orange solid; Ή NMR (300 MHz, DMSO-cfe) δ 8.48 (d ,J= 8.3 Hz, 1H), 8.35 (s, 1H), 8.18 (d, J= 1.5 Hz, 1H), 7.89 (dd, J= 8.2, 1.4 Hz, 1H), 7.54 (s, 2H), 5.23 (s, 2H), 3.91 (s, 3H), 1.41 (s, 9H); MS (ES+): 357 (M+l), (ES-): 355 (M-l).

Step-4: Preparation of 2-(4-amino-7-(methoxycarbonyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (41e) Compound 41e was prepared according to the procedure reported in step-2 of scheme-1, from methyl 4-amino-9-(2-(te/7-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-b]ind ole-7-carboxylate (41d) (0.67 g, 1.880 mmol) using TFA (4.29 g, 37.6 mmol) in DCM (20 mL) and stirring at RT for 16 h. This gave after workup 2-(4-amino-7-(methoxycarbonyl)-9H-pyrimido[4,5- b]indol-9-yl)acetic acid (41e) (3.70 g) TFA salt as a yellow solid; Ή NMR (300 MHz, DMSO-cfe) δ 8.71 - 8.47 (m, 4H), 8.36 (d, J= 1.4 Hz, 1H), 7.99 (dd, J= 8.3, 1.4 Hz, 1H), 5.36 (s, 2H), 3.93 (s, 3H); MS (ES+): 301 (M+l), (ES-): 299 (M-l).

Step-5: Preparation of methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2- yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H- pyrimido[4,5-b]indole-7- carboxylate (41f)

Compound 41f was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-7-(methoxycaibonyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (41e) (50 mg, 0.121 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)- 2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (38.5 mg, 0.121 mmol), HATU (55.1 mg, 0.145 mmol), DIPEA (78 mg, 0.603 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]i ndole-7-carboxylate (41f) (48 mg, 71% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-tife) δ 10.77 (s, 1H,

DzO exchangeable), 8.59 (d, J= 8.5 Hz, 1H), 8.57 (s, 1H), 8.45 (s, 2H, DzO exchangeable),

8.28 (s, 1H), 8.05 - 7.92 (m, 2H), 7.70 (t, J= 8.0 Hz, 1H), 7.31 (d, J= 7.7 Hz, 1H), 5.86 (d, J = 17.4 Hz, 1H), 5.49 (d, J= 17.3 Hz, 1H), 4.42 (dd, J= 9.1, 5.6 Hz, 1H), 3.92 (s, 4H), 2.39 -

2.29 (m, 1H), 2.29 - 2.16 (m, 1H), 2.01 - 1.87 (m, 1H), 1.15 - 1.03 (m, 1H), 0.76 - 0.69 (m, 1H); MS (ES+): 564/566 (M+l), (ES-): 562/564 (M-l); Analysis calculated for C25H22BrN ₇ 04.1.1.HCl.2.75.HzO: C, 45.91; H, 4.41; Cl, 5.96; N, 14.99; Found: C, 45.90; H, 4.21; Cl, 5.98; N, 14.69.

Scheme 42

Preparation of methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 5- methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimid o[4,5-b]indole-7-carboxylate

(42a)

Compound 42a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-7-(methoxycarbonyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (41e) (100 mg, 0.241 mmol) in DMF (5 mL) using HC1 salt of ( 1R,3 S,5R)-N -(6-bromopyridin-2- yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (80 mg, 0.241 mmol), HATIJ (110 mg, 0.290 mmol), DIPEA (156 mg, 1.207 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 5- methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimid o[4,5-b]indole-7-carboxylate (42a) (82 mg, 59% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-i/e) δ 10.77 (s, 1H, DzO exchangeable), 8.70 - 8.41 (m, 4H, 2H D2O exchangeable), 8.29 (d, ./= 1.4 Hz, 1H), 8.06 - 7.92 (m, 2H), 7.69 (t, 7.9 Hz, 1H), 7.31 (d, J= 7.7 Hz, 1H), 5.83 (d, 17.4

Hz, 1H), 5.43 (d, J= 17.3 Hz, 1H), 4.38 (dd, J= 9.0, 5.9 Hz, 1H), 3.92 (s, 3H), 3.73 - 3.70 (m, 1H), 2.54 - 2.44 (m, 1H), 1.99 (m, 1H), 1.32 (s, 3H), 1.09 - 1.01 (m, 1H), 0.93 - 0.85 (m, 1H); MS (ES+): 578/580 (M+l), (ES-): 576/578 (M-l); Analysis calculated for C26H24BrN7O4.HCl.2 5.H2O: C, 47.32; H, 4.58; Cl, 5.37; N, 14.86; Found: C, 47.48; H, 4.28; Cl, 5.23; N, 14.68.

Scheme 43

41f 43a

Preparation of 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyI)-9H-pyrimido[4,5-b]i ndoIe-7-carboxylic acid (43a)

Compound 43a was prepared according to the procedure reported in step-4 of scheme- 17, from methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyiimido[4,5-b]i ndole-7-carboxylate (41f) (78 mg, 0.138 mmol) in THF (1 mL) and water (2 mL) using 2M aqueous lithium hydroxide hydrate (0.138 mL, 0.276 mmol) and stirring at RT for 16 h. This gave after workup and purification by reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] 4-amino-9-(2-((lR,3S,5R)-3-((6- bromopyridin-2-yl)caibamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)- 2-oxoe1hyl)-9H-pyrimido[4,5- b]indole-7-carboxylic acid (43a) (34 mg, 45% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-tife) δ (a mixture of two rotamers) 10.85 (s) and 10.77 (s) (2s, 1H, DzO exchangeable), 8.93 (s, 2H, D2O exchangeable), 8.69 (d, J= 4.9 Hz, 1H), 8.63 (d, J= 8.3 Hz, 1H), 8.31 (s, 1H), 7.99 (d, J= 7.9 Hz, 2H), 7.67 (q, J= 7.7 Hz, 1H), 7.29 (dd, J= 7.7, 4.7 Hz, 1H), 5.87 (dd, 17.4, 11.5 Hz, 1H), 5.50 (dd, 17.3, 7.3 Hz, 1H), 4.42 (dd, J= 9.0, 5.5 Hz, 1H), 3.95 - 3.92 (m, 1H), 2.39 - 2.28 (m, 1H), 2.26 - 2.14 (m, 1H), 2.01 - 1.86 (m, 1H), 1.28 - 1.17 (m) and 1.16 - 1.04 (m) (2m, 1H), 1.02 - 0.83 (m) and 0.79 - 0.67 (m) (2m, 1H); MS (ES+): 550/552 (M+l), (ES-): 548/550 (M-l); Analysis calculated for C2*H2oBrN ₇ 04.1. IHCI.3H2O: C, 44.72; H, 4.24; Cl, 6.05; N, 15.21; Found: C, 44.67; H, 4.12; Cl, 6.07; N, 15.23.

Scheme 44

39f 44a

Preparation of 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]i ndole-6-carboxylic acid (44a)

Compound 44a was prepared according to the procedure reported in step-4 of scheme- 17, from TFA salt of methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyiimido[4,5-b]i ndole-6-carboxylate (39f) (156mg, 0.276 mmol) in in THF (2 mL) and water (4 mL) using 2M aqueous lithium hydroxide hydrate (0.553 mL, 0.553 mmol) and stirring at RT for 16 h. This gave after workup and purification by reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%) 4-amino-9-(2-((lR,3S,5R)- 3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1 ,0]hexan-2-yl)-2-oxoethyl)-9H- pyrimido[4,5-b]indole-6-carboxylic acid (44a) (31 mg, 20% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-flfc) (a mixture of two rotamers) δ 12.98 (s, 1H, D2O exchangeable), 10.86 and 10.77 (2s, 1H, DzO exchangeable), 9.11 (s, 1H), 8.60 and 8.58 (2s, 1H), 8.48 (s, 2H, D2O exchangeable), 8.11 (dt, J= 8.6, 2.1 Hz, 1H), 8.01 and 7.96 (2d, J=

8.3 Hz, 1H), 7.78 - 7.62 (m, 2H), 7.38 - 7.22 (m, 1H), 5.79 (d, J= 17.3 Hz, 1H), 5.44 (d, J= 17.4 Hz, 1H), 4.42 (dd,J= 9.1, 5.5 Hz, 1H), 3.91 (m, 1H), 2.40 - 2.12 (m, 2H), 1.93 (m, 1H), 1.30 - 0.53 (m, 2H). MS (ES+): 550.1 (M+l); (ES-): 548.0 (M-l); Analysis calculated for C2*H2oBrN ₇ 042.25H2O.0.95HC1: C, 46.08; H, 4.10; Cl, 5.38; N, 15.67; Found: C, 46.42; H, 4.03; Cl, 4.94; N, 15.29.

Scheme 45

NH ₂

C0 ₂ Et

45c 45d C<¾Et

Preparation of ethyl 3-(4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)caibamoy l)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]i ndol-6-yl)propanoate (45d)

Step-1: Preparation of (E)-ethyl 3-(4-amino-9-(2-(ter/-butoxy)-2-oxoethyl)-9H-pyrimido[4,5- b]indol-6-yl)acrylate (45a)

A mixture of tert- butyl 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (34c) (200 mg, 0.53 mmol), ethyl acrylate (80 mg, 0.795 mmol), Pd(PPh3)2Cb (37.2 mg, 0.053 mmol), and K2CO3 (220 mg, 1.591 mmol) were suspended in DMF (4 mL) in a sealed scintillation vial. The vial was flushed with nitrogen and the yellow mixture then heated at 100 °C for 16 h. The resulting black mixture was filtered. The filtrate was diluted with H2O (25 mL) and extracted with EtOAc (25 mL x 3). The combined extract was washed with H2O (25 mL x 4), brine (25 mL), dried, filtered and concentrated in vacuum. The residue obtained was purified by flash column chromatography (silica gel, 24 g, eluting with 0-60% EtOAc in hexane) to provide (E)-ethyl 3-(4-amino-9-(2-(tor/-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-b] indol-6- yl)acrylate (45a) ( 102 mg, 49 % yield) as a pale-yellow solid. ^! H NMR (300 MHz, DMSO- de) δ 8.78 (s, 1H), 8.32 (s, 1H), 7.79 (d, J = 15.9 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.48 (s, 2H), 6.86 (d, J = 15.9 Hz, 1H), 5.15 (s, 2H), 4.22 (q, J = 7.1 Hz, 2H), 1.41 (s, 9H), 1.29 (t, J = 7.1 Hz, 3H); MS (ES+): 397 (M+l), (ES-): 395 (M-l).

Step-2: Preparation of ethyl 3-(4-amino-9-(2-(ter/-butoxy)-2-oxoethyl)-9H-pyrimido[4,5- To a solution of (E)-ethyl 3-(4-amino-9-(2-(/er/-butoxy)-2-oxoethyl)-9H-pyrimido|4,5- b]indol-6-yl)acrylate (45a) (100 mg, 0.252 mmol) in THF/ethanol (15 mL, 1:2), was added palladium hydroxide on carbon (7 mg) and heated under a hydrogen atmosphere for 16 h at 100 °C. The reaction mixture was cooled to room temperature filtered through Celite, washed with ethyl acetate and concentrated in vacuum to dryness. The residue obtained was purified by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM 0-3%] to afford ethyl 3-(4-amino-9-(2-(/err-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-b] indol-6- yl)propanoate (45b) (80 mg, 80 % yield) as a white semisolid; *H NMR (300 MHz, DMSO- cfe) δ 8.25 (d, J= 9.1 Hz, 2H), 7.44 (d ,J= 8.3 Hz, 1H), 7.36 - 7.14 (m, 3H), 5.08 (s, 2H),

4.06 (q, J= 7.1 Hz, 2H), 3.01 (t, J= 7.8 Hz, 2H), 2.75 (t, J= 7.8 Hz, 2H), 1.40 (s, 9H), 1.17 (t ,J= 7.2 Hz, 3H); MS (ES+): 399 (M+l).

Step-3: Preparation of 2-(4-amino-6-(3-ethoxy-3-oxopropyl)-9H-pyrimido[4,5-b]indol- 9- yl)acetic acid (45c)

Compound 45c was prepared according to the procedure reported in step-2 of scheme- 1, from ethyl 3-(4-amino-9-(2-(te _/ 7-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-b]indol-6-yl)pro panoate

(45b) (78 mg, 0.196 mmol) in DCM (5 mL) using TFA (223 mg, 1.96 mmol) and stirring at RT for 16 h. This gave after workup 2-(4-amino-6-(3 -ethoxy-3 -oxopropy 1)-9H- pyrimido[4,5-b]indol-9-yl)acetic acid (45c) TFA salt as a pale yellow solid; ^! H NMR (300 MHz, DMSO-ife) δ 8.55 (s, 1H), 8.41 (d, ./= 10.5 Hz, 2H), 7.68 (d, J= 8.4 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 5.24 (s, 2H), 4.06 (q,7= 7.1 Hz, 3H), 3.04 (t, J = 7.7 Hz, 2H), 2.76 (t, J= 7.8 Hz, 2H), 1.17 (t, J= 7.1 Hz, 3H); ¹⁹ FNMR(282 MHz, DMSO-tife) δ -74.25; MS (ES+): 343 (M+l), (ES-): 341 (M-l).

Step-4: Preparation of ethyl 3-(4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2- yl)caibamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H- pyrimido[4,5-b]indol-6- yl)propanoate (45d)

Compound 45d was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-(3-ethoxy-3-oxopropyl)-9H-pyrimido[4,5-b]indol- 9-yl)acetic acid (45c) (96 mg, 0.21 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (67.0 mg, 0.210 mmol), HATU (96 mg, 0.252 mmol), DIPEA (136 mg, 1.05 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting chromatography [C 18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] ethyl 3-(4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)caibamoy l)-2- azabic>'clo[3.1.0]hexan-2-yl)-2-oxoetiiyl)-9H-pyrimido[4, 5-b]indol-6-yl)propanoate (45d)

(44 mg, 35% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-t/e) δ 10.75 (s, 1H, D2O exchangeable), 8.58 (s, 1H), 8.53 (s, 2H, DzO exchangeable), 8.39 (s, 1H), 8.00 (d, J=

8.1 Hz, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.59 (d,J= 8.4 Hz, 1H), 7.43 (dd, J= 8.3, 1.7 Hz, 1H), 7.32 (d ,J= 7.7 Hz, 1H), 5.73 (d,J= 17.3 Hz, 1H), 5.39 (d ,J= 17.3 Hz, 1H), 4.41 (dd,J= 9.0, 5.5 Hz, 1H), 4.05 (q, J= 7.1 Hz, 2H), 3.96 - 3.86 (m, 1H), 3.03 (t, J= 7.7 Hz, 2H), 2.74 (t ,J= 7.8 Hz, 2H), 2.39 - 2.26 (m, 1H), 2.26 - 2.13 (m, 1H), 1.98 - 1.84 (m, 1H), 1.16 (t, J =

7.1 Hz, 3H), 1.10 - 1.01 (m, 1H), 0.81 - 0.72 (m, 1H); MS (ES+): 606/608 (M+l), (ES-): 604/606 (M-l); Analysis calculated for C28H28BrN7O4.i 25.HCl l.75.H2O: C, 49.20; H, 4.83; Cl, 6.48; N, 14.34; Found: C, 49.16; H, 4.63; Cl, 6.68; N, 14.22.

Scheme 46

46f 46g

Preparation of ethyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]i ndole-5-carboxylate (46g) Step-1: Preparation of methyl 2-bromo-3-(2,2,2-trifluoroacetamido)benzoate (46b)

To a solution of methyl 3-amino-2-bromobenzoate (46a) (4.5 g, 19.56 mmol; CAS # 106896- 48-4) and triethylamine (6.82 mL, 48.9 mmol) in DCM (30 mL) was added trifluoracetic anhydride (4.08 mL, 29.3 mmol) dropwise and stirred at RT for 15 h. The reaction mixture was diluted with dichloromethane (75 mL), washed with water (50 mL), dried, filtered and concentrated in vacuum to afford methyl 2-bromo-3-(2,2,2-trifluoroacetamido)benzoate (46b) as a yellow gum (8.17 g) and was used as such for next step; MS (ES+): 325.90 (M+l); (ES-): 323.90 (M-l).

Step-2: Preparation of methyl 2-amino-3-cyano-lH-indole-4-carboxylate (46c)

Compound 46c was prepared according to the procedure reported in step-1 of scheme- 11 , from methyl 2-bromo-3-(2,2,2-trifluoroacetamido)benzoate (46b) (1594 g, 4.89 mmol) in DMSO (8 mL) using malononitrile (388 mg, 5.87 mmol), L-proline (0.113 g, 0.978 mmol), Cul (93 mg, 0.489 mmol), K2CO3 (1.352 g, 9.78 mmol) in water (8 mL) and heating at 60 °C for 13 h under an argon atmosphere. This gave after workup and purification [SiOzgel (24 g), eluting with EtOAc in hexane from 0-66%] methyl 2-amino-3-cyano- lH-indole-4- carboxylate (46c) (115 mg, 11% yield) as a brown solid; (ES-): 214.00 (M-l).

Step-3: Preparation of methyl/ethyl 4-amino-9H-pyrimido[4,5-b]indole-5-carboxylate (46d)

Compound 46d was prepared according to the procedure reported in step-2 of scheme-29, from methyl 2-amino-3 -cyano- 1 H-indole-4-carboxylate (46c) (105 mg, 0.488 mmol) in ethanol (10 mL) using formamidine acetate (513 mg, 4.88 mmol) and heating at 100°C in a microwave .The reaction mixture was filtered, washed with ethanol, and dried under vacuum. The residue was purified by flash column chromatography [SiOzgel (24 g), eluting with EtOAc in hexane from 0-100% and then using hexanes/10% methanol in ethyl acetate (1:1)] a mixture of methyl/ethyl 4-amino-9H-pyrimido[4,5-b]indole-5-carboxylate (46d) (66 mg) as abrown solid, which was used as such for the next step; MS (ES+): 243.10, 257.10 (M+l).

Step-4: Preparation of methyl/ethyl 4-amino-9-(2-(ter/-butoxy)-2-oxoethyl)-9H- pyrimido[4,5-b]indole-5-carboxylate (46e)

Compound 46e was prepared according to the procedure reported in step-1 of scheme- 1, from a mixture of methyl/ethyl 4-amino-9H-pyrimido[4,5-b]indole-5-carboxylate (46d) (65 mg) in 0.671 mmol) and stirring at RT for 14 h. This gave after woikup and purification by flash column chromatography [SiOzgel (24 g), eluting with 10% methanol in ethyl acetate in hexanes from 0-100%] methyl 4-amino-9-(2-(fert-butoxy)-2-oxoethyl)-9H-pyrimido[4,5- b]indole-5-carboxylate (7 mg, 7%); MS (ES+): 357.10 (M+l); ethyl 4-amino-9-(2-(terf- butoxy)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-5-carboxylate (46e) (16 mg, 9% yield) as a white solid; MS (ES+): 371.20 (M+l); (ES-): 369.00 (M-l).

Step-5: Preparation of 2-(4-amino-5-(ethoxycarbonyl)-9H-pyiimido[4,5-b]indol-9-yl)a cetic acid (46f)

Compound 46f was prepared according to the procedure reported in step-2 of scheme- 1, from ethyl 4-amino-9-(2-(terf-butoxy)-2-oxoethyl)-9H-pyrimido[4,5-b]ind ole-5-carboxylate (46e) (16 mg, 0.043 mmol) using TFA (0.20 mL, 2.59 mmol) in DCM (5 mL) and stirring at RT for 17 h. This gave after workup 2-(4-amino-5-(ethoxycarbonyl)-9H-pyrimido[4,5-b]indol-9- yl)acetic acid (46f) which was used as such in next step-6 without further purification; MS (ES+): 315.10 (M+l).

Step-6: Preparation of ethyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b ]indole-5-caiboxylate (46g)

Compound 46g was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-5-(ethoxycarbonyl)-9H-pyrimido[4,5-b]indol-9-yl)a cetic acid (46f) (13.5 lmg, 0.043 mmol) in DMF (7 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (4a) (54.8 mg, 0.172 mmol), HATU (65.4 mg, 0.172 mmol) DIPEA (0.045 mL, 0.258 mmol) and stirring at RT for 19 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with hexanes/10% MeOH in EtOAc from 0 - 100%] followed by conversion to HC1 salt by dissolving product in acetonitrile (1.5 mL) and 0.1% aq. HC1 (6 mL) and lyophilization ethyl 4-amino-9-(2- ((lR,3S,5R)-3-((6-bromopyridin-2-yl)caibamoyl)-2-azabicyclo[ 3.1.0]hexan-2-yl)-2- oxoethy l)-9H-pyri mi do [4,5 -b] i ndole-5 -carboxy late (46g) (6.5 mg, 26% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-flfe) 5 10.76 (s, 1H,), 8.57 (s, 1H), 8.14 - 7.93 (m, 4H,), 7.77 - 7.60 (m, 3H), 7.32 (d, J = 7.8 Hz, 1H), 5.82 (d, J= 17.4 Hz, 1H), 5.49 (d,7 =

17.3 Hz, 1H), 4.55 - 4.33 (m, 3H), 3.98 - 3.88 (m, 1H), 2.43 - 2.12 (m, 2H), 2.01 - 1.85 (m, 1H), 1.40 (t ,J= 7.1 Hz, 3H), 1.15 - 1.02 (m, 1H), 0.84 - 0.73 (m, 1H); MS (ES+): 578.10 & 580.10 (M+l). Scheme 47

CF ₃

NH ₂

47f

47g

Preparation of methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyI)-9H-pyrimido[4,5-b]i ndoIe-8-carboxylate (47g)

Step-1: Preparation of methyl 3-bromo-2-(2,2,2-trifluoroacetamido)benzoate (47b)

Compound 47b was prepared according to the procedure reported in step-1 of scheme-46, from methyl 2-amino-3-bromobenzoate (47a) (5 g, 21.73 mmol; CAS # 104670-74-8) in DCM (30 mL) using triethylamine (7.57 mL, 54.3 mmol), trifluoroacetic acid anhydride (4.53 mL, 32.6 mmol) and stirring at RT for 43 h. This gave after workup and purification by flash column chromatography [SiChgel (120 g), EtOAc in hexane from 0-14%] methyl 3- bromo-2-(2,2,2-trifluoroacetamido)benzoate (47b) as a yellow solid (5.27 g, 74% yield) and was used as such for next step; Ή NMR (300 MHz, DMSO-ifc) δ 11.40 (s, 1H), 8.03 (dd, J= 8.1, 1.4 Hz, 1H), 7.91 (dd,J= 7.8, 1.4 Hz, 1H), 7.48 (t, J= 7.9 Hz, 1H), 3.80 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-de) δ -74.44; MS (ES-): 323.90 & 325.90 (M-l).

Step-2: Preparation of methyl 2-amino-3-cyano- lH-indole-7-carboxylate (47c) Compound 47c was prepared according to the procedure reported in step-1 of scheme- 11, from methyl 3-bromo-2-(2,2,2-trifluoroacetamido)benzoate (47b) (2 g, 6.13 mmol) in DMSO (12 mL), using malononitrile (0.486 g, 7.36 mmol), L-proline (0.141 g, 1.227 mmol), Cul (0.117 g, 0.613 mmol), a solution of K2CO3 (1.695 g, 12.27 mmol) in water (12 mL) and heating at 60 °C for 13 h under an argon atmosphere. This gave after workup and purification by flash column chromatography [S1O2 gel (24 g), eluting with EtOAc in hexane from 0- 33%] methyl 2-amino-3-cyano-lH-indole-7-carboxylate (47c) (305 mg, 23% yield) as a brown solid; ^l H NMR (300 MHz, DMSO-i/e) δ 10.75 (s, 1H), 7.51 (dd, J= 7.8, 1.1 Hz, 1H), 7.41 (d, .7= 7.6 Hz, 1H), 7.09 (t, J= 7.7 Hz, 1H), 6.93 (s, 2H), 3.91 (s, 3H); MS (ES+): 216.00.

Step-3: Preparation of methyl 4-amino-9H-pyrimido[4,5-b]indole-8-carboxylate (47d) Compound 47d was prepared according to the procedure reported in step-2 of scheme-29, from methyl 2-amino-3 -cyano- 1 H-indole-7-carboxylate (47c) (300 mg, 1.394 mmol) in ethanol (10 mL) using formamidine acetate (1466 mg, 13.94 mmol) and heating at reflux for 45 h. This gave after workup a grey solid residue (268 mg) which was used as such for the next step; Ή NMR (300 MHz, DMSO-cfe) δ 8.59 (dd, J= 7.8, 1.2 Hz, 1H), 8.34 (s, 1H), 7.97 (dd, J= 7.8, 1.1 Hz, 1H), 7.41 - 7.28 (m, 3H), 3.97 (s, 3H); MS (ES+): 243.10.

Step-4: Preparation of methyl 4-amino-9-( 2-(tert-butoxy)-2-oxoethy l)-9H-pyrim ido [4,5 - b]indole-8-carboxylate (47e)

Compound 47e was prepared according to the procedure reported in step-1 of scheme- 1 , from methyl 4-amino-9H-pyrimido[4,5-b]indole-8-caiboxylate (47d) (240 mg, 0.991 mmol) in DMF (6 mL) using tert- butyl 2-bromoacetate (0.176 mL, 1.189 mmol), CszCCh (807 mg, 2.477 mmol) and stirring overnight at RT. This gave after workup and purification by flash column chromatography [SiOzgel (24 g), eluting with 10% methanol in ethyl acetate in hexanes from 0-100%] methyl 4-amino-9-(2-(tert-butoxy)-2-oxoethyl)-9H-pyrimido[4,5- b]indole-8-carboxylate (47e) (353 mg, 25% yield) as an off white solid; ^! H NMR (300 MHz, DMSO-d!s) δ 8.61 (dd, J= 7.9, 1.2 Hz, 1H), 8.36 (s, 1H), 7.84 - 7.79 (m, 1H), 7.49 (s, 2H), 7.37 (t, J= 7.8 Hz, 1H), 5.35 (s, 2H), 3.90 (s, 3H), 1.36 (s, 9H); MS (ES+): 357.15. Step-5: Preparation of 2-(4-amino-8-(methoxycarbony l)-9H-pyrimido [4, 5 -b] indol-9-yl)acetic acid (47f)

Compound 47f was prepared according to the procedure reported in step-2 of scheme- 1, from methyl 4-amino-9-(2-(tert-butoxy)-2-oxoethyl)-9H-pyrimido[45-b]indo le-8-carboxylate workup 2-(4-amino-8-(methoxycarbonyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (47f) which was used as such in next step-6 without purification; MS (ES+): 301.10 (M+l).

Step-6: Preparation of methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2- yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H- pyrimido[4,5-b]indole-8- caiboxylate (47g)

Compound 47g was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-8-(methoxycarbonyl)-9H-pyrimido[4,5-b]indol-9-yl) acctic acid (47f) (67.3 mg, 0.224 mmol) in DMF (10 mL) using HC1 salt of ( 1 R,3 S,5R)-N-(6-bromopytidin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (4a) (71.4 mg, 0.224 mmol), HATU (170 mg, 0.448 mmol), DIPEA (0.195 mL, 1.12 mmol) and stirring at RT for 18 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 5 %] followed by conversion to HC1 salt by dissolving product in acetonitrile (2 mL) and 0.1% aq. HC1 (8 mL) and lyophilization methyl 4-amino-9-(2-(( lR,3S,5R)-3-((6- bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)- 2-oxoethyl)-9H-pyrimido[4,5- b]indole-8-carboxylate (47g) (38 mg, 30% yield) HC1 salt as a white solid; ^! HNMR(300 MHz, DMSO-ifc) δ 10.72 (s, 1H, D ₂ 0 exchangeable), 8.65 (d, 7.7 Hz, 1H), 8.51 (s, 1H), 8.17 -

7.91 (m, 3H, 2H D20 exchangeable), 7.82 (d, J= 7.7 Hz, 1H), 7.69 (t ,J= 7.9 Hz, 1H), 7.41 (t, J= 7.7 Hz, 1H), 7.30 (d, J= 7.7 Hz, 1H), 5.95 (d ,J= 17.5 Hz, 1H), 5.64 (d, J= 17.3 Hz, 1H), 4.39 - 4.27 (m, 1H), 3.92 (s, 3H), 3.87 - 3.72 (m, 1H), 2.37 - 2.09 (m, 2H), 1.97 - 1.78 (m, 1H), 1.16 - 0.99 (m, 1H), 0.83 - 0.65 (m, 1H); MS (ES+): 564.10 & 566.10 (M+l); MS (ES-): 562.10 & 564.10 (M-l).

Scheme 48

Preparation of tort-butyl (4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl) -2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]i ndol-6-yl)carbamate (48d)

Step-1: Preparation of ethyl 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (48a)

Compound 48a was prepared according to the procedure reported in step-2 of scheme- 16, from 6-bromo-9H-pyrimido[4,5-b]indol-4-amine (34b) (540 mg, 2.053 mmol) in DMF (10 mL) using ethyl 2-bromoacetate (0.228 mL, 2.053 mmol), CS2CO3 (802 mg, 2.463 mmol), triethylamine (1.716 mL, 12.32 mmol) and stirring at RT for 27 h. This gave after workup 2- (4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (48a) (166 mg) as a light yellow solid; ‘HNMR (300 MHz, DMSO-tife) δ 8.63 (d, J= 1.8 Hz, 1H), 8.29 (s, 1H), 7.60 (d, J= 8.7 Hz, 1H), 7.54 (dd,J= 8.7, 1.8 Hz, 1H), 7.45 (s, 2H), 5.23 (s, 2H), 4.13 (q, 7.1 Hz,

2H), 1.19 (t, J= 7.0 Hz, 3H); MS (ES+): 349.00 & 350.90 (M+l).

Step-2: Preparation of ethyl 2-(4-amino-6-((tor/-butoxycarbonyl)amino)-9H-pyrimido[4,5- b]indol-9-yl)acetate (48b)

Compound 48b was prepared according to the procedure reported in step-3 of scheme- 17, from ethyl 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (48a) (150 mg, 0.430 mmol) in toluene (8 mL) using XPhos, t-butyl carbamate, Pch(dba)3, CS2CO3 (140 mg, 0.43 mmol) and heating at 90 °C for 20 h. This gave after work up and purification ethyl 2-(4- amino-6-((te/7-butoxycarbonyl)amino)-9H-pyrimido[4,5-b]indol -9-yl)acetate (48b) (10 mg, 6% i ld) MS (ES 38620 (M l) Step-3 : Preparation of 2-(4-amino-6-((terf-butoxycarbonyl)amino)-9H-pyrimido[4,5-b] indol- 9-yl)acetic acid (48c)

Compound 48c was prepared according to the procedure reported in step-4 of scheme- 17, from ethyl 2-(4-amino-6-((terr-butoxycarbonyl)amino)-9H-pyrimido[4,5-b] indol-9-yl)acetate (48b) (10 mg, 0.026 mmol) in THF (2 mL) and MeOH (2 mL) using lithium hydroxide hydrate (6.67 mg, 0.156 mmol) and stirring at RT for 18 h. This gave after work up 2-(4- amino-6-((fcri-butoxycarbonyl)amino)-9H-pyrimido[4,5-b]indol -9-yl)acetic acid (48c) which was used as such in next step-4; MS (ES+): 358.20 (M+l); (ES-): 356.10 (M-l).

Step-4: Preparation of tert-butyl (4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2- yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H- pyrimido[4,5-b]indol-6- yl)carbamate (48d)

Compound 48d was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-6-((fc/-f-butoxycarbonyl)amino)-9H-pyrimido[4,5-b ]indol-9-yl)acetic acid (48c) (from above step-3, 0.026 mmol) in DMF (6 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (71 mg, 0.224 mmol), HATU (40 mg, 0.104 mmol), DIPEA (0.027 mL, 0.156 mmol) and stirring at RT for 14 h. This gave after workup and purification by flash column chromatography [silica gel (4 g), eluting with MeOH in DCM from 0 - 5 %] followed by conversion to HC1 salt in acetonitrile (1 mL) using 0.1% aq. HC1 (5 mL) and lyophilization tert-butyl (4-amino-9-(2-((lR,3S,5R)- 3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1 ,0]hexan-2-yl)-2-oxoethyl)-9H- pyrimido[4,5-b]indol-6-yl)cafbamate (48d) (6 mg, 37% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-fife) δ 10.76 (s, 1H, DzO exchangeable), 9.26 (s, 1H, DzO exchangeable), 8.54 (s, 1H), 8.38 (s, 1H), 8.29 (s, 2H, DzO exchangeable), 8.01 (d ,J= 8.1 Hz, 1H), 7.70 (t ,J= 8.0 Hz, 1H), 7.56 (d, J= 8.8 Hz, 1H), 7.40 (d, J= 8.1 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 5.70 (d, J= 17.3 Hz, 1H), 5.37 (d, J= 17.2 Hz, 1H), 4.41 (dd,/= 9.1, 5.5 Hz, 1H), 3.96 - 3.85 (m, 1H), 2.44 - 2.07 (m, 2H), 1.98 - 1.81 (m, 1H), 1.49 (s, 9H), 1.13 - 0.98 (m, 1H), 0.85 - 0.62 (m, 1H); MS (ES+): 621.20 & 623.20 (M+l); MS (ES-): 619.10 & 621.10 (M-l).

Scheme 49

Preparation of(lR,3S,5R)-2-(2-(4-amino-6-cyano-9H-pyrimido[4,5-b]indol-9 -yl)acetyl)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (49c)

Step-1: Preparation of ethyl 2-(4-amino-6-cyano-9H-pyrimido[4,5-b]indol-9-yl)acetale (49a)

To a mixture of ethyl 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (48a) (300 mg, 0.859 mmol) and dicyanozinc (303 mg, 2.58 mmol) in DMF (8 mL) was added Pd(PPh3)4 (149 mg, 0.129 mmol), degassed, filled with nitrogen, and heated at 100 °C for 13 h. The reaction mixture was diluted with ethyl acetate (120 mL), washed with water (2 x 60 mL), brine (60 mL), dried, filtered, concentrated in vacuum and triturated with ethyl acetate (20 mL). The solid obtained was collected by filtration and dried in vacuum to afford ethyl 2- (4-amino-6-cyano-9H-pyrimido[4,5-b]indol-9-yl)acetate (49a) (160 mg, 63% yield) as a white solid; 1H NMR (300 MHz, DMSOntfc) δ 8.94 - 8.93 (m, 1H), 8.36 (s, 1H), 7.86 - 7.80 (m, 2H), 7.59 (s, 2H), 5.31 (s, 2H), 4.14 (q, J= 7.1 Hz, 2H), 1.20 (t ,J= 7.2 Hz, 3H); MS (ES+): 296.10 (M+l); (ES-): 294.10 (M-l)

Step-2: Preparation of 2-(4-amino-6-cyano-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (49b)

Compound 49b was prepared according to the procedure reported in step-4 of scheme- 17, from ethyl 2-(4-amino-6-cyano-9H-pyrimido[4,5-b]indol-9-yl)acetate (49a) (80 mg, 0.271 mmol) in THF (3 mL) and MeOH (3 mL) using a solution of lithium hydroxide hydrate (69.6 mg, 1.625 mmol) in water (3 mL) and stirring at RT for 15 h. This gave after workup 2-(4- amino-6-cyano-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (49b) (72 mg, 100% yield) which was used as such in next step-3 without further purification; MS (ES+) : 268. 10 (M+l) .

Step-3: Preparation of ( lR,3S,5R)-2-(2-(4-amino-6-cyano-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (49c)

Compound 49c was prepared according to the procedure reported in step-3 of scheme- 1 , from 2-(4-amino-6-cyano-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (49b) (0.072 g, 0.271 mmol) i DMF (10 L) i HC1 lt f ( lR 3S 5R) N (6 b idi 2 l) 2 azabicyclo[3.1 ,0]hexane-3-carboxamide (4a) (0.104 g, 0.325 mmol), HATU (0.206 g, 0.542 mmol), DIPEA (175 mg, 1.355 mmol) and stirring at RT for 22 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), 10% MeOH in EtOAc in hexane from 0 - 100 %] followed by conversion to HC1 salt in acetonitrile (5 mL) using 0.1% aq. HC1 (30 mL) and lyophilization (lR,3S,5R)-2-(2-(4-amino-6-cyano-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1.0]hexane-3-carboxamide (49c) (54 mg, 38% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-dk) δ 10.76 (s, 1H, DzO exchangeable), 9.09 (d, ./= 1.5 Hz, 1H), 8.74 - 8.54 (m, 3H, 2H D2O exchangeable), 8.00 (d, J= 8.2 Hz, 1H), 7.94 (dd 8.6, 1.4 Hz, 1H), 7.87 (d, J= 8.6 Hz, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.31 (d, J= 7.7 Hz, 1H), 5.81 (d, J= 17.4 Hz, 1H), 5.45 (d, J= 17.3 Hz, 1H), 4.42 (dd, J= 9.0, 5.5 Hz, 1H), 3.95 - 3.84 (m, 1H), 2.42 - 2.08 (m, 2H), 1.98 - 1.83 (m, 1H), 1.16 - 0.98 (m, 1H), 0.90 - 0.67 (m, 1H); MS (ES+): 531.10 & 533.10 (M+l); MS (ES-): 529.00 & 531.10 (M-l); Analysis calculated for C24Hi9BrN ₈ 02.0.85HC1.2.0H20: C, 48.17; H, 4.02; Cl, 5.04; N, 18.73; Found: C, 48.54; H, 4.17; Cl, 5.36; N, 18.40.

Scheme 50

Preparation of (lR,3S,5R)-2-(2-(4-amino-5-fluoro-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N- (6-bromopyridin-2-yI)-2-azabicyclo[3.1.0]hexane-3-carboxamid e (50f)

Step-1: Preparation of 2-amino-4-fluoro-lH-indole-3-carbonitrile (50b)

Compound 50b was prepared according to the procedure reported in step-1 of scheme- 11, from N-(2-bromo-3-fluorophenyl)-2,2,2-trifluoroacetamide (50a) (5 g, 17.48 mmol; CAS # (0.403 g, 3.50 mmol), Cul (0.333 g, 1.748 mmol), K2CO3 (4.83 g, 35.0 mmol) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification by flash column chromatography [SiOzgel (40 g), eluting with EtOAc in hexane from 0-50%] 2- amino-4-fluoro-lH-indole-3-carbonitrile (50b) (0.3 g, 10% yield) as an brown solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.97 (s, 1H), 6.98 (d, J= 7.8 Hz, 1H), 6.91 - 6.83 (m, 3H), 6.75 (ddd,v/= 10.8, 8.1, 1.0 Hz, 1H); MS (ES+): 176.0 (M+l), (ES-): 174.0 (M-l).

Step-2: Preparation of 5-fluoro-9H-pyrimido[4,5-b]indol-4-amine (50c)

Compound 50c was prepared according to the procedure reported in step-1 of scheme-6, from 2-amino-4-fluoro-lH-indole-3-cafbonitrile (50b) (0.3 g, 1.713 mmol) using trimethyl orthoformate (3.64 g, 34.3 mmol), AcOH (0.490 mL, 8.56 mmol) and NH4OAC (0.660 g,

8.56 mmol). Ibis gave after workup and purification by reverse phase column chromatography [Cl 8 column (30 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] 5-fluoro-9H-pyrimido[4,5-b]indol-4-amine (50c) (83 mg, 24% yield) as a brown yellow solid; Ή NMR (300 MHz, DMSO-tfc) δ 13.18 (s, 1H), 8.60 (s, 1H), 7.61 - 7.38 (m, 2H), 7.23 (dd, J= 11.3, 7.8 Hz, 1H); MS (ES+): 203.04 (M+l).

Step-3: Preparation of torf-butyl 2-(4-amino-5-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetate (50d)

Compound 50d was prepared according to the procedure reported in step-2 of scheme- 16, from HC1 salt of 5-fluoro-9H-pyrimido[4,5-b]indol-4-amine (50c) (80 mg, 0.335 mmol) in DMF (2.5 mL) using tort-butyl 2-bromoacetate (65.4 mg, 0.335 mmol) CS2CO3 (218 mg, 0.670 mmol) and stirring at RT for 1.5 h. The solid separated was collected by filtration, dried to give tort-butyl 2-(4-amino-5-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetate (50d) (83 mg, 78 % yield) as a pale yellow solid; Ή NMR (300 MHz, DMSO-cfe) δ 8.36 (s, 1H), 7.54 - 7.40 (m, 2H), 7.14 (ddd,7= 11.5, 7.2, 1.7 Hz, 1H), 5.16 (s, 2H), 1.41 (s, 9H); MS (ES+): 317.10 (M+l).

Step-4: Preparation of 2-(4-amino-5-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (50e)

Compound 50e was prepared according to the procedure reported in step-2 of scheme- 1, from tort-butyl 2-(4-amino-5-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetate (50d) (80 mg, 0.253 mmol) using 20% TFA in DCM (1452 μΐ, 3.79 mmol) and stirring at RT for 16 h. This gave after workup 2-(4-amino-5-fhioro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (50e) (85 mg, 90% yield) TFA salt as a yellow solid; Ή NMR (300 MHz, DMSO-ife) δ 8.46 (s, 1H), 7.58 (d, J= 8.2 Hz, 1H), 7.49 (td, J= 8.1, 5.5 Hz, 1H), 7.20 (dd, J= 11.3, 8.0 Hz, 1H), 5.22 (s, 2H); MS (ES+): 261.00 (M+l).

Step-5: Preparation of ( lR,3S,5R)-2-(2-(4-amino-5-fluoro-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (50f)

Compound 50f was prepared according to die procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-5-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (50e) (50 mg, 0.134 mmol) in DMF (1.5 mL) using TFA salt of (lR^S _j SRJ-N-iti-bromopyridin^-yl^- azabicyclop.l.OJhexane-S-caiboxamide (4a) (52.9 mg, 0.134 mmol), HATU (76 mg, 0.200 mmol), DIPEA (0.116 mL, 0.668 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-5-fluoro-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-caiboxamide (50f) (53 mg, 76% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfc) 5 10.77 (s, 1H, DzO exchangeable),

8.68 (s, 1H), 8.01 (d, J= 8.1 Hz, 1H), 7.71 (t ,J= 8.0 Hz, 1H), 7.62 - 7.49 (m, 2H), 7.35 - 7.20 (m, 2H), 5.79 (d, J= 17.4 Hz, 1H), 5.44 (d,./= 17.3 Hz, 1H), 4.43 (dd, J= 9.1, 5.5 Hz, 1H), 3.91 (ddd, J= 7.4, 5.4, 2.3 Hz, 1H), 2.40 - 2.14 (m, 2H), 1.92 (dq, J= 13.3, 6.5, 6.0 Hz, 1H), 1.08 (dt, J= 8.7, 5.4 Hz, 1H), 0.79 (td, J= 5.2, 2.4 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO-d!s) δ -113.23; MS (ES+): 524.0 (M+l); 546.0 (M+Na); (ES-): 522.0 (M-l); Analysis calculated for C23H19BrFN7O2-l.75H2O.lHCl: C, 46.64; H, 4.00; Cl, 5.99; N, 16.55; Found: C, 46.50; H, 3.71; Cl, 5.73; N, 16.29.

Scheme 51

51c 51d

OH H

/ ^■ — CO^/Bu f *

N V F TFA ^θΛ 1 F o rV ^Br f 4a

N

H ₂ N ATU, DIPEA _¾ w N. /

1 f N ^N On H i 2 N-/

NH r>

51e 51f NH ₂ ,,

* 51g

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-fluoro-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (51 g)

Step-1: Preparation of 2,2,2-trifluoro-N-(2-fluoro-6-iodophenyl)acetamide (51b)

Compound 51b was prepared according to the procedure reported in step-1 of scheme-46, from 2-fluoro-6-iodoaniline (51a) (5 g, 21.10 mmol; CAS # 886762-73-8) in DCM (50 mL) using triethylamine (5 mL, 35.9 mmol), trifluoroacetic acid anhydride (4.40 mL, 6.65 mmol) and stirring at RT for 16 h. This gave after workup 2,2,2-trifluoro-N-(2-fluoro-6- iodophenyl)acetamide (51b) (6.5 g, 93% yield) as a yellow solid, which was used as such for the next step; Ή NMR (300 MHz, DMSO-tife) δ 11.42 (s, 1H), 7.81 (dt, J= 8.0, 1.2 Hz, 1H), 7.43 (ddd, 9.6, 8.4, 1.3 Hz, 1H), 7.26 (td,J= 8.2, 5.6 Hz, 1H); MS (ES-): 331.80 (M-l).

Step-2: Preparation of 2-amino-7-fluoro-lH-indole-3-carbonitrile (51c)

Compound 51c was prepared according to the procedure reported in step-1 of scheme- 11, from 2,2,2-trifluoro-N-(2-fluoro-6-iodophenyl)acetamide (51b) (6.4 g, 19.22 mmol) in DMSO (20 mL) using malononitrile (1.452 mL, 23.06 mmol), L-proline (0.443 g, 3.84 mmol), Cul (0.366 g, 1.922 mmol), K2CO3 (5.31 g, 38.4 mmol) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification [SiOzgel (40 g), eluting with EtOAc in hexane from 0-50%] 2-amino-7-fluoro-lH-indole-3-carbonitrile (51c) (1 535 g, 46% yield) as a yellow solid; Ή NMR (300 MHz, DMSO-ifc) δ 11.33 (s, 1H), 7.03 - 6.88 (m, 2H), 6.88 - 6.66 (m, 3H); MS (ES+): 176.0 (M+l), (ES-): 174.0 (M-l).

Step-3: Preparation of 8-fluoro-9H-pyrimido[4,5-b]indol-4-amine (51d)

Compound 51d was prepared according to the procedure reported in step-1 of scheme-6, from 2-amino-7-fluoro-lH-indole-3-carbonitrile (51c) (1.5 g, 8.56 mmol) using trimethyl orthoformate (18.74 mL, 171 mmol), AcOH (2.449 mL, 42.8 mmol) and NHiOAc (3.30 g, 42.8 mmol). This gave after workup 8-fluoro-9H-pyrimido[4,5-b]indol-4-amine (51d) (1.54 g, 69% yield) as a pale yellow solid; Ή NMR (300 MHz, DMSO-ife) δ 12.33 (s, 1H), 11.98 (s, 1H), 8.29 (s, 1H), 8.18 - 8.03 (m, 1H), 7.27 (s, 2H), 7.26 - 7.16 (m, 2H), 1.92 (s, 3H); MS (ES+): 203.10 (M+l).

Step-4: Preparation of /erf-butyl 2-(4-amino-8-fluoro-9H-pyrimido[4,5-bJindol-9-yl)acetate

(51e)

Compound 51e was prepared according to the procedure reported in step-2 of scheme- 16, from AcOH salt of 8-fluoro-9H-pyrimido[4,5-b]indol-4-amine (51 d) (1.5 g, 5.72 mmol) in DMF (35 mL) using ter/-butyl 2-bromoacetate (1.171g, 6.01 mmol), CS2CO3 (4.10 g, 12.58 mmol) stirring at RT for 15 h, followed by the addition of K2CO3 (0.791 g, 5.72 mmol), tert- butyl 2-bromoacetate (0.845 mL, 5.72 mmol) and stirring for additional 3 h. This gave after workup tert-butyl 2-(4-amino-8-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetate (51e) (1.15 g, 64% yield) as a pale yellow solid; ‘HNMR (300 MHz, DMSO-ifc) δ 8.34 (s, 1H), 8.22 - 8.16 (m, 1H), 7.45 (s, 2H), 7.28 - 7.21 (m, 2H), 5.17 (d, J= 2.0 Hz, 2H), 1.42 (s, 9H); MS (ES+): 317.14 (M+l).

Step-5: Preparation of 2-(4-amino-8-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (51f)

Compound 51f was prepared according to the procedure reported in step-2 of scheme-1, from te/t-butyl 2-(4-amino-8-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetate (51e) (0.9 g, 2.85 mmol) using 20% TEA in DCM (16.33 mL, 42.7 mmol)) and stirring at RT for 16 h. This gave after workup 2-(4-amino-8-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (51f) (0.92 g, 86% yield) TEA salt as a white solid; ^! HNMR (300 MHz, DMSO-tife) δ 8.49 (s, 1H), 8.32 - 8.23 (m, 1H), 8.07 (s, 2H), 7.40 - 7.27 (m, 2H), 5.25 (d, J= 1.9 Hz, 2H); MS (ES+): 261.10 (M+l).

Step-6: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-fluoro-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (51 g) Compound 51 g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-ammo-8-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (51f) (75 mg, 0.200 mmol) in DMF (2 mL) using TFA salt of ( 1R,3 S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-caxboxamide (4a) (79 mg, 0.200 mmol), HATU (114 mg, 0.301 mmol), DIPEA (0.175 mL, 1.002 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-8-fluoro-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (51g) (81 mg, 77% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfe) δ 10.78 (s, 1H, D2O exchangeable),

8.60 (s, 1H), 8.45 (s, 2H, DzO exchangeable), 8.32 (dd,J= 5.8, 3.0 Hz, 1H), 8.02 (d,J= 8.2 Hz, 1H), 7.71 (t, J= 8.0 Hz, 1H), 7.41 - 7.26 (m, 3H), 5.81 (d ,J= 17.5 Hz, 1H), 5.57 - 5.38 (m, 1H), 4.44 (dd, J= 9.0, 5.6 Hz, 1H), 3.98 - 3.80 (m, 1H), 2.40 - 2.13 (m, 2H), 2.01-1.83 (m, 1H), 1.10 (dt,J= 9.3, 5.4 Hz, 1H), 0.64 (q, J= 3.8, 2.9 Hz, 1H). ¹⁹ F NMR (282 MHz, DMSO-i/e) δ -134.64. MS (ES+): 524.1 (M+l); (ES-): 522.1 (M-l); Analysis calculated for C23Hi9BrFN7O2.2H2O.0.9HCl: C, 46.57; H, 4.06; Cl, 5.38; N, 16.53; Found: C, 46.54; H, 3.90; Cl, 5.43; N, 16.32.

Scheme 52

Preparation of (lR,3S,5R)-2-(2-(4-amino-7-bromo-9H-pyrimido[4,5-b]indol-9-y l)acetyl)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (52f) Compound 52b was prepared according to the procedure reported in step-1 of scheme- 11, from N-(5-bromo-2-iodophenyl)-2,2,2-trifluoroacetamide (52a) (6.4 g, 16.25 mmol; CAS # 1870674-39-7) in DMSO (20 mL) using malononitrile (1.228 mL, 19.50 mmol), L-proline (0.374 g, 3.25 mmol), Cul (0.309 g, 1.625 mmol), K2CO3 (4.49 g, 32.5 mmol) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification [SiChgel (40 g), eluting with EtOAc in hexane from 0-50%] 2-amino-6-bromo- 1 H-indole-3 - carbonitrile (52b) (2.06 g, 54% yield) as a yellow solid; Ή NMR (300 MHz, DMSO-ds) 5 10.80 (s, 1H), 7.29 (d, J= 1.6 Hz, 1H), 7.17 - 7.00 (m, 2H), 6.95 (s, 2H); MS (ES+): 236.0 (M+l), (ES-): 233.9 (M-l).

Step-2: Preparation of 7-bromo-9H-pyrimido[4,5-b]indol-4-amine (52c)

Compound 52c was prepared according to the procedure reported in step-1 of scheme-6, from 2-amino-6-bromo- 1 H-indole-3 -carbonitrile (52b) (2 g, 8.47 mmol) using trimethyl orthoformate (17.98 g, 169 mmol), AcOH (2.54 g, 42.4 mmol) and NHUOAc (3.27 g, 42.4 mmol). This gave after workup 7-bromo-9H-pyrimido[4,5-b]indol-4-amine (52c) (2.29 g, 84% yield) as a pale yellow solid; Ή NMR (300 MHz, DMSO-tVe) δ 11.97 (s, 2H), 8.27 (t, J = 4.2 Hz, 2H), 7.58 (d ,J= 1.8 Hz, 1H), 7.36 (dd, J= 8.4, 1.8 Hz, 1H), 7.26 (s, 2H), 1.92 (s,

3H).

Step-3: Preparation of /erf-butyl 2-(4-amino-7-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (52d)

Compound 52d was prepared according to the procedure reported in step-2 of scheme- 16, from AcOH salt of 7-bromo-9H-pyrimido[4,5-b]indol-4-amine (52c) (2.2 g, 6.81 mmol) in DMF (75 mL) using ter/-butyl 2-bromoacetate (1.056 g, 7.15 mmol), CS2CO3 (4.88 g, 14.98 mmol) stirring at RT for 15 h, followed by the addition of K2CO3 (0.941 g, 6.81 mmol), tert- butyl 2-bromoacetate (1.006 mL, 6.81 mmol) and stirring for 3 h at RT. This gave after workup te/7-butyl 2-(4-amino-7-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (52d) (1.25 g, 49% yield) as a pale yellow solid; Ή NMR (300 MHz, DMSCWe) 58.31 (L .7= 4.2 Hz, 2H), 7.91 (d, 1.7 Hz, 1H), 7.46 - 7.36 (m, 3H), 5.14 (s, 2H), 1.41 (s, 9H).

Step-4: Preparation of 2-(4-amino-7 -bromo-9H-pyrimido [4,5 -b] indol-9-yl)acetic acid (52e)

Compound 52e was prepared according to the procedure reported in step-2 of scheme- 1, from tezT-butyl 2-(4-amino-7-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (52d) (0.3 g, 0.795 mmol) using 20% TFA in DCM (4.56 mL, 11.93 mmol) and stirring at RT for 16 h. This g, 90% yield) TFA salt as a white solid; Ή NMR (300 MHz, DMSO-i/e) δ 8.49 (s, 1H), 8.41 (d, J= 8.4 Hz, 1H), 8.08 (d ,J= 1.7 Hz, 1H), 7.54 (dd, J= 8.4, 1.7 Hz, 1H), 5.23 (s, 2H); MS (ES+): 321.00 (M+l).

Step-5: Preparation of (lR,3S,5R)-2-(2-(4-amino-7-bromo-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (52f)

Compound 52f was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-7-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (52e) (75 mg, 0.172 mmol) in DMF (2 mL) using TFA salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-caiboxamide (4a) (68.3 mg, 0.172 mmol), HATU (98 mg, 0.259 mmol), DIPEA (0.150 mL, 0.862 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-7-bromo-9H-pyrimido[4,5-b]indol-9-y l)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (52f) (79 mg, 78 % yield) HC1 salt as a white solid; ‘H NMR (300 MHz, DMSO-ifc) δ 10.79 (s, 1H, DzO exchangeable),

8.70 (s, 2H, DzO exchangeable), 8.64 (s, 1H), 8.49 (d, ./= 8.5 Hz, 1H), 8.08 - 7.97 (m, 2H),

7.71 (t, J= 8.0 Hz, 1H), 7.60 (dd, J= 8.5, 1.7 Hz, 1H), 7.32 (d, J= 7.7 Hz, 1H), 5.79 (d, J= 17.4 Hz, 1H), 5.42 (d, J= 17.3 Hz, 1H), 4.43 (dd, J= 9.0, 5.5 Hz, 1H), 3.90 (ddd, J= 7.6,

5.4, 2.4 Hz, 1H), 2.39 - 2.10 (m, 2H), 2.01 - 1.83 (m, 1H), 1.08 (dt, J= 8.8, 5.5 Hz, 1H),

0.79 (td, J= 5.2, 2.4 Hz, 1H). MS (ES+): 586.0 (M+l); (ES-): 584.0 (M-l); Analysis calculated for Cz3H19B1zN7Oz.2HzO.lHCl: C, 42.00; H, 3.68; Cl, 5.39; N, 14.91; Found: C, 42.08; H, 3.55; Cl, 5.18; N, 14.77.

Scheme 53

53b r ^N 'V-N

N N ¾ l\

HN H ₂ N 1

NH 11e CF, Λ °

O V-N

O- Br HATU, DIPEA

NH

53c ₂ 53d

Preparation of (S)-5-(2-(4-amino-6-(trifluoromethyl)-9H-pyriinido[4,5-b]ind ol-9-yl)acetyl)- N-(6-bromopyridin-2-yl)-5 -azaspiro [2.4] heptane-6-carboxam ide (53d)

Step-1: Preparation of (S)-/er/-but>'l 6-((6-bromopyridin-2-yl)carbamoyl)-5- azaspiro[2.4]heptane-5-carbox>'late (53b)

To a stirred solution of (S)-5-(/er/-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxy lic acid (53a) (0.5 g, 2.072 mmol) in DCM (15 mL) was added 1 -methyl- lH-imidazole (0.413 mL, 5.18 mmol) at 0-5 °C under a nitrogen atmosphere. The reaction mixture was stirred for 10 min at 0-5 °C, added methanesulfonyl chloride (0.192 mL, 2.487 mmol) followed by stirring at 0-5 °C for 1 h. To this mixture was added 6-bromopyridin-2-amine (0.359 g, 2.072 mmol) and stirred for 18 h at RT. Water (30 mL) was added to the reaction mixture, layers were separated, and aqueous layer was extracted with DCM (3 x 30 mL). The combined organics were washed with IN HC1 (30 mL), Sat. aqueous NaHCOs (30 mL), brine (30 mL), dried, filtered and concentrated in vacuum to afford (S)-/tr /-butyl 6-((6-bromopyridin-2- yl)carbamoyl)-5-azaspiro[2.4]heptane-5-cafboxylate (53b) (0.8 g, 97 % yield); Ή NMR (300 MHz, DMSOnofe) δ 10.90 (d,J= 18.6 Hz, 1H), 8.11 (dd,7= 13.0, 8.1 Hz, 1H), 7.75 (q,./= 7.8 Hz, 1H), 7.35 (d, J= 7.7 Hz, 1H), 4.57 - 4.39 (m, 1H), 3.32 - 3.16 (m, 2H), 2.15 (ddd, J = 27.3, 12.8, 8.3 Hz, 1H), 1.83 (ddd, J= 35.1, 12.6, 5.2 Hz, 1H), 1.33 (d,J= 36.8 Hz, 9H), 0.68 - 0.41 (m, 4H); MS (ES+): 396.00 (M+l).

Step-2: Preparation of (S)-N-(6-bromopyridin-2-yl)-5-azaspiro[2.4]heptane-6-carboxa mide

(53c) Compound 53c was prepared according to the procedure reported in step-2 of scheme- 1, from (S)-ter/-butyl 6-((6-bromopyridin-2-yl)carbamoyl)-5-azaspiro[2.4]heptane-5- carboxylate (53b) (0.8 g, 2.019 mmol) using TFA (0.778 mL, 10.09 mmol) in DCM (7 mL) and stirring overnight at RT. This gave after workup (S)-N-(6-bromopyridin-2-yl)-5- azaspiro[2.4]heptane-6-carboxamide (53c) (0.55 g, 92% yield) TFA salt; *H NMR (300 MHz, DMSO-i/6) δ 11.43 (s, 1H), 9.71 (s, 1H), 8.90 (s, 1H), 8.08 (d ,J= 8.2 Hz, 1H), 7.83 (t,J =

7.9 Hz, 1H), 7.45 (d, J= 7.7 Hz, 1H), 4.63 - 4.47 (m, 1H), 3.20 (d, J= 5.2 Hz, 2H), 2.33 (dd, J= 13.1, 8.6 Hz, 1H), 2.03 (dd, ./= 13.1, 7.0 Hz, 1H), 0.76 - 0.46 (m, 4H); MS (ES+): 295.93 (M+l).

Step-3: Preparation of (S)-5-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indo l-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-azaspiro[2.4]heptane-6- carboxamide (53d)

Compound 53d was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of (S)-N-(6-bromopyridin-2-yl)-5-azaspiro[2.4]heptane-6-carboxa mide (53c) (72.5 mg, 0.177 mmol) in DMF (2 mL) using TFA salt of 2-(4-amino-6-(trifluoromethyl)- 9H-pyrimido[4,5-b]indol-9-yl)acetic acid (lie) (75 mg, 0.177 mmol), HATU (101 mg, 0.265 mmol), DIPEA (0.154 mL, 0.884 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (S)-5- (2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl )acetyl)-N-(6-bromopyridin-2- yl)-5-azaspiro[2.4]heptane-6-carboxamide (53d)) (89 mg, 86% yield) HC1 salt as a white solid; ^l H NMR (300 MHz, DMSO-ds) (a mixture of two rotamers) δ 11.25 and 10.82 (2s, 1H, DzO exchangeable), 8.96 (s, 1H), 8.59 and 8.57 (2s, 1H), 8.52 (s, 2H, DzO exchangeable), 8.19 and 8.02 (2d, J= 8.2 Hz, 1H), 7.94 - 7.78 (m, 2H), 7.70 (t, J= 8.0 Hz, 1H), 7.41 and 7.32 (2d, ./= 7.7 Hz, 1H), 5.45 (d, J= 2.4 Hz, 2H), 4.65 (dd, ./= 8.5, 5.0 Hz, 1H), 3.90 - 3.74 (m, 2H), 2.25 (dd, J= 12.7, 8.4 Hz, 1H), 1.89 (dd, J= 12.6, 4.9 Hz, 1H), 0.81 - 0.49 (m, 4H). ¹⁹ F NMR (282 MHz, DMSO-t/e) δ -58.70. MS (ES+): 588.1 (M+l); (ES-): 586.1 (M-l); Analysis calculated for CzsHziBrFsNzOz LSHzO.l.lHCl: C, 45.81; H, 3.86; Cl, 5.95; N, 14.96; Found: C, 45.85; H, 3.73; Cl, 5.91; N, 14.70.

Scheme 54

54d NH ₂

<7 54e

H

OH N

H fu w

OMe 4a

Γ^¾Μβ ft- HATU, DIPEA N _¾ N. /

N Π

NH ₂ N-/ rs

NH

54f ₂

54g

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methoxy-9H-pyrimido[4,5-b]indol-9 -yl)acetyl)- N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxam ide (54g)

Step-1: Preparation of N-(2-bromo-6-methoxyphenyl)-2,2,2-trifluoroacetamide (54b)

Compound 54b was prepared according to the procedure reported in step-1 of scheme-46, from 2-bromo-6-methoxy aniline (54a) (5 g, 24.75 mmol; CAS # 5473-01-8) in DCM (50 mL) using triethylamine (5.86 mL, 42.1 mmol), trifluoroacetic acid anhydride (5.16 mL, 37.1 mmol) and stirring at RT for 16 h. This gave after workup N-(2-bromo-6-methoxyphenyl)- 2,2,2-trifluoroacetamide (54b) (7.35 g, 100% yield) as a pale yellow solid and was used as such for next step; Ή NMR (300 MHz, DMSO -ck) δ 11.03 (s, 1H), 7.40 - 7.26 (m, 2H), 7.18 (dd, J= 7.1, 2.5 Hz, 1H), 3.82 (s, 3H); MS (ES-): 295.9 (M-l).

Step-2: Preparation of 2-amino-7 -methoxy- 1 H-indole-3 -carbonitrile (54c)

Compound 54c was prepared according to the procedure reported in step-1 of scheme- 11, from N-(2-bromo-6-methoxyphenyl)-2,2,2-trifluoroacetamide (54b) (7.2 g, 24.16 mmol) in DMSO (20 mL) and using malononitrile (1.826 mL, 29.0 mmol), L-proline (0.556 g, 4.83 mmol), Cul (0.460 g, 2.416 mmol), K2CO3 (6.68 g, 48.3 mmol) and stirring at 60 °C for 16 h with EtOAc in hexane from 0-50%] 2-amino-7-methoxy-lH-indole-3-carbonitrile (54c) (2.308 g, 51% yield) as a yellow solid; Ή NMR (300 MHz, DMSO-cfe) δ 10.81 (s, 1H), 6.92 (t,J= 7.9 Hz, 1H), 6.77 (d, J= 7.7 Hz, 1H), 6.59 (d, J= 7.9 Hz, 1H), 6.37 (s, 2H), 3.86 (s, 3H); MS (ES+): 188.1 (M+l); (ES-): 186.0 (M-l).

Step-3: Preparation of 8-methoxy-9H-pyrimido[4,5-b]indol-4-amine (54d)

Compound 54d was prepared according to the procedure reported in step-1 of scheme-6, from 2-amino-7-methoxy-lH-indole-3-carbonitrile (54c) (2.3 g, 12.29 mmol) using trimethyl orthoformate (26.1 g, 246 mmol), AcOH (3.51 mL, 61.4 mmol) andNHrOAc (4.74 g, 61.4 mmol). This gave after workup 8-methoxy-9H-pyrimido[4,5-b]indol-4-amine (54d) (2.7 g, 80% yield) AcOH salt as a pale yellow solid; Ή NMR (300 MHz, DMSO-ifc) δ 11.99 (s, 1H), 11.91 (s, 1H), 8.23 (s, 1H), 7.88 (d, J= 7.8 Hz, 1H), 7.15 (t, J= 7.9 Hz, 1H), 7.08 (s, 2H), 6.98 (d ,J= 7.9 Hz, 1H), 3.95 (s, 3H), 1.91 (s, 3H).

Step-4: Preparation of tert-butyl 2-(4-amino-8-methoxy-9H-pyrimido[4,5-b]indol-9- yl)acetate (54e)

Compound 54e was prepared according to the procedure reported in step-2 of scheme- 16, from AcOH salt of 8-methoxy-9H-pyrimido[4,5-b]indol-4-amine (54d) (2.6 g, 9.48 mmol) in DMF (75 mL) using tort-butyl 2-bromoacetate (1.471 mL, 9.95 mmol), CszCOs (6.80 g, 20.86 mmol), stirring at RT for 15 h, followed by the addition of tert-butyl 2-bromoacetate (1.401 mL, 9.48 mmol), K2CO3 (1.31 g, 9.48 mmol) and stirring for 3 h. The solid separated was filtered and dried to give tert-butyl 2-(4-amino-8-methoxy-9H-pyrimido[4,5-b]indol-9- yl)acetate (54e) (1.87 g, 60% yield) as a pale yellow solid; Ή NMR (300 MHz, DMSO-efe) δ 8.28 (s, 1H), 7.94 (d, J= 7.8 Hz, 1H), 7.26 (s, 2H), 7.20 (t ,J= 7.9 Hz, 1H), 7.01 (d, J= 8.0 Hz, 1H), 5.19 (s, 2H), 3.89 (s, 3H), 1.42 (s, 9H).

Step-5: Preparation of 2-(4-amino-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (54f)

Compound 54f was prepared according to the procedure reported in step-2 of scheme- 1, from tort-butyl 2-(4-amino-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetate (54e) (0.9 g, 2.74 mmol) using 20% TFA in DCM (15.73 mL, 41.1 mmol)) and stirring at RT for 16 h. This gave after workup afford 2-(4-amino-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (54f) (0.46 g, 43% yield) TFA salt as a white solid; Ή NMR (300 MHz, DMSO-i/e) δ 8.51 (s, 1H), 8.20 (s, 2H), 8.05 (d, J= 7.9 Hz, 1H), 7.32 (t, J= 8.0 Hz, 1H), 7.13 (d, J= 8.0 Hz, 1H), 5.32 (s, 2H), 3.92 (s, 3H). Step-6: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methoxy-9H-pyrimido[4,5-b]indol-9 - yl)acetyl)-N -(6-bromopyridin-2-y l)-2-azabicyclo [3.1.0]hexane-3 -carboxamide (54g)

Compound 54g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (54f) (75 mg, 0.194 mmol) in DMF (2 mL) using TFA salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (4a) (77 mg, 0.194 mmol), HATU (111 mg, 0.291 mmol), DIPEA (0.169 mL, 0.971 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-8-methoxy-9H-pyrimido[4,5-b]indol-9 -yl)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (54g) (85 mg, 82% yield) as a white solid; ΉΝΜΚ.(300 MHz, DMSO-i/e) δ 10.74 (s, 1H, D2O exchangeable), 8.60 (s, 1H), 8.57 (s, 2H, D2O exchangeable), 8.08 (d ,J= 7.9 Hz, 1H), 8.02 (d, J= 8.2 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.40 - 7.24 (m, 2H), 7.15 (d, J= 8.0 Hz, 1H), 5.81 (d, J= 17.0 Hz, 1H), 5.59 (d, J= 16.9 Hz, 1H), 4.43 (dd, J= 8.9, 5.6 Hz, 1H), 3.94 (s, 3H), 3.85 (td, J= 6.3, 5.3, 2.3 Hz, 1H), 2.42 - 2.14 (m, 2H), 2.06-1.88 (m, 1H), 1.12 (dt, J= 10.0, 5.5 Hz, 1H), 0.67 (td, J= 5.3, 2.4 Hz, 1H). MS (ES+): 536.1 (M+l); (ES-): 534.1 (M-l); Analysis calculated for C24H22BrN7O3.2H2O.lHCl: C, 47.34; H, 4.47; Cl, 5.82; N, 16.10; Found: C, 47.34; H, 4.40; Cl, 5.48; N, 15.94.

Scheme 55

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N- (6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-c arboxamide (55a) Compound 55a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (30e) (50 mg, 0.135 mmol) in DMF (2 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-5- methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (8a) (44.9 mg, 0.135 mmol), HATU (77 mg, 0.203 mmol), DIPEA (0.118 mL, 0.675 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography (silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-8-methyl-9H-pyrimido(4,5-b]indol-9- yl)acetyl)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carb oxamide (55a) (47 mg, 65% yield) HC1 salt as a white solid; ‘HNMR (300 MHz, DMSO-ifc) δ 10.75 (s, 1H, D ₂ 0 exchangeable), 8.51 (s, 1H), 8.35 (s, 2H, DzO exchangeable), 8.24 (dd, J= 6.2, 3.0 Hz, 1H), 7.94 (d, J= 8.2 Hz, 1H), 7.64 (t ,J= 8.0 Hz, 1H), 7.27 - 7.14 (m, 3H), 5.81 (d, J= 18.0 Hz, 1H), 5.54 (d,J= 17.9 Hz, 1H), 4.31 (dd,J= 9.0, 6.1 Hz, 1H), 3.63 (dd,J= 5.6, 2.3 Hz, 1H), 2.62 (s, 3H), 2.48 - 2.45 (m, 1H), 1.91 (dd, J= 13.1, 6.1 Hz, 1H), 1.24 (s, 3H), 0.95 (t, ./=

5.4 Hz, 1H), 0.77 (dd, J= 5.4, 2.4 Hz, 1H); MS (ES+): 534.1 (M+l); (ES-): 532.1 (M-l); Analysis calculated for C25H2*BrN ₇ 02 1.5H2O.0.9HC1: C, 50.53; H, 4.73; Cl, 5.37; N, 16.50; Found: C, 50.38; H, 4.74; Cl, 5.68; N, 16.43.

Scheme 56

Preparation of (lR,3S,5R)-2-(2-(4-ammo-5-methyl-9H-pyrimido[4,5-b]indol-9-y l)acetyl)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (56g) Step-1: Preparation of 2, 2, 2-trifluoro-N-(2-iodo-3-methylphenyl)acetamide (56b)

Compound 56b was prepared according to the procedure reported in step-1 of scheme-46, from 2-iodo-3-methylaniline (56a) (5 g, 21.45 mmol; CAS # 89938-16-9) in DCM (75 mL) using triethylamine (5.08 mL, 36.5 mmol), trifluoroacetic acid anhydride (4.47 mL, 32.2 mmol) and stirring at RT for 16 h. This gave after workup 2,2,2-trifluoro-N-(2-iodo-3- methylphenyl)acetamide (56b) (6.9 g, 21% yield) as a pale yellow solid and was used as such for the next step; Ή NMR (300 MHz, DMSO -ck) δ 11.26 (s, 1H), 7.43 - 7.24 (m, 2H), 7.17 (dd, J= 6.1, 3.3 Hz, 1H), 2.47 (s, 3H); MS (ES-): 327.90 (M-l).

Step-2: Preparation of 2-amino-4-methyl-lH-indole-3-carbonitrile (56c)

Compound 56c was prepared according to the procedure reported in step-1 of scheme- 11, from 2,2,2-trifluoro-N-(2-iodo-3-methylphenyl)acetamide (56b) (4.9 g, 14.89 mmol) in DMSO (15 mL) using malononitrile (1.125 mL, 17.87 mmol), L-proline (0.343 g, 2.98 mmol), Cul (0.284 g, 1.489 mmol) K2CO3 (4.12 g, 29.8 mmol) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification [SiOzgel (80 g), eluting with EtOAc in hexane from 0-50%] 2-amino-4-methyl-lH-indole-3-carbonitrile (56c) (0.81 g, 32% yield) as a brown solid; Ή NMR (300 MHz, DMSO -i/e) δ 10.67 (s, 1H), 6.96 (d, J = 7.8 Hz, 1H), 6.79 (t, J= 7.6 Hz, 1H), 6.70 (dt, J= 7.3, 1.0 Hz, 1H), 6.62 (s, 2H), 2.48 (s, 3H); MS (ES-): 170.10 (M-l).

Step-3: Preparation of 5-methyl-9H-pyrimido[4,5-b]indol-4-amine (56d)

Compound 56d was prepared according to the procedure reported in step-2 of scheme-29, from 2-amino -4-methyl- 1 H-indole-3 -carbonitrile (56c) (0.8 g, 4.67 mmol) in ethanol (30 mL) using formamidine acetate (3.93 g, 37.4 mmol) and refluxing for 22 h. This gave after workup and purification by reverse-phase column chromatography [Cl 8 column (275 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] to afford 5-methyl-9H- pyrimido[4,5-b]indol-4-amine (56d) (114 mg, 12% yield) HC1 salt as a pale yellow solid; Ή NMR (300 MHz, DMSO-flfe) δ 13.15 (s, 1H), 8.65 (s, 1H), 8.03 (s, 2H), 7.49 - 7.32 (m, 2H), 7.22 - 7.05 (m, 1H), 2.94 (s, 3H); MS (ES+): 199.10 (M+l).

Step-4: Preparation of tert-butyl 2-(4-amino-5-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetate

(56e)

Compound 56e was prepared according to the procedure reported in step-2 of scheme- 16, from HC1 salt of 5-methyl-9H-pyrimido[4,5-b]indol-4-amine (56d) (110 mg, 0.469 mmol) in 1.031 mmol) and stirring at RT for 1.5 h. This gave after workup tert-butyl 2-(4-amino-5- methyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (56e) (130 mg, 89% yield) as a pale yellow solid; Ή NMR (300 MHz, DMSO-rfc) δ 8.27 (s, 1H), 7.42 - 7.24 (m, 2H), 7.04 (d, J= 7.1 Hz, 1H), 6.79 (s, 2H), 5.11 (s, 2H), 2.96 (s, 3H), 1.41 (s, 9H); MS (ES+): 313.20 (M+l). Step-5: Preparation of 2-(4-amino-5-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (56f)

Compound 56f was prepared according to the procedure reported in step-2 of scheme- 1, from terf-butyl 2-(4-amino-5-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (56e) (100 mg, 0.320 mmol) using 20% TFA in DCM ( 1837 pL, 4.80 mmol)) and stirring at RT for 16 h. This gave after workup 2-(4-ammo-5-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (56f) (115 mg, 97% yield) TFA salt as a white solid; MS (ES+): 257.10 (M+l ).

Step-6: Preparation of ( 1 R,3 S,5 R)-2-(2-(4-amino-5 -methyl-9H-pyrimido [4,5 -b] indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (56g)

Compound 56g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-5-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (56f) (50 mg, 0.135 mmol) in DMF (1.5 mL) using TFA salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (4a) (53.5 mg, 0.135 mmol), HATU (77 mg, 0.203 mmol), DIPEA (0.118 mL, 0.675 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%]

( 1 R, 3 S ,5 R)-2-(2-(4-amino-5 -methyl -9H-pyri mi do [4,5 -b] ί ndol-9-yl)acety 1 )-N-(6- bromopyiidin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (56g) (34 mg, 48% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-flfe) δ 10.76 (s, 1H, DzO exchangeable), 8.60 (s, 1H), 8.01 (d, J= 8.2 Hz, 1H), 7.79 - 7.65 (m, 3H, 2H DzO exchangeable), 7.52 - 7.37 (m, 2H), 7.32 (d, J= 7.7 Hz, 1H), 7.17 (d, J= 7.0 Hz, 1H), 5.74 (d, J= 17.3 Hz, 1H), 5.41 (d, J= 17.3 Hz, 1H), 4.42 (dd, J= 9.1, 5.4 Hz, 1H), 3.94 - 3.86 (m, 1H), 2.96 (s, 3H), 2.36 - 2.13 (m, 2H), 1.99 - 1.84 (m, 1H), 1.07 (dt, 9.3, 5.3 Hz, 1H), 0.78 (dt, J= 5.5, 2.7 Hz, 1H).

MS (ES+): 520.1 (M+l); 542.1 (M+Na); (ES-): 518.0 (M-l).

Scheme 57

Preparation of (lR,3S,5R)-2-(2-(4-amino-5-methoxy-9H-pyrimido[4,5-b]indol-9 -yl)acetyl)- N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxam ide (57g)

Step-1: Preparation of 2,2,2-trifluoro-N-(2-iodo-3-methoxyphenyl)acetamide (57b)

Compound 57b was prepared according to the procedure reported in step-1 of scheme-46, from 2-iodo-3-methoxyaniline (57a) (5 g, 20.08 mmol; CAS # 98991-09-4) in DCM (75 mL) using triethylamine (4.76 mL, 34.1 mmol), trifluoroacetic acid anhydride (4.19 mL, 30.1 mmol) and stirring at RT for 16 h. This gave after workup 2,2,2-trifluoro-N-(2-iodo-3- methoxyphenyl)acetamide (57b) (6.8 g, 98% yield) as a dark oil and was used as such for next step; MS (ES-): 343.90 (M-l).

Step-2: Preparation of 2-amino-4-mcthoxy- lH-indole-3-carbonitrile (57c)

Compound 57c was prepared according to the procedure reported in step-1 of scheme- 11, from 2,2,2-trifluoro-N-(2-iodo-3-methoxyphenyl)acetamide (57b) (5.1 g, 14.78 mmol) in DMSO (15 mL) using malononitrile (1.117 mL, 17.74 mmol), L-proline (0.340 g, 2.96 mmol), Cul (0.281 g, 1.478 mmol), K2CO3 (4.12 g, 29.8 mmol) and heating at 60 °C for 16 h chromatography [SiChgel (80 g), eluting with EtOAc in hexane from 0-50%] 2-amino-4- methoxy-lH-indole-3-carbonitrile (57c) (1.35 g, 49% yield) as a gray solid; Ή NMR (300 MHz, DMSO-Kfc) δ 10.54 (s, 1H), 7.00 (d, J= 8.4 Hz, 1H), 6.75 (d, J= 2.3 Hz, 1H), 6.63 - 6.56 (m, 3H), 3.71 (s, 3H); MS (ES+): 188.10 (M+l); (ES-): 186.10 (M-l).

Step-3: Preparation of 5-metfaoxy-9H-pyrimido[4,5-b]indol-4-amine (57d)

Compound 57d was prepared according to the procedure reported in step-2 of scheme-29, 2- amino-4-methoxy- 1 H-indolc-3 -carboni trile (57c) (1.3 g, 6.94 mmol) in ethanol (45 mL) using formamidine acetate (5.84 g, 55.6 mmol) and refluxing for 22 h. This gave after workup and purification by reverse phase column chromatography [C18 column (275 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] 5-methoxy-9H- pyrimido[4,5-b]indol-4-amine (57d) (0.9 g, 61% yield) HC1 salt as a pale yellow solid; Ή NMR (300 MHz, DMSO -ck) δ 12.97 (s, 1H), 8.60 (s, 2H), 8.55 (s, 1H), 8.40 (d, J= 8.7 Hz, 1H), 7.09 (d, J = 2.3 Hz, 1H), 7.03 (dd, J= 8.7, 2.4 Hz, 1H), 3.87 (s, 3H); MS (ES+): 215.10 (M+l);

Step-4: Preparation of tort-butyl 2-(4-amino-5-methoxy-9H-pyrimido[4,5-b]indol-9- yl)acetate (57e)

Compound 57e was prepared according to the procedure reported in step-2 of scheme- 16, from HC1 salt of 5 -methoxy-9H-py rimido [4,5 -b] indol-4-amine (57d) (810 mg, 3.23 mmol) in DMF (20 mL) using tert- butyl 2-bromoacetate (0.525 mL, 3.55 mmol), CS2CO3 (2316 mg,

7.11 mmol) and stirring at RT for 1.5 h. This gave after workup tort-butyl 2-(4-amino-5- methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetate (57e) (990 mg, 93% yield) as a pale yellow solid; Ή NMR (300 MHz, DMSO-cfe) δ 8.31 - 8.07 (m, 2H), 7.18 - 7.10 (m, 3H), 6.88 (dd, J = 8.6, 2.3 Hz, 1H), 5.10 (s, 2H), 3.84 (s, 3H), 1.41 (s, 9H); MS (ES+): 329.20 (M+l).

Step-5: Preparation of 2-(4-amino-5-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (57f)

Compound 57f was prepared according to the procedure reported in step-2 of scheme- 1, from tort-butyl 2-(4-amino-5-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetate (57e) (200 mg, 0.609 mmol) using 20% TFA in DCM (3496 pL, 9.14 mmol)) and stirring at RT for 16 h. This gave after workup 2-(4-amino-5 -methoxy-9H-pyrimido [4,5 -b] indol-9-yl)acetic acid (57f) (225 mg, 96% yield) TFA salt as a white solid; Ή NMR (300 MHz, DMSO-afe) δ 8.53 (s, 1H), 8.45 - 8.34 (m, 2H), 7.44 (d, ./= 2.2 Hz, 1H), 7.05 (dd, J= 8.7, 2.2 Hz, 1H), 5.26 (s, 2H), 3.88 (s, 3H); MS (ES+): 273.10 (M+l). Step-6: Preparation of (lR,3S,5R)-2-(2-(4-amino-5-methoxy-9H-pyrimido[4,5-b]indol-9 - yl)acetyl)-N -(6-bromopyridin-2-y l)-2-azabicyclo [3.1.0]hexane-3-carboxamide (57g)

Compound 57g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-5-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (57f) (50 mg, 0.129 mmol) in DMF (1.5 mL) using TFA salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (4a) (51.3 mg, 0.129 mmol), HATU (73.8 mg, 0.194 mmol), DIPEA (0.113 mL, 0.647 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-5-methoxy-9H-pyrimido[4,5-b]indol-9 -yl)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (57g) (35 mg, 50% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ds) δ 10.74 (s, 1H, D2O exchangeable),

8.53 (s, 1H), 8.42 - 8.19 (m, 3H, 2H DzO exchangeable), 8.02 (d, J= 8.2 Hz, 1H), 7.71 (t, J= 8.0 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.25 (d, J= 2.3 Hz, 1H), 7.04 (dd, J = 8.7, 2.2 Hz, 1H), 5.71 (d, J= 17.2 Hz, 1H), 5.42 (d, J= 17.2 Hz, 1H), 4.42 (dd, J= 9.0, 5.6 Hz, 1H), 3.97 - 3.86 (m, 4H), 2.28 (m, 2H), 1.99 - 1.86 (m, 1H), 1.08 (m, 1H), 0.81 - 0.70 (m, 1H). MS (ES+): 536.1 (M+l); 558.1 (M+Na); (ES-): 534.1 (M-l); Analysis calculated for C24H22BrN ₇ 0 ₃ 1.5H20.1HC1: C, 48.05; H, 4.37; Cl, 5.91; N, 16.34; Found: C, 48.01; H, 4.33; Cl, 5.97; N, 16.16.

Scheme 58

58c

Preparation of (lR,3S,5R)-2-(2-(6-acetyl-4-amino-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamid e (58c)

Step-1: Preparation of ethyl 2-(6-acety]-4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetate (58a)

To a suspension of ethyl 2-(4-amino-6-bromo-9H-pyiimido[4,5-b]indol-9-yl)acetate (48a) (200 mg, 0.573 mmol) in toluene (8 mL) was added tributy 1( 1 -ethoxyviny l)stannane (0.279 mL, 0.802 mmol) and the mixture was degassed and filled with nitrogen followed by addition of Pd(PPlti)4 (132 mg, 0.115 mmol) and heating for 14 h at 120 °C. Reaction mixture was cooled to RT, diluted with ethyl acetate (150 mL), treated with IN HC1 (30 mL), water (30 mL) followed by stirring at RT for 15 min. The mixture was treated with 2 M K2CO3, extracted, and separated. The organic layer was washed with brine (60 mL), dried, filtered and concentrated in vacuum. The residue obtained was purified by flash column chromatograph [silica gel (24 g), eluting with methanol in DCM (0-5%)] to afford ethyl 2-(6- acety l-4-amino-9H-pyrimido [4, 5 -b] indol-9-y l)acetate (58a) (20 mg, 11% yield) as a white solid; 1H NMR (300 MHz, DMS0 ^~ </6) δ 8. 96 (d, J= 1. 6 Hz, 1H), 8. 34 (s, 1H), 8.01 (dd, J= 8.6, 1. 6 Hz, 1H) , 7. 72 (d, J= 8. 7 Hz, 1H), 7. 60 (s, 2H), 5. 29 (s, 2H) , 4. 14 (q, J= 7. 1 Hz, 2H), 2. 71 (s, 3H), 1. 20 (t, J= 7. 1 Hz, 3H) ; MS (ES+): 313.10 (M+l).

Step-2: Preparation of 2-(6-acetyl-4-amino-9H-pyrimido[45-b]indol-9-yl)acetic acid (58b) Compound 58b was prepared according to the procedure reported in step-4 of scheme- 17, from ethyl 2-(6-acetyl-4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetate (58a) (18 mg, 0.058 mmol) in THE (3 mL) and methanol (3 mL) using a solution of lithium hydroxide hydrate (14.81 mg, 0.346 mmol) in water (3 mL) and stirring at RT for 14 h. This gave after workup 2-(6-acetyl-4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (58b) (17 mg, 100 %) which was used as such in next step-3 without further purification; MS (ES+): 285.10 (M+l), (ES-): 283.0 (M-l)

Step-3: Preparation of (lR,3S,5R)-2-(2-(6-acetyl-4-amino-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (58c)

Compound 58c was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(6-acetyl-4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (58b) (17 mg, 0.058 mmol) in DMF (8 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (4a) (74 mg, 0.232 mmol), HATU (88 mg, 0.232 mmol), DIPEA (0.061 mL, 0.348 mmol) and stirring at RT for 20 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 5%] followed by conversion of product obtained to HC1 salt by dissolving in acetonitrile (2 mL) and 0.1% aq. HC1 (15 mL) and lyophilization (lR,3S,5R)-2-(2-(6-acetyl- 4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyrid in-2-yl)-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (58c) (27 mg, 85% yield) HC1 salt as an off-white solid; ¾ NMR (300 MHz, DMSO-cfe) δ 10.76 (s, 1H, D ₂ 0 exchangeable), 9.09 (d, J = 1.6 Hz, 1H), 8.73 - 8.50 (m, 3H, 2H DzO exchangeable), 8.11 (dd, J= 8.7, 1.6 Hz, 1H), 8.00 (d, J= 8.2 Hz, 1H), 7.77 (d, J= 8.7 Hz, 1H), 7.70 (t, ./= 8.0 Hz, 1H), 7.31 (d, J= 7.7 Hz, 1H), 5.79 (d, J= 17.3 Hz, 1H), 5.45 (d, J= 17.3 Hz, 1H), 4.41 (dd, J= 9.0, 5.6 Hz, 1H), 4.00 - 3.84 (m, 1H), 2.72 (s, 3H), 2.39 - 2.12 (m, 2H), 1.99 - 1.82 (m, 1H), 1.14 - 1.01 (m, 1H), 0.89 - 0.71 (m, 1H); MS (ES+): 548.10 & 550.10 (M+l); MS (ES-): 546.00 & 548.10 (M-l).

Scheme 59

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-vinyl-9H-pyrimido[4,5-b]indol-9-y l)acetyl)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (59c)

Step-1: Preparation of ethyl 2-(4-amino-6-vinyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (59a)

To a degassed solution of ethyl 2-(4-amino-6-bromo-9H-pyrimido [4,5 -b] indol-9-yl)acetate (48a) (200 mg, 0.573 mmol) in dioxane (8 mL) was added potassium vinyltrifluoroborate (153 mg, 1.146 mmol), Pd(PPh.i)4 (132 mg, 0.115 mmol), a solution of K2CO3 (158 mg, 1.146 mmol) in water (2.3 mL) and heated at 80 °C for 20 h under nitrogen. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (50 mL), brine (50 mL), dried, filtered and concentrated in vacuum. The residue obtained was purified by flash column chromatography [silica gel (25 g) eluting with 10% methanol in ethyl acetate in hexanes from 0 - 50%] to afford ethyl 2-(4-amino-6-vinyl-9H-pyrimido[4,5-b]indol-9- yl)acetate (59a) (82 mg, 48% yield) as a light yellow solid; Ή NMR (300 MHz, DMSO-t/6) δ 8.49 (s, 1H), 8.28 (s, 1H), 7.56 (d ,J= 8.5 Hz, 1H), 7.50 (dd,7= 8.8, 1.5 Hz, 1H), 7.38 (s, 2H), 6.84 (dd, J= 17.7, 11.0 Hz, 1H), 6.03 - 5.95 (m, 1H), 5.29 - 5.16 (m, 3H), 4.14 (q, J= 7.1 Hz, 2H), 1.20 (t, J= 7.1 Hz, 3H); MS (ES+): 297.10 (M+l).

Step-2: Preparation of 2-(4-amino-6-vinyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (59b)

Compound 59b was prepared according to the procedure reported in step-4 of scheme- 17, from ethyl 2 (4 amino 6 vinyl 9H pyrimido[45 b]indol 9 yl)acetate (59a) (80 mg 0270 mmol) in THF (3 mL) and methanol (3 mL) using a solution of lithium hydroxide hydrate (69.4 mg, 1.620 mmol) in water (3 mL) and stirring at RT for 20 h. This gave after workup 2- (4-amino-6-vinyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (59b) (72 mg, 100 %) which was used as such in next step-3 without further purification; MS (ES+): 269.10 (M+l), (ES-): 267.0 (M-l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-vinyl-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (59c)

Compound 59c was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-6-vinyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (59b) (72 mg, 0.27 mmol) in DMF (12 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (4a) (172 mg, 0.540 mmol), HATU (308 mg, 0.810 mmol) DIPEA (0.235 mL, 1.350 mmol) and stirring at RT for 20 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH in DCM from 0 - 5%] followed by conversion of product obtained to HC1 salt by dissolving in acetonitrile (5 mL) and 0.1% aq. HC1 (30 mL) and lyophilization (lR,3S,5R)-2-(2-(4-amino- 6-vinyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyrid in-2-yl)-2- azabicyclo[3.1.OJhexane-3-carboxamide (59c) (54 mg, 38% yield) HC1 salt as a light brown solid; ¾NMR (300 MHz, DMSO-ofe) δ 10.76 (s, 1H, DzO exchangeable), 8.60 (s, 1H), 8.54 (s, 1H), 8.36 (s, 2H, DzO exchangeable), 8.01 (d, J= 8.2 Hz, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.63 (s, 2H), 7.32 (d, J= 7.7 Hz, 1H), 6.86 (dd, J= 17.8, 10.8 Hz, 1H), 6.01 (d, J= 17.7 Hz, 1H), 5.72 (d,J= 17.5 Hz, 1H), 5.39 (d,J= 17.1 Hz, 1H), 5.29 (d,J= 11.0 Hz, 1H), 4.47 - 4.36 (m, 1H), 3.96 - 3.85 (m, 1H), 2.43 - 2.13 (m, 2H), 2.00 - 1.83 (m, 1H), 1.14 - 0.99 (m, 1H), 0.85 - 0.67 (m, 1H); MS (ES+): 532.10 & 534.10 (M+l); MS (ES-): 530.05 & 532.10 (M-l); Analysis calculated for CzjHzzBrNzOz.1.0HC1.2.25HzO: C, 49.27; H, 4.55; Cl, 5.82; N, 16.09; Found: C, 49.02; H, 4.49; Cl, 5.61; N, 16.04.

Scheme 60

Preparation of 4-amino-9-(2-((IR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]i ndole-6-carboxamide (60c)

Step-1: Preparation of ethyl 2-(4-amino-6-carbamoyl-9H-pyrimido[4,5-b]indol-9-yl)acetate

(60a)

A suspension of ethyl 2-(4-amino-6-cyano-9H-pyrimido [4,5 -b] indol-9-y l)acetate (49a) (70 mg, 0.237 mmol) in ethanol (6 mL) was treated with cone. NH4OH (2.25 mL) followed by- hydrogen peroxide (0.084 mL, 0.948 mmol) and stirred at RT for 48 h. The solid obtained was collected by filtration, washed with ethanol and dried to obtain ethyl 2-(4-amino-6- carbamoyl-9H-pyiimido[4,5-b]indol-9-yl)acetate (60a) (40 mg, 54%) as a white solid residue which was used as such for next step; MS (ES+): 314.10 (M+l).

Step-2: Preparation of 2-(4-amino-6-carbamoyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (60b)

Compound 60b was prepared according to the procedure reported in step-4 of scheme- 17, from ethyl 2-(4-ami no-6-carbamoyl-9H-pyrim ido [4,5 -b] indol-9-yl )acetate (60a) (38 mg, 0.121 mmol) in THF (2 mL) and methanol (2 mL) using a solution of lithium hydroxide hydrate (31.2 mg, 0.728 mmol) in water (2 mL) and stirring at RT for 68 h. This gave after k 2 (4 i 6 b l 9H i id [45 b] i d l 9 l) ti id (60b) (35 100 %) which was used as such in next step-3 without further purification; MS (ES+): 286.10 (M+l), (ES-): 284.0 (M-l).

Step-3: Preparation of 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]i ndole-6-carboxamide (60c)

Compound 60c was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-6-carbamoyl-9H-pyrimido [4,5 -b] indol-9-y l)acetic acid (60b) (34.5 mg, 0.121 mmol) in DMF (8 mL) using HC1 salt of ( 1R,3 S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1 ,0]hexane-3-caiboxamide (4a) (77 mg, 0.242 mmol), HATU (92 mg, 0.242 mmol) DIPEA (0.105 mL, 0.605 mmol) and stirring at RT for 19 h. This gave after workup and purification by flash column chromatography [silica gel (4 g), eluting with MeOH in DCM from 0 - 10%] followed by purification by reverse phase column chromatography [Cl 8 column, eluting with ACN in water (containing 0.1% HC1) from 0-100%] of 4-amino-9-(2- ((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[ 3.1.0]hexan-2-yl)-2- oxoethy l)-9H-pyri mi do [4,5 -b] indole-6-carboxam ide (60c) (12 mg, 18% yield) HC1 salt as a white solid; *H NMR (300 MHz, DMSO-ifc) δ 10.76 (s, 1H), 9.03 (s, 1H), 8.57 (s, 1H), 8.36 (s, 2H, D2O exchangeable), 8.08 - 7.97 (m, 2H), 7.89 (s, 1H, D2O exchangeable), 7.78 - 7.63 (m, 2H), 7.47 (s, 1H, DzO exchangeable), 7.31 (d, J= 7.7 Hz, 1H), 5.76 (d,7= 17.3 Hz, 1H), 5.42 (d, J= 17.4 Hz, 1H), 4.42 (dd, J= 9.2, 5.5 Hz, 1H), 3.95 - 3.86 (m, 1H), 2.41 - 2.10 (m, 2H), 2.01 - 1.74 (m, 1H), 1.18 - 0.98 (m, 1H), 0.87 - 0.69 (m, 1H); MS (ES+): 549.10 & 551.10 (M+l); MS (ES-): 547.05 & 549.10 (M-l).

Scheme 61

48d 61a

Preparation of (lR,3S,5R)-N-(6-bromopyridin-2-yI)-2-(2-(4,6-diamino-9H-pyri mido[4,5- b]indol-9-yl)acetyl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (61a) Compound 61a was prepared according to the procedure reported in step-2 of scheme- 1, from tort-butyl (4-amino-9-(2-(( lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoetiiyl)-9H-pyrimido[4,5-b] indol-6-yl)carbamate (48d) (6 mg, 9.65 pmol) in DCM (5 mL) using TFA. This gave after workup and purification by reverse phase column chromatography [C18 column, eluting with ACN in water (containing 0.1% HC1) from 0-100%](lR,3S,5R)-N-(6-bromopyridin-2-yl)-2-(2-(4,6-diamino- 9H- pyrimido[4,5-b]indol-9-yl)acetyl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (61a) (3.9 mg, 77% yield) HC1 salt as a white solid; . Ή NMR (300 MHz, DMSO-tife) δ 10.76 (s, 1H), 8.47 (s, 1H), 8.28 (s, 1H), 8.09 (s, 2H), 8.01 (d, J= 8.2 Hz, 1H), 7.70 (t ,J= 8.1 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.46 - 7.35 (m, 1H), 7.32 (d, J= 7.6 Hz, 1H), 5.69 (d, J= 17.4 Hz, 1H), 5.37 (d, J= 17.4 Hz, 1H), 4.48 - 4.34 (m, 1H), 3.97 - 3.83 (m, 1H), 2.39 - 2.09 (m, 2H), 2.05 - 1.73 (m, 1H), 1.17 - 0.99 (m, 1H), 0.84 - 0.67 (m, 1H); MS (ES+): 521.10 & 523.10 (M+l).

Scheme 62

62c

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-phenyl-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamid e (62c)

Step-1: Preparation of ethyl 2-(4-amino-6-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (62a)

A degassed solution of ethyl 2-(4-amino-6-bromo-9H-pyrimido[45-b]indol-9-yl)acetate was treated with cesium carbonate (210 mg, 0.644 mmol) in water (1.8 mL), Pd(PPh3)2Ch (60.3 mg, 0.086 mmol) and heated at 100 °C for 14 h under nitrogen. The reaction mixture was diluted with ethyl acetate/methanol (2:1, 75 mL), filtered, washed with ethyl acetate/methanol (2: 1), and the filtrate was concentrated in vacuum. The residue obtained was purified by flash column chromatography [SiChgel (25 g), eluting with MeOH in DCM from 5-40%] to afford ethyl 2-(4-amino-6-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (62a) (86 mg, 58% yield) as an off-white solid; MS (ES+): 347.15.

Step-2: Preparation of2-(4-amino-6-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (62b)

Compound 62b was prepared according to the procedure reported in step-4 of scheme- 17, from ethyl 2-(4-amino-6-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (62a) (80 mg, 0.231 mmol) in THE (2 mL) and methanol (2 mL) using a solution of lithium hydroxide hydrate (59.3 mg, 1.386 mmol) in water (2 mL) and stirring at RT for 19 h. This gave after workup 2- (4-amino-6-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (62b) (59 mg, 80 %) which was used as such in next step-3 without further purification; MS (ES+): 319.10 (M+l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-phenyl-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (62c)

Compound 62c was prepared according to the procedure reported in step-3 of scheme- 1 , from 2-(4-amino-6-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (62b) (59 mg, 0.185 mmol) in DMF (8 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (4a) (89 mg, 0.278 mmol), HATU (141 mg, 0.371 mmol) DIPEA (0.097 mL, 0.556 mmol) and stirring at RT for 21 h. This gave after workup and purification by flash column chromatography [silica gel ( 12 g), eluting with hexanes/10% MeOH in EtOAc in hexanes from 0 - 100%] followed by conversion of product obtained to HC1 salt by dissolving in acetonitrile (2 mL) and 0.1% aq. HC1 (15 mL) and lyophilization (lR,3S,5R)-2-(2-(4-amino-6-phenyl-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (62c) (51.5 mg, 48% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.77 (s, 1H, D ₂ 0 exchangeable), 8.77 (s, 1H), 8.56 (s, 1H), 8.43 (s, 2H, D2O exchangeable), 8.01 (d, J= 8.1 Hz, 1H), 7.90 - 7.80 (m, 3H), 7.79 - 7.66 (m, 2H), 7.55 - 7.47 (m, 2H), 7.42 - 7.36 (m, 1H), 7.32 (d, 7.7 Hz, 1H), 5.77 (d,J= 17.3 Hz, 1H), 5.44 (d, J= 17.3 Hz, 1H), 4.42 (dd,J=

90 5 5 Hz 1H) 3 99 3 86 (m 1H) 242 2 15 (m 2H) 200 1 79 (m 1H) 1 16 099 (m, 1H), 0.85 - 0.70 (m, 1H); MS (ES+): 582.10 & 584.20 (M+l); MS (ES-): 580.10 & 582.10 (M-l); Analysis calculated for C29H24BrN ₇ 02.1 0HC1. l.SHzO: C, 53.92; H, 4.37; N, 15.18; Cl, 5.49; Found: C, 54.10; H, 4.48; N, 14.92; Cl, 5.28.

Scheme 63

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(aminomethyl)-9H-pyrimido[4,5-b]i ndol-9- yl)acet>'l)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]he xane-3-carboxamide (63d)

Step-1: Preparation of ethyl/methyl 2-(4-amino-6-((te/7-butoxycarbonylamino)methyl)-9H- pyrimido[4,5-b]indol-9-yl)acetate (63a)

To a solution of ethyl 2-(4-amino-6-cyano-9H-pyrimido[4,5-b]indol-9-yl)acetate (49a) (100 mg, 0.339 mmol) in MeOH (8 mL) cooled with ice/water and was added di-tert-butyl dicafbonate (299 mg, 1.355 mmol), nickel(II) chloride hexahydrate (40.2 mg, 0.169 mmol) followed by sodium borohydride (78 mg, 2.032 mmol) slowly over a period of 5 min and was stirred at RT for 1 h. The reaction mixture was treated with N 1 -(2-aminoethy l)ethane - 1 ,2- diamine (0.148 mL, 1.355 mmol) and stirred for 30 min at RT and concentrated to dryness. The residue obtained was purified by flash column chromatography [silica gel (25 g), with 10% methanol in ethyl acetate in hexanes/ from 0-100%, followed by methanol in dichloromethane from 0-33% and DMA80] to afford a mixture of ethyl/methyl 2-(4-amino-6- ((te t b t b l i ) th l) 9H ri id [45 b]i d l 9 l) t t (63 ) (7 5%) as a colorless gum; MS (ES+): 400.20 (M+l); 386.20 (M+l) and 2-(4-amino-6-(((te/7- butoxycarbonyl)amino)methyl)-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (63b) (15 mg, 12%) as a colorless gum; MS (ES+): 372.20 (M+l), (ES-): 370.15 (M-l).

Step-2: Preparation of 2-(4-arnino-6-(((ter/-butoxycarbonyl)arnino)methyl)-9H-pyrir nido[4,5- b]indol-9-yl)acetic acid (63b)

Compound 63b was prepared according to the procedure reported in step-4 of scheme- 17, from a mixture of ethyl/methyl 2-(4-amino-6-((/er/-butoxycarbonylamino)methyl)-9H- pyrimido[4,5-b]indol-9-yl)acetate (63a) (7 mg, 0.018 mmol) in THF (2 mL) and methanol (2 mL) using a solution of lithium hydroxide hydrate (6 mg, 0.140 mmol) in water (2 mL) and stirring at RT for 19 h. This gave after workup 2-(4-amino-6-(((terf- butoxycaibonyl)amino)methyl)-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (63b) which was used as such in next step-3 without further purification; MS (ES+): 372.20 (M+l), (ES-): 370.10 (M-l).

Step-3: Preparation of tert-butyl ((4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2- yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H- pyrimido[4,5-b]indol-6- yl)methyl)carbamate (63c)

Compound 63c was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-ammo-6-(((tort-butoxycarbonyl)amino)methyl)-9H-pyrimido [4,5-b]indol-9-yl)acetic acid (63b) (21 mg, 0.057 mmol) in DMF (8 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (55 mg, 0.171 mmol), HATU (65 mg, 0.171 mmol), DIPEA (0.05 mL, 0.285 mmol) and stirring at RT for 19 h.

This gave after workup and purification by flash column chromatography [silica gel (12 g), 10% MeOH in EtOAc in hexane from 0 - 100%] terf-butyl ((4-amino-9-(2-((lR,3S,5R)-3- ((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1 ,0]hexan-2-yl)-2-oxoethyl)-9H- pyrimido[4,5-b]indol-6-yl)methyl)carbamate (63c) (8 mg) as an off-white solid; MS (ES+): 635.20 & 637.20 (M+l), (ES-): 633.10 & 635.10 (M-l).

Step-4: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(aminomethyl)-9H-pyrimido[4,5-b]i ndol- 9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (63d)

Compound 63d was prepared according to the procedure reported in step-2 of scheme- 1, from fm-butyl ((4-amino-9-(2-(( lR,3S,5R)-3-((6-bromopyridin-2-yl)caibamoyl)-2- (63c) (8 mg, 0.013 mmol) in DCM (5 mL) using TFA (0.097 mL, 1.259 mmol) and stirring at RT for 21h. This gave after workup and purification by reverse phase column chromatography [C18 column, eluting with ACN in water (containing 0.1% HC1) from 0- 100%](IR,3S,5R)-2-(2-(4-amino-6-(aminomethyl)-9H-pyrimido[4, 5-b]indol-9-yl)acetyl)-N- (6-bromopy ridin-2-yl)-2-azabicy clo[3.1.0]hexane-3-carboxamide (63d) (1.6 mg, 24% yield) HC1 salt as a white solid; Ή NMR (300 MHz, Methanol-at.) 58.56 (s, 1H), 8.51 (d, 7= 1.5 Hz, 1H), 8.05 (d,J= 8.2 Hz, 1H), 7.86 (d, J= 8.5 Hz, 1H), 111 (dd, J= 8.6, 1.7 Hz, 1H), 7.61 (t, J= 8.0 Hz, 1H), 7.26 (dd, J= 7.7, 0.7 Hz, 1H), 5.84 - 5.61 (m, 2H), 4.58 - 4.45 (m, 1H), 4.33 (s, 2H), 3.98 - 3.88 (m, 1H), 2.57 - 2.30 (m, 2H), 2.13 - 1.95 (m, 1H), 1.29 - 1.14 (m, 1H), 0.95 - 0.81 (m, 1H); MS (ES+): 535.10 & 537.10 (M+l).

Scheme 64

Preparation of (2S,4R)- l-(2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetyl)-N-(3-c hloro- 2-fluorobenzyl)-4-fluoropyrrohdine-2-carboxamide (64a)

Compound 64a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-7H-pyrrolo [2,3 -d] pyrimidi n -7 -yl )acetic acid (5c) (158 mg, 0.515 mmol) in DMF (5 mL) using TFA salt of (2S,4R)-N-(3-chloro-2-fluorobenzyl)-4- fluoropyrrohdine-2-carboxamide (7a) (200 mg, 0.515 mmol), HATU (235 mg, 0.617 mmol) DIPEA (0.449 mL, 2.57 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)-1- (2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetyl)-N-(3-chl oro-2-fluorobenzyl)-4- fluoropyrrohdine 2 carboxamide (64a) (115 mg 50% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfe) (a mixture of two rotamers) δ 9.28 (bs, 1H, D2O exchangeable), 9.14 and 8.70 (2t ,J= 5.9 Hz, 1H), 8.54 (bs, 1H, D2O exchangeable), 8.35 and 8.34 (2s, 1H), 7.55 - 7.34 (m, 2H), 7.21 (dt, J= 22.4, 7.6 Hz, 1H), 7.07 (t ,J= 7.9 Hz, 1H), 6.95 (dd, J=

6.0, 3.4 Hz, 1H), 5.62 - 4.55 (m, 3H), 4.39 (td, J= 16.7, 6.9 Hz, 2H), 4.24 (dd, ./= 15.9, 5.7 Hz, 1H), 4.16 - 3.99 (m, 1H), 3.87 (ddd, 37.7, 12.3, 3.0 Hz, 1H), 2.62 - 2.38 (m, 1H), 2.22-1.92 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-zfc) δ -121.32, -121.65, -176.12, -176.32; MS (ES+): 449/451 (M+l).

Scheme 65

Preparation of (2S,4R)-l-(2-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)acety l)-N-(3-chloro-2- fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (65a)

Compound 65a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)acetic acid (2c) (150 mg, 0.49 mmol) in DMF (5 mL) using TFA salt of (2S,4R)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine- 2 -carboxamide (7a) (190 mg, 0.490 mmol), HATU ((224 mg, 0.588 mmol) DIPEA (0.428 mL, 2.449 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)-l-(2-(4- ammopyrrolo[2,l-f][l,2,4]triazin-7-yl)acetyl)-N-(3-chloro-2- fluorobenzyl)-4- fhioropyrrolidine-2-carboxamide (65a) (104 mg, 47.3 % yield) HC1 salt as a white solid; Ή NMR(300 MHz, DMSO-cfe) (a mixture of two rotamers) δ 9.81 (bs, 1H, D2O exchangeable), 9.21 - 8.91 (m, 1H, D2O exchangeable), 8.65 (t, J= 5.9 Hz, 1H), 8.14 and 8.12 (2s, 1H), 7.54 - 7.38 (m, 2H), 7.38 - 7.26 (m, 1H), 7.14 (dt, J= 15.6, 7.9 Hz, 1H), 6.78 and 6.66 (2d, J= 4.5 Hz, 1H), 5.56 - 5.20 (m, 1H), 4.51 - 4.22 (m, 3H), 4.18 - 3.34 (m, 4H), 2.63 - 2.38 (m, 176.45; MS (ES+) 449/451 (M+l); Analysis calculated for C20H19CIF2N6O2.HCI.I.75H2O: C, 46.48; H, 4.58; Cl, 13.72; N, 16.26 Found: C, 46.64; H, 4.31; Cl, 13.61; N, 15.94.

Scheme 66

Preparation of (lR,3S,5R)-2-(2-(4-aminopyrrolo[2,l -f][l,2,4]triazin-7-yl)acetyl)-N-(3- chloro-2-fluorobenzyl)-2-azabicyclo [3.1 ,0]hexane-3-carboxamide (66b)

Compound 66b was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-aminopyirolo[2,l-f][l,2,4]triazin-7-yl)acetic acid (2c) (100 mg, 0.327 mmol) in DMF (5 mL) using TFA salt of ( 1 R,3 S,5 R)-N-(3 -chloro-2-fluorobenzyl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (66a) (125 mg, 0.327 mmol; prepared according to the procedure reported by Wiles, Jason A. et al. PCT Int. Appl. (2017), WO 2017035349 A1 20170302), HATU (149 mg, 0.392 mmol) DIPEA (0.285 mL, 1.633 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%](lR,3S,5R)-2-(2-(4-aminopyrrolo[2,l-f][l,2,4]triazin- 7-yl)acetyl)- N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[3.1.0]hexane-3-carb oxamide (66b) (59 mg, 40.8 % yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-dis) (a mixture of two rotamers) δ 9.93 (s, 1H, DzO exchangeable), 9.14 (s, 1H, DzO exchangeable), 8.46 (t, J= 5.9 Hz, 1H, DzO exchangeable), 8.17 (s, 1H), 7.55 - 7.41 (m, 2H), 7.25 (t, 1H), 7.14 (t, J= 7.8 Hz, 1H), 6.82 (d, J= 4.6 Hz, 1H), 4.42 - 4.12 (m, 5H), 3.67 - 3.55 (m, 1H), 2.31 - 2.05 (m, 2H), 1.90 - 1.70 (m, 1H), 1.04 - 0.86 (m, 1H), 0.70 - 0.53 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-i¾) δ -121.74; MS (ES+): 443/445 (M+l); Analysis calculated for C21H20CffN6O2.HCL2.5H2O: C, 48.10; H, 5.00; Cl, 13.52; N, 16.03; Found: C, 48.08; H, 4.82; Cl, 13.96; N, 15.88.

Preparation of (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(3-chloro-2 -fluorobenzyl)- 5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (67c)

Compound 67c was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(6-amino-9H-purin-9-yl)acetic acid (67a) (65 mg, 0.337 mmol) in DMF (1.5 mL) and DMSO (0.5 mL) using (lR,3S,5R)-N-(3-chloro-2-fluorobenzyl)-5-methyl-2- azabicyclo[3.1.0]hexane-3-caiboxamide (67b) (114 mg, 0.404 mmol), HATU (96 mg, 0.252 mmol), DIPEA (0.293 mL, 1.683 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(3-chloro-2 -fluorobenzyl)-5-methyl-2- azabicyclo[3.1.0]hexane-3-carboxamide (67c) (92mg, 60% yield) HC1 salt as a white solid;

Ή NMR (300 MHz, DMSO -ck) δ 8.52 (t, ./= 5.9 Hz, 1H, DzO exchangeable), 8.39 (s, 1H), 8.33 (s, 1H), 7.47 (td, J= 7.6, 1.7 Hz, 1H), 7.28 - 7.19 (m, 1H), 7.13 (t, 7.9 Hz, 1H), 5.46

(d, J= 17.1 Hz, 1H), 5.20 (d, J= 17.0 Hz, 1H), 4.33 (d, J = 5.8 Hz, 2H), 4.24 (dd, J= 9.2, 4.7 Hz, 1H), 3.46 (dd, J= 5.5, 2.4 Hz, 1H), 2.40 (dd, J= 13.2, 9.2 Hz, 1H), 1.91 (dd, J= 13.2, 4.7 Hz, 1H), 1.25 (s, 3H), 1.00 (t, 5.3 Hz, 1H), 0.89 (dd,/= 5.3, 2.4 Hz, 1H); ¹⁹ FNMR

(282 MHz, DMSO-ifc) δ -121.57. MS (ES+): 458.1 (M+l), 480.1 (M+Na); (ES-): 456.7 (M- 1), 492.5 (M+Cl); Analysis calculated for C21H21CIFN7O2.HCU.75H2O: C, 47.96; H, 4.89; Cl, 13.48; N, 18.64; Found: C, 47.91; H, 4.55; Cl, 13.17; N, 18.43.

Scheme 68

Preparation of (2S,4R)-l-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(6-bromo-3-met hylpyridin-2- yl)-4-fluoropyrrolidine-2-carboxamide (68a)

Compound 68a was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(6-amino-9H-purin-9-yl)acetic acid (67a) (65 mg, 0.337 mmol) in DMF (1.5 mL) and DMSO (0.5 mL) using (2S,4R)-N-(6-bromo-3-methylpyridin-2-yl)-4-fluoropyrTolidine -2- carboxamide (3a) (102 mg, 0.337 mmol), HATU (192 mg, 0.505 mmol), DIPEA (0.293 mL, 1.683 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)-l-(2-(6-amino-9H- purin-9-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-4-fluoro pyrrolidine-2-carboxamide (68a) (45 mg, 28% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-tife) δ (a mixture of two rotamers) 10.92 (s) and 10.52 (s) (2s, 1H) (D2O exchangeable), 9.50 (s, 1H) (DzO exchangeable), 8.76 (s, 1H) (D2O exchangeable), 8.46 (m, J= 3.0 Hz, 1H), 8.39 (s,

1H), 7.71 (d, J= 8.0 Hz,) and 7.61 (d ,J= 8.0 Hz) (2d, 1H), 7.52 (d,J= 7.9 Hz) and 7.43 (d, J= 7.9 Hz) (2d, 1H), 5.71 - 5.17 (m, 3H), 4.60 (t, J= 8.5 Hz, 1H), 4.29 - 3.81 (m, 2H), 2.74 - 2.52 (m, 1H), 2.30 - 2.04 (m, 1H), 2.02 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -175.88; MS (ES+): 477.1 (M+l), 499.1 (M+Na); (ES-): 475.6 (M-l); Analysis calculated for Ci8Hi8BrFN ₈ 02.1.2HC1.2.5H20: C, 38.19; H, 4.31; Cl, 7.52; N, 19.79; Found: C: 38.33; H, 3.98; Cl, 7.31; N, 19.64.

Scheme 69

Preparation of (2S,4R)-l-(2-(4-aminopyrrolo[2,l-f][l,2,4]triazm-7-yl)acetyl )-N-(6- bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxantide (69a)

Compound 69a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-aminopyrrolo[2, l-f][l,2,4Jtriazin-7-yl)acetic acid (2c) (75 mg, 0.245 mmol) in DMF (5 mL) using TFA salt of (2S,4R)-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2- carboxamide (5d) (98 mg, 0.294 mmol), HATU (112 mg, 0.294 mmol) and DIPEA (158 mg, 1.225 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), MeOH in DCM from 0 - 5%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-60%] (2S,4R)-l-(2-(4-aminopyrrolo[2,l- f][l,2,4]triazin-7-yl)acetyl)-N-(6-bromopyridin-2-yl)-4-fluo ropyrrolidine-2-carboxamide (69a) (40 mg, 35 % yield) as a white solid; Ή NMR (300 MHz, DMSO-efe) δ (a mixture of rotamers) 11.28 (s) and 10.99 (s) (2s, 1H, DzO exchangeable), 9.86 (s, 1H, D2O exchangeable), 9.09 (s, 1H, D2O exchangeable), 8.16 (s, 1H), 8.11 - 7.99 (m, 1H), 7.81 - 7.70 (m, 1H), 7.51 - 7.39 (m, 1H), 7.35 (d, J= 8.2 Hz, 1H), 6.75 (dd,J= 12.6, 4.6 Hz, 1H), 5.45 (dt, J= 52.6, 2.9 Hz, 1H), 4.64 (t, J= 8.5 Hz, 1H), 4.18 - 3.97 (m, 2H), 3.90 (dd, J= 12.5, 3.1 Hz, 1H), 3.81 - 3.73 (m, 1H), 2.61 - 2.40 (m, 1H), 2.30 - 1.95 (m, 1H); ¹⁹ FNMR (282 MHz, DMSO-ffc) δ -175.77, -176.09; MS (ES+): 462.0 (M+l); (ES-): 460.0 (M-l).

Scheme 70

Preparation of ( 1 R,3S,5R)-2-(2-(4-aminopyrrolo[2, 1 -f] [ 1 ,2,4]triazin-7-yl)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (70a)

Compound 70a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)acetic acid (2c) (75 mg, 0.245 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.OJhexane-3-carboxamide (4a) (78 mg, 0.245 mmol), HATH (112 mg, 0.294 mmol), DIPEA (158 mg, 1.225 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 5%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-60%] (lR,3S,5R)-2-(2-(4-aminopyrrolo[2, 1 -f][l,2,4]triazin-7-yl)acetyl)-N-(6-bromopyridin-2-yl)- 2-azabicyclo[3.1.0]hexane-3-carboxamide (70a) (64 mg, 57% yield) HC1 salt as awhite solid; Ή NMR (300 MHz, DMSO-afe) δ 10.75 (s, 1H, DzO exchangeable), 9.91 (s, 1H, DzO exchangeable), 9.13 (s, 1H, DzO exchangeable), 8.19 (s, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.48 (d, J = 4.6 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 6.82 (d, J = 4.6 Hz, 1H), 4.43 (dd, J = 9.0, 5.5 Hz, 1H), 4.31 (d, J = 16.9 Hz, 1H), 4.15 (d, J = 16.9 Hz, 1H), 3.71 - 3.66 (m, 1H), 2.39 - 2.12 (m, 2H), 1.89 - 1.72 (m, 1H), 1.02 - 0.90 (m, 1H), 0.66 - 0.52 (m, 1H); MS (ES+): 456.0 (M+l); (ES-) : 454.0 (M-l); Analysis calculated for CipHisBrNzOz.1.25HC1.2.25HzO: C, 42.07; H, 4.41; Cl, 8.17; N, 18.08; Found: C, 42.33; H, 4.10; Cl, 7.92; N, 17.95.

Scheme 71

H ₂ N N

2c

71a

Preparation of (lR,3S,5R)-2-(2-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)ac etyl)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (71a)

Compound 71a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-aminopyrrolo[2, l-f][l,2,4Jtriazin-7-yl)acetic acid (2c) (75mg, 0.245 mmol) in DMF (2 mL) and using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-5-methyl-2- azabicyclo[3.1 ,0]hexane-3-caiboxamide (8a) (81 mg, 0.245 mmol), HATU (140 mg, 0.367 mmol), DIPEA (0.213 mL, 1.225 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)ac etyl)-N-(6-bromopyridin-2- _j 'l)- 5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (71a) (59 mg, 51% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.75 (s, 1H, D2O exchangeable), 9.98 (s, 1H, D2O exchangeable), 9.18 (s, 1H, D2O exchangeable), 8.19 (s, 1H), 8.05 (d,J= 8.2 Hz, 1H), 7.73 (t, ,7= 8.0 Hz, 1H), 7.50 (d, ,7 = 4.6 Hz, 1H), 7.34 (d, .7= 7.7 Hz, 1H), 6.81 (d, ,7 = 4.6 Hz, 1H), 4.39 (dd,J= 9.1, 5.7 Hz, 1H), 4.28 (d, J= 17.0 Hz, 1H), 4.10 (d ,J= 16.9 Hz, 1H), 3.46 (dd,J= 5.6, 2.3 Hz, 1H), 2.43 (dd,.7= 13.2, 9.1 Hz, 1H), 1.96 (dd,J= 13.2, 5.7 Hz,

1H), 1.24 (s, 3H), 0.89 (t, J= 5.4 Hz, 1H), 0.75 (dd, J= 5.4, 2.3 Hz, 1H); MS (ES+): 469.9 (M+l); (ES-): 468.0 (M-l); Analysis calculated for C2oH2oBrN ₇ 02.1.5H _z O.1.15HC1: C,

44.54; H, 4.51; Cl, 7.56; N, 18.18; Found: C, 44.79; H, 4.29; Cl, 7.53; N, 18.23.

Scheme 72

2c 72a

Preparation of ( 1 R,3S,5R)-2-(2-(4-aminopytrolo[2, 1 -f] [ 1 ,2,4]triazin-7-yl)acetyl)-N-(6- bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexa ne-3-carboxamide (72a)

Compound 72a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-aminopyrrolo[2, l-f][l,2,4]triazin-7-yl)acetic acid (2c) (75mg, 0.245 mmol) in DMF (2 mL) and using HC1 salt of (lR,3S,5R)-N-(6-bromo-3-methylpyridin-2-yl)-5- methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (10a) (85 mg, 0.245 mmol), HATU (140 mg, 0.367 mmol), DIPEA (0.213 mL, 1.225 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0- 100%] (1R,3 S,5R)-2-(2-(4-aminopytrolo[2, 1 -f] [ 1 ,2,4]triazin-7-yl)acetyl)-N-(6-bromo-3- methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-cai boxamide (72a) (68mg, 57.3 % yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ife) δ 10.29 (s, 1H, DzO exchangeable), 10.19 (s, 1H, D2O exchangeable), 9.33 (s, 1H, D2O exchangeable), 8.21 (s, 1H), 7.64 (d, 8.0 Hz, 1H), 7.57 (d, J= 4.6 Hz, 1H), 7.45 (d, J= 7.9 Hz, 1H), 6.83 (d, J=

4.6 Hz, 1H), 4.37 (dd, J= 9.2, 5.2 Hz, 1H), 4.27 (d, J= 17.0 Hz, 1H), 4.13 (d, J= 17.0 Hz, 1H), 3.44 (dd, J= 5.6, 2.4 Hz, 1H), 2.49 - 2.45 (m, 1H), 2.08 (s, 3H), 2.00 (dd, J= 13.3, 5.2 Hz, 1H), 1.26 (s, 3H), 0.91 (t, J= 5.4 Hz, 1H), 0.79 (dd, J= 5.3, 2.4 Hz, 1H); MS (ES+): 484.0 (M+l); (ES-): 482.0 (M-l); Analysis calculated for C2iH22BrN ₇ 02.35H2O.1 5HC1: C, 41.89; H, 5.11; N, 16.28; Found: C, 42.02; H, 5.02; N, 15.97.

Scheme 73

Preparation of (lR,3S,5R)-2-(2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ace tyl)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (73a)

Compound 73a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (5c) (75mg, 0.245 mmol) in DMF (2 mL) and using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-5-methyl- 2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (81 mg, 0.245 mmol), HATU (140 mg, 0.367 mmol), DIPEA (0.213 mL, 1.225 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-ammo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acet yl)-N-(6-bromopyridin-2- yl)-5 -methyl-2-azabicyclo [3.1.0]hexane-3-carboxamide (73a) (72mg, 63 % yield) HC1 salt as a white solid; ΉΝΜΡ (300 MHz, DMSO-ifc) δ 10.81 (s, 1H, D2O exchangeable), 9.33 (s,

1H, D2O exchangeable), 8.54 (s, 1H, D2O exchangeable), 8.38 (s, 1H), 8.04 (d, J= 8.2 Hz, 1H), 7.73 (t, J= 8.0 Hz, 1H), 7.44 (d, J= 3.6 Hz, 1H), 7.34 (d, J= 7.7 Hz, 1H), 6.95 (d, J= 3.6 Hz, 1H), 5.49 (d ,J= 17.1 Hz, 1H), 5.19 (d,J= 17.0 Hz, 1H), 4.40 (dd, .7= 9.1, 5.8 Hz, 1H), 3.54 (dd, .7= 5.6, 2.3 Hz, 1H), 2.46 - 2.36 (m, 1H), 1.97 (dd,J= 13.2, 5.8 Hz, 1H), 1.28 (s, 3H), 0.97 (t, J= 5.5 Hz, 1H), 0.84 (dd, J= 5.4, 2.4 Hz, 1H); MS (ES+): 470.0 (M+l); (ES-): 468.0 (M-l); Analysis calculated for C2oH2oBrN ₇ 02.1.75H20.1.1HC1: C, 44.32; H, 4.58; Cl, 7.20; N, 18.09; Found: C, 43.99; H, 4.67; Cl, 6.95; N, 17.78.

Scheme 74

Preparation of (lR,3S,5R)-2-(2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ace tyl)-N-(6- bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexa ne-3-carboxamide (74a)

Compound 74a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (5c) (75mg, 0.245 mmol) in DMF (2 mL) and using HC1 salt of (lR,3S,5R)-N-(6-bromo-3-methylpyridin-2-yl)- 5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (10a) (85 mg, 0.245 mmol), HATU (140 mg, 0.367 mmol), DIPEA (0.213 mL, 1.225 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography (silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ace tyl)-N-(6-bromo-3- methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3 -carboxamide (74a) (63 mg, 53% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.32 (s, 1H, D ₂ 0 exchangeable), 9.41 (s, 1H, D2O exchangeable), 8.58 (s, 1H, D2O exchangeable), 8.38 (s,

1H), 7.64 (d, J= 8.0 Hz, 1H), 7.49 - 7.38 (m, 2H), 6.99 (d, J= 3.5 Hz, 1H), 5.47 (d, J= 17.0 Hz, 1H), 5.20 (d,J= 16.9 Hz, 1H), 4.38 (dd, J= 9.2, 5.1 Hz, 1H), 3.55 - 3.47 (m, 1H), 2.50 - 2.44 (m, 1H), 2.06 (s, 3H), 2.04 - 1.96 (m, 1H), 1.30 (s, 3H), 1.00 (t, J= 5.4 Hz, 1H), 0.90 (dd, J= 5.3, 2.4 Hz, 1H); MS (ES+): 484.0 (M+l); (ES-): 482.0 (M-l); Analysis calculated for C2iH22BrN ₇ 02.2.5H20.1 55HC1.0.25DMSO: C, 42.78; H, 5.01; Cl, 8.81; N, 16.24;

Found: C, 42.52; H, 5.00; Cl, 8.87; N, 15.99.

Scheme 75

Preparation of (S)-N-(6-bromopyridin-2-yl)-l-(2-(4-(methylamino)-lH-pyrazol o[3,4- djpyrimidin- 1 -yl)acetyl)pyrrolidine-2-carboxamide (75d)

Step-1: Preparation of /erf-butyl 2-(4-(methylamino)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)acetate (75b)

To a solution of tort-butyl 2-(4-chloro-lH-pyrazolo[3,4-d]pyrimidin-l-yl)acetate (75a) (0.3 g, 1.116 mmol; prepared according to the procedure reported by Kotian, Fravin L. et al; From PCX hit. Appl., 2017136395, 10 Aug 2017) in THF (4 mL) was added methan amine in methanol (2.79 mL, 5.58 mmol) and stirred at RT for 2 h. The reaction mixture was concentrated and purified by flash column chromatography [silica gel (12 g), eluting with MeOH/EtOAc (9: 1) in hexanes from 0 to 100%] to afford /erf-butyl 2-(4-(methyl amino)- 1H- pyrazolo[3,4-d]pyrimidin-l -yl)acetate (75b); MS (ES+): 264.4 (M+l), (ES-): 262.3 (M-l). Step-2: Preparation of 2-(4-(methylamino)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)acetic acid

(75c)

Compound 75c was prepared according to the procedure reported in step-2 of scheme- 1, from tort-butyl 2-(4-(methylamino)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)acetate (75b) using TFA (1.720 mL, 22.33 mmol) in DCM (4 mL) and stirring at RT for 4 days. The reaction mixture was concentrated in vacuum and was suspended in toluene (10 mL) and evaporated. This gave after workup 2-(4-(methylamino)- lH-pyrazolo[3,4-d]pyrimidin- 1 -yl)acetic acid (75c) (0.23 g, 99 % yield) as white solid; ¾ NMR (300 MHz, DMSO-tfc) δ 9.43 (s, 1H), 8.40 (s, 1H), 8.25 (s, 1H), 5.16 (s, 2H), 3.06 (d, J= 4.8 Hz, 3H); MS (ES+): 208.3 (M+l).

Step-3: Preparation of (S)-N-(6-bromopyridin-2-yl)-l-(2-(4-(methylamino)-lH-pyrazol o[3,4- djpyrimidin- 1 -yl)acetyl)pyrrolidine-2-carboxamide (75d)

Compound 75d was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-(methylamino)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)acetic acid (75c) (0.08 g, 0.386 mmol) (0.104 g, 0.386 mmol), HATU (0.161 g, 0.425 mmol), DIPEA (0.101 mL, 0.579 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with CMA-80 in chloroform from 0 - 40%] (S)-N- (6-bromopyridin-2-yl)- 1 -( 2-(4-(methy lamino)- 1 H-pyrazolo [3 ,4-d] pyri midin- 1 - yl)acetyl)pyrrolidine-2-carboxamide (75d) (60 mg, 34% yield) as a white solid; 1HNMR (300 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.24 (s, 2H), 8.10 - 7.97 (m, 2H), 7.71 (t, J = 7.9 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 5.24 (s, 2H), 4.52 (dd, J = 8.5, 4.1 Hz, 1H), 3.80 - 3.61 (m, 2H), 2.98 (d, J = 4.5 Hz, 3H), 2.24 - 2.08 (m, 1H), 2.08 - 1.76 (m, 3H); MS (ES+): 459.4, (M+l); (ES-): 457.4, (M-l).

Scheme 76

75c 76b

Preparation of (S)-N-(3-chloro-2-fluorobenzyl)-l-(2-(4-(methylamino)-lH-pyr azolo[3,4- djpyrimidin- 1 -yl)acetyl)pyrrolidine-2-carboxamide (76b)

Compound 76b was prepared according to the procedure reported in step-3 of scheme- 1 , from 2-(4-(methylamino)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)acetic acid (75c) (0.08 g, 0.386 mmol) in DMF (3 mL) using TFA salt of (S)-N-(3-chloro-2-fluorobenzyl)pyrrolidine-2-carboxamide (76a) (0.143 g, 0.386 mmol; prepared according to the procedure reported by Kotian, Pravin L. et al., PCT Int. Appl. (2019), WO 2019195720 A1 20191010.), HATU (0.161 g, 0.425 mmol), DIPEA (0.202 mL, 1.158 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with CMA-80 in chloroform from 0 - 40%] (S)-N-(3-chloro-2-fluorobenzyl)-l-(2-(4-(methylamino)-lH- pyrazolo[3,4-d]pyrimidin-l-yl)acetyl)pyrrolidine-2-carboxami de (76b) (59 mg, 34% yield) as a white solid; 1H NMR (300 MHz, DMSO-ck) δ 8.46 (t, J = 5.9 Hz, 1H), 8.32 - 8.19 (m, 2H), 8.06 (s, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.08 (t, J = 7.9 Hz, 1H), 5.22 (s, 2H), 4.46 - 4.20 (m, 3H), 3.80 - 3.57 (m, 2H), 2.99 (d, J = 4.6 Hz, 3H), 2.17 - 1.70 (m, 4H); ¹⁹ F NMR (282 MHz, DMSO-flk) δ -121.60; MS (ES+): 446.5 (M+l).

Preparation of (S)-l-(2-(4-amino-lH-pyrazolo[3,4-d]pyrimidin-l-j'l)acetyl)- N-(6- bromopyridin-2-yI)pyrrolidine-2-carboxamide (77b)

Compound 77b was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-lH-pyrazolo[3,4-d]pyrimidin-l-yl)acetic acid (77a) (0.05 g, 0.259 mmol; prepared according to the procedure reported by Kotian, Pravin L. et al., PCT Int. Appl. (2017), WO 2017136395 Al 20170810; incorporated by reference) in DMF (3 mL) using (S)-N-(6-bromopyridin-2-yl)pyrrolidine-2-carboxamide (13a) (0.070 g, 0.259 mmol), HATU (0.108 g, 0.285 mmol), DIPEA (0.054 mL, 0.311 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with CMA-80 in chloroform from 0 - 40%] (S)-l-(2-(4-amino-lH-pyrazolo[3,4-d]pyrimidin- l-yl)acetyl)-N-(6-bromopyridin-2-yl)pyrrolidine-2-carboxamid e (77b) (43 mg, 37% yield) as a white solid; ΉΝΜΚ (300 MHz, DMSO-de) δ 10.89 (s, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 8.03 (d, J= 8.2 Hz, 1H), 7.71 (t, J= 7.9 Hz, 1H), 7.32 (d, J= 7.6 Hz, 1H), 5.23 (s, 2H), 4.56 - 4.45 (m, 1H), 3.79 - 3.66 (m, 2H), 2.24 - 2.08 (m, 1H), 2.06 - 1.80 (m, 3H); MS (ES+): 445.4 (M+l).

Scheme 78

Preparation of (S)- 1 -(2-(4-amino- lH-pyrazolo[3,4-d]pyrimidin- l-yl)acetyl)-N-(3-chloro-2- fluorobenzyl)p>'rrolidine-2-carboxamide (78a)

Compound 78a was prepared according to the procedure reported in step-3 of scheme- 1, from DMF (3 mL) using (S)-N-(3-chloro-2-fluorobenzyl)pyrrolidine-2-carboxamide (76a) (0.096 g, 0.259 mmol), HATU (0.108 g, 0.285 mmol) and DIPEA (0.136 mL, 0.777 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), CMA-80 in chloroform from 0 - 40%] (S)-l-(2-(4-amino- lH-pyrazolo[3,4-d]pyrimidin-l-yl)acetyl)-N-(3-chloro-2-fluor oben2yl)pyrrolidine-2- carboxamide (78a) (43 mg, 37% yield) as a white solid; The free based was converted to HC1 salt by dissolving in acetonitrile and 0.1% aq. HC1 followed by lyophilization to afford (S)-l- (2-(4-anrino-lH-pyra∞lo[3,4-d]pyrimidin-l-yl)acetyl)-N-(3- chloro-2- fhiorobenzyl)pyrrolidine-2-carboxamide (78a) HC1 salt as a white solid; ¹ HNMR(300 MHz, DMSCMO δ 8.46 (t, J = 5.9 Hz, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 7.08 (t, J = 7.9 Hz, 1H), 5.22 (s, 2H), 4.47 - 4.21 (m, 3H), 3.80 - 3.55 (m, 2H), 2.17 - 1.72 (m, 4H); 19F NMR(282 MHz, DMSO-cfs) δ -121.60; MS (ES+): 432.5 (M+l), MS (ES-): 466.4 (M+Cl).

Scheme 79

Preparation of (lR,3S,5R)-2-(2-(4-amino-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ac etyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (79a)

Compound 79a was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino- lH-pyrazolo[3,4-d]pytimidin- 1 -yl)acetic acid (77a) (279 mg, 0.909 mmol) in DMF (15 mL) using (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3- carboxamide (4a) (300 mg, 0.757 mmol), HATU (432 mg, 1.136 mmol), DIPEA (0.660 mL, 3.79 mmol) and stirring at RT for 16 h. This gave after workup and purification by reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0 - 50%] ( 1R,3 S,5R)-2-(2-(4-amino- lH-pyrazolo[3,4-d]pyrimidin- 1 - yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (79a) (202 mg, 58% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ife) δ 10.79 (s, 1H), Hz, 1H), 7.33 (dd, .7= 7.7, 0.7 Hz, 1H), 5.78 - 5.27 (m, 2H), 4.41 (dd, J= 9.0, 5.5 Hz, 1H), 3.86 - 3.76 (m, 1H), 2.38 - 2.11 (m, 2H), 1.95 - 1.80 (m, 1H), 1.05 - 0.92 (m, 1H), 0.70 - 0.60 (m, 1H); MS (ES+): 457.00 (M+l); (ES-): 455.00 (M-l).

Scheme 80

Preparation of (lR,3S,5R)-2-(2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ace tyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (80a)

Compound 80a was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (5c) (0.06 g, 0.312 mmol) in DMF (2 mL) using (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3- carboxamide (4a) (0.118 g, 0.312 mmol), HATU (0.142 g, 0.375 mmol), DIPEA (0.164 mL, 0.937 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH:EtOAc (9:1) in hexanes 0 to 100%] ( 1R,3 S,5R)-2-(2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetyl)- N -(6- bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (80a) (50 mg, 35% yield) as a white solid; Ή NMR (300 MHz, DMSO-tfc) δ 10.78 (s, 1H), 8.07 - 8.00 (m, 2H), 7.72 (t ,J= 8.0 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.08 (d, J= 3.5 Hz, 1H), 6.99 (brs, 2H), 6.52 (d, J = 3.5 Hz, 1H), 5.38-5.05 (m, 2H), 4.47 - 4.38 (m, 1H), 3.77 - 3.68 (m, 1H), 2.34 - 2.11 (m, 2H), 1.94 - 1.79 (m, 1H), 1.06 - 0.95 (m, 1H), 0.69 - 0.61 (m, 1H); MS (ES+) 456.2 (M+l), MS (ES-) 454.3, (M-l); Analysis calculated for CigHisBr^Ch.ifcO: C, 48.11; H, 4.25; N, 20.67; Found: C, 47.86; H, 4.22; N, 20.27.

Scheme 81

Preparation of (lR,3S,5R)-2-(2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ace tyl)-N-(3- chloro-2-fluorobenzyl)-2-azabicyclo[3.1 0]hexane-3-carboxamide (81a)

Compound 81a was prepared according to the procedure reported in step-3 of scheme-1, from 2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (5c) (0.075 g, 0.392 mmol) in DMF (3 mL) using TFA salt of (lR,3S,5R)-N-(3-chloro-2-fluorobenzyl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (66a) (0.15 g, 0.392 mmol), HATU (0.179 g, 0.470 mmol), DIPEA (0.205 mL, 1.176 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 to 50%) (lR,3S,5R)-2-(2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ace tyl)-N- (3-chloro-2-fluorobenzyl)-2-azabicyclo[3.1.0]hexane-3-carbox amide (81a) (65 mg, 37% yield) as a white solid; Ή NMR (300 MHz, DMSO-ifc) 58.47 (t, J= 5.9 Hz, 1H), 8.08 (s,

1H), 7.50 - 7.41 (m, 1H), 7.29 (s, 2H), 7.25 - 7.17 (m, 1H), 7.16 - 7.07 (m, 2H), 6.61 (d, J= 3.5 Hz, 1H), 5.30 (d, J= 17.1 Hz, 1H), 5.15 (d,./= 17.1 Hz, 1H), 4.33 (dd, J= 11.4, 6.0 Hz, 1H), 4.25 (q,J= 4.5 Hz, 1H), 3.69 - 3.58 (m, 1H), 2.30 - 2.18 (m, 1H), 2.18 - 2.06 (m, 1H), 1.90 - 1.76 (m, 1H), 1.06 - 0.96 (m, 1H), 0.73 - 0.63 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO- ifc) δ -121.78; MS (ES+) 443.2 (M+l); MS (ES-): 477.2 (M+Cl); Analysis Calculated for C21H20CIFN6O2.I.25H2O: C, 54.20; H, 4.87; N, 18.06; Found: C, 54.13; H, 4.90; N, 17.69.

Scheme 82

Preparation of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2-(2-(4-(methylamino)-lH- pyrazolo[3, 4- Compound 82a was prepared according to the procedure reported in step-3 of scheme- 1, from

2-(4-(methylamino)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)aceti c acid (75c) (0.06 g, 0.290 mmol) in DMF (2 mL) using (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-caiboxamide (4a) (0.110 g, 0.290 mmol), HATU (0.143 g, 0.376 mmol), DIPEA (0.152 mL, 0.869 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 to 80%] (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2-(2-(4-(methylamino)-lH- pyrazolo[3,4-d]pyrimidin-l-yl)acetyl)-2-azabicyclo[3.1.0]hex ane-3-cafboxamide (82a) (75 mg, 55% yield) as a white solid; TiNMR (300 MHz, DMSOncfc) δ 10.78 (s, 1H), 8.63 (brs, 1H), 8.29 (s, 1H), 8.13 (s, 1H), 8.03 (d, J= 8.2 Hz, 1H), 7.72 (t, J= 8.0 Hz, 1H), 7.33 (d, J= 7.7 Hz, 1H), 5.64-5.16 (m, 2H), 4.40 (dd, J= 9.1, 5.5 Hz, 1H), 3.83-3.75 (m, 1H), 3.00 (d, ./

= 4.5 Hz, 3H), 2.35 - 2.11 (m, 2H), 1.94 - 1.78 (m, 1H), 1.02 - 0.92 (m, 1H), 0.67 - 0.55 (m, 1H); MS (ES+): 471.3, 473.3 (M+l), 493.2, 495.2 (M+Na).

Scheme 83

Preparation of (lR,3S,5R)-2-(2-(4-amino-lH-pyrrolo[2,3-b]pyridin-l-yl)acety l)-N-(6- bromopyridin-2-yI)-2-azabicyclo[3.1.0]hexane-3-carboxamide (83d)

Step-1: Preparation of fert-butyl 2-(4-((ten-butoxycarbonyl)amino)- 1 H-pyrrolo[2,3- b]pyridin-l-yl)acetate (83b) Compound 83b was prepared according to the procedure reported in step-3 of scheme- 17, from tert-butyl 2-(4-chloro- 1 H-pyrrolo [2,3 -b] py ridin- 1 -yl)acetate (83a) (1.5 g, 5.62 mmol; CAS # 2243596-23-6; prepared according to the procedure reported in Kotian, P. L. et al., PCT Int. Appl. (2017), WO 2017136395 Al 20170810) in toluene (40 mL) using XPhos (0.268 g, 0.562 mmol), t-butyl carbamate (0.988 g, 8.44 mmol), Pdz(dba)3 (0.257 g, 0.281 mmol), cesium carbonate (1.832 g, 5.62 mmol) and heating at 90 °C for 20 h. This gave after work up and purification /erf-butyl 2-(4-((tori-butoxycarbonyl)amino)-lH-pyrrolo[2,3- bjpyridin- 1 -yl)acetate (83b) (1.4 g, 72% yield); Ή NMR (300 MHz, DMSO-i/e) δ 9.73 (s, 1H), 8.05 (d, 5.5 Hz, 1H), 7.61 (d, J= 5.5 Hz, 1H), 7.32 (d, J= 3.6 Hz, 1H), 6.90 (d, J=

3.6 Hz, 1H), 4.94 (s, 2H), 1.52 (s, 9H), 1.40 (s, 9H); MS (ES+): 348.3 (M+l); (ES-): 346.3 (M-l).

Step-2: Preparation of 2-(4-amino-lH-pyrrolo[2,3-b]pyridin-l-yl)acetic acid (83c)

Compound 83c was prepared according to the procedure reported in step-2 of scheme- 1 , from terf-butyl 2-(4-((tezt-butoxycarbonyl)ammo)-lH-pyrrolo[2,3-b]pyridin-l- yl)acetate (83b) (0.65 g, 2.159 mmol) using TFA (0.166 mL, 2.159 mmol) in DCM (10 mL) and stirring at RT for 16 h. This gave after work up 2-(4-amino-lH-pyrrolo[2,3-b]pyridin-l-yl)acetic acid (83c) (1.05 g) TFA salt as a light-orange solid; MS (ES+): 192.1 (M+l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-lH-pyrrolo[2,3-b]pyridin-l-yl)acety l)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (83d)

Compound 83d was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-lH-pyrrolo[2,3-b]pyridin-l-yl)acetic acid (83c) (0.09 g, 0.314 mmol) in DMF (2 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.OJhexane-3-carboxamide (4a) (0.1 g, 0.314 mmol), HATH (0.143 g, 0.377 mmol), DIPEA (0.274 mL, 1.569 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (4 g), eluting with DMA-80 in DCM from 0 to 80%] (lR,3S,5R)-2-(2-(4-amino-lH-pyrrolo[2,3-b]pyridin-l-yl)acety l)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (83d) (25 mg, 17% yield) as a white solid; Ή NMR (300 MHz, DMSO-tfe) δ 10.76 (s, 1H), 8.04 (d, J= 8.2 Hz, 1H), 7.76 - 7.67 (m, 2H), 7.32 (d, J= 7.7 Hz, 1H), 7.05 (d, J= 3.5 Hz, 1H), 6.49 (d, J= 3.5 Hz, 1H), 6.24

- 6.11 (m, 3H), 5.30 (d, J = 17.0 Hz, 1H), 5.11 (d, J= 16.9 Hz, 1H), 4.42 (dd, J = 9.0, 5.5 Hz, 1H), 3.76 - 3.68 (m, 1H), 2.33 - 2.10 (m, 2H), 1.91 - 1.78 (m, 1H), 1.04 - 0.94 (m, 1H), 0.68 060 (m 1H); MS (ES+): 4552 4572 (M+l) 4772 4792 (M+Na) MS (ES ): 453 2 455.3 (M-l); Analysis calculated for CzoHigBrNeChHzO; C, 50.75; H, 4.47; N, 17.76; Found C, 50.70; ¾ 4.53; N, 17.46.

Scheme 84

Preparation of ( 1 R,3 S ,5 R)-2-(2-(6-am ino-9H-purin-9-yl)acetyl )-N -(6-bromopyridi n -2-yl )-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (84a)

Compound 84a was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(6-amino-9H-purin-9-yl)acetic acid (67a) (0.05 g, 0.259 mmol) in DMF (1 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopytidin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (4a) (0.082 g, 0.259 mmol), HATU (0.118 g, 0.311 mmol), DIPEA (0.181 mL, 1.035 mmol) and stirring at RT for 2 days. This gave after workup and purification by flash column chromatography [silica gel (4 g), eluting with DMA-80 in DCM from 0 to 80%] (1R,3S,5R)- 2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(6-bromopyridin-2-yl)- 2-azabicyclo[3.1 ,0]hexane-3- carboxamide (84a) (31 mg, 26% yield) as a white solid; Ή NMR (300 MHz, DMSO-afe) δ 10.82 (s, 1H), 8.12 (s, 1H), 8.07 (s, 1H), 8.03 (d,J= 8.2 Hz, 1H), 7.72 (t, J= 8.0 Hz, 1H), 7.33 (d ,J= 7.7 Hz, 1H), 7.24 (s, 2H), 5.42 (d,J= 17.2 Hz, 1H), 5.15 (d ,J= 17.1 Hz, 1H), 4.45 (dd, J= 9.0, 5.4 Hz, 1H), 3.80 - 3.71 (m, 1H), 2.36 - 2.12 (m, 2H), 1.95 - 1.82 (m, 1H), 1.09 - 0.98 (m, 1H), 0.72 - 0.65 (m, 1H); MS (ES+): 457.2 (M+l), 479.2, 481.2 (M+Na).

Scheme 85 Preparation of ( lR,3S,5R)-2-(2-(4-amino- lH-indol- 1 -yl)acetyl)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-caiboxamide (85b)

Compound 85b was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino- lH-indol- 1 -yl)acetic acid (85a) (0.08 g, 0.279 mmol) in DMF (2 mL) using HC1 salt of ( lR,3S,5R)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (4a) (0.089 g, 0.279 mmol), HATU (0.127 g, 0.334 mmol), DIPEA (0.243 mL, 1.393 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (4 g), eluting with DMA-80 in DCM from 0 to 40%] to afford ( 1R,3 S,5R)-2-(2-(4-amino- 1 H-indol- 1 -yl)acetyl)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-caiboxamide (85b) (18 mg, 14% yield) as a white solid; ^! HNMR (300 MHz, DMSO-tifc) δ 10.77 (s, 1H), 8.03 (d, J= 8.2 Hz, 1H), 7.71 (t, J= 8.0 Hz, 1H), 7.35

- 7.29 (m, 1H), 7.05 (d, J= 3.2 Hz, 1H), 6.79 (t, J= 7.8 Hz, 1H), 6.56 - 6.46 (m, 2H), 6.15 (d, J= 7.4 Hz, 1H), 5.24 (d, J= 17.1 Hz, 1H), 5.18 (s, 2H), 5.03 (d, J= 17.1 Hz, 1H), 4.42 (dd, J= 9.0, 5.5 Hz, 1H), 3.80 - 3.71 (m, 1H), 2.33 - 2.10 (m, 2H), 1.92 - 1.76 (m, 1H), 1.01

- 0.92 (m, 1H), 0.69 - 0.58 (m, 1H); MS (ES+): 454.2, 456.2 (M+l), MS (ES-): 452.2, 454.2 (M-l).

Scheme 86

Preparation of (lR,3S,5R)-2-(2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ace tyl)-N-((S)-l- (3-chloro-2-fluorophenyl)ethyl)-2-azabicyclo[3.1.0]hexane-3- caiboxamide (86b)

Compound 86b was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (5c) (0.05 g, 0.260 mmol) in DMF (2 mL) using HC1 salt of (lR,3S,5R)-N-((S)-l-(3-chloro-2-fluorophenyl)ethyl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (86a) (0.083 g, 0.260 mmol; prepared according to the procedure reported by Altmann, E. et al., PCT Int. Appl. (2012), WO 2012093101 A1 1.041 mmol) and stirring at RT for 2 days. This gave after workup and purification by flash column chromatography [silica gel (4 g), eluting with DMA-80 in DCM from 0 to 80%] (lR,3S,5R)-2-(2-(4-amino-7H-pyrTOlo[2,3-d]pyrimidin-7-yl)ace tyl)-N-((S)-l-(3-chloro-2- fhxorophenyl)ethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (86b) (0.033 g, 28% yield) as a white solid; ^! HNMR (300 MHz, DMSO-de) 5 8.35 (d, 7.7 Hz, 1H), 8.05 (s, 1H), 7.48 -

7.39 (m, 1H), 7.35 - 7.27 (m, 1H), 7.20 - 7.04 (m, 5H), 6.56 (d ,J= 3.6 Hz, 1H), 5.35 - 4.96 (m, 3H), 4.26 (dd, J= 8.8, 4.9 Hz, 1H), 3.67 - 3.57 (m, 1H), 2.28 - 2.03 (m, 2H), 1.88 - 1.74 (m, 1H), 1.35 - 1.26 (m, 3H), 1.05 - 0.94 (m, 1H), 0.70 - 0.60 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-ife) δ -122.65; MS (ES+): 479.3, 481.2 (M+Na); MS (ES-): 491.3, 493.3 (M+Cl); Analysis calculated for C22H22CIFN6O2.I.5H2O; C, 54.60; a 5.21; N, 17.37; Found C, 54.97; ¾ 5.19; N, 17.39.

Scheme 87

87d 87e 87f

Preparation of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2-(2-(2,4-diamino-7H-pyrr olo[2, 3- d]py rimidin-7 -y l)acet\l)-2-azabic}'clo [3.1 ,0]hexane-3-carboxamide (87f)

Step-1: Preparation of tert-butyl 2-(2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)acetate (87b)

Compound 87b was prepared according to the procedure reported in step-1 of scheme- 1, from 4-chloro-7H-pyrrolo[2,3-d]pyTimidin-2-amine (87a) (6 g, 35.6 mmol; CAS# 651035- 58-4) in acetonitrile (400 rtiL) using tert- butyl 2-bromoacetate (5.78 mL, 39.1 mmol), K2CO3 flash column chromatography [silica gel (120 g), eluting with EtOAc/MeOH (9: 1) in Hexane from 0-100%] tort-butyl 2-(2-amino-4-chloro-7H-pyrrolo [2,3 -d] py rimidin-7 -y l)acetate (87b) (1.51 g, 15% yield) as an off-white solid; Ή NMR (300 MHz, DMSO-tife) δ 7.14 (d, J = 3.7 Hz, 1H), 6.71 (s, 2H), 6.31 (d, J = 3.7 Hz, 1H), 4.78 (s, 2H), 1.41 (s, 9H).

Step-2: Preparation of tort-butyl 2-(2-amino-4-azido-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate

(87c)

To a solution of tort-butyl 2-(2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (87b) (1.5 g, 5.31 mmol) in DMF (20 mL) was added sodium azide (1.725 g, 26.5 mmol) and heated at 80 °C for 10 h. The reaction was cooled to 25 °C, extracted with chloroform (3 X 50 mL) and the combined organics were dried, filtered and evaporated to dryness. The residue obtained was purified by flash column chromatography [silica gel (40 g), eluting with methanol in DCM from 0-100%] to afford tert- butyl 2-(2-amino-4-azido-7H-py rrolo [2,3 - d]pyrimidin-7-yl)acetate (87c) (0.556 g, 36% yield) as an off-white solid; Ή NMR (300 MHz, DMSO-cfe) δ 8.18 (s, 2H), 7.20 (d, J = 3.5 Hz, 1H), 6.76 (d, J = 3.5 Hz, 1H), 4.93 (s, 2H), 1.42 (s, 9H); MS (ES+): 290.3 (M+l); MS (ES-): 288.3 (M-l).

Step-3: Preparation of tort-butyl 2-(2,4-diamino-7H-pyrrolo[2,3-d]p>'rimidin-7-yl)acetate (87d)

To a solution of tort-butyl 2-(2-amino-4-azido-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (87c) (0.528 g, 1.825 mmol) in methanol (20 mL) was added palladium hydroxide on carbon (0.064 g, 0.091 mmol) and heated with stirring at 22 °C for 10 h. The reaction was cooled to 25 °C and extracted with chloroform (3 x 50 mL). The combined organics were dried, filtered, and evaporated to dryness. The residue obtained was purified by flash column chromatography [silica gel (24 g), eluting with methanol in DCM from 0-100%] to furnish tort-butyl 2-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (87d) (0.362 g, 75 % yield) as an off-white solid; MS (ES+): 264.3 (M+l); MS (ES-): 262.3 (M-l).

Step-4: Preparation of2-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (87e)

Compound 87e was prepared according to the procedure reported in step-2 of scheme- 1, from tort-butyl 2-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (87d) (0.351 g, 1.333 mmol) using TEA (1.027 mL, 13.33 mmol) in DCM (10 mL) and stirring at RT for 12 h. This gave after workup 2-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (87e) (0.428 g, 100% yield) TEA salt as a yellow solid; MS (ES+): 208.2 (M+l). Step-5 Preparation of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2-(2-(2,4-diamino-7H- pyrrolo[2,3-d]pyrimidin-7-yl)acetyl)-2-azabicyclo[3.1.0]hexa ne-3-carboxamide (87f)

Compound 87f was prepared according to the procedure reported in step-3 of scheme- 1, from (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamidetrifluoro acetate (4a) (0.259 g, 0.654 mmol) in DMF (10 mL) using TFA salt of 2-(2,4-diamino-7H- pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (87e) (0.21 g, 0.654 mmol), HATU (0.373 g, 0.981 mmol), DIPEA (0.911 mL, 5.23 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel 25 g] (lR,3S,5R)-N-(6- bromopyridin-2-yl)-2-(2-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimi din-7-yl)acetyl)-2- azabicyclo[3.1.0]hexane-3-caiboxamide (87f) (0.023 g, 8 % yield) as a white solid; ^! HNMR (300 MHz, DMSO-tifc) δ 11.92 (s, 1H), 10.83 (s, 1H), 8.37 (s, 1H), 8.03 (d,J= 8.2 Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.34 (d, J= 7.7 Hz, 1H), 7.23 (s, 2H), 6.96 (d, J= 3.7 Hz, 1H), 6.60 (d, J= 3.7 Hz, 1H), 5.23 (d, J= 17.0 Hz, 1H), 4.96 (d, J= 17.0 Hz, 1H), 4.42 (dd, J= 9.0, 5.5 Hz, 1H), 3.75 - 3.61 (m, 1H), 2.36 - 2.11 (m, 2H), 1.94 - 1.79 (m, 1H), 1.08 - 0.94 (m, 1H), 0.77 - 0.60 (m, 1H).

Scheme 88

O

H ^ΒΓ ΧΑ ₀ ^< OH N ^U

I

J

NaH

Cl m Cl — m Cl

88a 88b 88c

HN F

<!

<7 H N O

N N rv-c, W o F

H Cl >0 >r°Y° Ό o 66a F ¹ NH ₂ 88e N

Cl

Pd ₂ (dba) _3l XPhos,

HATU, DIPEA €ς¾ CS ₂ CO ₃ NH ₂

Cl

88d 88f

Preparation of (lR,3S,5R)-2-(2-(4-amino-lH-pyrrolo[3,2-c]pyridin-l-yl)acety l)-N-(3-chloro- 2-fluorobenzyl)-2-azabicyclo [3.1.0]hexane-3-carboxamide (88f)

Step-1: Preparation of lert- butyl 2-(4-chloro-lH-pyrrolo[3,2-c]pyridin-l-yl)acetate (88b) To a solution of 4-chloro-lH-pyrrolo[3,2-c]pyridine (88a) (0.3 g, 1.966 mmol; CAS # 60290- 21-3) in DMF (10 mL) was added sodium hydride (0.079 g, 1.966 mmol) in portions at 0 °C under an argon atmosphere. After stirring for 15 min was added tert-butyl bromoacetate (0.436 mL, 2.95 mmol) drop wise and stirred at RT for 2h. Reaction mixture was poured into sat. NH4CI solution and extracted with EtOAc (2 x 60 mL). The combined organics were washed with brine, dried, filtered and concentrated in vacuum. The residue obtained was purified by flash column chromatography [silica gel (40 g), eluting with EtOAc in hexane as eluents from 0 to 50%] to afford ter/-butyl 2-(4-chloro-lH-pyrrolo[3,2-c]pyridin-l-yl)acetate (88b) (0.45 g, 86 % yield) as a white solid; Ή NMR (300 MHz, DMSO -de) δ 8.01 (d, J — 5.8 Hz, 1H), 7.55 (d, J = 3.3 Hz, 1H), 7.52 (dd, J = 5.7, 0.9 Hz, 1H), 6.59 (dd, J = 3.3, 0.9 Hz, 1H), 5.13 (s, 2H), 1.41 (s, 9H).

Step-2: Preparation of 2-(4-chloro-lH-pyrrolo[3,2-c]pyridin-l-yl)acetic acid (88c)

Compound 88c was prepared according to the procedure reported in step-2 of scheme- 1 , from tert- butyl 2-(4-chloro-lH-pyrTolo[3,2-c]pyridin-l-yl)acetate (88b) (0.45 g, 1.687 mmol) using TFA (1.30 mL, 16.87 mmol) in DCM (10 mL) and stirring at RT for 16 h. This gave after workup 2-(4-chloro- 1 H-pyrrolo [3 ,2-c]pyridin- 1 -yl)acetic acid (88c) (0.34 g, 66% yield) TFA salt as an off-white solid; Ή NMR (300 MHz, DMSO-ί/β) δ 8.01 (d, J = 5.8 Hz, 1H), 7.60 - 7.52 (m, 2H), 6.59 (dd, J = 3.2, 0.9 Hz, 1H), 5.13 (s, 2H).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-chloro-lH-pyrrolo[3,2-c]pyridin-l-yl)acet yl)-N- (3-chloro-2-fluorobenzyl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (88d)

Compound 88d was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-chloro-lH-pyrrolo[3,2-c]pyridin-l-yl)acetic acid (88c) (0.13 g, 0.423 mmol) in DMF (3 mL) using HC1 salt of (lR,3S,5R)-N-(3-chloro-2-fluorobenzyl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (66a) (0.129 g, 0.423 mmol), HATU (0.193 g, 0.507 mmol), DIPEA (0.328 g, 2.54 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (4 g), eluting with MeOH:EtOAc (9: 1) in hexanes from 0 - 80%] (lR,3S,5R)-2-(2-(4-chloro-lH-pyrrolo[3,2-c]pyridin-l- yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[3.1.0]he xane-3-carboxamide (88d)

(0.16 g, 82% yield) as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 8.48 (t, J = 6.0 Hz, 1H), 7.95 (dd, J = 5.7, 1.2 Hz, 1H), 7.53 (d, J = 3.3 Hz, 1H), 7.51 - 7.41 (m, 2H), 7.18 (t, J = 7.3 Hz, 1H), 7.05 (t, J = 7.8 Hz, 1H), 6.58 (dd, J = 3.2, 1.0 Hz, 1H), 5.47 (d, J = 17.4 Hz, 1H), 527 (d J = 173 Hz 1H) 446 435 (m 1H) 433 420 (m 2H) 3 71 3 63 (m 1H) 232 2.08 (m, 2H), 1.94 - 1.79 (m, 1H), 1.07 - 0.97 (m, 1H), 0.82 - 0.71 (m, 1H); MS (ES+): 461.2 (M+l).

Step-4: Preparation of ( 1R,3 S,5R)-2-(2-(4-amino- lH-pyrrolo[3,2-c]pyridin- 1 -yl)acetyl)-N-(3- chloro-2-fluorobenz\'l)-2-azabicyclo[3.1.0Jhexane-3-carboxam ide (88f)

Compound 88f was prepared according to the procedure reported in step-3 of scheme- 17, from (lR,3S,5R)-2-(2-(4-chloro-lH-pyrrolo[3,2-c]pyridin-l-yl)acet yl)-N-(3-chloro-2- fluorobenzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (88d) (0.15 g, 0.325 mmol) in dioxane (5 mL) using XPhos (0.016 g, 0.033 mmol), tert- butyl carbamate (88e) (0.076 g, 0650 mmol), Pd2(dba)r (0.015 g, 0.016 mmol), cesium carbonate (0.106 g, 0.325 mmol) and heating at 90 °C for 20 h. This gave after work up and purification [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] (lR,3S,5R)-2-(2-(4-amino-lH-pyrrolo[3,2-c]pyridin- l-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (88f) (0.01 g, 7% yield) as a white solid; Ή NMR (300 MHz, DMSO-rfc) δ 8.52 - 8.41 (m, 1H), 7.57 - 7.40 (m, 2H), 7.27 - 7.15 (m, 1H), 7.14 - 7.02 (m, 2H), 6.70 - 6.57 (m, 2H), 6.19 (s, 2H), 5.25 (d, J= 17.3 Hz, 1H), 5.08 (d, J= 17.4 Hz, 1H), 4.48 - 4.18 (m, 3H), 3.70 - 3.61 (m, 1H), 2.32 - 2.06 (m, 2H), 1.92 - 1.77 (m, 1H), 1.06 - 0.94 (m, 1H), 0.76 - 0.64 (m, 1H); 19F NMR (282 MHz, DMSO-tifc) δ -121.81; MS (ES+) 442.3, 444.3 (M+l), MS (ES-) 476.3, 478.3 (M+Cl).

Scheme 89

Preparation of ( 1 R,3 S,5R)-2-(2-(2-amino-9H-purin-9-yl)acetyl)-N -(6-bromopyridin-2-yl)-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (89b)

Compound 89b was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(2-amino-9H-purin-9-yl)acetic acid (89a) (0.04 g, 0.207 mmol; CAS# 933477-63-5) in DMF (1 ttiL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- mmol), DIPEA (0.145 mL, 0.828 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (4 g), eluting with DMA-80 in DCM from 0 -100%] (lR,3S,5R)-2-(2-(2-amino-9H-purin-9-yl)acetyl)-N-(6-bromopyr idin-2- yl)-2-azabicyclo[3.1.0]hexane-3-caiboxamide (89b) (62 mg, 66% yield) as a white solid; ^! H NMR (300 MHz, DMSO-ifc) δ 10.85 (s, 1H), 8.58 (s, 1H), 8.07 - 7.97 (m, 2H), 7.72 (t ,J = 8.0 Hz, 1H), 7.35-7.31 (m, 1H), 6.61 (s, 2H), 5.32 (d, J = 17.3 Hz, 1H), 5.06 (d, J= 17.3 Hz, 1H), 4.44 (dd, J= 9.0, 5.4 Hz, 1H), 3.76 - 3.68 (m, 1H), 2.37 - 2.11 (m, 2H), 1.95 - 1.81 (m, 1H), 1.10 - 0.96 (m, 1H), 0.74 - 0.63 (m, 1H); MS (ES+): 457.2, 459.2 (M+l), 479.2, 481.2 (M+Na), MS (ES-): 455.3 (M-l); Analysis calculated for CisHnBrNsOz.HzO; C, 45.49; H, 4.03; N, 23.58; Found C, 44.88; H, 4.12; N, 22.82.

Scheme 90

90a 90b 90c

J'-i

<7 Br

N N

H Λ ' l O ® 4a O

Cl

HATU, DIPEA

TO

NH ₂

90d

Preparation of (lR,3S,5R)-2-(2-(4-amino-2-chloro-7H-pyr ^, rolo[2,3-d]pyrimidin-7-yl)acetyl)- N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (90d)

Step-1: Preparation of tort-butyl 2-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)acetate (90b)

Compound 90b was prepared according to the procedure reported in step-1 of scheme- 1, from 2-chloro-7H-pyrrolo [2,3 -d]pyrim idi n -4-amine (90a) (1 g, 5.93 mmol; CAS # 1192711- 88 8) i t itril (50 L) i tort b t l 2 b t t (0963 L 652 l) d K2CO3 (1.640 g, 11.86 mmol) and heating at 65 °C for 14 h. This gave after workup and purification by flash column chromatography [silica gel (40 g), eluting with EtOAc in Hexane from 0-100%] tort-butyl 2-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)acetate (90b) (1.102 g, 66% yield) as awhite solid; ‘H NMR (300 MHz, DMSO-^e) δ 7.52 (s, 2H), 7.12 (d, J = 3.5 Hz, 1H), 6.55 (d, J = 3.5 Hz, 1H), 4.83 (s, 2H), 1.41 (s, 9H); MS (ES+): 283.2 (M+l); (ES-): 281.3 (M-l).

Step-2: Preparation of2-(4-amino-2-chloro-7H-pynOlo[2,3-d]pyrimidin-7-yl)acetic acid

(90c)

Compound 90c was prepared according to the procedure reported in step-2 of scheme- 1, from tort-butyl 2-(4-ammo-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (90b) (0.251 g,

0.888 mmol) using TFA (0.684 mL, 8.88 mmol) in DCM (10 mL) and stirring at RT for 12 h. This gave after workup 2-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (90c) (0.302 g, 100% yield) TFA salt as a yellow solid; MS (ES+): 227.1 (M+l ).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-2-chloro-7H-pyrTolo[2,3-d]pyrimidin -7- yl)acet>'l)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (90d)

Compound 90d was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (90c) (0.175 g, 0.514 mmol) in DMF (10 mL) using TFA salt of (lR,3S,5R)-N-(6-bromopyridin-2- yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (0.204 g, 0.514 mmol), HATU (293 mg, 0.771 mmol), DIPEA (0.716 mL, 4.11 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (25 g), eluting with EtOAc in MeOH (9:1) from 0 - 100%] (lR,3S,5R)-2-(2-(4-amino-2-chloro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicycl o[3.1 0]hexane-3-carboxamide (90d) (132 mg, 52% yield) as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.81 (s, 1H, D2O exchangeable), 8.04 (d, J= 8.2 Hz, 1H), 7.72 (t, J= 8.0 Hz, 1H), 7.48 (s, 2H, D2O exchangeable), 7.33 (dd, J= 7.8, 0.7 Hz, 1H), 7.08 (d, J= 3.5 Hz, 1H), 6.53 (d, 3.5 Hz,

1H), 5.31 (d, J= 17.1 Hz, 1H), 5.03 (d, J= 17.1 Hz, 1H), 4.43 (dd, J= 9.0, 5.5 Hz, 1H), 3.82 - 3.68 (m, 1H), 2.36 - 2.11 (m, 2H), 1.93 - 1.75 (m, 1H), 1.07 - 0.94 (m, 1H), 0.74 - 0.62 (m, 1H); Analysis calculated for Ci9Hi7BrClN ₇ 02.H20: C, 44.86; H, 3.76; N, 19.27; Found: C, 44.79; H, 3.67; N, 19.12.

Scheme 91

91a

67a

Preparation of (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(3-chloro-2 -fluorobenzy])- 2-azabicyclo[3.1.0]hexane-3-carboxamide (91a)

Compound 91a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(6-amino-9H-purin-9-yl)acetic acid (67a) (0.188 g, 0.612 mmol) in DMF (15 mL) using HC1 salt of (lR,3S,5R)-N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[3.1.0]he xane-3- carboxamide (66a) (0.224 g, 0.734 mmol), HATU (349 mg, 0.918 mmol), DIPEA (0.533 mL, 3.06 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 15%] (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(3-chloro-2 -fluorobenzyl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (91a) (101 mg, 37% yield) as a white solid; ^! HNMR (300 MHz, DMSO-ifc) δ 8.47 (t, J= 6.0 Hz, 1H), 8.11 (s, 1H), 8.04 (s, 1H), 7.51 - 7.40 (m, 1H), 7.27 - 7.16 (m, 3H), 7.10 (t, 7.9 Hz, 1H), 5.44 - 5.10 (m, 2H), 4.48 - 4.19 (m, 3H),

3.77 - 3.59 (m, 1H), 2.34 - 2.05 (m, 2H), 1.94 - 1.76 (m, 1H), 1.13 - 0.96 (m, 1H), 0.77 - 0.65 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -121.75; MS (ES ⁺ ): 444.10 (M + 1); MS (ES-): 442.10 (M - 1).

Scheme 92

92a

92b Preparation of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2-(2-(2,6-diamino-9H-puri n-9- yl)acetyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (92b)

Compound 92b was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(2,6-diamino-9H-purin-9-yl)acetic acid (92a) (0.1 g, 0.328 mmol) in DMF (1 triL) and using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3- carboxamide (4a) (0.104 g, 0.328 mmol), HATU (0.150 g, 0.393 mmol), DIPEA (0.343 mL, 1.966 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (4 g), eluting with DMA-80 in DCM from 0 - 100%] (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2-(2-(2,6-diamino-9H-puri n-9-yl)acetyl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (92b) (0.06 g, 39% yield) as a white solid; ’HNMR (300 MHz, DMSO-tifc) δ 10.84 (s, 1H), 8.04 (d, J= 8.2 Hz, 1H), 7.72 (t, J= 8.0 Hz, 1H), 7.63 (s, 1H), 7.33 (d, J= 7.7 Hz, 1H), 6.69 (brs, 2H), 5.81 (brs, 2H), 5.19 (d, J= 17.3 Hz, 1H), 4.94 (d, J= 17.3 Hz, 1H), 4.44 (dd, ./= 9.1, 5.6 Hz, 1H), 3.75 - 3.64 (m, 1H), 2.34 - 2.10 (m, 2H), 1.94 - 1.79 (m, 1H), 1.07 - 0.96 (m, 1H), 0.72 - 0.60 (m, 1H); MS (ES+): 494.2, 496.2 (M+Na); MS (ES-): 470.3, 472.3 (M-l).

Scheme 93

^F i

^F x

OH H

N N. Br

N

^H 5d 0 N

HATU,

DIPEA

NH ₂ NH ₂

67a 93a

Preparation of (2S,4R)-l-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(6-bromopyridi n-2-yl)-4- fluoropyrrohdine-2-carboxamide (93a)

Compound 93a was prepared according to the procedure reported in step-3 of scheme- 1, from TEA salt of 2-(6-amino-9H-purin-9-yl)acetic acid (67a) (0.466 mmol, 190 mg) in DMF (15 mL) and using TFA salt of (2S,4R)-N-(6-bromopyridin-2-yl)-4-fluoropynOlidine-2- carboxamide (5d) (0.559 mmol, 250 mg), HATU (266 mg, 0.698 mmol), DIPEA (0.405 mL, 2.328 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash l h t h [ ili l (24 ) l ti ith DMA 80 i DCM f 0 25%] (2S,4R)-l-(2-(6-amino-9H-purin-9-yl)acet\'l)-N-(6-bromopyrid in-2-yl)-4-fluoropyrrolidine- 2-carboxamide (93a) (129 mg, 60% yield) as a white solid; Ή NMR (300 MHz, DMSO-ofe) δ 11.04 (s, 1H), 8.11 (s, 1H), 8.07 - 7.99 (m, 2H), 7.71 (t ,J= 8.0 Hz, 1H), 7.36 - 7.29 (m, 1H), 7.21 (s, 2H), 5.65 - 5.36 (m, 1H), 5.32 - 5.00 (m, 2H), 4.66 (t, J= 8.5 Hz, 1H), 4.29 - 3.74 (m, 2H), 2.67 - 1.95 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-tfc) δ -175.72; MS (ES+): 463.00 & 465.00 (M+l); MS (ES-): 461.00 & 463.00 (M-l); Analysis calculated for Ci7Hi6BrFN«O2.2.0 H2O: C, 40.89; H, 4.04; N, 22.44; Found: C, 41.06; H, 4.05; N, 22.30.

Scheme 94

Preparation of (lR,3S,5R)-benzyl 2-(2-(6-amino-9H-purin-9-yl)acetyl)-2- azabicyclo[3.1.0]hexane-3 -carboxy late (94b)

Compound 94b was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(6-amino-9H-puiin-9-yl)acetic acid (67a) (2.127 g, 11.01 mmol) in DMF (30 mL) and using TFA salt of ( lR,3S,5R)-benzyl 2-azabicyclo[3.1 ,0]hexane-3-carboxylate (94a) (4.56 g, 13.76 mmol; CAS # 1386459-65-9), HATU (6.28 g, 16.52 mmol), DIPEA (7.67 mL, 44.0 mmol) and stirring at RT for 16 h. This gave after woikup and purification by flash column chromatography [silica gel (40 g), DMA-80 in DCM from 0 - 50%] ( lR,3S,5R)-benzyl 2-(2- (6-amino-9H-purin-9-yl)acetyl)-2-azabicycIo[3.1 ,0]hexane-3-caiboxylate (94b) (2.83 g, 65.5 % yield) as a yellow solid; Ή NMR (300 MHz, DMSO-dk) δ 8.13 (s, 1H), 8.06 (s, 1H), 7.41 - 7.24 (m, 7H), 5.43 (d, J = 17.2 Hz, 1H), 5.20 - 5.03 (m, 3H), 4.33 (dd, J = 9.3, 5.6 Hz, 1H), 3.77 (ddd, J = 7.1, 5.5, 2.4 Hz, 1H), 2.42 - 2.28 (m, 1H), 2.23 - 2.09 (m, 1H), 1.94 - 1.83 (m, 1H), 1.07 - 0.94 (m, 1H), 0.81 - 0.71 (m, 1H); MS (ES+): 393.1 (M+l); Analysis calculated for C20H20N6O3.2H20.1.75HC1: C, 48.80; H, 5.27; N, 17.07; Found: C, 48.78; H, 5.17; N, 17.01.

Scheme 95

Preparation of (lR,3S,5R)-2-(2-(6-amino-9H-purm-9-yl)acetyl)-N-(3,3-dimethy lbutyl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (95c)

Step-1: Preparation of (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-2- azabicyclo[3.1 0]hexane-3-carboxylic acid (95a)

To a solution of ( lR,3S,5R)-benzyl 2-(2-(6-amino-9H-purin-9-yl)acetyl)-2- azabicyclo[3.1.0]hexane-3-carboxylate (94b) (300 mg, 0.765 mmol) in MeOH (20 mL) was added 10% Pd/C (100 mg, 0.093 mmol). The reaction mixture was shaken for 5 hours under a hydrogen atmosphere (50-55 psi), filtered through a pad of Celite and the pad was washed with methanol. The filtrate was concentrated in vacuum and residue obtained was purified by reverse-phase column chromatography [C-18 column (50 g), eluting with ACN in water (containing 0.1% HCl) from 0-100%] to afford (lR,3S,5R)-2-(2-(6-amino-9H-purin-9- yl)acetyl)-2-azabicyclo[3.1 ,0]hexane-3-carboxylic acid (95a) (145 mg, 63% yield) HCl salt as a white solid; Ή NMR (300 MHz, DMSO-fik) δ 9.62 (s, 1H), 8.88 (s, 1H), 8.52 (s, 1H), 8.46 (s, 1H), 5.57 (d, J = 17.2 Hz, 1H), 5.28 (d, J = 17.1 Hz, 1H), 4.20 (dd, J = 9.2, 5.2 Hz, 1H), 3.72 (td, J = 6.2, 5.2, 2.3 Hz, 1H), 2.38 - 2.25 (m, 1H), 2.19 (dq, J = 13.0, 6.4, 5.8 Hz, 1H), 1.28 (dd, J = 9.8, 6.5 Hz, 1H), 1.09 - 0.91 (m, 1H), 0.73 (td, J = 5.1, 2.5 Hz, 1H). MS (ES+): 303.1 (M+l), (ES-): 301.1 (M-l).

Step-2: Preparation of (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(3,3- dimethylbutyl)-2-azabicyclo[3.1 ,0]hexane-3-caiboxamide (95c)

Compound 95c was prepared according to the procedure reported in step-3 of scheme- 1, from (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-2-azabicyclo[ 3.1.0]hexane-3-cafboxylic acid (95a) 135mg, 0.447 mmol) in DMF (1.5 mL) using HCl salt of 3,3-dimethylbutan-l- amine (95b) (4.56 g, 13.76 mmol; CAS # 30654-98-8), HATU (255 mg, 0.670 mmol), DIPEA (0.311 mL, 1.786 mmol) and stirring at RT for 16 h. This gave after workup and purification by reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HCl) from 0-100%] followed by purification using flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 50%] (1R,3S,5R)- 2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(3,3-dimethyIbutyl)-2- azabicyclo[3.1.0]hexane-3- (s, 1H), 8.05 (s, 1H), 7.75 (t, J = 5.7 Hz, 1H), 7.22 (s, 2H), 5.35 (d, J = 17.1 Hz, 1H), 5.13 (d, J = 17.0 Hz, 1H), 4.18 (dd, J = 8.3, 5.0 Hz, 1H), 3.65-3.59 (m, 1H), 3.10 - 2.96 (m, 2H), 2.24 - 2.08 (m, 2H), 1.81 (s, 1H), 1.33 - 1.22 (m, 2H), 1.10 - 0.97 (m, 1H), 0.87 (s, 9H), 0.73 - 0.63 (m, 1H); MS (ES+): 386.2 (M+l); Analysis calculated for C19H27N7O2.1.25H ₂ 0: C, 55.93; H, 7.29; N, 24.03; Found: C, 56.04; H, 7.35; N, 23.94.

Scheme 96

NH, NH,

1 H H 1 H

/ N s

CI^ IN^ l N /) TEA \ ji 1 )

N^N^N •J K ₂ Uco ₃ -.J I Xt

I o

96a 96b 96c

NH· O F

.Cl

N'V'l N l H it·· NH \ N Vrn

LiOH 66a N N _x F

OH /

I HATH, DIPEA N^-N

96d O NH ₂ 96e

Preparation of (lR,3S,5R)-2-(2-(6-amino-2-(dimethylamino)-9H-purin-9-yl)ace tyl)-N-(3- chloro-2-fluorobenzyl)-2-azabicyclo [3.1 ,0]hexane-3-carboxamide (96e)

Step-1: Preparation of N2,N2-dimethyl-7H-purine-2,6-diamine (96b)

To a stirred suspension of 2-chloro-7H-purin-6-amine (96a) (1 g, 5.90 mmol; CAS# 1839-18- 5) in isopropanol (10 mL) was added triethylamine (1.644 mL, 11.79 mmol) and dimethylamine (0.717 mL, 7.08 mmol) and heated in a microwave atl50 °C for 1.5 h. The solid separated was collected by filtration to afford N2,N2-dimethyl-7H-purine-2,6-diamine (96b) (750mg, 71.4 % yield) as a white solid; ΉΝΜΚ (300 MHz, DMSO-cfc) δ 12.19 (s,

1H), 7.67 (s, 1H), 6.65 (s, 2H), 3.05 (s, 6H); MS (ES+): 179.10 (M+l).

Step-2: Preparation of tort-butyl 2-(6-amino-2-(dimethylamino)-9H-purin-9-yl)acetate (96c)

Compound 96c was prepared according to the procedure reported in step-1 of scheme- 1, from N2,N2-dimethyl-7H-purine-2, 6-diamine (96b) (500 mg, 2.81 mmol) in N,N- dimethylformamide (5 mL) using tort-butyl 2-bromoacetate (0.498 mL, 3.37 mmol), K2CO3 (582 mg, 4.21 mmol) and stirring at RT for 10 h. This gave after workup and purification by from 0-100%] tort-butyl 2-(6-amino-2-(dimethylamino)-9H-purin-9-yl)acetate (96c) (620 mg, 76% yield) as a bright yellow solid; Ή NMR (300 MHz, DMSO^) δ 7.68 (s, 1H), 6.74 (s, 2H), 4.75 (s, 2H), 3.04 (s, 6H), 1.42 (s, 9H); MS (ES+): 293.20 (M+l).

Step-3: Preparation of 2-(6-amino-2-(dimethylamino)-9H-purin-9-yl)acetic acid (96d)

Compound 96d was prepared according to the procedure reported in step-4 of scheme- 17, from tort-butyl 2-(6-amino-2-(dimethylamino)-9H-purin-9-yl)acetate (96c) (600 mg, 2.052 mmol) in THF (5 mL), methanol (5.0 mL), water (5 mL) using lithium hydroxide (147 mg, 6.16 mmol) and stirring overnight at RT. This gave after workup 2-(6-amino-2- (dimethylamino)-9H-purin-9-yl)acetic acid (96d) (352 mg, 73 % yield) as a yellow solid; Ή NMR (300 MHz, DMSO-ifc) δ 7.70 (s, 1H), 6.75 (s, 2H), 4.77 (s, 2H), 3.05 (s, 6H).

Step-4: Preparation of (lR,3S,5R)-2-(2-(6-amino-2-(dimethylamino)-9H-purin-9-yl)ace tyl)- N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[3.1.0]hexane-3-carb oxamide (96e)

Compound 96e was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(6-amino-2-(dimethylamino)-9H-purin-9-yl)acetic acid (96d) (150 mg, 0.635 mmol) in DMF (3 mL) using HC1 salt of (lR,3S,5R)-N-(3-chloro-2-fluorobenzyl)-2- azabicyclo[3.1 ,0]hexane-3-caiboxamide (66a) (242 mg, 0.794 mmol), HATU (362 mg, 0.952 mmol), DIPEA (0.442 mL, 2.54 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with EtOAc/MeOH (9: 1) in dioxane from 0 - 100%] followed by purification using reverse phase column chromatography [CIS column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] to afford (lR,3S,5R)-2-(2-(6-amino-2-(dimethylamino)-9H-purin-9- yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (96e) (240 mg, 78% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc + DzO) δ 8.57 (t, J = 6.0 Hz, 1H), 8.16 (d, J= 6.1 Hz, 1H), 7.45 (t ,J= 7.6 Hz, 1H), 7.21 (t ,J= 7.3 Hz, 1H), 7.10 (t, .7= 7.9 Hz, 1H), 5.29 (dd ,J= 17.1, 3.1 Hz, 1H), 5.15 (d,J= 17.0 Hz, 1H), 4.33 (t ,J= 6.9 Hz, 2H), 4.28 - 4.19 (m, 1H), 3.13 (s, 6H), 2.28 (dd,J= 13.5, 9.2 Hz, 1H), 2.14 (dt, J= 12.9, 6.0 Hz, 1H), 1.88 (p,J= 7.1 Hz, 2H), 1.07 (dt, J= 9.5, 5.4 Hz, 1H), 0.68 (d, J= 6.0 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO-de) δ -121.73; MS (ES+): 487.2 (M+l); (ES-): 485.10 (M-l).

Scheme 97

Preparation of (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(3,3-dimeth ylcyclohexyl)- 2-azabicyclo[3.1.0]hexane-3-carboxamide (97b)

Compound 97b was prepared according to the procedure reported in step-3 of scheme- 1, from ( lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-2-azabicyclo[3 .1 ,0]hexane-3- carboxylic acid (95a) 150mg, 0.496 mmol) in DMF (1.5 mL) using 3,3- dimethylcyclohexanamine (97a) (63.1 mg, 0.496 mmol; CAS # 226549-07-1), HATU (283 mg, 0.744 mmol) DIPEA (0.346 mL, 1.985 mmol) and stirring at RT for 2 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0-100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(3,3-dimeth ylcyclohexyl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (97b) (20mg, 10% yield) HC1 salt as awhile solid; 'HNMR (300 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.43 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 5.54 (d, J = 17.1 Hz, 1H), 5.24 (d, J = 17.1 Hz, 1H), 4.14 (dd, J = 8.9, 4.9 Hz, 1H), 3.70-3.65 (m, 2H), 2.28 - 2.00 (m, 2H), 1.95 - 1.77 (m, 1H), 1.77 - 1.60 (m, 1H), 1.60 - 1.16 (m, 4H), 1.11 - 0.91 (m, 4H), 0.87 (s, 6H), 0.74 - 0.56 (m, 1H); MS (ES+): 412.2 (M+l).

Scheme 98

Preparation of (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-((lR,2S)-2- (2- chlorophenyl)cyclopropyl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (98b) Compound 98b was prepared according to the procedure reported in step-3 of scheme- 1, from (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-2-azabicyclo[ 3.1 ,0]hexane-3- carboxylic acid (95a) (150mg, 0.496 mmol) in DMF (1.5 mL) using (lR,2S)-2-(2- chlorophenyl)cyclopropanamine (98a) (83 mg, 0.496 mmol; CAS # 1820575-68-5), HATU (283 mg, 0.744 mmol), DIPEA (0.346 mL, 1.985 mmol) and stirring at RT for 2 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-((lR,2S)-2- (2- chlorophenyl)cyclopropyl)-2-azabicyclo[3.1.0]hexane-3-carbox amide (98b) (39 mg, 17 % yield) HC1 salt as a white solid; *HNMR (300 MHz, DMSO-rfe) δ 8.50 — 8.33 (m, 2H), 8.23 (d, J= 4.8 Hz, 1H), 7.40 (dt,J= 7.4, 1.8 Hz, 1H), 7.31 - 7.14 (m, 2H), 7.08 (dd, J= 7.4, 2.1 Hz, 1H), 5.54 (d, J= 17.1 Hz, 1H), 5.25 (d, J = 17.0 Hz, 1H), 4.22 - 4.11 (m, 1H), 3.75 - 3.64 (m, 1H), 3.01 - 2.88 (m, 1H), 2.29 - 2.07 (m, 3H), 1.89 - 1.83 (m, 1H), 1.30 - 1.17 (m, 1H), 1.17 - 1.04 (m, 1H), 1.08 - 0.97 (m, 1H), 0.72 - 0.65 (m, 1H); MS (ES+) 452.1 (M+l); Analysis calculated for C22H22ClN7O2.HCl.3H2O: C, 48.71; H, 5.39; Cl, 13.07; N, 18.08; Found: C, 48.61; H, 5.22; Cl, 13.33; N, 18.00.

Scheme 99

Preparation of (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(2- (trifhioromethoxy)ethyl)-2-azabicyclo[3.1.0]hexane-3-carboxa mide (99b)

Compound 99b was prepared according to the procedure reported in step-3 of scheme- 1, from (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-2-azabicyclo[ 3.1.0]hexane-3-carboxylic acid (95a) (150 mg, 0.496 mmol) in DMF (1.5 mL) using 2-(trifluoromethoxy)ethanamine (99a) (64.1 mg, 0.496 mmol; CAS # 886050-51-7), HATU (283 mg, 0.744 mmol), DIPEA (0.346 mL, 1.985 mmol) and stirring at RT for 2 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(6-amino- 9H-purin-9-yl)acetyl)-N-(2-(trifluoromethoxy)ethyl)-2-azabic yclo[3.1 ,0]hexane-3- carboxamide (99b) (17 mg, 8% yield) as a white solid; Ή NMR (300 MHz, DMSO-tife) δ 9.55 (s, 1H), 8.86 (s, 1H), 8.51 (s, 1H), 8.45 (s, 1H), 8.26 (t, J= 5.7 Hz, 1H), 5.57 (d, J= 17.1 Hz, 1H), 5.25 (d, 17.0 Hz, 1H), 4.22 (dd, 9.0, 4.6 Hz, 1H), 4.04 (t ,J= 5.4 Hz, 2H), 3.69 -

3.64 (m, 1H), 3.39 - 3.16 (m, 2H), 2.30 - 2.01 (m, 2H), 1.89 - 1.74 (m, 1H), 1.11 - 0.94 (m, 1H), 0.78 - 0.61 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO-d6) δ -58.83; MS (ES+): 414.1 (M+l).

Scheme 100

Preparation of (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-((3- methylcyclobutyl)methyl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (100b)

Compound 100b was prepared according to the procedure reported in step-3 of scheme- 1, from ( lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-2-azabicyclo[3 .1 ,0]hexane-3- cafboxylic acid (95a) (150 mg, 0.496 mmol) in DMF (1.5 mL) using (3- methylcyclobutyl)methanamine (100a) (98 mg, 0.992 mmol; CAS # 1445951-46-1), HATU (283 mg, 0.744 mmol), DIPEA (0.346 mL, 1.985 mmol) and stirring at RT for 3 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] ( lR,3S,5R)-2-(2-(6-ammo-9H-purm-9-yl)acetyl)-N-((3-methylcycl obutyl)methyl)- 2-azabicyclo[3.1 ,0]hexane-3-carboxamide (100b) (19 mg, 10% yield) HC1 salt as a white solid; ¾ NMR (300 MHz, DMSO-cfc) δ 9.61 (s, 1H), 8.87 (s, 1H), 8.52 (s, 1H), 8.45 (s, 1H), 7.95 - 7.76 (m, 1H), 5.57 (dd, J= 17.2, 1.3 Hz, 1H), 5.26 (dd, J= 17.0, 1.5 Hz, 1H), 4.30 - 4.14 (m, 1H), 3.78 - 3.60 (m, 1H), 3.26 - 2.86 (m, 2H), 2.44 - 1.90 (m, 3H), 1.93 - 1.70 (m, 2H), 1.62 - 1.42 (m, 2H), 1.39 - 0.82 (m, 6H), 0.78 - 0.61 (m, 1H); MS (ES+): 384.2 (M+l). Scheme 101

Preparation of (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-benzyl-2- azabicyclo[3.1.0]hexane-3-carboxamide (101b)

Compound 101b was prepared according to the procedure reported in step-3 of scheme- 1, from ( 1 R,3 S ,5 R)-2-(2-(6-amino-9H-purin-9-yl)acety 1 )-2-azabicyclo [3.1 ,0]hexanc-3- carboxylic acid (95a) (150 mg, 0.496 mmol) in DMF (1.5 mL) using phenylmethanamine (101a) (80 mg, 0.744 mmol; CAS # 100-46-9), HATU (283 mg, 0.744 mmol), DIPEA (0.346 mL, 1.985 mmol) and stirring at RT for 2 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] ( 1R,3 S,5R)-2-(2-(6-amino- 9H-purin-9-yl)acetyl)-N-bcnzyl-2-azabicyclo[3.1.0]hexane-3-c arboxamide (101b) (51 mg, 26% yield) HC1 salt as a white solid; ^! H NMR (300 MHz, DMSO-tifc) δ 9.38 (s, 1H), 8.73 (s, 1H), 8.52 - 8.44 (m, 2H), 8.43 (s, 1H), 7.36 - 7.17 (m, 5H), 5.55 (d ,J= 17.1 Hz, 1H), 5.27 (d, J= 17.1 Hz, 1H), 4.35 - 4.19 (m, 3H), 3.73 - 3.67 (m, 1H), 2.33 - 2.10 (m, 2H), 1.93 - 1.84 (m, 1H), 1.13 - 1.01 (m, 1H), 0.77 - 0.67 (m, 1H); MS (ES+): 392.2 (M+l).

Scheme 102

Preparation of (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(3,3-dichlo rocyclohexyl)- 2-azabicyclo[3.1.0]hexane-3-carboxamide (102b)

Compound 102b was prepared according to the procedure reported in step-3 of scheme- 1, carboxylic acid (95a) (90 mg, 0.298 mmol) in DMF (1 mL) using 3,3- dichlorocyclohexanamine (102a) (50 mg, 0.298 mmol; CAS # 226549-07-1), HATU (170 mg, 0.446 mmol), DIPEA (0.207 mL, 1.190 mmol) and stirring at RT for 2 h. This gave after workup and purification twice by reverse phase column chromatography [C 18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] followed by purification twice using flash column chromatography [silica gel (12 g), DMA80 in DCM from 0 - 100%] (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(3,3-dichlo rocyclohexyl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (102b) (10 mg, 7% yield) as a white solid; ^! H NMR (300 MHz, DMSO-tife) δ 8.15 (s, 1H), 8.08 (d, J= 3.6 Hz, 1H), 7.80 (dd, 8.1, 2.1 Hz, 1H), 7.33 (s, 2H), 5.36 (dd,J= 17.1, 1.5 Hz, 1H), 5.14 (d ,J= 17.1 Hz, 1H), 4.13 (dd,J= 8.8, 5.2 Hz, 1H), 3.93 - 3.77 (m, 1H), 3.71 - 3.60 (m, 1H), 2.45 - 2.34 (m, 1H), 2.27 - 2.00 (m, 4H), 1.94 - 1.50 (m, 5H), 1.34 - 1.13 (m, 1H), 1.08 - 0.95 (m, 1H), 0.71 - 0.62 (m, 1H); MS (ES+): 452.1 (M+l).

Scheme 103

Preparation of (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-((2,2- dichlorocyclopropyl)methyl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (103b)

Compound 103b was prepared according to the procedure reported in step-3 of scheme- 1, from (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-2-azabicyclo[ 3.1.0]hexane-3- carboxylic acid (95a) (120 mg, 0.397 mmol) in DMF (1 mL) using (2,2- dichlorocyclopropyl)methanamine (103a) (55.6 mg, 0.397 mmol; CAS # 226549-07-1), HATU (226 mg, 0.595 mmol), DIPEA (0.207 mL, 1.191 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), using DMA-80 in DCM from 0 to 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-((2,2- dichlorocyclopropyl)methyl)-2-azabicyclo[3.1.0]hexane-3-carb oxamide (103b) (67 mg, 40% 8.20 - 8.10 (m, 1H), 5.49 (d, J= 17.1 Hz, 1H), 5.23 (d, J= 17.0 Hz, 1H), 4.28 - 4.19 (m,

1H), 3.72 - 3.63 (m, 1H), 3.30 - 3.11 (m, 2H), 2.30 - 2.02 (m, 2H), 1.93 - 1.75 (m, 2H), 1.68 (ddd, J= 10.8, 7.2, 3.6 Hz, 1H), 1.34 (t, J= 7.5 Hz, 1H), 1.05 (dt, J= 9.6, 5.3 Hz, 1H), 0.74 - 0.62 (m, 1H); MS (ES+) 424.1 (M+l).

Scheme 104

E %

Preparation of (2S,4R)-l-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(3-chloro-2-fl uorobenzyl)-4- fluoropyrrolidine-2-caiboxamide (104a)

Compound 104a was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(6-amino-9H-purin-9-yl)acetic acid (67a) (lOOmg, 0.518 mmol) in DMF (2 mL) using (2S,4R)-N-(3-chloro-2-fluorobenz>'l)-4-fluoropyrrolidine- 2-caiboxamide (7a) (142 mg, 0.518 mmol), HATU (295 mg, 0.777 mmol), DIPEA (0.271 mL, 1.553 mmol) and stirring at RT for 16 h. This gave after workup and purification by reverse phase column chromatography [Cl 8 column (30 g), eluting with ACN in water (containing 0.1% HC1) from 0- 100%] (2S,4R)- 1 -(2-(6-amino-9H-puiin-9-yl)acetyl)-N-(3-chloro-2-fluorobenzy l)-4- fluoropyrrolidine-2-carboxamide (104a) (57 mg, 24% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-flfe) δ 8.64 (t, J= 5.9 Hz, 1H), 8.40 - 8.33 (m, 1H), 8.33 - 8.25 (m, 1H), 7.52 - 7.34 (m, 1H), 7.29 - 7.14 (m, 1H), 7.06 (td, J= 7.9, 1.1 Hz, 1H), 5.63 - 5.06 (m, 3H), 4.92 - 3.72 (m, 5H), 2.21 - 1.86 (m, 1H); MS (ES+) 450.1 (M+l); Analysis calculated for C19H18CIF2N7O2.2.5H2O.HCI: C, 42.95; H, 4.55; Cl, 13.34; N, 18.45; Found: C, 42.80; H, 4.26; Cl, 13.15; N, 18.25.

Scheme 105

Preparation of (S)-3-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(3-chloro-2- fluorobenzyl)thiazolidine-2-carboxamide (105b)

Compound 105b was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(6-amino-9H-purin-9-yl)acetic acid (67a) (100 mg, 0.518 mmol) in DMF (2 mL) using (S)-N-(3-chloro-2-fluorobenzyl)thiazolidine-2-carboxamide (105a) [142 mg, 0.518 mmol; prepared according to the procedure reported by Altmann, Eva et al., PCT Int. Appl. (2012), WO 2012093101 Al 20120712], HATU (295 mg, 0.777 mmol), DIPEA (0.271 mL, 1.553 mmol) and stirring at RT for 16 h. The solid obtained was collected by filtration washed with water, ethyl acetate and dried to yield (S)-3-(2-(6-amino-9H-purin-9-yl)acetyl)- N-(3-chloro-2-fluorobenzyl)thiazolidine-2-carboxamide (105b) (75mg, 32% yield) as a white solid; ΉΝΜΚ (300 MHz, DMSO-tife) δ 8.62 (t, J= 5.9 Hz, 1H), 8.15 - 8.09 (m, 1H), 8.02 (s, 1H), 7.46 (td, J= 7.6, 1.8 Hz, 1H), 7.32 - 7.19 (m, 3H), 7.12 (td, J= 7.8, 1.0 Hz, 1H), 5.44 (s, 1H), 5.32 - 5.11 (m, 2H), 4.52 - 3.74 (m, 4H), 3.40 - 3.09 (m, 2H); MS (ES+): 450.1 (M+l); (ES-): 448.1 (M-l).

Scheme 106

H ₂ N

?

95a 106b

Preparation of (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(5-hydroxy- 3,3- dimethylcyclohexyl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (106b) Compound 106b was prepared according to the procedure reported in step-3 of scheme- 1, from ( lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-2-azabicyclo[3 .1 ,0]hexane-3- carbox>'lic acid (95a) (120 mg, 0.397 mmol) in DMF (1 mL) using racemic-(lR,5S)-5- amino-3 ,3-dimethylcyclohexan-ol (106a) (56.9 mg, 0.397 mmol); CAS # 1529781-98-3), HATU (189 mg, 0.496 mmol), DIPEA (0.207 mL, 1.191 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 to 100%] followed by purification using reverse phase column chromatography [C18 column (150 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(5-hydroxy- 3,3- dimethylcyclohexyl)-2-azabicyclo[3.1 0]hexane-3-carboxamide (106b) (40mg, 24% yield) (racemic mixture) HCl salt as a white solid; Ή NMR (300 MHz, DMSO-i/e) δ 8.47 (s, 1H), 8.42 (s, 1H), 7.65 - 7.54 (m, 1H), 5.53 (d,J= 17.1 Hz, 1H), 5.24 (d, J= 17.0 Hz, 1H), 4.21 - 4.07 (m, 1H), 3.89 - 3.22 (m, 3H), 2.24 - 1.99 (m, 2H), 1.94 - 1.76 (m, 2H), 1.60 - 1.42 (m, 1H), 1.42 - 1.27 (m, 1H), 1.08 - 0.89 (m, 4H), 0.89 (s, 3H), 0.85 (s, 3H), 0.73 - 0.57 (m,

1H); Analysis calculated for C21H29N7O3.I.5H2O.2.75HCI.: C, 45.46; H, 6.31; Cl, 17.57; N, 17.67; found: C, 45.75; H, 6.68; Cl, 17.63; N, 17.68.

Scheme 107

Preparation of (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(3- (trifluoromethoxy)phenyl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (107b)

Compound 107b was prepared according to the procedure reported in step-3 of scheme- 1, from (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-2-azabicyclo[ 3.1.0]hexane-3-carboxylic acid (95a) (120 mg, 0.397 mmol) in DMF (1 mL) using 3 -(trifluoromethoxy)aniline (107a) (55.6 mg, 0.397 mmol; CAS # 1535-73-5), HATU (226 mg, 0.595 mmol), DIPEA (0.207 mL, 1.191 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 to 100%] followed by purification using reverse phase column chromatography [C18 column (150 g), 9H-purin-9-yl)acetyl)-N-(3-(trifluoromethoxy)phenyl)-2-azabi cyclo[3.1.0]hexane-3- carboxamide (107b) (97 mg, 53% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO- db) δ 10.20 (s, 1H), 8.12 (s, 1H), 8.06 (s, 1H), 7.77 - 7.74 (m, 1H), 7.54 - 7.36 (m, 2H), 7.19 (s, 2H), 7.06 - 7.00 (m, 1H), 5.41 (d, J= 17.2 Hz, 1H), 5.18 (d, J= 17.1 Hz, 1H), 4.33 (dd, J = 8.8, 5.6 Hz, 1H), 3.76 (ddd, J= 7.2, 5.4, 2.4 Hz, 1H), 2.39 - 2.16 (m, 2H), 2.00 - 1.80 (m, 1H), 1.05 (dt, J= 8.7, 5.4 Hz, 1H), 0.74 (td, J= 5.1, 2.4Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO- de) δ -56.65; MS (ES+): 462.1 (M+l).

Scheme 108

95a 108b

Preparation of (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(2-fluoro-3 - methoxyphenyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (108b)

Compound 108b was prepared according to the procedure reported in step-3 of scheme- 1, from ( lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-2-azabicyclo[3 .1 ,0]hexane-3- carboxylic acid (95a) (120 mg, 0.397 mmol) in DMF (1 mL) using 2-fluoro-3- methoxyaniline (108a) (67.2 mg, 0.476 mmol; CAS # 801282-00-8), HATU (226 mg, 0.595 mmol), DIPEA (0.207 mL, 1.191 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 to 100%] followed by purification using reverse phase column chromatography [C18 column (150 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(2-fluoro-3 -methoxyphenyl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (108b) (65 mg, 39% yield) HC1 salt as a white solid; ¾NMR (300 MHz, DMSCMs) δ 9.69 (s, 1H), 8.48 (s, 1H), 8.44 (s, 1H), 7.40 - 7.33 (m, 1H), 7.05 (td,J= 8.3, 1.8 Hz, 1H), 6.93 (td, J= 8.2, 1.6 Hz, 1H), 5.58 (d,J= 17.2 Hz, 1H), 5.29 (d, J= 17.1 Hz, 1H), 4.52 (dd,J= 8.5, 5.5 Hz, 1H), 3.82 (s, 3H), 3.80 - 3.65 (m, 1H), 2.37 - 2.16 (m, 2H), 1.97 - 1.84 (m, 1H), 1.07 (dt, J= 9.2, 5.3 Hz, 1H), 0.72 (td, J= 5.1, 2.4 Hz, 1H); ¹⁹ FNMR (282 MHz, DMSO-ds) δ -147.09 (t, J = 7.3 Hz); MS (ES+): 426.1 (M+l). x

HATU, DIPEA Cl

NH ₂ 1098

Preparation of (IS, 3S,5S)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(3-chloro-2-flu orobenzyl)- 2-azabicyclo[3.1 ,0]hexane-3-caiboxamide (109e)

Step-1: Preparation of terf-butyl (lS,3S,5S)-3-((3-chloro-2-fhiorobenzyl)caibamoyl)-2- azabicyclo[3.1.0]hexane-2-carboxylate (109c)

Compound 109c was prepared according to the procedure reported in step-3 of scheme- 1, from ( 1 S,3S,5S)-2-(ter/-butoxycarbonyI)-2-azabicyclo[3.1.0]hexane-3 -carboxylic acid (109a) (0.5 g, 2.2 mmol; CAS # 197142-36-2) using (3-chloro-2-fluorophenyl)methanamine (109b) (0.386 g, 2.420 mmol; CAS # 72235-55-3), (HATU) (1.255 g, 3.30 mmol), DIPEA (1.150 mL, 6.60 mmol) in DMF (5 mL) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (40 g), eluting with MeOH in DCM 0-10%] tert-butyl (lS,3S,5S)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2- azabicyclo[3.1 0]hexane-2-carboxylate (109c) (0.8 g, 99% yield) as a pale-yellow gel; MS (ES+): 391.1 (M+Na).

Step-2: Preparation of (lS,3S,5S)-N-(3-chloro-2-fiuorobenzyl)-2-azabicyclo[3.1.0]he xane-3- carboxamide (109d)

Compound 109d was prepared according to the procedure reported in step-2 of scheme- 1, from /erf-butyl (lS,3S,5S)-3-((3-chloro-2-fIuorobenzyl)carbamoyl)-2- azabicyclo[3.1.0]hexane-2-carboxylate (109c) (0.75 g, 2.033 mmol) using TFA (0.627 mL, 8.13 mmol) in DCM (6 mL) and stirring overnight at room temperature. This gave after workup and purification by reverse phase column chromatography [C18 (140 g) eluting with fluorobenzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (109d); Ή NMR (300 MHz, DMSO-flfe) δ 10.33 (s, 1H), 9.11 (t ,J= 5.7 Hz, 1H), 8.79 (d,J = 9.1 Hz, 1H), 7.52 (ddd, J= 7.9, 7.1, 1.8 Hz, 1H), 7.33 (ddd, J= 7.8, 6.7, 1.8 Hz, 1H), 7.22 (td,J= 7.8, 1.1 Hz, 1H), 4.54 (s, 1H), 4.39 (d, ./= 5.6 Hz, 2H), 3.29 (s, 1H), 2.55 (s, 1H), 2.10 (dd, J= 13.7, 3.1 Hz, 1H), 1.75 (dq, J= 9.0, 5.4 Hz, 1H), 0.90 - 0.76 (m, 1H), 0.65 (ddd, 7.1, 5.0, 2.6 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO-de) δ -121.11; MS (ES+): 269.1 (M+l).

Step-3: Preparation of ( 1 S,3 S,5 S)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(3-chloro-2- fluorobenzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (109e)

Compound 109e was prepared according to the procedure reported in step-3 of scheme- 1, from (lS,3S,5S)-N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[3.1.0]he xane-3-carboxamide (109d) (139 mg, 0.518 mmol) in DMF (2 mL) using 2-(6-amino-9H-purin-9-yl)acetic acid (lOOmg, 0.518 mmol) (67a), HATU (295 mg, 0.777 mmol), DIPEA (0.271 mL, 1.553 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 to 100%] followed by purification using reverse phase column chromatography [C18 column (150 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lS,3S,5S)-2-(2-(6-amino-9H- purin-9-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[ 3.1.0]hexane-3-carboxamide (109e) (71mg, 31% yield) as a white solid; Ή NMR (300 MHz, DMSO-afe) δ 8.49 (t, J= 5.8 Hz, 1H), 8.42 (s, 1H), 8.35 (s, 1H), 7.52 - 7.37 (m, 1H), 7.29 - 7.18 (m, 1H), 7.10 (td,./= 7.9, 1.0 Hz, 1H), 5.52 (d ,J= 17.0 Hz, 1H), 5.27 (d, J= 17.0 Hz, 1H), 4.67 (dd, J= 11.2, 3.4 Hz, 1H), 4.49 - 4.10 (m, 2H), 3.86 - 3.69 (m, 1H), 2.63 - 2.51 (m, 1H), 1.89 - 1.67 (m, 2H), 1.16 (td, J= 5.1, 2.4 Hz, 1H), 0.89 - 0.78 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-ifc) δ - 121.60; MS (ES+): 444.1 (M+l).

Scheme 110

7a Cl H ₂ N ⁰

HATU, DIPEA

110d KJ ^~F

Cl

Preparation of (2S,4R)-l-(2-(6-amino-8-bromo-9H-purin-9-yl)acetyl)-N-(3-chl oro-2- fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (HOd)

Step-1: Preparation of te/7-butyl 2-(6-amino-8-bromo-9H-purin-9-yl)acetate (110b)

Compound 110b was prepared according to the procedure reported in step-1 of scheme- 1, from 8-bromo-9H-purin-6-amine (110a) (1 g, 4.67 mmol; CAS#6974-78-3) in DMF (10 mL) using terf-butyl 2-bromoacetate and K2CO3 (0.775 g, 5.61 mmol). This gave after workup and recrystallization with ethyl acetate tert- butyl 2-(6-amino-8-bromo-9H-purin-9-yl)acetate (110b) (550 mg, 36% yield); Ή NMR (300 MHz, DMSO-tife) δ 8.33 (s, 1H), 8.31 (s, 1H), 8.15 (s, 1H), 5.04 (s, 2H), 1.43 (s, 9H).

Step-2: Preparation of 2-(6-amino-8-bromo-9H-purin-9-yl)acetic acid (110c)

Compound 110c was prepared according to the procedure reported in step-4 of scheme- 17, from /erf-butyl 2-(6-amino-8-bromo-9H-purin-9-yl)acetate (110b) (0.5 g, 1.524 mmol) in THF (1.676 mL) and MeOH (1.676 mL) using 2N sodium hydroxide (0.838 mL, 1.676 mmol) and stirring at RT for 45 min. This gave after workup 2-(6-amino-8-bromo-9H-purin- 9-yl)acetic acid (110c) (346 mg, 83% yield); Ή NMR (300 MHz, DMSO-i/e) δ 8.31 (s, 1H), 5.04 (s, 2H).

Step-3: Preparation of (2S,4R)-l-(2-(6-amino-8-bromo-9H-purin-9-yl)acetyl)-N-(3-chl oro-2- fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (HOd)

Compound 1 lOd was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(6-amino-8-bromo-9H-purin-9-yl)acetic acid (110c) (141mg, 0.518 mmol) in DMF (2 mL) 0.518 mmol), HATU (296 mg, 0.777 mmol), DIPEA (0.271 mL, 1.555 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 to 100%] followed by purification using reverse phase column chromatography [C18 column (150 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)-l-(2-(6-amino-8-bromo-9H-purin-9-yl)acetyl)- N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamid e (HOd) (123 mg, 45% yield) as a white solid; Ή NMR (300 MHz, DMSO-i/e) δ 8.63 (t, J= 5.9 Hz, 1H), 8.38 (s, 2H), 8.29 (s, 1H), 7.52 - 7.32 (m, 1H), 7.28 - 7.13 (m, 1H), 7.07 - 7.00 (m, 1H), 5.64 - 5.12 (m, 3H), 4.94 - 3.75 (m, 5H), 2.57 - 1.93 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-flk) δ -121.69, -173.83 - -179.95; MS (ES+): 528.0 (M+l).

Scheme 111

Preparation of (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)ace1yl)-N-(2-fluoro-3 -methylbut-2- en- 1 -yl)-2-azabicyclo [3.1.0]hexane-3 -carboxamide (111b)

Compound 11 lb was prepared according to the procedure reported in step-3 of scheme- 1, from 2-fluoro-3-methy lbut-2-en- 1 -amine (111a) (61.4 mg, 0.595 mmol; prepared according to the procedure reported by Flohr, Stefanic et al; in PCX Int. Appl., 2014002052, 03 Jan 2014) in DMF (1 mL) using (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyI)-2- azabicyclo[3.1 ,0]hexane-3-carboxyhc acid (95a) (120 mg, 0.397 mmol), HATU (226 mg, 0.595 mmol), DIPEA (0.277 mL, 1.588 mmol) and stirring at RT for 16 h. This gave after workup and purification by reverse phase column chromatography [Cl 8 column (150 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(6-amino- 9H-purin-9-yl)acetyl)-N-(2-fluoro-3-methylbut-2-en- l-yl)-2-azabicyclo[3.1 ,0]hexane-3- carboxamide (111b) (35 mg, 23% yield) HC1 salt as a white solid; Ή NMR (300 MHz, OMSO-ck) δ 8.49 (s, 1H), 8.42 (s, 1H), 8.17 (t, J= 5.6 Hz, 1H), 5.53 (d,J= 17.1 Hz, 1H), 525 (d J= 17 1 Hz 1H) 423 (dd ./= 90 46 Hz 1H) 3 86 (dt ./= 21 9 5 6 Hz 2H) 3 70 = 3.3 Hz, 3H), 1.13 - 0.97 (m, 1H), 0.75 - 0.61 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-ifc) δ - 68.80; MS (ES+): 388.2 (M+l); (ES-): 386.2 (M-l).

Scheme 112

Preparation of (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(6-bromopyr azin-2-yl)-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (112b)

Compound 112b was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(6-amino-9H-purin-9-yl)acetic acid (67a) (47.8 mg, 0.247 mmol) in DMF (2 mL) using (lR,3S,5R)-N-(6-bromopyrazin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (112a) [70 mg, 0.247 mmol; prepared according to the procedure reported by Wiles, Jason A et al., PCT Int. Appl. (2017), WO 2017035355 Al 20170302], HATU (141 mg, 0.371 mmol), DIPEA (0.172 mL, 0.989 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 to 100%] followed by purification using reverse phase column chromatography [C18 column (150 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(6- amino-9H-purin-9-yl)acetyl)-N-(6-bromopyrazin-2-yl)-2-azabic yclo[3.1 ,0]hexane-3- carboxamide (112b) (14 mg, 12% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO- ek) δ 11.17 (s, 1H), 9.26 (d , J= 0.6 Hz, 1H), 8.55 (d , J= 0.6 Hz, 1H), 8.41 (s, 1H), 8.36 (s, 1H), 5.57 (d ,J= 17.2 Hz, 1H), 5.27 (d ,J= 17.1 Hz, 1H), 4.48 (dd, J= 8.9, 5.5 Hz, 1H), 3.86 - 3.70 (m, 1H), 2.39 - 2.15 (m, 2H), 1.97 - 1.81 (m, 1H), 1.14 - 0.94 (m, 1H), 0.73 (td, J = 5.1, 2.4 Hz, 1H); MS (ES+): 458.0, 460.0 (M+l).

Scheme 113

Preparation of (lR,3S,5R)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(6-bromo-3- methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (113a)

Compound 113a was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(6-amino-9H-purin-9-yl)acetic acid (67a) (65 mg, 0.337 mmol) in DMF (1.5 mL) using (IR,3S,5R)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyI-2-azabi cyclo[3.1.0]hexane-3- carboxamide (10a) [115 mg, 0.370 mmol), HATU (192 mg, 0.505 mmol), DIPEA (0.234 mL, 1.346 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 to 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] ( 1R,3 S,5R)-2-(2-(6-amino- 9H-purin-9-yl)acetyl)-N -(6-bromo-3 -methylpyridin-2-yl )-5 -methyl-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (113a) (39 mg, 24% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-tife) δ 10.35 (s, 1H, DzO exchangeable), 9.63 (s, 1H, DzO exchangeable), 8.88 (s, 1H, DzO exchangeable), 8.51 (s, 1H), 8.45 (s, 1H), 7.64 (d, 7= 8.0 Hz, 1H), 7.45 (d, 7= 7.9 Hz, 1H), 5.55 (d, 7= 17.1 Hz, 1H), 5.25 (d, 7= 17.1 Hz, 1H), 4.41 (dd, 7= 9.2, 5.1 Hz, 1H), 3.54 (dd, 7= 5.5, 2.4 Hz, 1H), 2.57 - 2.53 (m, 1H), 2.06 (s, 3H), 2.01 (d, 7= 5.1 Hz, 1H), 1.30 (s, 3H), 1.02 (t, 7 = 5.4 Hz, 1H), 0.92 (dd, 7= 5.2, 2.4 Hz, 1H); MS (ES+): 485.1 (M+l), 507.0 (M+Na); (ES-): 483.0 (M-l); Calculated for CzoHziBrNeOz.l .25(HCl).2.75(HzO): C, 41.38; H, 4.82; Cl, 7.63; N, 19.30 found: C, 41.65;

H, 4.62; Cl, 7.61; N, 19.04.

Scheme 114 HO _x „OH

B

Preparation of (2S,4R)-l-(2-(4-amino-5-(pyridin-3-j'l)-7H-pyrrolo[2,3-d]pyr imi<lin-7- yl)acet>'l)-N-(3-chloro-2-fluorobenz>'l)-4-fluoropyiTo lidine-2-caiboxamide (114ff)

Step-1: Preparation of tort-butyl 2-(4-amino-5 -bromo-7H-pyrrolo [ 2,3 -d] pyrimidin-7 - yl)acetate (114b)

Compound 114b was prepared according to the procedure reported in step-1 of scheme- 1, from 5-bromo-7H-pyrrolo [2, 3 -d] pyrimidin-4-amine (114a) (2 g, 9.39 mmol) in DMF (50 mL) using tort-butyl 2-bromoacetate (1.387 mL, 9.39 mmol), CS2CO3 (3.67 g, 11.27 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (40 g), eluting with EtOAc in Hexane from 0-50%] tort-butyl 2- (4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (114b) (2.68 g, 87% yield) as a light pink solid; MS (ES+): 327.00 (M+l).

Step-2: Preparation of tort-butyl 2-(4-ammo-5-(pyridm-3-yl)-7H-pyrrolo[2,3-d]pyrirniclin-7- yl)acetate (114d)

Compound 114d was prepared according to the procedure reported in step-1 of scheme-59, from tort-butyl 2-(4-amino-5 -bromo-7H-py rrolo [2, 3 -d]pyrimidin-7-yl)acetate (114b) in dioxane (10 mL) using pyridin-3-ylboronic acid (114c) (113 mg, 0.917 mmol; CAS # 1692- 25-7), bis(triphenylphosphine)palladium(n) chloride (97 mg, 0.138 mmol) a solution of potassium carbonate (380 mg, 2.75 mmol) in water (1.250 mL) and heating at 100 °C for 5 h. This gave after workup and purification by chromatography [silica gel (24 g), eluting with d]pyrimidin-7-yl)acetate (114d) (188 mg, 63% yield) as a yellow solid; Ή NMR (300 MHz, DMSO-flfe) δ 8.71 - 8.62 (m, 1H), 8.54 (dd, J= 4.9, 1.6 Hz, 1H), 8.16 (s, 1H), 7.90 - 7.75 (m, 1H), 7.48 (dd, J= 7.9, 4.8 Hz, 1H), 7.43 (s, 1H), 6.24 (s, 2H), 4.95 (s, 2H), 1.43 (s, 9H); MS (ES+): 326.1(M+1).

Step-3: Preparation of 2-(4-amino-5-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl) acetic acid (114e)

Compound 114e was prepared according to the procedure reported in step-4 of scheme- 17, from tert-butyl 2-(4-amino-5-(pyridm-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)a cetate (114d) in THF/MeOH (2 mL; ratio 1:1) using 2N sodium hydroxide (0.318 mL, 0.636 mmol) and stirring at RT for 2 h. This gave after workup 2-(4-amino-5 -(pyridi n -3 -yl )-7H-pyrrolo [2,3 - d]pyrimidin-7-yl)acetic acid (114e) (114 mg, 77% yield) as a yellow solid; ^! H NMR (300 MHz, DMSOntife) δ 8.68 (dd,J= 2.3, 0.9 Hz, 1H), 8.54 (dd, J = 4.8, 1.6 Hz, 1H), 8.16 (s, 1H), 7.84 (dt, J= 7.9, 1.9 Hz, 1H), 7.53 - 7.39 (m, 2H), 6.24 (s, 2H), 4.95 (s, 2H); MS (ES+): 270.10 (M+l).

Step-4: Preparation of (2S,4R)-l-(2-(4-amino-5-(pyri<lin-3-yl)-7H-pyrrolo[2,3-d] pyrimidin-7- yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrc>lidm e-2-carboxamide (114f)

Compound 114f was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-5-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-y]) acetic acid (114e) (lOOmg, 0.371 mmol) in DMF (5 mL) using (2S,4R)-N-(3-chloro-2-fluorobenzyl)-4- fluoropyrrolidine-2-carboxamide (7a) (122 mg, 0.446 mmol), HATU (212 mg, 0.557 mmol), DIPEA (0.259 mL, 1.486 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), using DMA80 in DCM from 0 to 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)-1- (2-(4-amino-5-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl )acetyl)-N-(3-chloro-2- fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (114f) (11 lmg, 57% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-tife) (a mixture of two rotamers) δ 8.91 (s, ./= 2.1 Hz, 1H), 8.82 (d, J= 5.6 Hz, 1H), 9.16 (t, J=5.7 Hz) and 8.69 (t, J= 5.9 Hz) (2t,lH) (DzO exchangeable), 8.57 - 8.18 (m, 2H), 7.98 (dd,J= 8.1, 5.5 Hz, 1H), 7.77 (s, 1H), 7.46 - 7.29 (m, 1H), 7.21 - 7.06 (m, 1H), 6.96 (td, J= 7.9, 1.1 Hz, 1H), 5.57 - 5.13 (m, 3H), 4.91 - 3.72 (m, 5H), 3.82 - 3.24 (s, 2H), 2.54 - 2.35 (m, 1H), 2.13 - 1.83 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-de) δ- 121.31, -121.62, -176.11; MS (ES+): 526.2 (M+l); (ES-): 524.1(M-1), 560.1 (M+Cl); Analysis Calculated for C25H22CIF2N7O2.2HCI.3.5H2O: C, 45.36; H, 4.72; N, 14.81; found: C, 45.43; H, 4.65; N, 14.67.

Scheme 115

Preparation of (2S,4R)- l-(2-(4-anrino-5-(3-(aminomethyl)phenyl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluor opyrrolidine-2-carboxamide

(H5e)

Step-1: Preparation of fert-butyl 2-(4-am ino-5 -(3 -{{(tert- butoxycarbonyl)amino)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimid in-7-yl)acetate (115b)

Compound 115b was prepared according to the procedure reported in step-lof scheme-59, from /erf-butyl 2-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (114b) (300 mg, 0.917 mmol) in dioxane (10 mL) using tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzylcarbamate (115a) (306 mg, 0.917 mmol), bis(triphenylphosphine)palladium(II) chloride (97 mg, 0.138 mmol) a solution of potassium carbonate (380 mg, 2.75 mmol) in water (1.250 mL) and heating at 100 °C for 4 h. This gave after woikup and purification by flash column chromatography [silica gel (24g), eluting with DMA-80 in DCM from 0-50%] tert- butyl 2-(4-amino-5-(3-(((tert- mg, 58% yield) as a clear gel; Ή NMR (300 MHz, DMSO^fe) δ 8.14 (s, 1H), 7.43 (t ,J= 7.5 Hz, 2H), 7.37 - 7.19 (m, 4H), 6.12 (s, 2H), 4.94 (s, 2H), 4.19 (d,7= 6.1 Hz, 2H), 1.43 (s, 9H), 1.39 (s, 9H); MS (ES+): 454.2 (M+l).

Step-2: Preparation of 2-(4-amino-5-(3-(((tort-butoxycarbonyl)amino)methyl)phenyl)- 7H- pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (115c)

Compound 115c was prepared according to the procedure reported in step-4 of scheme- 17, from tort-butyl 2-(4-amino-5-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)- 7H- pyrrolo[2,3-d]pyrimidin-7-yl)acetate (115b) (230 mg, 0.507 mmol) in THF/MeOH (2 mL; ratio 1:1) using 2N sodium hydroxide (0.292 mL, 0.583 mmol) and stirring for 1.5 h atRT. This gave after workup 2-(4-amino-5-(3-(((tort-butoxycarbonyl)amino)methyl)phenyl)- 7H- pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (115c) (137 mg, 68% yield) as a pink solid; ^! H NMR (300 MHz, DMSO-tifc) δ 8.13 (s, 1H), 7.43 (t, J= 7.6 Hz, 2H), 7.37 - 7.14 (m, 4H), 6.11 (s, 2H), 4.93 (s, 2H), 4.19 (d ,J= 6.1 Hz, 2H), 1.39 (s, 9H); MS (ES+): 398.20 (M+l).

Step-3: Preparation of tort-butyl 3-(4-amino-7-(2-((2S,4R)-2-((3-chloro-2- fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-l-yl)-2-oxoethyl) -7H-pyrrolo[2,3-d]pyrimidin-5- yl)benzylcaibamate (115d)

Compound 115d was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-5-(3-(((tort-butoxycarbonyl)amino)methyl)phenyl)- 7H-pyrrolo[2,3- d]pyrimidin-7-yl)acetic acid (115c) (100 mg, 0.252 mmol) in DMF (5 mL) using (2S,4R)-N- (3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (7a) (83 mg, 0.302 mmol), HATU (144 mg, 0.377 mmol), DIPEA (0.175 mL, 1.006 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 to 50 %] tort-butyl 3-(4-amino-7-(2-((2S,4R)-2-((3- chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-l-yl)-2- oxoethyl)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)benzylcarbamate (115d) (156 mg, 95% yield) as a white solid; MS (ES+): 654.3 (M+l).

Step-4: Preparation of (2S,4R)-l-(2-(4-amino-5-(3-(aminomethyl)phenyl)-7H-pyrrolo[2 ,3- d]pyrimidin-7-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluor opyrrolidine-2-carboxamide

(115e)

Compound 115e was prepared according to the procedure reported in step-2 of scheme- 1, from tort-butyl 3-(4-amino-7-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamo yl)-4- fluoropyrrolidin l yl) 2 oxoethyl) 7H pyrrolo[2 3 d]pyrimidin 5 yl)benzylcarbamate (115d) (150mg, 0.229 mmol) in DCM (3 mL) using TFA (0.353 mL, 4.59 mmol) and stirring at RT for 70 min. This gave after workup and purification by reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)-l-(2-(4-amino-5-(3-(aminomethyI)phenyl)-7H-pyrrolo[2 ,3-d]pyrimidin-7-yl)acetyI)- N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-caiboxamid e (115e) (92 mg, 72%yield) HC1 salt as a white solid; *H NMR (300 MHz, DMSO-tfc) (a mixture of two rotamers) 59.19 (t ,J= 5.8 Hz) and 8.74 (t, J= 5.9 Hz) (2t, 1H), 8.53 - 8.40 (m, 4H, 3H DzO exchangeable), 7.66 - 7.35 (m, 6H), 7.30 - 7.14 (m, 1H), 7.02 (t, J= 7.9 Hz, 1H), 5.66 - 5.15 (m, 3H), 4.96 - 3.88 (m, 7H), 2.59 - 2.41 (m, 1H), 2.23 - 1.89 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO) 5 - 121.29, -121.63, -175.96; MS (ES+): 554.2(M+1); (ES-): 552.2(M-1), 588.1 (MCI); Analysis calculated for C27H26ClF2N7O2.2HCl.3H2O: C, 47.62; H, 5.03; Cl, 15.62; N, 14.40; Found; C, 47.74; H, 4.94; Cl, 15.37; N, 14.30.

Scheme 116

Preparation of (2S,4R)-l-(2-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-y l)acetyl)-N- (3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (116b)

Step-1: Preparation of 2-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (116a)

Compound 116a was prepared according to the procedure reported in step-4 of scheme- 17, from fert-butyl 2-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (114b) (200 mg, 0.611 mmol) in THF/MeOH (2.4 mL; ratio 1:1) using 2N sodium hydroxide (0.367 mL, 0.734 mmol) and stirring for 1 h at RT. This gave after workup 2-(4-amino-5-bromo-7H- pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (116a) (138 mg, 83% yield) as a pale purple solid; ¾ NMR (300 MHz, DMSO-dk) 5 13.11 (s, 1H), 8.08 (s, 1H), 7.41 (s, 1H), 6.76 (s, 2H), 4.87 (s, 2H). Step-2: Preparation of (2S,4R)-l-(2-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7- yl)acetyl)-N -(3 -chloro-2-fluorobenzyl)-4-fluoropy rrolidine-2-carboxamide (116b)

Compound 116b was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-5 -bromo-7H-pyrrolo [2,3 -d]pyrimidin-7 -yl)acetic acid (116a) (50 mg, 0.184 mmol) in DMF (5 mL) using (2S,4R)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2- carboxamide (7a) (51 mg, 0.184 mmol), HATU (105 mg, 0.277 mmol), DIPEA (0.129 mL, 0.738 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 to 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HCl) from 0-100%] (2S,4R)-l-(2-(4-amino-5- bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetyl)-N-(3-chloro-2- fluorobenzyl)-4- fluoropyrrolidine-2-caiboxamide (116b) (29 mg, 30% yield) HCl salt as a white solid; ‘HNMR (300 MHz, DMSO-ifc) (a mixture of two rotamers) δ 9.04 (t, ./= 5.7 Hz) and 8.63 (t, J= 5.8 Hz) (2t,lH), 8.28 (s) and 8.26 (s) (2s, 1H), 7.83 (s, 3H, D ₂ 0 exchangeable), 7.53 (s, 1H), 7.49 - 7.34 (m, 1H), 7.29 - 7.13 (m, 1H), 7.08 (td,J= 7.9, 1.1 Hz, 1H), 5.47 (d,J= 52.8 Hz, 1H), 5.31 - 5.02 (m, 2H), 4.84 - 3.73 (m, 5H), 2.43 (m, 1H), 2.19 - 1.85 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-ΐ/β) δ -121.32, -121.62, -176.08. MS (ES+): 527.0 (M+l); (ES-): 525.0 (M-l); Analysis calculated for C ₂ oHi8BrClF2N602.HCl.1.SHzO: C, 40.63; H, 3.75; N, 14.21; Found: C, 40.70; H, 3.54; N, 13.95.

Scheme 117

N~f ^N NH ₂

\

CH ₃ N

117c 117d N^

Preparation of (2S,4R)-l-(2-(4-amino-5-(2-methylpyrimidin-5-yl)-7H-pyrrolo[ 2,3- d]pyriniidin-7-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluo ropyrrolidine-2-carboxamide

(H7d)

Step-1: Preparation of tert-butyl 2-(4-amino-5-(2-methy]pyrimidin-5-yl)-7H-pyrrolo[2,3- dJpyrimidin-7-yl)acetate (117b)

Compound 117b was prepared according to the procedure reported in step-1 of scheme-59, from tert-butyl 2-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (114b) (1 g, 3.06 mmol) in dioxane (30 mL) using 2-methy 1-5 -(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2- yl)pyrimidine (117a) (673 mg, 3.06 mmol; CAS # 1052686-67-5), bis(triphenylphosphine)palladium(II) chloride (322 mg, 0.458 mmol) a solution of potassium carbonate (1.267 g, 9.17 mmol) in water (3.75 mL) and heating at 100 °C for 3 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0-50%] te/7-butyl 2-(4-am ino-5 -( 2-methylpy rimidin -5 -y 1)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)acetate (117b) (375 mg, 36% yield) as a white solid; Ή NMR (300 MHz, DMSO-rik) δ 8.72 (s, 2H), 8.16 (s, 1H), 7.47 (s, 1H), 6.43 (s, 2H), 4.95 (s, 2H), 2.66 (s, 3H), 1.43 (s, 9H); MS (ES+): 341.1 (M+l).

Step-2: Preparation of 2-(4-amino-5-(2-methy]pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrim idin-7- Compound 117c was prepared according to the procedure reported in step-4 of scheme- 17, from tert-butyl 2-(4-amino-5-(2-methylpyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrim idin-7- yl)acetate (117b) (350 mg, 1.028 mmol) in THF/MeOH (4 mL; ratio 1:1) using 2N sodium hydroxide (0.6 mL, 1.20 mmol) and stirring for 3 h at RT. This gave after workup 2-(4- amino-5-(2-methylpyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)acetic acid (117c) (167 mg, 57% yield) as a white solid; Ή NMR (300 MHz, DMSO-cfe) δ 8.72 (s, 2H), 8.16 (s, 1H), 7.48 (s, 1H), 6.43 (s, 2H), 4.96 (s, 2H), 2.66 (s, 3H); MS (ES+): 285.1 (M+l).

Step-3: Preparation of (2S,4R)-l-(2-(4-amino-5-(2-methylpyrimidin-5-yl)-7H-pyrrolo[ 2,3- d]pyrimidin-7-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluor opyrrolidine-2-carboxamide

(117d)

Compound 117d was prepared according to the procedure reported in step-3 of scheme-1, from 2-(4-amino-5-(2-methylpyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrim idin-7-yl)acetic acid

(117c) (50 mg, 0.176 mmol) in DMF (3 mL) using (2S,4R)-N-(3-chloro-2-fluorobenzyl)-4- fluoropyrrolidine-2-carboxamide (7a) (48.3 mg, 0.176 mmol), HATU (100 mg, 0.264 mmol), DIPEA (0.123 mL, 0.704 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 to 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%]

(2S,4R)-l-(2-(4-amino-5-(2-methylpyrimidin-5-yl)-7H-pyrro lo[2,3-d]pyrimidin-7-yl)acetyl)-

N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxa mide (117d) (67 mg, 70% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 9.22 and 8.75 (2t, J= 5.9 Hz, 1H, DzO exchangeable), 8.80 (s, 2H), 8.52 (s, 1H), 8.40 (s, 2H, DzO exchangeable), 7.73 and 7.72 (2s, 1H), 7.49 - 7.34 (m, 1H), 7.29 - 7.13 (m, 1H), 7.02 (td, J= 7.9, 1.1 Hz, 1H), 5.63 - 4.68 (m, 3H), 4.52 - 3.76 (m, 5H), 2.72 (s, 3H), 2.60 - 2.19 (m, 1H), 2.18 - 1.93 (m, 1H). Ή NMR (300 MHz, DMSO-ifc/DzO) δ 8.80 (s, 2H), 8.48 and 8.46 (2s, 1H), 7.70 and 7.68 (2s, 1H), 7.49 - 7.33 (m, 1H), 7.28 - 7.13 (m, 1H), 7.04 (td, J= 7.9, 1.1 Hz, 1H), 5.63 - 5.15 (m, 3H), 4.52 - 3.84 (m, 5H), 2.73 (s, 3H), 2.52 - 2.25 (m, 1H), 2.23 - 1.90 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO) δ -121.30, -121.61, -176.09; MS (ES+): 541.2 (M+l); (ES-): 539.2 (M- 1); Analysis calculated for CZ5HZ3C1FZN ₈ OZ.1.65HC1.3.75HZO: C, 44.91; H, 4.85; Cl, 14.05; N, 16.76; Found: C, 45.01; H, 4.68; Cl, 14.10; N, 16.44.

Scheme 118

Preparation of (2S,4R)-l-(2-(4-amino-5-(2-methylpyrimidin-5-yl)-7H-pyrrolo[ 2,3- d]pyrimidin-7-yl)acet\"l)-N-(6-bromo-3-methylpyridin-2-yl)-4 -fluoropyrrolidine-2- carboxamide (118a)

Compound 118a was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-5-(2-methylpyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrim idin-7-yl)acetic acid (117c) (50 mg, 0.176 mmol) in DMF (3 mL) using (2S,4R)-N-(6-bromo-3-methylpyridin-2- yl)-4-fluoropyrrolidine-2-carboxamide (3a) (53 mg, 0.176 mmol), HATU (100 mg, 0.264 mmol) and DIPEA (0.123 mL, 0.704 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 to 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)-l-(2-(4-amino-5-(2-methylpyrimidin-5-yl)-7H-pyrrolo[ 2,3-d]pyiimidin-7- yl)acetyl)-N-(6-bromo-3-methylpyridm-2-yl)-4-fluoropyrrolidi ne-2-carboxamide (118a) (37 mg, 37% yield) HC1 salt as a pale yellow solid; Ή NMR (300 MHz, DMSO-Je) δ 10.92 and 10.50 (2s, 1H, DzO exchangeable), 8.78 (s, 2H), 8.50 (s, 1H), 8.32 (s, 2H, DzO exchangeable), 7.78 and 7.71 (2s, 1H), 7.64 - 7.57 (m, 1H), 7.52 and 7.43 (2d, J= 7.9 Hz, 1H), 5.65 - 5.21 (m, 3H), 4.61 (t, J= 8.5 Hz, 1H), 4.21 (dd, J= 21.7, 12.5 Hz, 1H), 3.94 (dd, J= 38.0, 12.6 Hz, 1H), 2.70 (s, 3H), 2.67-2.60 (m, 1H), 2.34-2.06 (m, 1H), 2.03 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-de) δ -176.04. MS (ES+): 568.1 (M+l); (ES-): 566.1 (M-l).

Scheme 119

Preparation of (S)-l-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(3-chloro-2- fluorobenzyl)pyrrolidine-2-caiboxamide (119a)

To a mixture of 2-(6-amino-9H-purin-9-yl)acetic acid (67a) (50 mg, 0.259 mmol) and (S)-N- (3-chloro-2-fluorobenzyl)pynolidine-2-caiboxamide (76a) (66.4 mg, 0.259 mmol) in DMF (1 mL) was added lH-benzo[d] [l,2,3]triazol-l-ol (HOBT) (17.49 mg, 0.129 mmol), Nl- ((ethylimino)methylene)-N3,N3-dimethylpropane-l, 3-diamine hydrochloride (EDC) (99 mg, 0.518 mmol), DIPEA (0.135 mL, 0.777 mmol) and stirred at RT for 16 h. This mixture was diluted with ethyl acetate (120 mL), washed with water (2 x 30 mL), brine (30 mL), dried, filtered and concentrated under vacuum. The residue obtained was purified by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 to 100 %] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] to afford (S)-l-(2-(6-amino-9H-purin-9- yl)acetyl)-N-(3-chloro-2-fluorobenzyl)pyrrolidine-2-carboxam ide (119a) (9 mg, 8% yield) HC1 salt as a white solid; ^! H NMR (300 MHz, DMSO-de) δ 8.49 (t, J= 5.9 Hz, 1H), 8.36 (s, 1H), 8.25 (s, 1H), 7.53 - 7.32 (m, 1H), 7.26- 7.15 (m, 1H), 7.09 (td,J= 7.9, 1.0 Hz, 1H), 5.30 - 5.11 (m, 2H), 4.78 - 4.40 (m, 1H), 4.36 - 4.25 (m, 2H), 3.79 - 3.61 (m, 2H), 2.20 - 1.69 (m, 4H). ¹⁹ F NMR (282 MHz, DMSO-cfe) δ -121.70; MS (ES+): 432.1 (M+l); (ES-): 430.1 (M-l), 466.1 (M+Cl).

Scheme 120

Preparation of (S)-5-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(3-chloro-2-fluoro benzyl)-5- azaspiro[2.4]heptane-6-carboxamide (120c)

Step-1: Preparation of (S)-tert-butyl 6-((3-chloro-2-fluorobenzyl)caibamoyl)-5- azaspiro[2.4]heptane-5-carboxylate (120a)

Compound 120a was prepared according to the procedure reported in step-3 of scheme- 1, from (S)-5-(ter/-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxy lic acid (53a) (0.5 g, 2.072 mmol) using (3-chloro-2-fluorophenyl)methanamine (109b) (0.331 mg, 2.072 mmol), (HATU) (1.182 g, 3.11 mmol), DIPEA (1.083 mL, 6.22 mmol) in DMF (5 mL) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (40 g), eluting with EtOAc/MeOH in Hexanes 0-100%] (S)-tert-butyl 6-((3-chloro-2- fluorobenzyl)caibamoyl)-5-azaspiro[2.4]heptane-5-carboxylate (120a) as a pale-yellow gel (0.758 g, 96% yield); MS (ES+): 405.1 (M+Na).

Step-2: Preparation of (S)-N-(3-chloro-2-fluorobenzyl)-5-azaspiro[2.4]heptane-6- carboxamide (120b)

Compound 120b was prepared according to the procedure reported in step-2 of scheme- 1, from (S)-terf-butyl 6-((3-chloro-2-fluorobenzyl)carbamoyl)-5-azaspiro[2.4]heptan e-5-carboxylate (120a) (0.758 g, 1.980 mmol) using TFA (0.763 mL, 9.90 mmol) in DCM (6 mL) and stirring overnight at room temperature. This gave after workup and purification by reverse phase column chromatography [Cl 8 (30 g), eluting with ACN in water (containing 0.1% HC1) from (0.535 g, 96% yield); Ή NMR (300 MHz, DMSO-cfc) δ 9.09 (t, J= 5.7 Hz, 1H), 8.78 (s, 1H), 7.53 (ddd, J = 7.9, 7.2, 1.8 Hz, 1H), 7.34 (ddd,J = 7.7, 6.7, 1.8 Hz, 1H), 7.22 (td, J = 7.8, 1.1 Hz, 1H), 4.56 - 4.26 (m, 3H), 3.14 (s, 2H), 2.23 (dd,J= 13.0, 8.3 Hz, 1H), 1.90 (dd,J= 13.0, 7.3 Hz, 1H), 0.78 - 0.42 (m, 4H); ¹⁹ F NMR (282 MHz, DMSO-rfe) δ -121.07; MS (ES+): 283.1 (M+Na).

Step-3: Preparation of (S)-5-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(3-chloro-2-fluoro benzyl)- 5-azaspiro[2.4]heptane-6-carboxamide (120c)

Compound 120c was prepared according to the procedure reported in scheme- 119, from (S)- N-(3-chloro-2-fluorobenzyl)-5-azaspiro[2.4]heptane-6-carboxa mide (120b) (73.2 mg, 0.259 mmol) in DMF (5 mL) using 2-(6-amino-9H-purin-9-yl)acetic acid (67a) (50 mg, 0.259 mmol), HOBT (17.49 mg, 0.129 mmol), EDC (99 mg, 0.518 mmol), DIPEA (0.180 mL, 1.035 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 to 100 %] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (S)-5-(2-(6-amino-9H-purin-9-yl)acetyl)- N-(3-chloro-2-fluorobenzyl)-5-azaspiro[2.4]heptane-6-carboxa mide (120c) (11 mg, 9% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-tfe) δ 8.94 and 8.64 (2t, J= 6.0 Hz, 1H), 8.45 (s, 1H), 8.37 and 8.32 (2s, 1H), 7.57 - 7.35 (m, 1H), 7.31 - 7.15 (m, 1H), 7.10 (td,J= 7.9, 1.1 Hz, 1H), 5.37 - 5.11 (m, 2H), 4.92 - 4.18 (m, 3H), 3.83 - 3.16 (m, 2H), 2.28 (dd,J= 12.7, 8.7 Hz, 1H), 1.88 - 1.61 (m, 1H), 0.76 - 0.29 (m, 4H). ¹⁹ F NMR (282 MHz, DMSO-ifc) δ - 121.60; MS (ES+): 458.1 (M+l); (ES-): 456.1 (M-l), 492.1 (M+Cl).

Scheme 121

NH ₂ 121d

Preparation of (2S,4R)-l-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(3-chloro-2-fl uorobenzyl)-4- methylpyrrolidine-2-carboxamide (121d)

Step-1: Preparation of (2S,4R)-ter/-butyl 2-((3-chloro-2-fluorobenzyl)carbamoyl)-4- methylpyrrolidine- 1 -carboxylate (121b)

Compound 121b was prepared according to the procedure reported in step-1 of scheme-5, from (2S,4R)- 1 -(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid (121a) (0.4 g, 1.745 mmol; CAS # 364750-80-1) using (3-chloro-2-fluorophenyl)methanamine (109b) (0.658 mL, 5.23 mmol; CAS # 72235-55-3), HATU (995 mg, 2.62 mmol), DIPEA (0.912 mL, 5.23 mmol) in DMF (5 mL) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (40 g), eluting with EtOAc/MeOH (ratio 9:1) in Hexanes from 0-100%] (2S,4R)-tert-butyl 2-((3-chloro-2-fluotobenzyl)carbamoyl)-4- methylpynolidine- 1 -carboxylate (121b) as a white solid (0.55 g, 85% yield); MS (ES+): 393.1 (M+Na).

Step-2: Preparation of (2S,4R)-N-(3-chloro-2-fluorobenzyl)-4-methylpyrrolidine-2- carboxamide (121c)

Compound 121c was prepared according to the procedure reported in step-2 of scheme- 1, from (2S,4R)-tert-butyl 2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-methylpyrrolidine-l - carboxylate (121b) (0.55 g, 1.483 mmol) using TEA (1.143 mL, 14.83 mmol) in DCM (6 mL) and stirring overnight at room temperature. This gave after workup and purification by reverse phase column chromatography [Cl 8 (30 g) eluting with ACN in water (containing carboxamide (121c) (0.34 g, 85% yield); Ή NMR (300 MHz, DMSO-tfc) δ 9.92 (s, 1H), 9.15 (t, J = 5.7 Hz, 1H), 8.56 (s, 1H), 7.52 (ddd, J= 8.9, 7.2, 1.8 Hz, 1H), 7.39 - 7.29 (m, 1H),

7.22 (td,J= 7.9, 1.1 Hz, 1H), 4.42 (d, J= 5.7 Hz, 2H), 4.32 (s, 1H), 3.47 - 3.36 (m, 1H), 2.87 - 2.64 (m, 1H), 2.29 (h, J= 7.2 Hz, 1H), 2.12 - 1.99 (m, 1H), 1.99 - 1.79 (m, 1H), 1.02 (d, J = 6.7 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -121.13; MS (ES+): 271.1 (M+l).

Step-3: Preparation of (2S,4R)-l-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(3-chloro-2- fluorobenzyl)-4-me1hylpyrTOlidine-2-carboxamide (121d)

Compound 121d was prepared according to the procedure reported in scheme- 119, from (2S,4R)-N-(3-chloro-2-fluorobenzyl)-4-methylpyrrolidme-2-car boxamidc (121c) (70.1 mg, 0.259 mmol) in DMF (5 mL) using 2-(6-amino-9H-purin-9-yl)acetic acid (67a) (50 mg, 0.259 mmol) HOBT (17.49 mg, 0.129 mmol), EDC (99 mg, 0.518 mmol), DIPEA (0.180 mL, 1.035 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 to 100 %] followed by purification using reverse phase column chromatography [Cl 8 column (15 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)-l-(2-(6-amino- 9H-purin-9-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-methylpy rrolidine-2-carboxamide (12ld) (11 mg, 9% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-tfc) δ 8.89 and 8.52 (2t,J= 5.9 Hz, 1H), 8.35 and 8.33 (2s, 1H), 8.25 and 8.22 (2s, 1H), 7.53 - 7.33 (m, 1H), 7.21 (td,7= 7.2, 6.5, 1.9 Hz, 1H), 7.09 (td, J= 7.9, 1.0 Hz, 1H), 5.20 (q, J= 17.0 Hz, 2H), 4.79 - 4.16 (m, 3H), 3.92 (t, J= 8.4 Hz, 1H), 3.73 - 3.56 (m, 1H), 3.22 (t, J= 9.3 Hz, 1H), 2.04 - 1.91 (m, 1H), 1.86 - 1.68 (m, 1H), 1.07 and 1.01 (2d, J= 6.4 Hz, 3H). ¹⁹ FNMR (282 MHz, DMSO-tfc) δ -121.70; MS (ES+): 446.1 (M+l), 468.1(M+Na); (ES-): 444.1 (M- 1), 480.1 (M+Cl).

Scheme 122

Preparation of (2S,4R)- 1 -(2-(6-amino-9H-purin-9-yl)acetyl)-N -(3-chloro-2-fluorobenzyl)-4- Step-1: Preparation of (2S,4R)-N-(3-chloro-2-fluorobenzyl)-4-fluoro-4-methylpyrroli dine-2- carboxamide (122b)

Compound 122b was prepared according to the procedure reported in step-2 of scheme- 1, from (2S,4R)-ferf-butyl 2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoro-4-methylpyrr olidine-l- carboxylate (122a) [(700 mg, 1.800 mmol); prepared according to the procedure reported by Altmann, Eva; et al., PCT Int. Appl. (2012), WO 2012093101 A1 20120712] using TEA (0.693 mL, 9.0 mmol) in DCM (7 mL) and stirring overnight at room temperature. This gave after workup and purification by flash column chromatography [Cl 8 (30 g), eluting with ACN in water (containing 0.1% HC1) from 0 to 100%] (2S,4R)-N-(3-chloro-2-fluorobenzyl)-4-fluoro- 4-methylpyrrolidine-2-carboxamide (122b) (449 mg, 86% yield); Ή NMR (300 MHz, DMSO- de) 59.23 (t, J = 5.7 Hz, 1H), 7.53 (ddd, 7 = 8.0, 7.2, 1.8 Hz, 1H), 7.35 (ddd, 7= 7.8, 6.7, 1.8 Hz, 1H), 7.23 (td, J= 7.9, 1.1 Hz, 1H), 4.53 - 4.32 (m, 3H), 3.60 - 3.22 (m, 3H), 2.66 (td, J= 14.3, 7.5 Hz, 1H), 2.20 - 1.92 (m, 1H), 1.54 (d, J= 21.3 Hz, 3H); MS (ES+): 289.1 (M+l). Step-2: Preparation of (2S,4R)-l-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(3-chloro-2- fluorobenzyl)-4-fluoro-4-methylpyrrohdine-2-carboxamide (122c)

Compound 122c was prepared according to the procedure reported in scheme- 119, from (2S,4R)-N-(3-chloro-2-fluorobenzyl)-4-fluoro-4-methylpyrroli dine-2-carboxamide (122b) (75 mg, 0.259 mmol) in DMF (5 mL) using 2-(6-amino-9H-purin-9-yl)acetic acid (67a) (50 mg, 0.259 mmol) HOBT (17.49 mg, 0.129 mmol), EDC (99 mg, 0.518 mmol), DIPEA (0.180 mL, 1.035 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 to 100 %] followed by purification using reverse phase column chromatography [Cl 8 column (15 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)-l-(2-(6-amino-9H- purin-9-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoro-4-me thylpyrrolidine-2-carboxamide (122c) (11 mg, 9% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfe) δ 9.06 and 8.67 (2t, J= 5.9 Hz, 1H), 8.37 (s, 1H), 8.31 (s, 1H), 7.57 - 7.37 (m, 1H), 7.25 - 7.13 (m, 1H), 7.07 (td, J = 7.9, 1.1 Hz, 1H), 5.45 - 5.03 (m, 2H), 4.92 - 3.57 (m, 5H), 2.44 (m, 1H), 2.14 - 1.82 (m, 1H), 1.55 (d, 7= 21.1, 3H). ¹⁹ F NMR (282 MHz, DMSO-7 ₆ ) δ -121.65, -139.64; MS (ES+): 464.1 (M+l), 486.1(M+Na); (ES-): 462.1 (M-l), 498.1 (M+Cl).

Scheme 123

Preparation of (2S,4R)- 1 -(2-(6-((2-aminoethyl)amino)-9H-purin-9-yl)acetyl)-N-(3-chlo ro-2- fluorobenzyl)-4-fluoropyrrolidine-2-caiboxamide (123g)

Step-1: Preparation of tort-butyl 2-(6-chloro-9H-purin-9-yl)acetate (123b)

Compound 123b was prepared according to the procedure reported in step-1 of scheme- 1, from 6-chloro-9H-purine (123a) (8 g, 51.8 mmol; CAS # 87-42-3) in acetonitrile (400 mL) using tort-butyl 2-bromoacetate (11.46 mL, 78 mmol), K2CO3 (14.31 g, 104 mmol) and heating at 65 °C for 48 h. This gave after workup and purification by flash column chromatography [silica gel (120 g), eluting with EtOAc in Hexane from 0-100%] tort-butyl 2- (6-chloro-9H-purin-9-yl)acetate (123b) (8.89 g, 64% yield) as an off-white solid; Ή NMR (300 MHz, DMSO-tik) δ 8.81 (s, 1H), 8.68 (s, 1H), 5.16 (s, 2H), 1.42 (s, 9H); MS (ES+): 269.10 (M+l).

Step-2: Preparation of tort-butyl 2-(6-((2-((tort-butoxycarbonyl)amino)ethyl)amino)-9H- purin-9-yl)acetate (123d) A mixture of tort-butyl 2-(6-chloro-9H-purin-9-yl)acetate (123b) (0.699 g, 2.6 mmol) and tort-butyl 2-aminoethylcarbamate (123c) (0.961 g, 6.0 mmol; CAS # 57260-73-8) in EtOH (20 mL) was refluxed for 6 h. The solvent was evaporated under reduced pressure, and the product was purified by flash column chromatography [silica gel (40 g), eluting with DMA- 80 in DCM from 0 to 100 %] yielding tort-butyl 2-(6-((2-((tort- butoxycarbonyl)amino)ethyl)amino)-9H-purin-9-yl)acetate (123d) (1.02 g, 100 % yield); *H NMR (300 MHz, DMSO-ifc) δ 8.20 (s, 1H), 8.11 (s, 1H), 7.75 (s, 1H), 6.93 (s, 1H), 4.95 (s, 2H), 3.52 (s, 2H), 3.17 (q, J= 6.1 Hz, 2H), 1.39 (d, J= 16.4 Hz, 18H); MS (ES+): 393.20 (M+l).

Step-3: Preparation of 2-(6-((2-((tort-butoxycarbonyl)amino)ethyl)amino)-9H-purin-9 - yl)acetic acid (123e)

To a stirred solution of tort-butyl 2-(6-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-9H- purin-9-yl)acetate (123d) (1.02 g, 2.60 mmol) in THF (3.00 mL) and MeOH (3.00 mL) was added 2N sodium hydroxide (1.5 mL, 3.00 mmol) and stirred at room temperature for 45 min. This gave after workup 2-(6-(2-(tort-butoxycarbonylamino)ethylamino)-9H-purin-9-yl) acetic acid (123e) (735mg, 84% yield); MS (ES+): 337.20 (M+l).

Step-4: Preparation of tort-butyl (2-((9-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)- 4-fluoropyrTolidin- 1 -yl)-2-oxoethyl)-9H-purin-6-yl)amino)ethyl)carbamate (123f)

Compound 123f was prepared according to the procedure reported in step-3 of scheme-1, from 2-(6-((2-((tort-butoxycarbonyl)amino)ethyl)amino)-9H-purin-9 -yl)acetic acid (123e) (100 mg, 0.297 mmol) in DMF (2 mL) using (2S,4R)-N-(3-chloro-2-fluorobenzyl)-4- fluoropyrrohdine-2-carboxamide (7a) (82 mg, 0.297 mmol), HATU (170 mg, 0.446 mmol), DIPEA (0.207 mL, 1.189 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0-100%] tort-butyl (2-((9-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4- fluoropy rrolidin- 1 -yl)-2-oxoethyl)-9H-purin-6-yl)amino)ethyl)carbamate (123f) (102 mg, 58% yield) HC1 salt as a white solid; MS (ES+): 593.2 (M+l).

Step-5: Preparation of (2S,4R)-l-(2-(6-((2-aminoethyl)amino)-9H-purin-9-yl)acetyl)- N-(3- chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (123g)

Compound 123g was prepared according to the procedure reported in step-2 of scheme- 1, from tert- butyl (2-((9-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4- 0.169 mmol) in DCM (2.5 mL) using TFA (0.260 mL, 3.37 mmol) and stirring at RT for 70 min. This gave after workup and purification by reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)-1- (2-(6-((2-aminoethyl)amino)-9H-purin-9-yl)acetyl)-N-(3-chlor o-2-fluorobenzyl)-4- fluoropyrrolidine-2-carboxamide (123g) (65 mg, 78% yield) HC1 salt as a white solid; *H NMR (300 MHz, DMSO-de) δ 9.26 and 8.82 (2t, 7= 5.9 Hz, 1H, DzO exchangeable), 8.38 (d, J= 11.2 Hz, 2H, 1H DzO exchangeable), 8.20 (s, 3H, 2H DzO exchangeable), 7.53 - 7.35 (m, 1H), 7.35 - 7.13 (m, 1H), 7.05 (t ,J= 7.9 Hz, 1H), 5.67 - 5.10 (m, 3H), 4.95 - 3.94 (m, 5H), 3.87 (m, 2H), 3.13 (m, 2H), 2.62 - 2.53 (m, 1H), 2.18 - 1.80 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO-cfe) δ -121.70, -176.23; MS (ES+): 493.1 (M+l); (ES-): 491.2 (M-l), 527.1 (M+Cl). Analysis calculated for CziHzzClFzNsOz.1.875HC1.2HzO: C, 42.23; H, 4.87; Cl, 17.06; N, 18.76; Found: C, 42.28; H, 4.81; Cl, 16.88; N, 18.54.

Scheme 124

Preparation of (lR,3S,4S)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(3-chloro-2 -fluorobenzyl)- 2-azabicyclo[2.2. l]heptane-3-carboxamide (124b)

Compound 124b was prepared according to the procedure reported in step-3 of scheme- 1, from (lR,3S,4S)-N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[2.2.1]he ptane-3-carboxamide (124a) (143 mg, 0.505 mmol; prepared according to the procedure reported by McDonald, Andrew; Qian, Shawn in PCT Int. Appl. (2018), WO 2018229543 A220181220) in DMF (1.5 mL) using 2-(6-amino-9H-purin-9-yl)acetic acid (67a) (65 mg, 0.337 mmol), HATU (192 mg, 0.505 mmol), DIPEA (0.293 mL, 1.683 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 to 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,4S)-2-(2-(6-amino-9H-purin-9-yl)acetyl)-N-(3-chloro-2 -fluorobenzyl)-2- solid; ^l H NMR (300 MHz, DMSO-dis) (a mixture of two ro tamers) δ 8.98 (t, J 5.8 Hz) and 8.56 (t ,J= 5.9 Hz) (2t, 1H, DzO exchangeable), 8.49 (s) and 8.47 (s) (2s, 1H), 8.43 (s) and 8.35 (s), (2s, 1H), 7.51 - 7.03 (m, 3H), 5.46 (d, J= 17.0 Hz, 1H), 5.10 (d, J= 16.9 Hz, 1H), 4.79 - 4.16 (m, 3H), 3.84 (s, 1H), 2.58 (s, 1H), 1.99 (d, J= 9.8 Hz, 1H), 1.88 - 1.21 (m, 5H); ¹⁹ F NMR (282 MHz, DMSO-tfc) δ -121.38, -121.65. MS (ES+): 458.1 (M+l); (ES-): 456.7 (M-l); Analysis calculated for C21H21CIFN7O2.HCI.2.25H2O: C, 47.16; H, 4.99; Cl, 13.26; N, 18.33; Found: C, 47.34; H,4.76; Cl, 13.09; N, 18.16.

Scheme 125

Q

NH _{2 F} -O. HO

Br

N T NaOH ft

N w

H CS ₂ CO ₃

^F NH ₂ ^F NH _Z

125a 125b 125c

F,

125d

Preparation of (2S,4R)-l-(2-(4-aniino-5-fluoro-7H-pj'rrolo[2,3-d]pyrimidin- 7-yl)acetyl)-N- (3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (125d)

Step-1: Preparation of tort-butyl 2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)acetate (125b)

Compound 125b was prepared according to the procedure reported in step-1 of scheme- 1, from 5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-amine (125a) (0.5 g, 3.29 mmol; CAS # 1080467-52-2) in DMF (15 mL) using tort-butyl 2-bromoacetate (0.510 mL, 3.45 mmol), CS2CO3 (1.285 g, 3.94 mmol) and stirring at RT for 1.5 h. This gave after woricup tort-butyl 2-(4-amino-5-fluoro-7H-pynOlo[2,3-d]pyrimidin-7-yl)acetate (125b) (0.75 g, 86% yield) as an off-white solid; Ή NMR (300 MHz, DMSO-tife) δ 8.05 (s, 1H), 7.13 (d, J= 2.3 Hz, 1H), 6.99 (s, 2H), 4.81 (s, 2H), 1.41 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -168.96; MS (ES+): 267.10 (M+l).

Step-2: Preparation of 2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (125c)

Compound 125c was prepared according to the procedure reported in step-4 of scheme- 17, from tert-butyl 2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (125b) (720 mg, 2.70 mmol) in THF/MeOH (10 mL; ratio 1:1) using 2N sodium hydroxide ( 1.487 mL, 2.97 mmol) and stirring the reaction mixture for 1.5 h at RT. This gave after workup 2-(4- anrino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (125c) (515 mg, 91% yield) as a pale purple solid; ¾NMR (300 MHz, DMSO-ifc) 58.05 (s, 1H), 7.14 (d, J= 2.3 Hz, 1H), 6.99 (s, 2H), 4.83 (s, 2H); MS (ES+): 211.1 (M+l).

Step-3: Preparation of (2S,4R)-l-(2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrroHdine-2- carboxamide (125d)

Compound 125d was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-am ino-5 -fluoro-7H-pyrrolo [2,3 -d]pyrim idi n -7 -y l)acetic acid (125c) (50 mg, 0.238 mmol) in DMF (2 mL) using (2S,4R)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2- carboxamide (7a) HC1 salt (74 mg, 0.238 mmol), HATU (113 mg, 0.297 mmol), DIPEA (0.166 mL, 0.952 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 to 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)-l-(2-(4- amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetyl)-N-(3- chloro-2-fluorobenzyl)-4- fluoropyrrotidine-2-carboxamide (125d) (59 mg, 53% yield) HC1 salt as a white solid; ^l H NMR (300 MHz, DMSO-tife) δ 9.19 (t, 5.7 Hz) and 8.75 (t, J= 5.9 Hz) (2t, 1H, DzO exchangeable), 8.87 (s, 2H, DzO exchangeable), 8.35 (s, 1H), 7.48 - 7.33 (m, 2H), 7.29 - 7.21 (m, 1H), 7.06 (td,J= 7.9, 1.1 Hz, 1H), 5.59 - 5.36 (m, 1H), 5.29 (d, J= 17.0 Hz, 1H), 5.12 (d, J= 16.9 Hz, 1H), 4.48 - 3.76 (m, 5H), 2.50 - 2.38 (m, 1H), 2.22 - 1.90 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -121.33, -121.64, -165.54, -176.28; MS (ES+): 467.0 (M+l); Calculated for CZOHI ₈ C1F3N ₆ OZ.(HZO).(HC1): C, 46.08; H, 4.06; Cl, 13.60; N, 16.12; Found: C, 45.98; H, 3.98; Cl, 13.26; N, 15.77.

Scheme 126

Preparation of (2S,4R)- l-(2-(4-amino-5-(lH-indol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7 - yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2 -caiboxamide (126f)

Step-1: Preparation of ie/7-butyl 3 -(4-am ino-7-(2-(tert-butoxy)-2-oxoethyl)-7H-pyrrolo [2,3- d]pyrimidin-5-yl)- lH-indole- 1 -carboxylate (126c)

Compound 126c was prepared according to the procedure reported in step-1 of scheme-59, from /erf-butyl 2-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (114b) (290 mg, 0.886 mmol) in dioxane (8 mL) using ( 1 -(te/7-butoxy carbonyl)- lH-indol-3 -yl)boronic acid (126b) (231 mg, 0.886 mmol), bis(triphenylphosphine)palladium(ll) chloride (93 mg, 0.133 mmol) a solution of potassium carbonate (368 mg, 2.66 mmol) in water (1 mL) and heating at 100 °C for 4 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0-50%] tez7-butyl 3- (4-amino-7-(2-(½r/-butoxy)-2-oxoethyl)-7H-pyiTolo[2,3-d]pyr imidin-5-yl)-lH-indo]e-l- carboxylate (126c) (165 mg, 40% yield) as a yellow solid; MS (ES+): 464.2 (M+l).

Step-2: Preparation of 2-(4-amino-5-(l-(ter/-butoxycarbonyl)-lH-indol-3-yl)-7H-pyrr olo[2, 3- d]pyrimidin-7-yl)acetic acid (126d)

Compound 126d was prepared according to the procedure reported in step-4 of scheme- 17, from tert-butyl 3-(4-amino-7-(2-(tert-butoxy)-2-oxoethyl)-7H-pyrrolo[2,3-d]p yrimidin-5-yl)- using 2N sodium hydroxide (0.190 mL, 0.380 mmol) and stirring for 1.5 h at RT. This gave after woikup 2-(4-amino-5-( 1 -(te/T-butoxy carbonyl)- 1 H-indol-3 -yl)-7H-pyrrolo [2,3 - d]pyrimidin-7-yl)acetic acid (126d) (97 mg, 69% yield) as a pale yellow solid; MS (ES+): 408.1 (M+l).

Step-3: Preparation of tert-butyl 3-(4-amino-7-(2-((2S,4R)-2-((3-chloro-2- fluorobenzyl)caibamoyl)-4-fluoropyrrolidin-l-yl)-2-oxoethyl) -7H-pyrrolo[2,3-d]pyrimidin-5- yl)-lH-indole-l -carboxylate (126e)

Compound 126c was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-5-(l-(fc/?-butoxycarbonyl)-lH-indol-3-yl)-7H-pyrr olo[2,3-d]pyrimidin-7- yl)acetic acid (126d) (60 mg, 0.147 mmol) in DMF (2 mL) using HC1 salt of (2S,4R)-N-(3- chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-caiboxamide (7a) (45.8 mg, 0.147 mmol), HATU (70 mg, 0.184 mmol), DIPEA (0.103 mL, 0.589 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] tert-butyl 3-(4-amino-7-(2-((2S,4R)-2-((3- chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-l-yl)-2- oxoethyl)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)-lH-indole-l-carboxylate (126e) (40 mg, 41% yield) as a white solid; MS (ES+): 664.2 (M+l).

Step-4: Preparation of (2S,4R)-l-(2-(4-amino-5-(lH-indol-3-yl)-7H-pyrrolo[2,3-d]pyr imidin- 7-yl)acet _\ i)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-c arboxamide (126f)

Compound 126f was prepared according to the procedure reported in step-2 of scheme- 1, from tert- butyl 3-(4-amino-7-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamo yl)-4- fluoropyrrolidin- 1 -yl)-2-oxoethyl)-7H-pyrrolo [2,3 -dJpyiimidin-5 -yl)- lH-indole- 1 - carboxylate (126e) (39 mg, 0.059 mmol) in DCM (1 mL) using TEA (0.090 mL, 1.175 mmol) and stirring at RT for 4 h. This gave after workup and purification by reverse phase column chromatography [Cl 8 column (50 g) eluting with ACN in water (containing 0.1% HCl) from 0-100%] (2S,4R)-l-(2-(4-amino-5-(lH-indol-3-yl)-7H-pyrrolo[2,3-d]pyr imidin-7-yl)acetyl)- N-(3-chloro-2-fluorobcnzyl)-4-fluoropyrrolidine-2-carboxamid c (126f) (15 mg, 45% yield) HCl salt as a white solid; Ή NMR (300 MHz, DMSO-cfe) (a mixture of two rotamers) δ 11.45 (d, J= 2.6 Hz, 1H), 9.08 (t, J= 5.7 Hz) and 8.64 (t, J= 5.9 Hz) (2t, 1H), 8.36 (d ,J=

4.2 Hz, 1H), 7.56 - 7.30 (m, 6H, 2H DzO exchangeable), 7.30 - 7.23 (m, 1H), 7.23 - 7.08 (m, 2H), 7.02 (q, J= 7.2 Hz, 1H), 6.92 (t, J= 7.9 Hz, 1H), 5.55 - 5.02 (m, 3H), 4.41 - 3.74 (m, 5H), 2.78 - 2.37 (m, 1H), 2.18 - 1.84 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO) δ -121.29, - 121.68, -176.38; MS (ES+): 564.2 (M+l).

Scheme 127

127c 127d

Preparation of methyl l-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-lH-pyrrolo[2,3-b]py ridine-5-caiboxylate (127d)

Step-1: Preparation of methyl 1 -(2-(te/7-butoxy)-2-oxoethyl)- 1 H-pyrrolo [2,3 -b]pyridine-5 - carboxylate (127b)

Compound 127b was prepared according to the procedure reported in step-1 of scheme- 1, from methyl lH-pyrrolo[2,3-b]pyridine-5-caiboxylate (127a) (0.5 g, 2.84 mmol; CAS # 849067-96-5) in DMF (15 mL) using /erf-butyl 2-bromoacetate (0.419 mL, 2.84 mmol), CS2CO3 (1.110 g, 3.41 mmol) and stirring at RT for 1.5 h. This gave after workup methyl 1- (2-(tezr-butoxy)-2-oxoethyl )- 1 H-pyrrolo [2 ,3 -b]pyridine-5 -carboxyl ate (127b) (746 mg, 91% yield) as an off-white solid; Ή NMR (300 MHz, DMSO-tife) δ 8.82 (d, J= 2.0 Hz, 1H), 8.58 (d, 2.0 Hz, 1H), 7.68 (d, 3.6 Hz, 1H), 6.68 (d, J= 3.6 Hz, 1H), 5.08 (s, 2H), 3.89 (s,

3H), 1.41 (s, 9H); MS (ES+): 235.00 (M+l).

Step-2: Preparation of 2-(5-(methoxycarbonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)acetic acid (127c) Compound 127c was prepared according to the procedure reported in step-2 of scheme-1, from methyl l-(2-(te/7-butoxy)-2-oxoethyl)-lH-pyrrolo[2,3-b]pyridine-5-c arboxylate (127b) (400 mg, 1.378 mmol) in DCM (8 mL) using TFA (1.582 mL, 20.67 mmol) and stirring at RT for 16 h. This gave after workup 2-(5 -(methoxycarbony 1)- 1 H-pyrrolo [2,3 -b] py ridin- 1 - yl)acetic acid (127c) (470 mg, 98% yield) TFA salt as a yellow solid; Ή NMR (300 MHz, DMSO-^fc) δ 8.82 (d ,J= 2.0 Hz, 1H), 8.58 (d, J= 2.0 Hz, 1H), 7.69 (d, J= 3.6 Hz, 1H), 6.67 (d ,J= 3.6 Hz, 1H), 5.10 (s, 2H), 3.89 (s, 3H); MS (ES+): 235.10 (M+l).

Step-3: Preparation of methyl l-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-lH-pyrrolo[2,3-b]py ridine-5-carboxylate (127d)

Compound 127d was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(5 -(methoxycarbony 1)- 1 H-py rrolo [2, 3 -b Jpyridin- 1 -yl)acetic acid (127c) (75 mg, 0.215 mmol) in DMF (2 mL) using (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (4a) HC1 salt (68.6 mg, 0.215 mmol), HATU (123 mg, 0.323 mmol), DIPEA (0.188 mL, 1.077 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 to 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] methyl l-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[3.1 ,0]hexan-2-yl)-2-oxoethyl)-lH-pyrrolo[2,3-b]pyridine-5-carbo xylate (127d) (95mg, 89% yield) as a white solid; Ή NMR (300 MHz, DMSO-ffc) δ 10.78 (s, 1H, D ₂ 0 exchangeable), 8.82 (d, J = 2.0 Hz, 1H), 8.56 (d,J= 2.0 Hz, 1H), 8.03 (d, J= 8.2 Hz, 1H), 7.72 (t ,J= 8.0 Hz, 1H), 7.64 (d,./= 3.6 Hz, 1H), 7.32 (d, J= 7.7 Hz, 1H), 6.66 (d,./= 3.6 Hz, 1H), 5.57 (d, J= 17.1 Hz, 1H), 5.31 (d, J= 17.0 Hz, 1H), 4.44 (dd, J= 9.0, 5.5 Hz, 1H), 3.89 (s, 3H), 3.79 (ddd, ./= 7.4, 5.5, 2.3 Hz, 1H), 2.39 - 2.11 (m, 2H), 1.89 (tt, ./= 6.5, 3.7 Hz, 1H), 1.03 (dt, J= 8.8, 5.4 Hz, 1H), 0.70 (td, J= 5.2, 2.3 Hz, 1H); MS (ES+): 497.9 (M+l), 519.9 (M+Na); (ES-): 496.0 (M-l); Analysis calculated for CzzHzoBrNsOt.IJSHzO: C, 49.87; H, 4.47; N, 13.22; Found: C, 49.80; H, 4.09; N, 13.01.

Scheme 128

127d 128a

Preparation of l-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-lH-pyrrolo[2,3-b]py ridine-5-carboxylic acid (128a)

Compound 128a was prepared according to the procedure reported in step-4 of scheme-17, from methyl 1 -(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-lH-pyrrolo[2,3-b]py ridine-5-carboxylate (127d) (67mg, 0.134 mmol) in THF (0.8 mL), acetonitrile (0.4 mL) and water (2 mL) using IN aqueous lithium hydroxide monohydrate (0.403 mL, 0.403 mmol) and stirring at RT for 16 h. This gave after workup and purification by reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] l-(2- ((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[ 3.1.0]hexan-2-yl)-2- oxoethyl)- 1 H-pyrrolo [2,3 -b]pyri dine-5 -carboxylic acid (128a) (6 mg, 9% yield) HC1 salt as a white solid; ¾ NMR (300 MHz, Methanol^) δ 8.96 - 8.84 (m, 2H), 8.02 (dd, J= 12.4, 8.6 Hz, 1H), 7.62 (m, 2H), 7.25 (dt, J= 7.5, 3.4 Hz, 1H), 6.86 (dt, J= 5.9, 3.1 Hz, 1H), 5.76 - 5.36 (m, 2H), 4.53 (d, J= 8.6 Hz, 1H), 3.77 (m, 1H), 2.43 (q, J= 6.0, 4.2 Hz, 1H), 2.13 - 1.80 (m, 2H), 1.27 - 1.11 (m, 1H), 1.03 - 0.76 (m, 1H); MS (ES+): 483.9 (M+l), 505.9 (M+Na); (ES-): 481.9 (M-l).

Scheme 129

Preparation of (lR,3S,5R)-2-(2-(5-amino-7H-p>Trolo[2,3-d]pyrimidin-7-yl) acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (129f)

Step-1: Preparation of tort-butyl 2-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (129b)

Compound 129b was prepared according to the procedure reported in step-1 of scheme- 1, from 5-bromo-7H-pyrrolo[2,3-d]pyrimidine (129a) (1 g, 5.05 mmol; CAS # 175791-49-8) in DMF (25 mL) using tort-butyl 2-bromoacetate (0.784 mL, 5.30 mmol), CS2CO3 (1.974 g, 6.06 mmol) and stirring at RT for 1.5 h. This gave after workup tort-butyl 2-(5-bromo-7H- pyrrolo[2,3-d]pyrimidin-7-yl)acetate (129b) (1.54 g, 98% yield) as a pale-yellow solid; *H NMR (300 MHz, DMSO-i/e) δ 8.96 (s, 1H), 8.90 (s, 1H), 7.89 (s, 1H), 5.06 (s, 2H), 1.42 (s, 9H); MS (ES+): 312.00 (M+l).\

Step-2: Preparation of tort-butyl 2-(5-((torf-butoxycarbonyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)acetate (129c)

Compound 129c was prepared according to the procedure reported in step-3 of scheme- 17, from tort-butyl 2-(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (129b) (500 mg, 1.602 mmol) in toluene (30 mL) using XPhos (153 mg, 0.320 mmol), t-butyl carbamate (563 mg, 4.81 mmol), Pdz(dba)3 (147 mg, 0.160 mmol), cesium carbonate (522 mg, 1.602 mmol) and heating at 95 °C for 16 h. This gave after work up and purification tort-butyl 2-(5-((tert- butoxycarbonyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetat e (129c) (29 mg, 5% yield); Ή NMR (300 MHz, DMSO-dk) δ 9.89 (s, 1H), 9.30 (s, 1H), 8.88 (s, 1H), 7.80 (s, 1H), 5.05 (s, 2H), 1.52 (s, 9H), 1.42 (s, 9H); MS (ES+): 349.20 (M+l).

Step-3: Preparation of 2-(5-((tert-butoxycarbonyl)amino)-7H-pyrrolo[2,3-d]pyrimidin -7- yl)acetic acid (129d)

Compound 129d was prepared according to the procedure reported in step-4 of scheme- 17, from tort-butyl 2-(5-((tert-butoxycarbonyl)amino)-7H-pyrrolo[2,3-d]pyrimidin -7-yl)acetate (129c) (80 mg, 0.23 mmol) in THF (2 mL) and MeOH (2 mL) using 1 N solution of aqueous lithium hydroxide hydrate (1.148 mL, 1.148 mmol) and stirring at RT for 15 h. This gave after workup 2-(5-((tort-butoxycarbonyl)amino)-7H-pyrrolo[2,3-d]pyrimidin -7-yl)acetic acid (129d) (62 mg, 92% yield); Ή NMR (300 MHz, DMSO-i/e) δ 9.89 (s, 1H), 9.30 (s, 1H), 8.87 (s, 1H), 7.80 (s, 1H), 5.06 (s, 2H), 1.52 (s, 9H); MS (ES+): 293.10 (M+l).

Step-4: Preparation of tort-butyl (7-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[3.1 ,0]hexan-2-yl)-2-oxoethy 1 )-7H-py rrolo [2 ,3 -d]pyrimidin-5 -yl)carbamate (129e)

Compound 129e was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(5-((tert-butoxycarbonyl)amino)-7H-pyrrolo[2,3-d]pyrimidin -7-yl)acetic acid (129d) (50 mg, 0.171 mmol) in DMF (1 mL) using TFA salt of (lR,3S,5R)-N-(6-bromopyridin-2- yl)-2-azabicyclo[3.1.OJhexane-3-carboxamide (4a) (74.5 mg, 0.188 mmol), HATU (98 mg, 0.257 mmol), DIPEA (0.149 mL, 0.855 mmol) and stirring at RT for 4 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), DMA-80 in DCM from 0 - 100%] tort-butyl (7-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7H-pyrrolo[2,3-d]py rimidin-5-yl)carbamate (129e) (85 mg, 89% yield) as a white solid; Ή NMR (300 MHz, DMSO-i/e) δ 10.77 (s, 1H), 9.77 (s, 1H), 9.19 (s, 1H), 8.73 (s, 1H), 8.04 (d, J= 8.2 Hz, 1H), 7.72 (t, J= 7.9 Hz, 1H), 7.64 (s, 1H), 7.33 (d, J= 7.7 Hz, 1H), 5.47 (d, J= 17.1 Hz, 1H), 5.20 (d, J= 17.0 Hz, 1H), 4.47 - 4.33 (m, 1H), 3.75 (s, 1H), 2.34 - 2.11 (m, 2H), 1.89 (d, J= 12.1 Hz, 1H), 1.51 (s, 9H), 1.03 (t ,J= 9.3 Hz, 1H), 0.72 (s, 1H); MS (ES+): 556.20 (M+l).

Step-5: Preparation of (lR,3S,5R)-2-(2-(5-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ace tyl)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamid e (129f)

Compound 129f was prepared according to the procedure reported in step-2 of scheme- 1, from tort-butyl (7-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[3.1 ,0]hexan-2-yl)-2-oxoethy 1 )-7H-py rrolo [2 ,3 -d]pyrimidin-5 -yl)carbamate (129e) for 16 h. This gave after workup (lR,3S,5R)-2-(2-(5-amino-7H-pynolo[2,3-d]pyrimidin-7- yl)acetyl)-N -(6-bromopyridin-2-yT)-2-azabicyclo [3.1.0 Jhexane-3 -carboxamide (129f) (59 mg, 90 % yield) HC1 salt as a yellow solid; Ή NMR (300 MHz, DMSOK/ ₆ ) δ 10.80 (s, 1H, DzO exchangeable), 9.34 (s, 1H), 9.04 (s, 1H), 8.03 (d,J= 8.1 Hz, 1H), 7.77 (s, 1H), 7.72 (t ,J= 8.0 Hz, 1H), 7.34 (d, J= 7.6 Hz, 1H), 5.65 (d, J= 17.1 Hz, 1H), 5.34 (d 17.0 Hz, 1H), 4.45 (dd, J= 9.0, 5.4 Hz, 1H), 3.78 (m, 1H), 2.26 (m, 2H), 1.90 (p ,J= 6.7 Hz, 1H), 1.04 (m, 1H), 0.73 (m, 1H). MS (ES+): 456.1 (M+l); (ES-): 454.1 (M-l); Analysis calculated for Ci9Hi ₈ BrN ₇ 022.25H20.2.25HC1: C, 39.42; H, 4.31; Cl, 13.78; N, 16.94; Found: C, 39.7; H, 4.28; Cl, 13.43; N, 16.71.

Scheme 130

O

Preparation of (2S,4R)-l-(2-(4-amino-5-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-y l)acetyl)-N- (3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (130e)

Step-1: Preparation of tert- butyl 2-(4-chloro-5-cyano-7H-pyrrolo[2,3-d]pyrimidin-7- yl)acetate (130b)

Compound 130b was prepared according to the procedure reported in step-1 of scheme- 1, from 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (130a) (2 g, 11.20 mmol; CAS # 24391-41-1) in DMF (50 mL) using sodium hydride (0.538 g, 13.44 mmol), tert- butyl 2- bromoacetate (1.986 mL, 13.44 mmol) and stirring at RT for 19 h. This gave after workup te/t-butyl 2-(4-chloro-5-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (130b) (2.005 g, 61% yield) as a white solid; Ή NMR (300 MHz, DMSO-i/6) δ 8.86 (s, 1H), 8.71 (s, 1H), 5.17 (s, 2H), 1.41 (s, 9H); MS (ES+): 293.05 (M+l).

Step-2: Preparation of2-(4-chloro-5-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (130c)

Compound 130c was prepared according to the procedure reported in step-2 of scheme- 1, from tert-butyl 2-(4-chloro-5-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (130b) (1.98 g, 6.76 mmol) in DCM (60 mL) using TFA (5.21 mL, 67.6 mmol) and stirring at RT for 20 h. This gave after workup 2-(4-chloro-5-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (130c) (2.38 g) as an off-white solid which was used as such for next step.

Step-3: Preparation of (2S,4R)-N-(3-chloro-2-fluorobenzyl)-l-(2-(4-chloro-5-cyano-7 H- pyrrolo[2,3-d]pyrimidin-7-yl)acetyl)-4-fluoropyirolidine-2-c arboxamide (130d)

Compound 130d was prepared according to the procedure reported in step-3 of scheme- 1, from of 2-(4-chloro-5 -cyano-7H-pyrrolo [2,3 -d] pyrimidin-7-yl)acetic acid (130c) (516 mg, 2.182 mmol) in DMF (30 mL) using (2S,4R)-N-(3-chloro-2-fluorobenzyl)-4- fluoropyrrolidine-2-carboxamide (7a) (472 mg, 1.718 mmol), HATU (1307 mg, 3.44 mmol), DIPEA (1110 mg, 8.59 mmol) and stirring at RT for 21 h. This gave after workup and purification by flash column chromatography [silica gel, eluting with MeOH:EtOAc (1:9) in hexanes] (2S,4R)-N-(3-chloro-2-fluorobenzyl)-l-(2-(4-chloro-5-cyano-7 H-pyrrolo[2,3- d]pyrimidin-7-yl)acetyl)-4-fluoropyrrolidine-2-carboxamide (130d) (155 mg, 18%) as a yellow solid; Ή NMR (300 MHz, DMSO-cfe) (a mixture of two rotamers) δ 9.03 (t) & 8.67 - 8.57 (m) (2H), 8.82 & 8.80 (2s, 1H),7.54 - 7.32 (m, 1H), 7.26 - 7.12 (m, 1H), 7.09 - 6.97 (m, 1H), 5.68 - 5.18 (m, 3H), 4.97 - 3.71 (m, 5H), 2.61 - 2.35 (m, 1H), 2.21 - 1.92 (m, 1H); ^!9 F NMR (282 MHz, DMSO-cfe) (a mixture of two rotamers) δ -121.32 & -121.57 (IF), -176.13 &- 176.41 (IF) MS (ES+): 493.10 & 495.00 (M+l).

Step-4: Preparation of (2S,4R)-l-(2-(4-amino-5-cyano-7H-pyrrolo[2,3-d]pyrimidin-7- yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2 -caiboxamide (130e)

To a solution of (2S,4R)-N-(3-chloro-2-fluorobenzyl)-l-(2-(4-chloro-5-cyano-7 H- pyrrolo[2,3-d]pyrimidin-7-yl)acet>'l)-4-fluoropyrrolidine -2-carboxamide (130d) (100 mg, 0.203 mmol) in dioxane (4 mL) was added ammonium hydroxide (3.84 niL, 56.8 mmol) and heated at 85 °C in a sealed tube for 14 h. The reaction mixture was concentrated to dryness 0-5 %] to afford (2S,4R)-l-(2-(4-amino-5-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-y l)acetyl)-N- (3-chloro-2-fluorobenzyl)-4-fluoropyrroUdine-2-carboxamide (130e) (37 mg, 39% yield) as a white solid. Ή NMR (300 MHz, DMSO-cfe) (a mixture of two retainers) δ 9.02 & 8.60 (2t, J = 5.9 Hz, 1H, D2O exchangeable), 8.18 & 8.17 (2s, 1H), 8.10 & 8.07 (2s, 1H), 7.53 - 7.33 (m, 1H), 7.27 - 7.13 (m, 1H), 7.10 - 7.01 (m, 1H), 6.86 (s, 2H, DzO exchangeable), 5.60 - 5.36 (m, 1H), 5.32 - 5.02 (m, 2H), 4.93 - 3.58 (m, 5H), 2.62-2.34 (m, 1H), 2.31 - 1.85 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-i/e) (a mixture of two rotamers) δ -121.36 & -121.64, - 176.12 & -176.39; MS (ES+): 474.10 (M+l); MS (ES-): 472.60 (M-l).

Scheme 131

X

Preparation of (2S,4R)- l-(2-(4-amino- lH-pyrrolo[2,3-b]pyridin-l-yl)acetyl)-N-(3-chloro-2- fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (131e)

Step-1: Preparation of tort-butyl 2-(4-chloro-lH-pyrrolo[2,3-b]pyridin- 1 -yl)acetate (131b)

Compound 131b was prepared according to the procedure reported in step-1 of scheme- 1, from 4-chloro- 1 H-pyrrolo [2,3 -b jpyridine (131a) (1 g, 6.55 mmol; CAS # 55052-28-3) in DMF (25 mL) using sodium hydride (0.315 g, 7.86 mmol), tort-butyl 2-bromoacetate (1.162 mL, 7.86 mmol) and stirring at RT for 14 h. This gave after workup and purification by flash column chromatography [silica gel (40 g), eluting with EtOAc in hexane from 0 to 85%] tort- butyl 2-(4-chloro-lH-pyrrolo[2,3-b]pyridin-l-yl)acetate (131b) (1.45 g, 83% yield) as a 1H), 7.26 (d, J= 5.2 Hz, 1H), 6.56 (d, J= 3.6 Hz, 1H), 5.05 (s, 2H), 1.40 (s, 9H); MS (ES+): 267.10 & 269.10 (M+l).

Step-2: Preparation of tort-butyl 2-(4-((tort-butoxycarbonyl)amino)-lH-pyrrolo[2,3- b]pyridin- 1 -vi)acetate (131c)

Compound 131c was prepared according to the procedure reported in step-3 of scheme-17, from (tort- butyl 2-(4-ch loro- 1 H-pyrrolo [2,3 -b]py ridin- 1 -yl)acetate (131b) (1 g, 3.75 mmol) in toluene (30 mL) using XPhos (0.179 g, 0.375 mmol), t-butyl carbamate (0.659 g, 5.62 mmol), Pdz(dba)3 (0.172 g, 0.187 mmol), cesium carbonate (1.222 g, 3.75 mmol) and heating at 90 °C for 19 h. This gave after work up and purification by flash column chromatography [silica gel, EtOAc in Hexane from 0 - 14% then 33%] tort-butyl 2-(4 -((tort- butoxycarbonyl)amino)-lH-pyrrolo[2,3-b]pyridin-l-yl)acetate (131c) (1.145 g, 88% yield) as a yellow gum; ΉΝΜΚ(300 MHz, DMSO-tife) δ 9.72 (s, 1H), 8.05 (d, J= 5.5 Hz, 1H), 7.61

(d,

J= 5.5 Hz, 1H), 7.32 (d, 3.6 Hz, 1H), 6.90 (d, .7= 3.6 Hz, 1H), 4.94 (s, 2H), 1.53 (s, 9H),

1.40 (s, 9H); MS (ES+): 348.20 (M+l).

Step-3: Preparation of 2-(4-amino-lH-pyrrolo[2,3-b]pyridin-l-yl)acetic acid (131d)

Compound 131d was prepared according to the procedure reported in step-2 of scheme-1, from tort-butyl 2-(4-((tort-butoxycarbonyl)amino)-lH-pyrrolo[2,3-b]pyridin-l -yl)acetate (131c) (1 g, 2.88 mmol) in DCM (30 mL) using TFA (1.711 mL, 23.03 mmol) and stirring at RT for 18 h. This gave after work up 2-(4-amino- lH-pyrrolo[2,3-b]pyridin- 1 -yl)acetic acid (131d) (1.62 g) as a yellow gum; MS (ES+): 192.10 (M+l).

Step-4: Preparation of (2S,4R)-l-(2-(4-amino-lH-pyrrolo[2,3-b]pyridin-l-yl)acetyl)- N-(3- cMoro-2-fluorobenzyl)-4-fluoropyrrolidine-2-caiboxamide (131 e)

Compound 131e was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-lH-pyrrolo[2,3-b]pyridin-l-yl)acetic acid (131d) (83 mg, 0.432 mmol) in DMF (10 mL) using (2S,4R)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2- carboxamide (7a) (148 mg, 0.540 mmol), HATU (329 mg, 0.864 mmol), DIPEA (0.376 mL, 2.160 mmol) and stirring at RT for 18 h. This gave after workup and purification using reverse phase column chromatography [Cl 8 column (26 g), eluting with ACN in water (containing 0.1%HC1) from 0-100%] (2S,4R)-l-(2-(4-amino-lH-pyrrolo[2,3-b]pyridin-l- yl)acetyl)-N -(3 -chloro-2-fluorobenzyl)-4-fluoropy rrolidine-2-carboxamide (131e) (23 mg, rotamers) δ 14.17 - 13.83 (m, 1H), 9.23 - 8.79 (m, 1H), 8.16 (s, 2H), 7.97 - 7.74 (m, 1H), 7.57 - 7.35 (m, 1H), 7.32 - 7.08 (m, 2H), 6.96 - 6.79 (m, 2H), 6.51 - 6.45 (m, 1H), 5.62 - 5.24 (m, 3H), 4.99 - 3.54 (m, 5H), 2.73 - 2.42 (m, 1H), 2.37 - 1.86 (m, 1H); ¹⁹ FNMR (282 MHz, DMSO-ife) (amixture of two retainers) δ -121.29 & -121.79, -175.81 & -175.96; MS (ES+): 448.10 (M+l); MS (ES-): 446.70 (M-l).

Scheme 132

NH ₂ 132d

Preparation of (2S,4R)- l-(2-(4-amino-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acety l)-N- (3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-caiboxamide (132d)

Step-1: Preparation of tort-butyl 2-(4-am ino-2-methyl -7H-pyrrolo [2 ,3 -d] pyrim idin-7- yl)acetate (132b)

Compound 132b was prepared according to the procedure reported in step-1 of scheme- 1, from 2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (132a) (500 mg, 3.37 mmol) in DMF (15 mL) using tort-butyl 2-bromoacetate (0.498 mL, 3.37 mmol), CszCOs (1.319 g, 4.05 mmol) and stirring at RT for 18 h. This gave after workup and purification by flash column chromatography [silica gel, eluting with MeOH in DCM from 0-5%, then 10% ] tort-butyl 2- (4-amino-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (132b) (700 mg, 79% yield) as off-white solid; Ή NMR (300 MHz, DMSO-cfc) δ 7.01 (d, J= 3.5 Hz, 1H), 6.87 (s, 2H), 6.46 (d, J= 3.5 Hz, 1H), 4.80 (s, 2H), 2.33 (s, 3H), 1.41 (s, 9H); MS (ES+): 263.10 (M+l). Step-2: Preparation of 2-(4-amino-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (132c)

Compound 132c was prepared according to the procedure reported in step-2 of scheme- 1, from tert- butyl 2-(4-amino-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (132b) (670 mg, 2.55 mmol) using TFA. This gave after workup 2-(4-amino-2-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)acetic acid (132c) (875 mg) off white solid; MS (ES+): 207.05 (M+l).

Step-3: Preparation of (2S,4R)-l-(2-(4-amino-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2 -carboxamide (132d)

Compound 132d was prepared according to the procedure reported in step-3 of scheme-1, from 2-(4-amino-2-methyl-7H-pyrTOlo[2,3-d]pyrimidin-7-yl)acetic acid (132c) (89 mg, 0.432 mmol) in DMF (10 rtiL) using (2S,4R)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2- carboxamide (7a) (148 mg, 0.540 mmol), HATU (329 mg, 0.864 mmol), DIPEA (0.376 mL, 2.160 mmol) and stirring at RT for 12 h. This gave after workup and purification using reverse phase column chromatography [Cl 8 column (26 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)-l-(2-(4-amino-2-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluor opyrrolidine-2-carboxamide (132d) (34 mg, 17% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) (a mixture of two rotamers) 5 13.94 (s, 1H, DzO exchangeable), 9.26 (s, 1H, DzO exchangeable), 9.15 - 8.61 (m, 1H, DzO exchangeable), 8.07 (s, 1H, DzO exchangeable),

7.51 - 7.35 (m, 1H), 7.33 - 7.20 (m, 2H), 7.16 & 7.06 (2t, J= 7.9 Hz, 1H), 6.93 - 6.86 (m, 1H), 5.64 - 4.94 (m, 3H), 4.92 - 3.69 (m, 5H), 2.77 - 2.25 (m, 4H), 2.27 - 1.89 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-de) (a mixture of two rotamers) δ -121.33 & -121.66 (IF), -176.06 & -176.34 (IF); MS (ES+): 463.10 & 465.10 (M+l).

Scheme 133

Preparation of (2S,4R)-l-(2-(4-amino-5-(lH-indol-2-yl)-7H-pyrrolo[2,3-d]pyr imidin-7- yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropynoliclme-2- carboxamide (133b)

Compound 133b was prepared according to the procedure reported in step-1 of scheme-59, from (2S,4R)-l-(2-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-y l)acetyl)-N-(3-chloro- 2-fluorobenzyl)-4-fluoropyrrolidine-2-caiboxamide (116b) (200 mg, 0.379 mmol), 1H- Indole-2-boronic acid pinacol ester (133a) (92 mg, 0.379 mmol), Pd(PPh3)zCl2 (26.6 mg, 0.038 mmol) in dioxane (5 mL) using a 3.3 M aqueous K2CO3 (0.345 mL, 1.137 mmol) and heating at 100 °C for 16 h under argon. This gave after workup and purification by flash column chromatography (S1O2, 12 g, eluting with 0-5% MeOH in DCM) followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1%HC1) from 0-100%] (2S,4R)- 1 -(2-(4-amino-5-( lH-indol-2- yl)-7H-pyrrolo[2,3-d]pjrimidin-7-yl)acetyl)-N-(3-chloro-2-fl uorobenzyl)-4- fluoropyrrohdine-2-caiboxamide (133b) (37 mg, 17 % yield) HC1 salt as a pale-orange solid; Ή NMR (300 MHz, DMSO-i¾) (mixture of two rotamers) δ 11.65 - 11.50 (m, 1 H, D2O exchangeable), 8.69 (t, J = 5.9 Hz, 1H), 8.45 (t, J = 2.3 Hz, 1H), 7.89 (s, 2H, D2O exchangeable), 7.66 (dd, J = 3.8, 1.2 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.52 - 7.40 (m, 1H), 7.40 - 7.29 (m, 1H), 7.29 - 7.20 (m, 1H), 7.19 - 7.10 (m, 1H), 7.04 (dt, J = 12.1, 7.7 Hz, 2H), 6.59 (d, J = 2.0 Hz, 1H), 5.67 - 5.10 (m, 3H), 4.41 (m, 2H), 4.31 - 4.09 (m, 1H), 3.90 (m, 1H), 2.22 - 1.93 (m, 1H). ¹⁹ FNMR(282 MHz, DMSO^fe) δ -121.30, -121.63, -176.11, -176.32; MS (ES+) 564/566 (M+l), (ES-) 560/562 (M-l); Analysis calculated for C28H24C1F2N702-HC1-2.75H20: C, 51.74; H, 4.73; Cl, 10.91; N, 15.08; Found: C, 51.74; H, 4.56; Cl, 10.98; N, 15.07.

Scheme 134

Preparation of (2S,4R)- l-(2-(4-amino-5-( lH-indol-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrohdine-2- carboxamide (134b)

Compound 134b was prepared according to the procedure reported in step-1 of scheme-59, from (2S,4R)-l-(2-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-y l)acetyl)-N-(3-chloro- 2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (116b) (200 mg, 0.379 mmol), 1H- Indole-7-boronic acid pinacol ester (134a) (92 mg, 0.379 mmol), Pd(PPlu)2Cl2 (26.6 mg, 0.038 mmol) in dioxane (5 mL) using a 3.3 M aqueous K2CO3 (0.345 mL, 1.137 mmol) and heating at 100 °C for 16 h under argon. This gave after workup and purification by flash column chromatography (S1O2, 12 g, eluting with 0-5% MeOH in DCM) followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)- l-(2-(4-amino-5-( lH-indol-7- yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetyl)-N-(3-chloro-2-fl uorobenzyl)-4- fluoropyrrolidine-2-carboxamide (134b) (47 mg, 22 % yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) (mixture of two rotamers) δ 11.03 (q, J = 4.1, 3.2 Hz, 1H, D2O exchangeable), 8.68 (t, J = 5.9 Hz, 1H), 8.45 (d, J = 3.7 Hz, 1H), 7.64 (dt, J = 7.7, 1.7 Hz, 1H), 7.56 (d, J = 6.4 Hz, 1H), 7.50 - 7.30 (m, 2H, D2O exchangeable), 7.30 - 7.20 (m, 1H), 7.15 (t, J = 7.5 Hz, 1H), 7.11 - 7.06 (m, 1H), 7.01 - 6.92 (m, 1H), 6.57 (dd, J = 3.1, 1.7 Hz, 1H), 5.62 - 5.13 (m, 3H), 4.52 - 4.31 (m, 2H), 4.29 - 4.11 (m, 2H), 3.88 (m, 1H), 2.21 - 1.92 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO-tfc) δ -121.29, -121.67, -176.13, -176.29; MS (ES+): 564/566 (M+l), (ES-): 560/562 (M-l); Analysis calculated for

C28H24C1F ₂ N702· 1.25HC1-2.5H20: C, 51.37; H, 4.66; Cl, 12.19; N, 14.98; Found: C, 51.69; H, 4.49; Cl, 11.79; N, 14.99.

Scheme 135

Preparation of (2S,4R)-l-(2-(4-amino-5-phenyl-7H-pynOlo[2,3-dJpyrimidin-7-y l)acetyl)-N- (3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (135a)

Compound 135a was prepared according to the procedure reported in step-1 of scheme-59, from (2S,4R)-l-(2-i4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-y l)acetyl)-N-(3-chloro- 2-fluorobenzyl)-4-fhioropyrrolidine-2-caiboxamide (116b) (200 mg, 0.379 mmol), phenylboronic acid (46.2 mg, 0.379 mmol), Pd(PPh3)zClz (26.6 mg, 0.038 mmol) in dioxane (5 mL) using a 3.3 M aqueous K2CO3 (0.345 mL, 1.137 mmol) and heating at 100 °C for 16 h under argon. This gave after workup and purification by flash column chromatography (SiOz, 12 g, eluting with 0-5% MeOH in DCM) followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%](2S,4R)-l-(2-(4-amino-5-phenyl-7H-pyrrolo[2,3-d]pjnim idin-7- yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2 -caiboxamide (135a) (53 mg, 27 % yield) HC1 salt as a white solid after lyophilization. Ή NMR (300 MHz, DMSO-cfe) (mixture of two retainers) δ 8.69 (t, J = 6.0 Hz, 1H), 8.45 (d, J = 4.3 Hz, 1H), 7.97 - 7.34 (m, 9H), 7.22 (m, 1H), 7.00 (m, 1H), 5.58 - 5.16 (m, 3H), 4.51 - 4.09 (m, 5H), 4.02 - 3.77 (m,

1H), 2.21 - 1.92 (m, 1H). ¹⁹ FNMR(282 MHz, DMSO-ifc) δ -121.29, -121.64, -176.12, - 176.32; MS (ES+): 525/527 (M+l), (ES-): 521/523 (M-l); Analysis calculated for CZ6HZ3C1FZN60Z*HC1*2H20: C, 52.27; H, 4.72; Cl, 11.87; N, 14.07; Found: C, 52.01; H, 4.69; Cl, 11.63; N, 13.99.

Scheme 136 F,

116b 136a

Preparation of (2S,4R)-l-(2-(4-amino-5-(2-chlorophenyl)-7H-pyrrolo[2,3-d]py rimidin-7- yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2 -carboxamide (136a)

Compound 136a was prepared according to the procedure reported in step-1 of scheme-59, from (2S,4R)-l-(2-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidm-7-yl )acetyl)-N-(3-chloro- 2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (116b) (200 mg, 0.379 mmol), 2- chlorophenylboronic acid (59.3 mg, 0.379 mmol), Pd(PPh3)2Clz (26.6 mg, 0.038 mmol) in dioxane (5 mL) using a 3.3 M aqueous K2CO3 (0.345 mL, 1.137 mmol) and heating at 100 °C for 16 h under argon. This gave after workup and purification by flash column chromatography (SiOz, 12 g, eluting with 0-5% MeOH in DCM) followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with 0-60% ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)-l-(2-(4-amino-5-(2-chlorophenyl)- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetyl)-N-(3-chloro-2-fluoro benzyl)-4-fluoropyrrolidine-2- carboxamide (136a) (43 mg, 20 % yield) HC1 salt as awhile solid after lyophilization. ^X H NMR (300 MHz, DMSO-afe) (mixture of two rotamers) δ 8.70 (t, J = 5.9 Hz, 1H), 8.43 (d, J = 4.3 Hz, 1H), 7.83 - 7.61 (m, 2H), 7.54 - 7.35 (m, 6H), 7.30 - 7.23 (m, 1H), 7.02 (t, J = 7.9 Hz, 1H), 5.61 - 5.17 (m, 3H), 4.51 - 4.09 (m, 5H), 4.02 - 3.77 (m, 1H), 2.21 - 1.91 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -121.28, -121.65, -176.10, -176.29; MS (ES+) 559/561 (M+l), (ES-) 555/557 (M-l); Analysis calculated for CzeHzzChFzNeOz'HCWHzO: C, 49.42; H, 4.31; Cl, 16.83; N, 13.30; Found: C, 49.20; H, 4.24; Cl, 16.72; N, 13.24.

Scheme 137

116b

137b

Preparation of (2S,4R)-l-(2-(4-amino-5-(lH-indol-6-yl)-7H-pyrrolo[2,3-d]pyr imidin-7- yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2 -carboxamide (137b)

Compound 137b was prepared according to the procedure reported in step-1 of scheme-59, from (2S,4R)-l-(2-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-y l)acetyl)-N-(3-chloro- 2-fluorobenzyl)-4-fluoropyrrohdine-2-carboxamide (116b) (200 mg, 0.379 mmol), indole-6- boronic acid pinacol ester (137a) (92 mg, 0.379 mmol), Pd(PPh3)zCl2 (26.6 mg, 0.038 mmol) in dioxane (5 mL) using a 3.3 M aqueous K2CO3 (0.345 mL, 1.137 mmol) and heating at 100 °C for 16 h under argon. This gave after workup and purification by flash column chromatography (S1O2, 12 g, eluting with 0-5% MeOH in DCM) followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with 0-60% ACN in water (containing 0.1% HC1) from 0-100%](2S,4R)-l-(2-(4-amino-5-(lH-indol-6-yl)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)acetyl)-N-(3-chloro-2-fluoroben 2yl)-4-fluoropyrrolidine-2- carboxamide (137b) (30 mg, 14 % yield) HC1 as a white solid; Ή NMR (300 MHz, DMSO- de) (mixture of two rotamers) δ 11.30 (d, J = 2.3 Hz, 1H, D2O exchangeable), 8.67 (t, J = 5.9 Hz, 1H), 8.43 (d, J = 4.0 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.51 - 7.41 (m, 3H), 7.36 (m, 1H), 7.28 - 7.18 (m, 1H), 7.11 (m, 1H), 7.05 - 6.96 (m, 1H), 6.51 (t, J = 2.5 Hz, 1H), 5.78 - 5.13 (m, 2H), 4.93 - 4.32 (m, 2H), 4.32 - 4.06 (m, 1H), 3.89 (m, 1H), 2.22 - 1.90 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO-cfc) δ -121.28, -121.64, -176.09, -176.30; MS (ES+): 564/566 (M+l), (ES-): 560/562 (M-l); Analysis calculated for C28H24ClF2N7O2.HCl.2H2O: C, 52.10; H, 4.68; Cl, 10.98; N, 15.19; Found: C, 51.79; H, 4.31; Cl, 11.23; N, 15.29.

Scheme 138 ₂

138d

Preparation of (2S,4R)-1 -(2-(4-aminoquinazolin-8-yl)acetyI)-N-(3-chloro-2-fluorobenz yl)-4- fluoropyrrolidine-2-carboxamide (138d)

Step-1: Preparation of ter/-butyl 2-(4-aminoquinazolin-8-yl)acetate (138b)

Compound 138b was prepared according to the procedure reported in step-1 of scheme-2, from 8-bromoquinazolin-4-amine (138a) (1.00 g, 4.46 mmol; CAS # 1260657-19-9) using zinc (1.752 g, 26.8 mmol), TMSC1 (0.283 mL, 2.232 mmol) in THF (5 mL), Pdz(dba) ₃ (0.409 g, 0.446 mmol), XPhos (0.426 g, 0.893 mmol) in THF (10 mL). This gave after work up and purification using flash column chromatography [silicagel (24 g), eluting with EtOAc in hexane from 0-50%] fcrf-butyl 2-(4-aminoquinazolin-8-yl)acetate (138b) (97 mg, 8.4%) as a yellow solid; ΉΝΜΚ(300 MHz, DMSO-ifc) δ 8.39 (s, 1H), 8.12 (dd, J = 8.4, 1.4 Hz, 1H), 7.90 - 7.68 (m, 2H), 7.65 (dd, J = 7.0, 1.2 Hz, 1H), 7.42 (dd, J = 8.3, 7.1 Hz, 1H), 3.94 (s, 2H), 1.39 (s, 9H); MS (ES+): 260 (M+l).

Step-2: Preparation of 2-(4-aminoquinazolin-8-yl)acetic acid (138c)

Compound 138c was prepared according to the procedure reported in step-2 of scheme- 1, from tert- butyl 2-(4-aminoquinazolin-8-yl)acetate (138b) (95 mg, 0.366 mmol) using TFA (2.103 mL, 5.50 mmol) in DCM (5 mL) and stirring at RT for 16 h. This gave after work up 2-(2-(4-aminoquinazolin-8-yl)acetic acid (138c) (106 mg, 91%) TFA salt as an orange solid; Ή NMR (300 MHz, DMSO-cfc) δ 9.88 - 9.57 (m, 2H), 8.76 (s, 1H), 8.36 (dd, J = 8.4, 1.2 Hz, 1H), 7.97 (dd, J = 7.4, 1.2 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 4.07 (s, 2H). ¹⁹ F NMR (282 MHz, DMSO-tfc) δ -74.37; LC-MS: t = 0.56 min; MS (ES+): 204 (M+l).

Step-3: Preparation of (2S,4R)-l-(2-(4-aminoquinazolin-8-yl)acet>'l)-N-(3-chloro -2- fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (138d)

Compound 138d was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-aminoquinazolin-8-yl)acetic acid (138c) (93 mg, 0.293 mmol) in DMF (5 mL) using (2S,4R)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-ca rboxamide (7a) (114 mg, 0.293 mmol), HATU (134 mg, 0.352 mmol), DIPEA (0.490 mL, 2.81 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography (SiOz, 12 g, eluting with 0-3% MeOH in DCM) followed by reverse phase column chromatography [C-18 column, 100 g, eluting with 0.1% aqueous HC1 in HzO and MeCN from 0-100%] (2S,4R)-l-(2-(4-aminoquinazolin-8-yl)acetyl)-N-(3-chloro-2-f luorobenzyl)-4- fluoropyrrohdine-2-carboxamide (138d) (22 mg, 16 % yield) HC1 salt as a pale-yellow solid; Ή NMR (300 MHz, DMSO-flfe) (mixture of two rotamers) δ 9.80 (s, 2H, DzO exchangeable), 8.82 (q, J = 5.6, 4.1 Hz, 1H, DzO exchangeable), 8.52 (s, 1H), 8.39 (d, J = 8.3 Hz, 1H), 7.91 (d, J = 7.3 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.40 (td, J = 7.6, 1.6 Hz, 1H), 7.30 - 7.15 (m, 1H), 6.92 (t, J = 8.2 Hz, 1H), 5.65 - 5.19 (m, 1H), 4.50 - 3.90 (m, 9H), 2.25 - 1.95 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO-tife) δ -121.15, -121.69, -175.82; MS (ES+): 460/462 (M+l), (ES-): 457/459 (M-l).

Scheme 139

116b 139b

Preparation of (2S,4R)-l-(2-(4-amino-5-(lH-indo]-5-yl)-7H-pyrrolo[2,3-d]pyr imidin-7- yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolicliine -2-carboxamide (139b) Compound 139b was prepared according to the procedure reported in step-1 of scheme-59, from (2S,4R)-l-(2-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-y l)acetyl)-N-(3-chloro- 2-fluorobenzyl)-4-fluoropyrrolidine-2-caiboxamide (116b) (200 mg, 0.379 mmol), indole-5- boronic acid pinacol ester (139a) (92 mg, 0.379 mmol), Pd(PPh3)2Ch (26.6 mg, 0.038 mmol) in dioxane (5 mL) using a 3.3 M aqueous K2CO3 (0.345 mL, 1.137 mmol) and heating at 100 °C for 16 h under argon. This gave after workup and purification by flash column chromatography (S1O2, 12 g, eluting with 0-3% MeOH in DCM) followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%](2S,4R)-l-(2-(4-amino-5-(lH-indol-5-yl)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)acety])-N-(3-chloro-2-fluoroben zyl)-4-fluoropyrrolidine-2- carboxamide (139b) (73 mg, 34 % yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) (a mixture of two rotamers) 5 11.31 (d, J = 2.6 Hz, 1H, DzO exchangeable), 8.67 (t, J = 6.0 Hz, 1H), 8.42 (d, J = 4.0 Hz, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.44 (m, 3H), 7.37 (m, 1H), 7.29 - 7.22 (m, 1H), 7.19 (m, 2H), 7.02 (t, J = 7.9 Hz, 1H), 6.51 (d, J = 2.6 Hz, 1H), 5.64 - 5.10 (m, 4H), 4.41 (m, 3H), 4.20 (m, 2H), 4.03 - 3.78 (m, 1H), 2.22 - 1.93 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO-ifc) 5 -121.29, -121.64, -176.11, -176.30; MS (ES+): 564/566 (M+l), (ES-): 560/562 (M-l); Analysis calculated for C28H24C1F2N702.HC1.2.25H20: C, 52.47; H, 4.64; Cl, 11.06; N, 15.30 Found: C, 52.27; H, 4.40; Cl, 11.42; N, 15.41.

Scheme 140

Preparation of 4-amino-7-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl) -4- fluoropyrrolidin-l-yl)-2-oxoethyl)-7H-pyrrolo[2,3-d]pyrimidi ne-5-carboxamide (140a)

Compound 140a was prepared according to the procedure reported in step-1 of scheme-60, fr ( S ) ( l d ri idi l l) ( hl 2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (130e) (150 mg, 0.317 mmol) in ethanol (8 mL) using cone. NH4OH (3 mL) and hydrogen peroxide (0.112 mL, 1.266 mmol) and stirring at RT for 5 h. This gave after workup and purification by reverse phase column chromatography [C18 column (26 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] 4-amino-7-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl) -4-fluoropyrrolidin- 1 -yl)-2-oxoethyl )-7H-pyrrolo [2 ,3 -d]pyrim idine-5 -carboxamide (140a) (134 mg, 86% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc/TfcO) (a mixture of two retainers) δ 8.81 - 8.65 (m, 1H), 8.38 (d, .7= 4.6 Hz, 1H), 8.15 (s, 1H), 7.42 (q ,J= 10.2, 9.0 Hz, 1H),

7.21 (q, J= 8.7, 8.1 Hz, 1H), 7.07 (t, J= 7.9 Hz, 1H), 5.64 - 5.11 (m, 3H), 4.93 - 3.87 (m, 5H), 2.51 (s, 1H), 2.23 - 1.85 (m, 1H); ¹⁹ FNMR(282 MHz, DMSO-tfc) (a mixture of two rotamers) δ -121.33 & -121.61, -176.20 &-176.51; MS (ES+): 492.10, 494.10 (M+l); Analysis calculated for C21H20CIF2N7O3.HCI.2H2O: C, 44.69; H, 4.46; N, 17.37; Cl, 12.56; Found: C, 44.49; H, 4.44; N, 17.34; Cl, 12.42.

Scheme 141

Preparation of (2S,4R)-l-(2-(4-ainino-5-(aininomethyl)-7H-pyrrolo[2,3-d]pyr imidin-7- yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2 -carboxamide (141a)

To a cooled solution of (2S,4R)-l-(2-(4-amino-5-cyano-7H-pyrrolo[2,3-d]pyrimidin-7- yl)acet>'l)-N-(3-chloro-2-fluorobenz>'l)-4-fluoropyrro lidine-2-carboxamide (130e) (300 mg, 0.633 mmol) in methanol (20 mL) was added nickel(II) chloride hexahydrate (37.6 mg, 0.158 mmol) followed by sodium borohydride (144 mg, 3.80 mmol) in several portions over a period of 10 min and stirred at RT for 1 h. To this mixture was added Nl-(2- aminoethyl)ethane- 1,2-diamine (0.137 mL, 1.266 mmol) and stirred at RT for 0.5 h and concentrated under vacuum. The residue was treated with ethyl acetate (120 mL), washed The combined organics were washed with brine (75 mL), dried, filtered and concentrated in vacuum. The obtained residue was purified by reverse phase column chromatography [Cl 8 column (26 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] to afford (2S,4R)-l-(2-(4-amino-5-(aminomethyl)-7H-pyrrolo[2,3-d]pyrim idin-7-yl)acetyl)-N-(3- chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (141a) (48 mg, 16% yield) HC1 salt as a white solid; ¾i NMR (300 MHz, DMSO-tfc) (a mixture of two rotamers) 59.18 - 8.53 (m, 3H, DiO exchangeable), 8.39 - 8.36 (m, 1H), 8.23 (s, 3H, D2O exchangeable), 7.52 &7.51 (2s, 1H), 7.49 - 7.05 (m, 3H), 5.65 - 5.07 (m, 3H), 4.99 - 3.72 (m, 7H), 2.61 - 2.40 (m, 1H), 2.21 - 1.88 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-cfe) (a mixture of two rotamers) 5 -121.32 & -121.61, -176.11 & -176.32; MS (ES+): 478.10 & 480.10 (M+l); Analysis calculated for C21H22CIF2N7O2.I.85 HCl.1.75 H2O: C, 43.72; H, 4.78; N, 17.00; Cl, 17.52; Found: C, 43.89; H, 4.62; N, 16.93; Cl, 17.84.

Scheme 142

NH ₂ 142d

Preparation of (2S,4R)- 1 -(2-(4-amino-6-methyl- lH-pyrazolo[3,4-dJpyrimidin- 1 -yl)acetyl)-N- (3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-caiboxamide (142d)

Step-1: Preparation of /e/7-butyl 2-(4-am ino-6-methy 1- 1 H-pyrazolo[3 ,4-d] pyrimidi n-1- yl)acetate (142b) Compound 142b was prepared according to the procedure reported in step-1 of scheme- 1, from 6-methyl-lH-pyrazolo[3,4-d]pyrimidin-4-amine (142a) (500 mg, 3.35 mmol; CAS # 5326-80-7) in DMF (15 mL) using tort-butyl 2-bromoacetate (0.495 mL, 3.35 mmol),

CS2CO3 (1.311 g, 4.02 mmol) and stirring at RT for 18 h. This gave after workup and purification by flash column chromatography [silica gel; eluting with MeOH in DCM from 0- 5%] tort-butyl 2-(4-amino-6-methyl- lH-pyrazolo[3,4-d]pyrimidin- l-yl)acetate (142b) (360 mg, 41% yield) as a yellow solid; Ή NMR (300 MHz, DMSO-i/e) δ 8.03 (s, 1H), 7.62 (s,

2H), 4.97 (s, 2H), 2.37 (s, 3H), 1.40 (s, 9H); MS (ES+): 264.1 (M+l).

Step-2: Preparation of 2-(4-amino-6-methyl-lH-pyrazolo[3,4-d]pyrimidin-l-yl)acetic acid (142c)

Compound 142c was prepared according to the procedure reported in step-2 of scheme- 1, from tort-butyl 2-(4-amino-6-methyl-lH-pyrazolo[3,4-d]pyrimidin-l-yl)acetate (142b) (335 mg, 1.272 mmol) using TFA in DCM (20 mL). This gave after workup 2-(4-amino-6-methyl- lH-pyrazolo[3,4-d]pyrimidin-l-yl)acetic acid (142c) (715 mg) and used as such for the next step; MS (ES+): 208.10 (M+l).

Step-3: Preparation of (2S,4R)-l-(2-(4-amino-6-methyl-lH-pyrazolo[3,4-d]pyrimidin-l - yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2 -carboxamide (142d)

Compound 142d was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-6-methyl- lH-pyrazolo[3,4-d]pyrimidin- 1 -yl)acetic acid (142c) (0.432 mmol) in DMF (10 mL) using (2S,4R)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolicline-2- carboxamide (7a) (0.540 mmol), HATU (0.329 g, 0.864 mmol), DIPEA (0.376 mL, 2.160 mmol) and stirring at RT for 20 h. This gave after workup and purification using reverse phase column chromatography [Cl 8 column (26 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)-l-(2-(4-amino-6-methyl-lH-pyrazolo[3,4-d]pyrimidin-l - yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2 -carboxamide (142d) (92 mg, 46% yield) HC1 salt as a white solid; NMR (300 MHz, DMSO-dfc) (a mixture of two rotamers) δ 10.00 (s, 1H, D2O exchangeable), 9.09 (t,J= 5.9 Hz) & 8.73 - 8.57 (m) (2H, D2O exchangeable), 8.45 & 8.44 (2s, 1H), 7.52 - 7.41 (m, 1H), 7.40 - 7.19 (m, 1H), 7.16 & 7.06 (2t, J= 7.9 Hz, 1H), 5.62 - 5.17 (m, 3H), 4.96 - 3.73 (m, 5H), 2.54 & 2.52 (2s, 3H), 2.60 - 2.40 (m, 1H), 2.19 - 1.90 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-tife) (a mixture of two rotamers) δ -121.30 & -121.65, -176.29 & -176.51; MS (ES+): 464.10 & 466.10 (M+l); Analysis calculated for C20H20CIF2N7O2.HCI.2.25H2O: C, 44.41; H, 4.75; Cl, 13.11; N, 18.13; Found: C, 44.52; H, 4.47; Cl, 12.80; N, 17.95.

Scheme 143

Preparation of (2S,4R)-l-(2-(4-amino-5-(furan-3-yl)-7H-pyrrolo[2,3-d]pyrimi din-7- yl)acetyl)-N -(3 -chloro-2-fluorobenzyl)-4-fluoropy rrolidine-2-carboxamide (143d)

Step-1: Preparation of tert-butyl 2-(4-amino-5-(furan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)acetate (143b)

Compound 143b was prepared according to the procedure reported in step-1 of scheme-59, from tert-butyl 2-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidm-7-yl)acetate (114b) (500 mg, 1.528 mmol) in dioxane (15 mL) using furan-3-ylboronic acid (143a) (171 mg, 1.528 mmol), bis(triphenylphosphine)palladium(n) chloride (161 mg, 0.229 mmol) a solution of potassium carbonate (634 mg, 4.58 mmol) in water (1.8 mL) and heating at 100 °C for 11 h. This gave after workup and purification by flash column chromatography [silica gel, eluting with EtOAc in hexane from 0-67% followed by 10% methanol in EtOAc (1:1)] tert-butyl 2- (4-amino-5-(furan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acet ate (143b) (190 mg, 40% yield) as a yellow solid; Ή NMR (300 MHz, DMSO-cfe) 58.11 (s, 1H), 7.83 (s, 1H), 7.81 - 7.78 (m, 1H), 7.27 (s, 1H), 6.69 (dd,J= 1.8, 0.9 Hz, 1H), 6.25 (s, 2H), 4.90 (s, 2H), 1.42 (s, 9H); MS (ES+): 315.10 (M+l). Step-2: Preparation of 2-(4-amino-5-(furan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ac etic acid (143c)

Compound 143c was prepared according to the procedure reported in step-2 of scheme- 1, from tert- butyl 2-(4-amino-5-(furan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ac etate (143b) (175 mg, 0.557 mmol) using TFA in DCM (10 mL). This gave after workup 2-(4-amino-5- (furan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (143c) which was used as such for the next step; MS (ES+): 259.05 (M+l).

Step-3: Preparation of (2S,4R)-l-(2-(4-amino-5-(fiiran-3-yl)-7H-pyrrolo[2,3-d]pyrim idin-7- yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2 -carboxamide (143d)

Compound 143d was prepared according to the procedure reported in step-3 of scheme- 1, 2- (4-amino-5-(furan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acet ic acid (143c) (0.557 mmol) in DMF (15 mL) using (2S,4R)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2- carboxamide (7a) (0.668 mmol), HATU (0.424 g, 1.114 mmol), DIPEA (0.485 mL, 2.79 mmol) and stirring at RT for 13 h. This gave after workup and purification using flash column chromatography [silica column, DCM in MeOH from 0-5%] followed by purification using reverse phase column chromatography [Cl 8 column (26 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)-l-(2-(4-amino-5-(furan-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluor opyrrolidine-2-carboxamide (143d) (30 mg, 10% for two steps) HC1 salt as a white solid; ¹ !! NMR (300 MHz, DMSO-ifc) (a mixture of two rotamers) δ 9.11 & 8.68 (2t ,J= 5.9 Hz, 1H), 8.43 & 8.42 (2s, 1H), 7.91 - 7.89 (m, 1H), 7.88 - 7.83 (m, 1H), 7.51 &7.50 (2s, 1H), 7.49 - 6.97 (m, 3H), 6.72 - 6.69 (m, 1H), 5.63 - 5.08 (m, 3H), 4.93 - 3.70 (m, 5H), 2.67-2.30 (m, 1H), 2.23 - 1.89 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-ifc) (a mixture of two rotamers) δ -121.31 & -121.64, -176.12 & - 176.34; MS (ES+): 515.10 & 517.10 (M+l); Analysis calculated for C24H21CIF2N6O3.HCI.I.75H2O: C, 49.45; H, 4.41; N, 14.42; Cl, 12.16; Found: C, 49.31; H, 4.13; N, 14.34; Cl, 11.94.

Scheme 144 Λ

Η _Μ ar^Jk _c h\ Μ_ _Ν X°Y NH° ₂ C *°N

Pd ₂ (db aH C a) ₃ , XPhos,

N N CN

CI Cl CS ₂ CO ₃

BocHN

144a 144b 144c f¾. ,0

*. :l

R

HO H HN H

I %

^N ]T ^N r° F' r\ o H ₂ O ₂ /

NaOH 7a NH ₃

Cl

HATU, DIPEA NC

NHBoc i¾

NHBoc

144e

144d

144f 144g

Preparation of 4-amino-l-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl) -4- fluoropyrrolidin-l-yl)-2-oxoethyl)-lH-pyrrolo[2,3-b]pyridine -5-carboxamide (144g)

Step-1: Preparation of tort-butyl 2-(4-chloro-5-cyano-lH-pyrrolo[2,3-b]pyridin-l-yl)acetate (144b)

Compound 144b was prepared according to the procedure reported in step-1 of scheme-88, from 4-chloro-lH-pyrrolo[2,3-b]pyridine-5-carbonitrile (144a) (950 mg, 5.35 mmol; CAS # 920966-02-5) in DMF (25 mL) using sodium hydride (0.257 g, 6.42 mmol), tort-butyl bromoacetate (0.949 mL, 6.42 mmol) and stirring at RT for 18 h. This gave after workup and purification by flash column chromatography [silica gel, EtOAc in hexane from 0 - 14%] tort-butyl 2-(4-chloro-5-cyano-lH-pyrrolo[2,3-b]pyridin-l-yl)acetate (144b) (970 mg, 62% yield) as a white solid; Ή NMR (300 MHz, DMSO-cfe) δ 8.73 (s, 1H), 7.88 (d ,J= 3.7 Hz, 1H), 6.78 (d, J= 3.6 Hz, 1H), 5.12 (s, 2H), 1.40 (s, 9H). MS (ES+): 292.10 & 294.10 (M+l). Step-2: Preparation of /erf-butyl 2-(4-((ter/-butoxycarbonyl)amino)-5-cyano-lH-pyrrolo[2,3- b]pyridin- 1 -yl)acetate (144c)

Compound 144c was prepared according to the procedure reported in step-3 of scheme- 17, from fert-butyl 2-(4-chloro-5-cyano-lH-pyrrolo[2,3-b]pyridin- 1 -yl)acetate (144b) (950 mg, 3.26 mmol) in toluene (30 mL) using XPhos (155 mg, 0.326 mmol), t-butyl carbamate (572 mg, 4.88 mmol), Pch(dba)3 (149 mg, 0.163 mmol), cesium carbonate (1061 mg, 3.26 mmol) and heating at 90 °C for 19 h. This gave after work up and purification by flash column chromatography [silica gel, EtOAc in hexane from 0 - 33%] tert-butyl 2-(4-((tert- butoxycarbonyl)amino)-5-cyano-lH-pyrrolo[2,3-b]pyridin-l-yl) acetate (144c) (1.13 g, 93 % yield); Ή NMR (300 MHz, DMSO-ifc) δ 10.19 (s, 1H), 8.51 (s, 1H), 7.61 (d, J = 3.7 Hz, 1H), 6.68 (d, J= 3.6 Hz, 1H), 5.04 (s, 2H), 1.51 (s, 9H), 1.40 (s, 9H); MS (ES+): 373.20 (M+l).

Step-3: Preparation of 2-(4-((tezt-butoxycarbonyl)amino)-5-cyano-lH-pyrrolo[2,3-b]p yridin- l-yl)acetic acid (144d)

Compound 144d was prepared according to the procedure reported in step-4 of scheme- 17, from fert-butyl 2-(4-((tert-butoxycarbonyl)amino)-5-cyano-lH-pyrrolo[2,3-b]p yridin- 1 - yl)acetate (144c) (1.1 g, 2.95 mmol) in THE (5 mL) and MeOH (5 mL) using 2M sodium hydroxide (1.698 mL, 3.40 mmol) and stirring at RT for 25 h. This gave after workup 2-(4- ((tert-butoxycarbonyl)amino)-5-cyano-lH-pyrrolo[2,3-b]pyridi n-l-yl)acetic acid (144d) (782 mg, 84% yield) as a light yellow solid; MS (ES+): 317.10 (M+l).

Step-4: Preparation of tert-butyl (l-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4- fluoropyrrolidin-l-yl)-2-oxoethyl)-5-cyano-lH-pyrrolo[2,3-b] pyridin-4-yl)carbamate (144e)

Compound 144e was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-((te/-r-butoxycarbonyl)amino)-5 -cyano- 1 H-pyrrolo [2,3 -b] pyridin- 1 -y l)acetic acid (144d) (600 mg, 1.897 mmol) in DMF (30 mL) using (2S,4R)-N-(3-chloro-2-fluorobenzyl)- 4-fluoropyTrolidine-2-carboxamide (7a) (625 mg, 2.276 mmol), HATU (1442 mg, 3.79 mmol), DIPEA (1.652 mL, 9.48 mmol) and stirring at RT for 13 h. This gave after workup and purification by flash column chromatography [silica gel, eluting with MeOH in DCM from 0 - 5%] fcrf-butyl (l-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4- fluoropyrrolidin-l-yl)-2-oxoethyl)-5-cyano-lH-pyrrolo[2,3-b] pyridin-4-yl)carbamate (144e) (855 mg, 79% yield) as a white solid; ¾ NMR (300 MHz, DMSO-tfc) (a mixture of two 7.37 (m, 2H), 7.28 - 7.13 (m, 1H), 7.09 - 7.00 (m, 1H), 6.69 & 6.66 (2d, J= 3.6 Hz, 1H), 5.68 - 5.05 (m, 3H), 4.91 - 3.66 (m, 5H), 2.61 - 2.04 (m, 2H), 1.52 (s, 9H); ¹⁹ F NMR (282 MHz, DMSOK/6) (amixture of two rotamers) δ -121.32 & -121.71 (IF), -176.11 & -176.35 (IF); MS (ES+): 573.20 & 575.20 (M+l);

Step-5: Preparation of tert-butyl (5-carbamoyl-l-(2-((2S,4R)-2-((3-chloro-2- fluorobenzyl)carbamoyl)-4-fluoropyrrolidin- 1 -yl)-2-oxoethyl)- lH-pyrrolo[2,3-b]pyridin-4- yl)carbamate (144f)

Compound 144f was prepared according to the procedure reported in step-1 of scheme-60, from /erf-butyl ( 1 -(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoro pyrrolidin- 1 - yl)-2-oxoethyl)-5-cyano-lH-pyrrolo[2,3-b]pyridin-4-yl)carbam ate (144e) (150 mg, 0.262 mmol) in ethanol (8 mL) using cone. NH4OH (3 mL), hydrogen peroxide (0.093 mL, 1.047 mmol) and stirring for 5 h at RT. This gave after workup and purification by flash column chromatography [silica gel, eluting with MeOH in DCM from 0 - 5%] tert-butyl (5- carbamoyl-l-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoy l)-4-fluoropyrrolidm-l-yl)-2- oxoethyl)- 1 H-pyrrolo[2,3-b]pyridin-4-yl)carbamate (144f) (42 mg, 27% yield) as a white solid; Ή NMR (300 MHz, DMSO-ifc) (a mixture of two rotamers) δ 11.15 & 11.14 (2s, 1H), 9.02 & 8.60 (2t, 1H), 8.51 & 8.50 (2s, 1H), 8.23 (s, 1H), 7.62 (s, 1H), 7.53 - 7.37 (m, 1H), 7.34 & 7.31 (2d, J= 3.6

Hz, 1H), 7.28 - 7.15 (m, 1H), 7.11 - 7.02 (m, 1H), 6.72 & 6.70 (2d, J= 3.8 Hz, 1H), 5.60 - 5.36 (m, 1H), 5.34 - 5.03 (m, 2H), 4.93 - 3.65 (m, 5H), 2.63 - 1.77 (m, 2H), 1.50 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-ifc) (a mixture of two rotamers) δ -121.36 & -121.74 (1 F) , -176.10 & -176.38 (1 F); MS (ES+): 591.10 & 593.20 (M+l);

Step-6: Preparation of 4-amino-l-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl) -4- fluoropyrrolidin-l-yl)-2-oxoethyl)-lH-pyrrolo[2,3-b]pyridine -5-carboxamide (144g)

Compound 144g was prepared according to the procedure reported in step-2 of scheme- 1, from fert-butyl (5-carbamoyl-l-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carba moyl)-4- fluoropyrrolidin- 1 -yl)-2-oxoethyl)- lH-pyrrolo[2,3-bJpyridin-4-yl)carbamate (144f) (40 mg, 0.068 mmol) in DCM (10 mL) using TFA (0.101 mL, 1.354 mmol) and stirring atRT for 25 h. This gave after workup and purification by reverse phase column chromatography [Cl 8 column (26 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] 4-amino- 1- (2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluorop yrrolidin-l-yl)-2-oxoethyl)- lH pyrrolo[23 b]pyridine 5 carboxamide (144g) (21 mg 63% yield) HC1 salt as a white solid; ^l HNMR (300 MHz, DMSO-dis) (a mixture of two rotamers) δ 9.09 & 8.76 (2t ,J= 6.1 Hz, 1H, DzO exchangeable), 8.47 & 8.42 (2s, 1H), 8.16 (s, 1H, DzO exchangeable), 7.59 (s, 1H, DzO exchangeable), 7.53 - 7.33 (m, 1H), 7.30 - 6.85 (m, 4H), 5.62 - 5.56 & 5.45 - 5.39 (2m, 1H), 5.37 (s, 2H), 4.91 - 3.81 (m, 5H), 2.64 - 2.41 (m, 1H), 2.31 - 1.93 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-tfc) (a mixture of two rotamers) δ -121.31 & -121.669, -175.78 & - 175.96; MS (ES+): 491.10 & 493.10 (M+l).

Scheme 145

Preparation of (2S,4R)-N-(3-chloro-2-fluorobenzyl)-l-(2-(2,4-dioxo-3, 4-dihydro- 1H- pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-7(2H)-yl)acetyl)-4- fluoropyrrolidine-2-carboxamide

(145a)

Compound 145a was prepared according to the procedure reported in step-2 of scheme- 1, from tert-butyl (l-(2-((2S,4R)-2-((3-chloro-2-fIuorobenzyl)carbamoyl)-4-fluo ropyrrolidin-l - yl)-2-oxoethyl)-5-cyano-lH-pyrrolo[2,3-b]pyridin-4-yl)carbam ate (144e) (100 mg, 0.175 mmol) in DCM (10 mL) using TFA (0.104 mL, 1.396 mmol) and stirring at RT for 22 h. This gave after workup and purification by reverse phase column chromatography [Cl 8 column (26 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)-N-(3- chloro-2-fluorobenzyl)-l-(2-(2,4-dioxo-3,4-dihydro-lH-pyrrol o[3',2':5,6]pyrido[4,3- d]pyrimidin-7(2H)-yl)acetyl)-4-fluoropyrrolidine-2-carboxami de (145a) (8 mg, 9% yield) as a white solid; Ή NMR (300 MHz, DMSO-de) (a mixture of two rotamers) 5 11.84 (s, 1H, DzO exchangeable), 11.35 (s, 1H, DzO exchangeable), 9.08 - 8.99 & 8.62 - 8.56 (2t, 1H,

DzO exchangeable), 8.64 (s, 1H) 7.52 - 6.92 (m, 5H), 5.60 - 5.11 (m, 3H), 4.95 - 3.69 (m, 5H), 2.78 - 1.84 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-ifc) (a mixture of two rotamers) δ - 121.32 &- 121.71, -176.10 & -176.32; MS (ES+): 517.10 & 519.10 (M+l).

Scheme 146

Preparation of methyl 4-amino-7-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl) -4- fluoropyrrolidin-l-yl)-2-oxoethyl)-7H-pyrrolo[2,3-d]pyrimidi ne-5-carboxylate (146a)

To a solution of (2S,4R)-I-(2-(4-amino-5-cyano-7H-pyrroIo[2,3-d]pyrimidin-7-y l)acetyl)-N- (3-chloro-2-fluorobenzyl)-4-fluoropynolidine-2-carboxamide (190 mg, 0.401 mmol) (130e) in methanol (10 mL) was added cone, sulfuric acid (0.214 mL, 4.01 mmol) and refluxed for 43 h. The reaction mixture was cooled to RT diluted with ethyl acetate (100 mL) and 0.5 M K2CO3 (40 mL). The organic layer was washed with brine (50 mL), dried, filtered and concentrated in vacuum. The residue obtained was purified using reverse-phase column chromatography [C18 column (26 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] to afford methyl 4-amino-7-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl) -4- fluoropyrrolidin- 1 -yl)-2-oxoethy 1) -7H-pyrrolo [2, 3-d] pyrimidine-5 -carboxylate HC1 salt (146a) (1.3 mg, 0.64% yield) HC1 salt as a white solid. Ή NMR (300 MHz, DMSO-i/e) (a mixture of two rotamers) δ 9.11 - 8.42 (m, 3H, D2O exchangeable), 8.39 - 8.35 (m, 1H), 8.17 & 8.16 (2s, 1H), 7.57 - 6.99 (m, 3H), 5.65 - 5.08 (m, 3H), 4.88 - 3.91 (m, 5H), 3.88 (s, 3H), 2.62 - 2.36 (m, 1H), 2.24 - 1.87 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-ίά) (a mixture of two rotamers) δ -121.64, -176.14; MS (ES+): 507.10 & 509.10 (M+l).

Scheme 147 Preparation of methyl 4-amino- l-(2-((2S, 4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4- fluoropyrrolidin-l-yl)-2-oxoethyl)-lH-pyrrolo[2,3-b]pyridine -5-cafboxylate (147a)

Compound 147a was prepared according to the procedure reported in scheme-146, from tert- butyl (l-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluo ropyrrolidin-l-yl)-2- oxoethyl)-5-cyano-lH-pynOlo[2,3-b]pyridin-4-yl)carbamate (144e) (200 mg, 0.349 mmol) in methanol (10 mL) using cone, sulfuric acid (0.186 mL, 3.49 mmol) and refluxing for 14 h. This gave after work up and purification using reverse-phase column chromatography [Cl 8 column (26 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] methyl 4- amino-l-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4 -fluoropyrrolidin-l-yl)-2- oxoethyl)-lH-pyrrolo[2,3-b]pyridine-5-cafboxylate (147a) (2.3 mg, 1.3% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfe) (a mixture of two rotamers) δ 9.03 & 8.64 (2t, J = 5.8 Hz, 1H, D2O exchangeable), 8.52 & 8.44 (2s, 1H), 7.56 - 6.83 (m, 5H), 5.63 - 5.07 (m, 3H), 4.93 - 3.71 (m, 8H), 2.68 - 2.37 (m, 1H), 2.32 - 1.90 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-ifc) (amixture of two rotamers) δ -121.33 & -121.68, -175.91 &-176.15; MS (ES+): 506.10 & 508.15 (M+l).

Scheme 148

148d

Preparation of (2S,4R)-l-(2-(4-amino-5-iodo-7H-pyn _O lo[2,3-d]pyrimidin-7-yl)acetyl)-N-(3- Step-1: Preparation of tert- butyl 2-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (148b)

Compound 148b was prepared according to the procedure reported in step-1 of scheme- 1, from 5-iodo-7H-pyrrolo[2,3-dJpyrimidin-4-amine (148a) (5 g, 19.23 mmol; CAS # 163622- 50-2) in DMF (20 mL) using tert-butyl 2-bromoacetate (3.75 g, 19.23 mmol), CS2CO3 (7.52 g, 23.07 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH in DCM from 0-3%] tert- butyl 2-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetatc (148b) (5 g, 70% yield) as a pale orange solid; ^! HNMR (300 MHz, DMSO-de) δ 8.09 (s, 1H), 7.43 (s, 1H), 6.86 - 6.41 (m, 2H), 4.87 (s, 2H), 1.41 (s, 9H). MS (ES+): 375 (M+l).

Step-2: Preparation of 2-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (148c)

Compound 148c was prepared according to the procedure reported in step-2 of scheme- 1, from tert- butyl 2-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (148b) (2.50 g, 6.68 mmol) using TFA (38.3 mL, 100 mmol; 20% TFA in DCM) and stirring at RT for 16 h. This gave after workup 2-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (148c) (2.91 g) TFA salt as a purple solid; Ή NMR (300 MHz, DMSO-i/s) δ 8.32 (d, J = 1.2 Hz, 1H), 7.66 (d, J = 1.3 Hz, 1H), 4.97 (s, 2H). ¹⁹ F NMR (282 MHz, DMSO -d ₆ ) δ -74.24; MS (ES+): 319 (M+l).

Step-3: Preparation of (2S,4R)-l-(2-(4-amino-5-iodo-7H-pyrrolo[2,3-dJpyrimidin-7- yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2 -carboxamide (148d)

Compound 148d was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (148c)

(2.88 g, 6.67 mmol) in DCM (10 mL) using (2S,4R)-N-(3-chloro-2-fluorobenzyl)-4- fluoropyrroUdine-2-carboxamide (7a) (2.59 g, 6.67 mmol), HATH (3.04 g, 8.00 mmol), DIPEA (5.82 mL, 33.3 mmol) and stirring at RT for 16 h. This gave after workup and purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HCl) from 0-60%] (2S,4R)-l-(2-(4-amino-5-iodo-7H- pyrrolo[2,3-d]pyrimidin-7-yl)acetyl)-N-(3-chloro-2-fluoroben zyl)-4-fluoropyrrolidine-2- carboxamide (148d) (55 mg, 0.096 mmol) HCl salt as a white solid; ^! H NMR (300 MHz, DMSO-ifc) δ (a mixture of two rotamers) 9.08 (t, J= 5.9 Hz) and 8.67 (t, J= 5.9 Hz) (2t, 1H), 8.36 (d, J= 3.8 Hz, 1H), 8.01 (s, 2H, D2O exchangeable), 7.61 (d, J= 5.6 Hz, 1H), 7.52 - 17.1 Hz, 1H), 5.19 - 5.03 (m, 1H), 4.50 - 4.31 (m, 2H), 4.31 - 4.03 (m, 2H), 3.85 (ddd, J= 38.4, 12.6, 3.1 Hz, 1H), 2.60 - 2.21 (m, 1H), 2.20 - 1.90 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO) δ -121.32, -121.62, -176.13, -176.34; MS (ES+): 575.0 (M+l); (ES-): 573.0 (M-l); Analysis calculated for C20Hi8ClF2IN6O2.HCl.2H2O: C, 37.11; H, 3.58; Cl, 10.96; N, 12.98: Found: C, 37.13; H, 3.20; Cl, 10.93; N, 13.12.

Scheme 149

Preparation of (2S,4R)-l-(2-(4-amino-5-(lH-pyirol-2-yl)-7H-pyrrolo[2,3-d]py rimidin-7- yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2 -carboxamide (149b)

Compound 149b was prepared according to the procedure reported in step-1 of scheme-62, from (2S,4R)-l-(2-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-y l)acetyl)-N-(3-chloro- 2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamidc (116b) (200 mg, 0.379 mmol) in dioxane (5 niL) using 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pynole (149a) (110 mg, 0.568 mmol; CAS # 476004-79-2), Pd(PPh3)zCh (26.6 mg, 0.038 mmol), 3.3 M aqueous K2CO3 (0.345 mL, 1.137 mmol) and heating at 100 °C for 16 h under argon. This gave after workup and purification using flash column chromatography [silica column (12 g), eluting with MeOH in DCM from 0-5%] followed by purification using reverse phase column chromatography [C 18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-60%] (2S,4R)-l-(2-(4-amino-5-(lH-pyrrol-2-yl)-7H-pyrrolo[2,3-d]py rimidin-7- yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2 -carboxamide (149b) (27 mg, 14 % yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ofe) δ (a mixture of two rotamers) 11.31 (d, J= 8.3 Hz, 1H, DzO exchangeable), 9.08 (t), 8.65 (t, J= 5.8 Hz) (2t,lH), 8.39 (d, J= 3.6 Hz, 1H), 7.64 (s, 2H, DzO exchangeable), 7.50 - 7.34 (m, 2H), 7.29 - 7.13 (m, 1H), 7.02 (t ,J= 7.9 Hz, 1H), 6.91 (p,J= 2.0 Hz, 1H), 6.22 (t, J= 2.2 Hz, 2H), 5.66 - 5 04 ( 3H) 456 407 ( 4H) 401 3 72 ( 1H 262 237 ( 1H) 221 1 89 ( 1H); ¹⁹ F NMR (282 MHz, DMSO^fc) δ -121.31, -121.64, -176.11, -176.31; MS (ES+) 514.0 (M+l), 512.0 (M-l); Analysis calculated for: C24H22CIF2N7O2 HCI 2.50HzO: C, 48.41; H, 4.74; Cl, 11.91; N, 16.47; Found: C, 48.22; H, 4.49; Cl, 12.01; N, 16.36.

Scheme 150

NH ₂

150d

Preparation of (2S ,4R)- 1 -(2-(4-am ino-5 -methy l-7H-pyrrolo [2 ,3 -d]pyrimidin-7 -yl )acetyl)-N- (3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (150d)

Step-1: Preparation of tert- butyl 2-(4-amino-5-methyl-7H-p>Trolo[2,3-d]pyrimidin-7- yl)acetate (150b)

Compound 150b was prepared according to the procedure reported in step-1 of scheme- 1, from 5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (150a) (0.5 g, 3.37 mmol; CAS # 1501- 10-6) in DMF (20 mL) using te/7-butyl 2-bromoacetate (0.658 g, 3.37 mmol), CS2CO3 (1.319 g, 4.05 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH in DCM from 0-3%] tert-butyl 2-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (150b) (0.30 g, 34% yield) as a pale orange solid; *H NMR (300 MHz, DMSO-tife) δ 7.99 (s, 1H), 6.86 (d ,J= 1.3 Hz, 1H), 6.55 (s, 2H), 4.78 (s, 2H), 2.34 (s, 3H), 1.41 (s, 9H).

Step-2: Preparation of 2-(4-amino-5 -methyl-7H-pyrrolo [2,3 -d] py rimidin-7-y l)acetic acid (150c) Compound 150c was prepared according to the procedure reported in step-2 of scheme- 1, from te/7-butyl 2-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (150b) (300 mg, 1.144 mmol) using TFA (9781 mg, 17.16 mmol; 20% TFA in DCM) and stirring at RT for 16 h. This gave after workup TFA salt of 2-(4-amino-5-methyl-7H-pyrrolo[2,3- d]pyrimidin-7-yl)acetic acid (150c) (470 mg) as a pale-orange solid; Ή NMR (300 MHz, DMSO-tife) δ 8.68 - 8.38 (m, 2H), 8.35 (s, 1H), 7.26 (d ,J= 1.3 Hz, 1H), 4.98 (s, 2H), 2.41 (d, J= 1.2 Hz, 3H).

Step-3: Preparation of (2S,4R)-l-(2-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7- yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2 -carboxamide (150d)

Compound 150d was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-5 -methy l-7H-pyrrolo [2, 3 -d Jpyrimidin-7 -y l)acetic acid (150c) (150 mg, 0.468 mmol) in DMF (5 mL) using TFA salt of (2S,4R)-N-(3-chloro-2- fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (7a) (182 mg, 0.468 mmol), HATU (214 mg, 0.562 mmol), DIPEA (0.409 mL, 2.342 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 5%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)-l-(2-(4-ammo-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-y l)acetyl)-N- (3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (150d) (83 mg, 38% yield) as a white solid; Ή NMR (300 MHz, DMSO-tife) δ (a mixture of two rotamers) 9.15 (t ,J= 5.8 Hz) and 8.71 (t, J= 5.9 Hz) (2s, 1H), 8.47 (s, 2H, D ₂ 0 exchangeable), 8.34 (d, J= 3.2 Hz,

1H), 7.53 - 7.40 (m, 1H), 7.31 - 7.21 (m, 1H), 7.20 - 7.11 (m, 1H), 7.07 (t, J = 7.9 Hz, 1H), 5.59 - 5.33 (m, 1H), 5.26 (d, J= 17.0 Hz, 1H), 5.09 (d, J= 17.1 Hz, 1H), 4.39 (ddd, J= 21.1, 10.2, 5.7 Hz, 2H), 4.23 (dd, J= 21.7, 5.8 Hz, 1H), 4.16 - 4.02 (m, 1H), 3.86 (ddd, ./= 37.2, 12.9, 3.3 Hz, 1H), 2.82 - 2.47 (m, 1H), 2.39 (s, 3H), 2.16 - 1.91 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-tife) δ -121.32, -121.66, -176.15, -176.34; MS (ES+): 463.0 (M+l), (ES-): 461.0 (M-l); Analysis calculated for C21H21CIF2N6O2 HC1-2.25H20: C, 46.72; H, 4.95; Cl, 13.13; N, 15.57; Found: C, 46.35; H, 4.56; Cl, 13.52; N, 15.40.

Scheme 151

Preparation of 4-amino- l-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4- fluoropyrrolidin- 1 -yl)-2-oxoethyl)- lH-pyrrolo[2,3-b]pyridine-5-carboxylic acid (151a)

Compound 151a was prepared according to the procedure reported in step-4 of scheme- 17, from methyl 4-amino- l-(2-((2S,· 4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4- fluoropyrrolidm-l-yl)-2-oxoethyl)-lH-pyrrolo[2,3-b]pyridine- 5-carboxylate (147a) (22 mg, 0.043 mmol) in THF (3 mL) and MeOH (3 mL) using a solution of lithium hydroxide (18.62 mg, 0.435 mmol) in water (3 mL) and stirring at RT for 19 h. Additional lithium hydroxide hydrate (25 mg, and 50 mg), 2N sodium hydroxide solution (0.4 mL and 0.6 mL) were added and stirred at RT overnight after each addition. This gave after workup and purification by reverse phase column chromatography [Cl 8 column (26 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] 4-amino- l-(2-((2S,4R)-2-((3-chloro-2- fluorobenzyl)carbamoyl)-4-fluoropyrrolidin- 1 -yl)-2-oxoethyl)- 1 H-pyrrolo[2,3-b]pyridine-5- carboxylic acid (151a) (2.2 mg, 10% yield) HC1 salt as a white solid; ^l H NMR (300 MHz, DMSO-i/e) (a mixture of two retainers) δ 8.64 (t, J= 5.7 Hz, 1H, DzO exchangeable), 8.53 & 8.48 (2s, 1H), 7.55 - 6.92 (m, 5H), 5.62 - 5.14 (m, 3H), 4.97 - 3.70 (m, 5H), 2.68 - 2.38 (m, 1H), 2.27 (s, 1H); ¹⁹ F NMR (282 MHz, DMSO-i/e) (a mixture of two retainers) δ -121.32 & - 121.65 (IF), -175.81 & -176.07 (IF); MS (ES+): 492.00 & 494.00 (M+l); MS (ES-): 490.00 & 492.00 (M-l).

Scheme 152

152c 152d

Preparation of (2S,4R)-l-(2-(6-amino-8-methyl-9H-purin-9-yl)acetyl)-N-(3-ch loro-2- fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (152d)

Step-1: Preparation of tort-butyl 2-(6-amino-8-methyl-9H-purin-9-yl)acetate (152b)

Compound 152b was prepared according to the procedure reported in step-1 of scheme- 1, from 8-methyl-7H-purin-6-amine (152a) (500 mg, 3.35 mmol; CAS # 22387-37-7) in DMF (15 mL) using tort-butyl 2-bromoacetate and K2CO3 (556 mg, 4.02 mmol). This gave after workup tort-butyl 2-(6-amino-8-methyl-9H-purin-9-yl)acetate (152b) (390 mg, 44 % yield) as a yellow solid; 1HNMR (300 MHz, DMSO-i/6) δ 8.07 (s, 1H), 7.11 (s, 2H), 4.90 (s, 2H), 2.42 (s, 3H), 1.42 (s, 9H); MS (ES+): 264.10 (M+l).

Step-2: Preparation of 2-(6-amino-8-methyl-9H-purin-9-yl)acetic acid (152c)

Compound 152c was prepared according to the procedure reported in step-2 of scheme- 1, from tort-butyl 2-(6-amino-8-methyl-9H-purin-9-yl)acetate (152b) (150 mg, 0.570 mmol) in DCM (10 mL) using TFA and stirred at RT. This gave after workup 2-(6-amino-8-methyl- 9H-purin-9-yl)acetic acid (152c) which was used as such in the next step; MS (ES+): 208.10 (M+l).

Step-3: Preparation of (2S,4R)-l-(2-(6-amino-8-methyl-9H-purin-9-yl)acetyl)-N-(3-ch loro-2- fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (152d)

Compound 152d was prepared according to the procedure reported in step-3 of scheme- 1 , from TFA salt of 2 (6 amino 8 methyl 9H purin 9 yl)acetic acid (152c) (118 mg 057 mmol) in DMF (10 mL) using TFA salt of (2S,4R)-N-(3-chloro-2-fluorobenzyl)-4- fluoropyrrolidine-2-carboxamide (7a) (188 mg, 0.684 mmol), HATU (433 mg, 1.140 mmol), DIPEA (0.496 mL, 2.85 mmol) and stirring at RT overnight. This gave after workup and purification by flash column chromatography [silica gel, eluting with DCM/methanol (1:0 to 19:1)] (2S,4R)-l-(2-(6-amino-8-methyl-9H-purin-9-yl)acetyl)-N-(3-ch loro-2-fluorobenzyl)- 4-fluoropyrrolidine-2-carboxamide (152d) (31 mg, 12% yield) as a white solid; ¾ NMR (300 MHz, DMSO-tik) (a mixture of two rotamers) δ 9.00 & 8.64 (2t, J = 6.2 Hz, 1H), 8.22 & 8.20 (2s, 1H), 7.54 - 7.39 (m, 1H), 7.31 - 7.17 (m, 1H), 7.11 - 7.00 (m, 1H), 5.62 - 5.36 (m, 1H), 5.31 (d, J= 17.5 Hz, 1H), 5.03 (d ,J= 17.6 Hz, 1H), 4.61 - 3.74 (m, 5H), 2.60-1.90 (m, 2H), 2.37 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -121.28, -175.82; MS (ES+): 464.0 (M+l).

Scheme 153

Preparation of 4-amino-7-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl) -4- fluoropyrrolidin-l-yl)-2-oxoethyl)-7H-pyrrolo[2,3-d]pyrimidi ne-5-carboxylic acid (153a)

Compound 153a was prepared according to the procedure reported in step-4 of scheme- 17, from methyl 4-amino-7-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl) -4- fluoropyrrolidin- 1 -yl)-2-oxoethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (146a) (15 mg, 0.030 mmol) in THE (3 mL) and MeOH (3 mL) using a solution of lithium hydroxide (25.3 mg, 0.592 mmol) in water (3 mL) and stirring at RT overnight. This gave after workup and purification by reverse phase column chromatography [Cl 8 column (26 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] 4-amino-7-(2-((2S,4R)-2-((3-chloro-2- fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-l-yl)-2-oxoethyl) -7H-pyrrolo[2,3-d]pyrimidine- 5 -carboxylic acid (153a) (4.6 mg, 32%) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO / ) ( i t f t t ) δ 908 & 8 65 (2t J 5 9 H 1H D O exchangeable), 8.49 (s, 2H, D ₂ 0 exchangeable), 8.38 & 8.36 (2s, 1H), 8.11 & 8.10 (2s, 1H), 7.52 - 7.01 (m, 3H), 5.66 - 5.04 (m, 3H), 4.89 - 3.70 (m, 5H), 2.75 - 2.30 (m, 1H), 2.23 - 1.89 (m, 1H); ¹⁹ FNMR(282 MHz, DMSO-ifc) (amixture of two retainers) δ -121.34 & - 121.63 (IF), -176.12 & -176.34 (IF); MS (ES+): 493.00 & 495.00 (M+l); MS (ES-): 491.00 & 493.00 (M-l).

Scheme 154

C0 ₂ ¾u

_M H N H

NH N Br" COz'Bu TFA

[f

CS2CO ₃

C| SMe NH ₂ SMe NH ₂ SMe

154a 154c

154b

K m 4a ATU, DIPEA r N N

H

NH ₂ SMe

NH ₂ S wMe

154d 154e

Preparation of (lR,3S,5R)-2-(2-(4-amino-5-(methylthio)-7H-pyrrolo[2,3-d]pyr imidin-7- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (154e)

Step-1: Preparation of 5-(methylthio)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (154b)

Compound 154b was prepared according to the procedure reported in step-4 of scheme-130, from 4-chloro-5-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine (154a) (3.96 g, 19.83 mmol; CAS # 144927-56-0)) in isopropanol (20 mL) using ammonium hydroxide (11.26 g, 198 mmol; 30 wt.% in water) in a sealed tube and heating at 100 °C for 16 h. This gave after workup and purification by flash column chromatography [SiCh (24 g), eluting with MeOH in DCM from 0-3%] 5-(methylthio)-7H-pyirolo[2,3-d]pyrimidin-4-amine (154b) (1.94 g, 54.3 % yield) as a yellow solid. ΉΝΜΚ(300 MHz, DMSO-de) δ 11.83 (s, 1H), 8.06 (s, 1H), 7.31 (s, 1H), 6.75 (s, 2H), 2.32 (s, 3H); MS (ES+): 181 (M+l).

Step-2: Preparation of tert- butyl 2-(4-amino-5 -(methy lthio)-7H-pyrrolo [2,3 -d] py rimidin-7 - yl)acetate (154c)

Compound 154c was prepared according to the procedure reported in step-1 of scheme- 1, DMF (20 mL) using /erf-butyl 2-bromoacetate (2.100 g, 10.76 mmol), CS2CO3 (4.21 g, 12.92 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH in DCM from 0-3%] /erf-butyl 2-(4- amino-5-(methylthio)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (154c) (2.73 g, 86% yield) as a pale orange solid; Ή NMR (300 MHz, DMSO -ck) δ 8.09 (s, 1H), 7.37 (s, 1H), 6.83 (s, 2H), 4.87 (s, 2H), 2.34 (d, J= 1.0 Hz, 3H), 1.41 (s, 9H); MS (ES+) 295 (M+l).

Step-3: Preparation of 2-(4-amino-5-(methylthio)-7H-pynOlo[2,3-d]pyrimidin-7-yl)ace tic acid (154d)

Compound 154d was prepared according to the procedure reported in step-2 of scheme- 1 , from /erf-butyl 2-(4-amino-5-(methylthio)-7H-pyrrolo[2,3-d]pyrimidin-7-yI)ac etate (154c) (2.73 g, 9.27 mmol) in DCM (20 mL) using TFA (106 g, 185 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with MeOH in DCM from 0-3%] 2-(4-amino-5-(methylthio)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)acetic acid (154d) (4.50 g) TFA salt as a pale-orange solid. Ή NMR (300 MHz, DMSO-tfc) δ 8.37 (s, 1H), 7.64 (s, 1H), 5.00 (s, 2H), 2.40 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-de) δ -74.22; MS (ES+): 239 (M+l), (ES-): 237 (M-l).

Step-4: Preparation of (lR,3S,5R)-2-(2-(4-amino-5-(methylthio)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicycl o[3.1 ,0]hexane-3-carboxamide (154e)

Compound 154e was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-5-(methylthio)-7H-pynolo[2,3-d]pyrimidin-7-yl)ace tic acid (154d) (80 mg, 0.227 mmol) in DMF (5 mL) using (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-caiboxamide (4a) (72.3 mg, 0.227 mmol), HATU (104 mg, 0.273 mmol), DIPEA (147 mg, 1.135 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), using MeOH in DCM from 0 to 3%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-5-(methylthio)-7H-pyrrolo[2,3-d]pyr imidin-7-yl)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (154e) (46 mg, 40% yield)

HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.80 (s, 1H, D ₂ 0 exchangeable), 8.41 (s and bs, 3H, 2H D2O exchangeable), 8.02 (d,J= 8.2 Hz, 1H), 7.72 (t, J = 8.0 Hz, 1H), 7.63 (s, 1H), 7.33 (d, J= 7.7 Hz, 1H), 5.50 (d, J= 17.0 Hz, 1H), 5.20 (d, J= 17.0 Hz, 1H), 13.6, 9.2 Hz, 1H), 2.19 (dt,J= 12.9, 5.9 Hz, 1H), 1.95 - 1.81 (m, 1H), 1.06 - 0.95 (m, 1H), 0.73 - 0.62 (m, 1H); MS (ES+): 502.0 (M+l); (ES-): 500.0 (M-l); Analysis calculated for C2oH2oBrN ₇ 02S.1.1.HCI.2.H2O: C, 41.52; H, 4.37; Cl, 6.74; N, 16.95; Found: C, 41.36; H, 4.35; Cl, 6.99; N, 16.87.

Scheme 155

Preparation of 4-amino- 1 -(2-(( 1R,3 S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-lH-pyrrolo[2,3-b]py ridine-5-carboxylic acid (155f)

Step-1: Preparation of methyl l-(2-(fc/7-butoxy)-2-oxoethyl)-4-chloro-lH-pyrrolo[2,3- b]pyridine-5-carboxylate (155b)

Compound 155b was prepared according to the procedure reported in step-1 of scheme- 1, from methyl 4-chloro-lH-pyrrolo[2,3-b]pyridine-5-carboxylate (155a) (450 mg, 2.137 mmol; CAS # 951625-93-7) in DMF (10 mL) using tert-butyl 2-bromoacetate (0.379 mL, 2.56 mmol), CS2CO3 (835 mg, 2.56 mmol) and stirring at RT for 20 h. This gave after workup and purification by flash column chromatography [silica gel, eluting with EtOAc in Hexane from 0-14%] methyl l-(2-(tert-butoxy)-2-oxoethyl)-4-chloro-lH-pyrrolo[2,3-b]pyr idine-5- carboxylate (155b) (605 mg, 87% yield) as a white solid; Ή NMR (300 MHz, DMSO-ofe) δ 8.73 (s, 1H), 7.77 (d, J= 3.7 Hz, 1H), 6.71 (d,J= 3.6 Hz, 1H), 5.09 (s, 2H), 3.89 (s, 3H),

1.40 (s, 9H); MS (ES+): 325.00 (M+l). Step-2: Preparation of methyl l-(2-(fe/7-butoxy)-2-oxoethyl)-4-((fer/-butoxycarbonyl)amino )- lH-pyrrolo[2,3-b]pyridine-5-carboxylate (155c)

Compound 155c was prepared according to the procedure reported in step-3 of scheme- 17, from methyl l-(2-(terf-butoxy)-2-oxoethyl)-4-chloro-lH-pyrrolo[2,3-b]pyr idine-5- carboxylate (155b) (560 mg, 1.724 mmol) in toluene (16 mL) using XPhos (82 mg, 0.172 mmol), t-butyl carbamate (303 mg, 2.59 mmol), Pdz(dba)3 (79 mg, 0.086 mmol), cesium carbonate (562 mg, 1.724 mmol) and heating at 90 °C for 16 h. This gave after work up and purification by flash column chromatography (silica gel, eluting with EtOAc in Hexane from 0-17%] methyl l-(2-(fe/t-butoxy)-2-oxoethyl)-4-((torf-butoxycarbonyl)amino )-lH- pyrrolo[2,3-b]pyridine-5-carboxylate (155c) (628 mg, 90% yield); Ή NMR (300 MHz, DMSO-ifc) δ 10.19 (s, 1H), 8.56 (s, 1H), 7.48 (d, J= 3.7 Hz, 1H), 6.78 (d, J= 3.6 Hz, 1H), 5.01 (s, 2H), 3.81 (s, 3H), 1.49 (s, 9H), 1.40 (s, 9H); MS (ES+): 406.10 (M+l).

Step-3: Preparation of 2-(4-amino-5-(methoxycarbonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl )acetic acid (155d)

Compound 155d was prepared according to the procedure reported in step-2 of scheme- 1, from methyl l-(2-(terf-butoxy)-2-oxoethyl)-4-((terf-butoxycarbonyl)amino )-lH-pyrrolo[2,3- b]pyridine-5-carboxylate (155c) (0.620 g, 1.529 mmol) using TFA. This gave after work up 2-(4-amino-5-(methoxycarbonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl )acetic acid (155d) (840 mg) which was used as such for the next step; MS (ES+): 250.00 (M+l).

Step-4: Preparation of methyl 4-amino-l-(2-((lR,3S,5R)-3-((6-bromopyridin-2- yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-lH- pyrrolo[2,3-b]pyridine-5- carboxylate (155e)

Compound 155e was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-5-(methoxycarbonyl)- lH-pyrrolo[2,3-b]pyridin- l-yl)acetic acid (155d) (95 mg, 0.383 mmol) in DMF (10 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (4a) (122 mg, 0.383 mmol), HATU (291 mg, 0.766 mmol), DIPEA (0.334 mL, 1.915 mmol) and stirring at RT for 20 h. This gave after workup and purification by flash column chromatography (silica gel, MeOH in DCM from 0 - 5%] methyl 4-amino- 1 -(2-(( 1 R,3 S ,5 R)-3 -((6-bromopyridi n -2-yl )carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-lH-pyrrolo[2,3-b]py ridine-5-carboxylate (155e)

(115 mg, 59% yield) as a yellow solid; Ή NMR (300 MHz, DMSO-cfe) δ 10.76 (s, 1H), 8.49 1H), 7.14 (d, J= 3.5 Hz, 1H), 6.75 (d ,J= 3.6 Hz, 1H), 5.38 (d, J= 17.0 Hz, 1H), 5.15 (d ,J= 17.0 Hz, 1H), 4.42 (dd,J= 9.0, 5.6 Hz, 1H), 3.80 (s, 3H), 3.77 - 3.66 (m, 1H), 2.36 - 2.07 (m, 2H), 1.94 - 1.68 (m, 1H), 1.08 - 0.91 (m, 1H), 0.76 - 0.50 (m, 1H); MS (ES+): 513.00 (M+l).

Step-5: Preparation of 4-amino-l-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyI)- 2- azabicyclo[3.1 ,0]hexan-2-yl)-2-oxoethyl)- 1 H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (155f)

Compound 155f was prepared according to the procedure reported in step-4 of scheme- 17, from methyl 4-amino- 1 -(2-(( 1 R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[3.1 ,0]hexan-2-yl)-2-oxoethyl)- lH-pyTrolo[2,3-b]pyridine-5-carboxylate (155e)

(110 mg, 0.214 mmol) in THF (2 mL) and acetonitrile (2 mL) using a solution of lithium hydroxide hydrate (27.5 mg, 0.643 mmol) in water (2 mL) and stirring at RT for 20 h. This gave after workup and purification by reverse phase column chromatography [Cl 8 column (26 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] 4-amino- 1 -(2- ((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2-azabicyclo[ 3.1.0]hexan-2-yl)-2- oxoethyl)- 1 H-pyrrolo [2,3 -b]pyridi ne-5 -carboxyl ic acid (155f) (10 mg, 9% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ife) (a mixture of two rotamers) δ 10.88 & 10.77 (2s, 1H, DzO exchangeable), 8.60 & 8.60 (2s, 1H), 8.07 - 7.93 (m, 1H), 7.78 - 7.65 (m, 1H), 7.42 - 7.21 (m, 2H), 7.05 - 6.93 (m, 1H), 5.75-5.15 (m, 2H), 4.92 & 4.43 (2dd, J= 8.9, 5.7 Hz, 1H), 3.82-3.62 (m, 1H), 2.43 - 1.63 (m, 3H), 1.34 - 0.63 (m, 2H);MS (ES+): 498.90 & 500.90 (M+l); MS (ES-): 496.90 & 498.90 (M-l).

Scheme 156

VX-

H _M .0^0

Br J M r°.

UpL U< i NH ₂

OH

CS2CO ₃ OH Pd ₂ (dba)3, XPhos,

Cl CS2CO3 VX^JL^O

Cl NH H

156a

156b rx 156c Preparation of(lR,3S,5R)-2-(2-(4-amino-5-formyl-lH-pyrrolo[2,3-b]pyridin -l-yl)acetyl)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamid e (156e)

Step-1: Preparation of tort-butyl 2-(4-chloro-5-(hydroxymethyl)-lH-pyrrolo[2,3-b]pyridin-l- yl)acetate (156b)

Compound 156b was prepared according to the procedure reported in step-1 of scheme- 1, from (4-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)methanol (156a) (115 mg, 0.630 mmol; CAS # 1015610-07-7) in DMF (6 mL) using tort-butyl 2-bromoacetate (0.112 mL, 0.756 mmol), CS2CO3 (246 mg, 0.756 mmol) and stirring at RT for 13 h. This gave after workup and purification by flash column chromatography [silica gel, eluting with EtOAc in Hexane from 0-50%] tort-butyl 2-(4-chloro-5 -(hydroxymethyl)- 1 H-pyrrolo [2,3 -b] py ridin- 1 -yl)acetate (156b) (155 mg, 83% yield) as a white solid; Ή NMR (300 MHz, DMSO-db) δ 8.30 (s, 1H), 7.63 (d, J= 3.6 Hz, 1H), 6.53 (d, J= 3.5 Hz, 1H), 5.30 (t, J= 5.6 Hz, 1H), 5.03 (s, 2H), 4.69 (d, J= 5.5 Hz, 2H), 1.40 (s, 9H); MS (ES+): 297.00 (M+l).

Step-2: Preparation of tort-butyl 2-(4-((tort-butoxycarbonyl)amino)-5-formyl-lH-pyrrolo[2,3- b jpyridin- 1 -yl)acetate (156c)

Compound 156c was prepared according to the procedure reported in step-3 of scheme-17, from tort-butyl 2-(4-chloro-5-(hydroxymethyl)- 1 H-pyrrolo[2,3-b]pyridin- 1 -yl)acetate (156b) (132 mg, 0.445 mmol) in toluene (10 mL) using XPhos (21.2 lmg, 0.044 mmol), t-butyl carbamate (78 mg, 0.667 mmol), Pda(dba)3 (20.37 mg, 0.022 mmol), cesium carbonate (145 mg, 0.445 mmol) and heating at 90 °C for 12 h. This gave after work up and purification by flash column chromatography [silica gel, eluting with EtOAc in Hexane from 0-20%] tort- butyl 2-(4-((tort-butoxycarbonyl)amino)-5-formyl-lH-pyrrolo[2,3-b] pyridin-l-yl)acetate (156c) (50 mg, 30% yield); Ή NMR (300 MHz, DMSO-tfe) δ 10.76 (s, 1H), 10.00 (s, 1H), 8.58 (s, 1H), 7.50 (d, J= 3.7 Hz, 1H), 6.94 (d, J= 3.7 Hz, 1H), 5.04 (s, 2H), 1.52 (s, 9H), 1.41 (s, 9H); MS (ES+): 376.10 (M+l).

Step-3: Preparation of 2-(4-ammo-5-formyl-lH-pyrrolo[2,3-b]pyridin-l-yl)acetic acid (156d)

Compound 156d was prepared according to the procedure reported in step-2 of scheme-1, from tort-butyl 2-(4-((tort-butoxycarbonyl)amino)-5-formyl-lH-pyrrolo[2,3-b] pyridin-l- yl)acetate (156c) (45 mg, 0.12 mmol) in DCM (10 mL) using TEA. This gave after work up 2-(4-amino-5 -formyl- 1 H-pyrrolo [2,3 -b] py ridin- 1 -y l)acetic acid (156d), which was used as Step-4: Preparation of (lR,3S,5R)-2-(2-(4-amino-5-formyl-lH-pyrrolo[2,3-b]pyridin-l - yl)acetyl)-N -(6-bromopyridin-2-y l)-2-azabicyclo [3.1.0Jhexane-3-carboxamide (156e)

Compound 156e was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-5 -formyl- 1 H-pyrrolo [2,3 -b] pyridin- 1 -y l)acetic acid (156d) (0.12 mmol) in DMF (6 mL) using TFA salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (4a) (0.144 mmol), HATU (91 mg, 0.240 mmol), DIPEA (0.105 mL, 0.600 mmol) and stirring at RT for 14 h. This gave after workup and purification using flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0-5%] (lR,3S,5R)-2-(2-(4-amino-5-formyl-lH-pyrrolo[2,3-b]pyridin-l - yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (156e) (36 mg, 62% yield) as a light yellow solid; Ή NMR (300 MHz, DMSO-cfc) δ 10.76 (s, 1H, DzO exchangeable), 9.84 (s, 1H), 8.25 (s, 1H), 8.03 (d,7= 8.2 Hz, 1H), 7.72 (t, J= 7.9 Hz, 1H), 7.33 (d ,J= 7.7 Hz, 1H), 7.16 (d, J= 3.6 Hz, 1H), 6.77 (d ,J= 3.6 Hz, 1H), 5.45 - 5.12 (m, 2H), 4.43 (dd, J= 9.0, 5.5 Hz, 1H), 3.82 - 3.65 (m, 1H), 2.35 - 2.10 (m, 2H), 1.93 - 1.78 (m, 1H), 1.27 - 1.19 (m, 1H), 1.08 - 0.94 (m, 1H); MS (ES+): 482.900 & 485.00 (M+l); MS (ES-): 480.90 & 483.00 (M-l).

Scheme 157

Preparation of (lR,3S,5R)-2-(2-(4-amino-5-(hydroxymethyl)-lH-pyrrolo[2,3-b] pyridin-l- yl)acetyl)-N -(6-bromopyridin-2-y l)-2-azabicyclo [3.1.0Jhexane-3-carboxamide (157a)

To a solution of (lR,3S,5R)-2-(2-(4-amino-5-formyl-lH-pyrrolo[2,3-b]pyridin-l -yl)acetyl)- N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxam ide (156e) (23 mg, 0.048 mmol) in THF (4 mL) and MeOH (2 mL) was added sodium borohydride (5.51 mg, 0.143 mmol) stirred at RT for 19 h and diluted with ethyl acetate (100 mL), sat. NH4CI (50 mL). The organic phase was washed with brine (50 mL), dried, filtered and concentrated in ac m The resid e obtained as p rified b flash col mn chromatograph [silica gel (4 g) eluting with MeOH in DCM (0 - 5%)] to give (lR,3S,5R)-2-(2-(4-amino-5-(hydroxymethyl)- lH-pyrrolo[2,3-b]pyridin-l-yl)acetyl)-N-(6-bromopyridin-2-yl )-2-azabicyclo[3.1.0]hexane-3- carboxamide (157a) (12 mg, 52% yield) as a white solid; Ή NMR (300 MHz, DMSO-<fc) δ 10.74 (s, 1H, DzO exchangeable), 8.03 (d, J= 8.2 Hz, 1H), 7.78 - 7.61 (m, 2H), 7.32 (d, J= 7.7 Hz, 1H), 7.06 (d, J= 3.5 Hz, 1H), 6.55 (d, J= 3.6 Hz, 1H), 5.99 (s, 2H, DzO exchangeable), 5.29 (d,J= 17.0 Hz, 1H), 5.10 (d, J= 16.9 Hz, 1H), 4.82 (t, J = 5.2 Hz, 1H), 4.48 (d, J= 5.0 Hz, 2H), 4.42 (dd,J= 9.0, 5.5 Hz, 1H), 3.76 - 3.68 (m, 1H), 2.36 - 2.08 (m, 2H), 1.92 - 1.72 (m, 1H), 1.05 - 0.92 (m, 1H), 0.70 - 0.56 (m, 1H); MS (ES+): 484.95 & 487.00 (M+l); MS (ES-): 482.95 & 484.95 (M-l).

Scheme 158

H ₃ c-\ ll H3C-4

CS2C03 L^N Pd ₂ (dba)3, XPhos, H ₃ C-\ 1 CS2CO ₃

Cl Cl NH ₂

158d 158e

Preparation of(lR,3S,5R)-2-(2-(4-amino-6-methyl-7H-pyrTOlo[2,3-d]pyrimid in-7-yl)acetyl)- N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (158e)

Step-1: Preparation of ethyl 2-(4-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (158b)

Compound 158b was prepared according to the procedure reported in step-1 of scheme- 1, from 4-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine (158a) (1 g, 5.97 mmol; CAS # 35808- 68-5) in DMF (25 mL) using ethyl 2-bromoacetate (0.794 mL, 7.16 mmol), CszCCk (2.33 g, 7.16 mmol) and stirring at 0 °C for 20 min. This gave after workup and purification by flash column chromatography [silica gel, eluting with EtOAc in Hexane from 0-25%] ethyl 2-(4- chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (158b) (1.32 g, 87% yield) as a (s, 2H), 4.16 (q, J= 7.1 Hz, 2H), 2.43 (d ,J= 1.1 Hz, 3H), 1.21 (t, J= 7.1 Hz, 3H); MS (ES+): 254.00 (M+l).

Step-2: Preparation of ethyl 2-(4-amino-6-methyl-7H-p>Trolo[2,3-d]pyrimidin-7-yl)aceta te (158c)

Compound 158c was prepared according to the procedure reported in step-3 of scheme- 17, from ethyl 2-(4-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (158b) (500 mg, 1.971 mmol) in toluene (15 mL) using XPhos (94 mg, 0.197 mmol), /-butyl carbamate (346 mg, 2.96 mmol), P(h(dba)3 (90 mg, 0.099 mmol), cesium carbonate (642 mg, 1.971 mmol) and heating at 90 °C for 13 h under nitrogen. This gave after work up and purification by flash column chromatography [silica gel, eluting with EtOAc in Hexane/ 10% MeOH from 0- 50%] ethyl 2-(4-amino-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (158c) (110 mg, 24% yield); MS (ES+): 235.10 (M+l).

Step-3: Preparation of 2-(4-amino-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (158d)

Compound 158d was prepared according to the procedure reported in step-4 of scheme- 17, from ethyl 2-(4-amino-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (158c) (100 mg, 0.427 mmol) in THF (3 mL) and MeOH (3 mL) using a solution of lithium hydroxide hydrate (110 mg, 2.56 mmol) in water (3 mL) and stirring at RT for 19 h. This gave after work up 2- (4-amino-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (158d) (88 mg, 100% yield) which was used as such for the next step; MS (ES+): 207.10 (M+l).

Step-4: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-methyl-7H-pyrrolo[2,3-d]pyrimidin -7- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (158e)

Compound 158e was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (158d) (0.427 mmol) in DMF (15 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.OJhexane-3-carboxamide (4a) (163 mg, 0.512 mmol), HATU (325 mg, 0.854 mmol), DIPEA (0.372 mL, 2.135 mmol) and stirring at RT for 23 h. This gave after workup and purification using flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0-5%] followed by conversion of product obtained to HC1 salt by dissolving in acetonitrile (2 mL) and 50 mM aq. HC1 (8 mL) and lyophilization (lR,3S,5R)-2-(2-(4-amino- azabicyclo[3.1 ,0]hexane-3-carboxamide (158e) (50 mg, 25% yield) as an off white solid; ^l H NMR (300 MHz, DMSO-flfe) δ 10.80 (s, 1H, D2O exchangeable), 8.33 (s, 1H), 8.02 (d, J= 8.1 Hz, 1H), 7.72 (t, J= 8.0 Hz, 1H), 7.33 (d, J= 7.7 Hz, 1H), 6.68 (d, J= 1.3 Hz, 1H), 5.47 (d ,J= 17.4 Hz, 1H), 5.20 (d,J= 17.3 Hz, 1H), 4.43 (dd, J= 9.1, 5.5 Hz, 1H), 3.83 (td,J= 6.7, 6.2, 2.3 Hz, 1H), 2.42 - 2.12 (m, 5H), 1.95 - 1.77 (m, 1H), 1.12 - 0.93 (m, 1H), 0.78 - 0.59 (m, 1H); MS (ES+): 470.10 & 472.10 (M+l); MS (ES-): 468.10 & 470.10 (M-l); Analysis calculated for C2oH2oBrN ₇ 02.1.2HC1.2.5H20: C, 42.96; H, 4.72; Cl, 7.61; N, 17.54; Found: C, 42.96; H, 4.48; Cl, 7.38; N, 17.36.

Scheme 159

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-methoxy-9H-pyrimido[4,5-b]indol-9 -yl)acetyl)- N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (159a)

Compound 159a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (38e) (100 mg, 0.259 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-5- methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (95 mg, 0.285 mmol), HATU (148 mg, 0.388 mmol), DIPEA (167 mg, 1.294 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0-3%J followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6-methoxy-9H-pyrimido[4,5-b]indol-9 -yl)acetyl)- N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3 -carboxamide (159a) (117 mg, 82% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO -de) δ 10.77 (s, 1H,

D2O exchangeable), 8.75 (s, 2H, D2O exchangeable), 8.60 (s, 1H), 8.08 (d, J = 2.3 Hz, 1H), 801 (d J = 8 2 Hz 1H) 7 70 (t J = 80 Hz 1H) 762 (d J = 90 Hz 1H) 732 (d J = 77 Hz 1H), 7.19 (dd, J = 9.1, 2.3 Hz, 1H), 5.69 (d, J = 17.3 Hz, 1H), 5.35 (d, J = 17.3 Hz, 1H), 4.37 (dd, J = 9.1, 5.9 Hz, 1H), 3.88 (s, 3H), 3.71 - 3.66 (m, 1H), 2.44 (s, 1H), 1.98 (dd, J = 13.3, 5.8 Hz, 1H), 1.31 (s, 3H), 1.07 - 0.98 (m, 1H), 0.98 - 0.83 (m, 1H); MS (ES+): 550 (M+l), (ES-): 548 (M-l); Analysis calculated for CzsHwBrNzOz.HCU^SHzO: C, 47.86; H, 4.74; Cl, 5.65; N, 15.63; Found: C, 47.64; H, 4.71; Cl, 5.77; N, 15.34.

Scheme 160

H ,N. ,Br

N

C0 ₂ H < H^V ^r N ¾ i \

N \ o ^H 8a O , DIPEA Λ ⁰

HATU N.

NH ₂ c f N¾

Br XZn

Br

NH ₂

34d

160a

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-y l)acetyl)-N- (6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-c arboxamide (160a)

Compound 160a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (34d) (50 mg, 0.115 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-5- methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (42 mg, 0.126 mmol), HATU (65.5 mg, 0.172 mmol), DIPEA (74.3 mg, 0.575 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [silica gel (12 g), MeOH in DCM from 0-3%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] to afford ( 1 R,3 S, 5 R)-2-(2-(4-amino-6-bromo-9H-pyrimido [4,5 -b] indol-9-yl)acetyl)-N -(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carb oxamide (160a) (42 mg, 61% yield) HC1 salt as a white solid; ’HNMR (300 MHz, DMSO-t/e) δ 10.77 (s, 1H, DzO exchangeable), 8.96 - 8.69 (m, 3H, 2H D2O exchangeable), 8.65 (s, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.77 - 7.64 (m, 3H), 7.32 (d, J = 7.7 Hz, 1H), 5.73 (d, J = 17.4 Hz, 1H), 5.37 (d, J = 17.3 Hz, 1H), 4.37 (dd, J = 9.1, 5.9 Hz, 1H), 3.69 - 3.65 (m, 1H), 2.45 (d, J = 8.9 Hz, 1H), 1.98 (dd, J = 13.3, 5.9 Hz, 1H), 1.31 (s, 3H), 1.01 (m, 1H), 0.93 (m, 1H); MS (ES+): 598 (M+l), (ES-): 596 (M-l); Analysis calculated for CMHziBnNvOz-HCl.1.5.HzO: C, 43.49; H, 3.80; Cl, Scheme 161

40a 161a

Preparation of 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 5-methyl-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]i ndole-6-carboxylic acid (161a)

Compound 161a was prepared according to the procedure reported in step-4 of scheme- 17, from methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 5-methyl-2- azabicyclo[3.1 0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]indole-6-carboxy late (40a)

(107 mg, 0.185 mmol) in THF (3 ttiL) and using 2M aqueous lithium hydroxide hydrate (0.111 mL, 0.222 mmol) and stirring at RT for 16 h. This gave after workup and purification by reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2- yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoe thyl)-9H-pyrimido[4,5- b]indole-6-carboxylic acid (161a) (33 mg, 32% yield) HC1 salt as a white solid; ¾i NMR (300 MHz, DMSO-rik) δ 10.77 (s, 1H, DzO exchangeable), 9.10 (s, 1H), 8.81 - 8.40 (m, 3H, 2H DzO exchangeable), 8.11 (dt, J= 8.8, 2.0 Hz, 1H), 7.97 (dd, ./= 18.4, 8.2 Hz, 1H), 7.70 (ddd, 16.5, 8.4, 3.9 Hz, 2H), 7.30 (dd, J= 7.8, 5.2 Hz, 1H), 5.74 (d ,J= 17.8 Hz, 1H),

5.39 (dd, J= 17.2, 3.4 Hz, 1H), 4.37 (dd, J= 9.0, 5.9 Hz, 1H), 3.70 - 3.68 (m, 1H), 2.45 - 2.33 (m, 1H), 2.12 - 1.90 (m, 1H), 1.28 (s, 3H), 1.07 - 0.80 (m, 2H); MS (ES+) 564.0 (M+l); (ES-): 562.0 (M-l).

Scheme 162

NH ₂

162d

162e

^■ i ·.";

N N N _Br ψ _Λ f — CO ₂ H H

N

N _xx j ^ N HATU, DIPEA

V N Λ

H ₂ N N N f N¾ W '

162f

NH ₂ 162g

Preparation of (lR,3S,5R)-2-(2-(4-amino-9H-pyrido[3 ^, ,2 ^, :4,5]pyrrolo[2,3-d]pyriniidin-9- yl)acet\l)-N -(6-bromopyridin-2-y l)-2-azabicyclo [3.1.0Jhexane-3-carboxamide (162g)

Step-1: Preparation of 2-(2-nitropyridin-3-yl)malononitrile (162b)

NaH (1.958 g, 49.0 mmol) was added portion-wise to a cold solution of malononitrile (3.23 g, 49.0 mmol) in THF (50 mL) at 0 °C, during which hydrogen gas liberated and a white precipitate formed. The resulting cloudy white mixture was stirred at 0 °C for 1 h, followed by addition of 3-bromo-2-nitropyridine (162a) (4.92 g, 24.24 mmol). The resulting deep red/black suspension was then heated at 60 °C under argon for 3 h. The cooled reaction was quenched with saturated NH4CI (50 mL) and diluted with EtOAc (50 mL). After 30-min stirring at rt, the two layers were separated. The aqueous layer was extracted with EtOAc (30 mL x 3). The combined extract was concentrated to provide the crude product 2-(2- nitropyridin-3-yl)malononitrile (162b) (5.75 g,) as a brown/black solid, which was used as such in the next reaction.; MS (ES+): 159 (M+l), (ES-): 157 (M-l).

Step-2: Preparation of 2-amino- lH-pyrrolo[2,3-b]pyridme-3-carbonitrile (162c)

Crude 2-(2-nitropyridin-3-yl)malononitrile (162b) (5.75 g) from step-1 above was diluted in acetic acid (36.7 g, 611 mmol), followed by slow addition of zinc (10.00 g, 153 mmol) at rt. thoroughly with boiling EtOH. The filtrate was concentrated to dryness. The residue was suspended in HzO (50 mL), neutralized with 3 M aqueous NaOH until pH 7, and then extracted with EtOAc (50 mL x 3). The combined extract was washed with HzO (30 mL x 2), brine (30 mL), dried, filtered and concentrated in vacuum. The residue obtained was purified by flash column chromatography (SiOz, 40 g, eluting with 0-20% DMA80 in DCM) to provide 2-amino- 1 H-pyrrolo [2,3 -b] pyridine-3 -carbonitrile (162c) (1.00 g, 21 % yield) as a beige solid; Ή NMR (300 MHz, DMSO-iAs) δ 11.43 (s, 1H), 7.89 (dd, J = 5.0, 1.5 Hz, 1H), 7.47 (dd, J = 7.7, 1.5 Hz, 1H), 7.11 - 6.84 (m, 3H); MS (ES+): 159 (M+l), (ES-): 157 (M-l).

Step-3: Preparation of 9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (162d)

Compound 162d was prepared according to the procedure reported in step-2 of scheme-29, from 2-amino-lH-pyrrolo[2,3-b]pyridine-3-carbonitrile (162c) (1.00 g, 6.32 mmol) in ethanol (30 mL) using formamidine acetate (5.27 g, 50.6 mmol), NH*OAc (1.462 g, 18.97 mmol), glacial AcOH (1.139 g, 18.97 mmol), HC(OMe)3 (6.71 g, 63.2 mmol) and heating at 80 °C for 5 days. The solid obtained was collected by filtration washed with boiling EtOH and air- dried to provide 9H-pyrido[3',2 ^, :4,5]pyrrolo[2,3-d]pyrimidin-4-amine (162d) (0.27 g, 23% yield) as a brown solid; Ή NMR (300 MHz, DMSO-ifc) δ 12.36 (s, 1H), 8.68 (dd, J = 7.8, 1.6 Hz, 1H), 8.36 (dd, J = 4.9, 1.5 Hz, 1H), 8.31 (s, 1H), 7.34 (s, 2H), 7.25 (dd, J = 7.8, 4.9 Hz, 1H); MS (ES+): 186 (M+l), (ES-): 184 (M-l).

Step-4: Preparation of fert-butyl 2-(4-amino-9H-pyrido[3 ^, ,2 ^, :4,5]pyrrolo[2,3-d]pyrimidin-9- yl)acetate (162e)

Compound 162e was prepared according to the procedure reported in step- 1 of scheme- 1, from 9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidm-4-amme (162d) (0.27 g, 1.458 mmol) in DMF (10 mL) using /erf-butyl 2-bromoacetate (0.341 g, 1.750 mmol) and CszCO.i (0.950 g, 2.92 mmol). This gave after workup and purification using flash column chromatography [SiOzgel (24 g), eluting with MeOH in DCM from 0-4%] tert- butyl 2-(4-amino-9H- py rido [3 ',2' : 4,5 ]py rrolo [2,3 -d]py rimidin-9-yl)acetate (162e) (0.27 g, 0.902 mmol, 62% yield) as a pale-yellow solid; Ή NMR (300 MHz, DMSO-de) δ 8.75 (dd, J = 7.8, 1.5 Hz, 1H), 8.40 (dd, J = 4.9, 1.5 Hz, 1H), 8.36 (s, 1H), 7.50 (s, 2H), 7.34 (dd, J = 7.8, 4.9 Hz, 1H), 5.06 (s, 2H), 1.40 (s, 9H); MS (ES+): 300 (M+l), (ES-): 298 (M-l).

Step-5: Preparation of 2-(4-am ino-9H-pyrido [3 ',2' : 4,5 ]pyrrolo [2 ,3 -djpyrim idin-9-y 1 )acetic acid (1620 Compound 162f was prepared according to the procedure reported in step-2 of scheme- 1, from te/7-butyl 2-(4-amino-9H-pyrido[3 ^, ,2 ^, :4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetate (162e) (0.27 g, 0.902 mmol) in DCM (10 mL) using TFA (1.029 g, 9.02 mmol) and stirring at RT for 16 h. This gave after workup TFA salt of 2-(4-am ino-9H-pyrido [3 2' : 4,5 ]pyrrolo [2,3 - d]pyrimidin-9-yl)acetic acid (162f) (311 mg, 97 % yield) as a pale-yellow solid; Ή NMR (300 MHz, DMSO-tik) δ 8.84 (dd, J = 7.9, 1.5 Hz, 1H), 8.59 - 8.44 (m, 2H), 8.04 (s, 2H), 7.43 (dd, J = 7.8, 4.9 Hz, 1H), 5.14 (s, 2H). ¹⁹ F NMR (282 MHz, DMSO) δ -74.47; MS (ES+): 244 (M+l), (ES-): 242 (M-l).

Step-6: Preparation of (lR,3S,5R)-2-(2-(4-amino-9H-pyrido[3',2':4,5]pyrrolo[2,3- d]pyrimidin-9-yI)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicycl o[3.1 ,0]hexane-3-carboxamide

(162g)

Compound 162g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-9H-pyrido[3 ^, ,2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetic acid (162f) (75 mg, 0.210 mmol) in DMF (5 mL) using (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-caiboxamide (4a) (80 mg, 0.252 mmol), HATU (120 mg, 0.315 mmol), DIPEA (136 mg, 1.050 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0-6%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-9H-pyrido[3 ^, ,2 ^, :4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (162g) (75 mg, 70% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-afe) δ 10.78 (s, 1H, DzO exchangeable), 9.29 - 8.91 (m, 3H, 2H D ₂ 0 exchangeable), 8.74 (s, 1H), 8.59 (dd, J = 4.8, 1.4 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.53 (dd, J = 7.9, 4.8 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 5.78 (d, J = 17.0 Hz, 1H), 5.41 (d, J = 16.9 Hz, 1H), 4.42 (m, 1H), 4.03 - 3.84 (m, 1H), 2.39 - 2.27 (m, 1H), 2.27 - 2.18 (m, 1H), 1.99 - 1.86 (m, 1H), 1.11 (m, 1H), 0.70 (m, 1H); MS (ES+): 507/509 (M+l), 505/507 (M-l).

Scheme 163

163f 163g

Preparation of (lR,3S,5R)-2-(2-(4-amino-9H-pyrido[3',4':4,5]pyrrolo[2,3-d]p yrimidin-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (163g)

Step-1: Preparation of2-(4-nitropyridin-3-yl)malononitrile (163b)

Compound 163b was prepared according to the procedure reported in step-1 of scheme- 162 from 3-bromo-4-nitropyridine (163a) (5.00 g, 24.63 mmol) using NaH (1.990 g, 49.8 mmol) malononitrile (3.29 g, 49.8 mmol) in THF (100 mL). This gave after workup 2-(4- nitropyridin-3-yl)malononitrile (163b) (5.27 g) as a brown/black solid, which was used as such in the next reaction; MS (ES+): 159 (M+l), (ES-): 157 (M-l).

Step-2: Preparation of 2-amino-lH-pyrrolo[3,2-c]pyridine-3-caibonitrile (163c)

Compound 163c was prepared according to the procedure reported in step-2 of scheme- 162 from 2-(4-nitropyridin-3-yl)malononitrile (163b) (5.27 g, 28.0 mmol) in acetic acid (16.82 g, 280 mmol), using zinc (9.16 g, 140 mmol). This gave after workup and purification by flash column chromatography (S1O2, 40 g, eluting with 0-20% DMA-80 in DCM) 2-amino- 1H- pyrrolo[3,2-c]pyridine-3-cafbonitrile (163c) (0.23 g, 1.454 mmol, 5.19 % yield) as a beige solid; ¾NMR (300 MHz, DMSO-ifc) δ 11.30 (s, 1H), 8.34 (<U = 0.9 Hz, 1H), 8.04 (d, J = 5.4 Hz, 1H), 7.33 - 7.01 (m, 3H). LC-MS: t = 0.54 min; MS (ES+): 159 (M+l), (ES-): 157 (M-l).

Step-3: Preparation of 9H-pyrido[3',4':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (163d) Compound 163d was prepared according to the procedure reported in step-2 of scheme-29, from 2-amino-lH-pyrrolo[3,2-c]pyridine-3-caibonitrile (163c) (0.23 g, 1.454 mmol) in ethanol (20 mL) using formamidine acetate (1.211 g, 11.63 mmol), NHtOAc (0.336 g, 4.36 mmol), glacial AcOH (0.262 g, 4.36 mmol), HC(OMe)3(0.772 g, 7.27 mmol) and heating at 80 °C for 5 days. This gave after work up 9H-pyrido[3 ^, ,4':4,5]pyrrolo[2,3-d]pyrimidin-4- amine (163d) (0.14 g, 52% yield) as a brown solid; Ή NMR (300 MHz, DMSO-ifc) δ 12.24 (s, 1H), 9.47 (d, J = 1.0 Hz, 1H), 8.42 (d, J = 5.6 Hz, 1H), 8.32 (s, 1H), 7.42 (dd, J = 5.6, 1.0 Hz, 1H), 7.37 (s, 2H). MS (ES+): 186 (M+l); (ES-): 184 (M-l).

Step-4: Preparation of tert- butyl 2-(4-amino-9H-pyrido[3 ^, ,4':4,5]pyrrolo[2,3-d]pyrimidin-9- yl)acetate (163e)

Compound 163e was prepared according to the procedure reported in step-1 of scheme- 1, from 9H-pyrido[3',4':4,5]pyrrolo[2,3-d]pyTimidin-4-anmie (163d) (0.14 g, 0.756 mmol) in DMF (10 mL) using /erf-butyl 2-bromoacetate (0.177 g, 0.907 mmol) and CszCO.3 (0.493 g, 1.512 mmol). This gave after workup and purification using flash column chromatography [SiOzgel (24 g), eluting with MeOH in DCM from 0-6%] tert- butyl 2-(4-amino-9H- py rido [3 ',4' : 4,5 ]py rrolo [2,3 -d]py rimidin-9-yl)acetate (163e) (0.11 g, 49 % yield) as a pale- yellow solid; Ή NMR (300 MHz, DMSO-afe) δ 9.51 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.37 (s, 1H), 7.64 (dd, J= 5.7, 0.9 Hz, 1H), 7.52 (s, 2H), 5.16 (s, 2H), 1.40 (s, 9H).

Step-5: Preparation of 2-(4-ammo-9H-pyrido[3',4 ^, :4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetic acid (163f)

Compound 163f was prepared according to the procedure reported in step-2 of scheme- 1, from fe/7-butyl 2-(4-amino-9H-pyrido[3 ^, ,4 ^, :4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetate (163e) (0.108 g, 0.361 mmol) in DCM (10 mL) using TEA (411 mg, 3.61 mmol) and stirring at RT for 16 h. This gave after work up TFA salt of 2-(4-amino-9H-pyrido[3 ^, ,4 ^, :4,5]pyrrolo[2,3- d]pyrimidin-9-yl)acetic acid (163f) (202 mg) as a pale-yellow solid; Ή NMR (300 MHz, DMSO-^) δ 9.87 (d, J = 2.1 Hz, 1H), 8.85 (dd, J = 6.9, 2.1 Hz, 1H), 8.55 (d, J = 2.1 Hz, 1H), 8.37 (dd, J = 6.7, 2.1 Hz, 1H), 8.10 (s, 2H), 5.37 (d, J = 2.0 Hz, 2H). ¹⁹ F NMR (282 MHz, DMSO-i/e) δ -74.58; MS (ES+): 244 (M+l), (ES-): 242 (M-l). Step-6: Preparation of (lR,3S,5R)-2-(2-(4-aniino-9H-pyrido[3 ^, ,4 ^, :4,5]pyrrolo[2,3- d]pyrimidin-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicycl o[3.1 ,0]hexane-3-carboxamide (163g)

Compound 163g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt 2-(4-amino-9H-pyrido[3 ^, ,4':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetic acid (163f) (75 mg, 0.210 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-caiboxamide (4a) (80 mg, 0.252 mmol), HATU (120 mg, 0.315 mmol), DIPEA (136 mg, 1.050 mmol) and stirring at RT for 16 h.

This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0-7%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-9H-pyrido[3',4':4,5]pyrrolo[2,3-d]p yrimidin- 9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (163g) (43 mg, 40% yield) HC1 salt as a pale yellow solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.78 (s, 1H, DzO exchangeable), 10.08 (s, 1H), 8.83 (d, J = 6.6 Hz, 1H), 8.62 (s, 1H), 8.44 (s, 2H,

DzO exchangeable),), 8.25 (d, J = 6.7 Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 5.92 (d, J = 17.4 Hz, 1H), 5.53 (d, J = 17.4 Hz, 1H), 4.48 - 4.37 (m, 1H), 3.97 - 3.83 (m, 1H), 2.37 - 2.29 (m, 1H), 2.28 - 2.17 (m, 1H), 1.99 - 1.85 (m, 1H), 1.15 - 1.02 (m, 1H), 0.91 - 0.78 (m, 1H); MS (ES+): 507/509 (M+l); (ES-): 505/507 (M-l).

Scheme 164

159a 164a

Preparation of ( lR^S^R^-^-^-amino-e-hydroxy^H-pyrimido^S-blindol^-ylJacetylJ - N-fb-bromopyridin^-yl^-methyl^-azabicyclop.l.Olhexane-S-carb oxamide (164a)

To a solution of (lR,3S,5R)-2-(2-(4-amino-6-methoxy-9H-pyrimido[4,5-b]indol-9 -yl)acetyl)- 0.127 mmol) in DCM (5 mL) was added 1.0 M BBn in DCM (0.636 mL, 0.636 mmol) drop wise at 0 °C under argon and stirred at RT for 16 h. The reaction mixture was quenched with H2O (2 mL) and concentrated in vacuum. The residue was purified by reverse-phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] to provide (lR,3S,5R)-2-(2-(4-amino-6-hydroxy-9H-pyrimido[4,5-b]indol-9 - yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (164a) (41 mg, 60% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.77 (s, 1H, DzO exchangeable), 9.46 (s, 1H, D2O exchangeable), 8.54 (s, 1H), 8.46 (s, 2H, D20 exchangeable), 8.01 (d, J = 8.2 Hz, 1H), 7.84 (d ,J= 2.2 Hz, 1H), 7.70 (t,J= 7.9 Hz, 1H), 7.47 (d, J= 8.8 Hz, 1H), 7.32 (d, J= 7.7 Hz, 1H), 7.06 (dd,J= 8.8, 2.3 Hz, 1H), 5.63 (d, J= 17.3 Hz, 1H), 5.29 (d, ./= 17.3 Hz, 1H), 4.36 (m, 1H), 3.66 (dd, J= 5.4, 2.3 Hz, 1H), 2.52 - 2.39 (m, 1H), 1.97 (dd, 13.2, 5.9 Hz, 1H), 1.29 (s, 3H), 1.06 - 0.94 (m, 1H), 0.94 - 0.84 (m, 1H); MS (ES+): 536/538 (M+l), (ES-): 534/536 (M-l).

Scheme 165

Preparation of 3-(4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoy l)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]i ndol-6-yl)propanoic acid (165a)

Compounds 165a was prepared according to the procedure reported in step-4 of scheme- 17, from ethyl 3-(4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoy l)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]i ndol-6-yl)propanoate (45d) (78 mg, 0.129 mmol) in THF (3 mL) using 2M aqueous lithium hydroxide (0.077 mL, 0.154 mmol) and stirring at RT for 16 h. This gave after workup and purification by reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] 3-(4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoy l)-2- (165a) (55 mg, 74 % yield) HC1 salt as a white solid; ΉΝΜΚ (300 MHz, DMSO-tfc) δ 10.77 (s, 1H, DzO exchangeable), 8.59 (d, J= 4.5 Hz, 1H), 8.51 (d,J= 9.2 Hz, 2H, DzO exchangeable), 8.43 - 8.34 (m, 1H), 7.98 (dd, J= 16.3, 8.2 Hz, 1H), 7.70 (td,J= 8.1, 6.0 Hz, 1H), 7.59 (dd, J= 8.4, 2.2 Hz, 1H), 7.44 (d, J= 8.7 Hz, 1H), 7.31 (dd, J= 7.8, 5.4 Hz, 1H), 5.74 (d, J= 17.3 Hz, 1H), 5.39 (dd, J= 17.3, 3.0 Hz, 1H), 4.48 - 4.35 (m, 1H), 4.05 - 3.85 (m, 1H), 3.01 (t, J= 7.8 Hz, 2H), 2.67 (dd, J= 8.6, 6.9 Hz, 2H), 2.40 - 2.27 (m, 1H), 2.27 - 2.14 (m, 1H), 1.99 - 1.87 (m, 1H), 1.28 - 1.02 (m, 1H), 0.96 - 0.74 (m, 1H); MS (ES+): 578/580 (M+l), (ES-): 576/578 (M-l); Analysis calculated for C26H24BrN7O4.HCl.2H2O: C, 47.98; H, 4.49; Cl, 5.45; N, 15.06; Found: C, 47.70; H, 4.29; Cl, 5.69; N, 14.77.

Scheme 166

38e 166a

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-hydroxy-9H-pyrimido[4,5-b]indol-9 -yl)acetyl)- N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-caiboxam ide (166a)

Compound 166a was prepared according to the procedure reported in scheme- 164, from (lR,3S,5R)-2-(2-(4-amino-6-methoxy-9H-pyrimido[4,5-b]indol-9 -yl)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (38e) (85 mg, 0.158 mmol) in DCM (5 mL) using a solution of 1.0 M BBn in DCM (0.792 mL, 0.792 mmol) and stirring at RT for 30 min. This gave after work up and purification using reverse phase column chromatography [C 18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6-hydroxy-9H-pyrimido[4,5-b]indol-9 -yl)acetyl)- N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxam ide (166a) (30 mg, 36% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-flfe) δ 10.77 (s, 1H, DzO exchangeable), 9.91 - 9.13 (m, 1H, D2O exchangeable), 8.68 (s, 2H, D2O exchangeable), 8.60 (s, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.87 (d, J = 2.2 Hz, 1H), 7.71 (t, J = 7.9 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 7.11 (dd, J = 8.8, 2.3 Hz, 1H), 5.70 (d, J = 17.3 Hz, 1H) 5 36 (d J 172 H 1H) 442 (dd J 9 1 5 5 H 1H) 3 89 ( d J 62 54 22 H 1H), 2.39 - 2.26 (m, 1H), 2.26 - 2.14 (m, 1H), 1.98 - 1.84 (m, 1H), 1.12 - 0.98 (m, 1H), 0.83 - 0.69 (m, 1H); MS (ES+): 522/524 (M+l), 520/522 (M-l).

Scheme 167

36e 167a

Preparation of (lR,3S,5R)-2-(2-(4-amino-7-hydroxy-9H-pyrimido[4,5-b]indol-9 -yl)acetyl)- N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (167a)

Compound 167a was prepared according to the procedure reported in scheme- 164, from (lR,3S,5R)-2-(2-(4-amino-7-methoxy-9H-pyrimido[4,5-b]indol-9 -yl)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (36e) (82 mg, 0.153 mmol) in DCM (5 mL) using a solution of 1.0 M BBrs in DCM (0.764 mL, 0.764 mmol) and stirring at RT for 16 h. This gave after work up and purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-ammo-7-hydroxy-9H-pyrimido[4,5-b]indol-9- yl)acetyl)- N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxam ide (167a) (30 mg, 38% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-de) δ 10.79 (s, 1H, D2O exchangeable), 9.97 (s, 1H, D2O exchangeable), 8.53 (d, J= 3.1 Hz, 1H), 8.37 (s, 2H, D2O exchangeable), 8.28 (d ,J= 8.5 Hz, 1H), 8.01 (d,./= 8.1 Hz, 1H), 7.70 (t ,J= 8.0 Hz, 1H), 7.32 (d, 7.7 Hz, 1H), 6.97 (d, J= 2.0 Hz, 1H), 6.89 (dd,J= 8.6, 2.1 Hz, 1H), 5.66 (d, J=

17.3 Hz, 1H), 5.31 (d, J= 17.4 Hz, 1H), 4.42 (dd, J= 9.0, 5.5 Hz, 1H), 3.90 (td, J= 6.9, 6.3, 2.5 Hz, 1H), 2.38 - 2.29 (m, 1H), 2.26 - 2.15 (m, 1H), 1.98 - 1.87 (m, 1H), 1.12 - 1.02 (m, 1H), 0.77 - 0.70 (m, 1H); MS (ES+): 522/524 (M+l), (ES-): 520/522 (M-l).

Scheme 168

Preparation of (lR,3S,5R)-2-(2-(6-acetamido-4-amino-9H-pyrimido[4,5-b]indol -9-yl)acetyl)- N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxam ide (168g)

Step-1: Preparation ofN-(4-acetamido-2-bromophenyl)-2,2,2-trifluoroacetamide (168b)

Compound 168b was prepared according to the procedure reported in step-1 of scheme-46, from N-(4-amino-3-bromophenyl)acetamide (168a) (0.88 g, 3.84 mmol; CAS # 860745-87-5) in DCM (30 mL) using triethylamine (0.661 g, 6.53 mmol), trifluoroacetic acid anhydride (1.210 g, 5.76 mmol) and stirring at RT for 3 h. This gave after workup N-(4-acetamido-2- bromophenyl)-2,2,2-trifluoroacetamide (168b) (400 mg, 32% yield) as a yellow solid which was used as such for the next step; Ή NMR (300 MHz, DMSO-dis) δ 11.18 (s, 1H), 10.25 (s, 1H), 8.09 (d, J = 2.2 Hz, 1H), 7.55 (dd, J = 8.6, 2.3 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 2.07 (s, 3H). ¹⁹ F NMR (282 MHz, DMSO) δ -74.07; MS (ES+): 325/327 (M+l); (ES-): 323/325 (M-

1).

Step-2: Preparation of N-(2-amino-3 -cyano- 1 H-indol-5 -y l)acetamide (168c)

Compound 168c was prepared according to the procedure reported in step-1 of scheme- 11, from N-(4-acetamido-2-bromophenyl)-222-trifluoroacetamide (168b) (400 mg 1 230 0.492 mmol), Cul (46.9 mg, 0.246 mmol), a solution of K2CO3 (340 mg, 2.461 mmol) in water (10 mL) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification [S1O2 gel (24 g), eluting with MeOH in DCM from 0-5%] N-(2- amino-3-cyano-lH-indol-5-yl)acetamide (168c) (120 mg, 46% yield) as a yellow solid; Ή NMR (300 MHz, DMSO-de) δ 10.58 (s, 1H), 9.72 (s, 1H), 7.52 (d, J = 1.5 Hz, 1H), 7.01 (d, J = 1.3 Hz, 2H), 6.72 (s, 2H), 2.01 (s, 3H). LC-MS: t = 1.47 min; MS (ES+): 215 (M+l); (ES-): 213 (M-l).

Step-3: Preparation ofN-(4-amino-9H-pyrimido[4,5-bJindol-6-yl)acetamide (168d)

Compound 168d was prepared according to the procedure reported in step-2 of scheme-29, from N -(2-amino-3 -cyano- 1 H-indol-5-yl)acetamide (168c) (1.77 g, 8.26 mmol) in ethanol (30 mL) using formamidine acetate (6.88 g, 66.1 mmol), NH*OAc (1.911 g, 24.79 mmol), HC(OMe)3(8.77 g, 83 mmol) and heating at 80 °C for 16 h. This gave after work up N-(4- amino-9H-pyrimido[4,5-b]indol-6-yl)acetamide (168d) (1.48 g, 74% yield) as a tan solid; Ή NMR (300 MHz, DMSO-ifc) δ 11.76 (s, 1H), 9.81 (s, 1H), 8.22 (d ,J = 2.2 Hz, 2H), 7.46 - 7.31 (m, 2H), 7.09 - 6.90 (m, 2H), 2.06 (s, 3H); MS (ES+): 242 (M+l), (ES-): 240 (M-l).

Step-4: Preparation of tert-butyl 2-(6-acetamido-4-amino-9H-pyrimido[4,5-b]indol-9- yl)acetate (168e)

Compound 168e was prepared according to the procedure reported in step-1 of scheme- 1, from N-(4-amino-9H-pyrimido[4,5-b]indol-6-yl)acetamide (168d) (0.74 g, 3.07 mmol) in DMF (10 mL) using tert-butyl 2-bromoacetate (0.718 g, 3.68 mmol) and CS2CO3 (1.999 g, 6.13 mmol). This gave after workup and purification using flash column chromatography [SiCfegel (40 g), eluting with MeOH in DCM from 0-6%] fc/f-butyl 2-(6-acetamido-4- amino-9H-pyrimido[4,5-b]indol-9-yl)acetate (168e) (0.77 g, 71% yield) as a pale-yellow solid; Ή NMR (300 MHz, DMSO-ifc) δ 9.86 (s, 1H), 8.28 (s, 2H), 7.56 - 7.40 (m, 2H), 7.14 (s, 2H), 5.09 (s, 2H), 2.07 (s, 3H), 1.41 (s, 9H); MS (ES+): 356 (M+l), (ES-): 354 (M-l).

Step-5: Preparation of 2-(6-acetamido-4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (168i)

Compound 168f was prepared according to the procedure reported in step-2 of scheme-1, from tert-butyl 2-(6-acetamido-4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetate (168e) (0.77 g, This gave after work up TFA salt of 2-(6-acetamido-4-amino-9H-pyrimido[4,5-b]indol-9- yl)acetic acid (168f) (1.34 g) as a pale-yellow solid; Ή NMR (300 MHz, DMSO-i/ ₆ ) δ 10.04 (s, 1H), 8.66 (s, 2H), 8.62 (s, 1H), 8.54 (d, J = 1.9 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.54 (dd, J = 8.8, 1.9 Hz, 1H), 5.27 (s, 2H), 2.09 (s, 3H). ¹⁹ F NMR (282 MHz, DMSO- de) δ -74.68; MS (ES+): 300 (M+l); (ES-): 298 (M-l).

Step-6: Preparation of (lR,3S,5R)-2-(2-(6-acetamido-4-amino-9H-pyrimido[4,5-b]indol -9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (168g)

Compound 168g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(6-acetamido-4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (168f) (200 mg, 0.484 mmol) in DMF (5 triL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2- yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (170 mg, 0.532 mmol), HATU (276 mg, 0.726 mmol), DIPEA (313 mg, 2.420 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 to 7%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(6-acetamido-4-amino-9H-pyrimido[4,5-b]indol -9-yl)acetyl)- N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxam ide (168g) (70 mg, 26% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.77 (s, 1H, D20 exchangeable), 10.09 (s, 1H, D2O exchangeable), 8.77 (s, 2H, D2O exchangeable), 8.66 (s, 1H), 8.52 (d, 1.9 Hz, 1H), 8.00 (d, J= 8.2 Hz, 1H), 7.75 - 7.60 (m, 2H), 7.55 (dd, J= 8.8,

1.8 Hz, 1H), 7.31 (d, 1H), 5.76 (d, J= 17.4 Hz, 1H), 5.40 (d ,J= 17.3 Hz, 1H), 4.42 (dd,./= 9.0, 5.4 Hz, 1H), 3.94 - 3.86 (m, 1H), 2.40 - 2.26 (m, 1H), 2.26 - 2.15 (m, 1H), 2.08 (s, 3H), 1.97 - 1.85 (m, 1H), 1.12 - 0.98 (m, 1H), 0.83 - 0.72 (m, 1H); MS (ES+): 563/565 (M+l), (ES-): 561/563 (M-l); Analysis calculated for C25H23BrN8O3.L75HCl.3H2O: C, 44.08; H, 4.55; N, 16.45; Found: C, 44.12; H, 4.67; N, 15.87.

Scheme 169

Preparation of 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 2- azabicyclo[3.1 0]hcxan-2-yl)-2-oxoethyl)-N-(cyclopropylmcthyl)-9H-pyrimido[ 4,5-b]indole- 6-carboxamide (169f)

Step-1: Preparation of 4-amino-9H-pyrimido[4,5-b]indoIe-6-carboxylic acid (169a)

Compound 169a was prepared according to the procedure reported in step-4 of scheme- 17, from methyl 4-amino-9H-pyrimido[4,5-b]indole-6-carboxylate (39c) (400 mg, 1.651 mmol) in THE (5 mL) and MeOH (5 mL) using a solution of lithium hydroxide hydrate (424 mg, 9.91 mmol) in water (5 mL) and stirring at RT for 16 h. Additional lithium hydroxide hydrate (212 mg) in water (2 mL) and stirring for 6 h at RT was required for complete hydrolysis. This gave after work up 4-amino-9H-pyrimido[4,5-b]indole-6-carboxylic acid (169a) (305 mg, 81% yield) as a gray solid which was used as such for the next step; Ή NMR (300 MHz, DMSO-cfe) δ 12.16 (s, 1H), 8.90 (d,J= 1.5 Hz, 1H), 8.27 (s, 1H), 7.97 (dd,J= 8.5, 1.5 Hz, 1H), 7.48 (d, J= 8.5 Hz, 1H), 7.32 (s, 2H); MS (ES+): 229.00 (M+l).

Step-2: Preparation of 4-amino-N-(cyclopropylmethyl)-9H-pyrimido[4,5-b]indole-6- carboxamide (169c)

Compound 169c was prepared according to the procedure reported in scheme- 119, from 4- amino-9H-pyrimido [4,5 -b] indole -6-carboxylic acid (169a) (100 mg, 0.438 mmol) in DMF (3 mL) using cyclopropylmethanamine (169b) (93 mg, 1.315 mmol), HOBT (29.6 mg, 0.219 mmol), EDC (168 mg, 0.876 mmol), DIPEA (0.153 mL, 0.876 mmol) and stirring at RT for 41 h This gave after workup 4 amino N (cyclopropylmethyl) 9H pyrimido[45 b]indole 6 carboxamide (169c) (12 mg, 10% yield) as a yellow solid which was used as such for the next step; MS (ES+): 282.10 (M+l).

Step-3: Preparation of tert-butyl 2-(4-amino-6-((cyclopropylmethyl)caibamoyl)-9H- pyrimido[4,5-b]indol-9-yl)acetate (169d)

Compound 169d was prepared according to the procedure reported in step-1 of scheme- 1, from 4-amino-N-(cyclopropylmethyl)-9H-pyrimido[4,5-b]indole-6-car boxamide (169c) (12 mg, 0.043 mmol) in DMF (4 mL) using ter/-butyl 2-bromoacetate (7.56 pL, 0.051 mmol), CS2CO3 (34.7 mg, 0.107 mmol) and stirring at RT for 19 h. This gave after workup terf-butyl 2-(4-amino-6-((cyclopropylmethyl)caibamoyl)-9H-pyrimido[4,5- b]indol-9-yl)acetate (169d) (21 mg) as a yellow gum which was used as such for the next step; MS (ES+): 396.20 (M+l).

Step-4: Preparation of 2-(4-amino-6-((cyclopropylmethyl)carbamoyl)-9H-pyrimido[4,5- b]indol-9-yl)acetic acid (169e)

Compound 169e was prepared according to the procedure reported in step-2 of scheme- 1, from tert-butyl 2-(4-amino-6-((cyclopropylmethyl)carbamoyl)-9H-pyrimido[4,5- b]indol-9- yl)acetate (169d) (0.017 g, 0.043 mmol) in DCM (5 mL) using TFA and stirring at RT. This gave after workup 2-(4-amino-6-((cyclopropylmethyl)caibamoyl)-9H-p>'rimido[ 4,5-b]indol- 9-yl)acetic acid (169e) (15 mg) and was used as such for the next step; MS (ES+): 340.20 (M+l).

Step-5: Preparation of 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-N-(cyclopropylmethy l)-9H-pyrimido[4,5-b]indole- 6-carboxamide (169f).

Compound 169f was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-((cyclopropylmethyl)carbamoyl)-9H-pyrimido[4,5- b]indol-9- yl)acetic acid (169e) (14.59 mg, 0.043 mmol) in DMF (7 mL) using HC1 salt of (1R,3S,5R)- N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxam ide (4a) (55 mg, 0.172 mmol), HATH (65 mg, 0.172 mmol), DIPEA (0.045 mL, 0.258 mmol) and stirring at RT for 18 h. This gave after workup and purification by flash column chromatography [silica gel (4 g), eluting with dichloromethane/methanol (1 :0 to 19: 1)] followed by conversion of product obtained to HC1 salt by dissolving in acetonitrile (2 mL) and 0.1% aq. HC1 (15 mL) and lyophilization 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 2- 6-caiboxamide (169f) (4 mg, 15% yield) HC1 salt as a white solid; ^l H NMR (300 MHz, DMSO-flfe) δ 10.76 (s, 1H), 8.97 (s, 1H), 8.58 - 8.44 (m, 2H), 8.06 - 7.97 (m, 2H), 7.75 - 7.64 (m, 2H), 7.31 (d,J= 7.7 Hz, 1H), 5.74 (d, 17.4 Hz, 1H), 5.41 (d ,J= 17.4 Hz, 1H),

4.48 - 4.35 (m, 1H), 3.95 - 3.86 (m, 1H), 3.31 - 3.10 (m, 2H), 2.41 - 2.12 (m, 2H), 1.97 - 1.83 (m, 1H), 1.30 - 1.01 (m, 2H), 0.84 - 0.70 (m, 1H), 0.54 - 0.39 (m, 2H), 0.36 - 0.21 (m, 2H); MS (ES+): 603.15 & 605.10 (M+l); MS (ES-): 601.10 & 603.10 (M-l).

Scheme 170

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(l-hydroxyethyl)-9H-pyrimido[4,5- b]mdol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (170c)

Step-1: Preparation of ethyl 2-(4-amino-6-(l-hydroxyethyl)-9H-pyrimido[4,5-b]indol-9- yl)acetate (170a)

Compound 170a was prepared according to the procedure reported in scheme- 157, from ethyl 2-(6-acetyl-4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetate (58a) (32 mg, 0.102 mmol) in THF (6 mL) and MeOH (3 mL) using sodium borohydride (11.87 mg, 0.307 mmol) and stirring at RT for 24 h. The residue obtained after work up was used as such for the next step; MS (ES+): 301.10 (M+l).

Step-2: Preparation of 2-(4-amino-6-( 1 -hydroxyethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic Compound 170b was prepared according to the procedure reported in step-4 of scheme-17, from ethyl 2-(4-amino-6-(l-hydroxyethyl)-9H-pyrimido[4,5-b]indol-9-yl)a cetate (170a) (0.032 mg, 0.102 mmol) in THE (3 mL) and MeOH (3 mL) using a solution of lithium hydroxide hydrate (0.026 g) and stirring at RT for 20 h. The obtained residue after work up was used as such for the next step; MS (ES+): 287.10 (M+l ).

Step-3: Preparation of ( 1 R,3S,5R)-2-(2-(4-amino-6-( 1 -hydroxyethyl)-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1.0]hexane-3-carboxamide (170c)

Compound 170c was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-amino-6-(l-hydroxyethyl)-9H-pyrimido[4,5-b]indol-9-yl)a cetic acid (170b) (29.2 mg, 0.102 mmol) in DMF (8 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (65 mg, 0.204 mmol), HATU (97 mg, 0.255 mmol), DIPEA (0.071 mL, 0.408 mmol) and stirring at RT for 20 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with dichloromethane/methanol (1:0 to 19: 1)] followed by conversion of product obtained to HC1 salt by dissolving in acetonitrile (2 mL) and 0.1% aq. HC1 (15 mL) and lyophilization( 1 R,3 S,5R)-2-(2-(4-amino-6-( 1 -hydroxyethyl)-9H-pyrimido [4,5 -b] indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (170c) ( 12 mg, 21% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ife) δ 10.76 (s, 1H), 8.62 (s, 2H), 8.61 (s, 1H), 8.45 (s, 1H), 8.00 (d, J= 8.2 Hz, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.67 - 7.55 (m, 2H), 7.31 (d, J= 7.7 Hz, 1H), 5.75 (d, J= 17.4 Hz, 1H), 5.41 (d, J= 17.3 Hz, 1H), 4.91 (q, J= 6.4 Hz, 1H), 4.40 (dd,J= 9.1, 5.5 Hz, 1H), 3.99 - 3.86 (m, 1H), 2.43 - 2.10 (m, 2H), 2.01 - 1.78 (m, 1H), 1.43 (d, ./= 6.4 Hz, 3H), 1.14 - 0.99 (m, 1H), 0.82 - 0.69 (m, 1H); MS (ES+): 550.10 & 552.10 (M+l); MS (ES-): 548.00 & 550.10 (M-l).

Scheme 171 Preparation of (S)-3-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indo l-9-yl)acetyl)- N -(6-bromopyridin-2-yl)thiazolidine-2-carboxamide (171b)

Compound 171b was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-ammo-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)a cetic acid (lie) (75 mg, 0.177 mmol) in DMF (2 mL) using TFA salt of (S)-N-(6-bromopyridin-2- yl)thiazolidine-2-cafboxamide (171a) (71.1 mg, 0.177 mmol; prepared according to the procedure reported by Yang, Chao-Yie in ACS Med. Chem. Lett. 2016, 7, 1092-1096.), HATU (101 mg, 0.265 mmol), DIPEA (0.154 mL, 0.884 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 to 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (S)-3-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indo l-9- yl)acetyl)-N-(6-bromopyridin-2-yl)thiazolidine-2-carboxamide (171b) (61 mg, 60% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-dk) (a mixture of two rotamers) δ 11.39 and 11.03 (2s, 1H, D ₂ 0 exchangeable), 8.99 (s, 1H), 8.62 (m, 3H, 2H DzO exchangeable),

8.11 and 7.96 (2dd, J= 8.4, 4.5 Hz, 2H), 7.87 (dd, J= 8.8, 1.7 Hz, 1H), 7.73 (t, J= 8.0 Hz, 1H), 7.42 and 7.34 (2d, ./= 7.7 Hz, 1H), 5.75 - 5.46 (m, 3H), 4.40 (dt, J= 9.9, 4.8 Hz, 1H), 4.21 - 4.05 (m, 1H), 3.38 (dd, J= 8.3, 5.4 Hz, 2H). ¹⁹ F NMR (282 MHz, DMSO-i/e) δ -58.73. MS (ES+): 580.0 (M+l); (ES-): 578.0 (M-l); Analysis calculated for CzzHnBrFs^OzS 1.75H20.HC1: C, 40.75; H, 3.34; Cl, 5.47; N, 15.12; Found: C, 40.84; H, 3.18; Cl, 5.40; N, 14.93.

Scheme 172

H Br

X N ,N.

CO2H HN H N ¾ l\ r A ⁰ i rs HA *TJU, DICPEAr

NH ₂

\

NH ₂

\

57f 172a

Preparation of (lR,3S,5R)-2-(2-(4-amino-5-methoxy-9H-pyrimido[4,5-b]indol-9 -yl)acetyl)- N (6 b ridi 2 l) 5 h l 2 bi l [3 1 0]h 3 b id (172 ) Compound 172a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-ammo-5-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (57f) (50 mg, 0.129 mmol) in DMF (2 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-5- methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (43.1 mg, 0.129 mmol), HATU (73.8 mg, 0.194 mmol), DIPEA (0.113 mL, 0.647 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 to 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0- 100%] ( 1R,3 S,5 R)-2-(2-(4-amino-5 -methoxy-9H-pyrimido [4,5 -b] indol-9-yl)acety 1)-N -(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carb oxamide (172a) (51mg, 72% yield) HC1 salt as a white solid; ‘HNMR (300 MHz, DMSO-ifc) δ 10.74 (s, 1H, D2O exchangeable), 8.65 (s, 2H, D2O exchangeable), 8.60 (s, 1H), 8.42 (d ,J= 8.8 Hz, 1H), 8.02 (d, J= 8.1 Hz, 1H), 7.71 (t, J= 8.0 Hz, 1H), 7.36 - 7.25 (m, 2H), 7.06 (dd, J= 8.8, 2.3 Hz, 1H), 5.69 (d ,J= 17.3 Hz, 1H), 5.38 (d, J= 17.3 Hz, 1H), 4.38 (dd,J= 9.1, 6.0 Hz, 1H), 3.89 (s, 3H), 3.69 (dd, J= 5.6, 2.4 Hz, 1H), 2.47 (d, J= 9.0 Hz, 1H), 2.00 (dd, J= 13.3, 6.0 Hz, 1H), 1.32 (s, 3H), 1.03 (t, 5.4 Hz, 1H), 0.92 (dd, J= 5.3, 2.4 Hz, 1H); MS (ES+): 550.1

(M+l), 572.1 (M+Na); (ES-): 548.1 (M-l); Analysis calculated for C25H24BrN ₇ 03.1.2HC1.1 5H2O: C, 48.34; H, 4.58; Cl, 6.85; N, 15.78; Found: C, 48.20; H, 4.62; Cl, 6.50; N, 15.83.

Scheme 173

<3

HN H IL/V* xozH N l\ I Or"

N

< Nas ΓΛ 8a rVy* if 1 N A ⁰

N-V HATU, DIPEA f l

NH ₂ NH ₂

54f 173a

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methoxy-9H-pyrimido[4,5-b]indol-9 -yl)acetyl)- N -(6-bromopyridin-2-yl)-5 -methy 1-2-azabicycl o [3.1.0]hexane-3-caiboxamide (173a)

Compound 173a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (54f) (50 methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (8a) (43.1 mg, 0.129 mmol), HATU (73.8 mg, 0.194 mmol), DIPEA (0.113 mL, 0.647 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 to 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0- 100%] (1R,3 S ,5 R)-2-(2-(4-amino-8 -methoxy-9H-pyrimido [4,5 -bj indol-9-yl)acetyl)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (173a) (47 mg, 66% yield) HC1 salt as a white solid; 'HNMR (300 MHz, DMSO-tfc) δ 10.73 (s, 1H, DzO exchangeable), 8.69 - 8.50 (m, 3H, 2H D2O exchangeable), 8.05 (dd, J- 16.9, 8.1 Hz, 2H), 7.71 (t, J= 8.0 Hz, 1H), 7.40 - 7.27 (m, 2H), 7.14 (d, J= 8.1 Hz, 1H), 5.76 (d,J= 17.0 Hz, 1H), 5.55 (d, J= 16.9 Hz, 1H), 4.39 (dd, J= 9.0, 5.9 Hz, 1H), 3.93 (s, 3H), 3.62 (dd,J= 5.4, 2.3 Hz, 1H), 2.49 - 2.41 (m, 1H), 2.05 - 1.91 (m, 1H), 1.31 (s, 3H), 1.06 (t ,J= 5.4 Hz, 1H), 0.83 (dd, J= 5.3, 2.3 Hz, 1H); MS (ES+): 550.1 (M+l), 572.1 (M+Na); (ES-): 548.1 (M-l); Analysis calculated for C2sH24BrN7O3.HCl.2H2O: C, 48.20; H, 4.69; Cl, 5.69; N, 15.74; Found: C, 48.00; H, 4.59; Cl, 5.46; N, 15.60 .

Scheme 174 Preparation of (lR,3S,5R)-2-(2-(4-amino-8-(trifluoromethyl)-9H-pyrimido[4,5 -b]indol-9- yl)acetyl)-N -(6-bromopyridin-2-y l)-2-azabicyclo [3.1.0]hexane-3-carboxamide (174g)

Step-1: Preparation ofN-(2-bromo-6-(trifluoromethyl)phenyl)-2,2,2-trifluoroaceta mide (174b)

Compound 174b was prepared according to the procedure reported in step-1 of scheme-46, from 2-bromo-6-(trifluoromethyl)aniline (174a) (5 g, 20.83 mmol; CAS # 58458-13-2) in DCM (50 mL) using triethylamine (4.94 mL, 35.4 mmol) and trifluoroacetic acid anhydride (4.34 mL, 31.2 mmol) and stirring at RT for 16 h. This gave after workup N-(2-bromo-6- (trifluoromethyl)phenyl)-2,2,2-trifluoroacetamide (174b) as a pale yellow solid (7 g, 100% yield) which was used as such for next step; Ή NMR (300 MHz, DMSO-ds) δ 11.72 (s, 1H), 8.16 (dd, J= 8.2, 1.3 Hz, 1H), 7.91 (dd,J= 8.0, 1.3 Hz, 1H), 7.61 (t, .7= 8.0 Hz, 1H); MS (ES-): 333.90 (M-l).

Step-2: Preparation of 2-amino-7-(trifluoromethyl)- lH-indole-3-carbonitrile (174c)

Compound 174c was prepared according to the procedure reported in step-1 of scheme-11, from N-(2-bromo-6-(trifluoromethyl)phenyl)-2,2,2-trifluoroacetami de (174b) (3 g, 8.93 mmol) in DMSO (9 mL) using malononitrile (0.675 mL, 10.71 mmol), L-proline (0.206 g, 1.786 mmol), Cul (0.170 g, 0.893 mmol), a solution of K2CO3 (2.468 g, 17.86 mmol) in water (9 mL) and heating at 60 °C for 16 h under an aigon atmosphere. This gave after workup and purification [SiChgel (80 g), eluting with EtOAc in hexane from 0-50%] 2- amino-7 -(trifluoromethyl)- 1 H-indole-3 -carbonitrile (174c) (650 mg, 32% yield) as a yellow solid; ΉΝΜΚ (300 MHz, DMSO-ifc) δ 11.04 (s, 1H), 7.43 (d, J= 7.5 Hz, 1H), 7.29 - 7.09 (m, 2H), 6.79 (s, 2H); MS (ES-): 224.00 (M-l).

Step-3: Preparation of 8-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-4-amine (174d)

Compound 174d was prepared according to the procedure reported in step-1 of scheme-6, from 2-amino-7-(trifluoromethyl)-lH-indole-3-carbonitrile (174c) (600 mg, 2.66 mmol) using trimethyl orthoformate (5830 pL, 53.3 mmol), AcOH (762 pL, 13.32 mmol), NHtOAc (1027 mg, 13.32 mmol) and heating at 100 °C for 16 h in a pressure vessel. This gave after workup acetic acid salt of 8-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-4-amine (174d) (478 mg, 58% yield) as a yellow solid; Ή ΝΜΚ(300 MHz, DMSO-cfe) δ 12.30 (s, 1H), 11.98 (s, 1H), 8.61 (d, J= 7.9 Hz, 1H), 8.35 (s, 1H), 7.67 (d, J= 7.7 Hz, 1H), 7.50 - 7.29 (m, 3H),

1.91 (s, 3H); MS (ES+): 253.00 (M+l). Step-4: Preparation of te/7-butyl 2-(4-amino-8-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9- yl)acetate (174e)

Compound 174e was prepared according to the procedure reported in step-1 of scheme-1, from acetic acid salt of 8-(trifluoromethyl)-9H-pyrimido[4,5-bJindol-4-amine (174d) (450 mg, 1.441 mmol) in DMF (10 mL) using te/7-butyl 2-bromoacetate (0.234 mL, 1.585 mmol), CS2CO3 (1033 mg, 3.17 mmol) and stirring at RT for 15 h. This gave after work up and purification using flash column chromatography [SiChgel (40 g), eluting with ethyl acetate in hexanes from 0-100%] tert- butyl 2-(4-amino-8-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9- yl)acetate (174e) (180 mg, 34% yield) as a pale yellow solid; Ή NMR (300 MHz, DMSO-tife) δ 8.56 - 8.48 (m, 2H), 7.54 (d, J= 7.6 Hz, 1H), 7.20 (t, J= 7.7 Hz, 1H), 5.14 (s, 2H), 1.42 (s, 9H); MS (ES+): 367.10 (M+l).

Step-5 : Preparation of 2-(4-amino-8-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (174f)

Compound 174f was prepared according to the procedure reported in step-2 of scheme- 1, from /erf-butyl 2-(4-amino-8-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl) acetate (174e) (175 mg, 0.478 mmol) using 20% TFA in DCM (2742 pL, 7.17 mmol) and stirring at RT for 16 h. This gave after work up TFA salt of 2-(4-amino-8-(trifluoromethyl)-9H-pyrimido[4,5- b]indol-9-yl)acetic acid (174f) (198 mg, 98% yield) as a pale yellow solid; MS (ES+): 311.08 (M+l).

Step-6: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-(trifluoromethyl)-9H-pyrimido[4,5 - b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1.0]hexane-3-carboxamide (174g)

Compound 174g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (174f) (60mg, 0.141 mmol) in DMF (1.5 mL) using TFA salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (56.0 mg, 0.141 mmol), HATU (81 mg, 0.212 mmol), DIPEA (0.123 mL, 0.707 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 to 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR3S,5R)-2-(2-(4-amino-8-(trifluoromethyl)-9H-pyrimido[4,5- b]indol- mg, 92% yield) HCl salt as a white solid; Ή NMR (300 MHz, DMSO^fe/DzO) δ 8.82 - 8.69 (m, 2H), 7.98 (d, J= 8.1 Hz, 1H), 7.88 (d, J= 7.7 Hz, 1H), 7.69 (t ,J= 8.0 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.31 (d ,J= 7.7 Hz, 1H), 6.01 (d, J= 17.2 Hz, 1H), 5.64 (d ,J= 17.2 Hz, 1H), 4.45 (dd, ./= 9.0, 5.7 Hz, 1H), 3.73 (ddd, J= 7.4, 5.5, 2.3 Hz, 1H), 2.36 (dd,J= 13.2, 9.5 Hz, 1H), 2.23 (dt, 13.0, 6.2 Hz, 1H), 1.96 6.6, 3.5 Hz, 1H), 1.10 (dt, 8.6, 5.5 Hz,

1H), 0.86 (t d,J= 5.3, 2.3 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO-t/e) δ -59.64. MS (ES+): 574.00 & 576.1 (M+l); (ES-): 572.10 & 574.10 (M-l); Analysis calculated for C24Hi9BrF3N ₇ (h l.SHzO.HCI: C, 45.19; H, 3.63; Cl, 5.56; N, 15.37; Found: C, 44.94; H, 3.71; Cl, 5.32; N, 15.36.

Scheme 175

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-(trifluoromethyl)-9H-pyrimido[4,5 -b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (175a)

Compound 175a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-ammo-8-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)a cetic acid (174f) (60 mg, 0.141 mmol) in DMF (1.5 mL) using HCl salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (8a) (47 mg, 0.141 mmol), HATU (81 mg, 0.212 mmol) DIPEA (0.123 mL, 0.707 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), using DMA-80 in DCM from 0 to 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HCl) from 0-100%] ( 1 R,3S,5R)-2-(2-(4-ammo-8-(trifluoromethyl)-9H-pyrimido[4,5-b] indol- 9-yl)ace1yl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3 .1 ,0]hexane-3-carboxamide (175a) (47 mg, 57% yield) HCl salt as a white solid; Ή NMR (300 MHz, DMSOtMkO) δ 1H), 7.58 - 7.40 (m, 1H), 7.26 (d ,J= 7.7 Hz, 1H), 5.85 (d, J= 17.2 Hz, 1H), 5.52 (d, J=

17.0 Hz, 1H), 4.36 (dd, J= 9.0, 6.1 Hz, 1H), 3.47 - 3.42 (m, 1H), 2.43 - 2.38 (m, 1H), 1.95 (dd, J= 13.3, 6.0 Hz, 1H), 1.26 (s, 3H), 1.02 - 0.92 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-ife) δ -59.60; MS (ES+): 588.1 (M+l), 610.1 (M+Na); (ES-): 586.1 (M-l); Analysis calculated for C25H2iBrF ₃ N7022H2O.HCI: C, 45.44; H, 3.97; Cl, 5.36; N, 14.84; Found: C, 45.71; H, 3.97; Cl, 5.09; N, 14.63.

Scheme 176

Preparation of (lR,3S,5R)-2-(2-(4-amino-5-methyl-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N- (6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-c arboxamide (176a)

Compound 176a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-5-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (561)

(50mg, 0.135 mmol) in DMF (1.5 mL) using HC1 salt of ( 1R,3 S,5R)-N-(6-bromopyridin-2- yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (8a) (44.9 mg, 0.135 mmol), HATU (77 mg, 0.203 mmol), DIPEA (0.118 mL, 0.675 mmol) and stirring at RT for 4 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting DMA-80 in DCM from 0 to 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%](lR,3S,5R)-2-(2-(4-amino-5-methyl-9H-pyrimido[4,5-b]i ndol-9-yl)acetyl)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carb oxamide (176a) (53 mg, 73% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.77 (s, 1H, D ₂ 0 exchangeable), 8.63 (s, 1H), 8.01 (d, J= 8.1 Hz, 1H), 7.86 (s, 2H, D2O exchangeable), 7.70 (t, 8.0 Hz, 1H), 7.46 (dt, J= 15.3, 8.0 Hz, 2H), 7.32 (d, J= 7.7 Hz, 1H), 7.18 (d ,J= 7.0

Hz, 1H), 5.71 (d, J= 17.4 Hz, 1H), 5.37 (d,J= 17.3 Hz, 1H), 4.37 (dd,J= 9.1, 5.9 Hz, 1H), 1H), 1.31 (s, 3H), 1.02 (t, 5.4 Hz, 1H), 0.93 (dd,J= 5.4, 2.4 Hz, 1H). MS (ES+):

534.1(M+1), 556.1 (M+Na); (ES-): 532.0 (M-l); Analysis calculated for CasHo+BrNvOz 1.25H20.HC1: C, 50.60; H, 4.67; Cl, 5.97; N, 16.52; Found: C, 50.63; H, 4.76; Cl, 5.73; N, 16.55.

Scheme 177

CF ₃

177c 177d

Preparation of (2S,4S)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b] indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-4-cyanopyrrolidine-2-carb oxamide (177d)

Step-1: Preparation of (2S,4S)-te/t-butyl 2-((6-bromopyridin-2-yI)caibamoyI)-4- cyanopyrrolidine- 1 -caiboxylate (177b)

Compound 177b was prepared according to the procedure reported in step-1 of scheme-53, from (2S,4S)-l-(tert-butoxycarbonyl)-4-cyanopyrrolidine-2-carboxy lic acid (177a) (0.5 g, 2.081 mmol; CAS # 132622-71-0) in DCM (15 mL) using 1 -methyl- lH-imidazole (0.415 mL, 5.20 mmol), methanesulfonyl chloride (0.193 mL, 2.497 mmol), 6-bromopyridin-2- amine (0.360 g, 2.081 mmol) and stirring at RT for 18 h. This gave after workup (2S,4S)-terf- butyl 2-((6-bromopyridin-2-yl)carbamoyl)-4-cyanopyrrolidine- 1 -carboxylate (177b) (0.5 g, 61% yield); Ή NMR (300 MHz, DMSO-flfe) δ 11.05 (d, J = 14.5 Hz, 1H), 8.17 - 8.05 (m,

1H), 7.77 (q, J= 7.7 Hz, 1H), 7.37 (d,J= 7.7 Hz, 1H), 4.39 (q, ./= 7.9 Hz, 1H), 3.82 (d, J= 13.5 Hz, 1H), 3.49 (d, J= 6.0 Hz, 2H), 2.70 (dd, J= 14.3, 7.6 Hz, 1H), 2.10 (dt, J= 13.7, 8.0 Hz, 1H), 1.33 (d,J= 43.3 Hz, 9H); MS (ES+): 395.10 (M+l).

Step-2: Preparation of (2S,4S)-N-(6-bromopyridin-2-yl)-4-cyanopyrrolidine-2-caiboxa mide (177c)

Compound 177c was prepared according to the procedure reported in step-2 of scheme- 1, from (2S,4S)-/er/-butyl 2-((6-bromopyridin-2-yl)carbamoyl)-4-cyanopyrrolidine- 1 - carboxylate (177b) (200 mg, 0.506 mmol) in DCM (2.5 mL) using TFA (404 mg, 3.54 mmol) and stirring overnight at RT. This gave after workup TFA salt of (2S,4S)-N-(6- bromopyridin-2-yl)-4-cyanopyrrolidine-2-caiboxamide (177c) (0.2 g, 97% yield) as a clear gel; ΉΝΜΚ (300 MHz, DMSO-ifc) δ 11.52 (s, 1H), 8.06 (d, J= 8.1 Hz, 1H), 7.83 (t, J= 8.0 Hz, 1H), 7.46 (d ,J= 7.7 Hz, 1H), 4.48 (t ,J= 8.3 Hz, 1H), 3.67 (dt, J= 12.9, 8.0 Hz, 2H), 3.55 (dd, J= 9.9, 5.8 Hz, 1H), 2.87 (dt, J= 13.6, 7.9 Hz, 1H), 2.32 (dt, J= 14.3, 7.3 Hz, 1H); MS (ES+): 295.00 (M+l).

Step-3: Preparation of (2S,4S)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b] indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-4-cyanopyrrolidine-2-carb oxamide (177d)

Compound 177d was prepared according to the procedure reported in step-3 of scheme-1 , from TFA salt of (2S,4S)-N-(6-bromopyridin-2-yl)-4-cyanopyrrolidine-2-carboxa mide (177c) (0.2 g, 0.489 mmol) in DMF (1.5 mL) using TFA salt of 2-(4-amino-6-(trifluoromethyl )-9H- pyrimido[4,5-b]indol-9-yl)acetic acid (lie) (0.207 g, 0.489 mmol), HATU (0.279 g, 0.733 mmol), DIPEA (0.426 mL, 2.444 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 to 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4S)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyriniido[4,5-b ]indol-9-yl)acetyl)-N-(6- bromopyridin-2-yl)-4-cyanopyrrolidine-2-carboxamide (177d) (173 mg, 60% yield) HC1 salt as a white solid; ^! H NMR (300 MHz, DMSO-tife) (a mixture of two rotamers) δ 11.40 and 10.97 (2s, 1H, DzO exchangeable), 8.93 (s, 1H), 8.54 (s, 1H), 8.33 (s, 2H, DzO exchangeable), 8.17 and 8.01 (2d, J = 8.2 Hz, 1H), 7.84 (d, J= 4.7 Hz, 2H), 7.71 (t, J= 7.9 Hz, 1H), 7.43 and 7.34 (2d, J= 7.7 Hz, 1H), 5.77 and 5.50 (2s, 2H), 4.55 (t, J= 7.5 Hz, 1H), 4.39 (dd, ./= 10.0, 7.8 Hz, 1H), 4.07 (dd, J= 10.1, 7.8 Hz, 1H), 3.77 - 3.68 (m, 1H), 2.82 - 2.68 (m, 1H), 2.19 (dt, J= 14.0, 7.6 Hz, 1H). ¹⁹ F NMR (282 MHz, DMSO-i¾) δ -58.53. MS (ES+): 587.1 (M+l); (ES-): 585.0 (M-l); Analysis calculated for CztHieBrFaNgOz 2HzO.HCl: Scheme 178

NH ₂

CF ₃

178d

Preparation of (2S,4R)- l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-4-cyanopyrrolidine-2-carb oxamide (178d)

Step-1: Preparation of (2S,4R)-tert-butyl 2-((6-bromopyridin-2-yl)carbamoyl)-4- cyanopyrrolidine- 1 -carboxylate (178b)

Compound 178b was prepared according to the procedure reported in step-1 of scheme-53, from (2S,4R)- 1 -(fer/-butoxycarbonyl)-4-cyanopyrrolidine-2-caiboxylic acid (178a) (0.5 g, 2.081 mmol; CAS # 273221-94-6) in DCM (15 mL) using 1-methyl-lH-imidazole (0.415 mL, 5.20 mmol), methanesulfonyl chloride (0.193 mL, 2.497 mmol), 6-bromopyridin-2- amine (0.360 g, 2.081 mmol) and stirring at RT for 18 h. This gave after workup (2S,4R)- tert-butyl 2-((6-bromop> ^, ridin-2-yl)carbamoyl)-4-c>'anop> ^, rrolidine- 1 -carboxylate (178b) (747 mg, 91% yield); ^! H NMR (300 MHz, DMSO -ck) 5 11.07 (d, ./= 17.6 Hz, 1H), 8.07 (dd, J= 12.9, 8.1 Hz, 1H), 7.77 (q, 8.0 Hz, 1H), 7.37 (d 7.7 Hz, 1H), 4.53 (ddd, J= 13.0, 8.2,

4.9 Hz, 1H), 3.73 (dd, J= 10.4, 7.1 Hz, 1H), 3.57 (dt, J= 10.6, 5.7 Hz, 1H), 3.46 (tt, J= 7.1, 4.2 Hz, 1H), 2.46 (d, J= 8.2 Hz, 1H), 2.30 (dt,J= 12.6, 6.1 Hz, 1H), 1.40 (s, 3H), 1.27 (s,

6H).

Step-2: Preparation of (2S,4R)-N-(6-bromopyri<im-2-yl)-4-cyanopyrrolidine-2-carb oxamide (178c) Compound 178c was prepared according to the procedure reported in step-2 of scheme-1, from (2S,4R)-/er/-butyl 2-((6-bromopyridin-2-yl)carbamoyl)-4-cyanopyrrolidine-l- carboxylate (178b) (0.2 g, 0.506 mmol) in DCM (2.5 mL) using TFA (0.273 mL, 3.54 mmol) and stirring overnight at RT. This gave after workup TFA salt of (2S,4R)-N-(6-bromopyridin- 2-yl)-4-cyanopyrrolidine-2-carboxamide (178c) (0.2 g, 97% yield) as a clear gel; *H NMR (300 MHz, DMSO-tifc) δ 11.50 (s, 1H), 8.04 (d,7= 8.2 Hz, 1H), 7.82 (t, J= 8.0 Hz, 1H), 7.45 (dd, J= 7.8, 0.7 Hz, 1H), 4.62 (t, J= 7.8 Hz, 1H), 3.76 - 3.51 (m, 3H), 2.68 (ddd, J= 11.2, 8.0, 5.5 Hz, 1H), 2.49 - 2.40 (m, 1H); MS (ES+): 295.00 (M+l).

Step-3: Preparation of (2S,4R)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b] indol- 9-yl)acetyl)-N-(6-bromopyridin-2-yl)-4-cyanopytTolidine-2-ca rboxamide (178d)

Compound 178d was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of (2S,4R)-N-(6-bromopyridin-2-yl)-4-cyanopyrrolidine-2-carboxa mide (178c) (200 mg, 0.488 mmol) in DMF (5 mL) using TFA salt of 2-(4-amino-6- (trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (lie) (207 mg, 0.488 mmol), HATU (0.278 g, 0.732 mmol), DIPEA (0.425 mL, 2.440 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 to 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%](2S,4R)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido [4,5-b]indol-9- yl)acetyl)-N-(6-bromopyridm-2-yl)-4-cyanopyrrolidine-2-carbo xamide (178d) (177 mg, 62% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) (a mixture of two rotamers) δ 11.38 and 11.00 (2s, 1H, DzO exchangeable), 8.95 (s, 1H), 8.56 and 8.52 (2s, 1H), 8.42 (s, 2H, DzO exchangeable), 8.16 and 7.99 (2d, J= 8.2 Hz, 1H), 7.85 (d, J= 2.2 Hz, 2H), 7.71 (t, J= 8.0 Hz, 1H), 7.43 and 7.33 (2d, J= 7.7 Hz, 1H), 5.53 (d, J= 2.91 Hz , 2H), 4.68 (dd, J= 8.4, 4.5 Hz, 1H), 4.31 (dd, J= 10.0, 7.5 Hz, 1H), 4.19 (dd, J= 10.0, 6.9 Hz, 1H), 3.70 (p ,J = 7.2 Hz, 1H), 2.59 - 2.52 (m, 1H), 2.46 - 2.36 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-cfe) δ - 58.55; MS (ES+): 587.1 (M+l); (ES-): 585.0 (M-l).

Scheme 179

Preparation of (S)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indo l-9-yl)acetyl)- N-(6-bromopyridin-2-yl)indoline-2-carboxamide ( 179d)

Step-1: Preparation of (S)-tert-butyl 2-((6-bromopyridin-2-yl)carbamoyl)indoline- 1 - carboxylate (179b)

Compound 179b was prepared according to the procedure reported in step-1 of scheme-53, from (S)-l-(/er/-butoxycarbonyl)indoline-2-carboxylic acid (179a) (1 g, 3.80 mmol; CAS # 144069-67-0) in DCM (30 mL) using 1 -methyl- 1 H-i mi dazole (0.780 mL, 9.50 mmol), methanesulfonyl chloride (0.353 mL, 4.56 mmol), 6-bromopyridin-2-amine (0.657 g, 3.80 mmol) and stirring at RT for 18 h. This gave after workup (S)-fert-butyl 2-((6-bromopyridin- 2-yl)carbamoyl)indol ine- 1 -carboxylate (179b) (1.49 g, 94% yield); ^! H NMR (300 MHz, DMSO-ΐ/β) δ 11.21 (s, 1H), 8.08 (d,./= 8.3 Hz, 1H), 7.77 (t ,./= 8.3 Hz, 2H), 7.37 (d ,J= 7.7 Hz, 1H), 7.17 (d ,J= 7.4 Hz, 2H), 6.94 (t, J= 7.4 Hz, 1H), 5.04 (dd, J= 11.1, 4.6 Hz, 1H), 3.49 (dd, J= 17.0, 11.2 Hz, 1H), 3.06 (d, J= 17.0 Hz, 1H), 1.44 (d,J= 53.8 Hz, 9H); MS (ES+): 418.10 (M+l).

Step-2: Preparation of (S)-N-(6-bromopyridin-2-yl)indoline-2-carboxamide (179c)

Compound 179c was prepared according to the procedure reported in step-2 of scheme- 1, from (S)-terf-butyl 2-((6-bromopyridin-2-yl)carbamoyl)indoline- 1 -carboxylate (179b) (1 g, 2.391 mmol) in DCM (10 mL) using TFA (1.289 mL, 16.74 mmol) and stirring overnight at [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (S)-N- (6-bromopyridin-2-yl)indoline-2-carboxamide (179c) (0.66 g, 78% yield) HC1 salt as an off white solid; Ή NMR (300 MHz, DMSO-tfe) δ 10.59 (s, 1H), 8.10 (d, J= 8.1 Hz, 1H), 7.76 (t, J= 8.0 Hz, 1H), 7.37 (d, J= 7.7 Hz, 1H), 7.06 - 6.92 (m, 2H), 6.68 - 6.56 (m, 2H), 4.51 (dd, J= 10.5, 6.9 Hz, 1H), 3.35 (dd, 16.2, 10.5 Hz, 1H), 3.11 (dd, 16.2, 6.8 Hz, 1H); MS (ES+): 318.00 (M+l).

Step-3: Preparation of (S)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indo l-9- yl)acetyl)-N-(6-bromopyridin-2-yl)indoline-2-carboxamide (179d)

Compound 179d was prepared according to the procedure reported in step-3 of scheme-1 , from HC1 salt of (S)-N-(6-bromopyridin-2-yl)indoline-2-carboxamide (179c) (83mg, 0.234 mmol) in DMF (2 mL) using TFA salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5- bJindol-9-yl)acetic acid (lie) (99 mg, 0.234 mmol), HATU (133 mg, 0.351 mmol), DIPEA (0.204 mL, 1.170 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 to 50%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (S)-l-(2-(4-amino-6- (trifhroromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6- bromopyridin-2-yl)indoline-2- carboxamide (179d) (71 mg, 49% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfe) (a mixture of two rotamers) δ 11.58 and 11.08 (2s, 1H, D2O exchangeable), 8.98 (s, 1H), 8.55 (s, 1H), 8.45 (s, 3H, D2O exchangeable), 8.14 (d, J= 8.2 Hz, 1H), 8.01 - 7.70 (m, 4H), 7.44 - 7.25 (m, 2H), 7.16 (t, J= 7.6 Hz, 1H), 7.05 (t ,J= 7.4 Hz, 1H), 5.80 - 5.60 (m, 2H), 5.16 (d, J= 17.1 Hz, 1H), 3.82 and 3.58 (2dd,J= 17.1, 11.5 Hz, 1H), 3.38 and 3.13 (2d, J= 17.1 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO-cfe) δ -58.46; MS (ES+): 610.50 (M+l); (ES-): 608.50 (M-l).

Scheme 180

NHFmoc

Preparation of (2S,4S)-4-amino- 1 -(2-(4-amino-6-(trifluoromcthyl)-9H-pyri mi do[4,5 -b] i ndol- 9-yl)acetyl)-N-(6-bromopyridin-2-yl)pyrrolidine-2-carboxamid e ( 180e)

Step-1: Preparation of (2S,4S)-te/f-butyl 4-((((9H-fluoren-9-yl)mcthoxy)carbonyl)amino)-2- ((6-bromopyridin-2-yl)carbamoyl)pyrrolidine-l-carboxylate (180b)

Compound 180b was prepared according to the procedure reported in step-1 of scheme-53, from (2S,4S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)- 1 -(Jert- butoxycarbonyl)pyrrolidine-2-carboxyhc acid (180a) (1 g, 2.210 mmol; CAS # 174148-03-9) in DCM (30 mL) using 1 -methyl- 1 H-imidazole (0.440 mL, 5.52 mmol), methanesulfonyl chloride (0.205 mL, 2.65 mmol), 6-bromopyridin-2 -amine (0.382 g, 2.210 mmol) and stirring at RT for 18 h. This gave after workup (2S,4S)-/erf-butyl 4-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-2-((6-bromopyridin-2-yl)carbamoyl )pyrrolidine-l-carboxylate (180b) (1.22 g, 91% yield); Ή NMR (300 MHz, DMSOA) δ 10.98 (d, J= 18.4 Hz, 1H), 8.22 - 8.06 (m, 1H), 7.89 (d, J= 7.5 Hz, 2H), 7.78 (t, J= 8.1 Hz, 1H), 7.67 (d, ./= 7.4 Hz, 2H), 7.56 (d, J= 7.7 Hz, 1H), 7.36 (ddt, J= 20.7, 12.9, 7.3 Hz, 5H), 4.40 - 4.27 (m, 3H),

4.21 (t, J= 6.8 Hz, 1H), 4.02 (d, J= 8.1 Hz, 1H), 3.82 - 3.56 (m, 1H), 3.14 (s, 1H), 2.51 (p, J = 1.9 Hz, 1H), 1.78 (d, J= 10.0 Hz, 1H), 1.39 (s, 3H), 1.25 (s, 6H); MS (ES+): 607.20 (M+l).

Step-2: Preparation of (9H-fluoren-9-yl)methyl ((3S,5S)-5-((6-bromopyridin-2- Compound 180c was prepared according to the procedure reported in step-2 of scheme- 1, from (2S,4S)-/m-butyl 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-((6-bromopyr idin- 2-yl)carbamoyl)pyrrolidine-l-carboxylate (180b) (1 g, 1.646 mmol) in DCM (8 mL) using TFA (0.888 mL, 11.52 mmol) and stirring overnight at RT. This gave after work up and purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (9H-fluoren-9-yl)methyl ((3S,5S)-5-((6- bromopyridin-2-yl)carbamoyl)pyrrolidin-3-yl)carbamate (180c) (0.62 g, 69% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-tife) δ 11.45 (s, 1H), 9.71 (s, 1H), 8.87 (s, 1H), 8.07 (d, J= 8.1 Hz, 1H), 7.93 - 7.79 (m, 3H), 7.67 (d, J= 7.4 Hz, 2H), 7.58 (d, J= 6.2 Hz, 1H), 7.48 - 7.29 (m, 5H), 4.48 - 4.31 (m, 3H), 4.19 (dt, J= 19.5, 6.7 Hz, 2H), 3.40 (s, 1H), 3.16 (d,J= 9.0 Hz, 1H), 2.77 - 2.63 (m, 1H), 1.92 (dt,J= 15.1, 8.1 Hz, 1H); MS (ES+): 507.10 (M+l).

Step-3: Preparation of (9H-fluoren-9-yl)methyl ((3S,5S)-l-(2-(4-amino-6-(trifluoromethyl)- 9H-pyrimido[4,5-b]indol-9-yl)acetyl)-5-((6-bromopyridin-2-yl )carbamoyl)pyrrolidin-3- yl)carbamate (180d)

Compound 180d was prepared according to the procedure reported in step-3 of scheme- 1 , from HC1 salt of (9H-fluoren-9-yl)methyl ((3S,5S)-5-((6-bromopyridin-2- yl)carbamoyl)pyrrolidin-3-yl)carbamate (180c) (200 mg, 0.368 mmol) in DMF (3 mL) using TFA salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (lie) (156 mg, 0.368 mmol), HATU (210 mg, 0.552 mmol), DIPEA (0.320 mL, 1.839 mmol) and stirring at RT for 16 h. This gave after woikup and purification by flash column chromatography [silica gel (40 g), eluting with DMA-80 in DCM from 0 - 50%] (9H-fluoren- 9-yl)methyl ((3S,5S)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b ]indol-9- yl)acetyl)-5-((6-bromopyridin-2-yl)carbamoyl)pyrrolidin-3-yl )carbamate (180d) (280 mg, 95% yield) as a white solid; MS (ES+): 799.38 (M+l).

Step-4: Preparation of (2S,4S)-4-amino-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimid o[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)pyrrolidine-2-ca rboxamide (180e)

To a stirred solution of (9H-fluoren-9-yl)methyl ((3S,5S)-l-(2-(4-amino-6-(trifluoromethyl)- 9H-pyrimido[4,5-b]indol-9-yl)acetyl)-5-((6-bromopyridin-2-yl )caibamoyl)pyjTolidin-3- yl)carbamate (180d) (150mg, 0.188 mmol) in DMF (0.8 mL) was added piperidine (0.185 mL, 1.876 mmol) and stirred at RT for lh. The reaction mixture was concentrated and purified using reverse phase column chromatography [Cl 8 column (50 g) eluting with ACN in water (containing 0.1% HC1) from 0-100%] yielding (2S,4S)-4-amino-l-(2-(4-amino-6- (trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6- bromopyridin-2-yl)pyrrolidine- 2-carboxamide (180e) (27 mg, 25% yield) as a white solid; Ή NMR (300 MHz, DMSO-db)

(a mixture of two rotamers) δ 11.51 and 11.12 (2s, 1H, D2O exchangeable), 8.94 (s, 1H), 8.53 (s, 1H), 8.45 - 8.29 and 8.27 - 8.17 (m, 4H, D2O exchangeable), 7.99 (d ,J= 8.2 Hz, 1H), 7.90 - 7.78 (m, 2H), 7.72 (t, J= 8.0 Hz, 1H), 7.45 and 7.35 (d, J= 7.7 Hz, 1H), 5.49 (s, 2H), 4.57 (t, J= 7.5 Hz, 1H), 4.23 (dd, J= 10.3, 6.1 Hz, 1H), 4.08 - 3.95 (m, 1H), 3.88 (dd, J= 10.2, 6.2 Hz, 1H), 2.64 (dt,./= 14.3, 7.4 Hz, 1H), 2.05 (dt,./= 13.2, 6.5 Hz, 1H); ¹⁹ FNMR (282 MHz, DMSO-tife) δ -58.43. MS (ES+): 576.5 (M+l); 598.5(M+Na); (ES-): 574.6 (M-l); Analysis calculated for C23H2oBrF ₃ N ₈ 022HC13.5H2O 0.5DMSO: C, 38.31; H, 4.29; N, 14.89; Found: C, 38.58; H, 4.28; N, 14.59.

Scheme 181

163f 181a

Preparation of (lR,3S,5R)-2-(2-(4-amino-9H-pyrido[3 ^, ,4':4,5]pyrrolo[2,3-d]pyrimidin-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (181a)

Compound 181a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-9H-pyrido[3',4 ^, :4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetic acid (163f) (96 mg, 0.269 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-caiboxamide (8a) (98 mg, 0.296 mmol), HATU (153 mg, 0.403 mmol), DIPEA (174 mg, 1.344 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 to 7%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-9H-pyrido[3 ^, ,4 ^, :4,5]p>'rrolo[2,3-d]pyrimidin- (181a) (62 mg, 44% yield) as a white solid; Ή NMR (300 MHz, DMSO-de) δ 10.78 (s, 1H, DzO exchangeable), 10.06 (s, 1H), 8.83 (d, J = 6.7 Hz, 1H), 8.60 (s, 1H), 8.42 (s, 2H, DzO exchangeable), 8.25 (d, J = 6.7 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 5.87 (d, J = 17.3 Hz, 1H), 5.48 (d, J = 17.2 Hz, 1H), 4.39 (dd, J = 9.0, 5.8 Hz, 1H), 3.68 (dd, J = 5.5, 2.4 Hz, 1H), 2.49 - 2.42 (m, 1H), 2.05 - 1.92 (m, 1H), 1.31 (s, 3H), 1.04 (t, J = 5.5 Hz, 1H), 1.01 - 0.94 (m, 1H); MS (ES+): 521/523 (M+l), (ES-): 519/521 (M-l).

Scheme 182

Preparation of (lR,3S,5R)-2-(2-(4-amino-9H-pyrido[4 ^, ,3 ^, :4,5]pyrrolo[2,3-d]pyrimidin-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (182a)

Compound 182a was prepared according to the procedure reported in step-3 of scheme- 1, from TEA salt of 2-(4-amino-9H-pyrido[4 ^, ,3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetic acid (29e) (100 mg, 0.280 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carb oxamide (8a) (102 mg, 0.308 mmol), HATU (160 mg, 0.420 mmol), DIPEA (181 mg, 1.400 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 to 7%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]p yTimidin- 9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3 .1 ,0]hexane-3-carboxamide (182a) (87 mg, 60% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-de) δ 10.80 (s, 1H, DzO exchangeable), 9.48 (s, 1H), 9.07 (d, J = 6.3 Hz, 1H), 8.93 - 8.53 (m, 4H, 2H DzO exchangeable), 8.01 (d, J = 8.2 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 7.7 Hz, (dd, J = 5.4, 2.6 Hz, 1H), 2.48 - 2.42 (m, 1H), 1.98 (dd, J = 13.3, 5.7 Hz, 1H), 1.31 (s, 3H), 1.08 - 0.97 (m, 2H); MS (ES+): 521/523 (M+l), (ES-): 519/521 (M-l).

Scheme 183

Preparation of (lR,3S,5R)-2-(2-(4-ammo-9H-pyrido[3 ^, ,2':4,5]pyrrolo[2,3-<l]pyrimi<lm-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (183a)

Compound 183a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-9H-pyrido[3 ^, ,2':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetic acid (162f) (100 mg, 0.280 mmol) in DMF (5 ml) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (8a) (102 mg, 0.308 mmol), HATU (160 mg, 0.420 mmol), DIPEA (181 mg, 1.400 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 to 7%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HCl) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]p yrimidin- 9-yl)ace1yl)-N-(6-bromopytidin-2-yl)-5-methyl-2-azabicyclo[3 .1.0]hexane-3-carboxamide (183a) (110 mg, 75% yield) HCl salt as a white solid; Ή NMR (300 MHz, DMSO-de) δ 10.77 (s, 1H, DzO exchangeable), 8.97 (dd, J = 7.9, 1.5 Hz, 1H), 8.74 (s, 2H, D ₂ 0 exchangeable), 8.66 (s, 1H), 8.56 (dd, J = 4.9, 1.5 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.49 (dd, J = 7.9, 4.9 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 5.71 (d, J = 17.0 Hz, 1H), 5.34 (d, J = 16.9 Hz, 1H), 4.37 (dd, J = 9.0, 5.9 Hz, 1H), 3.72 (dd, J = 5.4, 2.3 Hz, 1H), 2.48 - 2.42 (m, 1H), 1.98 (dd, J = 13.2, 5.9 Hz, 1H), 1.31 (s, 3H), 1.05 (t, J = 5.5 Hz, 1H), 0.86 (dd, J = 5.4, 2.3 Hz, 1H); MS (ES+): 521/523 (M+l), (ES-): 519/521 (M-l); Analysis calculated for CyHziBrNsOz.1. lHCl.1 5HzO: C, 46.94; H, 4.30; Cl, 6.63; N, 19.04; Found: Scheme 184

CF ₃

184f 184g

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyr imido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azab icyclo[3.1 ,0]hexane-3- carboxamide (184g)

Step-1 : Preparation of N-(2-bromo-6-methyl-4-(trifluoromethyl)phenyl)-2,2,2- trifluoroacetamide (184b)

Compound 184b was prepared according to the procedure reported in step-1 of scheme-46, from 2-bromo-6-methyl-4-(trifluoromethyl)aniline (184a) (5.34 g, 21.02 mmol; CAS #

1100212-65-4) in DCM (30 mL) using triethylamine (3.62 g, 35.7 mmol), trifluoroacetic acid anhydride (6.62 g, 31.5 mmol) and stirring at RT for 1 h. This gave after workup N-(2- bromo-6-methyl-4-(trifluoromethyl)phenyl)-2,2,2-trifluoroace tamide (184b) (7.50 g, 102% yield) as a pale-orange solid.; Ή NMR (300 MHz, DMSO-i/e) 5 11.55 (s, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H), 2.31 (s, 3H). ¹⁹ F NMR (282 MHz, DMSOncfc) 5 -61.20, -74.06; MS (ES-): 348/350 (M-l).

Step-2: Preparation of 2-amino-7-methyl-5-(trifluoromethyl)-lH-indole-3-carbonitril e (184c) Compound 184c was prepared according to the procedure reported in step-1 of scheme- 11, from N-(2-bromo-6-methyl-4-(trifluoromethyl)phenyl)-2,2,2-trifluo roacetamide (184b) (7.50 g, 21.43 mmol) in DMSO (25 mL) using malononitrile (1.698 g, 25.7 mmol), L-proline (0.493 g, 4.29 mmol), Cul (0.408 g, 0.2.143 mmol), K2CO3 (5.92 g, 42.9 mmol) in water (25 mL) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification [S1O2 gel (80 g), eluting with EtOAc in hexane from 0-40%] to provide 2-amino- 7-me1hyl-5-(trifluoromethyl)-lH-indole-3-carbonitrile (184c) (3.68 g, 72% yield) as a pale- green solid; ¾ NMR (300 MHz, DMSO-ifc) δ 11.23 (s, 1H), 7.30 - 7.17 (m, 1H), 7.07 (d, J = 1.8 Hz, 1H), 6.84 (s, 2H), 2.41 (s, 3H). ¹⁹ F NMR (282 MHz, DMSO-cfc) δ -58.92; MS (ES+) 240 (M+l); (ES-): 238 (M-l).

Step-3: Preparation of 8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-4-amine (184d)

Compound 184d was prepared according to the procedure reported in step-2 of scheme-29, from 2-amino-7-methyl-5-(trifluoromethyl)-lH-indole-3-carbonitril e (184c) (3.68 g, 15.38 mmol) in ethanol (10 mL) using formamidine acetate (8.01 g, 77 mmol) and NHtOAc (3.56 g, 46.2 mmol) and heating at 90 °C for 16 h. This gave after work up 8-methyl-6- (trifluoromethyl)-9H-p>rimido[4,5-b]indol-4-amine (184d) (2.69 g, 66% yield) as a tan solid; Ή NMR (300 MHz, DMSO-dk) δ 12.26 (s, 1H), 8.60 (s, 1H), 8.32 (s, 1H), 7.48 (d, J= 1.6 Hz, 1H), 7.41 (s, 2H), 2.59 (s, 3H); ¹⁹ F NMR (282 MHz, DMSOK/ ₆ ) δ -58.08; MS (ES+): 267 (M+l), (ES-): 265 (M-l).

Step-4: Preparation of tort-butyl 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5- b]indol-9-yl)acetate (184e)

Compound 184e was prepared according to the procedure reported in step-1 of scheme-1, from 8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-4-amine (184d) (0.56 g, 2.104 mmol) in DMF (10 mL) using tort-butyl 2-bromoacetate (0.492 g, 2.52 mmol) CszCOs (1.371 g, 4.21 mmol) and stirring at RT for 16 h. This gave after work up and purification [SiChgel (24 g), eluting with methanol in DCM from 0-6%] tort-butyl 2-(4-amino-8-methyl-6- (trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetate (184e) (0.74 g, 92% yield) as a pale- yellow solid; MS (ES+): 381 (M+l), (ES-): 379 (M-l).

Step-5 : Preparation of 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]in dol-9- yl)acetic acid (184f)

Compound 184f was prepared according to the procedure reported in step-2 of scheme- 1, yl)acetate (184e) (0.74 g, 1.946 mmol) using TFA (2.218 g, 19.46 mmol) in DCM (15 mL) and stirring at RT for 16 h. This gave after work up TFA salt of 2-(4-amino-8-methyl-6- (trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (184f) (0.88 g, 103 % yield) as a pale-yellow solid; MS (ES+): 325 (M+l), (ES-): 323 (M-l).

Step-6: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopjTidin-2-yl)-5- methyl-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (184g)

Compound 184g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]in dol-9- yl)acetic acid (184f) (100 mg, 0.228 mmol) in DMF (5 mL) using HC1 salt of (1R,3S,5R)-N- (6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (8a) (83 mg,

0.251 mmol), HATU (130 mg, 0.342 mmol) DIPEA (147 mg, 1.14 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 to 2%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5- methyl-2- azabicyclo[3.1 ,0]hexane-3-caxboxamide (184g) (76 mg, 55% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfc) δ 10.83 (s, 1H, D2O exchangeable), 8.79 (s, 1H), 8.72 (s, 2H, DzO exchangeable), 8.64 (s, 1H), 8.00 (d ,J= 8.2 Hz, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.60 (s, 1H), 7.31 (d,J= 7.7 Hz, 1H), 5.92 (d,J= 18.0 Hz, 1H), 5.64 (d,J= 17.9 Hz, 1H), 4.38 (dd,J = 9.0, 6.1 Hz, 1H), 3.71 (dd, ./= 5.6, 2.4 Hz, 1H), 2.75 (s, 3H), 2.48 - 2.44 (m, 1H), 1.97 (dd, J= 13.2, 6.0 Hz, 1H), 1.30 (s, 3H), 1.02 (t 5.4 Hz, 1H), 0.85 (dd, 5.4, 2.4 Hz, 1H);

¹⁹ F NMR (282 MHz, DMSO-ds) δ -58.78; MS (ES+): 602/604 (M+l), (ES-): 600/602 (M-l).

Scheme 185 Preparation of (lR,3S,5R)-2-(2-(6-acetamido-4-amino-9H-pyrimido[4,5-b]indol -9-yl)acetyl)- N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3 -carboxamide (185a)

Compound 185a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(6-acetamido-4-amino-9H-pyiimido[4,5-b]indol-9-yl)acetic acid (168f) (75 mg, 0.181 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)- 5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (66.4 mg, 0.200 mmol), HATU (103 mg, 0.272 mmol) DIPEA (117 mg, 0.907 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 to 7%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(6-acetamido-4-amino-9H-pyrimido[4,5-b]indol -9-yl)ace1yl)- N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3 -carboxamide (185a) (57 mg, 54% yield) HC1 salt as a white solid; ^! H NMR (300 MHz, DMSCWe) δ 10.78 (s, 1H, DzO exchangeable), 10.06 (s, 1H, DzO exchangeable), 8.82 - 8.52 (m, 3H, 2H DzO exchangeable), 8.49 (d,7 = 1.9 Hz, 1H), 8.01 (d ,J= 8.1 Hz, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.62 (d, J= 8.8 Hz, 1H), 7.53 (dd, J= 8.8, 1.8 Hz, 1H), 7.31 (d, J= 7.7 Hz, 1H), 5.70 (d ,J= 17.3 Hz, 1H), 5.34 (d, ./= 17.3 Hz, 1H), 4.37 (dd, J= 9.1, 5.9 Hz, 1H), 3.68 (dd, J= 5.5, 2.4 Hz, 1H), 2.47 - 2.41 (m, 1H), 2.08 (s, 3H), 1.97 (dd, 7 = 13.3, 5.9 Hz, 1H), 1.30 (s, 3H), 1.00 (t, 7= 5.5 Hz, 1H), 0.93 (dd, 7= 5.4, 2.4 Hz, 1H); MS (ES+): 577/579 (M+l); (ES-): 575/577 (M-l).

Scheme 186

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-bromo-9H-pyrimido[4,5-b]indol-9-y l)acetyl)-N- (6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (186a)

Compound 186a was prepared according to the procedure reported in step-3 of scheme- 1, mg, 0.172 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-5- methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (57.3 mg, 0.172 mmol), HATU (79 mg, 0.207 mmol), DIPEA (111 mg, 0.862 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 to 3%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-8-bromo-9H-pyrimido[4,5-b]indol-9-y l)acetyl)-N- (6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-c arboxamide (186a) (69 mg, 67% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfc) δ 10.77 (s, 1H, D2O exchangeable), 8.57 (s, 1H), 8.49 (d,J= 7.9 Hz, 1H), 8.37 (s, 2H, D2O exchangeable), 8.01 (d, J= 8.2 Hz, 1H), 7.75 - 7.61 (m, 2H), 7.29 (t, J= 8.0 Hz, 2H), 5.93 (d, J= 17.7 Hz, 1H), 5.72 (d, J= 17.6 Hz, 1H), 4.36 (dd, 8.9, 6.1 Hz, 1H), 3.66 (dd, J= 5.5, 2.4 Hz, 1H), 2.43 (d, J= 6.6 Hz, 1H), 1.97 (dd, J= 13.1, 5.9 Hz, 1H), 1.30 (s, 3H), 1.00 (t, J= 5.5 Hz, 1H), 0.89 (dd, J= 5.6, 2.3 Hz, 1H); MS (ES+): 598/600 (M+l), 596/598 (M-l).

Scheme 187

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-ethj'l-9H-pjTimido[4,5-b]indol-9- yl)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (187c)

Step-1: Preparation of ethyl 2-(4-amino-6-ethyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (187a)

A solution of ethyl 2-(4-amino-6-vinyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (59a) (100 mg, 0.337 mmol) in ethyl acetate (5 mL) and ethanol (5.00 mL) was treated with palladium (53.9 mg, 0.051 mmol) and hydrogenated for 2 h. The reaction mixture was filtered, washed with ethyl acetate/ethanol. The filtrate was concentrated to afford ethyl 2-(4-amino-6-ethyl -9H- pyrimido[4,5-b]indol-9-yl)acetate (187a) which was used as such for next step; MS (ES+): 299.10 (M+l).

Step-2: Preparation of 2-(4-amino-6-ethyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (187b) Compound 187b was prepared according to the procedure reported in step-4 of scheme- 17, from ethyl 2-(4-amino-6-ethyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (187a) (67 mg, 0.225 mmol) in THF (3 mL) and MeOH (3 mL) using a solution of lithium hydroxide hydrate (57.7 mg, 1.347 mmol) in water (3 mL) and stirring at RT for 20 h. This gave after workup 2-(4- amino-6-ethyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (187b) which used as such for the next step; MS (ES+): 271.10 (M+l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-ethyl-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N -(6-bromopyridin-2-yl)-2-azabicyclo [3.1.0 Jhexane-3 -carboxamide (187c)

Compound 187c was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-6-ethyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (187b) (61 mg, 0.225 mmol) in DMF (10 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (4a) (108 mg, 0.338 mmol), HATU (171 mg, 0.450 mmol), DIPEA (0.157 mL, 0.900 mmol) and stirring at RT for 18 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with dichloromethane/methanol (1:0 to 19:1)] followed by purification using reverse phase column chromatography [C18 column, eluting with ACN in water (containing 0.1% HC1) from 0- 100%] (lR,3S,5R)-2-(2-(4-amino-6-ethyl-9H-pyrimido[4,5-b]indol-9-y l)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (187c) (25 mg, 21% yield)

HCl salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.75 (s, 1H), 8.58 (s, 1H), 8.52 (s, 2H), 8.35 (s, 1H), 8.00 (d,J= 8.2 Hz, 1H), 7.70 (t ,J= 8.0 Hz, 1H), 7.60 (d,J= 8.4 Hz, 1H), 7.45 - 7.39 (m, 1H), 7.32 (d, J = 7.7 Hz, 1H), 5.73 (d, J= 17.3 Hz, 1H), 5.40 (d, J =

17.3 Hz, 1H), 4.40 (dd, J= 9.0, 5.5 Hz, 1H), 4.04 - 3.78 (m, 1H), 2.78 (q, J= 7.6 Hz, 2H), 2.41 - 2.13 (m, 2H), 2.00 - 1.78 (m, 1H), 1.28 (t, J= 7.5 Hz, 3H), 1.12 - 0.98 (m, 1H), 0.82 - 0.67 (m, 1H); MS (ES+): 534.10 & 536.10 (M+l); MS (ES-): 532.00 & 534.10 (M-l); Analysis calculated for C2 ₅ H24BrN702.HC1.2.25H20: C, 49.11; H, 4.86; N, 16.04; Found: C, 49.18; H, 4.52; N, 15.67.

Scheme 188 H ₂ N

I

Et ₃ N I r%

Cul K2CO3

N0 ₂ NO ₂

N0 ₂

188f 188g

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-nitro-9H-pyrimido[4,5-b]indol-9-y l)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (188g)

Step-1: Preparation of2,2,2-trifluoro-N-(2-iodo-4-nitrophenyl)acetamide (188b)

Compound 188b was prepared according to the procedure reported in step-1 of scheme-46, from 2-iodo-4-nitroani line (188a) (5 g, 18.94 mmol; CAS # 6293-83-0) in DCM (35 mL) using triethylamine (6.60 mL, 47.3 mmol), trifluoroacetic acid anhydride (3.95 mL, 28.4 mmol) and stirring at RT for 19 h. This gave after workup 2,2,2-trifluoro-N-(2-iodo-4- nitrophenyl)acetamide (188b) (8.986 g) as a brown gum which was used as such for the next step; (ES-): 358.90 (M-l).

Step-2: Preparation of 2-amino-5 -nitro- 1 H-indole-3-carbonitrile (188c)

Compound 188c was prepared according to the procedure reported in step-1 of scheme- 11, from 2,2,2-trifluoro-N-(2-iodo-4-nitrophenyl)acetamide (188b) (6.819 g, 18.94 mmol) in Cul (0.361 g, 1.894 mmol), a solution of K2CO3 (5.235 g, 37.9 mmol) in water (25 mL) and heating at 60 °C for 13 h under an argon atmosphere. This gave after workup and purification [SiChgel (120 g), eluting with EtOAc in hexane from 0-67%] 2-amino-5-nitro-lH-indole-3- carbonitrile (188c) (531 mg, 14% yield) as a red solid; ^! H NMR (300 MHz, DMSO -ck) δ 11.43 (s, 1H), 7.92 (d, J= 2.3 Hz, 1H), 7.85 (dd, J = 8.7, 2.3 Hz, 1H), 7.34 (s, 2H), 7.28 (d, J = 8.7 Hz, 1H); (ES+): 203.05 (M+l); (ES-): 201.00 (M-l).

Step-3: Preparation of 6-ni tro-9H-pyrimido [4,5 -b] indol-4-amine (188d)

Compound 188d was prepared according to the procedure reported in step-2 of scheme-29, from 2-amino-5-nitro-lH-indole-3-carbonitrile (188c) (520 mg, 2.57 mmol) in ethanol (12 mL) using formamidine acetate (2.164 g, 20.58 mmol) and refluxing for 44 h. This gave after work up 6-nitro-9H-pyrimido[4,5-b]indol-4-amine (188d) (497 mg, 84% yield) as a gray solid; ¾NMR (300 MHz, DMSO-tifc) δ 12.54 (s, 1H), 9.34 (d, J= 2.2 Hz, 1H), 8.33 (s, 1H), 8.26 (dd, J= 8.9, 2.2 Hz, 1H), 7.62 (s, 2H), 7.58 (d, J= 9.0 Hz, 1H); (ES+): 230.10 (M+l); (ES-): 228.05 (M-l).

Step-4: Preparation of ethyl 2-(4-amino-6-nitro-9H-pyrimido[4,5-b]indol-9-yl)acetate (188e)

Compound 188e was prepared according to the procedure reported in step-1 of scheme- 1, from 6-nitro-9H-pyrimido[4,5-b]indol-4-amine (188d) (300 mg, 1.309 mmol) in DMF (15 mL) using ethyl 2-bromoacetate (0.160 mL, 1.440 mmol), CS2CO3 (1.066 g, 3.27 mmol) and stirring at RT for 18 h. This gave after work up ethyl 2-(4-amino-6-nitro-9H-pyrimido[4,5- b]indol-9-yl)acetate (188e) (0.373 g, 90% yield) as a yellow solid; Ή NMR (300 MHz, DMSO-ifc) δ 9.39 (d, .7 = 2.2 Hz, 1H), 8.38 (s, 1H), 8.32 (dd, J= 9.0, 2.2 Hz, 1H), 7.85 (d ,J= 9.1 Hz, 1H), 7.78 (s, 2H), 5.35 (s, 2H), 4.15 (q,7= 7.1 Hz, 2H), 1.20 (t, J= 7.1 Hz, 3H); (ES+): 316.15 (M+l); (ES-): 314.00 (M-l).

Step-5: Preparation of 2-(4-amino-6-nitro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (188f)

Compound 188f was prepared according to the procedure reported in step-4 of scheme- 17, from ethyl 2-(4-amino-6-nitro-9H-pyrimido[4,5-b]indol-9-yl)acetate (188e) (0.100 g, 0.317 mmol) in THE (3 mL) and MeOH (3 mL) using a solution of lithium hydroxide hydrate (81 mg, 1.903 mmol) in water (3 mL) and stirring at RT for 22 h. This gave after work up 2-(4- amino-6-nitro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (188f) which was used as such for the next step; (ES+): 287.80 (M+l). Step-6: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-nitro-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N -(6-bromopyridin-2-y l)-2-azabicyclo [3.1.0]hexane-3-carboxamide (188g)

Compound 188g was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-6-nitro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (188f) (61 mg, 0.225 mmol) in DMF (12 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (4a) (151 mg, 0.476 mmol), HATU (241 mg, 0.634 mmol), DIPEA (0.276 mL, 1.585 mmol) and stirring at RT for 15 h. This gave after workup and purification by reverse phase column chromatography [Cl 8 column, eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6-nitro-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1 ,0]hexane-3- carboxamide (188g) (50 mg, 29% yield) HC1 salt as a white solid; *H NMR (300 MHz, DMSO-cfe) δ 10.76 (s, 1H), 9.52 (d, J= 2.2 Hz, 1H), 8.73 (s, 3H), 8.64 (s, 1H), 8.41 (dd, J = 9.1, 2.2 Hz, 1H), 8.00 (d, J= 8.1 Hz, 1H), 7.88 (d, ./= 9.2 Hz, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.31 (d, .7= 7.7 Hz, 1H), 5.84 (d, .7= 17.4 Hz, 1H), 5.48 (d, .7= 17.3 Hz, 1H), 4.42 (dd, .7 = 9.0, 5.5 Hz, 1H), 3.97 - 3.86 (m, 1H), 2.44 - 2.12 (m, 2H), 1.99 - 1.79 (m, 1H), 1.17 - 0.96 (m, 1H), 0.88 - 0.67 (m, 1H); (ES+): 551.10 & 553.10 (M+l); (ES-): 549.00 & 551.00 (M-l); Analysis calculated for C23Hi ₉ BrN ₈ O4.0.85HC1.1.75H2O: C, 45.00; H, 3.83; N, 18.25; Cl, 4.91; Found: C, 45.22; H, 3.59; N, 17.88; Cl, 4.90.

Scheme 189

Preparation of (lR,3S,5R)-2-(2-(4-amino-6,8-dimethyl-9H-pyrimido[4,5-b]indo l-9- yl)acet>'l)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (189g)

Step-1: Preparation of N-(2-bromo-4,6-dimethylphenyl)-2,2,2-trifluoroacetamide (189b)

Compound 189b was prepared according to the procedure reported in step-1 of scheme-46, from 2-bromo-4,6-dimethylaniline (189a) (7 g, 35.0 mmol; CAS # 41825-73-4) in DCM (30 mL) using triethylamine (6.02 g, 59.5 mmol), trifluoroacetic acid anhydride (11.02 g, 52.5 mmol) and stirring at RT for 1 h. This gave after workup N-(2-bromo-4,6-dimethylphenyl)- 2,2,2-trifluoroacetamide (189b) (10.32 g, 100% yield) as a pale-yellow solid; ^l H NMR (300 MHz, DMSOntife) δ 11.12 (s, 1H), 7.43 (s, 1H), 7.18 (s, 1H), 2.30 (s, 3H), 2.16 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-i/ ₆ ) δ -74.08; MS (ES+): 296/298 (M+l); (ES-): 294/296 (M-l). Step-2: Preparation of 2-amino-5,7-dimethyl-lH-indole-3-carbonitrile (189c)

Compound 189c was prepared according to the procedure reported in step-1 of scheme- 11, ftomN-(2-bromo-4,6-dimethylphenyl)-2,2,2-trifIuoroacetamide (189b) (10.32 g, 34.9 mmol) in DMSO (30 mL), using malononitrile (2.76 g, 41.8 mmol), L-proline (0.803 g, 6.97 mmol), C l (0664 349 l) d l ti f K CO (963 697 l) i t (30 L) d heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification [SiChgel (40 g), eluting with EtOAc in hexane from 0-40%] 2-amino-5,7-dimethyl-lH- indole-3-carbonitrile (189c) (3.97 g, 62% yield) as a pale-orange solid; Ή NMR (300 MHz, DMSO-ΐ/β) δ 10.60 (s, 1H), 6.77 (s, 1H), 6.54 (d, ./= 1.6 Hz, 1H), 6.43 (s, 2H), 2.28 (s, 3H), 2.27 (s, 3H); MS (ES+): 186 (M+l); (ES-): 184 (M-l).

Step-3: Preparation of 6,8-dimethyl-9H-pyrimido[4,5-b]indol-4-amine (189d)

Compound 189d was prepared according to the procedure reported in step-2 of scheme-29, from 2-amino-5 ,7-dimethyl- 1 H-indole-3 -carbonitrile (189c) (3.97 g, 21.43 mmol) in ethanol (10 mL) using trimethoxymethane (11.37 g, 107 mmol), NKUOAc (4.96 g, 64.3 mmol) and heating at 90 °C for 16 h. This gave after work up 6,8-dimethyl-9H-pyrimido[4,5-b]indoI-4- amine (189d) (4.07 g, 89% yield) as a pale-yellow solid; Ή NMR (300 MHz, DMSO-i/s) δ 11.68 (s, 1H), 8.22 (s, 1H), 7.93 (s, 1H), 7.03 (s, 2H), 6.98 (s, 1H), 2.47 (s, 3H), 2.42 (s, 3H); MS (ES+): 213 (M+l), (ES-): 211 (M-l).

Step-4: Preparation of tert- butyl 2-(4-amino-6,8-dimethyl-9H-pyrimido[4,5-b]indol-9- yl)acetate (189e)

Compound 189e was prepared according to the procedure reported in step-1 of scheme- 1, from 6,8-dimethyl-9H-pyrimido[4,5-b]indol-4-amine (189d) (2.00 g, 9.42 mmol) in DMF (15 mL) using /erf-butyl 2-bromoacetate (2.206 g, 11.31 mmol), CS2CO3 (6.14 g, 18.85 mmol) and stirring at RT for 16 h. This gave after work up /erf-butyl 2-(4-amino-6,8-dimethyl-9H- pyrimido[4,5-b]indol-9-yl)acetate (189e) (1.79 g, 58%) as a tan solid which was used as such for the next step; Ή NMR (300 MHz, DMSO-i/e) δ 8.26 (s, 1H), 8.02 (s, 1H), 7.19 (s, 2H), 6.98 (s, 1H), 5.29 (s, 2H), 2.59 (s, 3H), 2.41 (s, 3H), 1.42 (s, 9H); MS (ES+): 327 (M+l). Step-5: Preparation of 2-(4-amino-6,8-dimethyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (1891)

Compound 189f was prepared according to the procedure reported in step-2 of scheme- 1, from tert-butyl 2-(4-amino-6,8-dimethyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (189e) (300 mg, 0.919 mmol) using TFA (1048 mg, 9.19 mmol) in DCM (15 mL) and stirring at RT for 16 h. This gave after work up TFA salt of 2-(4-amino-6,8-dimethyl-9H-pyrimido[4,5-b]indol- 9-yl)acetic acid (I89f) (0.366 g, 104% yield) as a pale-yellow solid; Ή NMR (300 MHz, DMSO-de) δ 8.66 (s, 2H), 8.61 (s, 1H), 8.19 (s, 1H), 7.16 (s, 1H), 5.43 (s, 2H), 2.65 (s, 3H), 2.45 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -74.52; MS (ES+): 271 (M+l); (ES-): 269 (M l) Step-6: Preparation of (lR,3S,5R)-2-(2-(4-amino-6,8-dimethyl-9H-pyrimido[4,5-b]indo l-9- yl)acetyl)-N -(6-bromopyridin-2-y l)-2-azabicyclo [3.1.0]hexane-3-carboxamide (189g)

Compound 189g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6,8-dimethyl-9H-pyrimido[4,5-bJindol-9-yl)acetic acid (189f) (75 mg, 0.195 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)- 2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (62.2 mg, 0.195 mmol), HATU (89 mg, 0.234 mmol), DIPEA (126 mg, 0.976 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6,8-dimethyl-9H-pyrimido[4,5-b]indo l-9-yl)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (189g) (75 mg, 72% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.82 (s, 1H, DzO exchangeable), 8.68 (s, 2H, DzO exchangeable), 8.62 (s, 1H), 8.17 (s, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.11 (s, 1H), 5.88 (d, J = 17.9 Hz, 1H), 5.60 (d, J = 17.8 Hz, 1H), 4.41 (dd, J = 9.1, 5.7 Hz, 1H), 3.91 (ddd, J = 7.3, 5.4, 2.4 Hz, 1H), 2.66 (s, 3H), 2.42 (s, 3H), 2.40 - 2.29 (m, 1H), 2.26 - 2.14 (m, 1H), 1.99 - 1.85 (m, 1H), 1.14 - 0.98 (m, 1H), 0.74 - 0.62 (m, 1H); MS (ES+): 534/536 (M+l), (ES-): 532/534 (M-l); Analysis calculated for CzsHz+BrNzOz HCl.lJSHzO: C, 49.85; H, 4.77; Cl, 5.89; N, 16.28; Found: C, 49.82; H, 4.65; Cl, 5.83; N, 16.03.

Scheme 190

190a

Preparation of ethyl 3-(4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoy l)-5- methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimid o[4,5-b]indol-6- yl)propanoate (190a) Compound 190a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-(3 -ethoxy-3 -oxopropy 1) -9H-py rimido [4,5 -bj indol-9-yl)acetic acid (45c) (75 mg, 0.164 mmol) in DMF (5 ml) using HC1 salt of (lR,3S,5R)-N-(6- bromopyiidin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (8a) (65.6 mg, 0.197 mmol), HATU (94 mg, 0.247 mmol) DIPEA (106 mg, 0.822 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] ethyl 3-(4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoy l)- 5-methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrim ido[4,5-b]indol-6- yl)propanoate (190a) (78 mg, 76% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-de) δ 10.77 (s, 1H, D2O exchangeable), 8.80 - 8.54 (m, 3H, 2H D2O exchangeable), 8.46 - 8.36 (m, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.61 (d, J = 8.5 Hz,

1H), 7.45 (dd, J = 8.5, 1.5 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 5.70 (d, J = 17.3 Hz, 1H), 5.35 (d, J = 17.2 Hz, 1H), 4.37 (dd, J = 9.0, 6.0 Hz, 1H), 4.05 (q, J = 7.1 Hz, 2H), 3.69 (dd, J = 5.6, 2.4 Hz, 1H), 3.03 (t, J = 7.7 Hz, 2H), 2.75 (t, J = 7.7 Hz, 2H), 2.49 - 2.40 (m, 1H), 2.05 - 1.92 (m, 1H), 1.31 (s, 3H), 1.16 (t, J = 7.1 Hz, 3H), 1.01 (t, J = 5.5 Hz, 1H), 0.97 - 0.88 (m, 1H); MS (ES+): 620/622 (M+l), (ES-): 618/620 (M-l); Analysis calculated for C29H30BrN7O4.HCLl.5H2O: C, 50.92; H, 5.01; N, 14.33; Found: C, 50.82; H, 4.90; N, 14.05.

Scheme 191

189f 191a

Preparation of (lR,3S,5R)-2-(2-(4-amino-6,8-dimethyl-9H-pyrimido[4,5-b]indo l-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (191a)

Compound 191a was prepared according to the procedure reported in step-3 of scheme- 1, (75 mg, 0.195 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)- 5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (64.9 mg, 0.195 mmol), HATU (89 mg, 0.234 mmol), DIPEA (126 mg, 0.976 mmol)and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6,8-dimethyl-9H-pyrimido[4,5-b]indo l-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (191a) (63 mg, 59% yield) HC1 as a white solid; Ή NMR (300 MHz, DMSO-cfc) δ 10.80 (s, 1H, D2O exchangeable), 8.70 (s, 2H, D2O exchangeable), 8.61 (s, 1H), 8.16 (s, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 7.11 (s, 1H), 5.82 (d, J =

18.0 Hz, 1H), 5.55 (d, J = 17.9 Hz, 1H), 4.37 (dd, J = 9.0, 6.2 Hz, 1H), 3.69 - 3.67 (m, 1H), 2.63 (s, 3H), 2.48 - 2.33 (m, 4H), 1.97 (dd, J = 13.2, 6.1 Hz, 1H), 1.30 (s, 3H), 1.01 (t, J = 5.5 Hz, 1H), 0.83 (dd, J = 5.4, 2.3 Hz, 1H); MS (ES+) 548/550 (M+l), 546/548 (M-l); Analysis calculated for C26H26BrN7O2.HCl.2H2O: C, 50.29; H, 5.03; Cl, 5.71; N, 15.79; Found: C, 50.14; H, 4.95; Cl, 5.64; N, 15.56.

Scheme 192

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-bromo-8-methyl-9H-pyrimido[4,5-b] indol-9- yl)acetyl)-N -(6-bromopyridin-2-y l)-2-azabicyclo [3.1.0Jhexane-3-carboxamide (192g)

Step-1: Preparation of N-(2,4-dibromo-6-methylphenyl)-2,2,2-trifluoroacetamide (192b)

Compound 192b was prepared according to the procedure reported in step-1 of scheme-46, mL) using triethylamine (6.49 g, 64.2 mmol), trifluoroacetic acid anhydride (11.89 g, 56.6 mmol) and stirring at RT for 1 h. This gave after workup N-(2,4-dibromo-6-methylphenyl)- 2,2,2-trifluoroacetamide (192b) (13.29 g, 98% yield) as a purple solid; Ή NMR (300 MHz, DMSO-ifc) δ 11.30 (s, 1H), 7.88 (s, 1H), 7.66 (s, 1H), 2.21 (s, 3H); ¹⁹ FNMR(282 MHz, DMSO-ifc) δ -74.09; MS (ES-): 358/360 (M-l).

Step-2: Preparation of 2-amino-5-bromo-7-methyl-lH-indole-3-carbonitrile (192c)

Compound 192c was prepared according to the procedure reported in step-1 of scheme- 11, from N-(2,4-dibromo-6-methylphenyl)-2,2,2-trifluoroacetamide (192b) (13.29 g, 36.8 mmol) in DMSO (20 mL) using malononitrile (2.92 g, 44.2 mmol), L-proline (0.848 g, 7.36 mmol), Cul (0.701 g, 3.68 mmol), a solution of K2CO3 (10.18 g, 73.6 mmol) in water (30 mL) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification [SiOzgel (40 g), eluting with MeOH in DCM from 0-6%] 2-amino-5-bromo-7-methyl-lH- indole-3-cafbonitrile (192c) (5.54 g, 60% yield) as a deep green-black solid; Ή NMR (300 MHz, DMSO-cfe) δ 10.97 (s, 1H), 7.06 (d, J = 1.9 Hz, 1H), 6.89 (d, J = 1.9 Hz, 1H), 6.71 (s, 2H), 2.32 (s, 3H); MS (ES+): 250/252 (M+l); (ES-): 248/250 (M-l).

Step-3: Preparation of 6-bromo-8-methyl-9H-pyrimido[4,5-b]indol-4-amine (192d)

Compound 192d was prepared according to the procedure reported in step-2 of scheme-29, from 2-amino-5-bromo-7-methyl-lH-indole-3-carbonitrile (192c) (5.54 g, 22.15 mmol) in ethanol (10 mL) using trimethoxymethane (11.75 g. 111 mmol),NH40Ac (5.12 g, 66.5 mmol) and heating at 80 °C for 16 h. This gave after work up 6-bromo-8-methyl-9H- pyrimido[4,5-b]indol-4-amine (192d) (5.57 g, 91% yield) as a green solid; ΉΝΜΚ (300 MHz, DMSO-tifo) δ 12.01 (s, 1H), 8.40 (d, J = 1.8 Hz, 1H), 8.27 (s, 1H), 7.33 (dd, J = 1.9, 0.9 Hz, 1H), 7.26 (s, 2H), 2.50 (d, J = 2.2 Hz, 3H); MS (ES+): 277/279 (M+l), (ES-): 275/277 (M-l).

Step-4: Preparation of tert- butyl 2-(4-amino-6-bromo-8-methyl-9H-pyrimido[4,5-b]indol-9- yl)acetate (192e)

Compound 192e was prepared according to the procedure reported in step-1 of scheme- 1, from 6-bromo-8-methyl-9H-pyrimido[4,5-b]indol-4-amine (192d) (2.00 g, 7.22 mmol) in DMF (15 mL) using tort-butyl 2-bromoacetate (1.689 g, 8.66 mmol), CS2CO3 (4.70 g, 14.43 mmol) and stirring at RT for 16 h. This gave after work up and purification [S1O2 gel (40 g), eluting with methanol in DCM from 0-4%] tort-butyl 2-(4-amino-6-bromo-8-methyl-9H- MHz, DMSO-i/e) δ 8.47 (d,J= 1.9 Hz, 1H), 8.31 (s, 1H), 7.43 (s, 2H), 7.38 - 7.30 (m, 1H), 5.33 (s, 2H), 2.62 (s, 3H), 1.42 (s, 9H); MS (ES+): 391/393 (M+l), (ES-): 389/391 (M-l). Step-5 : Preparation of 2-(4-amino-6-bromo-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)ace tic acid (192f)

Compound 192f was prepared according to the procedure reported in step-2 of scheme-1, from tert-butyl 2-(4-amino-6-bromo-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)ace tate (192e) (300 mg, 0.767 mmol) using TFA (874 mg, 7.67 mmol) in DCM (15 mL) and stirring at RT for 16 h. This gave after work up TFA salt of 2-(4-amino-6-bromo-8-methyl-9H- pyrimido[4,5-b]indol-9-yl)acetic acid (192f) (0.357 g) as a pale-yellow solid; ^! HNMR (300 MHz, DMSO-ife) δ 8.62 (d, J= 1.9 Hz, 1H), 8.55 (s, 1H), 8.45 (s, 2H), 7.48 (d, J= 1.9 Hz, 1H), 5.42 (s, 2H), 2.67 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-i/e) δ -74.55; MS (ES+): 335/337 (M+l); (ES-): 333/335 (M-l).

Step-6: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-bromo-8-methyl-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1.0]hexane-3-carboxamide (192g)

Compound 192g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-bromo-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)ace tic acid (192f) (75 mg, 0.167 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (53.2 mg, 0.167 mmol), HATU (76 mg, 0.200 mmol), DIPEA (108 mg, 0.835 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6-bromo-8-methyl-9H-pyrimido[4,5-b] indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (192g) (83 mg, 83% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-i/e) δ 10.83 (s, 1H, DzO exchangeable), 8.76 (s, 2H, DzO exchangeable), 8.68 - 8.56 (m, 2H), 8.00 (d, J = 8.1 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.48 (d, J = 1.9 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 5.90 (d, J = 18.0 Hz, 1H), 5.63 (d, J = 17.9 Hz, 1H), 4.42 (dd, J = 9.0, 5.7 Hz, 1H), 3.91 (td, J = 5.4, 3.0 Hz, 1H), 2.69 (s, 3H), 2.41 - 2.29 (m, 1H), 2.26 - 2.10 (m, 1H), 2.00 - 1.83 (m, 1H), 1.18 - 0.97 (m, 1H), 0.75 - 0.60 (m, 1H); MS (ES+): 598/600 (M+l); (ES-): 596/598 (M-l); Analysis calculated for Cz^iBnNzOz.1. lHCl.1 ,75H ₂ 0: C, 42.96; H, 3.85; Cl, 5.81; N, Scheme 193

192f 193a

Preparation of (1 R,3S,5R)-2-(2-(4-amino-6-bromo-8-methyl-9H-pyrimido[4,5-b]in dol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-caiboxamide (193a)

Compound 193a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-bromo-8-methyl-9H-pyiimido[4,5-b]indol-9-yl)ace tic acid (192f) (75 mg, 0.167 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carb oxamide (8a) (55.5 mg, 0.167 mmol), HATU (76 mg, 0.200 mmol), DIPEA (108 mg, 0.835 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography (silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6-bromo-8-methyl-9H-pyrimido[4,5-b] indol- 9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3 .1 ,0]hexane-3-carboxamide (193a) (83 mg, 81% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-^e) δ 10.82 (s, 1H, DzO exchangeable), 8.60 (d, J = 1.9 Hz, 1H), 8.57 (s, 1H), 8.51 (s, 2H, DzO exchangeable), 8.01 (d, J = 8.2 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.45 (d, J = 1.8 Hz, 1H),

7.31 (d, J = 7.7 Hz, 1H), 5.84 (d, J = 18.0 Hz, 1H), 5.58 (d, J = 17.9 Hz, 1H), 4.37 (dd, J = 9.0, 6.1 Hz, 1H), 3.70 - 3.66 (m, 1H), 2.67 (s, 3H), 2.48 - 2.40 (m, 1H), 1.97 (dd, J = 13.2, 6.1 Hz, 1H), 1.30 (s, 3H), 1.01 (t, J = 5.5 Hz, 1H), 0.83 (dd, J = 5.4, 2.4 Hz, 1H); MS (ES+): 612/614 (M+l), (ES-): 610/612 (M-l); Analysis calculated for CzsHzaBrzNzOz.HCl.1 75HzO : C, 44.07; H, 4.07; Cl, 5.20; N, 14.39; Found: C, 44.02; H, 3.91; Cl, 5.46; N, 14.13.

Scheme 194

184f

194a

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyr imido[4,5- bJindol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1.0]hexane-3-carboxamide (194a)

Compound 194a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]in dol-9-yl)acetic acid (184f) (100 mg, 0.228 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (80 mg, 0.251 mmol), HATU (130 mg, 0.342 mmol), DIPEA (147 mg, 1.141 mmol)and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 2%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromcthyl)-9H-pyr imido[4,5-b]indol- 9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (194a) (33 mg, 25% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.83 (s, 1H, D ₂ 0 exchangeable), 8.78 (s, 1H), 8.59 (s, 1H), 8.50 (s, 2H, D2O exchangeable), 8.01 (d, J = 8.2 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.64 - 7.57 (m, 1H), 7.32 (d, J = 7.7 Hz, 1H), 5.96 (d, J = 18.0 Hz, 1H), 5.69 (d, J = 17.9 Hz, 1H), 4.43 (dd, J = 9.1, 5.6 Hz, 1H), 3.97 - 3.92 (m, 1H), 2.78 (s, 3H), 2.40 - 2.30 (m, 1H), 2.30 - 2.15 (m, 1H), 2.00 - 1.86 (m, 1H), 1.15 - 1.04 (m, 1H), 0.74 - 0.64 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-ds) δ -58.71; MS (ES+): 588/590 (M+l), (ES-): 586/588 (M-l).

Scheme 195

Preparation of ( lR,3S,5R)-2-(2-(4-amino-6-(hydrox _} onethyl)-9H-pyrimido[4,5-bjindol-9- yl)acet>'l)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (195e)

Step-1: Preparation of ethyl 2-(4-amino-6-(l,2-dihydroxyethyl)-9H-pyrimido[4,5-b]indol-9- yl)acetate (195a)

To a solution of ethyl 2-(4-amino-6-viny l-9H-pyrimido [4,5 -bj indol-9-y l)acetate (59a) (300 mg, 1.012 mmol) in acetonitrile (20 mL) and water (10 mL) was added 4-methylmorpholine 4-oxide (232 mg, 1.924 mmol) followed by osmium(VIII) oxide (4 % in water) (0.619 mL, 0.101 mmol) and stirred at RT for 22 h. Reaction mixture was quenched with 1 M aqueous Ν32$2θ3 solution (10 mL), diluted with water (50 mL), and extracted with ethyl acetate (100 mL, 2 x 75 mL). The combined organics were dried, filtered and concentrated in vacuum.

The residue obtained was purified by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM (from 0-10%)] to afford ethyl 2-(4-amino-6-( 1 ,2-dihydroxyethyl)-9H- pyrimido[4,5-b]indol-9-yl)acetate (195a) (122 mg, 37%) as a yellow solid; ^] HNMR (300 MHz, DMSOncfe) δ 8.29 - 8.24 (m, 2H), 7.51 (d, ./= 8.4 Hz, 1H), 7.44 - 7.38 (m, 1H), 7.25 (s, 2H), 5.27 - 5.15 (m, 3H), 4.75 - 4.64 (m, 2H), 4.13 (q ,J= 7.1 Hz, 2H), 3.55 (t ,J= 5.9 Hz, 2H), 1.20 (t ,J= 7.1 Hz, 3H).; MS (ES+): 331.15 (M+l); (ES-): 329.10 (M-l).

Step-2: Preparation of ethyl 2-(4-amino-6-formyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (195b)

To a solution of ethyl 2-(4-amino-6-(l,2-dihydroxyethyl)-9H-pyrimrdo[4,5-b]indol-9- sodium periodate (152 mg, 0.708 mmol) and stirred at RT for 1 h. The reaction mixture was diluted with ethyl acetate (100 mL), water (50 mL), 1 M aqueous Ν32$2θ3 solution (1 mL) and filtered. The filtrate was separated washed with brine (50 mL), dried, filtered and concentrated in vacuum to afford ethyl 2-(4-amino-6-formyl-9H-pyrimido[4,5-b]indol-9- yl)acetate (195b) as an off-white solid (101 mg) which was used as such for next step; *H NMR (300 MHz, DMSO-ifc) δ 10.06 (s, 1H), 9.00 (d,J= l .5 Hz, 1H), 8.35 (s, 1H), 7.96 (dd, J= 8.6, 1.5 Hz, 1H), 7.81 (d ,J= 8.5 Hz, 1H), 7.58 (s, 2H), 5.32 (s, 2H), 4.15 (q,J= 7.1 Hz, 2H), 1.20 (t, J= 7.1 Hz, 3H); MS (ES+): 299.10 (M+l).

Step-3: Preparation of methyl/ethyl 2-(4-amino-6-(hydroxymethyl)-9H-pyrimido[4,5-bJindol- 9-yl)acetate (195c)

Compound 195c was prepared according to the procedure reported in scheme-157, from ethyl 2-(4-amino-6-formyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (195b) (0.106 g, 0.354 mmol) in THF (10 mL) and MeOH (5 mL) using sodium borohydride (0.027 g, 0.708 mmol) and stirring at RT for 2 h. This gave after work up a mixture of methyl/ethyl 2-(4-amino-6- (hydroxymethyl)-9H-pyrimido [4,5 -b] indol-9-yl)acetate (195c) as a white sohd (90 mg) which was used as such for the next step; MS (ES+): 301.10 & 287.10 (M+l).

Step-4: Preparation of 2-(4-amino-6-(hydroxymethyl)-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (195d)

Compound 195d was prepared according to the procedure reported in step-4 of scheme- 17, from a mixture of methyl/ethyl 2-(4-amino-6-(hydroxymcthy l)-9H-pyri mi do [4,5 -b] i ndol-9- yl)acetate (195c) (90 mg, 0.3 mmol) in THF (5 mL) and MeOH (5 mL) using a solution of lithium hydroxide hydrate (77 mg, 1.798 mmol) in water (5 mL) and stirring at RT for 20 h. This gave after work up 2-(4-amino-6-(hydroxymethyl)-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (195d) which was used as such for the next step; MS (ES+): 272.80 (M+l).

Step-5: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(hydroxymethyl)-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1.0]hexane-3-catboxamide (195e)

Compound 195e was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-6-(hydroxymethy 1 )-9H-pyrimido [4,5 -b] indol -9-yl)acetic acid (195d) (82 mg, 0.3 mmol) in DMF (12 mL) using HC1 salt of ( lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3 1 0jhexane 3 carboxamide (4a) (143 mg 0450 mmol) HATU (228 mg 0600 mmol), DIPEA (0.261 mL, 1.500 mmol) and stirring at RT for 15 h. This gave after workup and purification using reverse phase column chromatography [Cl 8 column, eluting with ACN in water (containing 0.1% HC1) from 0-100%] ( 1R,3 S,5R)-2-(2-(4-amino-6- (hydroxymethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-br omopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (195e) (33 mg, 21% yield) HC1 salt as a white solid; ¾ NMR (300 MHz, DMSO-flk) δ 10.76 (s, 1H), 8.58 (s, 1H), 8.52 (s, 3H), 8.44 (s, 1H), 8.00 (d, J= 8.2 Hz, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.65 (d,J= 8.7 Hz, 1H), 7.58 - 7.51 (m, 1H), 7.31 (d, J= 7.7 Hz, 1H), 5.75 (d, J= 17.3 Hz, 1H), 5.41 (d, J= 17.2 Hz, 1H), 4.66 (s, 2H), 4.41 (dd, J= 9.1, 5.6 Hz, 1H), 3.96 - 3.86 (m, 1H), 2.41 - 2.13 (m, 2H), 2.01 - 1.79 (m, 1H), 1.14 - 0.99 (m, 1H), 0.87 - 0.59 (m, 1H); MS (ES+): 536.10 & 538.10 (M+l); MS (ES-): 534.10 & 536.10 (M-l); Analysis calculated for CatHarBrNrOs.1 0HC1.2.75H2O: C, 46.31; H, 4.62; N, 15.75; Found: C, 46.28; H, 4.29; N, 15.40.

Scheme 196

N HATU, DIPEA

•O

NH ₂ f ^N x_n

HN N¾

'CH ₃ O

NH ₂

HN

196c 196d "CH ₃

Preparation of 4-amino-9-(2-(( lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-5-methyl-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-N-methyl-9H-pyrimid o[4,5-b]indole-6- carboxamide (196d)

Step-1: Preparation of4-arnino-N-methyl-9H-pyrirnido[4,5-b]indole-6-carboxarnide (196a) Compound 196a was prepared according to the procedure reported in scheme- 119, from 4- amino-9H-pyrimido [4,5 -b] indole -6-carboxylic acid (169a) (200 mg, 0.876 mmol) in DMSO (12 mL) using methanamine hydrochloride (178 mg, 2.63 mmol; CAS # 593-51-1), HOBT (59.2 mg, 0.438 mmol), EDC (336 mg, 1.753 mmol), DIPEA (0.458 mL, 2.63 mmol) and stirring at RT for 20 h. The residue obtained after work up of 4-amino-N-methyl-9H- pyrimido[4,5-b]indole-6-carboxamide (196a) was used as such for the next step; MS (ES+): 241.90 (M+l); (ES-): 239.85 (M-l).

Step-2: Preparation of te/7-butyl 2-(4-amino-6-(methylcarbamoyl)-9H-pyrimido[4,5-b]indol- 9-yl)acetate (196b)

Compound 196b was prepared according to the procedure reported in step-1 of scheme- 1, from 4-amino-N -methyl -9H-pyri mi do [4,5 -b] i ndole-6-carboxam ide (196a) (211 mg, 0.876 mmol) in DMF using /erf-butyl 2-bromoacetate, CS2CO3 and stirring at RT. This gave after workup te/7-butyl 2-(4-amino-6-(methylcarbamoyl)-9H-pyrimido[4,5-b]indol-9-yl) acetate (196b) which was used as such in the next step; MS (ES+): 356.20 (M+l); (ES-): 354.10 (M-

1).

Step-3: Preparation of 2-(4-amino-6-(methylcarbamoyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (196c)

Compound 196c was prepared according to the procedure reported in step-2 of scheme- 1, from tert-butyl 2-(4-amino-6-(methylcarbamoyl)-9H-pyrimido[4,5-b]indol-9-yl) acetate (196b) (311 mg, 0.876 mmol) in DCM ( 10 mL) using TFA and stirring at RT. This gave after workup 2-(4-amino-6-(methylcarbamoyl)-9H-pyiimido[4,5-b]indol-9-yl) acetic acid (196c) which was used as such in the next step; MS (ES+): 300.10 (M+l); (ES-): 298.05 (M-l).

Step-4: Preparation of 4-amino-9-(2-(( 1 R,3 S,5R)-3 -((6-bromopyridin-2-yl)carbamoy l)-5- methyl-2-azabicyclo[3.1.0Jhexan-2-yl)-2-oxoethyl)-N-methyl-9 H-pyrimido[4,5-b]indole-6- carboxamide (196d)

Compound 196d was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-6-(me1hylcarbamoyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (196c) (131 mg, 0.438 mmol) in DMF (12 mL) using HC1 salt of ( lR,3S,5R)-N-(6-bromopyridin-2-yl)-5- methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (146 mg, 0.438 mmol), HATU (333 mg, 0.876 mmol) DIPEA (0.381 mL, 2.190 mmol) and stirring at RT for 21 h. This gave after MeOH in DCM from 0 - 10%] followed by purification using reverse phase column chromatography [C18 column eluting with ACN in water (containing 0.1% HC1) from 0- 100%] 4-ammo-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-y])carbamoy])-5 -methyl-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-N-methyl-9H-pyrimid o[4,5-b]indole-6- carboxamide (196d) (19 mg, 7.5% yield) as a white solid; Ή NMR (300 MHz, DMSO-i/e) δ 10.77 (s, 1H), 9.05 (s, 1H), 8.58 (s, 1H), 8.51 - 8.35 (m, 4H), 8.05 - 7.96 (m, 2H), 7.76 - 7.65 (m, 2H), 7.31 (d, J= 7.7 Hz, 1H), 5.73 (d ,J= 17.4 Hz, 1H), 5.37 (d,J= 17.3 Hz, 1H), 4.37 (dd, J= 9.1, 5.8 Hz, 1H), 3.72 - 3.64 (m, 1H), 2.86 (d, J= 4.4 Hz, 3H), 2.58 - 2.38 (m, 1H), 1.98 (dd, 13.2, 5.9 Hz, 1H), 1.30 (s, 3H), 1.09 - 0.97 (m, 1H), 0.96 - 0.90 (m, 1H); MS (ES+): 577.15 & 579.20 (M+l); MS (ES-): 575.10 & 577.10 (M-l).

Scheme 197

197b 197c

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(o-tolyl)-9H-pyrimido[4,5-b]indol -9-yl)acetyl)- N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (197c)

Step-1: Preparation of ethyl 2-(4-amino-6-(o-tolyl)-9H-pyrimido[4,5-b]indol-9-yl)acetate (197a) Compound 197a was prepared according to the procedure reported in step-1 of scheme-59, from ethyl 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (48a) (150 mg, 0.430 mmol) in dioxane (15 mL) using o-tolylboronic acid (88 mg, 0.644 mmol; CAS # 16419-60- 6), bis(triphenylphosphine)palladium(ll) chloride (60.3 mg, 0.086 mmol) a solution of cesium carbonate (210 mg, 0.644 mmol) in water (1.8 mL) and heating at 100 °C for 17 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0-5%] ethyl 2-(4-amino-6-(o-tolyl)-9H-pyrimido[4,5-b]indol-9- yl)acetate (197a) (70 mg, 45% yield) as an off-white solid; MS (ES+): 361.20 (M+l).

Step-2: Preparation of 2-(4-amino-6-(o-tolyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (197b)

Compound 197b was prepared according to the procedure reported in step-4 of scheme- 17, from ethyl 2-(4-amino-6-(o-tolyl)-9H-pyrimido[4,5-b]indol-9-yl)acetate (197a) (64 mg, 0.178 mmol) in THE (3 mL) and methanol (3 mL) using a solution of lithium hydroxide hydrate (45.6 mg, 1.065 mmol) in water (3 mL) and stirring at RT for 14 h. This gave after workup 2-(4-amino-6-(o-tolyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (197b) which was used as such for the next step; MS (ES+): 333.15 (M+l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(o-tolyl)-9H-pyrimido[4,5-b]indol -9- yl)acetyl)-N-(6-bromopyiidin-2-yI)-2-azabicycIo[3.1 ,0]hexane-3-carboxamide (197c)

Compound 197c was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-6-(o-tolyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (197b) (59.2 mg,

0.178 mmol) in DMF (8 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0jhexane-3-carboxamide (4a) (85 mg, 0.267 mmol), HATH (169 mg, 0.445 mmol), DIPEA (0.186 mL, 1.068 mmol) and stirring at RT for 19 h. This gave after workup and purification by flash column chromatography [silica gel (25 g), MeOH in DCM from 0 - 10%] followed by purification using reverse phase column chromatography [Cl 8 column, eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino- 6-(o-tolyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromop yridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (197c) (23 mg, 22% yield) as a white solid; 'HNMR (300 MHz, DMSO-tik) δ 10.79 (s, 1H), 8.61 (s, 1H), 8.52 - 8.50 (m, 2H), 8.02 (d ,J= 8.2 Hz, 1H), 7.78 - 7.66 (m, 2H), 7.52 (dd,J= 8.4, 1.5 Hz, 1H), 7.38 - 7.26 (m, 6H), 5.81 (d ,J=

17.4 Hz, 1H), 5.45 (d, J= 17.2 Hz, 1H), 4.44 (dd, J= 9.1, 5.5 Hz, 1H), 4.01 - 3.84 (m, 1H), 2.46 - 2.14 (m, 5H), 2.02 - 1.83 (m, 1H), 1.17 - 1.03 (m, 1H), 0.89 - 0.72 (m, 1H); MS (ES+): 596.15 & 598.15; (ES-): 594.10 & 596.10 (M-l).

Scheme 198

51f 198a

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-fluoro-9H-pyrimido[4,5-b]indol-9- yl)acet _j '])-N- (6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-c arboxamide (198a)

Compound 198a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-fluoro-9H-pyrimido[4,5-b]indol-9-yI)acetic acid (51f) (50 mg, 0.134 mmol) in DMF (1.5 mL) using HC1 salt of ( lR,3S,5R)-N-(6-bromopyridin-2-yl)-5- methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (44.4 mg, 0.134 mmol), HATU (76 mg, 0.200 mmol), DIPEA (0.116 mL, 1.068 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-8-fhxoro-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carb oxamide (198a) (48 mg, 67% yield) HC1 salt as a white solid; . Ή NMR (300 MHz, DMSO-tfc) δ 10.78 (s, 1H, DzO exchangeable), 8.58 (s, 1H), 8.40 (s, 2H, DzO exchangeable), 8.30 (dd, J= 5.9, 3.0 Hz, 1H), 8.02 (d, J= 8.1 Hz, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.38 - 7.29 (m, 3H), 5.75 (d, J= 17.5 Hz, 1H), 5.41 (d, J= 17.5 Hz, 1H), 4.39 (dd, J= 9.0, 6.0 Hz, 1H), 3.66 (dd, J = 5.4, 2.3 Hz, 1H), 2.47 - 2.41 (m, 1H), 1.99 (dd,J= 13.3, 5.9 Hz, 1H), 1.30 (s, 3H), 1.03 (t, J= 5.4 Hz, 1H), 0.86 - 0.71 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO) δ -134.67. MS (ES+): 538.1 (M+l); (ES-): 536.1 (M-l); Analysis calculated for Cz4HziBrFN ₇ 0z.1 75HzO.HCl: C, 47.54; H, 4.24; Cl, Scheme 199

CF ₃

16d NH ₂

199a

Preparation of (lR,3S,5R)-2-(2-(4-amino-7-(trifluoromethyl)-9H-pyrimido[4,5 -b]indol-9- yl)acet}'l)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3. 1 ,0]hexane-3-carboxamide (199a)

Compound 199a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-7-(trifluoromethyl)-9H-pyrimido[4,5-b]mdol-9-yl)a cetic acid (16d) (50 mg, 0.118 mmol) in DMF (1.5 ml) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-caiboxamide (8a) (39.2 mg, 0.118 mmol), HATU (67.2 mg, 0.177 mmol), DIPEA (0.103 mL, 0.589 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-( 2-(4-amino-7 -(trifluoromcthyl)-9H-pyri mi do [4,5 - b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azab icyclo[3.1 ,0]hexane-3- carboxamide (199a) HC1 salt (50 mg, 72% yield) HC1 salt as a white solid; ^l H NMR (300 MHz, DMSO-tife) δ 10.77 (s, 1H, DzO exchangeable), 8.84 - 8.69 (m, 3H, 2H DzO exchangeable), 8.66 (s, 1H), 8.18 (s, 1H), 8.00 (d, J= 8.1 Hz, 1H), 7.79 - 7.61 (m, 2H), 7.31 (d, J= 7.6 Hz, 1H), 5.85 (d, J= 17.4 Hz, 1H), 5.46 (d, J= 17.3 Hz, 1H), 4.38 (dd, J= 9.0, 5.9 Hz, 1H), 3.69 (dd, J= 5.6, 2.4 Hz, 1H), 2.48 - 2.40 (m, 1H), 1.99 (dd, J= 13.2, 5.9 Hz, 1H), 1.32 (s, 3H), 1.03 (t, J= 5.4 Hz, 1H), 0.92 (dd, J= 5.4, 2.4 Hz, 1H). ¹⁹ FNMR(282 MHz, DMSO) δ -59.34. MS (ES+): 588.1(M+1); (ES-): 586.1 (M-l); Analysis calculated for Cz5Hz1BrF3N7Oz.2HzO.HCl: C, 45.44; H, 3.97; Cl, 5.36; N, 14.84; Found: C, 45.44; H, 3.85; Cl, 5.30; N, 14.74.

Preparation of (lR,3S,5R)-2-(2-(4-arnino-7-bromo-9H-pyrirnido[4,5-b]indol-9 -yl)acetyl)-N- (6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-c arboxamide (200a)

Compound 200a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-7-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (52e) (60 mg, 0.138 mmol) in DMF (1.5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-5- methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (8a) (45.9 mg, 0.138 mmol), HATU (79 mg, 0.207 mmol), DIPEA (0.120 mL, 0.689 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-7-bromo-9H-pyrimido[4,5-b]indol-9-y l)acet>'l)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carb oxamide (200a) (59 mg, 71% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-de) δ 10.78 (s, 1H, DzO exchangeable), 8.67 - 8.50 (m, 3H, 2H DzO exchangeable), 8.46 (d, J= 8.5 Hz, 1H), 8.06 - 7.95 (m, 2H), 7.70 (t, J= 8.0 Hz, 1H), 7.57 (dd, J= 8.4, 1.7 Hz, 1H), 7.32 (d, J= 7.7 Hz,

1H), 5.73 (d, 17.4 Hz, 1H), 5.36 (d ,J= 17.3 Hz, 1H), 4.38 (dd,J= 9.1, 6.0 Hz, 1H), 3.67

(dd, J= 5.6, 2.4 Hz, 1H), 2.48 - 2.42 (m, 1H), 1.98 (dd, J = 13.3, 5.9 Hz, 1H), 1.31 (s, 3H), 1.02 (t, J= 5.6 Hz, 1H), 0.94 (dd, J= 5.3, 2.4 Hz, 1H). MS (ES+): 598.0/600.1 (M+l); (ES-): 596/598.0 (M-l); Analysis calculated for Cz^iBnNzOz 2HzO.HCl: C, 42.91; H, 3.90; Cl, 5.28; N, 14.60; Found: C, 43.02; H, 3.69; Cl, 5.09; N, 14.47.

Scheme 201

Preparation of (2S,4R)-4-amino-l-(2-(4-amino-6-(trifluorotne1hyl)-9H-pyrimi do[4,5-b]indol- 9-yl)acet>'l)-N-(6-bromopyridin-2-yl)pyrrolidine-2-carbox amide (201e)

Step-1: Preparation of (2S,4R)-te/t-butyl 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2- ((6-bromopyridin-2-yl)carbamoyl)pyrrolidine- 1-carboxylate (201b)

Compound 201b was prepared according to the procedure reported in step-1 of scheme-53, from (2S,4R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-l-(ter t- butoxycarbonyl)pyrrolidine-2-carboxylic acid (201a) (1 g, 2.210 mmol; CAS # 176486-63-8) in DCM (30 mL) using 1 -methyl- lH-imidazole (0.440 mL, 5.52 mmol), methanesulfonyl chloride (0.205 mL, 2.65 mmol) and 6-bromopyridin-2-amine (0.382 g, 2.210 mmol) and stirring atRT for 18 h. This gave after workup (2S,4R)-tert-butyl 4-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-2-((6-bromopyridin-2-yl)carbamoyl )p>Trolidine-l-carboxylate (201b) (1.22 g, 91% yield); MS (ES+): 607.60 (M+l).

Step-2: Preparation of (9H-fluoren-9-yl)methyl ((3R5S)-5-((6-bromopyridin-2- yl)carbamoyl)pyrrohdin-3-yl)carbamate (201c)

Compound 201c was prepared according to the procedure reported in step-2 of scheme- 1, from (2S,4R)-terf-butyl 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-((6-bromopyr idin- 2-yl)carbamoyl)pyrrolidine- 1-carboxylate (201b) (1.2 g, 1.975 mmol) in DCM (11 mL) using TFA (1 065 mL 13 83 mmol) and stirring overnight at RT This gave after workup and purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] HC1 salt of (9H-fluoren-9-yl)methyl ((3R,5S)-5-((6-bromopyridin-2-yl)carbamoyl)pyrrolidin-3-yl)c arbamate (201c) (720 mg, 67% yield); Ή NMR (300 MHz, DMSO-i/e) δ 11.47 (s, 1H), 10.15 (s, 1H), 8.94 (s, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.99 - 7.62 (m, 6H), 7.39 (dt, J= 25.2, 7.3 Hz, 5H), 4.63 - 4.51 (m, 1H), 4.46 - 4.31 (m, 2H), 4.31 - 4.14 (m, 2H), 3.52 (dd,J= 11.7, 6.9 Hz, 1H), 3.14 (dd, J= 12.1, 5.6 Hz, 1H), 2.36 (t, J= 6.7 Hz, 1H), 2.23 (dt, J= 13.9, 7.2 Hz, 1H); MS (ES+): 507.10 (M+l).

Step-3: Preparation of (9H-fluoren-9-yl)methyl ((3R,5S)-l-(2-(4-amino-6-(trifluoromethyl)- 9H-pyrintido[4,5-b]indol-9-yl)acetyl)-5-((6-bromopyridin-2-y l)caibamoyl)pyrrolidin-3- yl)carbamate (201 d)

Compound 201 d was prepared according to the procedure reported in step-3 of scheme- 1, from HC1 salt of (9H-fluoren-9-yl)methyl ((3R,5S)-5-((6-bromopyridm-2- yl)carbamoyl)pyrrolidin-3-yl)carbamate (201c) (120 mg, 0.221 mmol) in DMF (3 mL) using TFA salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-bJindol-9-yl) acetic acid (lie) (94 mg, 0.221 mmol), HATU (126 mg, 0.331 mmol), DIPEA (0.192 mL, 1.103 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatograph)' [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 50%] (9H-fluoren- 9-yl)methyl ((3R,5S)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b ]indol-9- yl)acetyl)-5-((6-bromopyridin-2-yl)carbamoyl)pyrrolidin-3-yl )carbamate (201 d) (173 mg, 98% yield) as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.88 (s, 1H), 8.79 (s, 1H), 8.34 (s, 1H), 8.01 (d, J= 8.2 Hz, 1H), 7.92 (d,7= 7.4 Hz, 2H), 7.77 - 7.64 (m, 5H), 7.55 (s, 2H), 7.38 (ddd, J= 27.2, 13.4, 7.5 Hz, 6H), 5.34 (s, 2H), 4.55 (s, 1H), 4.43 (d, J= 6.7 Hz, 2H), 4.28 (d, ./= 6.7 Hz, 1H), 4.17 (d, J= 9.2 Hz, 1H), 3.61 (s, 1H), 3.22 - 3.02 (m, OH),

2.24 (d, J= 19.2 Hz, 1H), 2.09 (d, J= 6.0 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO-cfe) δ -58.18. Step-4: Preparation of (2S,4R)-4-ammo-l-(2-(4-amino-6-(trifhioromethyl)-9H-pyrimido [4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)pyrrolidine-2-ca rboxamide (201 e)

Compound 201e was prepared according to the procedure reported in step-4 of scheme- 180, from (9H-fluoren-9-yl)methyl ((3R,5S)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-5-((6-bromopyridin-2-yl)carbamoyl)pyrro lidin-3-yl)carbaniate (201d) (170 mg, 0.213 mmol) in DMF (0.8 mL) using piperidine (0.210 mL, 2.126 mmol) and stirring at RT for 1 h This gave after work up and purification using flash column by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)-4-amino-l-(2-(4-amino-6- (trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6- bromopyridin-2-yl)pyrrolidine- 2-carboxamide (201 e) (59 mg, 48% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ (a mixture of two rotamers) 11.50 and 11.04 (2s, 1H, D2O exchangeable), 9.02 (s, 1H), 8.91 (s, 2H, D2O exchangeable), 8.69 (m, 4H, 3H D2O exchangeable), 8.21 - 7.96 (m, 2H), 7.89 - 7.81 (m, 1H), 7.71 (t,J= 8.0 Hz, 1H), 7.43 and 7.34 (2d, J= 7.7 Hz, 1H), 5.63-5.49 (m, 2H), 4.70 (dd,./= 8.5, 6.0 Hz, 1H), 4.21 (dd,J= 11.2, 6.2 Hz, 1H), 4.13 - 3.97 (m, 2H), 2.48 (m, 1H), 2.27 (dt, J= 13.1, 6.1 Hz, 1H). ¹⁹ F NMR (282 MHz, DMSO-cfc) δ - 58.58. MS (ES+): 577.1 (M+l); (ES-): 575.1 (M-l); Analysis calculated for C23H2oBrF ₃ N ₈ 02 1.25H20.1.9HC1.0.5DMSO: C, 40.70; H, 3.90; Cl, 9.51; N, 15.82; Found: C, 40.41; H, 3.65; Cl, 9.32; N, 15.85.

Scheme 202

188f

202a

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-nitro-9H-pyrimido[4,5-b]indol-9-y l)acetyl)-N-(6- bromopyridin-2-yI)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (202a)

Compound 202a was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-6-nitro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (188f) (91 mg, 0.317 mmol) in DMF (12 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-5-methyl-2- azabicyclo[3.1.0]hexane-3-caiboxamide (8a) (105 mg, 0.317 mmol), HATU (241 mg, 0.634 mmol) and DIPEA (0.276 mL, 1.585 mmol) and stirring at RT for 13 h. This gave after workup and purification using reverse phase column chromatography [Cl 8 column, eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6-nitro- 9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl) -5-methyl-2- bi l [3 1 0]h 3 b id (202 ) (42 23% i ld) hi lid ^! HNMR (300 MHz, DMSO-ifc) δ 10.77 (s, 1H), 9.52 (d ,J= 2.2 Hz, 1H), 8.72 (s, 2H), 8.63 (s, 1H), 8.40 (dd, J = 9.1, 2.2 Hz, 1H), 8.00 (d, J= 8.2 Hz, 1H), 7.87 (d, J= 9.1 Hz, 1H), 7.69 (t ,J= 8.0 Hz, 1H), 7.31 (d,J= 7.7 Hz, 1H), 5.79 (d, J= 17.4 Hz, 1H), 5.43 (d, J= 17.3 Hz, 1H), 4.37 (dd, ./= 9.0, 6.0 Hz, 1H), 3.68 (dd, J= 5.6, 2.4 Hz, 1H), 2.50 - 2.42 (m, 1H), 1.98 (dd, J = 13.2, 5.9 Hz, 1H), 1.31 (s, 3H), 1.02 (t ,J= 5.4 Hz, 1H), 0.95 (dd, J= 5.4, 2.4 Hz, 1H); MS (ES+): 565.10 & 567.10 (M +1); MS (ES-): 563.10 & 565.00 (M -1); Analysis calculated for C24H2iBrN ₈ 04.0.85HC1.2.0H20: C, 45.58; H, 4.12; N, 17.72; Cl, 4.77; Found: C, 45.65; H, 3.97; N, 17.42.; Cl, 4.59.

Scheme 203

60b 203a

Preparation of 4-amino-9-(2-(( 1 R,3 S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-5-methyl-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]i ndole-6-carboxamide (203a)

Compound 203a was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-6-carbamoyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (60b) (0.079 g, 0.278 mmol) in DMF (10 mL) using HC1 salt of ( 1 R,3 S,5R)-N-(6-bromopyridin-2-yl)-5- methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (8a) (111 mg, 0.334 mmol), HATU (211 mg, 0.556 mmol), DIPEA (0.242 mL, 1.39 mmol) and stirring at RT for 22 h. This gave after workup and purification using reverse phase column chromatography [Cl 8 column , eluting with ACN in water (containing 0.1% HC1) from 0-100%] 4-amino-9-(2-(( 1 R,3 S,5R)-3-((6- bromopyridin-2-yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hex an-2-yl)-2-oxoethyl)-9H- pyrimido[4,5-b]indole-6-carboxamide (203a) (42 mg, 27% yield) as a white solid; *H NMR (300 MHz, DMSCM,) δ 10.77 (s, 1H), 9.14 (d, J= 1.6 Hz, 1H), 8.66 (s, 3H), 8.62 (s, 1H), 8.07 (dd, ./= 8.7, 1.5 Hz, 1H), 8.01 (d, J= 8.2 Hz, 1H), 7.96 (s, 1H), 7.76 - 7.64 (m, 2H), 748 (s 1H) 731 (d J= 77 Hz 1H) 5 75 (d J= 174 Hz 1H) 5 38 (d J= 173 Hz 1H) 5.8 Hz, 1H), 1.30 (s, 3H), 1.07 - 0.97 (m, 1H), 0.96 - 0.89 (m, 1H); MS (ES+): 563.20 & 565.10 (M+l); MS (ES-): 561.10 & 563.10 (M-l); Analysis calculated for C2sH23BrN ₈ O3.1.0HC1.2.75H2O: C, 46.24; H, 4.58; N, 17.25; Found: C, 46.38; H, 4.51; N, 16.99.

Scheme 204

Preparation of 4-amino-9-(2-(( lR,3S,5R)-3-((6-bromopyiidin-2-yl)carbamoyl)-2- azabicyclo[3.1 0]hexan-2-yl)-2-oxoethyl)-N-methyl-9H-pyrimido[4,5-b]indole- 6- carboxamide (204a)

Compound 204a was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-6-(me1hylcarbamoyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (196c) (0.131 g, 0.438 mmol) in DMF (12 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2- yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (4a) (167 mg, 0.526 mmol), HATU (333 mg, 0.876 mmol), DIPEA (0.381 mL, 2.19 mmol) and stirring at RT for 21 h. This gave after workup and purification by flash column chromatography [silica gel (40 g), eluting with MeOH in DCM from 0 - 8% then 15%] followed by purification using reverse phase column chromatography [C18 column, eluting with ACN in water (containing 0.1% HC1) from 0- 100%] 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-N-methyl-9H-pyrimid o[4,5-b]indole-6- carboxamide (204a) (12 mg, 5% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-flfe) δ 10.77 (s, 1H), 9.13 (s, 1H), 8.66 (s, 2H), 8.62 (s, 1H), 8.55 - 8.44 (m, 1H), 8.06 - 7.95 (m, 2H), 7.78 - 7.66 (m, 2H), 7.31 (d,J= 7.7 Hz, 1H), 5.79 (d ,J= 17.3 Hz, 1H), 5.43 (d,J= 17.3 Hz, 1H), 4.42 (dd, .7= 9.1, 5.4 Hz, 1H), 3.98 - 3.83 (m, 1H), 2.86 (d, .7= 4.4 Hz, 3H) 241 - 2 14 (m 2H) 201 - 1 82 (m 1H) 1 17 - 094 (m 1H) 087 - 060 (m 1H); MS Scheme 205

CH ₃

205b 205c

Preparation of (lR,3S,5R)-2-(2-(4-ammo-6-(p-tolyl)-9H-pyrimido[4,5-b]indol- 9-yl)acetyl)- N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxam ide (205c)

Step-1: Preparation of ethyl 2-(4-amino-6-(p-tolyl)-9H-pyrimido[4,5-b]indol-9-yl)acetate (205a)

Compound 205a was prepared according to the procedure reported in step-1 of scheme-62, from ethyl 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (48a) (200 mg, 0.573 mmol) in dioxane (18 rtiL) using /J-tolylboronic acid (117 mg, 0.859 mmol; CAS # 16419-60- 6), bis(triphenylphosphine)palladium(n) chloride (80 mg, 0.115 mmol) a solution of cesium carbonate (280 mg, 0.859 mmol) in water (2.2 mL) and heating at 100 °C for 13 h. This gave after workup and purification by flash column chromatography [silica gel (25 g), eluting with MeOH in DCM from 0-5%] ethyl 2-(4-amino-6-(p-tolyl)-9H-pyrimido[4,5-b]indol-9- yl)acetate (205a) (52 mg, 25% yield) as an off-white solid; 1H NMR (300 MHz, DMSO-i/6) δ 8.62 (d, 1.6 Hz, 1H), 8.29 (s, 1H), 7.76 (d, J= 8.0 Hz, 2H), 7.71 (dd, 8.6, 1.6 Hz,

1H), 7.65 (d, J= 8.5 Hz, 1H), 7.44 (s, 2H), 7.29 (d, J= 7.9 Hz, 2H), 5.26 (s, 2H), 4.15 (q,J= Step-2: Preparation of 2-(4-amino-6-(p-tolyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (205b)

Compound 205b was prepared according to the procedure reported in step-4 of scheme- 17, from ethyl 2-(4-amino-6-(p-tolyl)-9H-pyrimido[4,5-b]indol-9-yl)acetate (205a) (50 mg, 0.139 mmol) in THF (3 mL) and methanol (3 mL) using a solution of lithium hydroxide hydrate (35.6 mg, 0.832 mmol) in water (3 mL) and stirring at RT for 18 h. This gave after workup 2-(4-amino-6-(p-tolyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (205b) which was used as such for the next step; MS (ES+): 333.10 (M+l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(p-tolyl)-9H-pyrimido[4,5-b]indol -9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (205c)

Compound 205c was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-6-(p-tolyl)-9H-pyrimido[4,5-b]mdol-9-yl)acetic acid (205b) (46 mg, 0.139 mmol) in DMF (8 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (4a) (66.4 mg, 0.209 mmol), HATU (106 mg, 0.278 mmol), DIPEA (0.121 mL, 0.695 mmol) and stirring at RT for 14 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 5%] followed by purification using reverse phase column chromatography [C18 column, eluting with ACN in water (containing 0.1% HC1) from 0-100%] (1R,3S,5R)- 2-(2-(4-amino-6-(p-tolyl)-9H-pyrimido[4,5-b]indol-9-yl)acety l)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (205c) (42 mg, 51% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfc) δ 10.77 (s, 1H), 8.77 (d, J= 1.6 Hz, 1H), 8.70 (s, 2H), 8.62 (s, 1H), 8.01 (d, J= 8.2 Hz, 1H), 7.86 (dd, J= 8.6, 1.6 Hz, 1H), 7.78 - 7.65 (m, 4H), 7.34 - 7.29 (m, 3H), 5.78 (d, J= 17.3 Hz, 1H), 5.44 (d, J= 17.3 Hz, 1H), 4.42 (dd, J= 9.0, 5.5 Hz, 1H), 4.01 - 3.84 (m, 1H), 2.40 - 2.29 (m, 4H), 2.28 - 2.13 (m, 1H), 2.01 - 1.85 (m, 1H), 1.16 - 1.02 (m, 1H), 0.84 - 0.73 (m, 1H); MS (ES+): 596.20 & 598.10 (M+l), MS (ES-): 594.10 & 596.10 (M-l); Analysis calculated for C3aH26BrN ₇ 02.HC1.2.25H20: C, 53.50; H, 4.71; N, 14.56; Cl, 5.26; Found: C, 53.68; H, 4.56; N, 14.58.; Cl, 5.07.

Scheme 206 = Έ iV " TFA

Boc 5 Cr Boc o II Try»

121a \ o 206a

206b

206c

Preparation of (2S,4R)- l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-4-methylpyrrolidine-2-car boxamide (206c)

Step-1: Preparation of (2S,4R)-terf-butyl 2-((6-bromopyridin-2-yl)carbamoyl)-4- methylpyrrohdine- 1 -carboxylate (206a)

Compound 206a was prepared according to the procedure reported in step-1 of scheme-53, from (2S,4R)-l-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carbox ylic acid (121a) (0.5 g, 2.181 mmol) in DCM (15 mL) using 1 -methyl - 1 H-imidazole (0.435 mL, 5.45 mmol), methanesulfonyl chloride (0.203 mL, 2.62 mmol), 6-bromopyridin-2-amine (0.377 g, 2.181 mmol) and stirring at RT for 18 h. This gave after workup (2S,4R)-tert-butyl 2-((6- bromopyridin-2-yl)carbamoyl)-4-methylpyrrolidine- 1 -carboxylate (206a) (656 mg, 78% yield); ¾NMR (300 MHz, DMSO-ffc) δ 10.90 (d, J= 12.5 Hz, 1H), 8.07 (dd, J= 11.8, 8.1 Hz, 1H), 7.74 (q, 7.6 Hz, 1H), 7.34 (d, J= 7.7 Hz, 1H), 4.50 - 4.30 (m, 1H), 3.58 (dt, J=

10.0, 6.7 Hz, 1H), 2.91 - 2.79 (m, 1H), 2.33 (dt, J = 15.6, 7.4 Hz, 1H), 1.97 (q, J= 4.4 Hz, 1H), 1.89 - 1.72 (m, 1H), 1.32 (d ,J= 39.6 Hz, 9H), 0.96 (d, J= 6.6 Hz, 3H); MS (ES+): 284.00 (M-Boc+1).

Step-2: Preparation of (2S,4R)-N-(6-bromopyridin-2-yl)-4-methylpyirolidine-2-carbox amide (206b) Compound 206b was prepared according to the procedure reported in step-2 of scheme- 1, from (2S,4R)-/er/-butyl 2-((6-bromopyridin-2-yl)carbamoyl)-4-methylpyrrolidine- 1- carboxylate (206a) (650 mg, 1.692 mmol) in DCM (9 mL) using TFA (0.912 mL, 11.84 mmol) and stirring overnight at RT. This gave after workup and purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] HC1 salt of (2S,4R)-N-(6-bromopyridin-2-yl)-4-methylpyrrolidine- 2-carboxamide (206b) (541 mg, 100% yield) as a white solid; Ή NMR (300 MHz, DMSO- db) δ 11.44 (s, 1H), 9.63 (s, 1H), 8.68 (s, 1H), 8.05 (d, J= 8.2 Hz, 1H), 7.82 (t, J= 7.9 Hz, 1H), 7.44 (d, 7.7 Hz, 1H), 4.49 (s, 1H), 3.45 (s, 1H), 2.80 (s, 1H), 2.32 (dd,J= 14.9, 7.6

Hz, 1H), 2.19 (dt, J= 12.5, 6.0 Hz, 1H), 1.98 (dt,J= 13.1, 8.7 Hz, 1H), 1.03 (d, J= 6.6 Hz,

3H).

Step-3: Preparation of (2S,4R)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b] indol- 9-yl)acetyl)-N-(6-bromopyridin-2-yl)-4-methylpyrrolidine-2-c arboxamide (206c)

Compound 206c was prepared according to the procedure reported in step-3 of scheme- 1, from HC1 salt of (2S,4R)-N-(6-bromopyridin-2-yl)-4-methylpyrrolidine-2-carbox amide (206b) (50 mg, 0.156 mmol) in DMF (1.5 mL) using TFA salt of 2-(4-amino-6- (trifluoromethy 1 )-9H-pyrimido [4,5 -b] indol -9-yl)acetic acid (lie) (66.2 mg, 0.156 mmol), HATH (89 mg, 0.234 mmol), DIPEA (0.136 mL, 0.780 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 50%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b] indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-4-methylpyrrolidine-2-car boxamidc (206c) (41 mg, 46% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-d!s) (a mixture of two rotamers) δ 11.22 and 10.78 (2s, 1H, D2O exchangeable), 8.94 (s, 1H), 8.81 (s, 2H, D2O exchangeable), 8.61 and 8.58 (2s, 1H), 8.10 and 7.93 (2d ,J= 8.1 Hz, 1H), 7.89 - 7.72 (m, 2H), 7.63 (t, J = 8.0 Hz, 1H), 7.33 and 7.24 (d, J= 7.7 Hz, 1H), 5.43 (q, J= 17.3 Hz, 2H), 4.60 - 4.43 (m,

1H), 4.03 (t, J= 8.5 Hz, 1H), 3.34 (t, 1H), 2.54 - 2.46 (m, 1H), 2.00 (dd, J= 13.2, 6.6 Hz, 1H), 1.88 - 1.70 (m, 1H), 1.04 and 0.96 (2d, J = 6.5 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO) δ -58.59. MS (ES+): 576.1 (M+l); (ES-): 574.1 (M-l); Analysis calculated for C2*H2iBrF ₃ N702 I.5H2O.HCI: C, 45.05; H, 3.94; Cl, 5.54; N, 15.32; Found: C, 45.09; H, 3.91; Cl, 5.42; N, 15.09.

Preparation of (2S,4R)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b] indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-4-fluoro-4-methylpyrrolid ine-2-carboxamide (207b)

Compound 207b was prepared according to the procedure reported in step-3 of scheme- 1 , from TFA salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (lie) (60 mg, 0.141 mmol) in DMF (1.2 mL) using TFA salt of (2S,4R)-N-(6-bromopyridin- 2-yl)-4-fluoro-4-methylpyrrolidine-2-carboxamide (207a) (58.9 mg, 0.141 mmol; prepared according to the procedure reported in Wiles, Jason A. etal., PCT Int. Appl. (2017), WO 2017035353 A1 20170302), HATU (81 mg, 0.212 mmol), DIPEA (0.123 mL, 0.707 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 50%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)-l-(2-(4-amino-6- (trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6- bromopyridin-2-yl)-4-fluoro-4- methylpyrrolidine-2-carboxamide (207b) (55 mg, 65% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-dls) (a mixture of two rotamers) δ 11.35 and 10.96 (2s, 1H, D2O exchangeable), 8.95 (s, 1H), 8.57 (s, 1H), 8.47 (s, 2H, D2O exchangeable), 8.21 and 7.98 (2d, J= 8.2 Hz, 1H), 7.84 (s, 2H), 7.68 (t ,J= 8.0 Hz, 1H), 7.43 and 7.31 (2d ,J = 7.7 Hz, 1H), 5.61 (d, J= 17.4 Hz, 1H), 5.38 (d, J= 17.3 Hz, 1H), 4.62 (t, J= 8.6 Hz, 1H), 4.30 (dd,J= 18.9, 12.0 Hz, 1H), 3.97 (dd,J= 35.2, 11.9 Hz, 1H), 2.54 (m, 1H), 2.20 - 1.93 (m, 1H), 1.62 (d, J= 21.0 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -58.50, -139.31. MS (ES+): 594.1 (M+l); (ES-): 592.0 (M-l); Analysis calculated for C2*H2oBrF4N ₇ 02 I.25H2O.HCI.: C,

44.12; H, 3.63; Cl, 5.43; N, 15.01; Found: C, 44.16; H, 3.67; Cl, 5.59; N, 14.84.

Scheme 208 H ₂ N o _x Xr Ν-χ H

B TFA

N ■OH oc

Boc O O II

^/ S s ry*

208a ou' ¹ ci

208b r CO ₂ H

-N. if 1 N· H

HN· VN

NH _{2 /} N.

Γ * N O O

NH 11e CF ₃ N

O V-N

Cr ^Br HATU, DIPEA H ₂ N \

CF ₃

208c 208d

Preparation of (2S,4S)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b] indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-4-methylpyrrolidine-2-car boxamide (208d)

Step-1: Preparation of (2S,4S)-te/t-butyl 2-((6-bromopyiidin-2-yI)caibamoyI)-4- methylpy rrolidine- 1 -caiboxylate (208b)

Compound 208b was prepared according to the procedure reported in step-1 of scheme-53, from (2S,4S)-l-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carbox ylic acid (208a) (0.45 g, 1.963 mmol; CAS # 364750-81-2) in DCM (15 mL) using 1 -methyl- lH-imidazole (0.391 mL, 4.91 mmol), methanesulfonyl chloride (0.182 mL, 2.355 mmol), 6-bromopyridin-2- amine (0.340 g, 1.963 mmol) and stirring at RT for 18 h. This gave after workup (2S,4S)-terf- butyl 2-((6-bromopyridin-2-yl)carbamoyl)-4-methylpyrrolidine- 1 -caiboxylate (208b) (623 mg, 83% yield); Ή NMR (300 MHz, DMSO-i/e) δ 10.92 (d, J= 16.6 Hz, 1H), 8.10 (dd, J= 14.1, 8.2 Hz, 1H), 7.76 (t, J= 8.1 Hz, 1H), 7.34 (d, J= 7.7 Hz, 1H), 4.32 (t, J= 8.3 Hz, 1H), 3.70 - 3.49 (m, 1H), 2.93 - 2.79 (m, 1H), 2.40 - 2.10 (m, 2H), 1.30 (d, J = 43.9 Hz, 10H), 1.00 (t, J= 6.1 Hz, 3H); MS (ES+): 384.10 (M+l).

Step-2: Preparation of (2S,4S)-N-(6-bromopyridin-2-yl)-4-methylpyrrolidine-2-carbox amide (208c)

Compound 208c was prepared according to the procedure reported in step-2 of scheme- 1, from (2S,4S)-te/t-butyl 2-((6-bromopyridin-2-yl)carbamoyl)-4-methylpyrrolidine-l- b l (208b) (610 1 587 l) i DCM (9 L) i TF (0856 L 11 11 mmol) and stirring overnight at RT. This gave after workup TFA salt of (2S,4S)-N-(6- bromopyridin-2-yl)-4-methylpyrrolidine-2-carboxamide (208c) (621 mg, 98% yield); Ή NMR (300 MHz, DMSO-ifc) δ 11.41 (s, 1H), 9.31 (s, 1H), 8.75 (s, 1H), 8.07 (d, J= 8.2 Hz, 1H), 7.82 (t, J= 8.0 Hz, 1H), 7.44 (d, J= 7.7 Hz, 1H), 4.51 - 4.27 (m, 1H), 3.54 - 3.26 (m, 1H), 2.91 - 2.64 (m, 1H), 2.59 (dd, J= 13.2, 7.1 Hz, 1H), 2.38 - 2.14 (m, 1H), 1.53 (dt, J= 12.6, 10.0 Hz, 1H), 1.04 (d, J= 6.6 Hz, 3H); MS (ES+): 284.00 (M+l).

Step-3: Preparation of (2S,4S)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b] indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-4-methylpynolidine-2-carb oxamide (208d)

Compound 208d was prepared according to the procedure reported in step-2 of scheme- 1 , from TFA salt of (2S,4S)-N-(6-bromopyridin-2-yl)-4-methylpyrrolidine-2-carbox amide (208c) (56.3 mg, 0.141 mmol) in DMF (1.2 mL) using TFA salt of 2-(4-amino-6- (trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (lie) (60 mg, 0.141 mmol) HATU (81 mg, 0.212 mmol), N-ethyl-N-isopropylpropan-2-amine (0.123 mL, 0.707 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 50%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1%HC1) from 0-100%] (2S,4S)-l-(2-(4-amino-6- (trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6- bromopyridin-2-yl)-4- methylpyrrolidine-2-carboxamide (208d) (60 mg, 74% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-d!s) (a mixture of two rotamers) δ 11.31 and 10.86 (2s, 1H, D2O exchangeable), 8.97 (s, 1H), 8.61 (s, 3H, 2H DzO exchangeable), 8.20 and 7.99 (2d, J = 8.2 Hz, 1H), 7.92 - 7.81 (m, 2H), 7.68 (t, J= 8.0 Hz, 1H), 7.41 and 7.30 (2d ,J= 7.7 Hz, 1H), 5.55 (d, J= 17.3 Hz, 1H), 5.38 (d,J= 17.3 Hz, 1H), 4.44 (t, J= 8.1 Hz, 1H), 4.14 (t, J= 8.4 Hz, 1H), 3.34 (t ,J= 9.6 Hz, 1H), 2.54 (m, 1H), 2.42 (t ,J= 7.2 Hz, 1H), 1.49 (q, J= 9.6 Hz, 1H), 1.13 andl.02 (2d, 6.6 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO-tfc) δ -58.53. MS (ES+):

576.1 (M+l); (ES-): 574.0 (M-l); Analysis calculated for Ci+FbiBrFs^Cfc I.5H2O.HCL: C, 45.05; H, 3.94; Cl, 5.54; N, 15.32; Found: C, 45.08; H, 4.01; Cl, 5.43; N, 15.12.

Scheme 209

Preparation of (2S,4R)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b] indol-9- yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-4-fluoro-4-methy lpyrrolidine-2-carboxamide

(209b)

Compound 209b was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-ammo-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)a cetic acid (lie) (60 mg, 0.141 mmol) in DMF (1.2 mL) using HC1 salt of (2S,4R)-N-(6-bromo-3- methylpyridin-2-yl)-4-fluoro-4-methylpyrrolidine-2 -carboxamide (209a) (50 mg, 0.141 mmol; prepared according to the procedure reported in Wiles, Jason A. et al., PCT Int. Appl. (2018), WO 2018160889 Al 20180907.), HATU (81 mg, 0.212 mmol) DIPEA (0.123 mL, 0.707 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 50%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)-l-(2-(4-amino-6- (trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6- bromo-3-methylpyridin-2-yl)-4- fluoro-4-methylpyrrolidine-2-carboxamide (209b) (33 mg, 38% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ofe) (a mixture of two retainers) δ 10.83 and 10.40 (2s, 1H, D2O exchangeable), 8.94 (s, 1H), 8.69 (s, 2H, D2O exchangeable), 8.56 (s, 1H), 7.76 (qd, J= 10.7, 9.7, 6.2 Hz, 2H), 7.66 and 7.51 (d, J= 8.0 Hz, 1H), 7.46 and 7.35 (2d, J= 7.9 Hz, 1H), 5.58 (d ,J= 17.3 Hz, 1H), 5.31 (d, J= 17.3 Hz, 1H), 4.51 (dd, J= 9.8, 7.5 Hz, 1H), 4.24 (dd, J= 18.9, 12.3 Hz, 1H), 3.89 (dd,J= 35.1, 12.0 Hz, 1H), 2.56 (td,J= 14.9, 7.6 Hz, 1H), 2.18 - 1.93 (m, 1H), 1.85 (s, 3H), 1.58 (d, J= 21.1 Hz, 3H). ¹⁹ FNMR (282 MHz, DMSO-ifc) δ - 58.56, -139.44; MS (ES+): 608.1 (M+l), 630.1 (M+Na); (ES-): 606.1 (M-l); Analysis calculated for C2sH22BrF4N ₇ 02 I.25H2O.HCL: C, 44.99; H, 3.85; N, 14.69; Found: C, 45.03; H, 3.79; N, 14.43.

210d

210c

Preparation of (S)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indo l-9-yl)acetyl)- N-(6-bromopyridin-2-yl)-4,4-dimethylpyrrolidine-2-cafboxamid e (210d)

Step-1: Preparation of (S)-te/7-butyl 2-((6-bromopyridin-2-yl)carbamoyl)-4,4- dimethy lpyrrolidine- 1 -carboxylate (210b)

Compound 210b was prepared according to the procedure reported in step-1 of scheme-53, from (S)-l-(tert-butoxycafbonyl)-4,4-dimethylpyrrolidine-2-caibox ylic acid (210a) (0.45 g, 1.850 mmol; CAS # 87691-27-8) in DCM (15 mL) using 1 -methyl- lH-imidazole (0.369 mL, 4.62 mmol), methanesulfonyl chloride (0.172 mL, 2.219 mmol), 6-bromopyridin-2-amine (0.320 g, 1.850 mmol) and stirring at RT for 18 h. This gave after workup (S)-tert-butyl 2- ((6-bromopyridin-2-yl)carbamoyl)-4,4-dimethy lpyrrolidine- 1 -carboxylate (210b) (570 mg, 77% yield); Ή NMR (300 MHz, DMSO-i/e) δ 10.89 (d, J= 19.4 Hz, 1H), 8.10 (dd, J= 14.6, 8.2 Hz, 1H), 7.75 (q, ./= 8.3 Hz, 1H), 7.34 (d, J= 7.7 Hz, 1H), 4.53 - 4.32 (m, 1H), 3.22 (dd, J= 10.2, 5.8 Hz, 1H), 3.09 (dd,J= 10.2, 5.2 Hz, 1H), 2.01 (dt, 12.5, 6.5 Hz, 1H), 1.70 - 1.55 (m, 1H), 1.31 (d, 7 = 40.7 Hz, 9H), 1.07 (d, J= 5.3 Hz, 3H), 1.00 (s, 3H); MS (ES+): 398.10 (M+l).

Step-2: Preparation of (S)-N-(6-bromopyridin-2-yl)-4,4-dimethylpyrrolidine-2-carbox amide (210c) Compound 210c was prepared according to the procedure reported in step-2 of scheme-1, from (S)-tert-butyl 2-((6-bromopyridin-2-y l)carbamoy l)-4,4-dimethylpyrrolidine- 1 - carboxylate (210b) (570 mg, 1.431 mmol) in DCM (8 mL) using TFA (0.772 mL, 10.02 mmol) and stirring overnight at RT. This gave after workup and purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] to afford the HC1 salt of (S)-N-(6-bromopyridin-2-yl)-4,4- dimethylpyrrolidine-2-carboxamide (210c) (375 mg, 78% yield); Ή NMR (300 MHz, DMSO-<sfc) δ 11.44 (s, 1H), 10.24 (s, 1H), 8.81 (s, 1H), 8.06 (d, 7= 8.2 Hz, 1H), 7.83 (t, 7= 7.9 Hz, 1H), 7.44 (d,7= 7.7 Hz, lH), 4.52 (s, 1H), 3.04 (q,7= 5.6, 5.1 Hz, 2H), 2.30 (dd,7 = 12.8, 8.3 Hz, 1H), 1.80 (dd, 7= 12.9, 9.4 Hz, 1H), 1.11 (d, 7= 2.5 Hz, 6H); MS (ES+):

298.10 (M+l).

Step-3: Preparation of (S)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indo l-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-4,4-dimethylpyrrolidine-2 -carboxamide (210d)

Compound 210d was prepared according to the procedure reported in step-3 of scheme-1, from HC1 salt of (S)-N-(6-bromopyridin-2-yl)-4,4-dimethylpyrrolidine-2-carbox amide (210c) (47.3 mg, 0.141 mmol) in DMF (1.2 mL) using TFA salt of 2-(4-amino-6-(trifluoromethyl)- 9H-pyrimido[4,5-b]indol-9-yl)acetic acid (lie) (60 mg, 0.141 mmol), HATU (81 mg, 0.212 mmol), DIPEA (0.123 mL, 0.707 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 50%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (S)-l- (2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl )acetyl)-N-(6-bromopyridin-2- yl)-4,4-dimethylpyrrolidine-2-carboxamide (210d) (34 mg, 41% yield) HC1 salt as a white solid; 'HNMR (300 MHz, DMSO-zfe) (a mixture of two rotamers) δ 11.26 and 10.83 (2s, 1H, D2O exchangeable), 8.92 (s, 1H), 8.53 and 8.49 (2s, 1H), 8.26 (s, 2H, D2O exchangeable), 8.20 and 7.99 (2d, 7= 8.2 Hz, 1H), 7.81 (s, 2H), 7.68 (t, 7= 8.0 Hz, 1H), 7.41 and 7.31 (2d, 7 = 7.7 Hz, 1H), 5.52 (d ,7= 17.3 Hz, 1H), 5.34 (d ,7= 17.3 Hz, 1H), 4.54 (t ,7= 8.3 Hz, 1H), 3.77 (d, 7= 9.8 Hz, 1H), 3.60 (d, 7= 9.9 Hz, 1H), 2.08 (dd, 7= 12.4, 7.9 Hz, 1H), 1.71 (dd, 7 = 12.4, 9.0 Hz, 1H), 1.21 and 1.10 (2s, 3H), 1.14 and 1.08 (2s, 3H). ¹⁹ F NMR(282 MHz, DMSO-ifc) δ -58.42. MS (ES+): 590.0 (M+l), 612.0 (M+Na); (ES-): 588.0 (M-l); Analysis calculated for C25H23BrF3N ₇ 02 I.25H2O.HCI: C, 46.24; H, 4.11; Cl, 5.46; N, 15.10; Found:

C, 46.21; H, 4.05; Cl, 5.62; N, 14.78.

211d 211e

Preparation of (2S,4S)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b] indol-9- yl)acet\l)-4-(aminomethyl)-N-(6-bromop}Tidin-2-yl)pyrrolidin e-2-carboxamide (21 le)

Step-1: Preparation of (2S,4S)-tert-butyl 4-(((((9H-fluoren-9- yl)methoxy)carbonyl)amino)methyl)-2-((6-bromopyridin-2-yl)ca rbamoyl)pyrrolidine-l- caiboxylate (211b)

Compound 211b was prepared according to the procedure reported in step-1 of scheme-53, from (2S,4S)-4-(((((9H-fluoren-9-yl)methoxy)carbonyl)amino)methyl )-l-(te _/ 7- butoxycarbonyl)pyrrolidine-2-carboxyhc acid (211a) (0.25 g, 0.536 mmol; CAS # 273221- 98-0) in DCM (10 mL) using 1 -methyl- 1 H-imidazole (0.107 mL, 1.340 mmol), methanesulfonyl chloride (0.050 mL, 0.643 mmol), 6-bromopyridin-2-amine (0.093 g, 0.536 mmol) and stirring at RT for 18 h. This gave after workup (2S,4S)-terf-butyl 4-(((((9H- fluoren-9-yl)methoxy)carbonyl)amino)methyl)-2-((6-bromopyrid in-2- yl)carbamoyl)py rrolidine- 1 -carboxy late (211b) (67 mg, 20% yield); MS (ES+): 621.20 (M+l).

Step-2: Preparation of (9H-fluoren-9-yl)methyl (((3R,5S)-5-((6-bromopyridin-2- yl)caibamoyl)pyrrolidin-3-yl)methyl)caibamate (211c) Compound 211c was prepared according to the procedure reported in step-2 of scheme- 1, from (2S,4S)-te/t-butyl 4-(((((9H-fluoren-9-yl)methoxy)carbonyl)amino)methyl)-2-((6- bromopyridin-2-yl)caibamoyl)p>Trolidine-l-caiboxylate (211b) (65 mg, 0.105 mmol) in DCM (1 mL) using TFA (0.056 mL, 0.732 mmol) and stirring overnight at RT. This gave after workup TFA salt of (9H-fluoren-9-yl)methyl (((3R,5S)-5-((6-bromopyridin-2- yl)carbamoyl)pyrrolidin-3-yl)methyl)caibamate (211c) (60 mg, 90% yield); ¾ NMR(300 MHz, DMSO-tife) δ 11.44 (s, 1H), 9.38 (s, 1H), 8.75 (s, 1H), 8.06 (d, J= 8.2 Hz, 1H), 7.87 (dd, J= 15.0, 7.7 Hz, 3H), 7.67 (d, J= 7.4 Hz, 2H), 7.51 - 7.26 (m, 6H), 4.47 (s, 1H), 4.36 (d, J= 6.8 Hz, 2H), 4.22 (t, J= 6.7 Hz, 1H), 3.42 (s, 1H), 3.02 (dt, J= 33.5, 7.9 Hz, 3H), 2.41 (t, .7= 7.6 Hz, 1H), 2.10 (t, J= 8.9 Hz, 2H).

Step-3: Preparation of (9H-fluoren-9-yl)methyl (((3S,5S)-l-(2-(4-amino-6-(trifluoromethyl)- 9H-pyrimido[4,5-b]indol-9-yl)acetyl)-5-((6-bromopyridin-2-yl )carbamoyl)pynOlidin-3- yl)methyl)carbamate (21 Id)

Compound 21 Id was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of (9H-fluoren-9-yl)methyl (((3R,5S)-5-((6-bromopyridin-2- yl)carbamoyl)pyrrolidin-3-yl)methyl)carbamate (211c) (55 mg, 0.087 mmol) in DMF (1 mL) using TFA salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (lie) (36.7 mg, 0.087 mmol), HATU (49.4 mg, 0.130 mmol), DIPEA (0.075 ml, 0.433 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 50%] (9H-fluoren- 9-yl)methyl (((3S,5S)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5- b]indol-9- yl)acetyl)-5-((6-bromopyridin-2-yl)carbamoyl)pyrrolidin-3-yl )methyl)carbamate (211d) (70 mg, 99% yield) as a white solid; ΉΝΜΚ(300 MHz, DMSOK/ ₆ ) δ 10.87 (s, 1H), 8.80 (s,

1H), 8.33 (s, 1H), 8.02 (d, ./= 8.2 Hz, 1H), 7.88 (d, J= 7.4 Hz, 2H), 7.74 - 7.66 (m, 5H),

7.55 (s, 3H), 7.44 - 7.26 (m, 5H), 5.34 (q, 17.3 Hz, 2H), 4.57 (s, 1H), 4.39 (d, J= 6.7 Hz,

2H), 4.25 (t, J= 6.7 Hz, 1H), 4.00 (t, J= 8.6 Hz, 1H), 3.71 - 3.44 (m, 1H), 3.21 - 3.04 (m, 3H), 1.98 (d, J= 7.8 Hz, 2H), 1.22 (s, 1H); MS (ES+): 813.10 (M+l).

Step-4: Preparation of (2S,4S)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b] indol-9- yl)acetyl)-4-(aminomethyl)-N-(6-bromopyridin-2-yl)pyrrolidin e-2-carboxamide (21 le)

Compound 211e was prepared according to the procedure reported in step-4 of scheme-180, from (9H-fluoren-9-yl)methyl (((3 S,5 S)- 1 -(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-5-((6-bromopyridin-2-yl)carbamoyl)pyrro lidin-3-yl)methyl)carbamate stirring at RT for 1 h. This gave after work up and purification using flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1%HC1) from 0-100%] (2S,4S)-l-(2-(4-amino-6- (trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-4-(am inomethyl)-N-(6- bromopyridin-2-yl)pyrrolidine-2-carboxamide (21 le) (21 mg, 48% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ofe) (a mixture of two retainers) δ 11.40 and 10.93 (2s, 1H, DzO exchangeable), 9.00 (s, 1H), 8.79 (s, 2H, DzO exchangeable), 8.66 and 8.62 (2s, 1H), 8.26 (s, 3H, DzO exchangeable), 8.02 - 7.78 (m, 3H), 7.71 (t, J= 8.0 Hz, 1H), 7.42 and 7.33 (2d, J= 7.6 Hz, 1H), 5.53 (s, 2H), 4.63 (d, J= 8.3 Hz, 1H), 4.13 (dd, J= 9.9, 7.2 Hz, 1H), 3.73 (t, J= 8.8 Hz, 1H), 3.05 - 2.88 (m, 2H), 2.84 - 2.69 (m, 1H), 2.28 - 1.99 (m, 2H). ¹⁹ F NMR (282 MHz, DMSO-t/e) δ -58.56. MS (ES+): 591.1(M+1); (ES-): 589.1 (M-l).

Scheme 212

212d 212e

Preparation of (2S,4R)- l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-4-(aminomethyl)-N -(6-bromopyridin-2-yl)pyrrolidine-2-carboxamide (212e)

Step-1: Preparation of (2S,4R)-terf-butyl 4-(((((9H-fluoren-9- yl)methoxy)carbonyl)amino)methyl)-2-((6-bromopyridin-2-yl)ca rbamoyl)pyrrolidine-l- Compound 212b was prepared according to the procedure reported in step-1 of scheme-53, from (2S,4R)-4-(((((9H-fluoren-9-yl)methoxy)carbonyl)amino)methyl )- 1 -(tert- butoxycarbonyl)pyrrolidine-2-carboxylic acid (212a) (0.25 g, 0.536 mmol; CAS # 2173052- 84-9) in DCM (10 mL) using 1 -methyl- lH-imidazole (0.107 mL, 1.340 mmol), methanesulfonyl chloride (0.050 mL, 0.643 mmol), 6-bromopyridin-2-amine (0.093 g, 0.536 mmol) and stirring at RT for 18 h. This gave after workup (2S,4R)-fc/†-butyl 4-(((((9H- fluoren-9-yl)methoxy)carbonyl)amino)methyl)-2-((6-bromopyrid in-2- yl)carbamoyl)pyrrolidme-l -carboxylate (212b) (231 mg, 69% yield); ‘HNMR (300 MHz, DMSO-ife) δ 10.93 (d ,J= 15.8 Hz, 1H), 8.11 (dd, J= 14.0, 8.1 Hz, 1H), 7.89 (d,/= 7.4 Hz, 2H), 7.81 - 7.60 (m, 3H), 7.52 - 7.39 (m, 2H), 7.39 - 7.27 (m, 4H), 4.26 (dd, J= 27.9, 7.3 Hz, 4H), 3.52 (t ,J= 9.2 Hz, 1H), 3.05 (d ,J= 9.3 Hz, 3H), 2.28 (s, 2H), 1.57 (d, J= 10.8 Hz, 1H), 1.31 (d,J= 42.3 Hz, 9H).

Step-2: Preparation of (9H-fluoren-9-yl)methyl (((3S,5S)-5-((6-bromopyridin-2- yl)carbamoyl)pyrrolidin-3-yl)methyl)carbamate (212c)

Compound 212c was prepared according to the procedure reported in step-2 of scheme- 1, from (2S,4R)-/er/-butyl 4-(((((9H-fluoren-9-yl)methoxy)carbonyl)amino)methyl)-2-((6- bromopyridin-2-yI)cafbamoyI)p>Trolidine- 1 -carboxylate (212b) (220 mg, 0.354 mmol) in DCM (2 mL) using TFA (0.191 mL, 2.478 mmol) and stirring overnight at RT. This gave after workup TFA salt of (9H-fluoren-9-yl)methyl (((3S,5S)-5-((6-bromopyridin-2- yl)carbamoyl)pyrrolidin-3-yl)methyl)carbamate (212c) (210 mg, 93% yield); 'HNMR (300 MHz, DMSO-cfe) δ 11.42 (s, 1H), 9.32 (s, 1H), 8.83 (s, 1H), 8.07 (d,J= 8.2 Hz, 1H), 7.95 - 7.74 (m, 3H), 7.66 (d ,J= 7.4 Hz, 2H), 7.52 - 7.25 (m, 6H), 4.33 (d, J= 6.9 Hz, 3H), 4.20 (t, J= 6.7 Hz, 1H), 3.35 (s, 1H), 3.09 (t, J= 6.0 Hz, 2H), 2.97 (s, 1H), 2.57 - 2.53 (m, 1H), 2.43 (s, 1H), 1.73 - 1.58 (m, 1H); MS (ES+): 521.10 (M+l).

Step-3: Preparation of (9H-fluoren-9-yl)methyl (((3R,5S)-l-(2-(4-amino-6-(trifluoromethyl)- 9H-pyrimido[4,5-b]indol-9-yl)acetyl)-5-((6-bromopyridin-2-yl )carbamoyl)pynOhdin-3- yl)methyl)carbamate (212d)

Compound 212d was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of (9H-fluoren-9-yl)methyl (((3S,5S)-5-((6-bromopyridin-2- yl)carbamoyl)pyrrolidin-3-yl)methyl)carbamate (212c) (200 mg, 0.315 mmol) in DMF (2 mL) using TFA salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (lie) (134 mg, 0.315 mmol), HATU (180 mg, 0.472 mmol), DIPEA (0.274 mL, 1.574 chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 50%] (9H-fluoren- 9-yl)methyl (((3R,5S)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5- b]indol-9- yl)acet>'l)-5-((6-bromopyridin-2-yl)carbamoyl)pyrrolidin- 3-yl)methyl)carbamate (212d) (248 mg, 97% yield) as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.86 (s, 1H), 8.79 (s,

1H), 8.34 (s, 1H), 8.01 (d, J= 8.2 Hz, 1H), 7.90 (d, J= 7.3 Hz, 2H), 7.74 - 7.63 (m, 5H),

7.55 (d, J= 4.2 Hz, 3H), 7.43 - 7.29 (m, 5H), 5.41 (d, J= 17.3 Hz, 1H), 5.25 (d, J= 17.1 Hz, 1H), 4.44 (t, J= 8.1 Hz, 1H), 4.37 (d, J= 6.7 Hz, 2H), 4.24 (t ,J= 6.8 Hz, 1H), 4.05 (t, J=

8.7 Hz, 1H), 3.50 (t, J= 9.5 Hz, 1H), 3.15 - 3.06 (m, 3H), 2.33 (dt, J= 16.9, 8.7 Hz, 1H),

1.62 (q,J= 10.1 Hz, 1H).

Step-4: Preparation of (2S,4R)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b] indol- 9-yl)acetyl)-4-(aminomethyi)-N-(6-bromopyridin-2-yi)pyrrolid ine-2-carboxamide (212e)

Compound 212e was prepared according to the procedure reported in step-4 of scheme- 180, from (9H-fluoren-9-yl)methyl (((3R,5S)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-5-((6-bromopyTidin-2-yl)caibamoyl)pyrro lidin-3-yl)methyl)carbamate (212d) (240 mg, 0.295 mmol) in DMF (1.2 mL) using piperidine (0.291 mL, 2.95 mmol) and stirring at RT for 1 h. This gave after work up and purification using flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)-l-(2-(4-amino-6- (trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-4-(am inomethyl)-N-(6- bromopyridin-2-yl)pyrrolidine-2-carboxamide (212e) (65 mg, 37% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ffc) (a mixture of two rotamers) δ 11.42 and 10.95 (2s, 1H, DzO exchangeable), 9.07 - 8.93 (m, 3H, 2H DzO exchangeable), 8.71 and 8.68 (2s, 1H), 8.37 (s, 3H, DzO exchangeable), 7.98 (dd, J= 8.5, 5.6 Hz, 2H), 7.89 - 7.81 (m, 1H), 7.69 (t, J= 8.0 Hz, 1H), 7.42 and 7.31 (2d, J= 7.7 Hz, 1H), 5.53 (s, 2H), 4.49 (t, 7.8 Hz, 1H), 4.13

(dd, J= 10.1, 7.0 Hz, 1H), 3.76 (dd, J= 10.2, 7.4 Hz, 1H), 3.19-3.03 (m, 1H), 3.01- 2.86 (m, 1H), 2.81- 2.67 (m, 1H), 2.61 - 2.57 (m, 1H), 1.78 (dt,./= 12.8, 7.7 Hz, 1H). ¹⁹ FNMR(282 MHz, DMSO-cfe) δ -58.60. MS (ES+): 591.2 (M+l); (ES-): 589.1 (M-l); Analysis calculated for CztHzzBrFaNsOz 2Hz0.1.9HCl: C, 41.38; H, 4.04; Cl, 9.67; N, 16.08; Found: C, 41.53; H, 3.96; Cl, 9.47; N, 15.72.

Scheme 213 %

TFA HN· H

^~ A O ^/ s o vy irci ^X N ^5S ' _* O ^y V ^Br

\ o

213d

Preparation of (2S,4R)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b] indol-9- yl)acetyl)-N-(6-bromopyrazin-2-yl)-4-fluoro-4-methylpyrrolid ine-2-carboxamide (213d)

Step-1: Preparation of (2S,4R)-te/t-butyl 2-((6-bromopyrazin-2-yl)carbamoyl)-4-fluoro-4- methylpyrrolidine- 1 -carboxylate (213b)

Compound 213b was prepared according to the procedure reported in step-1 of scheme-53, from (2S,4R.)-l-(tert-butoxycarbonyl)-4-fluoro-4-methylpyrrolidin e-2 -carboxylic acid (213a) (0.5 g, 2.022 mmol; CAS # 1386458-93-0) in DCM (15 mL) using 1 -methyl- lH-imidazole (0.403 mL, 5.06 mmol), methanesulfonyl chloride (0.188 mL, 2.427 mmol), 6-bromopyrazin- 2-amine (0.352 g, 2.022 mmol; CAS # 54237-53-5) and stirring at RT for 18 h. This gave after workup (2S,4R)-tert-butyl 2-((6-bromopyrazin-2-yl)carbamoyl)-4-fluoro-4- methylpyrrolidine- 1 -caiboxylate (213b) (0.5 g, 61% yield); MS (ES+): 403.10 (M+l).

Step-2: Preparation of (2S,4R)-N-(6-bromopyrazin-2-yl)-4-fluoro-4-methylpyrrolidine -2- carboxamide (213c)

Compound 213c was prepared according to the procedure reported in step-2 of scheme- 1, from (2S,4R)-ter/-butyl 2-((6-bromopyrazin-2-yl)carbamoyl)-4-fluoro-4-methylpyrrolid ine- 1 -caiboxylate (213b) (0.5 g, 1.240 mmol) in DCM (7 mL) using TFA (0.669 mL, 8.68 mmol) and stirring overnight at RT. This gave after workup and purification using reverse phase HC1) from 0-100%] (2S,4R)-N-(6-bromopyrazin-2-yl)-4-fluoro-4-methylpyrrolidine -2- carboxamide (213c) (176 mg, 47% yield); Ή NMR (300 MHz, DMSO-zfc) δ 11.76 (s, 1H), 9.60 (s, 1H), 9.30 (s, 1H), 8.68 (s, 1H), 4.66 (dd, J= 10.8, 7.6 Hz, 1H), 3.66 - 3.51 (m, 1H), 3.41 (dd,./= 35.2, 13.1 Hz, 1H), 2.77 (td,./= 14.6, 7.5 Hz, 1H), 2.27 (ddd,./= 37.3, 14.2, 10.9 Hz, 1H), 1.56 (d, J= 21.4 Hz, 3H); MS (ES+): 303.00 (M+l).

Step-3: Preparation of (2S,4R)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b] indol- 9-yl)acetyl)-N-(6-bromopyrazijn-2-yl)-4-f]uoro-4-mcthylpyrro lidine-2 -carboxamide (213d)

Compound 213d was prepared according to the procedure reported in step-3 of scheme- 1 , from HC1 salt of (2S,4R)-N-(6-bromopyrazin-2-yl)-4-fluoro-4-methylpyrrolidine -2- carboxamide (213c) (48.0 mg, 0.141 mmol) in DMF (1.2 mL) using TFA salt of 2-(4-amino- 6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (lie) (60 mg, 0.141 mmol), HATU (81 mg, 0.212 mmol), DIPEA (0.123 mL, 0.707 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 50%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)-l-(2-(4-amino-6-(trifhxoromethyl)-9H-pyrimido[4,5-b] indol-9- yl)acetyl)-N-(6-bromopyrazin-2-yl)-4-fluoro-4-methylpyrrolid ine-2-carboxamide (213d) (35 mg, 42% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfe) (a mixture of two retainers) δ 11.67 and 11.33 (2s, 1H, DzO exchangeable), 9.44 and 9.21 (2s, 1H), 8.99 (s, 1H), 8.73 (s, 2H, D2O exchangeable), 8.64 (s, 1H), 8.54 (s, 1H), 7.93 - 7.83 (m, 2H), 5.65 (d, J= 17.4 Hz, 1H), 5.42 (d, J= 17.4 Hz, 1H), 4.65 (dd, 10.0, 7.3 Hz, 1H), 4.32 (dd, J= 18.9, 12.0 Hz, 1H), 3.99 (dd, J= 35.3, 11.9 Hz, 1H), 2.68 - 2.55 (m, 1H), 2.32 - 1.99 (m,

1H), 1.64 and 1.54 (2d, .7= 21.1 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO-flfe) δ -58.57, -139.00. MS (ES+): 595.1 (M+l); (ES-): 593.0 (M-l); Analysis calculated for CzsHigBrFtNsOa 2.5H2O.HCL: C, 40.81; H, 3.72; Cl, 5.24; N, 16.56; Found: C, 40.91; H, 3.67; Cl, 5.37; N, 16.25.

Scheme 214

45c

214a 214b

Preparation of 3-(4-amino-9-(2-(( 1 R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-5-methyl- 2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrintido[4,5- b]indol-6-yl)propanoic acid (214b)

Step-1: Preparation of ethyl 3-(4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2- yl)carbamoyl)-5-methyl-2-azabicyclo[3.1 ,0]hexan-2-yl)-2-oxoeth _\ T)-9H-pyrimido[4,5- b]indol-6-yl)propanoate (214a)

Compound 214a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-(3-ethoxy-3-oxopropyl)-9H-pyrimido[4,5-b]indol- 9-yl)acetic acid (45c) (75 mg, 0.164 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (8a) (65.6 mg, 0.197 mmol), HATU (94 mg, 0.247 mmol), DIPEA (106 mg, 0.822 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] ethyl 3-(4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoy l)- 5-methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrim ido[4,5-b]indol-6- yl)propanoate (214a) (78 mg, 76% yield) as a white solid; Ή NMR (300 MHz, DMSO-ofe) δ 10.77 (s, 1H), 8.80 - 8.54 (m, 3H), 8.46 - 8.36 (m, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.45 (dd, J = 8.5, 1.5 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 5.70 (d, J = 17.3 Hz, 1H), 5.35 (d, J = 17.2 Hz, 1H), 4.37 (dd, J = 9.0, 6.0 Hz, 1H), 4.05 (q, J = 7.1 Hz, 2H), 3.69 (dd, J = 5.6, 2.4 Hz, 1H), 3.03 (t, J = 7.7 Hz, 2H), 2.75 (t, J = 7.7 Hz,

2H), 2.49 - 2.40 (m, 1H), 2.05 - 1.92 (m, 1H), 1.31 (s, 3H), 1.16 (t, J = 7.1 Hz, 3H), 1.01 (t, J = 5.5 Hz, 1H), 0.93 (dd, J = 5.4, 2.4 Hz, 1H); MS (ES+): 620/622 (M+l), (ES-): 618/620 (M-

1). Step-2: Preparation of 3-(4-amino-9-(2-((lR,3S, 5R)-3-((6-bromopyridin-2-yl)carbamoyl)-5- methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimid o[4,5-b]indol-6-yl)propanoic acid (214b)

Compound 214b was prepared according to the procedure reported in step-4 of scheme- 17, from ethyl 3-(4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoy l)-5-methyl-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]i ndol-6-yl)propanoate (214a) (50 mg, 0.081 mmol) in THF (2 mL) and water (1 mL) using 2M aqueous hthium hydroxide hydrate (0.040 mL, 0.081 mmol) and stirring at RT for 16 h. This gave after workup and purification by reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HCl) from 0-100%] 3-(4-amino-9-(2-((lR,3S,5R)-3-((6- bromopyridin-2-yl)carbamoyl)-5-methyl-2-azabicyclo[3.1 ,0]hexan-2-yl)-2-oxoethyl)-9H- pyrimido[4,5-b]indol-6-yl)propanoic acid (214b) (33 mg, 69% yield) HCl salt as a white solid; ¾NMR (300 MHz, DMSO-tife) (a mixture of two rotamers) δ 10.85 and 10.76 (2s, 1H, DzO exchangeable), 8.71 (s, 2H, DzO exchangeable), 8.63 and 8.62 (2s, 1H), 8.41 (s, 1H), 8.00 and 7.94 (2d, J= 8.1 Hz, 1H), 7.69 (td, J= 8.0, 4.5 Hz, 1H), 7.60 (dd, J= 8.6, 2.5 Hz, 1H), 7.45 (d, J= 8.5 Hz, 1H), 7.30 (dd, J= 7.7, 4.9 Hz, 1H), 5.70 (d, J= 17.3 Hz, 1H), 5.35 (d, J= 17.3 Hz, 1H), 4.36 (dd, ./= 9.0, 5.9 Hz, 1H), 3.71 - 3.67 (m, 1H), 3.00 (t, J= 7.8 Hz, 2H), 2.67 (t, J= 7.8 Hz, 2H), 2.48 - 2.39 (m, 1H), 2.05 - 1.92 (m, 1H), 1.31 (s, 3H), 1.01 (t, J = 5.5 Hz, 1H), 0.97 - 0.78 (m, 1H); MS (ES+): 592/594 (M+l), (ES-): 590/592 (M-l); Analysis calculated for C27H26BrN ₇ 04.UHC1.2.75H20: C, 47.54; H, 4.82; Cl, 5.72; N,

14.37; Found: C, 47.62; H, 4.56; Cl, 5.97; N, 14.24.

Scheme 215

Preparation of ( 1 R,3 S ,5 R)-2-(2-(4-amino-6-(dimethy lamino)-9H-pyrimido [4,5 -b] indol-9- yl)acet>'l)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo [3.1 ,0]hexane-3-carboxamide (215g)

Step-1: Preparation ofN-(2-bromo-4-(dimethylamino)phenyl)-2,2,2-trifluoroacetami de (215b)

Compound 215b was prepared according to the procedure reported in step-1 of scheme-46, from 3-bromo-N 1 ,N 1 -dimethylbenzene- 1 ,4-diamine (215a) (1.75 g, 8.14 mmol; CAS #107100-00-5) in DCM (25 mL) using triethylamine (1.40 g, 13.83 mmol) trifluoroacetic acid anhydride (2.56 g, 12.20 mmol) in DCM (5 mL) and stirring at RT for 1 h. This gave after workup N-(2-bromo-4-(dimethylamino)phenyl)-2,2,2-trifluoroacetamide (215b) as a black solid (2.59 g, 102% yield) which was used as such for the next step; Ή NMR (300 MHz, DMSO-cfe) δ 10.92 (s, 1H), 7.17 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 2.8 Hz, 1H), 6.74 (dd, J = 8.9, 2.8 Hz, 1H), 2.93 -74.03; MS (ES+): 311/313 (M+l), (ES-): 30 Compound 215c was prepared according to the procedure reported in step-1 of scheme-11, from N-(2-bromo-4-(dimethylamino)phenyl)-2,2,2-trifluoroacetamide (215b) (2.59 g, 8.33 mmol) in DMSO (20 mL) using malononitrile (0.660 g, 9.99 mmol), L-proline (0.192 g,

1.665 mmol), Cul (159 mg, 0.833 mmol) a solution of K2CO3 (2.301 g, 16.65 mmol) in water (20 mL) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification [SiChgel (40 g), eluting with EtOAc in hexane from 0-60%] 2-amino-5- (dimethylamino)-lH-indole-3-carbonitrile (215c) (0.94 g, 56% yield) as a plum solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.32 (s, 1H), 6.96 (d, J= 8.5 Hz, 1H), 6.56 (s, 2H), 6.48 (d, J = 2.3 Hz, 1H), 6.44 (dd, J= 8.6, 2.4 Hz, 1H), 2.82 (s, 6H); MS (ES+): 201 (M+1), (ES-): 199 (M-1).

Step-3: Preparation of N6,N6-dimethyl-9H-pyrimido[4,5-b]indole-4,6-diamine (215d)

Compound 215d was prepared according to the procedure reported in step-2 of scheme-29, from 2-amino-5-(dimethylamino)-lH-indole-3-carbonitrile (215c) (0.94 g, 4.69 mmol) in ethanol (30 mL) using formamidine acetate (3.91 g, 37.6 mmol) and heating at 80 °C for 16 h. This gave after work up and purification by flash column chromatography [SiChgel (24 g), eluting with CMA-80 in DCM from 0-20%] N6,N6-dimethyl-9H-pyrimido[4,5-b]indole-4,6- diamine (215d) (0.26 g, 24% yield) as a pale-green solid; Ή NMR (300 MHz, DMSO-ffc) δ 11.42 (s, 1H), 8.17 (s, 1H), 7.56 (d, J = 2.4 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 7.09 (s, 2H), 6.91 (dd, J = 8.8, 2.4 Hz, 1H), 2.93 (s, 6H); MS (ES+): 228 (M+l), (ES-): 226 (M-l).

Step-4: Preparation of tort-butyl 2-(4-amino-6-(dimethylamino)-9H-pyrimido[4,5-b]indol-9- yl)acetate (215e)

Compound 215e was prepared according to the procedure reported in step-1 of scheme- 1, from N6,N6-dimethyl-9H-pyrimido[4,5-b]indole-4, 6-diamine (215d) (0.26 g, 1.144 mmol) in DMF (10 mL) using tort-butyl 2-bromoacetate (0.268 g, 1.373 mmol), CS2CO3 (0.746 g, 2.288 mmol) and stirring at RT for 16 h. This gave after work up and purification using flash column chromatography [SiChgel (40 g), methanol in DCM from 0-6%] tort-butyl 2-(4- amino-6-(dimethylamino)-9H-pyrimido[4,5-b]indol-9-yl)acetate (215e) (0.23 g, 59% yield) as a pale-yellow solid; Ή NMR (300 MHz, DMSO-cfe) δ 8.21 (s, 1H), 7.61 (d, J= 2.3 Hz, 1H), 7.36 (d, J= 8.9 Hz, 1H), 7.23 (d, J= 2.8 Hz, 2H), 6.94 (dd, J= 9.0, 2.3 Hz, 1H), 5.02 (s, 2H), 2.95 (s, 6H), 1.40 (s, 9H); MS (ES+): 342 (M+1).

Step-5 : Preparation of 2-(4-amino-6-(dimethylamino)-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (215f) Compound 215f was prepared according to the procedure reported in step-2 of scheme-1, from te/7-butyl 2-(4-amino-6-(dimethylamino)-9H-pyrimido[4,5-b]indol-9-yl)ac etate (215e) (230 mg, 0.674 mmol) using TFA (768 mg, 6.74 mmol) in DCM (10 mL) and stirring at RT for 16 h. This gave after work up TFA salt of 2-(4-amino-6-(dimethylamino)-9H- pyrimido[4,5-b]indol-9-yl)acetic acid (2150 (315 mg); Ή NMR (300 MHz, DMSO -ds) δ 8.54 (s, 3H), 8.02 (s, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.27 (d, J = 9.8 Hz, 1H), 5.22 (d, J = 4.3 Hz, 2H), 3.09 (s, 6H). ^!9 F NMR (282 MHz, DMSO-ί/β) δ -74.29; MS (ES+): 286 (M+l), (ES- ): 284 (M-l).

Step-6: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(dimethylamino)-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azab icyclo[3.1.0]hexane-3- carboxamide (215g)

Compound 215g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-(dimethylamino)-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (215f) (75 mg, 0.188 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carb oxamide (8a) (62.5 mg, 0.188 mmol), HATU (86 mg, 0.225 mmol), DIPEA (121 mg, 0.939 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6-(dimethylamino)-9H-pyrimido[4,5-b ]indol- 9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3 .1.0]hexane-3-caiboxamide (215g) (13 mg, 12% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSCWe/DiO) δ 8.44 (s, 1H), 8.25 (s, 1H), 7.92 (d, J= 8.2 Hz, 1H), 7.71 - 7.57 (m, 2H), 7.44 (dd, J= 9.0, 2.3 Hz, 1H), 7.28 (d, J= 7.7 Hz, 1H), 5.58 (d, J= 17.5 Hz, 1H), 5.36 (d, J= 17.4 Hz, 1H), 4.37 - 4.22 (m, 1H), 3.67 - 3.50 (m, 1H), 3.14 (s, 6H), 2.56 - 2.41 (m, 1H), 1.94 (dd, J= 13.3, 6.1 Hz, 1H), 1.27 (s, 3H), 1.00 (t ,J= 5.5 Hz, 1H), 0.95 - 0.81 (m, 1H); MS (ES+): 563/565 (M+l), (ES-): 561/563 (M-l).

Scheme 216 CF ₃

H ₂ N Me λ— NH Me FaCO^O O- CO ₂ H H ₂ N

NC [J Me

(C CN H

Et ₃ N in Cul, K2CO3

C0 ₂ Me C0 ₂ Me

CO _z Me

216a 216b 216c r C0 ₂ ^f Bu

H

Me Br'^CO Me TFA

NH _A OAC z'Bu

N

HC(OMe) ₃ r<sV f λ CS2CO ₃ oc f %

NH ₂ NH ₂

C0 ₂ Me C0 ₂ Me

216d 216e

<7

C0 ₂ H N i\

N l\ c:r Me H O 8a f 1 TU. DIPEA Λ Me

HA ⁰

NH ₂

C0 ₂ Me ex f s

NH ₂

C0 ₂ Me

216f

216g

Preparation of methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 5- methyl-2-azabicyclo[3.1 ,0]hexan-2-yl)-2-oxoethyl)-8-methyl-9H-pyrimido[4,5-b]indole -6- carboxylate (216g)

Step-1: Preparation of methyl 3-bromo-5-methyl-4-(2,2,2-trifluoroacetamido)benzoate (216b)

Compound 216b was prepared according to the procedure reported in step-1 of scheme-46, from methyl 4-amino-3 -bromo-5 -methy lbenzoate (216a) (5.00 g, 20.48 mmol; CAS # 900019-52-5) in DCM (25 mL) using triethylamine (3.52 g, 34.8 mmol) and trifluoroacetic acid anhydride (6.45 g, 30.7 mmol) in DCM (5 mL) and stirring at RT for 1 h. This gave after workup methyl 3-bromo-5-methyl-4-(2,2,2-trifluoroacetamido)benzoate (216b) (7.04 g) as a purple solid; Ή NMR (300 MHz, DMSO-cfc) δ 11.49 (s, 1H), 8.08 (d, J = 1.8 Hz, 1H), 7.96 (d, J = 1.9 Hz, 1H), 3.88 (s, 3H), 2.29 (s, 3H). ¹⁹ F NMR (282 MHz, DMSO-i/s) δ -74.06; MS (ES-): 338/340 (M-l).

Step-2: Preparation of methyl 2-amino-3 -cyano-7-methy 1 - 1 H-indole-5 -carboxylate (216c) Compound 216c was prepared according to the procedure reported in step-1 of scheme- 11, from methyl 3-bromo-5-methyl-4-(2,2,2-trifluoroacetamido)benzoate (216b) (7.04 g, 20.70 mmol) in DMSO (30 mL) using malononitrile (1.641 g, 24.84 mmol), L-proline (0.477 g, 4.14 mmol), Cul (394 mg, 2.070 mmol), a solution of K2CO3 (5.72 g, 41.4 mmol) in water (30 mL) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification [SiOzgel (40 g), eluting with EtOAc in hexane from 0-50%] methyl 2- amino-3-cyano-7-methyl-lH-indole-5-carboxylate (216c) (2.75 g, 58% yield) as an orange solid; ^l HNMR (300 MHz, DMSO-tik) δ 11.18 (s, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.41 (dd, J = 1.6, 0.9 Hz, 1H), 6.79 (s, 2H), 3.82 (s, 3H), 2.39 (s, 3H). MS (ES+): 230 (M+l), (ES-): 228 (M-l).

Step-3: Preparation of methyl 4-amino-8-methy l-9H-pyrimido [4,5 -b] indole -6-carboxylate (216d)

Compound 216d was prepared according to the procedure reported in step-2 of scheme-29, from methyl 2-amino-3-cyano-7-methyl-lH-indole-5-carboxylate (216c) (2.75 g, 12 mmol) using NHUOAc (2.77 g, 36.0 mmol), HC(OMe)3 (12.73 g, 120 mmol) and heating at 90 °C for 16 h. This gave after work up methyl 4-amino-8-methyl-9H-pyrimido[4,5-b]indole-6- carboxylate (216d) (2.65 g, 86% yield) as a pale-yellow solid; ‘HNMR (300 MHz, DMSO- ek) δ 12.22 (s, 1H), 8.78 (s, 1H), 8.30 (s, 1H), 7.80 (s, 1H), 7.34 (s, 2H), 3.88 (s, 3H), 2.57 (s, 3H); MS (ES+): 257 (M+l), (ES-): 255 (M-l).

Step-4: Preparation of methyl 4-amino-9-(2-(tert-butoxy)-2-oxoethyl)-8-methyl-9H- pyrimido[4,5-b]indole-6-carboxylate (216e)

Compound 216e was prepared according to the procedure reported in step-1 of scheme- 1, from methyl 4-amino-8-methyl-9H-pyrimido[4,5-b]indole-6-carboxylate (216d) (2.00 g, 7.80 mmol) in DMF (15 mL) using tort-butyl 2-bromoacetate (1.827 g, 9.37 mmol), CS2CO3 (5.09 g, 15.61 mmol) and stirring at RT for 16 h. This gave after work up methyl 4-amino-9-(2- (tert-butoxy)-2-oxoethyl)-8-methyl-9H-pyrimido[4,5-b]indole- 6-caiboxylate (216e) (2.25 g, 78 % yield) as a beige solid; Ή NMR (300 MHz, DMSOK/ ₆ ) δ 8.82 (d, J= 1.6 Hz, 1H), 8.34 (s, 1H), 7.79 (s, 1H), 7.51 (s, 2H), 5.39 (s, 2H), 3.90 (s, 3H), 2.69 (s, 3H), 1.43 (s, 9H); MS (ES+): 371 (M+l), (ES-): 369 (M-l).

Step-5: Preparation of 2-(4-arnino-6-(methoxycarbonyl)-8-me1hyl-9H-pyrimido[4,5-b]i ndol- 9-yl)acetic acid (216f) Compound 216f was prepared according to the procedure reported in step-2 of scheme-1, from methyl 4-amino-9-(2-(te/f-butoxy)-2-oxoethyl)-8-methyl-9H-pyrimido[ 4,5-b]indole-6- carboxylate (216e) (1.10 g, 2.97 mmol) in DCM (15 mL) using TFA (3.39 g, 29.7 mmol) and stirring at RT for 16 h. This gave after work up TFA salt of 2-(4-amino-6- (methoxycarbonyl)-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)acet ic acid (216f) (1.65 g); Ή NMR (300 MHz, DMSO-fife) δ 8.96 (s, 1H), 8.75 - 8.62 (m, 2H), 8.60 (s, 1H), 7.89 (s, 1H), 5.48 (s, 2H), 3.92 (s, 3H), 2.74 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO) δ -74.69; MS (ES+): 315 (M+l), (ES-): 313 (M-l).

Step-6: Preparation of methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2- yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoe thyl)-8-methyl-9H- pyrimido[4,5-b]indole-6-carboxylate (216g)

Compound 216g was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-amino-6-(methoxycarbonyl)-8-methyl-9H-pyrimido[4,5-b]in dol-9- yl)acetic acid (216f) (125 mg, 0.292 mmol) in DMF (5 ml) using HC1 salt of (1R,3S,5R)-N- (6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-c arboxamide (8a) (97 mg, 0.292 mmol), HATU (133 mg, 0.350 mmol), DIPEA (189 mg, 1.459 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2- yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoe thyl)-8-methyl-9H- pyrimido[4,5-b]indole-6-carboxylate (216g) (105 mg, 61% yield) HC1 salt as awhile solid; ^! HNMR (300 MHz, DMSO-ifc) δ 10.83 (s, 1H, DzO exchangeable), 8.94 (s, 1H), 8.85 (s, 2H, DzO exchangeable), 8.66 (s, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.86 (s, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 5.91 (d, J = 18.0 Hz, 1H), 5.62 (d, J = 17.9 Hz, 1H), 4.39 (dd, J = 9.0, 6.1 Hz, 1H), 3.90 (s, 3H), 3.71 (dd, J = 5.5, 2.3 Hz, 1H), 2.73 (s, 3H), 2.48 - 2.44 (m, 1H), 1.98 (dd, J = 13.3, 6.0 Hz, 1H), 1.31 (s, 3H), 1.03 (t, J = 5.5 Hz, 1H), 0.85 (dd, J = 5.5, 2.4 Hz, 1H); MS (ES+): 592/594 (M+l), (ES-): 590/592 (M-l); Analysis calculated for C27H26BrN ₇ O4.0.9HC1.2.5H2O: C, 48.38; H, 4.80; Cl, 4.76; N, 14.63; Found: C, 48.38; H, 4.71; Cl, 4.94; N, 14.34.

Scheme 217

217a

Preparation of methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-8-methyl-9H-pyrimid o[4,5-b]indole-6-carboxylate (217a)

Compound 217a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-(methoxycarbonyl)-8-methyl-9H-pyrimido[4,5-b]in dol-9- yl)acetic acid (216f) (125 mg, 0.292 mmol) in DMF (5 mL) using HC1 salt of (1R,3S,5R)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (4a) (93 mg, 0.292 mmol), HATU (133 mg, 0.350 mmol), DIPEA (189 mg, 1.459 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-8-methyl-9H-pyrim ido[4,5-b]indole-6- cafboxylate (217a) (110 mg, 65% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-de) δ 10.83 (s, 1H, DzO exchangeable), 8.94 (s, 1H), 8.79 - 8.43 (m, 3H, 2H DzO exchangeable), 8.00 (d, J = 8.2 Hz, 1H), 7.86 (s, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 5.95 (d, J = 18.0 Hz, 1H), 5.67 (d, J = 18.0 Hz, 1H), 4.42 (dd, J = 9.1, 5.7 Hz, 1H), 3.96-3.89 (m, 4H), 2.75 (s, 3H), 2.43 - 2.29 (m, 1H), 2.29 - 2.11 (m, 1H), 2.01 - 1.87 (m, 1H), 1.18 - 1.04 (m, 1H), 0.77 - 0.63 (m, 1H); MS (ES+): 578/580 (M+l), (ES-): 576/578 (M-l); Analysis calculated for Cz6Hz4BrN7O*.0.9HC1.2.25HzO: C, 47.91; H, 4.55; Cl, 4.90; N, 15.04; Found: C, 47.86; H, 4.52; Cl, 4.67; N, 15.08.

Scheme 218

217a 218a

Preparation of 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 2- azabic>'clo[3.1.0]hexan-2-yl)-2-oxoethyl)-8-methyl-9H-pyr imido[4,5-b]indole-6-carboxylic acid (218a)

Compound 218a was prepared according to the procedure reported in step-4 of scheme- 17, from methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-8-methyl-9H-pyiimid o[4,5-b]indole-6-carboxylate (217a) (60 mg, 0.104 mmol) in THF (2 mL) and HbO (1 mL) using 2 M aqueous LiOH (0.052 mL, 0.104 mmol) and stirring for 16 h at RT. This gave after workup and purification by reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] HC1 salt of 4-amino-9-(2-((lR,3S,5R)-3-((6- bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1 ,0]hexan-2-yl)-2-oxoethyl)-8-methyl-9H- pyrimido[4,5-b]indole-6-carboxylic acid (218a) (15 mg, 26 % yield) as a white solid. Ή NMR (300 MHz, DMSO-flk) (mixture of two retainers) δ 12.93 (bs, 1 H, D2O exchangeable), 10.89 and 10.83 (s, 1H, DzO exchangeable), 8.91 (s, 1H), 8.60 (d, J = 1.9 Hz, 1H), 8.53 (s, 2H, D2O exchangeable), 8.02 and 7.96 (d, J = 8.1 Hz, 1H), 7.85 (s, 1H), 7.69 (q, J = 8.0 Hz, 1H), 7.30 (dd, J = 7.7, 5.0 Hz, 1H), 5.94 (dd, J = 17.9, 2.4 Hz, 1H), 5.67 (d, J = 17.9 Hz, 1H), 4.91 and 4.44 (dd, J = 10.1, 4.7 Hz, 1H), 3.97 - 3.91 (m, 1H), 2.79 and 2.74 (s, 3H), 2.44 - 2.15 (m, 2H), 1.97 - 1.81 (m, 1H), 1.27 - 1.02 (m, 1H), 0.97 and 0.70 (m, 1H); MS (ES+): 564/566 (M+l), (ES-): 562/564 (M-l).

Scheme 219

216g 219a

Preparation of 4-amino-9-(2-(( lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-5-methyl-2- azabicyclo[3.1 0]hexan-2-yl)-2-oxoethyl)-8-methyl-9H-pyrimido[4,5-b]indole- 6-carboxylic acid (219a)

Compound 219a was prepared according to the procedure reported in step-4 of scheme- 17, from methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 5-methyl-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyI)-8-methyl-9H-pyrimid o[4,5-b]indole-6-carboxylate (216g) (64 mg, 0.108 mmol) in THF (2 mL) and water (1 mL) using 2M aqueous lithium hydroxide hydrate (0.054 mL, 0.108 mmol) and stirring at RT for 16 h. This gave after workup and purification by reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0- 100%]4-amino-9-(2-(( 1R,3 S,5R)- 3-((6-bromopyridin-2-yl)carbamoyl)-5-methyl-2-azabicyclo[3.1 ,0Jhexan-2-yl)-2-oxoethyl)-8- methyl-9H-pyrimido[4,5-b]indole-6-carboxylic acid (219a) (23 mg, 37 % yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifo) (mixture of two rotamers) δ 12.97 (bs, 1H, DzO exchangeable), 10.89 and 10.82 (s, 1H, DzO exchangeable), 8.91 (s, 1H), 8.61 (d, J = 2.5 Hz, 1H), 8.60 (s, 2H, D2O exchangeable), 8.02 and 7.95 (d, J = 8.1 Hz, 1H), 7.85 (s, 1H), 7.69 (q, J = 7.8 Hz, 1H), 7.30 (dd, J = 7.7, 4.9 Hz, 1H), 5.90 (d, J = 18.0 Hz, 1H), 5.62 (d, J = 17.9 Hz, 1H), 4.91 and 4.41 (dd, J = 10.0, 4.7 Hz, 1H), 3.71 - 3.68 (m, 1H), 2.77 and 2.73 (s, 3H), 2.53 - 2.33 (m, 1H), 2.13 - 1.93 (m, 1H), 1.31 (s, 3H), 1.07 - 0.98 (m, 1H), 0.91 - 0.81 (m, 1H); MS (ES+): 578/580 (M+l), (ES-): 576/578 (M-l).

Scheme 220 H N Br

47g 220a

Preparation of 4-amino-9-(2-(( lR,3S,5R)-3-((6-bromopyiidin-2-yI)carbamoyI)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]i ndole-8-carboxylic acid (220a)

Compound 220a was prepared according to the procedure reported in step-4 of scheme- 17, from methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]i ndole-8-carboxylate (47g)

(130 mg, 0.230 mmol) in THF (2 mL) and water (4 mL) using IN aqueous lithium hydroxide hydrate (0.461 mL, 0.461 mmol) and stirring at RT for 16 h. This gave after workup and purification by reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-50%] 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin- 2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9 H-pyrimido[4,5-b]indole-8- carboxylic acid (220a) (10 mg, 8% yield) HC1 salt as a white solid; ^! H NMR (300 MHz, DMSO-tfc) δ 13.28 (s, 1H), 10.70 (s, 1H), 8.61 (d,J= 7.8 Hz, 1H), 8.49 (s, 1H), 7.97 (d,J= 8.2 Hz, 1H), 7.84 (d, J= 7.5 Hz, 1H), 7.67 (t, J= 8.0 Hz, 1H), 7.39 (t, J= 7.8 Hz, 1H), 7.29 (d, J= 7.7 Hz, 1H), 6.00 (d ,J= 17.4 Hz, 1H), 5.68 (d, J= 17.3 Hz, 1H), 4.34 (dd, J= 8.8, 5.7 Hz, 1H), 3.87 - 3.67 (m, 1H), 2.38 - 2.10 (m, 2H), 1.96 - 1.80 (m, 1H), 1.14 - 0.97 (m, 1H), 0.89 - 0.77 (m, 1H); MS (ES+): 552.10 (M+l); MS (ES+): 550.10 & 552.10 (M+l), MS (ES- ): 548.10 & 550.00 (M-l).

Scheme 221

(R = Me, Et mixture)

Preparation of methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 5- methvi-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimid o[4,5-b]indole-5-carboxviate

(221c)

Step-1: Preparation of methyl 4-amino-9-( 2-(tert-butoxy)-2-oxoethyl)-9H-pyrim ido [4,5- b]indole-5-carboxylate (221a)

Compound 221a was prepared according to the procedure reported in step-1 of scheme- 1, from a mixture of methyl/ethyl 4-amino-9H-pyrimido[4,5-b]indole-5-carboxylate (46d) (230 mg) in DMF (15 mL) using tort-butyl 2-bromoacetate (0.168 mL, 1.139 mmol), CS2CO3 (773 mg, 2.374 mmol) and stirring at RT for 14 h. This gave after work up and purification using flash column chromatography [S1O2 gel (25 g), eluting with methanol/ethyl acetate (1:9) in hexanes from 0-50%] methyl 4-amino-9-(2-(tert-butoxy)-2-oxoethyl)-9H-pyrimido[4,5- b]indole-5-carboxylate (221a) (76 mg); Ή NMR (300 MHz, DMSO-ifc) δ 8.33 (s, 1H), 7.92 (dd, J= 8.2, 1.1 Hz, 1H), 7.83 (dd,J= 7.8, 1.1 Hz, 1H), 7.56 (t ,J= 7.9 Hz, 1H), 7.25 (s, 2H), 5.23 (s, 2H), 4.01 (s, 3H), 1.40 (s, 9H); MS (ES+): 357.20 (M+l).

Step-2: Preparation of 2-(4-amino-5-(methoxycarbony l)-9H-pyrimido [4, 5 -b] indol-9-yl)acetic acid (221b) Compound 221b was prepared according to the procedure reported in step-2 of scheme-1, from methyl 4-amino-9-(2-(te/†-butoxy )-2-oxoethyl)-9H-pyrimido [4,5 -b] indole-5 - carboxylate (221a) (75 mg, 0.21 mmol) in DCM (10 mL) using TFA (0.486 mL, 6.31 mmol) and stirring at RT for 17 h. This gave after work up 2-(4-amino-5-(methoxycarbonyl)-9H- pyrimido[4,5-b]indol-9-yl)acetic acid (221b) (99 mg) as TFA salt which was used as such for the next step; MS (ES+): 301.10 (M+l).

Step-3: Preparation of 2methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2- yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoe thyl)-9H-pyrimido[4,5- b]indole-5-carboxylate (221c)

Compound 221c was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-amino-5-(methoxycarbonyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (221b) (63 mg, 0.210 mmol) in DMF (10 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.OJhexane-3-carb oxamide (8a) (84 mg, 0.252 mmol), HATU (160 mg, 0.420 mmol), DIPEA (0.183 mL, 1.05 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH/EtOAc (1:9) in hexanes from 0 - 60%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin- 2-yl)carbamoyl)-5-methyl-2-azabicyclo[3.1 ,0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5- b]indole-5-carboxylate (221c) (52 mg, 43% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-Kfc) δ 10.77 (s, 1H), 8.64 (s, 1H), 8.34 (s, 2H), 8.04 - 7.97 (m, 3H), 7.73 - 7.64 (m, 2H), 7.31 (d, J= 7.7 Hz, 1H), 5.81 (d, J= 17.4 Hz, 1H), 5.46 (d, ./= 17.3 Hz, 1H), 4.37 (dd, J= 9.1, 5.9 Hz, 1H), 4.00 (s, 3H), 3.70 (dd, J= 5.5, 2.4 Hz, 1H), 2.54 - 2.39 (m, 1H), 1.98 (dd, J= 13.2, 5.9 Hz, 1H), 1.31 (s, 3H), 1.02 (t, J= 5.5 Hz, 1H), 0.96 (dd,J= 5.3, 2.4 Hz, 1H); MS (ES+): 578.10 & 580.10 (M+l), MS (ES-): 576.10 & 578.10 (M-l); Analysis calculated for C26H24BrN7O4.HCl.2H2O: C, 47.98; H, 4.49; Cl, 5.45; N, 15.06; Found: C, 48.24; H, 4.63; Cl, 5.30; N, 15.14.

Scheme 222

Preparation of 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 5-methyl-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyI)-9H-pyrimido[4,5-b]i ndoIe-5-carboxylic acid (222a)

Compound 222a was prepared according to the procedure reported in step-4 of scheme- 17, from methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 5-methyl-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]i ndole-5-carboxylate (221c) (100 mg, containing ethyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 5- methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimid o[4,5-b]indole-5-carboxylate, ratio: 1:1) in THF (2 mL) and water (4 mL) using IN aqueous lithium hydroxide hydrate (0.346 mL, 0. 346 mmol) and stirring at RT for 16 h. This gave after workup and purification by reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-50%] 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2- yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoe thyl)-9H-pyrimido[4,5- b]indole-5-carboxylic acid (222a) (6 mg, 6% yield) HC1 salt as a white solid; ¾i NMR (300 MHz, DMSO-ofe) δ 10.85 (s, 1H), 8.55 (s, 1H), 8.27 (s, 2H), 8.01 - 7.86 (m, 3H), 7.68 (t, J= 8.0 Hz, 1H), 7.62 (t, J= 7.9 Hz, 1H), 7.30 (d, J= 7.6 Hz, 1H), 5.80 - 5.71 (m, 1H), 5.44 (d, J = 17.0 Hz, 1H), 4.96 - 4.84 (m, 1H), 3.77 - 3.67 (m, 1H), 2.46 - 2.35 (m, 1H), 2.12 - 1.99 (m, 1H), 1.46 - 1.37 (m, 1H), 1.31 (s, 3H), 0.92 - 0.82 (m, 1H); MS (ES+): 564.10 & 566.10 (M+l), MS (ES-): 562.00 & 564.10 (M-l).

Scheme 223

47f

223a

Preparation of methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridm-2-yl)carbamoyl)-5 - methvi-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimid o[4,5-b]indole-8-carboxviate

(223a)

Compound 223a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-(methoxycarbonyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (47f) (152 mg, 0.505 mmol) in DMF (10 rtiL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hcxane-3-carb oxamide (8a) (168 mg, 0.505 mmol), HATU (288 mg, 0.758 mmol), DIPEA (0.440 mL, 2.53 mmol) and stirring at RT for 19 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 5%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-70%] methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 5-methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrim ido[4,5-b]indole-8- carboxylate (223a) (215 mg, 74% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-d!s) δ 10.74 (s, 1H), 8.73 (dd, J= 7.9, 1.2 Hz, 1H), 8.64 (s, 1H), 8.58 (s, 3H), 7.99 (d, J= 8.2 Hz, 1H), 7.87 (dd, J= 7.7, 1.1 Hz, 1H), 7.69 (t, 8.0 Hz, 1H), 7.47 (t, J= 7.8 Hz,

1H), 7.30 (d, J= 7.7 Hz, 1H), 5.93 (d ,J= 17.5 Hz, 1H), 5.62 (d, J= 17.4 Hz, 1H), 4.31 (dd,./ = 9.0, 6.0 Hz, 1H), 3.92 (s, 3H), 3.59 (dd, J= 5.3, 2.2 Hz, 1H), 2.51 - 2.35 (m, 1H), 1.96 (dd, J= 13.2, 6.0 Hz, 1H), 1.30 (s, 3H), 1.04 (ζ J= 5.5 Hz, 1H), 0.90 (dd, J= 5.5, 2.3 Hz, 1H);

MS (ES+): 578.10 & 580.10 (M+l), MS (ES-): 576.10 & 578.10 (M-l); Analysis calculated for C26H24BrN7O4.0.95HC1.2.25H2O: C, 47.78; H, 4.54; Cl, 5.15; N, 15.00; Found: C, 47.67; H, 4.37; Cl, 4.86; N, 14.71.

Scheme 224

Preparation of 4-amino-9-(2-(( lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoe1hyl)-9H-pyrimido[4,5-b]i ndole-5-carboxylic acid (224b)

Step-1: Preparation of methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2- yl)caibamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyI)-9H- pyrimido[4,5-b]indoIe-5- carboxylate (224a)

Compound 224a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-5-(methoxycarbonyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (221b) (61 mg, containing 2-(4-amino-5-(ethoxycarbonyl)-9H-pyrimido[4,5-b]indol-9- yl)acetic acid, ratio: 1:1) in DMF (10 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin- 2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (77 mg, 0.242 mmol), HATU (154 mg, 0.404 mmol), DIPEA (0.176 mL, 1.010 mmol) and stirring at RT for 19 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH/EtOAc (1:9) in hexanes from 0 - 60%] methyl 4-amino-9-(2-(( 1R,3 S,5R)-3-((6- bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)- 2-oxoethyl)-9H-pyrimido[4,5- bJindole-5-carboxylate (224a) (115 mg, containing ethyl 4-amino-9-(2-(( 1R,3 S,5R)-3-((6- bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1 ,0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5- b]indole-5-carboxylate, ratio: 1:1) as a white solid; MS (ES+): 564.10 (M+l).

Step-2: Preparation of 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 2- azabicyclo[3.1.0]hexan-2-yI)-2-oxoethyl)-9H-pyrimido[4,5-b]i ndole-5-carboxylic acid (224b)

Compound 224b was prepared according to the procedure reported in step-4 of scheme- 17, from methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 2- azabicyclo[3.1 0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-bJindole-5-carboxy late (224a) azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]i ndole-5-carboxylate, ratio:

1:1) in THF (2 mL) and water (4 mL) using IN aqueous lithium hydroxide hydrate (0.354 mL, 0.354 mmol) and stirring at RT for 16 h. This gave after workup and purification by reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-50%] 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2- yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H- pyrimido[4,5-b]indole-5- carboxylic acid (224b) (2 mg, 2% yield) HC1 salt as a white solid; ^! H NMR (300 MHz, DMSO-ifc) δ 10.85 (s, 1H), 8.56 (s, 1H), 8.28 (s, 2H), 8.00 - 7.88 (m, 3H), 7.74 - 7.57 (m, 2H), 7.31 (d, 1H), 5.80 (d ,J= 17.3 Hz, 1H), 5.48 (d ,J= 17.2 Hz, 1H), 4.90 (dd,J= 11.5, 3.8 Hz, 1H), 4.03 - 3.88 (m, 1H), 2.69 - 2.52 (m, 1H), 2.02 - 1.72 (m, 2H), 1.33 - 1.15 (m, 1H), 1.03 - 0.86 (m, 1H); MS (ES+): 550.10 & 552.10 (M+l), MS (ES-): 548.10 & 550.00 (M-l).

Scheme 225

Preparation of methyl (4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl) -2- azabic>'clo[3.1.0]hexan-2-yl)-2-oxoe1hyl)-9H-pyrimido[4,5 -b]indol-6-yl)carbamate (225e)

Step-1: Preparation of 4-amino-9H-pyiimido[4,5-b]indole-6-carbonyl azide (225a)

To a suspension of 4-amino-9H-pyrimido[4,5-b]indole-6-carboxylic acid (169a) (1 g, 4.38 mmol) in THF (25 mL) and DMF (25.00 mL) was added triethylamine (1.832 pL, 13.15 (2.93 mL, 13.15 mmol; CAS # 26386-88-9) and stirred at RT for 22 h. The reaction mixture was concentrated to dryness to afford 4-amino-9H-pyrimido [4, 5 -b] indole-6-carbonyl azide (225a) (4.29 g) which was used as such for the next step; MS (ES+): 254.10 (M+l).

Step-2: Preparation of methyl (4-amino-9H-pyrimido[4,5-b]indol-6-yl)carbamate (225b)

To a suspension of 4-amino-9H-pyrimido[4,5-b]indole-6-carbonyl azide (225a) (111 mg) in toluene (4 mL) was added methanol (6.03 mL, 149 mmol), triethylamine (0.366 mL, 2.63 mmol) and stirred at 115 °C for 4 h in a microwave. The reaction mixture was concentrated in vacuum and purified using flash column chromatography [silica gel (24 g), eluting with MeOH in DCM from 0-10%] to afford methyl (4-amino-9H-pyrimido[4,5-b]indol-6- yl)carbamate (225b) (96 mg) as a white solid; MS (ES+): 258.10 (M+l).

Step-3: Preparation of ter/-butyl 2-(4-amino-6-((methoxycarbonyl)amino)-9H-pyrimido[4,5- b]indol-9-yl)acetate (225c)

Compound 225c was prepared according to the procedure reported in step-1 of scheme- 1 , from methyl (4-amino-9H-pyrimido[4,5-b]indol-6-yl)carbamate (225b) (90 mg, 0.350 mmol) in DMF (10 mL) using tert- butyl 2-bromoacetate (0.062 mL, 0.420 mmol) CS2CO3 (285 mg, 0.875 mmol) and stirring at RT for 20 h. This gave after workup terf-butyl 2-(4-amino-6- ((methoxycarbonyl)amino)-9H-pyrimido[4,5-b]indol-9-yl)acetat e (225c) as a brown solid (75 mg) which was used as such for the next step; MS (ES+): 372.20 (M+l).

Step-4: Preparation of 2-(4-amino-6-((methoxycarbonyl)amino)-9H-pyrimido[4,5-b]indo l-9- yl)acetic acid (225d)

Compound 225d was prepared according to the procedure reported in step-2 of scheme- 1, from fert-butyl 2-(4-amino-6-((methoxycarbonyl)amino)-9H-pyrimido [4,5 -b] indol-9- yl)acetate (225c) (75 mg) in DCM (10 mL) using TFA and stirring at RT. This gave after workup TFA salt of 2-(4-amino-6-((methoxycarbonyl)amino)-9H-pyrimido[4,5-b]indo l-9- yl)acetic acid (225d) which was used as such for next step; MS (ES+): 316.10 (M+l).

Step-5: Preparation of methyl (4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2- yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H- pyrimido[4,5-b]indol-6- yl)carbamate (225e)

Compound 225e was prepared according to the procedure reported in step-3 of scheme- 1, yl)acetic acid (225d) (64 mg, 0.202 mmol) in DMF (12 mL) using HC1 salt of (1R,3S,5R)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamid e (4a) (97 mg, 0.303 mmol), HATU (154 mg, 0.404 mmol), DIPEA (0.176 mL, 1.010 mmol) and stirring at RT for 20 h. This gave after woikup and purification by flash column chromatography [silica gel (25 g), eluting with MeOH in DCM from 0-5%] followed by purification using reverse phase column chromatography [C18 column, eluting with ACN in water (containing 0.1% HC1) from 0-100%] methyl (4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl) -2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]i ndol-6-yl)carbamate (225e) (52 mg, 44 % yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-t/6) δ 10.77 (s, 1H), 9.61 (s, 1H), 8.67 - 8.59 (m, 3H), 8.43 (d, J= 1.9 Hz, 1H), 8.00 (d, J= 8.2 Hz, 1H),

7.70 (t, ./= 8.0 Hz, 1H), 7.63 (d, J= 8.8 Hz, 1H), 7.46 (dd, J= 8.8, 1.9 Hz, 1H), 7.32 (d, J= 7.7 Hz, 1H), 5.74 (d, J= 17.3 Hz, 1H), 5.40 (d ,J= 17.3 Hz, 1H), 4.42 (dd, J= 9.1, 5.5 Hz, 1H), 3.99 - 3.78 (m, 1H), 3.69 (s, 3H), 2.43 - 2.09 (m, 2H), 2.02 - 1.79 (m, 1H), 1.14 - 0.96 (m, 1H), 0.85 - 0.68 (m, 1H); MS (ES+): 579.10 & 581.10 (M+l), MS (ES-): 577.00 & 579.10 (M-l); Analysis calculated for CzsHzsBrNeO+.l .15HC1.2.25H20: C, 45.37; H, 4.36;

N: 16.93; Cl, 6.16. Found: C, 45.49; H, 4.22; N, 16.61; Cl: 5.98.

Scheme 226

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(pyridin-4-yl)-9H-pyrimido[4,5-b] indol-9- yl)acet>'l)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (226c)

Step-1: Preparation of ethyl 2-(4-amino-6-(pyridin-4-yl)-9H-pyrimido[4,5-b]indol-9- yl)acetate (226a)

Compound 226a was prepared according to the procedure reported in step-1 of scheme-62, from ethyl 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (48a) (200 mg, 0.573 mmol) in dioxane (18 mL) using pyridin-4-ylboronic acid (106 mg, 0.859 mmol), cesium carbonate (280 mg, 0.859 mmol) in water (2.2 mL), Pd(PPh3)2Ch (80 mg, 0.115 mmol) and heating at 100 °C for 13 h under nitrogen. This gave after workup and purification using flash column chromatography [silica gel (25 g), eluting with MeOH in DCM from 0 - 8%] ethyl 2- (4-amino-6-(pyridin-4-yl)-9H-pyrimido[4,5-b]indol-9-yl)aceta te (226a) (34 mg, 17% yield) as a white solid; ; Ή NMR (300 MHz, DMSO-fife) δ 8.81 (d, J= 1.7 Hz, 1H), 8.68 - 8.60 (m, 2H), 8.32 (s, 1H), 7.96 - 7.88 (m, 3H), 7.75 (d, J= 8.6 Hz, 1H), 7.54 (s, 2H), 5.29 (s, 2H), 4.15 (q ,J= 7.1 Hz, 2H), 1.21 (t,./= 7.1 Hz, 3H); MS (ES+): 348.20 (M+l). Step-2: Preparation of 2-(4-amino-6-(pyridin-4-yl)-9H-pyrimido[4,5-b]indol-9-yl)ace tic acid (226b)

Compound 226b was prepared according to the procedure reported in step-4 of scheme- 17, from ethyl 2-(4-amino-6-(pyridin-4-yl)-9H-pyrimido[4,5-b]indol-9-yl)ace tate (226a) (32 mg, 0.092 mmol) in THF (3 mL) and methanol (3 mL) using a solution of lithium hydroxide hydrate (23.67 mg, 0.553 mmol) in water (3 mL) and stirring at RT for 14 h. This gave after workup 2-(4-amino-6-(pyridin-4-yl)-9H-pyrimido[4,5-b]indol-9-yl)ace tic acid (226b) which was used as such for the next step; MS (ES+): 320.10 (M+l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(pyridin-4-yl)-9H-pyrimido[4,5-b] indol- 9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexa ne-3-carboxamide (226c)

Compound 226c was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-6-(pyridin-4-yl)-9H-pyrimido[4,5-b]indol-9-yl)ace tic acid (226b) (0.029 g, 0.092 mmol) in DMF (8 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (4a) (44 mg, 0.138 mmol), HATU (70 mg, 0.184 mmol), DIPEA (0.080 mL, 0.460 mmol) and stirring at RT for 19 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 10%] followed by purification using reverse phase column chromatography [C18 column, eluting with ACN in water (containing 0.1% HC1) from 0-100%] (1R,3S,5R)- 2-(2-(4-amino-6-(pyridin-4-yl)-9H-pyrimido[4,5-b]indol-9-yl) acetyl)-N-(6-bromopyridin-2- yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (226c) (29 mg, 51% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-tife) δ 10.77 (s, 1H), 9.19 (d, J = 1.8 Hz, 1H), 8.97 (d, J = 6.5 Hz, 2H), 8.70 - 8.53 (m, 5H), 8.25 (dd, J= 8.9, 1.7 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H),

7.89 (d, J= 8.8 Hz, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.31 (d, J= 7.7 Hz, 1H), 5.82 (d, J= 17.4 Hz, 1H), 5.47 (d, ./= 17.3 Hz, 1H), 4.42 (dd, J= 9.1, 5.5 Hz, 1H), 4.03 - 3.83 (m, 1H), 2.45 - 2.08 (m, 2H), 2.00 - 1.79 (m, 1H), 1.21 - 0.98 (m, 1H), 0.88 - 0.68 (m, 1H); MS (ES+): 583.10 & 585.10 (M+l), MS (ES-): 581.10 & 583.10 (M-l); Analysis calculated for C28H23BrN ₈ O2.2.75HC1.3.0 HzO: C, 45.58; H, 4.34; N, 15.19; Found: C, 45.81; H, 4.30; N, 15.10.

Scheme 227

227b 227c

Preparation of (lR,3S,5R)-2-(2-(4-amino-7-phenyl-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamid e (227c)

Step-1: Preparation of tert-butyl 2-(4-amino-7-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (227a)

Compound 227a was prepared according to the procedure reported in step-1 of scheme-62, from tort-butyl 2-(4-amino-7-bromo-9H-pyrimido[4,5-bJindol-9-yl)acetate (17c) (400 mg, 1.06 mmol) in dioxane (10 mL) using phenyl boronic acid (194 mg, 1.591 mmol), a solution of 3.3 M aqueous K2CO3 (0.964 mL, 3.18 mmol), Pd(PPh3)zCl2 (74 mg, 0.106 mmol) and heating at 100 °C for 16 h under nitrogen. This gave after workup and purification using flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 4%] tert- butyl 2-(4-amino-7-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (227a) (242 mg, 61% yield) as a pale-brown solid; Ή NMR (300 MHz, DMSO-tfc) δ 8.42 (d, J= 8.2 Hz, 1H), 8.30 (s, 1H), 7.92 (s, 1H), 7.82 (d, 2H), 7.60 (dd, J= 8.1, 1.5 Hz, 1H), 7.51 (t, J= 7.6 Hz, 2H), 7.43 - 7.37 (m, 1H), 7.35 (d,J= 5.5 Hz, 2H), 5.22 (s, 2H), 1.41 (s, 9H); MS (ES+): 375 (M+l). Step-2: Preparation of 2-(4-amino-7-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (227b)

Compound 227b was prepared according to the procedure reported in step-2 of scheme- 1 , from firf-butyl 2-(4-amino-7-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (227a) (242 mg, 0.646 mmol) in DCM (5 mL) using TFA (737 mg, 6.46 mmol) and stirring at RT for 16 h. yl)acetic acid (227b) (343 mg) which was used as such for the next step; Ή NMR (300 MHz, DMSO-ifc) δ 8.68 - 8.48 (m, 4H), 8.19 (s, 1H), 7.88 (d, J = 1.5 Hz, 1H), 7.87 (s, 1H), 7.79 (dd, J = 8.3, 1.5 Hz, 1H), 7.53 (dd, J = 8.3, 6.9 Hz, 2H), 7.46 - 7.38 (m, 1H), 5.38 (s, 2H). ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -74.50; MS (ES+): 319 (M+l), (ES-): 317 (M-l); Analysis calculated for Cz9Hz4BrN ₇ Oz.HC1.2.5HzO: C, 52.46; H, 4.55; Cl, 5.34; N, 14.77; Found: C, 52.45; H, 4.40; Cl, 5.47; N, 14.76.

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-7-phenyl-9H-pyriznido[4,5-b]indol-9 - yl)acet>'l)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (227c)

Compound 227c was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-7-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (227b) (75 mg, 0.173 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (4a) (55.3 mg, 0.173 mmol), HATU (79 mg, 0.208 mmol), DIPEA (112 mg, 0.867 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-7-phenyl-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (227c) (54 mg, 53% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.77 (s, 1H, DzO exchangeable), 8.71 (s, 2H, DzO exchangeable), 8.64 (s, 1H), 8.60 (d, J = 8.3 Hz, 1H), 8.07 - 7.95 (m, 2H), 7.84 (d, J = 1.5 Hz, 1H), 7.81 (s, 1H), 7.75 (dd, J = 8.2, 1.5 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.46 - 7.39 (m, 1H), 7.30 (d, J = 7.7 Hz, 1H), 5.85 (d, J = 17.3 Hz, 1H), 5.52 (d, J = 17.2 Hz, 1H), 4.43 (dd, J = 9.1, 5.5 Hz, 1H), 3.99 - 3.90 (m, 1H), 2.40 - 2.29 (m, 1H), 2.29 - 2.10 (m, 1H), 1.99 - 1.81 (m, 1H), 1.16 - 0.98 (m, 1H), 0.83 - 0.62 (m, 1H); MS (ES+): 582/584 (M+l), (ES-): 580/582 (M-l).

Scheme 228 H

H N; Br

N. Br a N r cozH <3 N

N i\

N l\

8a H o O

Ό cc. HATU, DIPEA

*

NH ₂ U f \

NH ₂ \J

227b 228a

Preparation of (lR,3S,5R)-2-(2-(4-amino-7-phenyl-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N- (6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (228a)

Compound 228a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-7-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (227b) (75 mg, 0.173 mmol) in DMF (5 mL) using HC1 salt of ( 1 R,3 S,5R)-N-(6-bromopyridin-2-yl)-5- methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (8a) (57.7 mg, 0.173 mmol), HATU (79 mg, 0.208 mmol), DIPEA (112 mg, 0.867 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1%HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-7-phenyl-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N- (6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-c arboxamide (228a) (68 mg, 66% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-rfe) δ 10.77 (s, 1H, D2O exchangeable), 8.75 (s, 2H, DzO exchangeable), 8.64 (s, 1H), 8.60 (d, J = 8.3 Hz, 1H), 7.99 (d, J = 8.1 Hz, 2H), 7.84 (s, 1H), 7.82 - 7.72 (m, 2H), 7.67 (t, J = 8.0 Hz, 1H), 7.53 (t, J = 7.5 Hz, 2H), 7.43 (t, J = 7.3 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 5.81 (d, J = 17.3 Hz, 1H), 5.47 (d, J = 17.3 Hz, 1H), 4.39 (dd, J = 9.1, 6.0 Hz, 1H), 3.74 - 368 (m, 1H), 2.49 - 2.42 (m, 1H), 1.99 (dd, J = 13.2, 5.8 Hz, 1H), 1.32 (s, 3H), 1.03 (t, J = 5.5 Hz, 1H), 0.96 - 0.82 (m, 1H); MS (ES+): 596/598 (M+l); (ES-): 594/596 (M-l); Analysis calculated for C ₃ oH26BrN ₇ 02.1.15HC1.1.75H2O: C, 53.78; H, 4.61; Cl, 6.09; N, 14.64; Found: C, 53.70; H, 4.48; Cl, 6.02; N, 14.64.

Scheme 229

229c

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-phenyl-9H-pyrimido[4,5-b ]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (229c)

Step-1: Preparation of terf-butyl 2-(4-amino-8-methyl-6-phenyl-9H-pyrimido[4,5-b]indol-9- yl)acetate (229a)

Compound 229a was prepared according to the procedure reported in step-1 of scheme-62, from fert-butyl 2-(4-amino-6-bromo-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)ace tate (192e) (300 mg, 0.767 mmol) in dioxane (4 mL) using phenyl boronic acid (140 mg, 1.150 mmol), a solution of 3.3 M aqueous K2CO3 (0.697 mL, 2.30 mmol), Pd(PPh3)zCl2 (53.8 mg, 0.077 mmol) and heating at 100 °C for 16 h under nitrogen. This gave after workup and purification using flash column chromatography [silica gel (24 g), eluting with MeOH in DCM from 0 - 3%] /erf-butyl 2-(4-amino-8-methyl-6-phenyl-9H-pyrimido[4,5-b]indol-9-yl)ac etate (229a) (200 mg, 67% yield) as a yellow solid; Ή NMR (300 MHz, DMSO^) δ 8.52 - 8.43 (m, 1H), 8.31 (s, 1H), 7.91 - 7.82 (m, 2H), 7.47 (dd, J = 15.8, 8.1 Hz, 5H), 7.34 (t, J = 7.3 Hz, 1H),

5.36 (s, 2H), 2.70 (s, 3H), 1.45 (s, 9H); MS (ES+): 389 (M+l), (ES-): 387 (M-l).

Step-2: Preparation of 2-(4-amino-8-methyl-6-phenyl-9H-p>'rimido[4,5-b]indol-9-y l)acetic acid (229b) Compound 229b was prepared according to the procedure reported in step-2 of scheme- 1, from tert-butyl 2-(4-amino-8-methyl-6-phenyl-9H-pyrimido[4,5-b]indol-9-yl)ac etate (229a) (198 mg, 0.510 mmol) in DCM (5 mL) using TFA (581 mg, 5.10 mmol) and stirring at RT for 16 h. This gave after work up TFA salt of 2-(4-amino-8-methyl-6-phenyl-9H- pyrimido[4,5-b]indol-9-yl)acetic acid (229b) (282 mg) which was used as such for the next step; Ή NMR (300 MHz, DMSO-ifc) δ 8.59 (s, 1H), 8.54 (s, 1H), 8.35 (s, 2H), 7.86 (d, 2H), 7.63 (s, 1H), 7.51 (t, J= 8.4, 6.9 Hz, 2H), 7.38 (t, J= 7.2 Hz, 1H), 5.46 (s, 2H), 2.76 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO) δ -74.28; MS (ES+): 333 (M+l); (ES-): 331 (M-l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-phenyl-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1.0] hexane-3 -carboxam ide (229c)

Compound 229c was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-phenyl-9H-pyrimido[4,5-b]indol-9-yI)ac etic acid (229b) (75 mg, 0.168 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (4a) (53.5 mg, 0.168 mmol), HATU (77 mg, 0.202 mmol), DIPEA (109 mg, 0.84 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C 18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0- 100%] ( 1 R,3 S,5R)-2-(2-(4-amino-8-methyl-6-phenyl-9H-pyrimido[4,5-b]indo l-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (229c) (82 mg, 82% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO -de) δ 10.84 (s, 1H,

DzO exchangeable), 8.83 (s, 2H, DzO exchangeable), 8.65 (s, 1H), 8.61 (s, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 7.6 Hz, 2H), 7.71 (t, J = 8.0 Hz, 1H), 7.65 (s, 1H), 7.51 (t, J = 7.6 Hz, 2H), 7.38 (t, J = 7.4 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 5.95 (d, J = 17.9 Hz, 1H), 5.67 (d, J = 17.9 Hz, 1H), 4.44 (dd, J = 9.0, 5.7 Hz, 1H), 3.99 - 3.88 (m, 1H), 2.78 (s, 3H), 2.45 - 2.30 (m, 1H), 2.30 - 2.14 (m, 1H), 2.02 - 1.87 (m, 1H), 1.20 - 0.99 (m, 1H), 0.80 - 0.63 (m, 1H); MS (ES+): 596/598 (M+l); (ES-): 594/596 (M-l); Analysis calculated for C3oH26BrN ₇ 02.HC1.2.25H20: C, 53.50; H, 4.71; Cl, 5.26; N, 14.56; Found: C, 53.29; H, 4.53; Cl, 5.28; N, 14.47.

Scheme 230

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-phenyl-9H-pyrimido[4,5-b ]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (230a)

Compound 230a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-phenyl-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (229b) (75 mg, 0.168 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyiidin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carb oxamide (8a) (55.9 mg, 0.168 mmol), HATU (77 mg, 0.202 mmol), DIPEA (109 mg, 0.840 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-phenyl-9H-pyrimido[4,5-b ]indol- 9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-mcthyl-2-azabicyclo[3 .1 ,0]hexane-3-carboxamide (230a) (68 mg, 66% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.84 (s, 1H, D2O exchangeable), 8.79 (s, 2H, DzO exchangeable), 8.64 (s, 1H), 8.61 (s, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.85 (d, 2H), 7.71 (t, J = 8.0 Hz, 1H), 7.64 (s, 1H), 7.50 (t, J = 8.3, 6.9 Hz, 2H), 7.42 - 7.34 (m, 1H), 7.32 (d, J = 7.7 Hz, 1H), 5.90 (d, J = 18.0 Hz, 1H), 5.62 (d, J = 17.9 Hz, 1H), 4.40 (dd, J = 9.0, 6.1 Hz, 1H), 3.71 (dd, J = 5.5, 2.3 Hz, 1H), 2.76 (s, 3H), 2.53- 2.43 (m, 1H), 1.99 (dd, J = 13.3, 6.1 Hz, 1H), 1.32 (s, 3H), 1.03 (t, J = 5.5 Hz, 1H), 0.86 (dd,

J = 5.4, 2.4 Hz, 1H); MS (ES+): 610/612 (M+l), (ES-): 608/610 (M-l); Analysis calculated for CziHzsBrNzOz.1.1HC1.2.25H ₂ 0: C, 53.87; H, 4.90; Cl, 5.64; N, 14.19; Found: C, 53.71; H, 4.64; Cl, 5.59; N, 14.27.

Scheme 231

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrido[2 ^, ,3':4,5]pyrrolo[2, 3- d]pyrimidin-9-yl)acetyl)-N -(6-bromopy ridin-2-y l)-5 -methyl-2-azabicyclo [3.1 0]hexane-3- carboxamide (231g)

Step-1: Preparation ofN-(2-brOmo-6-(trifluoromethyl)pyridin-3-yl)-2,2,2-trifluor oacetamide (231b)

Compound 231b was prepared according to the procedure reported in step-1 of scheme-46, from 2-bromo-6-(trifluoromethyl)pyridin-3-amine (231a) (5 g, 20.75 mmol; CAS # 117519- 16-1) in DCM (30 mL) using triethylamine (3.57 g, 35.3 mmol), trifluoroacetic acid anhydride (6.54 g, 31.1 mmol) and stirring at RT for 1 h. This gave after workup N-(2- bromo-6-(trifluoromethyl)pyridin-3-yl)-2,2,2-trifluoroacetam ide (231b) as a plum solid (6.94 g, 99% yield) and was used as such for next step; Ή NMR (300 MHz, DMSO-ak) δ 11.81 (s, 1H), 8.28 (d, J = 8.1 Hz, 1H), 8.13 (d, J = 8.1 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO-ί/β) δ - 66.38, -74.12.

Step-2: Preparation of 2-amino-5-(trifluoromethyl)- 1 H-pyrrolo[3,2-b]pyridine-3-carbonitrile (231c)

Compound 231c was prepared according to the procedure reported in step-1 of scheme- 11, from N-(2-bromo-6-(trifluoromethyl)pyridin-3-yl)-2,2,2-trifluoroa cetamide (231b) (6.94 g, 20.59 mmol) in DMSO (30 mL) using malononitrile (1.632 g, 24.71 mmol), L-proline (0.474 g, 4.12 mmol), Cul (0.392 g, 2.059 mmol), a solution of K2CO3 (5.69 g, 41.2 mmol) in water (30 mL) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup (trifluoromethyl)-lH-pyrrolo[3,2-b]pyridine-3-carbonitrile (231c) (3.47 g, 75% yield) as a deep pink solid; Ή NMR (300 MHz, DMSO-ifc) 6 11.27 (s, 1H), 7.60 (s, 2H), 7.53 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO-A) δ -64.41; MS (ES+): 227 (M+l), (ES-): 225 (M-l).

Step-3: Preparation of 6-(trifluoromethyl)-9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimi din-4- amine (231d)

Compound 231d was prepared according to the procedure reported in step-2 of scheme-29, from 2-amino-5-(trifluoromethyl)-lH-pyrrolo[3,2-b]pyridine-3-carb onitrile (231c) (3.47 g, 15.34 mmol) in ethanol (10 mL) using NHtOAc (3.55 g, 46.0 mmol), HC(OMe)3 (8.14 g, 77 mmol) and heating at 90 °C for 16 h. This gave after work up 6-(trifluoromethyl)-9H- pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (231 d) (1.90 g, 49% yield) as a pale-gray solid; ^l HNMR (300 MHz, DMSO^) δ 12.49 (s, 1H), 8.43 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H). ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -64.04; MS (ES+): 254 (M+l); (ES-): 252 (M-l).

Step-4: Preparation of tert-butyl 2-(4-amino-6-(trifluoromethyl)-9H- pyridof2 ^, ,3':4,5]pyTrolo[2,3-d]pyrimidin-9-yl)acetate (231e)

Compound 231 e was prepared according to the procedure reported in step-1 of scheme- 1 , from 6-(trifluoromethyl)-9H-pyrido[2',3 ^, :4,5]pyrrolo[2,3-d]pyrimidin-4-amine (231d) (1.90 g, 7.50 mmol) in DMF (15 niL) using /erf-butyl 2-bromoacetate (1.610 g, 8.25 mmol), CS2CO3 (4.89 g, 15.01 mmol) and stirring at RT for 16 h. This gave after work up terf-butyl 2-(4-amino-6-(trifluoromethyl)-9H-pyiido[2 ^, ,3 ^, :4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetate (231e) (1.74 g, 63% yield) as a pale gray solid; Ή NMR (300 MHz, DMSO-cfc) δ 8.48 (s, 1H), 8.30 (d, J = 8.5 Hz, 1H), 8.19 (s, 1H), 7.94 (d, J = 8.6 Hz, 1H), 6.64 (s, 1H), 5.25 (s, 2H), 1.40 (s, 9H). ¹⁹ F NMR (282 MHz, DMSO-tfc) δ -64.07; MS (ES+): 368 (M+l), (ES-): 366 (M-l).

Step-5 : Preparation of 2-(4-amino-6-(trifluoromethyl)-9H-pyrido[2 ^, ,3':4,5]pyrrolo[2,3- d]pyrimidin-9-yl)acetic acid (231f)

Compound 231f was prepared according to the procedure reported in step-2 of scheme- 1, from tert-butyl 2-(4-amino-6-(trifluoromethyl)-9H-pyrido[2 ^, ,3 ^, :4,5]pyrrolo[2,3-d]pyrimidin- 9-yl)acetate (231e) (1.00 g, 2.72 mmol) using TFA (3.10 g, 27.2 mmol) in DCM (5 mL) and 9H-pyrido[2 ^, ,3 ^, :4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetic acid (231f) (1.47 g) as a beige solid; Ή NMR (300 MHz, DMSO-de) δ 8.55 (s, 1H), 8.39 (d, J = 8.6 Hz, 1H), 7.98 (d, J = 8.5 Hz, 1H), 5.30 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -64.10, -74.90; MS (ES+): 312 (M+l). Step-6: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H- pyrido[2',3':4,5|pyrrolo[2,3-d]pyrimidin-9-yl)acetyl)-N-(6-b romopyridin-2-yl)-5-methyl-2- azabicyclo[3.1.OJhexane-3-carboxamide (231g)

Compound 231g was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrido[2',3 ^, :4,5]pyrrolo[2,3- d]pyrimidin-9-yl)acetic acid (231f) (75 mg, 0.176 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hcxane-3-carboxamidc (8a) (58.7 mg, 0.176 mmol), HATU (80 mg, 0.212 mmol), DIPEA (114 mg, 0.882 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6- (trifluoromethyl)-9H-pyrido[2 ^, ,3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetyl)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carb oxamide (23 lg) (73 mg, 70% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.77 (s, 1H, D2O exchangeable), 8.74 (bs, 1H, D2O exchangeable), 8.65 (s, 1H), 8.33 (d, J = 8.6 Hz, 1H), 8.01 (d, J = 8.5 Hz, 2H), 7.70 (t, J = 8.0 Hz, 1H), 7.47 (bs, 1H, D2O exchangeable), 7.32 (d, J = 7.7 Hz, 1H), 5.79 (d, J = 17.4 Hz, 1H), 5.43 (d, J = 17.3 Hz, 1H), 4.38 (dd, J = 9.1, 5.9 Hz, 1H), 3.62 - 3.52 (m, 1H), 2.49 - 2.42 (m, 1H), 1.99 (dd, J = 13.2, 5.8 Hz, 1H), 1.31 (s, 3H), 1.02 (t, J = 5.5 Hz, 1H), 0.96 - 0.88 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO-i/s) δ -64.14; MS (ES+): 589/591 (M+l); (ES-): 587/589 (M-l); Analysis calculated for

C2*H2oBrF3N ₈ 02.0.9HC1.1.75H20: C, 44.10; H, 3.76; Cl, 4.88; N, 17.14; Found: C, 44.01; H, 3.64; Cl, 4.96; N, 17.07.

Scheme 232

223a 232a

Preparation of 4-amino-9-(2-(( lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-5-methyl-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]i ndole-8-carboxylic acid (232a)

Compound 232a was prepared according to the procedure reported in step-4 of scheme- 17, from methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 5-methyl-2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-9H-pyrimido[4,5-b]i ndole-8-carbox>'late (223a) (140 mg, 0.242 mmol) in THF (2 mL) and water (4 mL) using IN aqueous lithium hydroxide hydrate (0.242 mL, 0.242 mmol) and stirring at RT for 16 h. This gave after workup and purification using reverse phase column chromatography [Cl 8 column, eluting with ACN in water (containing 0.1% HC1) from 0-70%] 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2- yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoe thyl)-9H-pyrimido[4,5- b]indole-8-carboxylic acid (232a) (17 mg, 12% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.71 (s, 1H), 8.69 (d, J= 7.9 Hz, 1H), 8.62 (s, 1H), 8.54 (d, J=

12.5 Hz, 3H), 7.98 (d,J= 8.2 Hz, 1H), 7.89 (d,J= 7.6 Hz, 1H), 7.67 (t, J= 8.1 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 5.98 (d, J= 17.4 Hz, 1H), 5.68 (d, J = 17.3 Hz, 1H), 4.31 (dd, J= 9.0, 5.9 Hz, 1H), 3.54 (m, 1H), 2.49 - 2.32 (m, 1H), 1.95 (dd,J= 13.2, 5.9 Hz, 1H), 1.29 (s, 3H), 1.08 - 0.91 (m, 2H); MS (ES+): 565.10; (ES-): 563.10 (M-l).

Scheme 233

Preparation of (lS,3R,5S)-2-(ll-amino-6H-benzo[e]p> ^, rimido[5 ^, ,4 ^, :4,5]pyrrolo[l,2- c][l ,3]oxazine-6-carbonyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[ 3.1 ,0]hexane-3- carboxamide (233h)

Step-1: Preparation of 6-bromo-4-(methylthio)-7H-pyrrolo [2,3 -d]py ri mi dine (233b)

To a solution of 6-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (233a) (1.02 g, 4.39 mmol; CAS# 784150-41-0) in DMSO (10 mL) at 50 °C was added sodium methanethiolate (1.230 g, 17.55 mmol; CAS # 5188-07-8) in three portions over a 3 h interval and heated at 50 °C overnight. The reaction mixture was poured into water (80 mL) and the solution was allowed to stand for 5 h. The solid obtained was collected by filtration washed with water, dried in vacuo to afford 6-bromo-4-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine (233b) (1.01 g, 4.14 mmol, 94 % yield) as a white solid; ‘HNMR(300 MHz, DMSOafe) δ 12.99 (s, 1H), 8.58 (s, 1H), 6.66 (s, 1H), 2.64 (s, 3H); MS (ES+): 243.95/245.9 (M+l).

Step-2: Preparation of 2-(4-(methylthio)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenol (233c) Compound 233c was prepared according to the procedure reported in step-1 of scheme-62, from 6-bromo-4-(methylthio)-7H-pyrrolo [2,3 -d] pyrimidine (233b) (922 mg, 3.78 mmol) in 1,4-dioxane (12 mL) using (2-hydroxyphenyl)boronic acid (625 mg, 4.53 mmol), a solution of K2CO3 (1566 mg, 11.33 mmol) in water (1.5 mL) and PdCl2(dppf)-CH2Ch adduct (308 mg, 0.378 mmol) and heating at 80 °C for 6 h under nitrogen. This gave after workup and purification using flash column chromatography [silica gel (40 g), eluting with EtOAc/MeOH (9:1) in hexanes from 0 - 100%] 2-(4-(methylthio)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenol (233c) (655 mg, 67% yield) as a yellow solid; Ή NMR (300 MHz, DMSO-cfe) δ 12.22 (s,

1H), 10.34 (s, 1H), 8.59 (s, 1H), 7.83 (dd, J= 7.9, 1.6 Hz, 1H), 7.28 - 7.14 (m, 1H), 7.02 (dd, J= 8.6, 1.3 Hz, 2H), 6.92 (t, J= 7.4 Hz, 1H), 2.67 (s, 3H); MS (ES+): 258.0 (M+l).

Step-3: Preparation of ethyl 1 l-(methylthio)-6H-benzo[e]pyrimido[5',4':4,5]pyrrolo[l,2- c][l,3]oxazine-6-carboxylate (233d)

A mixture of 2-(4-(methylthio)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenol (233c) (470 mg, 1.827 mmol), ethyl 2,2-dibromoacetate (1347 mg, 5.48 mmol) and potassium carbonate (757 mg, 5.48 mmol) in DMF (10 mL) was heated to 100 °C and stirred at 100 °C for 100 min. The reaction mixture was cooled to room temperature, diluted with EtOAc (200mL), washed with water (lOOmL), brine (lOOmL), dried and concentrated in vacuo. The residue obtained was purified using flash column chromatography [silica gel (12 g), eluting with EtOAc/MeOH (9: 1) in hexanes from 0-50%] to provide ethyl 1 l-(mcthylthio)-6H- benzo[e]pyrimido[5',4':4,5]pyrrolo[l ,2-c][l,3]oxazine-6-carboxylate (233d) (298 mg, 48 % yield) as a white yellow solid; Ή NMR (300 MHz, DMSO-ifc) 58.68 (s, 1H), 8.01 (dd,

7.9, 1.6 Hz, 1H), 7.41 (td, J= 7.7, 1.6 Hz, 1H), 7.29 (s, 1H), 7.26 - 7.17 (m, 3H), 4.12 - 3.98 (m, 2H), 2.71 (s, 3H), 1.01 (t ,J= 7.1 Hz, 3H).

Step-4: Preparation of ethyl 1 l-(methylsulfonyl)-6H-benzo[e]pyrimido[5',4':4,5]pyrrolo[l,2 - c][l,3]oxazine-6-carboxylate (233e)

To a solution of ethyl 11 -(methy lthio)-6H-benzo [e] py rimido [5 ',4' : 4, 5 ]py rrolo [ 1,2- c][l,3]oxazine-6-carboxylate (233d) (180 mg, 0.527 mmol) in DCM (35 mL) was added m- CPBA (354mg) at 0 °C, warmed to RT and stirred overnight. An additional amount of m- CPBA (98mg) was added, the mixture was stirred at RT for 2 h. The reaction mixture was diluted with DCM (25mL), washed with Sat. NaHCOi (40 mL), dried, filtered and concentrated in vacuo to afford ethyl 1 l-(me1hylsulfonyl)-6H- benzotelpyrimidotS'^M.Slpyrrolotl ,2-c] [ l,3]oxazine-6-carboxylate (233e) (197 mg, 100 % yield) as a yellow solid which was used for the next step; MS (ES+): 374.10 (M+l);

Step-5: Preparation of ll-(methylsulfonyl)-6H-benzo[e]pyrimido[5',4':4,5]pyrrolo[l, 2- c] [ 1 ,3]oxazine-6-carboxylic acid (233f)

Compound 233f was prepared according to the procedure reported in step-4 of scheme- 17, from ethyl 11 -(methy lsulfony l)-6H-benzo [e]py rimido [5 ',4' : 4,5 ]py rrolo [ 1 ,2-c][l,3]oxazine-6- carboxylate (233e) (197 mg, 0.528 mmol) in MeOH (1.5 mL), THF (1.5 mL), acetonitrile (3 mL) using a solution of lithium hydroxide hydrate and stirring at RT. The reaction mixture was concentrated in vacuo and was used for the next step without further purification; MS (ES+): 346.0 (M+l);

Step-6: Preparation of 1 l-amino-6H-benzo[e]pyrimido[5',4':4,5]pyrrolo[l,2-c][l,3]oxa zine-6- caiboxylic acid (233g)

To a solution of ll-(methylsulfonyl)-6H-benzo[e]pyrimido[5',4 ^, :4,5]pyrrolo[l,2- c] [ 1 ,3]oxazine-6-carboxy lie acid (233f) (182 mg) in 1,4-Dioxane (4 mL) was added ammonium hydroxide (3 mL, 23.11 mmol) and stirred at RT overnight. An additional amount of NHrOH (lmL) was added and the reaction mixture was heated to 50 °C for 5 h. The reaction mixture was concentrated in vacuum and residue obtained was purified by reverse phase column chromatography [Cl 8 (50g), eluting with ACN in water (without HC1) from 0- 100%] to provide 1 l-amino-6H-benzo[e]pyrimido[5',4’:4,5]pyrrolo[l,2-c][l,3]o xazine-6- carboxylic acid (233g) (90 mg, 61 % yield) as a white solid; MS (ES+): 283.0 (M+l).

Step-7: Preparation of (lS,3R,5S)-2-(l l-amino-6H-benzo[e]pyrimido[5 ^, ,4':4,5]pyrrolo[l,2- c] [ 1 ,3]oxazine-6-carbonyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[ 3.1.0]hexane-3- carboxamide (233h)

Compound 233h was prepared according to the procedure reported in step-3 of scheme- 1 , from 1 l-amino-6H-benzo[e]pyrimido[5',4':4,5]pyrrolo[ 1 ,2-c] [ 1 ,3 ]oxazine-6-carboxylic acid (233g) (40 mg, 0.142 mmol) in DMF (3 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (51 mg, 0.160 mmol), HATU (81 mg, 0.213 mmol), DIPEA (0.123 mL, 0.709 mmol) and stirring at RT for 14 h. This gave after workup and purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0- 100%]( 1 S,3R,5 S)- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (233h) (48 mg, 62.0 % yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfe) δ 10.71 (d, J= 2.2 Hz, 1H), 8.11 - 8.06 (m, 1H), 7.98 - 7.85 (m, 1H), 7.69 - 7.51 (m, 2H), 7.34 - 7.24 (m, 2H), 7.24 - 7.09 (m, 4H), 7.00 - 6.92 (m, 1H), 4.48 - 4.26 (m, 1H), 4.24 - 3.99 (m, 1H), 2.34 - 2.03 (m, 2H), 2.03 - 1.83 (m, 1H), 1.47 - 1.12 (m, 1H), 0.78 - 0.43 (m, 1H); Ή NMR (300 MHz, DMSO- tifsZDzO) δ 8.13 - 8.01 (m, 1H), 7.98 - 7.84 (m, 1H), 7.70 - 7.46 (m, 2H), 7.38 - 7.23 (m, 2H), 7.23 - 7.09 (m, 2H), 7.02 - 6.93 (m, 1H), 4.33 (dd, J= 28.1, 7.0 Hz, 1H), 4.11 (dt, J= 30.4, 7.2 Hz, 1H), 2.33 - 2.02 (m, 2H), 1.99 - 1.83 (m, 1H), 1.47 - 1.12 (m, 1H), 0.78 - 0.43 (m, 1H). MS (ES+): 546.1, 548.1 (M+l); (ES-): 544.1, 546.1 (M-l); Analysis calculated for: C25H2oBrN ₇ 0 ₃ .0. ISHCl.O.SHzO: C, 53.54; H, 3.80; N, 17.48; Cl, 0.95; Found: C, 53.39; H, 3.70; N, 17.41; Cl, 0.95.

Scheme 234

H Br

Ό N N.

C0 ₂ H f W N \

O u 4a Ό

HATU, DIPEA

L W CF ₃ L W CF ₃

231 f 234a

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrido[2 ^, ,3 ^, :4,5]pyrrolo[2, 3- d]pyrimidin-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicycl o[3.1 ,0]hexane-3-carboxamide (234a)

Compound 234a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrido[2 ^l ,3 ^, :4,5]pyrrolo[2,3-d]pyrimidin-9- yl)acetic acid (231f) (75 mg, 0.176 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (56.2 mg, 0.176 mmol), HATU (80 mg, 0.212 mmol), DIPEA (114 mg, 0.882 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-p> ^, rido[2 ^, ,3 ^, :4,5]pynOlo[2,3- (234a) (67 mg, 66% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfe) δ 10.77 (s, 1H, DzO exchangeable), 8.82 (bs, 1H, DzO exchangeable), 8.67 (s, 1H), 8.34 (d, J= 8.6 Hz, 1H), 8.06 - 7.97 (m, 2H), 7.70 (t, J= 8.0 Hz, 1H), 7.45 (bs, 1H, DzO exchangeable), 7.32 (d, J = 7.7 Hz, 1H), 5.84 (d,J= 17.4 Hz, 1H), 5.49 (d,J= 17.3 Hz, 1H), 4.43 (dd,J= 9.1, 5.5 Hz, 1H), 3.90 (ddd, 7.5, 5.4, 2.3 Hz, 1H), 2.40 - 2.27 (m, 1H), 2.27 - 2.16 (m, 1H), 1.99 - 1.86 (m, 1H), 1.20 - 1.00 (m, 1H), 0.88 - 0.68 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-ds) δ -64.12; MS (ES+): 575/577 (M+l), (ES-): 573/575 (M-l); Analysis calculated for

CzzHieBrFzNsOz.1.15HC1.1 ,75HzO: C, 42.58; H, 3.52; Cl, 6.28; N, 17.27; Found: C, 42.53; H, 3.36; Cl, 6.33; N, 17.08.

Scheme 235

144e 235a

Preparation of (2S,4R)-N-(3-chloro-2-fluorobenzyI)-4-fIuoro- 1 -(2-(2-oxo-3,4-dihydro-lH- pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-7(2H)-yl)acetyl)pyr rolidine-2-carboxamide (235a)

To a suspension of /erf-butyl (l-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4- fluoropyirolidin-l-yl)-2-oxoethyl)-5-cyano-lH-pyrrolo[2,3-b] pyridin-4-yl)carbamate (144e) (300 mg, 0.524 mmol) in methanol cooled with ice/water was added nickel(H) chloride hexahydrate (31.1 mg, 0.131 mmol), sodium borohydride (119 mg, 3.14 mmol) in several portions over a period of 10 min and stirred at RT for 1 h. The reaction mixture was treated with Nl-(2-aminoethyl)ethane- 1,2-diamine (0.113 mL, 1.047 mmol) stirred at RT for 0.5 h and concentrated to dryness. The residue was treated with ethyl acetate (120 mL) and washed with water (60 mL). The aqueous phase was extracted again with ethyl acetate (60 mL). The combined extracts were washed with brine (75 mL), dried, filtered and concentrated in vacuum The erode product was purified by flash column chromatography [silica gel eluting (10 mL) added TFA (0.077 mL, 1.040 mmol) and at RT for 22 h. The reaction mixture was concentrated to dryness and purified by reverse phase column chromatography using [Cl 8 column (26 g), eluting with ACN in water (containing 0.1%HC1) from 0-100%] to give (2S,4R)-N-(3-chloro-2- fluorobenzyl)-4-fluoro-l-(2-(2-oxo-3,4-dihydro-lH-pyrrolo[3 ^, ,2 ^, :5,6]pyrido[4,3-d]pyrimidin- 7(2H)-yl)acet>l)pyrrolidine-2-carboxamide (235a) (58 mg, 22% yield for two steps) HC1 salt as a white solid; ^! H NMR (300 MHz, DMSO-tife) (a mixture of two rotamers) δ 10.54 (s, 1H, DzO exchangeable), 9.01 & 8.66 (2t, ./= 6.0 Hz, 1H, DzO exchangeable), 7.97 (s, 1H), 7.50 - 7.29 (m, 3H, 1H D2O exchangeable), 7.16 - 7.03 (m, 1H), 6.95 (d, J= 3.5 Hz, 1H), 6.84 (t, J = 7.9 Hz, 1H), 5.56 - 5.07 (m, 3H), 4.84 - 3.71 (m, 7H), 2.59 - 2.23 (m, 1H), 2.23 - 1.81 (m, 1H); ^!9 F NMR (282 MHz, DMSO-i/e) (a mixture of two rotamers) δ -121.34 & -121.74 (IF), -175.94 & -176.13 (IF); MS (ES+): 503.10 & 505.10 (M+l); Analysis calculated for C23H21CIF2N6O3.I.O HCl.2.25 H2O: C, 47.64; H, 4.61; N, 14.49; Cl, 12.23; Found: C, 47.97; H, 4.46; N, 14.55; Cl, 11.93.

Scheme 236

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-chloro-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamid e (236f)

Step-1: Preparation of 2-amino-5-chloro- lH-indole-3 -carbonitrile (236b)

Compound 236b was prepared according to the procedure reported in step-1 of scheme- 11 , 784183-51-3) in DMSO (20 mL) using malononitrile (1.406 g, 21.29 mmol), L-proline (0.409 g, 3.55 mmol), Cul (0.338 g, 1.774 mmol), K2CO3 (4.90 g, 35.5 mmol) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification using flash column chromatography [S1O2 gel (40 g), eluting with EtOAc in hexane from 0-50%] 2- amino-5-chloro-lH-indole-3-carbonitrile (236b) (2.02 g, 59% yield) as a yellow solid; Ή NMR (300 MHz, DMSO-fife) δ 10.86 (s, 1H), 7.11 (d, J= 8.3 Hz, 1H), 7.08 (d, J= 2.1 Hz, 1H), 6.97 (s, 2H), 6.90 (dd, J= 8.3, 2.1 Hz, 1H); MS (ES+): 192.0 (M+l); (ES-): 190.0 (M-

1).

Step-2: Preparation of 6-chloro-9H-pyrimido[4,5-b]indol-4-amine (236c)

Compound 236c was prepared according to the procedure reported in step-1 of scheme-6, from 2-amino-5 -chloro- 1 H-indole-3 -carbonitrile (236b) (2.0 g, 10.44 mmol) using trimethyl orthoformate (22.84 mL, 209 mmol), AcOH (2.98 mL, 52.2 mmol) and NH4OAC (4.02 g,

52.2 mmol). This gave after workup 6-ch loro-9H-pyrimido [4,5-b] indol-4-amine (236c) (2.3 g, 89% yield) as a pale-yellow sohd; Ή NMR (300 MHz, DMSO-cfe) δ 11.98 (s, 1H), 8.45 (d, .7= 2.0 Hz, 1H), 8.26 (s, 1H), 7.44 (d, J= 8.6 Hz, 1H), 7.36 (dd,J= 8.6, 2.0 Hz, 1H), 7.30 (s, 2H); MS (ES+): 219.00 (M+l).

Step-3: Preparation of ter/-butyl 2-(4-amino-6-chloro-9H-pyrimido[4,5-b]indol-9-yl)acetate (236d)

Compound 236d was prepared according to the procedure reported in step-1 of scheme- 1, from 6-chloro-9H-pyrimido[4,5-b]indol-4-amine (236c) (2.25 g, 9.05 mmol) in DMF (60 mL) using fert-butyl 2-bromoacetate (1.471 mL, 9.95 mmol), CS2CO3 (6.49 g, 19.91 mmol) and stirring at RT for 2 h. This gave after workup and purification using reverse phase column chromatography [C18 column (150 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] tert-butyl 2-(4-amino-6-chloro-9H-pyrimido[4,5-b]indol-9-yl)acetate (236d) (1.216 g, 40% yield) as apale yellow solid; Ή NMR (300 MHz, DMSO-Je) δ 8.60 (d, J= 2.0 Hz, 1H), 8.44 (s, 1H), 7.70 (d, J= 8.7 Hz, 1H), 7.51 (dd,J= 8.8, 2.0 Hz, 1H), 5.20 (s, 2H), 1.41 (s, 9H); MS (ES+): 333.10 (M+l).

Step-4: Preparation of 2-(4-amino-6-chloro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (236e)

Compound 236e was prepared according to the procedure reported in step-2 of scheme- 1, from tert- butyl 2-(4-amino-6-chloro-9H-pyrimido[4,5-b]indol-9-yl)acetate (236d) (1 g, 3.00 mmol) using 20% TFA in DCM (17.25 mL, 45.1 mmol) and stirring at RT for 16 h. This gave after workup 2-(4-amino-6-chloro-9H-pyrimido[45-b]indol-9-yl)acetic acid (236e) (d, J= 2.0 Hz, 1H), 8.54 (s, 1H), 8.35 (s, 2H), 7.81 (d, J= 8.8 Hz, 1H), 7.56 (dd, J= 8.8, 2.0 Hz, 1H), 5.25 (s, 2H); MS (ES+): 277.00 (M+l).

Step-5: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-chloro-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (236f)

Compound 236f was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-chloro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (236e) (60mg, 0.154 mmol) in DMF (1.5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2- yl)-2-azabicyclo[3.1.0]hexane-3-caiboxamide (4a) (48.9 mg, 0.154 mmol), HATU (88 mg, 0.230 mmol), DIPEA (0.134 mL, 0.768 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6-chloro-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-caiboxamide (2361) (71 mg, 85% yield)

HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ofc) δ 10.77 (s, 1H, DzO exchangeable), 8.68 (d, J= 2.0 Hz, 1H), 8.60 (s, 1H), 8.56 (s, 2H, DzO exchangeable), 8.01 (d, J= 8.2 Hz, 1H), 7.77 - 7.67 (m, 2H), 7.58 (dd, ./= 8.8, 2.0 Hz, 1H), 7.33 (d, J= 7.7 Hz, 1H), 5.77 (d, ./= 17.4 Hz, 1H), 5.42 (d, J= 17.3 Hz, 1H), 4.41 (dd, J= 9.0, 5.5 Hz, 1H), 3.90 (td, J= 6.2, 5.3, 2.3 Hz, 1H), 2.38 - 2.12 (m, 2H), 1.97 - 1.85 (m, 1H), 1.07 (dt, J= 9.2, 5.4 Hz, 1H), 0.78 (td, J= 5.2, 2.4 Hz, 1H). MS (ES+): 540.1 (M+l); (ES-): 538.0 (M-l); Analysis calculated for CzzHigBrClNvOz 1.75HzO. 0.9HC1.:C, 45.65; H, 3.90; Cl, 11.13; N, 16.20; Found: C, 45.60; H, 3.80; Cl, 11.17; N, 15.84.

Scheme 237 Preparation of ( lR,3S,5R)-2-(2-(4-amino-6-chloro-9H-pyriniido[4,5-b]indol-9- yl)acetyl)-N- (6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-c arboxamide (237a)

Compound 237a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-chloro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (236e) (60 mg, 0.154 mmol) in DMF (1.5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-5- methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (51.1 mg, 0.154 mmol), HATU (88 mg, 0.230 mmol), DIPEA (0.134 mL, 0.768 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6-chloro-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carb oxamide (237a) (59 mg, 69% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.77 (s, 1H, D ₂ 0 exchangeable), 8.68 (d, J- 2.0 Hz, 1H), 8.67 - 8.54 (m, 3H, 2H DzO exchangeable), 8.01 (d, J= 8.2 Hz, 1H), 7.78 - 7.66 (m, 2H), 7.58 (dd, J= 8.7, 1.9 Hz, 1H), 7.33 (d, J= 7.7 Hz, 1H), 5.73 (d, J= 17.4 Hz, 1H), 5.37 (d, J= 17.3 Hz, 1H), 4.37 (dd, J= 9.1, 5.9 Hz, 1H), 3.68 (dd, J= 5.5, 2.4 Hz, 1H), 2.57 - 2.52 (m, 1H), 1.98 (dd, J= 13.3, 5.9 Hz, 1H), 1.31 (s, 3H), 1.01 (t, J = 5.4 Hz, 1H), 0.93 (dd, J= 5.5, 2.4 Hz, 1H). MS (ES+): 554.1(M+1); (ES-): 552.1 (M- 1); Analysis calculated for C24H21B1CIN7O2 2H2O.HCI: C, 45.95; H, 4.18; Cl, 11.30; N, 15.63; Found: C, 46.26; H, 4.12; Cl, 10.92; N, 15.48.

Scheme 238

238f 238g

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-chloro-8-methoxy-9H-pyrimido[4,5- b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (238g)

Step-1: Preparation ofN-(2-bromo-4-chloro-6-methoxyphenyl)-2,2,2-trifIuoroacetam ide (238b)

Compound 238b was prepared according to the procedure reported in step-1 of scheme-46, from 2-bromo-4-chloro-6-methoxyaniline (238a) (5 g, 21.14 mmol; CAS # 1261895-84-4) in DCM (75 mL) using triethylamine (5.01 mL, 35.9 mmol), trifluoroacetic acid anhydride (4.41 mL, 31.7 mmol) and stirring at RT for 16 h. This gave after workup N-(2-bromo-4- chloro-6-methoxyphenyl)-2,2,2-trifIuoroacetamide (238b) (6.93 g, 99% yield) as a dark solid and was used as such for next step; Ή NMR (300 MHz, DMSO-dk) δ 11.10 (s, 1H), 7.48 (d, J= 2.1 Hz, 1H), 7.32 (d,J = 2.2 Hz, 1H), 3.85 (s, 3H); MS (ES+): 331.90 (M+l).

Step-2: Preparation of 2-amino-5-chloro-7-methoxy-lH-indole-3-carbonitrile (238c)

Compound 238c was prepared according to the procedure reported in step-1 of scheme- 11, mmol) in DMSO (20 mL) using malononitrile (1.568 mL, 24.90 mmol), L-proline (0.478 g, 4.15 mmol), Cul (0.395 g, 2.075 mmol), a solution of K2CO3 (5.74 g, 41.5 mmol) in water (20 mL) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification using flash column chromatography [SiOzgel (40 g), eluting with EtOAc in hexane from 0-50%] 2-amino-5-chloro-7-methoxy-lH-indole-3-carbonitrile (238c) (1.85 g, 40% yield) as a pale-yellow solid; Ή NMR (300 MHz, DMSO-tfc) 5 11.04 (s, 1H), 6.76 (d, J = 1.7 Hz, 1H), 6.64 (d,J= 1.8 Hz, 1H), 6.55 (s, 2H), 3.88 (s, 3H); MS (ES+): 222.00(M+1). Step-3: Preparation of 6-chloro-8-methoxy-9H-pyrim ido [4,5 -b] indol -4-amine (238d)

Compound 238d was prepared according to the procedure reported in step-1 of scheme-6, from 2-amino-5-chloro-7-methoxy-lH-indole-3-carbonitrile (238c) (1.8 g, 8.12 mmol) using trimethyl orthoformate (17.77 triL, 162 mmol), AcOH (2.322 mL, 40.6 mmol), NHtOAc (3.13 g, 40.6 mmol) and heating at 100 °C for 1 h. This gave after workup 6-chloro-8- methoxy-9H-pyrimido[4,5-b]indol-4-amine (238d) (2.33 g, 93% yield) ACOH salt as a pale- yellow solid; MS (ES+): 249.1 (M+l).

Step-4: Preparation of tort-butyl 2-(4-amino-6-chloro-8-methoxy-9H-pyrimido[4,5-b]indol-9- yl)acetate (238e)

Compound 238e was prepared according to the procedure reported in step-1 of scheme- 1 , from AcOH salt of 6-chloro-8-methoxy-9H-pyrimido[4,5-b]indol-4-amine (238d) (1 g, 3.24 mmol) in DMF (25 mL) using tort-butyl 2-bromoacetate (0.503 mL, 3.40 mmol), CszCOs (2.64 g, 8.10 mmol) and stirring at RT for 15 h. This gave after workup and purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] tort-butyl 2-(4-amino-6-chloro-8-methoxy-9H- pyrimido[4,5-b]indol-9-yl)acetate (238e) (1.175 g, 9% yield) as a pale-yellow solid; ‘HNMR (300 MHz, DMSO-dSs) δ 8.48 (s, 1H), 8.23 (d, ./= 1.7 Hz, 1H), 8.17 (s, 2H), 7.17 (d,J= 1.7 Hz, 1H), 5.23 (s, 2H), 3.94 (s, 3H), 1.42 (s, 9H); MS (ES+): 363.10 (M+l).

Step-5: Preparation of 2-(4-amino-6-chloro-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)a cetic acid (238f)

Compound 238f was prepared according to the procedure reported in step-2 of scheme- 1, from tort-butyl 2-(4-ammo-6-chloro-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)ac etate (238e) (100 mg, 0.276 mmol) using 20% TFA in DCM (1582 pL, 4.13 mmol) and stirring at RT for 16 h. This gave after workup 2-(4-amino-6-chloro-8-methoxy-9H-pyrimido[4,5-b]indol-9- MHz, DMSO-cfe) δ 8.48 (s, 1H), 8.23 (d, J= 1.7 Hz, 1H), 8.15 (s, 2H), 7.18 (d, J= 1.7 Hz, 1H), 5.28 (s, 2H), 3.94 (s, 3H); MS (ES+): 307.00 (M+l).

Step-6: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-chloro-8-methoxy-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1.0]hexane-3-carboxamide (238g)

Compound 238g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-chloro-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)a cetic acid (238f) (55 mg, 0.131 mmol) in DMF (1.5 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (41.6 mg, 0.131 mmol), HATU (74.6 mg, 0.196 mmol), DIPEA (0.114 mL, 0.654 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6-chloro-8-methoxy-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1.0]hexane-3-carboxamide (238g) (52 mg, 70% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.74 (s, 1H, D2O exchangeable), 8.67 - 8.46 (m, 3H, 2H D2O exchangeable), 8.26 (d, J= 1.7 Hz, 1H), 8.02 (d, J= 8.2 Hz, 1H), 7.71 (t, J= 8.0 Hz, 1H), 7.32 (d, J= 7.7 Hz, 1H), 7.19 (d, J= 1.7 Hz, 1H), 5.78 (d, J= 17.0 Hz, 1H), 5.54 (d, J= 17.0 Hz, 1H), 4.42 (dd, J= 9.0, 5.6 Hz, 1H), 3.95 (s, 3H), 3.89 - 3.75 (m, 1H), 2.41 - 2.15 (m, 2H), 2.00 - 1.86 (m, 1H), 1.11 (dt, J= 9.3, 5.4 Hz, 1H), 0.74 - 0.56 (m, 1H). MS (ES+): 570.1 (M+l); (ES-): 568.1 (M-l); Analysis calculated for C24H2iBrClN7032HzO. 0.9HC1. C, 45.06; H, 4.08; Cl, 10.53; N, 15.33; Found: C, 45.34; H, 3.93; Cl, 10.64; N, 15.21.

Scheme 239 Preparation of (lR,3S,5R)-2-(2-(4-amino-6-chloro-8-methoxy-9H-pyrimido[4,5- b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (239a)

Compound 239a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-chloro-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)a cetic acid (238f) (55 mg, 0.131 mmol) in DMF (1.5 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carb oxamide (8a) (43.5 mg, 0.131 mmol), HATU (74.6 mg, 0.196 mmol), DIPEA (0.114 mL, 0.654 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1%HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6-chloro-8-methoxy-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5- methyl-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (239a) (40 mg, 52% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-fife) δ 10.74 (s, 1H, DzO exchangeable), 8.59 - 8.46 (m, 3H, 2H DzO exchangeable), 8.25 (d, J= 1.7 Hz, 1H), 8.02 (d, J= 8.2 Hz, 1H), 7.71 (t, J= 8.0 Hz, 1H), 7.32 (d,./= 7.7 Hz, 1H), 7.18 (d, J= 1.7 Hz, 1H), 5.78 - 5.66 (m, 1H), 5.49 (d, J= 17.0 Hz, 1H), 4.38 (dd, J= 9.0, 6.0 Hz, 1H), 3.94 (s, 3H), 3.63 - 3.61 (m, 1H), 2.47 - 2.39 (m, 1H), 1.99 (dd, J= 13.3, 5.9 Hz, 1H), 1.31 (s, 3H), 1.05 (t ,J= 5.4 Hz, 1H), 0.82 (dd, J= 5.3, 2.4 Hz, 1H). MS (ES+): 584.1 (M+l); (ES-): 582.0 (M-l); Analysis calculated for CzsHzBBrClNvOz 1.75HzO. HC1 :C, 45.99; H, 4.25; Cl, 10.86; N, 15.02; Found: C, 46.07; H, 4.22; Cl, 10.49; N, 14.90.

Scheme 240

Preparation of methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-8-methoxy-9H-pyrimi do[4,5-b]indole-6- carboxylate (240g)

Step-1: Preparation of methyl 3-iodo-5-methoxy-4-(2,2,2-trifluoroacetamido)benzoate (240b)

Compound 240b was prepared according to the procedure reported in step-1 of scheme-46, methyl 4-amino-3-iodo-5-methoxybenzoate (240a) (5 g, 16.28 mmol; CAS # 180624-10-6) in DCM (60 mL) using triethylamine (3.86 mL, 27.7 mmol), trifluoroacetic acid anhydride (3.39 mL, 24.42 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [SiChgel (40 g), eluting with EtOAc in hexane from 0- 50%] methyl 3-iodo-5-methoxy-4-(2,2,2-trifluoroacetamido)benzoate (240b) (5.51 g, 84% yield) as a yellow solid; Ή NMR (300 MHz, DMSO-cfe) 5 11.25 (s, 1H), 8.02 (d, J= 1.7 Hz, 1H), 7.61 (d, 1.7 Hz, 1H), 3.89 (s, 3H), 3.87 (s, 3H).

Step-2: Preparation of methyl 2-amino-3 -cyano-7-methoxy- 1 H-indole-5 -carboxy late (240c) Compound 240c was prepared according to the procedure reported in step-1 of scheme- 11, from methyl 3-iodo-5-methoxy-4-(2,2,2-trifluoroacetamido)benzoate (240b) (5.5 g, 13.64 mmol) in DMSO (20 mL) using malononitrile (1.031 mL, 16.37 mmol), L-proline (0.314 g, 2.73 mmol), Cul (0.260 g, 1.364 mmol), a solution of K2CO3 (3.77 g, 27.3 mmol) in water (20 mL) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification using flash column chromatography [S1O2 gel (40 g), EtOAc in hexane from 0-50%] methyl 2-amino-3-cyano-7-methoxy- 1 H-indole-5-carboxylate (240c) (1.83 g, 55% yield) as a yellow solid; Ή NMR (300 MHz, DMSO-ifc) δ 11.30 (s, 1H), 7.46 (d,./= 1.3 Hz, 1H), 7.16 (d, 1.3 Hz, 1H), 6.66 (s, 2H), 3.93 (s, 3H), 3.84 (s, 3H); MS (ES+): 246.0

(M+l); (ES-): 244.1 (M-l).

Step-3: Preparation of methyl 4-amino-8-methoxy-9H-pyrimido[4,5-b]indole-6-carboxylate (240d)

Compound 240d was prepared according to the procedure reported in step-1 of scheme-6, from methyl 2-amino-3 -cyano-7 -methoxy- lH-indole -5 -carboxy late (240c) (1.8 g, 7.34 mmol) using trimethyl ordiofonnate (16.06 mL, 147 mmol), AcOH (2.099 mL, 36.7 mmol), NH4OAC (2.83 g, 36.7 mmol) and stirring at 100 °C for 16 h. This gave after workup methyl 4-amino-8-methoxy-9H-pyrimido[4,5-b]indole-6-carboxylate (240d) (1.82 g, 87% yield) AcOH salt as a pale-yellow solid; Ή NMR (300 MHz, DMSO-tife) δ 12.36 (s, 1H), 8.62 (d, J = 1.2 Hz, 1H), 8.28 (s, 1H), 7.51 (d, J= 1.3 Hz, 1H), 7.34 (s, 2H), 4.01 (s, 3H), 3.90 (s, 3H); MS (ES+): 273.10 (M+l).

Step-4: Preparation of methyl 4-amino-9-(2-(ter/-butoxy)-2-oxoethyl)-8-methoxy-9H- pyrimido[4,5-b]indole-6-carboxylate (240e)

Compound 240e was prepared according to the procedure reported in step-1 of scheme- 1, from AcOH salt of methyl 4-amino-8-methoxy-9H-pyrimido[4,5-b]indole-6-carboxylate (240d) (1 g, 3.67 mmol) in DMF (30 mL) using te/7-butyl 2-bromoacetate (0.651 mL, 4.41 mmol), CS2CO3 (2.99 g, 9.18 mmol) and stirring at RT for 30 min. This gave after workup methyl 4-amino-9-(2-(/er/-butoxy)-2-oxoethyl)-8-methoxy-9H-pyrimido [4,5-b]indole-6- carboxylate (240e) (1.085 g, 76% yield) as a pale-yellow solid; ‘H NMR (300 MHz, DMSO- de) δ 8.65 (d, J= 1.3 Hz, 1H), 8.33 (s, 1H), 7.52 (t, J = 2.0 Hz, 3H), 5.23 (s, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 1.42 (s, 9H); MS (ES+): 387.20 (M+l).

Step-5: Preparation of 2-(4-amino-8-methoxy-6-(me1hoxycarbonyl)-9H-pyrimido[45- Compound 240f was prepared according to the procedure reported in step-2 of scheme- 1, from methyl 4-amino-9-(2-(te/f-butoxy)-2-oxoethyl)-8-methoxy-9H-pyrimido [4,5-b]indole- 6-carboxylate (240e) (700 mg, 1.812 mmol) using 20% TFA in DCM (10.40 mL, 27.2 mmol) and stirring at RT for 16 h. This gave after workup 2-(4-amino-8-methoxy-6- (methoxycarbonyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (240f) (0.8 g, 99% yield) TFA salt as a pale-yellow solid; ^l H NMR (300 MHz, DMSO-i/e) δ 8.76 (d, J= 1.3 Hz, 1H), 8.53 (s, 1H), 8.37 (s, 2H), 7.60 (d, J= 1.2 Hz, 1H), 5.35 (s, 2H), 3.98 (s, 3H), 3.93 (s, 3H); MS (ES+): 331.10 (M+l).

Step-6: Preparation of methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2- yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-8-m ethoxy-9H-pyrimido[4,5- b]indole-6-carboxylate (240g)

Compound 240g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methoxy-6-(methoxycarbonyl)-9H-pyrimido[4,5-b]i ndol-9- yl)acetic acid (240f) (75mg, 0.169 mmol) in DMF (1.5 mL) using HC1 salt of (1R,3S,5R)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamid e (4a) (53.8 mg, 0.169 mmol), HATU (96 mg, 0.253 mmol), DIPEA (0.147 mL, 0.844 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 2- azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-8-methoxy-9H-pyrimi do[4,5-b]indole-6- carboxylate (240g) (70 mg, 70% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-i/e) δ 10.73 (s, 1H, D ₂ 0 exchangeable), 8.75 (d, J= 1.2 Hz, 1H), 8.57 (s, 1H), 8.60 - 8.37 (m, 2H, D2O exchangeable), 8.02 (d, J= 8.2 Hz, 1H), 7.71 (t, J= 8.0 Hz, 1H), 7.59 (d, J = 1.2 Hz, 1H), 7.32 (d, J= 7.7 Hz, 1H), 5.82 (d, J= 17.0 Hz, 1H), 5.59 (d, J= 17.0 Hz, 1H), 4.43 (dd, J= 8.9, 5.6 Hz, 1H), 3.99 (s, 3H), 3.92 (s, 3H), 3.89 - 3.82 (m, 1H), 2.39 - 2.15 (m, 2H), 2.01 - 1.85 (m, 1H), 1.18 - 1.03 (m, 1H), 0.73 - 0.61 (m, 1H). MS (ES+): 594.1 (M+l); (ES-): 592.1 (M-l); Analysis calculated for C2eH2*BrN70s2H20. 0.9HC1 :C, 47.08; H, 4.39; Cl, 4.81; N, 14.78; Found: C, 47.15; H, 4.28; Cl, 4.90; N, 14.68.

Scheme 241

Preparation of methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)- 5- methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-8-methoxy- 9H-pyrimido[4,5-b]indole-6- carboxylate (241a)

Compound 241a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methoxy-6-(methoxycarbonyl)-9H-pyrimido[4,5-b]i ndol-9- yl)acetic acid (240f) (75mg, 0.169 mmol) in DMF (1.5 mL) using HC1 salt of (1R,3S,5R)-N- (6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-c arboxamide (8a) (56.1 mg, 0.169 mmol), HATU (96 mg, 0.253 mmol), D1PEA (0.147 mL, 0.844 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] methyl 4-amino-9-(2-((lR,3S,5R)-3-((6-bromopyridin- 2-yl )carbamoyl )-5 -methy 1-2-azabi cyclo [3.1.0]hexan-2-yl)-2-oxoethyl)-8-methoxy-9H- pyrimido[4,5-b]indole-6-carboxylate (241a) (69 mg, 67% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-flfe) δ 10.73 (s, 1H, DzO exchangeable), 8.75 (d, J= 1.3 Hz, 1H), 8.58 (s, 1H), 8.54 (s, 2H, DzO exchangeable), 8.02 (d, J= 8.2 Hz, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.58 (d, ./= 1.3 Hz, 1H), 7.31 (d, J= 7.7 Hz, 1H), 5.77 (d, ./= 17.0 Hz, 1H), 5.54 (d, J= 16.9 Hz, 1H), 4.39 (dd,/= 8.9, 5.9 Hz, 1H), 3.98 (s, 3H), 3.92 (s, 3H), 3.63 (dd,J= 5.5, 2.3 Hz, 1H), 2.49 - 2.40 (m, 1H), 2.00 (dd,7= 13.2, 5.9 Hz, 1H), 1.32 (s, 3H), 1.12 - 0.99 (m, 1H), 0.85 - 0.77 (m, 1H); MS (ES+): 608.1 (M+l); (ES-): 606.1 (M-l); Analysis calculated for CzzHzeBrNzOs 1.5HzO. 0.9HC1 :C, 48.53; H, 4.51; Cl, 4.77; N, 14.67; Found: C, 48.51; H, 4.47; Cl, 4.66; N, 14.59.

Scheme 242

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methoxy-6-nitro-9H-pyrimido[4,5-b ]indol-9- yl)acetyI)-N-(6-bromopyiidin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (242g)

Step-1: Preparation of N -(2-bromo-6-methoxy-4-nitrophenyl)-2,2,2-trifluoroacetamide (242b)

Compound 242b was prepared according to the procedure reported in step-1 of scheme-46, from 2-bromo-6-methoxy-4-nitroaniline (242a) (5 g, 20.24 mmol; CAS # 16618-66-9) in DCM (75 mL) using triethylamine (4.80 mL, 34.4 mmol), trifluoroacetic acid anhydride (4.22 mL, 30.40 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [S1O2 gel (40 g), eluting with EtOAc in hexane from 0- 50%] N-(2-bromo-6-methoxy-4-nitrophenyl)-2,2,2-trifluoroacetamide (242b) (6.7 g, 96% yield) as a yellow solid; MS (ES+): 342.90 (M+l).

Step-2: Preparation of 2 -amino-7 -methoxy-5-nitro- 1 H-indole-3-carbonitrile (242c)

Compound 242c was prepared according to the procedure reported in step-1 of scheme- 11, from N-(2-bromo-6-methoxy-4-nitrophenyl)-2,2,2-trifluoroacetamide (242b) (6.7 g, 19.53 3.91 mmol), Cul (0.372 g, 1.953 mmol), K2CO3 (5.40 g, 39.1 mmol) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification using flash column chromatography [SiChgel (40 g), eluting with EtOAc in hexane from 0-50%] 2-amino-7- methoxy-5-nitro-lH-indole-3-carbonitrile (242c) (290 mg, 6% yield) as a yellow solid; Ή NMR (300 MHz, DMSO-i/e) δ 11.71 (s, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.47 (d, 2.0 Hz,

1H), 6.91 (s, 2H), 3.99 (s, 3H).

Step-3: Preparation of 8-methoxy-6-nitro-9H-pyrimido[4,5-b]indol-4-amine (242d)

Compound 242d was prepared according to the procedure reported in step-1 of scheme-6, from 2-amino-7-methoxy-5-nitro-lH-indole-3-carbonitrile (242c) (0.28 g, 1.206 mmol) using trimethyl orthoformate (2.64 mL, 24.12 mmol), AcOH (0.345 mL, 6.03 mmol), NfUOAc (0.465 g, 6.03 mmol) and heating at 100 °C for 16 h. This gave after workup 8-methoxy-6- nitro-9H-pyrimido[4,5-b]indol-4-amine (242d) (245 mg, 78% yield) as a pale-yellow solid; Ή NMR (300 MHz, DMSO-i/e) δ 12.73 (s, 1H), 9.05 (d, J= 1.9 Hz, 1H), 8.32 (s, 1H), 7.81 (d, J= 1.9 Hz, 1H), 7.57 (s, 2H), 4.08 (s, 3H); MS (ES+): 260.00 (M+l).

Step-4: Preparation of tert- butyl 2-(4-amino-8-methoxy-6-nitro-9H-pyrimido[4,5-b]indol-9- yl)acetate (242e)

Compound 242e was prepared according to the procedure reported in step-1 of scheme- 1, from 8-methoxy-6-nitro-9H-pyrimido[4,5-b]indol-4-amine (242d) (0.24 g, 0.926 mmol) in DMF (7 mL) using fcrf-butyl 2-bromoacetate (0.164 mL, 1.111 mmol), CS2CO3 (0.754 g,

2.315 mmol) and stirring at RT for 30 min. This gave after workup te/t-butyl 2-(4-amino-8- methoxy-6-nitro-9H-pyrimido[4,5-b]indol-9-yl)acetate (242e) (155 mg, 45% yield) as a pale- yellow solid; ^! HNMR (300 MHz, DMSO-ifc) δ 9.08 (d, J= 1.9 Hz, 1H), 8.38 (s, 1H), 7.83 (d, J = 1.9 Hz, 1H), 7.75 (s, 2H), 5.26 (s, 2H), 4.03 (s, 3H), 1.42 (s, 9H); MS (ES+): 374.17 (M+l).

Step-5: Preparation of 2-(4-amino-8-methoxy-6-nitro-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (242f)

Compound 242f was prepared according to the procedure reported in step-2 of scheme- 1, from tert- butyl 2-(4-amino-8-methoxy-6-nitro-9H-pyrimido[4,5-b]indol-9-yl)ac etate (242e) (150 mg, 0.402 mmol) using 20% TFA in DCM (2.306 pL, 6.03 mmol) and stirring at RT for 16 h. This gave after workup 2-(4-amino-8-methoxy-6-nitro-9H-pyrimido[4,5-b]indol-9- yl)acetic acid (242f) (170 mg, 98% yield) TFA salt as a pale-yellow solid; Ή NMR (300 MHz, DMSO-cfe) δ 9.15 (d, J= 1.9 Hz, 1H), 8.53 (s, 1H), 8.38 (s, 2H), 7.88 (d, J= 1.9 Hz, 1H), 5.35 (s, 2H), 4.04 (s, 3H); MS (ES+): 318.10 (M+l).

Step-6: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methoxy-6-nitro-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1 ,0]hexane-3-carboxamide (242g)

Compound 242g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methoxy-6-nitro-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (242f) (60mg, 0.139 mmol) in DMF (1.5 ml) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (44.3 mg, 0.139 mmol), HATU (79 mg, 0.209 mmol), DIPEA (0.121 mL, 0.696 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-8-methoxy-6-nitro-9H-pyrimido[4,5-b ]indol- 9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexa ne-3-carboxamide (242g) (31 mg, 38% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO -ck) δ 10.73 (s, 1H, D2O exchangeable), 9.15 (d,J= 1.9 Hz, 1H), 8.66 (s, 2H, D2O exchangeable), 8.61 (s, 1H), 8.01 (d, J= 8.2 Hz, 1H), 7.86 (d, J= 1.9 Hz, 1H), 7.71 (t ,J= 8.0 Hz, 1H), 7.31 (d, J= 7.7 Hz, 1H), 5.82 (d, J= 17.1 Hz, 1H), 5.57 (d, J= 17.0 Hz, 1H), 4.43 (dd, J= 8.9, 5.6 Hz, 1H), 4.04 (s, 3H), 3.86 (td, J= 6.2, 5.6, 2.2 Hz, 1H), 2.43 - 2.13 (m, 2H), 2.01 - 1.83 (m, 1H), 1.19 - 1.05 (m, 1H), 0.74 - 0.60 (m, 1H); MS (ES+): 581.1 (M+l); (ES-): 579.1 (M-l); Analysis calculated for C24H2iBrN ₈ C>5.1.75H2O.0.8HCl :C, 44.89; H, 3.97; Cl, 4.42; N, 17.45; Found: C, 44.96; H, 3.81; Cl, 4.49; N, 17.30.

Scheme 243

242f 243a

Preparation of ( lR,3S,5R)-2-(2-(4-amino-8-methoxy-6-nitro-9H-pyrimido[4,5-b] indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (243a)

Compound 243a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methoxy-6-nitro-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (242f) (60mg, 0.139 mmol) in DMF (1.5 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-caiboxamide (8a) (46.3 mg, 0.139 mmol), HATU (79 mg, 0.209 mmol), DIPEA (0.121 mL, 0.696 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-8-methoxy-6-nitro-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azab icyclo[3.1 ,0]hexane-3- carboxamide (243a) (49 mg, 59% yield) HC1 salt as a pale-yellow solid; ^l H NMR (300 MHz, DMSO-cfe) δ 10.74 (s, 1H, DzO exchangeable), 9.15 (d,7= 1.9 Hz, 1H), 8.79 - 8.42 (m, 3H, 2H DzO exchangeable), 8.02 (d, J= 8.1 Hz, 1H), 7.85 (d,J= 1.9 Hz, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.31 (d,J= 7.7 Hz, 1H), 5.77 (d,./= 17.0 Hz, 1H), 5.52 (d,J= 17.0 Hz, 1H), 4.39 (dd,J = 9.0, 5.9 Hz, 1H), 4.03 (s, 3H), 3.63 (dd, J= 5.6, 2.3 Hz, 1H), 2.48 - 2.41 (m, 1H), 2.00 (dd, J= 13.3, 5.9 Hz, 1H), 1.32 (s, 3H), 1.11 - 1.00 (m, 1H), 0.90 - 0.77 (m, 1H). MS (ES+):

595.1 (M+l); (ES-): 593.1 (M-l); Analysis calculated for CzsHzsBrNeOs lTSHzO.O.SHChC, 45.77; H, 4.19; Cl, 4.32; N, 17.08; Found: C, 45.83; H, 3.98; Cl, 4.65; N, 17.07.

Scheme 244

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-phenyI-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (244d)

Step-1: Preparation of ethyl 2-(4-amino-8-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (244a)

Compound 244a was prepared according to the procedure reported in step-1 of scheme- 1, from 8-bromo-9H-pyrimido[4,5-b]indol-4-amine (35c) (2 g, 7.60 mmol) in DMF (50 mL) using ethyl 2-bromoacetate (1.012 mL, 9.12 mmol), CS2CO3 (3.72 g, 11.40 mmol) and stirring at RT for 1.5 h. This gave after workup and purification ethyl 2-(4-amino-8-bromo- 9H-pyrimido[4,5-b]indol-9-yl)acetate (244a) (1.35 g, 51% yield) as a pale-yellow solid; Ή NMR (300 MHz, DMSO-flfe) δ 8.40 (dd, J= 7.8, 1.0 Hz, 1H), 8.34 (s, 1H), 7.60 (dd, J= 7.9, 1.0 Hz, 1H), 7.54 - 7.43 (m, 2H), 7.22 (t, J= 7.8 Hz, 1H), 5.55 (s, 2H), 4.18 (q, J= 7.1 Hz, 2H), 1.22 (t, J= 7.1 Hz, 3H); MS (ES+): 349.10 (M+l).

Step-2: Preparation of ethyl 2-(4-amino-8-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (244b)

Compound 244b was prepared according to the procedure reported in step-1 of scheme-62, from ethyl 2-(4-amino-8-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (244a) (500 mg, 1.432 mmol) in dioxane (36 mL) using phenylboronic acid (0.262 g, 2.148 mmol), a solution of cesium carbonate (0.700 g, 2.148 mmol) in water (4.5 mL), Pd(PPh3)2Clz (0.201 g, 0.286 mmol) and heating at 100 °C for 16 h under nitrogen. This gave after workup and purification hexane from 0-75%] ethyl 2-(4-amino-8-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (244b) (495 mg, 100% yield) as an off-white solid; Ή NMR (300 MHz, DMSO-t/e) δ 8.41 (dd, J= 7.8, 1.2 Hz, 1H), 8.29 (s, 1H), 7.48 (dd, J= 4.9, 1.8 Hz, 3H), 7.40 (s, 2H), 7.37 - 7.30 (m, 3H), 7.17 (dd, J= 7.4, 1.1 Hz, 1H), 4.65 (s, 2H), 3.89 (q, J= 7.1 Hz, 2H), 1.05 (t ,J= 7.1 Hz, 3H); MS (ES+): 347.20 (M+l).

Step-3: Preparation of 2-(4-amino-8-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (244c)

Compound 244c was prepared according to the procedure reported in step-4 of scheme- 17, from ethyl 2-(4-amino-8-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (244b) (300 mg, 0.866 mmol) in THF (4.5 mL) and methanol (4.5 mL) using a solution of IN lithium hydroxide hydrate (4.33 mL, 4.33 mmol) and stirring at RT for 19 h. This gave after work up 2-(4- amino-8-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (244c) (210 mg, 76% yield) which was used as such for the next step; *H NMR (300 MHz, DMSO-ifc) δ 12.67 (s, 1H), 8.40 (dd, J= 7.8, 1.2 Hz, 1H), 8.29 (s, 1H), 7.71 - 7.52 (m, 1H), 7.48 (dd, J= 5.0, 2.0 Hz, 3H), 7.43 - 7.24 (m, 4H), 7.17 (dd, J= 7.4, 1.1 Hz, 1H), 4.53 (s, 2H); MS (ES+): 319.10 (M+l).

Step-4: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-phenyl-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (244d)

Compound 244d was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-8-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (244c) (0.060 g, 0.188 mmol) in DMF (1.5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (4a) (60.1 mg, 0.188 mmol), HATU (108 mg, 0.283 mmol), DIPEA (0.164 mL, 0.942 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), DMA80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4- ammo-8-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-brom opyridin-2-yl)-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (244d) (69 mg, 63% yield) as a white solid; Ή NMR (300 MHz, DMSO-cfe) δ 10.70 (s, 1H, DzO exchangeable), 8.72 - 8.59 (m, 3H, 2H DzO exchangeable), 8.55 (dd, J= 7.9, 1.2 Hz, 1H), 8.00 (d, J= 8.2 Hz, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.60 - 7.37 (m, 5H), 7.37 - 7.19 (m, 3H), 5.28 (d, J= 17.6 Hz, 1H), 4.71 (d, J= 17.6 Hz, 1H), 4.22 (t ,J= 7.3 Hz, 1H), 3.18 - 3.07 (m, 1H), 2.13 (dd, J= 8.5, 3.4 Hz, 2H), 1.81 - 1.63 (m, 1H), 0.68 - 0.58 (m, 1H), 0.04 - -0.08 (m, 1H). MS (ES+): 582.1 (M+l); (ES-): 580 1 (M-l); Analysis calculated for CzsHMBrNzOz 1 75HzO 09HC1 :C 53 85; H 443; Cl Scheme 245

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-phenjd-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N- (6-bromopyridin-2-yl)-5 -methyl -2-azabicycl o [3.1 ,0]hexane-3-carboxamide (245a)

Compound 245a was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-ammo-8-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (244c) (60 mg, 0.188 mmol) in DMF (1.5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-5-methyl-2- azabicyclo[3.1.0]hexane-3-carboxamide (8a) (62.7 mg, 0.188 mmol), HATU (108 mg, 0.283 mmol), DIPEA (0.164 mL, 0.942 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-8-phenyl-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (245a) (71 mg, 63% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfe) δ 10.69 (s, 1H, DzO exchangeable), 8.63 - 8.41 (m, 4H, 2H D2O exchangeable), 8.00 (d, J= 8.2 Hz, 1H), 7.68 (t, J= 7.9 Hz, 1H), 7.62 - 7.36 (m, 5H), 7.36 - 7.06 (m, 3H), 5.21 (d, J= 17.9 Hz, 1H), 4.65 (d, J= 17.5 Hz, 1H), 4.17 (dd, 8.8, 6.2 Hz, 1H), 2.95 - 2.81 (m, 1H), 2.35 - 2.17 (m, 1H), 1.88 (dd, J= 13.0, 6.2 Hz, 1H), 1.18 (s, 3H), 0.64 - 0.51 (m, 1H), 0.28 - 0.12 (m, 1H). MS (ES+): 596.1(M+1); (ES-): 594.1 (M-l); Analysis calculated for C ₃ oH2 ₆ BrN702 1.75H20.HC1 :C, 54.23; H, 4.63; Cl, 5.34; N, 14.76; Found: C, 54.38; H, 4.44; Cl, 5.04; N, 14.68.

Scheme 246

Preparation of (2S,4R)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b] indol-9- yl)acetyl)-N-(6-chloropyridin-2-yl)-4-fluoropyrrolidine-2-ca rboxamide (246b)

Compound 246b was prepared according to the procedure reported in step-3 of scheme- 1 , from HC1 salt of 2-(4-ammo-6-(trifluoromethyl)-9H-pyiimido[4,5-b]indol-9-yl)a cetic acid (lie) (50 mg, 0.144 mmol), in DMF (1 mL) using TFA salt of (2S,4R)-N-(6-chloropyridin- 2-yl)-4-fluoropyrrolidine-2-carboxamide (246a) (51.6 mg, 0.144 mmol; prepared according to the procedure reported by Wiles, Jason A. et al. PCT Int. Appl. (2017), WO 2017035351 A1 20170302.), HATU (82 mg, 0.216 mmol), DIPEA (0.126 mL, 0.721 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)-l-(2-(4-amino-6-(trifluoromethyl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-chloropyridin-2-yl)-4 -fluoropyrrolidine-2- carboxamide (246b) (51 mg, 66% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfe) (a mixture of two rotamers) δ 11.37 and 10.97 (2s, 1H, D2O exchangeable), 9.01 (s, 1H), 8.86 (s, 2H, DzO exchangeable), 8.67 and 8.64 (2s, 1H), 8.22 - 7.71 (m, 4H), 7.30 and 7.19 (2d,J= 7.7 Hz, 1H), 5.76 - 5.01 (m, 3H), 4.62 (dd, J= 9.6, 7.4 Hz, 1H), 4.33 (dd, J = 22.2, 12.5 Hz, 1H), 4.09 (ddd, J= 38.3, 12.5, 3.2 Hz, 1H), 2.65 - 2.54 (m, 1H), 2.31 - 2.02 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO-tifc) δ -58.61, -175.54. MS (ES+): 536.2 (M+l); (ES-): 534.1 (M-l); Analysis calculated for CzaHisClFtNzOz 2H2O.0.95HC1 : C, 45.54; H, 3.81; Cl, 11.40; N, 16.16; Found: C, 45.53; H, 3.72; Cl, 11.16; N, 15.83.

Scheme 247

247c 247d

Preparation of (2S,4S)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b] indol-9- yl)acetyl)-N-(6-broinopyridin-2-yl)-4-methoxypyrroIidine-2-c arboxamide (247d)

Step-1: Preparation of (2S,4S)-/m-butyT 2-((6-bromopyridin-2-yl)carbamoyl)-4- methoxvpyrrolidine- 1 -carboxvlate (247b)

Compound 247b was prepared according to the procedure reported in step-1 of scheme-53, from (2S,4S)-l-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carbo xylic acid (247a) (0.5 g, 2.039 mmol; CAS # 83623-93-2) in DCM (15 mL) using 1 -methyl- lH-imidazole (0.406 mL, 5.10 mmol), methanesulfonyl chloride (0.189 mL, 2.446 mmol), 6-bromopyridin-2-amine (0.353 g, 2.039 mmol) and stirring at RT for 18 h. This gave after workup (2S,4S)-tert-butyl 2-((6-bromopyridin-2-yl)carbamoyl)-4-methoxypyrrolidine- 1 -carboxylate (247b) (681 mg, 83% yield); Ή NMR (300 MHz, DMSO-tfc) δ 10.68 (d, J= 27.7 Hz, 1H), 8.09 (q, J= 11.2, 10.0 Hz, 1H), 7.75 (q,./= 7.8 Hz, 1H), 7.35 (d, J= 7.7 Hz, 1H), 4.34 (q, J= 8.5, 7.9 Hz, 1H),

3.96 (t, J= 5.7 Hz, 1H), 3.70 - 3.59 (m, 1H), 3.30 - 3.15 (m, 4H), 2.43 (d, .7= 17.1 Hz, 1H),

1.96 - 1.75 (m, 1H), 1.33 (d,J= 42.4 Hz, 9H).

Step-2: Preparation of (2S,4S)-N-(6-bromopyridin-2-yl)-4-methoxypyrrolidine-2- carboxamide (247c)

Compound 247c was prepared according to the procedure reported in step-2 of scheme- 1, carboxylate (247b) (670 mg, 1.674 mmol) in DCM (9 mL) using TFA (0.903 mL, 11.72 mmol) and stirring overnight at RT. This gave after workup TFA salt of (2S,4S)-N-(6- bromopyridm-2-yl)-4-mcthoxypyrrolidme-2 -carboxamide (247c) (0.96 g, 98% yield) as a pale-yellow oil; Ή NMR (300 MHz, DMSO-ifc) δ 11.42 (s, 1H), 9.65 (s, 1H), 8.83 (s, 1H), 8.04 (d, J= 8.3 Hz, 1H), 7.82 (t ,J= 8.0 Hz, 1H), 7.45 (dd, J= 7.6, 3.1 Hz, 1H), 4.47 (s, 1H), 4.08 (d, J= 5.2 Hz, 1H), 3.50 - 3.31 (m, 2H), 3.18 (s, 3H), 2.63 - 2.54 (m, 1H), 2.20 (dd, J= 13.5, 4.7 Hz, 1H); MS (ES+): 300.00 (M+l).

Step-3: Preparation of (2S,4S)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b] indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-4-methoxypyrrolidine-2-ca rboxamide (247d)

Compound 247d was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of (2S,4S)-N-(6-bromopyridin-2-yl)-4-methoxypyrrolidine-2 -carboxamide

(247c) (84 mg, 0.144 mmol) in DMF (1 mL) using HC1 salt of 2-(4-amino-6- (trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (lie) (50 mg, 0.144 mmol), HATU (82 mg, 0.216 mmol), DIPEA (0.151 mL, 0.865 mmol) and stirring at RT for 16 h. Ibis gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4S)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b] indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-4-mcthoxypyrTolidine-2-ca rboxamide (247d) (55 mg, 64% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-dis) (a mixture of two rotamers) δ 11.07 and 10.55 (2s, 1H, DzO exchangeable), 8.98 (s, 1H), 8.74 - 8.47 (m, 3H, 2H DzO exchangeable), 8.18 - 7.91 (m, 2H), 7.91 - 7.76 (m, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.40 and 7.33 (2d, J= 7.7 Hz, 1H), 5.61 - 5.40 (m, 2H), 4.51 (dd,J= 9.1, 5.1 Hz, 1H), 4.21 - 4.08 (m, 2H), 3.85 (q, J= 6.4 Hz, 1H), 3.30 and 3.15 (2s, 3H), 2.55-2.45 (m, 1H), 2.12 - 1.96 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO-tfc) δ -58.53. MS (ES+): 592.1 (M+l), 614.1 (M+Na); (ES-): 590.1 (M-l); Analysis calculated for CztHziBrFaNzOa 1.5Hz0.1.15HCl.:C, 43.59; H, 3.83; Cl, 6.17; N, 14.83; Found: C, 43.64; H, 3.61; Cl, 6.14; N, 14.50.

Scheme 248

248c 248d

Preparation of (2S,4R)- l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-4-methoxypyrrolidinc-2-ca rboxamide (248d)

Step-1: Preparation of (2S,4R)-te/t-butyl 2-((6-bromopyridin-2-yl)carbamoyl)-4- methoxvpyrrolidine- 1 -carboxylate (248b)

Compound 248b was prepared according to the procedure reported in step-1 of scheme-53, from (2S,4R)-l-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carbo xylic acid (248a) (0.5 g, 2.039 mmol; CAS # 83624-01-05) in DCM (15 mL) using 1 -methyl- lH-imidazole (0.406 mL, 5.10 mmol), methanesulfonyl chloride (0.189 mL, 2.446 mmol), 6-bromopyridin-2- amine (0.353 g, 2.039 mmol) and stirring at RT for 18 h. This gave after workup (2S,4R)- tert- butyl 2-((6-bromopyridin-2-yl)carbamoyl)-4-methoxypyrrolidine- 1 -carboxylate (248b) (730 mg, 89% yield); Ή NMR (300 MHz, DMSO-Je) δ 10.97 (d 18.3 Hz, 1H), 8.10 (dd, J= 14.4, 8.1 Hz, 1H), 7.76 (q, J= 8.2 Hz, 1H), 7.36 (d, J = 7.7 Hz, 1H), 4.39 (q, J= 8.2 Hz, 1H), 3.96 (d, J= 5.1 Hz, 1H), 3.45 (q,J= 3.5 Hz, 2H), 3.23 (s, 3H), 2.39 - 2.23 (m, 1H),

1.93 (ddd, ./= 13.4, 8.6, 4.9 Hz, 1H), 1.32 (d, J= 42.4 Hz, 9H); MS (ES+): 400.10 (M+l). Step-2: Preparation of (2S,4R)-N-(6-bromopyridin-2-yl)-4-methoxypyrrolidine-2- carboxamide (248c) Compound 248c was prepared according to the procedure reported in step-2 of scheme- 1, from (2S,4R)-/er/-butyl 2-((6-bromopyridin-2-yl)carbamoyl)-4-methoxypyrrolidine- 1 - carboxylate (248b) (720 mg, 1.799 mmol) in DCM (10 mL) using TFA (0.970 mL, 12.59 mmol) and stirring overnight at RT. This gave after workup TFA salt of (2S,4R)-N-(6- bromopyridin-2-yl)-4-methoxypyrrolidine-2-carboxamide (248c) (1.05 g, 100% yield) as a pale-yellow oil; ^! H NMR (300 MHz, DMSO-tife) δ 11.44 (s, 1H), 9.70 (s, 1H), 8.90 (s, 1H), 8.06 (d, J= 8.1 Hz, 1H), 7.82 (t, J= 7.9 Hz, 1H), 7.44 (dd, J= 7.8, 0.7 Hz, 1H), 4.50 - 4.38 (m, 1H), 4.18 - 4.10 (m, 1H), 3.42 - 3.32 (m, 2H), 3.27 (s, 3H), 2.65 (dd, ./= 13.7, 7.1 Hz, 1H), 2.07 - 1.93 (m, 1H); MS (ES+): 300.0 (M+l).

Step-3: Preparation of (2S,4R)-l-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b] indol- 9-yl)acetyl)-N-(6-bromopyridin-2-yl)-4-methoxypyrrolidine-2- caiboxamide (248d)

Compound 248d was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of (2S,4R)-N-(6-bromopyridin-2-yl)-4-methoxypyrrolidine-2-carbo xamide (248c) (84 mg, 0.144 mmol) in DMF (1 mL) using HC1 salt of 2-(4-amino-6- (trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (lie) (50 mg, 0.144 mmol), HATU (82 mg, 0.216 mmol), DIPEA (0.151 mL, 0.865 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] (2S,4R)-l-(2-(4-amino-6-(trifluoromethyl)- 9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl) -4-methoxypyrTOhdine-2- carboxamide (248d) (57 mg, 67% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfe) (a mixture of two rotamers) δ 11.34 and 10.91 (2s, 1H, D2O exchangeable), 9.00 (s, 1H), 8.77 (s, 2H, DzO exchangeable), 8.65 and 8.61 (2s, 1H), 8.20 and 7.99 (2d, J= 8.2 Hz, 1H), 7.94 - 7.79 (m, 2H), 7.69 (t, J= 8.0 Hz, 1H), 7.42 and 7.30 (2d, 1H), 5.61 (d, J= 17.3 Hz, 1H), 5.45 (d, ./= 17.3 Hz, 1H), 4.52 (t, ./= 8.0 Hz, 1H), 4.27 - 4.13 (m, 1H), 4.07 - 3.94 (m, 2H), 3.36 and 3.26 (2s, 3H), 2.40 - 2.29 (m, 1H), 2.11 - 1.94 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO-tifc) δ -58.57. MS (ES+): 592.1 (M+l), (ES-): 590.0 (M-l); Analysis calculated forCMFbiBrFsNzOs 1.75H20.1.1HC1 :C, 43.41; H, 3.89; Cl, 5.87; N, 14.77; Found: C, 43.38; H, 3.60; Cl, 5.84; N, 14.60.

Scheme 249 OH ΗΝ H K _^ -V l ^Br

0=^ Ν ¾ \

N. )

1 Λ °

Η 0 ₂ Ν 3 0a ,Ν. Ν ίΓ *

\ HATU, DIPEA

MeO ΝΗ ₂

MeO

57f 249a

Preparation of (lR,3S,5R)-2-(2-(4-antino-5-methoxy-9H-pyrimido[4,5-b]indol- 9-yl)acetyl)- N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0 ]hexane-3-carboxamide (249a)

Compound 249a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-5-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (57f) (60 mg, 0.155 mmol) in DMF (1.5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromo-3- methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (10a) (53.8 mg, 0.155 mmol), HATU (89 mg, 0.233 mmol), DIPEA (0.135 mL, 0.777 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-5-methoxy-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromo-3-methylpyridin -2-yl)-5-methyl-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (249a) (52 mg, 59% yield) HC1 salt as a white solid; ¹ HNMR(300 MHz, DMSO-cfe) δ 10.31 (s, 1H, D ₂ 0 exchangeable), 8.57 (s, 1H), 8.56 - 8.48 (m, 2H, DzO exchangeable), 8.41 (d, J= 8.7 Hz, 1H), 7.62 (d, J= 8.0 Hz, 1H), 7.45 (d, J= 7.9 Hz, 1H), 7.26 (d, J = 2.3 Hz, 1H), 7.04 (dd, J= 8.7, 2.3 Hz, 1H), 5.63 (d, J = 17.3 Hz, 1H), 5.42 (d, ./= 17.3 Hz, 1H), 4.36 (dd, J= 9.3, 5.4 Hz, 1H), 3.78 (s, 3H), 3.69 (dd,J= 5.6, 2.4 Hz, 1H), 2.63 - 2.53 (m, 1H), 2.09 - 2.00 (m, 1H), 1.99 (s, 3H), 1.35 (s, 3H), 1.09 - 1.01 (m, 1H), 1.01 - 0.90 (m, 1H); MS (ES+): 564.1 (M+l); (ES-): 562.1 (M-l); Analysis calculated for C26H26BrN ₇ 03 l.StoOHCLC, 49.73; H, 4.82; Cl, 5.65; N, 15.61; Found: C, 49.92; H, 4.81; Cl, 5.80; N, 15.54.

Scheme 250

Preparation of (S)-l-(2-(4-ammo-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(4- cyanobenzyl)pyrrolidine-2-carboxamide (250b)

Compound 250b was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (lc) (75 mg, 0.211 mmol) in DMF (5 mL) using HC1 salt of (S)-N-(4-cyanobenzyl)pyrrolidine-2-carboxamide (250a) (55.9 mg, 0.211 mmol; CAS # 182291-72-1), HATU (89 mg, 0.233 mmol), DIPEA (136 mg, 1.053 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 6%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (S)-l-(2-(4-amino-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(4-cyanobenzyl)pyrrolidi ne-2-carboxamide (250b) (55 mg, 58% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 8.70 - 8.40 (m, 5H, 3H DzO exchangeable), 7.68 (td, J= 5.2, 4.5, 2.4 Hz, 1H), 7.56 - 7.44 (m, 2H), 7.39 (qd, J= 7.6, 3.9 Hz, 2H), 7.27 (d ,J= 8.1 Hz, 2H), 5.37 (s, 2H), 4.46 - 4.13 (m, 3H), 3.94 - 3.78 (m, 1H), 3.78 - 3.67 (m, 1H), 2.23 - 1.64 (m, 4H); MS (ES+): 454 (M+l); (ES-): 452 (M-l); IR 2233 (cm ^"1 ) Analysis calculated for C25H23N7O2.1.05HC1.3.5H2O: C, 54.12; H, 5.64; Cl, 6.71; N, 17.67; Found: C, 54.43; H, 5.27; Cl, 6.90; N, 17.37.

Scheme 251

Preparation of (S)-3-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indo l-9-yl)acetyl)- N-(3-chloro-2-fluorobenzyl)-2-oxooxazolidine-4-carboxamide (251f)

Step-1: Preparation of perfluorophenyl 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5- b]indol-9-yl)acetate (251b)

To a stirred solution of TFA salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol- 9-yl)acetic acid (lie) (500 mg, 1.179 mmol) in DMF (2 mL) was added pyridine (0.200 mL, 2.475 mmol) followed by pentafluorophenyl triflouroacetate (251a) (0.253 mL, 1.473 mmol; CAS # 14533-84-7) and stirred for 45 min at RT. The reaction mixture was diluted with ethyl acetate (50 mL), washed with 0.1 N aqueous HC1 (2 x 30 mL), 5% aqueous NaHCCh (1 x 30 mL), dried, filtered and concentrated in vacuo to afford perfluorophenyl 2-(4-amino-6- (trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetate (251b) (475 mg, 85 % yield) as a white solid and was used as such for the next step; MS (ES+): 477.10 (M+l).

Step-2: Preparation of (S)-benzyl 3-(2-(4-arnino-6-(trifluoromethyl)-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-2-oxooxazolidine-4-carboxylate (251 d)

To a stirred solution of (S)-benzyl 2-oxooxazolidine-4-carboxylate (251c) (218 mg, 0.987 mmol; CAS # 203736-21-4) in dry DMF (1 mL) was added DIPEA (0.345 mL, 1.974 mmol), DMAP (12.06 mg, 0.099 mmol), followed by perfluorophenyl 2-(4-amino-6- (trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetate (251b) (470 mg, 0.987 mmol) and stirred for at RT 2 h. The reaction mixture was diluted with ethyl acetate (50 mL), washed concentrated in vacuo. The residue obtained was purified using flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 to 50 %] to give (S)-benzyl 3-(2-(4- amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acety l)-2-oxooxazolidine-4- carboxylate (251d) (140mg, 28% yield) as a white solid; Ή NMR (300 MHz, OMSO-de) δ 8.84 (s, 1H), 8.34 (s, 1H), 7.69 (d, J= 1.1 Hz, 2H), 7.63 (s, 2H), 7.32 (s, 5H), 5.92 (d, J=

18.6 Hz, 1H), 5.74 (d, J= 18.6 Hz, 1H), 5.17 (s, 2H), 5.06 (dd, J= 9.4, 3.7 Hz, 1H), 4.78 (t, J = 9.3 Hz, 1H), 4.64 (dd, J= 9.2, 3.7 Hz, 1H); MS (ES+): 514.10 (M+l).

Step-3: Preparation of (S)-3-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indo l-9- yl)acetyl)-2-oxooxazolidine-4-carboxyhc acid (251e)

Compound 251e was prepared according to the procedure reported in step-2 of scheme-45, from (S)-benzyl 3-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-2- oxooxazolidine-4-carboxylate (251 d) (135 mg, 0.263 mmol) in MeOH (30 mL) using palladium hydroxide on carbon (36.9 mg, 0.053 mmol) in a hydrogen atmosphere (balloon) for 2 h at RT. The reaction mixture was filtered and filtrate was concentrated in vacuum to give (S)-3-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indo l-9-yl)acetyl)-2- oxooxazolidine-4-carboxylic acid (251e) (0.070 g, 63% yield) as an off-white solid; 'HNMR (300 MHz, DMSO-ifc) δ 8.84 (s, 1H), 8.35 (s, 1H), 7.71 (d, J= 1.1 Hz, 2H), 7.62 (s, 2H),

5.89 (d, J= 18.6 Hz, 1H), 5.74 (d, J= 18.7 Hz, 1H), 4.90 - 4.80 (m, 1H), 4.75 (t, J= 9.1 Hz, 1H), 4.56 (dd, J= 8.9, 3.3 Hz, 1H); MS (ES+): 424.10 (M+l).

Step-4: Preparation of (S)-3-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indo l-9- yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2-oxooxazolidine-4-ca rboxamide (251f)

Compound 251f was prepared according to the procedure reported in step-3 of scheme- 1, from (S)-3-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indo l-9-yl)acetyl)-2- oxooxazolidine-4-carboxylic acid (251e) (30 mg, 0.071 mmol) in DMF (1 mL) using (3- chloro-2-fluorophenyl)methanamine (109b) (8.91 pL, 0.071 mmol; CAS # 182291-72-1), HATU (40.4 mg, 0.106 mmol), DIPEA (0.037 mL, 0.213 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (30 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (S)-3-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indo l-9- yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2-oxooxazolidine-4 -carboxamide (251f) (12 mg, 30% yield) HC1 salt as a white solid; Ή NMR (300 MHz DMSO-i/e) δ 899 - 8 92 (m 2H) 855 7.11 (m, 1H), 7.00 (t, .7= 7.9 Hz, 1H), 6.01 - 5.73 (m, 2H), 4.86 (dd, .7= 9.3, 3.6 Hz, 1H), 4.73 (t, J= 9.1 Hz, 1H), 4.37 (dt, J = 15.1, 4.3 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO) δ - 58.50, -121.33. MS (ES+): 565.1(M+1); (ES-): 563.0 (M-l).

Scheme 252

/°

38d 252a

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-methoxy-9H-pyrimido[4,5-b]indol-9 -yl)acetyl)- N-(6-bromo-3-methylp>Tidin-2-yl)-5-methyl-2-azabicyclo[3. 1.0]hexane-3-carboxamide (252a)

Compound 252a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (38d) (60 mg, 0.155 mmol) in DMF (1.5 mL) using HC1 salt of ( lR,3S,5R)-N-(6-bromo-3- methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (10a) (53.8 mg, 0.155 mmol), HATU (89 mg, 0.233 mmol), DIPEA (0.135 mL, 0.777 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6-methoxy-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromo-3-methylpyridin -2-yl)-5-methyl-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (252a) (50 mg, 57% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfe) δ 10.29 (s, 1H, D ₂ 0 exchangeable), 8.63 - 8.45 (m, 3H, 2H DzO exchangeable), 8.06 (d, J= 2.4 Hz, 1H), 7.62 (d, J= 8.0 Hz, 1H), 7.57 (d, J= 9.0 Hz, 1H), 7.45 (d, J= 7.9 Hz, 1H), 7.15 (dd ,J= 8.9, 2.4 Hz, 1H), 5.64 (d, J= 17.3 Hz, 1H), 5.37 (d, J= 17.3 Hz, 1H), 4.36 (dd,J= 9.2, 5.2 Hz, 1H), 3.89 (s, 3H), 3.65 (dd, J= 5.4, 2.4 Hz, 1.00 - 0.93 (m, 1H). MS (ES+): 564.1 (M+l); (ES-): 562.1 (M-l); Analysis calculated for C2 ₆ H26BrN ₇ 03 I.75H2O.HCL: C, 49.38; H, 4.86; Cl, 5.61; N, 15.50; Found: C, 49.41; H, 4.63; Cl, 5.39; N, 15.43.

Scheme 253

HIM H

⁰⁼ S 10a fjr y* Ki

N ¾ i\ s

N Λ ⁰

HATU, DIPEA N

H ₂ N 1

O

36d NH ₂ w

253a

Preparation of (lR,3S,5R)-2-(2-(4-amino-7-methoxy-9H-pyrimido[4,5-b]indol-9 -yl)acetyl)-

N-(6-bromo-3-methylpyridin-2-yl)-5-mcthyl-2-azabicyclo[3. 1.0]hexane-3-carboxamide

(253a)

Compound 253a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (36d) (60 mg, 0.155 mmol) in DMF (1.5 ttiL) using HC1 salt of (lR,3S,5R)-N-(6-bromo-3- methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0Jhexane-3-car boxamide (10a) (53.8 mg, 0.155 mmol), HATU (89 mg, 0.233 mmol), DIPEA (0.135 mL, 0.777 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1%HC1) from 0-100%] ( 1 R,3 S,5R)-2-(2-(4-amino-7-methoxy-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromo-3-methylpyridin -2-yl)-5-methyl-2- azabicyclo[3.1.0]hexane-3-carboxamide (253a) (46 mg, 53% yield) HC1 salt as a white solid; ^! HNMR (300 MHz, DMSO-rib) δ 10.31 (s, 1H, DzO exchangeable), 8.67 - 8.46 (m, 3H, 2H D2O exchangeable), 8.42 (d, J= 8.7 Hz, 1H), 7.62 (d, J= 8.0 Hz, 1H), 7.45 (d, J= 7.9 Hz, 1H), 7.26 (d 2.3 Hz, 1H), 7.05 (dd, 8.7, 2.2 Hz, 1H), 5.63 (d ,J= 17.3 Hz, 1H), 5.42 (d, J= 17.2 Hz, 1H), 4.36 (dd, J = 9.3, 5.4 Hz, 1H), 3.78 (s, 3H), 3.69 (dd, J= 5.6, 2.4 Hz, 1H) 261 253 (m 1H) 204 (dd J 13 5 5 7 H 1H) 1 99 (s 3H) 1 35 (s 3H) 1 12 0.98 (m, 1H), 0.98 - 0.90 (m, 1H). MS (ES+): 564.2 (M+l); (ES-): 562.2 (M-l); Analysis calculated for CjdfceBrNTOs LSEhO HCl :C, 49.73; H, 4.82; Cl, 5.65; N, 15.61; Found: C, 49.88; H, 4.80; Cl, 5.77; N, 15.66.

Scheme 254

HN· H o=/ rVy _* N H i\

10a f* y-N N* 1 j p.

HATU, DIPEA

H ₂ N Λ ⁰

54f v '2¾ 2 ^° 54a

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methoxy-9H-pyrimido[4,5-b]indol-9 -yl)acetyl)-

N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabic>'cl o[3.1.0]hexane-3-cafboxamide

(254a)

Compound 254a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methoxy-9H-pyiimido[4,5-b]indol-9-yl)acetic acid (54f) (60 mg, 0.155 mmol) in DMF (1.5 mL) using HC1 salt of ( lR,3S,5R)-N-(6-bromo-3- methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (10a) (53.8 mg, 0.155 mmol), HATU (89 mg, 0.233 mmol), DIPEA (0.135 mL, 0.777 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-8-methoxy-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromo-3-methylpyridin -2-yl)-5-methyl-2- azabicyclo[3.1 ,0]hexane-3-caiboxamide (254a) (55 mg, 63% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfc) δ 10.28 (s, 1H, D _z O exchangeable), 8.69 - 8.54 (m, 3H, 2H DzO exchangeable), 8.10 (d, J= 7.9 Hz, 1H), 7.61 (d, J= 8.0 Hz, 1H), 7.43 (d, .7= 7.9 Hz, 1H), 7.36 (t, J= 8.0 Hz, 1H), 7.14 (d, J= 8.1 Hz, 1H), 5.77 (d, J= 17.0 Hz, 1H), 5.56 (d, J= 16.9 Hz, 1H), 4.37 (dd, J= 9.1, 5.3 Hz, 1H), 3.90 (s, 3H), 3.60 (dd, J= 5.6, 2.4 Hz, 1H), 2.60 255 ( 1H) 2 10 203 ( 1H) 201 ( 3H) 1 34 ( 3H) 1 14 1 04 ( 1H) 092 0.78 (m, 1H). MS (ES+): 564.1 (M+l); (ES-): 562.1 (M-l); Analysis calculated for C26H26BrN ₇ 03 1.5H20.HC1 : C, 49.73; H, 4.82; Cl, 5.65; N, 15.61; Found: C, 49.71; H, 4.81; Cl, 5.55; N, 15.62.

Scheme 255

255b 255c

Preparation of ( 1 R,3S,5R)-2-(2-(4-amino-8-methyl-6-(p-tolyl)-9H-pyrimido[4,5- b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (255c)

Step-1: Preparation of tert-butyl 2-(4-amino-8-methyl-6-(p-tolyl)-9H-pyrimido[4,5-b]indol-9- yl)acetate (255a)

Compound 255a was prepared according to the procedure reported in step-1 of scheme-59, from tert-butyl 2-(4-amino-6-bromo-8-methyl-9H-pyiimido[4,5-b]indol-9-yl)ace tate (192e) (300 mg, 0.767 mmol) in dioxane (4 mL) using jMolylboronic acid (156 mg, 1.150 mmol), bis(triphenylphosphine)palladium(II) chloride (53.8 mg, 0.077 mmol) a solution of 3.3 M potassium carbonate (0.697 mL, 2.300 mmol) and stirring at 100 °C for 16 h. This gave after MeOH in DCM from 0-3%] terf-butyl 2-(4-amino-8-methyl-6-(p-tolyl)-9H-pyrimido[4,5- b]indol-9-yl)acetate (255a) (190 mg, 62% yield) as a white solid; Ή NMR (300 MHz, DMSO-i/e) δ 8.44 (d, J= 1.7 Hz, 1H), 8.30 (s, 1H), 7.78 (s, 1H), 7.76 (s, 1H), 7.48 (d, J= 1.7 Hz, 1H), 7.42 (s, 2H), 7.30 (s, 1H), 7.27 (s, 1H), 5.35 (s, 2H), 2.69 (s, 3H), 2.36 (s, 3H), 1.44 (s, 9H); MS (ES+): 403 (M+l), (ES-): 401 (M-l).

Step-2: Preparation of 2-(4-amino-8-methyl-6-(p-tolyl)-9H-pyrimido[4,5-b]indol-9-yl )acetic acid (255b)

Compound 255b was prepared according to the procedure reported in step-2 of scheme- 1 , from /erf-butyl 2-(4-amino-8-methyl-6-(p-tolyl)-9H-pyrimido[4,5-b]indol-9-yl )acetate (255a) (190 mg, 0.472 mmol) in DCM (5 mL) using TFA (538 mg, 4.72 mmol) and stirring at RT for 16 h. This gave after work up TFA salt of 2-(4-amino-8-methyl-6-(p-tolyl)-9H- pyrimido[4,5-b]indol-9-yl)acetic acid (255b) (250 mg); Ή NMR (300 MHz, DMSO-ifc) δ 8.77 - 8.51 (m, 4H), 7.77 (d, 2H), 7.64 (s, 1H), 7.32 (d, J= 8.0 Hz, 2H), 5.47 (s, 2H), 2.75 (s, 3H), 2.38 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO) δ -74.46; MS (ES+): 347 (M+l), (ES-): 345 (M-l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(p-tolyl)-9H-pyrimido[4, 5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azab icyclo[3.1 ,0]hexane-3- carboxamide (255c)

Compound 255c was prepared according to the procedure reported in step-3 of scheme- 1 , from TFA salt of 2-(4-amino-8-methyl-6-(p-tolyl)-9H-pyrimido[4,5-b]indol-9-yl )acetic acid (255b) (75 mg, 0.163 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carb oxamide (8a) (54.2 mg, 0.163 mmol), HATU (74.3 mg, 0.195 mmol) DIPEA (105 mg, 0.814 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(p-tolyl)-9H-pyrimido[4, 5-b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (255c) (65 mg, 64% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-de) δ 10.84 (s, 1H, D2O exchangeable), 8.72 (bs, 2H, DzO exchangeable), 8.62 (s, 1H), 8.57 (s, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.81 - 7.65 (m, 3H), 7.61 (s, 1H), 7.38 - 7.21 (m, 3H), 5.87 (d, J = 17.9 Hz 1H) 5 61 (d J = 179 Hz 1H) 440 (dd J = 90 62 Hz 1H) 3 74 - 3 67 (m 1H) 274 (t, J = 5.5 Hz, 1H), 0.85 (dd, J = 5.6, 2.4 Hz, 1H); MS (ES+) 624/626 (M+l), (ES-) 622/624 (M-l); Analysis calculated for C3zH3oBrN70z.l.lHC1.2.25HzO: C, 54.50; H, 5.09; Cl, 5.53; N, 13.90; Found: C, 54.21; H, 5.00; Cl, 5.39; N, 13.87.

Scheme 256

256a

255b

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(p-tolyl)-9H-pyrimido[4, 5-b]indol-9- yl)acetyl)-N -(6-bromopyridin-2-y l)-2-azabicyclo [3.1.0]hexane-3-carboxamide (256a)

Compound 256a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(p-tolyl)-9H-pyrimido[4,5-b]indol-9-yl )acetic acid (255b) (75 mg, 0.163 mmol) in DMF (5 ml) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-caiboxamide (4a) (51.9 mg, 0.163 mmol), HATU (74.3 mg, 0.195 mmol), DIPEA (105 mg, 0.814 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1%HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(p-tolyl)-9H-pyrimido[4, 5-b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (256a) (70 mg, 70% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO^fe) δ 10.83 (s, 1H, DzO exchangeable), 8.80 (s, 2H, DzO exchangeable), 8.63 (s, 1H), 8.57 (s, 1H), 8.01 (d, J= 8.1 Hz, 1H), 7.81 - 7.66 (m, 3H), 7.61 (s, 1H), 7.37 - 7.21 (m, 3H), 5.93 (d, J= 18.0 Hz,

1H), 5.64 (d, ./= 17.9 Hz, 1H), 4.43 (dd, J= 9.1, 5.7 Hz, 1H), 3.98 - 3.87 (m, 1H), 2.75 (s, 3H), 2.42 - 2.29 (m, 4H), 2.29 - 2.12 (m, 1H), 2.00 - 1.81 (m, 1H), 1.17 - 0.99 (m, 1H), 0.79 060 ( 1H) MS (ES+) 610/612 (M+l) (ES ) 608/610 (M l) A l i l l t d f C ₃ iH28BrN702.1.15 HO.1.75 H _z O: C, 54.44; H, 4.81; Cl, 5.96; N, 14.34; Found: C, 54.27; H, 4.91; Cl, 5.93; N, 14.46.

Scheme 257

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-methoxy-8-methyl-9H-pyrimido[4,5- b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (257g)

Step-1: Preparation of N-(2-bromo-4-methoxy-6-methylphenyl)-2,2,2-trifluoroacetamid e (257b)

Compound 257b was prepared according to the procedure reported in step-1 of scheme-46, from 2-bromo-4-methoxy-6-methylaniline (257a) (5.00 g, 23.14 mmol; CAS # 1100394-71- 5) in DCM (25 mL) using triethylamine (3.98 g, 39.3 mmol), a solution of trifluoroacetic acid anhydride (7.29 g, 34.7 mmol) in DCM (5 mL) and stirring at RT for 1 h. This gave after workup N-(2-bromo-4-methoxy-6-methylphenyl)-2,2,2-trifluoroacetamid e (257b) (7.05 g, 98% yield) as a plum solid; Ή NMR (300 MHz, DMSO-ifc) δ 11.02 (s, 1H), 7.17 (d, J= 2.8 Hz, 1H), 6.96 (d, 1H), 3.79 (s, 3H), 2.17 (s, 3H).

¹⁹ F NMR (282 MHz DMSO-i/e) δ -7407; MS (ES-): 310/312 (M-l) Step-2: Preparation of 2-amino-5-methoxy-7-methyl-lH-indole-3-carbonitrile (257c)

Compound 257c was prepared according to the procedure reported in step- 1 of scheme- 11, from N-(2-bromo-4-methoxy-6-methylphenyl)-2,2,2-trifluoroacetamid e (257b) (7.05 g, 22.59 mmol) in DMSO (20 mL) using malononitrile (1.791 g, 27.1 mmol), L-proline (0.520 g, 4.52 mmol), Cul (0.430 g, 2.259 mmol), a solution of K2CO3 (6.24 g, 45.2 mmol) in water (20 mL) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification [SiOzgel (40 g), MeOH in DCM from 0-6%] 2-amino-5-methoxy-7-methyl-lH- indole-3-carbonitrile (257c) (2.72 g, 60% yield) as a pale-brown solid; Ή NMR (300 MHz, DMSO-ΐ/ί) δ 10.57 (s, 1H), 6.51 (d, J = 2.4 Hz, 1H), 6.43 (s, 2H), 6.35 (dd, J = 2.4, 0.9 Hz, 1H), 3.71 (s, 3H), 2.29 (s, 3H); MS (ES+): 202 (M+l), (ES-): 200 (M-l).

Step-3: Preparation of 6-methoxy-8-methyl-9H-pyrimido[4,5-b]indol-4-amine (257d)

Compound 257d was prepared according to the procedure reported in step-2 of scheme-29, from 2-amino-5-methoxy-7-methyl-lH-indole-3-caibonitrile (257c) (2.72 g, 13.52 mmol) using NHrOAc (3.13 g, 40.6 mmol), HC(OMe)3 (7.17 g, 67.6 mmol) and heating at 90 °C for 16 h. This gave after work up 6-methoxy-8 -methyl-9H-pyrimido[4,5 -b J indol-4-amine (257d) (2.97 g, 96% yield) as a pale-yellow solid; Ή NMR (300 MHz, DMSO-de) δ 11.64 (s, 1H), 8.21 (s, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.13 (s, 2H), 6.79 (d, J = 2.3 Hz, 1H), 3.83 (s, 3H), 2.48 (s, 3H); MS (ES+): 229 (M+l), (ES-): 227 (M-l).

Step-4: Preparation of torf-butyl 2-(4-ami no-6-m ethoxy-8 -methyl -9H-pyrimi do [4,5 -b] i ndol- 9-yl)acetate (257e)

Compound 257e was prepared according to the procedure reported in step-1 of scheme- 1, from 6-methoxy-8-methyl-9H-pyrimido[4,5-b]indol-4-amine (257d) (2.00 g, 8.76 mmol) in DMF (15 mL) using tort-butyl 2-bromoacetate (1.880 g, 9.64 mmol), CS2CO3 (5.71 g, 17.52 mmol) and stirring at RT for 16 h. This gave after work up and purification using flash column chromatography [SiOzgel (40 g), methanol in DCM from 0-4%] tort-butyl 2-(4- amino-6-methoxy-8-methy l-9H-pyrim ido [4,5 -b] indol -9-y 1 )acetate (257e) (1.37 g, 46% yield) as a tan solid; ^l HNMR (300 MHz, DMSO-dk) δ 8.25 (s, 1H), 7.71 (d, J= 2.5 Hz, 1H), 7.30 (s, 2H), 6.79 (d, J= 2.4 Hz, 1H), 5.28 (s, 2H), 3.85 (s, 3H), 2.58 (s, 3H), 1.42 (s, 9H).

Step-5 : Preparation of 2-(4-amino-6-methoxy-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)a cetic acid (257f) Compound 257f was prepared according to the procedure reported in step-2 of scheme- 1, from tert-butyl 2-(4-amino-6-methoxy-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)a cetate (257e) (1.00 g, 2.92 mmol) in DCM (10 mL) using TFA (3.33 g, 29.2 mmol) and stirring at RT for 16 h. This gave after work up TFA salt of 2-(4-amino-6-methoxy-8-methyl-9H- pyrimido[4,5-b]indol-9-yl)acetic acid (2570 (1.51 g); Ή NMR (300 MHz, DMSO-tfc) δ 8.82 (s, 2H), 8.61 (s, 1H), 7.87 (d, J = 2.4 Hz, 1H), 6.97 (d, J = 2.4 Hz, 1H), 5.42 (s, 2H), 3.87 (s, 3H), 2.65 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -74.55; MS (ES+): 287 (M+l), (ES-): 285 (M-l).

Step-6: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-methoxy-8-methyl-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1.0] hexane-3 -carboxam ide (257g)

Compound 257g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-methoxy-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)a cetic acid (257f) (125 mg, 0.312 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (4a) (99 mg, 0.312 mmol), HATU (142 mg, 0.375 mmol), DIPEA (202 mg, 1.561 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C 18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0- 100%] ( 1 R,3 S,5R)-2-(2-(4-amino-6-methoxy-8-methyl-9H-pyrimido[4,5-b]ind ol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (257g) (116 mg, 68% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.82 (s, 1H, DzO exchangeable), 8.69 (bs, 2H, DzO exchangeable), 8.58 (s, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 6.94 (d, J = 2.4 Hz, 1H), 5.88 (d, J = 17.9 Hz, 1H), 5.60 (d, J = 17.9 Hz, 1H), 4.42 (dd, J = 9.1, 5.7 Hz, 1H), 3.96 - 3.87 (m, 1H), 3.85 (s, 3H), 2.66 (s, 3H), 2.42 - 2.28 (m, 1H), 2.25 - 2.12 (m, 1H), 2.00 - 1.83 (m, 1H), 1.13 - 0.99 (m, 1H), 0.71 - 0.62 (m, 1H); MS (ES+): 550/552 (M+l), (ES-): 548/550 (M-l); Analysis calculated for C25H24BrN7O3.HCL2.5H2O: C, 47.52; H, 4.79; Cl, 5.61; N, 15.52; Found: C, 47.55; H, 4.64; Cl, 5.61; N, 15.28.

Scheme 258

257f 258a

Preparation of ( lR,3S,5R)-2-(2-(4-amino-6-methoxy-8-methyl-9H-pyrimido[4,5-b ]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (258a)

Compound 258a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-methoxy-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)a cetic acid (257f) (125 mg, 0.312 mmol) in DMF (5 ml) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-caib oxamide (8a) (104 mg, 0.312 mmol), HATU (142 mg, 0.375 mmol), DIPEA (202 mg, 1.561 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C 18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6-methoxy-8-methyl-9H-pyrimido[4,5- b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (258a) (131 mg, 74% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.83 (s, 1H, D2O exchangeable), 8.67 (bs, 2H, D2O exchangeable), 8.58 (s, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 6.94 (d, J = 2.3 Hz, 1H), 5.84 (d, J = 18.0 Hz, 1H), 5.57 (d, J = 17.9 Hz, 1H), 4.38 (dd, J = 9.0, 6.2 Hz, 1H), 3.86 (s, 3H), 3.72 - 3.66 (m, 1H), 2.65 (s, 3H), 2.49 - 2.39 (m, 1H), 1.98 (m, 1H), 1.31 (s, 3H), 1.01 (m, 1H), 0.83 (m, 1H); MS (ES+): 564/566 (M+l), (ES-): 562/564 (M-l); Analysis calculated for C26H26BrN ₇ 03.1 2HC1.2.5H20: C, 47.81; H, 4.97; Cl, 6.51; N, 15.01; Found: C, 47.85; H, 4.89; Cl, 6.51; N, 14.94.

Scheme 259

259c 259d

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5 -b]indol-9- yl)acetyl)-N-(2-bromopyridin-4-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (259d)

Step-1: Preparation of (lR,3S,5R)-/ert-butyl 3-((2-bromopyridin-4-yl)carbamoyl)-2- azabicyclo[3.1 ,0]hexane-2-carboxylate (259b)

Compound 259b was prepared according to the procedure reported in step-1 of scheme-53, from (lR,3S,5R)-2-(fer/-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane -3-carboxylic acid (259a) (0.5 g, 2.200 mmol; CAS # 197142-34-0) in DCM (15 mL) using 1-methyl-lH- imidazole (0.438 mL, 5.50 mmol), methanesulfonyl chloride (0.204 mL, 2.64 mmol), 2- bromopyridin-4-amine (0.381 g, 2.200 mmol; CAS # 7598-35-8) and stirring at RT for 18 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), EtOAc in hexane from 0 - 50%] ( 1R,3 S,5R)-te/t-butyl 3-((2-bromopyridin-4-yl)caibamoyl)- 2-azabicyclo[3.1.0]hexane-2-carboxylate (259b) (0.798 g, 95% yield) as a colorless gum; MS (ES+): 382.1 (M+l).

Step-2: Preparation of (lR,3S,5R)-N-(2-bromopyridin-4-yl)-2-azabicyclo[3.1.0]hexane -3- carboxamide (259c)

Compound 259c was prepared according to the procedure reported in step-2 of scheme- 1, from ( lR,3S,5R)-tert-butyl 3-((2-bromopyridin-4-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane - 2 b l (259b) (078 2041 l) i DCM (11 L) i TFA (1 100 L 1428 mmol) and stirring overnight at RT. This gave after work up and purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] HC1 salt of (lR,3S,5R)-N-(2-bromopyridin-4-yl)-2- azabicyclo[3.1.0]hexane-3-caiboxamide (259c) (450 mg, 69% yield); Ή NMR (300 MHz, DMSO-ifc) δ 11.53 (s, 1H), 10.11 (s, 1H), 9.28 (s, 1H), 8.32 (d, J= 5.5 Hz, 1H), 7.92 (d ,J = 1.8 Hz, 1H), 7.60 (dd, J= 5.6, 1.9 Hz, 1H), 4.24 (t, J= 9.4 Hz, 1H), 3.45 - 3.29 (m, 1H), 2.65 (dd, J= 12.8, 7.7 Hz, 1H), 2.11 (td, J= 12.0, 4.8 Hz, 1H), 1.84 (dq, J= 9.9, 5.1 Hz, 1H), 0.91 - 0.79 (m, 2H); MS (ES+): 282.0 (M+l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyiimido[4,5 - b]indol-9-yl)acctyl)-N-(2-bromopyridin-4-yl)-2-azabicyclo[3. 1.0] hexane-3 -carboxam ide (259d)

Compound 259d was prepared according to the procedure reported in step-3 of scheme- 1, from HC1 salt of (lR,3S,5R)-N-(2-bromopyridin-4-yl)-2-azabicyclo[3.1.0]hexane -3- carboxamide (259c) (55.1 mg, 0.173 mmol) in DMF (1.5 mL) using HC1 salt of 2-(4-amino- 6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (lie) (60mg, 0.173 mmol), HATU (99 mg, 0.260 mmol), DIPEA (0.151 mL, 0.865 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5 -b]indol- 9-yl)acetyl)-N-(2-bromopyridin-4-yl)-2-azabicyclo[3.1.0]hexa ne-3-carboxamide (259d) (54 mg, 54% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ife) δ 10.59 (s, 1H,

DzO exchangeable), 8.99 (s, 1H), 8.79 - 8.53 (m, 3H, 2H DzO exchangeable), 8.20 (d, J- 5.6 Hz, 1H), 7.96 - 7.80 (m, 3H), 7.47 (dd, J= 5.6, 1.9 Hz, 1H), 5.84 (d,J= 17.4 Hz, 1H), 5.50 (d, J= 17.3 Hz, 1H), 4.28 (dd, ./= 9.0, 6.0 Hz, 1H), 4.02 - 3.89 (m, 1H), 2.38 (dd, J= 13.4, 9.2 Hz, 1H), 2.29 - 2.15 (m, 1H), 2.00 - 1.86 (m, 1H), 1.16 - 1.00 (m, 1H), 0.92 - 0.64 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -58.55. MS (ES+): 574.1/576.1 (M+l); (ES-): 572.1/574.1 (M-l); Analysis calculated for CztHwBrFaNzCh 2.5H20.1.25HC1: C, 43.35; H, 3.83; Cl, 6.66; N, 14.74; Found: C, 43.46; H, 3.57; Cl, 6.83; N, 14.67.

Scheme 260

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5 -b]indol-9- yl)acetyl)-N-(6-bromopyrazin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (260a)

Compound 260a was prepared according to the procedure reported in step-3 of scheme- 1, from HC1 salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (lie) (60mg, 0.173 mmol) in DMF (1.5 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyrazin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (112a) (55.3 mg, 0.173 mmol), HATU (99 mg, 0.260 mmol), DIPEA (0.151 mL, 0.865 mmol) and stirring atRT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0- 100%] ( 1 R,3 S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyrazin-2-yl)-2-azabicyclo[3. 1.0]hexane-3-cafboxamide (260a) (37 mg, 37% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfe) 5 11.14 (s, 1H, DzO exchangeable), 9.24 (s, 1H), 8.98 (s, 1H), 8.68 - 8.56 (m, 3H, 2H DzO exchangeable), 8.54 (s, 1H), 7.94 - 7.82 (m, 2H), 5.83 (d ,J= 17.4 Hz, 1H), 5.48 (d ,J= 17.3 Hz, 1H), 4.44 (dd, J= 9.0, 5.6 Hz, 1H), 3.93 (td, J= 6.5, 5.7, 2.3 Hz, 1H), 2.42 - 2.20 (m, 2H), 2.00 - 1.86 (m, 1H), 1.12 - 1.01 (m, 1H), 0.90 - 0.74 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO) 5 -58.53. MS (ES+): 575.1/577.1 (M+l); (ES-): 573.1/575.1 (M-l); Analysis calculated for CzsHieBrFzNsOz 2.5H20.1.15HC1.:C, 41.71; H, 3.68; Cl, 6.16; N, 16.92; Found: C, 41.73; H, 3.45; Cl, 5.90; N, 16.76.

Scheme 261

261c CF ₃

261 d

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5 -b]indol-9- yl)acetyl)-N-(6-bromopyrazin-2-yi)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (261 d)

Step-1: Preparation of (lR,3S,5R)-ter/-butyl 3-((6-bromopyrazin-2-yl)carbamoyl)-5-methyl- 2-azabicyclo [3.1 ,0]hexane-2-carboxylate (261b)

Compound 261b was prepared according to the procedure reported in step-1 of scheme-53, from (lR,3S,5R)-2-(terf-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxylic acid (261a) (0.53 g, 2.197 mmol; CAS # 1306734-44-0) in DCM (15 mL) using 1-methyl- lH-imidazole (0.438 mL, 5.49 mmol), methanesulfonyl chloride (0.204 mL, 2.64 mmol) and 6-bromopyrazin-2-amine (0.382 g, 2.197 mmol; CAS # 54237-53-5) and stirring at RT for 18 h. This gave after workup and purification using flash column chromatography [silica gel (24 g), eluting with EtOAc in hexane from 0 - 50%] ( 1R,3 S,5R)-tert-butyl 3 -((6-bromopyrazin -2- yl)carbamoyl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-2-carboxylate (261b) (0.418 g, 48% yield) as a colorless gum; MS (ES+): 397.1/399.1 (M+l).

Step-2: Preparation of (lR,3S,5R)-N-(6-bromopyrazin-2-yl)-5-methyl-2- azabicyclo[3.1.0]hexane-3-carboxamide (261c)

Compound 261c was prepared according to the procedure reported in step-2 of scheme- 1 , from ( lR 3S 5R) tert butyl 3 ((6 bromopyrazin 2 yl)carbamoyl) 5 methyl 2 azabicyclo[3.1 ,0]hexane-2-carboxylate (261b) (0.41 g, 1.032 mmol) in DCM (6 mL) using TFA (0.557 mL, 7.22 mmol) and stirring overnight at RT. This gave after work up and purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1%HC1) from 0-100%] HC1 salt of (lR,3S,5R)-N-(6- bromopyrazin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carb oxamide (261c) (232 mg, 67% yield); Ή NMR (300 MHz, DMSO-cfe) δ 11.70 (s, 1H), 9.67 (s, 2H), 9.27 (s, 1H), 8.67 (s, 1H), 4.23 (dd, J= 11.0, 7.7 Hz, 1H), 3.10 (dd, J= 6.9, 2.4 Hz, 1H), 2.65 (dd, J= 12.7, 7.7 Hz, 1H), 2.00 (t,J= 11.8 Hz, 1H), 1.25 (s, 3H), 1.02 (dd, .7= 7.2, 2.4 Hz, 1H), 0.78 (t,J= 7.0 Hz, 1H); MS (ES+): 297.0 (M+l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5 - b]indol-9-yl)acetyl)-N-(6-bromopyrazin-2-yl)-5-methyl-2-azab icyclo[3.1.0]hexane-3- carboxamide (261d)

Compound 261d was prepared according to the procedure reported in step-3 of scheme-1, from HC1 salt of (lR,3S,5R)-N-(6-bromopyrazin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hexane- 3-carboxamide (261c) (58 mg, 0.173 mmol) in DMF (1.5 mL) using HC1 salt of 2-(4-amino- 6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (lie) (60mg, 0.173 mmol), HATU (99 mg, 0.260 mmol), DIPEA (0.151 mL, 0.865 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6-(trifluorome1hyl)-9H-pyrimido[4,5 -b]indol- 9-yl)acetyl)-N-(6-bromopyrazin-2-yl)-5-methyl-2-azabicyclo[3 .1 ,0]hexane-3-carboxamide (261 d) (62 mg, 61% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-c/e) δ 11.14 (s, 1H, DzO exchangeable), 9.25 (s, 1H), 8.95 (s, 1H), 8.56 (s, 1H), 8.54 (s, 1H), 8.40 (s, 2H, D2O exchangeable), 7.88 - 7.80 (m, 2H), 5.76 (d, J= 17.4 Hz, 1H), 5.42 (d, J= 17.3 Hz, 1H), 4.39 (dd, J= 9.1, 6.0 Hz, 1H), 3.71 (dd, .7= 5.5, 2.5 Hz, 1H), 2.48 - 2.42 (m, 1H), 2.03 (dd, J = 13.3, 6.0 Hz, 1H), 1.32 (s, 3H), 1.05 - 0.91 (m, 2H). ¹⁹ F NMR (282 MHz, DMSO-i/e) δ - 58.48; MS (ES+): 589.1/591.1 (M+l); (ES-): 587.1/589.1 (M-l); Analysis calculated for C24H2oBrF ₃ N ₈ 021.75H20.1.1HC1.:C, 43.61; H, 3.75; Cl, 5.90; N, 16.95; Found: C, 43.54; H, 3.74; Cl, 5.59; N, 16.70.

Scheme 262

215f 262a

Preparation of ( lR,3S,5R)-2-(2-(4-amino-6-(dimethylamino)-9H-pyrimido[4,5-b] indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (262a)

Compound 262a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-(dimethylamino)-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (215f) (75 mg, 0.188 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (4a) (59.8 mg, 0.188 mmol), HATU (86 mg, 0.225 mmol), DIPEA (121 mg, 0.939 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6-(dimethylamino)-9H-pyrimido[4,5-b ]indol-9- yl)acetyl)-N -(6-bromopyridin-2-yl)-2-azabicyclo [3.1.0]hexane-3 -carboxamide (262a) (13 mg, 13% yield) as a pale-yellow solid; Ή NMR (300 MHz, DMSO -de) δ 10.77 (s, 1H, DzO exchangeable), 9.08 - 8.52 (m, 4H, 2H DzO exchangeable), 8.01 (d, J = 8.2 Hz, 1H), 7.88 - 7.55 (m, 3H), 7.32 (d, J = 7.7 Hz, 1H), 5.77 (d, J = 17.4 Hz, 1H), 5.42 (d, J = 17.2 Hz, 1H), 4.41 (dd, J = 9.1, 5.6 Hz, 1H), 3.91 (td, J = 6.4, 5.6, 2.4 Hz, 1H), 3.18 (s, 6H), 2.41 - 2.28 (m, 1H), 2.27 - 2.14 (m, 1H), 1.99 - 1.84 (m, 1H), 1.13 - 1.02 (m, 1H), 0.84 - 0.73 (m, 1H); MS (ES+): 549/551 (M+l); (ES-): 547/549 (M-l).

Scheme 263

263b 263c

Preparation of ( lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(pyridin-4-yl)-9H-pyrimid o[4,5- b]indol-9-yI)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1.0]hexane-3-carboxamide (263c)

Step-1: Preparation of tert- butyl 2-(4-annno-8-methyl-6-(pyridm-4-yl)-9H-pyriniido[4,5- b]indol-9-yl)acetate (263a)

To a suspension of terf-butyl 2-(4-amino-6-bromo-8-methyl-9H-pyrimido[4,5-b]indol-9-y])ace tate (192e) (300 mg, 0.767 mmol), pyridin-4-ylboronic acid (141 mg, 1.150 mmol), Pd2(dba)3 (70.2 mg, 0.077 mmol), XPhos (73.1 mg, 0.153 mmol), and 1.27 M aqueous K3PO4 (1.207 mL, 1.533 mmol) in n-BuOH (4 mL) in a scintillation vial. The vial was flushed with nitrogen and then heated at 100 °C under nitrogen for 16 h. The resulting cooled deep red mixture was concentrated to dryness and the residue was suspended in HzO (30 mL) and EtOAc (30 mL), stirred for 30 min, and then filtered. The filtered cake was washed with H2O (20 mL) and EtOAc (20 mL) to provide 263a as a pale-yellow solid. The filtrate separated from aqueous layer and the aqueous layer was extracted with EtOAc (25 mL). The combined organic extract was washed withH ₂ 0 (25 mL), brine (25 mL), dried, filtered and concentrated, and residue obtained was purified by flash column chromatography (Silica gel, 12 g, 0-7% MeOH in DCM) to provide additional 263a as a white solid. Total yield: tert-butyl 2-(4- amino-8-methy l-6-(py ridin-4-y l)-9H-py riniido [4, 5-b] indol-9-y l)acetate (263a) (250 mg, 84 % yield). 7.52 (s, 2H), 5.38 (s, 2H), 2.72 (s, 3H), 1.44 (s, 9H). LC-MS: t = 1.73 min; MS (ES+) 390 (M+l), (ES-) 388 (M-l).

Step-2: Preparation of 2-(4-amino-8-methyl-6-(pyridin-4-yl)-9H-pyrimido[4,5-b]indol -9- yl)acetic acid (263b)

Compound 263b was prepared according to the procedure reported in step-2 of scheme- 1 , from tert- butyl 2-(4-amino-8-methyl-6-(pyridin-4-yl)-9H-pyrimido[4,5-b]indol -9-yl)acetate (263a) (250 mg, 0.642 mmol) in DCM (5 mL) using TFA (732 mg, 6.42 mmol) and stirring at RT for 16 h. This gave after work up TFA salt of 2-(4-amino-8-methyl-6-(pyridin-4-yl)- 9H-pyrimido[4,5-b]indol-9-yl)acetic acid (263b) (394 mg); ^l HNMR (300 MHz, DMSO-tik) δ 8.94 (d, J = 6.1 Hz, 2H), 8.89 (s, 1H), 8.60 - 8.44 (m, 3H), 8.19 (s, 2H), 7.99 (s, 1H), 5.46 (s, 2H), 2.79 (s, 3H). ¹⁹ F NMR (282 MHz, DMSO-cfe) δ -74.43;

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(pyridin-4-yl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1 _, 0]hexane-3- carboxamide (263c)

Compound 263c was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(pyridin-4-yl)-9H-pyrimido[4,5-b]indol -9-yl)acetic acid (263b) (56 mg, 0.125 mmol) in DMF (5 ml) using HC1 salt of (lR,3S,5R)-N-(6- bromopyiidin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (39.9 mg, 0.125 mmol), HATU (57.1 mg, 0.150 mmol), DIPEA (81 mg, 0.626 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 8%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(pyridin-4-yl)-9H-pyrimi do[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1 ,0]hexane-3-carboxamide (263c) (32 mg, 43% yield) HC1 salt as a pale-yellow solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.84 (s, 1H, D2O exchangeable), 9.02 (s, 1H), 8.96 (d, J= 6.5 Hz, 2H), 8.83 (s, 2H, DzO exchangeable), 8.68 - 8.57 (m, 3H), 8.09 - 7.92 (m, 2H), 7.70 (t, J= 8.0 Hz, 1H), 7.30 (d, ./= 7.7 Hz, 1H), 5.97 (d, J= 18.0 Hz, 1H), 5.67 (d, J= 17.9 Hz, 1H), 4.43 (dd, J= 9.0, 5.7 Hz, 1H), 3.99 - 3.90 (m, 1H), 2.81 (s, 3H), 2.42 - 2.29 (m, 1H), 2.28 - 2.14 (m, 1H), 2.02 - 1.85 (m, 1H), 1.17 - 1.03 (m, 1H), 0.79 - 0.59 (m, 1H); MS (ES+): 597/599 (M+l), (ES-):

595/597 (M-l); Analysis calculated for C29H25BrN ₈ 02.1.9HC1.4.25H20: C, 46.86; H, 4.80; Scheme 264

263b 264a

Preparation of ( lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(pyridin-4-yl)-9H-pyrimid o[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azab icyclo[3.1 ,0]hexane-3- carboxamide (264a)

Compound 264a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(pyridin-4-yl)-9H-pyrimido[4,5-b]indol -9-yl)acetic acid (263b) (75 mg, 0.168 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (8a) (55.8 mg, 0.168 mmol), HATU (76 mg, 0.201 mmol), DIPEA (108 mg, 0.838 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 8%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(pyridin-4-yl)-9H-pyrimi do[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azab icyclo[3.1.0]hexane-3- carboxamide (264a) (69 mg, 67% yield) HC1 salt as a pale-yellow solid; Ή NMR (300 MHz, DMSO-de) δ 10.85 (s, 1H, D2O exchangeable), 9.11 (bs, 2H, D2O exchangeable), 9.01 (s,

1H), 8.94 (d, J = 6.3 Hz, 2H), 8.73 - 8.55 (m, 3H), 8.01 (d, J = 8.2 Hz, 1H), 7.96 (s, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 5.93 (d, J = 18.0 Hz, 1H), 5.59 (d, J = 17.9 Hz, 1H), 4.40 (dd, J = 9.0, 6.2 Hz, 1H), 3.75 (m, 1H), 2.78 (s, 3H), 2.50 - 2.44 (m, 1H), 1.99 (m, 1H), 1.33 (s, 3H), 1.15 - 0.96 (m, 1H), 0.86 (m, 1H); MS (ES+): 611/613 (M+l), (ES-): 609/611 (M-l).

Scheme 265

258a 265a

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-hydroxy-8-methyl-9H-pyrimido[4,5- b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (265a)

Compound 265a was prepared according to the procedure reported in scheme- 164, from (lR,3S,5R)-2-(2-(4-amino-6-methoxy-8-methyl-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carb oxamide (258a) (78 mg, 0.138 mmol) in DCM (5 mL) using a solution of 1.0 M BBn in DCM (0.691 mL, 0.691 mmol) and stirring at RT for 16 h. This gave after work up and purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6-hydroxy-8-methyl-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azab icyclo[3.1.0]hexane-3- carboxamide (265a) (30 mg, 36% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-efe) (a mixture of two rotamers) δ 10.89 and 10.82 (2s, 1H, D2O exchangeable), 9.39 (s, 1H, D2O exchangeable), 8.77 - 8.41 (m, 3H, 2H D2O exchangeable), 8.01 and 7.94 (2d, ./ = 8.2 Hz, 1H), 7.77 - 7.62 (m, 2H), 7.35 - 7.27 (m, 1H), 6.82 (s, 1H), 5.80 (d, J= 17.9 Hz, 1H), 5.53 (d, J= 17.8 Hz, 1H), 4.38 (dd, J= 9.1, 6.2 Hz, 1H), 3.72 - 3.63 (m, 1H), 2.65 and 2.60 (2s, 3H), 2.48 - 2.40 (m, 1H), 1.97 (m, 1H), 1.30 (s, 3H), 1.00 (m, 1H), 0.91 - 0.76 (m, 1H); MS (ES+): 550/552 (M+l), (ES-): 548/550 (M-l); Analysis calculated for C25H24BrN7O3.Li5HCl.2H2O: C, 47.79; H, 4.68; Cl, 6.49; N, 15.60; Found: C, 47.69; H, 4.42; Cl, 6.41; N, 15.42.

Scheme 266

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5 -b]indol-9- yl)acetyl)-N-(3-bromophenyl)-2-azabicyclo[3.1.0]hexane-3-car boxamide (266b)

Compound 266b was prepared according to the procedure reported in step-3 of scheme- 1, from HC1 salt of 2-(4-amino-6-(trifluorome1hyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (lie) (60mg, 0.173 mmol) in DMF (1.5 mL) using HC1 salt of (lR,3S,5R)-N-(3- bromophenyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (266a) [(55.0 mg, 0.173 mmol); prepared according to the procedure reported by Lorthiois, E. etal. mJ Med. Cherrt. (2017), 60(13), 5717-5735.], HATU (99 mg, 0.260 mmol), DIPEA (0.151 mL, 0.865 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6- (trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(3- bromophenyl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (266b) (73 mg, 74% yield) as a white solid; *H NMR (300 MHz, DMSO-ifc) δ 10.09 (s, 1H, D ₂ 0 exchangeable), 8.99 (s, 1H), 8.65 - 8.45 (m, 3H, 2H DzO exchangeable), 7.97 - 7.81 (m, 3H), 7.45 (dt, J= 6.9, 2.3 Hz, 1H), 7.28 - 7.18 (m, 2H), 5.82 (d, J = 17.4 Hz, 1H), 5.50 (d, J= 17.3 Hz, 1H), 4.27 (dd, J= 9.0, 5.8 Hz, 1H), 3.99 - 3.87 (m, 1H), 2.42 - 2.28 (m, 1H), 2.28 - 2.17 (m, 1H), 1.99 - 1.86 (m, 1H), 1.14 - 1.02 (m, 1H), 0.83 - 0.74 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -58.53; MS (ES+): 573.1/575.1 (M+l); (ES-): 571.1/573.1 (M-l); Analysis calculated for C25H20BrF3N6O2.L25H2O.HCl: C, 47.48; H, 3.75; Cl, 5.61; N, 13.29; Found: C, 47.47; H, 3.43; Cl, 5.35; N, 13.23.

Scheme 267

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5 -b]indol-9- yl)acetyl)-N-(6-chlorop> ^, ridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (267c)

Step-1: Preparation of ( 1R,3 S,5R)-teri-butyl 3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[3.1 ,0]hexane-2-carboxyIate (267a)

Compound 267a was prepared according to the procedure reported in step-1 of scheme-53, from (lR,3S,5R)-2-(terr-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane -3-cafboxylic acid (259a) (0.5 g, 2.200 mmol) in DCM (15 mL) using 1-methyl-lH-imidazole (0.438 mL, 5.50 mmol), methanesulfonyl chloride (0.204 mL, 2.64 mmol), 6-chloropyridin-2-amine (0.283 g, 2.200 mmol; CAS # 45644-21-1) and stirring at RT for 18 h. This gave after workup and purification using flash column chromatography [silica gel (24 g), eluting with EtOAc in hexane from 0 - 50%] (lR,3S,5R)-tert-butyl 3-((6-chloropyridin-2-yl)carbamoyl)-2- azabicyclo[3.1 ,0]hexane-2-carboxylate (267a) (0.580 g, 78% yield) as a white solid; ‘H NMR (300 MHz, DMSO-tife) δ 10.80 (s, 1H), 8.11 - 8.01 (m, 1H), 7.86 (t,J= 8.0 Hz, 1H), 7.22 (d, J= 7.7 Hz, 1H), 4.20 - 4.00 (m, 1H), 3.44 - 3.37 (m, 1H), 2.30 (dd, J= 13.2, 8.8 Hz, 1H), 2.21 - 2.01 (m, 1H), 1.59 (s, 1H), 1.45 - 1.08 (m, 9H), 0.80 - 0.65 (m, 1H), 0.48 - 0.27 (m, 1H); MS (ES+): 338.1(M+1).

Step-2: Preparation of ( lR,3S,5R)-N-(6-chloropyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3- carboxamide (267b) Compound 267b was prepared according to the procedure reported in step-2 of scheme- 1, from ( lR,3S,5R)-te/7-butyl 3-((6-chloropyiidin-2-yl)carbamoyl)-2-azabicyclo[3.1.OJhexan e- 2-carboxylate (267a) (0.565 g, 1.673 mmol) in DCM (9 mL) using TFA (0.902 mL, 11.71 mmol) and stirring overnight at RT. This gave after work up and purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] HC1 salt of (lR,3S,5R)-N-(6-chloropyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (267b) (413 mg, 90% yield); Ή NMR (300 MHz, DMSO-ifc) δ 11.35 (s, 1H), 10.01 (s, 1H), 9.23 (s, 1H), 8.06 - 7.88 (m, 2H), 7.33 (dd, J= 7.6, 0.9 Hz, 1H), 4.21 - 4.08 (m, 1H), 3.39 - 3.27 (m, 1H), 2.62 (dd, J= 12.8, 7.7 Hz, 1H), 2.15 - 2.02 (m, 1H), 1.89 - 1.76 (m, 1H), 0.90 - 0.76 (m, 2H); MS (ES+): 238.1 (M+l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5 - b]indol-9-yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[3 .1.0]hexane-3-carboxamide (267c)

Compound 267c was prepared according to the procedure reported in step-3 of scheme- 1, from HC1 salt of ( lR,3S,5R)-N-(6-chloropyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3- carboxamide (267b) (47.4 mg, 0.173 mmol) in DMF (1.5 mL) using HC1 salt of 2-(4-amino- 6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (lie) (60 mg, 0.173 mmol), HATU (99 mg, 0.260 mmol), DIPEA (0.151 mL, 0.865 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-( 2-(4-amino-6-(trifluoromethyl)-9H-pyri mi do [4,5 - b]indol-9-yl)acetyl)-N-(6-chloropyridin-2-yl)-2-azabicyclo[3 .1 ,0]hexane-3-carboxamide (267c) (67 mg, 73% yield) as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.75 (s, 1H, D2O exchangeable), 8.98 (s, 1H), 8.61 (s, 1H), 8.58 (s, 2H, D2O exchangeable), 7.98 (d ,J= 8.2 Hz, 1H), 7.89 - 7.76 (m, 3H), 7.19 (d, J= 7.7 Hz, 1H), 5.82 (d, J= 17.4 Hz, 1H), 5.47 (d, J= 17.3 Hz, 1H), 4.42 (dd, J= 9.1, 5.5 Hz, 1H), 3.92 (td, J= 6.2, 5.4, 2.3 Hz, 1H), 2.40 - 2.15 (m, 2H), 2.00 - 1.83 (m, 1H), 1.15 - 0.98 (m, 1H), 0.86 - 0.74 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -58.53. MS (ES+): 530.2 (M+l); (ES-): 528.1 (M-l); Analysis calculated for C24H19CIF3N7O2.2H2O.O.85HCI: C, 48.29; H, 4.03; Cl, 10.99; N, 16.43; Found: C, 48.33; H, 3.79; Cl, 10.82; N, 16.28

11e 268b

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5 -b]indol-9- yl)acetyl)-N-(3-bromo-2-fluorophenyl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (268b)

Compound 268b was prepared according to the procedure reported in step-3 of scheme- 1 , from HC1 salt of 2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (lie) (60mg, 0.173 mmol) in DMF (1.5 ml) using HC1 salt of (lR,3S,5R)-N-(3-bromo-2- fluorophenyl)-2-azabicyclo[3.1.0Jhexane-3-carboxamide (268a) [(58.1 mg, 0.173 mmol); prepared according to the procedure reported by Lorthiois, E. et al. J. Med. Chem. (2017), 60(13), 5717-5735.], HATU (99 mg, 0.260 mmol) and DIPEA (0.151 mL, 0.865 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [silica gel (24 g), eluting with DMA80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HCl) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6- (trifluoromethyl)-9H-pyrimido[4 _, 5-b]indol-9-yl)acetyl)-N-(3-bromo-2-fluorophenyl)-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (268b) (98 mg, 96% yield) as a white solid; Ή NMR (300 MHz, DMSO-dSs) δ 9.85 (s, 1H, D ₂ 0 exchangeable), 8.96 (s, 1H), 8.55 (s, 1H), 8.36 (s, 2H, DzO exchangeable), 7.90 - 7.78 (m, 2H), 7.78 - 7.67 (m, 1H), 7.49 - 7.38 (m, 1H), 7.11 (td, J= 8.1, 1.4 Hz, 1H), 5.77 (d, J= 17.5 Hz, 1H), 5.49 (d, J= 17.3 Hz, 1H), 4.46 (dd, J= 8.8, 5.5 Hz, 1H), 3.94 - 3.84 (m, 1H), 2.38 - 2.22 (m, 2H), 2.00 - 1.84 (m, 1H), 1.10 (m,

1H), 0.86 - 0.71 (m, 1H); ¹⁹ FNMR (282 MHz, DMSO-ifc) δ -58.45, -117.67; MS (ES+): 591.1/593.1 (M+l); (ES-): 589.1/591.1 (M-l); Analysis calculated for C25Hi9BrF4N6O2.1.5H2O.0.95HCl :C, 45.98; H, 3.54; Cl, 5.16; N, 12.87; Found: C, 45.92; H, 3.41; Cl, 4.94; N, 12.73.

Scheme 269

Preparation of (1R,3S, 5R)-2-(2-(4-ammo-6-(trifhioromethyl)-9H-pyrimido[4,5-b]indol -9- yl)acetyl)-N-(6-chloropyridin-2-yl)-5-methyl-2-azabicyclo[3. 1.0]hexane-3-carboxamide (269c)

Step-1: Preparation of ( 1R,3 S,5R)-tert-butyl 3-((6-chloropyridin-2-yl)carbamoyl)-5-methyl- 2-azabicyclo [3.1 ,0]hexane-2-carboxylate (269a)

Compound 269a was prepared according to the procedure reported in step-1 of scheme-53, from ( 1 R,3 S, 5 R)-2-(te/7-butoxycarbonyl)-5 -methyl-2-azabicyclo [3.1.0]hexane-3-carboxylic acid (261a) (0.531 g, 2.200 mmol) in DCM (15 mL) using 1 -methyl- lH-imidazole (0.438 mL, 5.50 mmol), methanesulfonyl chloride (0.204 mL, 2.64 mmol), 6-chloropyridin-2-amine (0.283 g, 2.200 mmol; CAS # 45644-21-1) and stirring at RT for 18 h. This gave after workup and purification using flash column chromatography [silica gel (24 g), eluting with EtOAc in hexane from 0 - 50%] ( 1 R,3 S,5R)-tert-butyl 3-((6-chloropyridin-2-yl)carbamoyl)- 5-methyl-2-azabicyclo[3.1.0]hexane-2-carboxylate (269a) (0.667 g, 86% yield) as a white solid; ¾ NMR (300 MHz, DMSO-cfe) δ 10.80 (s, 1H), 8.16 - 7.96 (m, 1H), 7.86 (t ,J= 7.9 Hz, 1H), 7.22 (d, J= 7.7 Hz, 1H), 4.19 - 4.01 (m, 1H), 3.23 - 3.06 (m, 1H), 2.39 (dd,J= 12.8, 8.7 Hz, 1H), 1.95 - 1.81 (m, 1H), 1.51 - 1.08 (m, 12H), 0.71 - 0.62 (m, 1H), 0.62 - 0.52 (m, 1H); MS (ES+): 352.1(M+1).

Step-2: Preparation of (lR 3S 5R)-N-(6-chloropyridin-2-yl)-5-methyl-2- Compound 269b was prepared according to the procedure reported in step-2 of scheme- 1, from ( lR,3S,5R)-fc?/†-butyl 3-((6-chloropyridin-2-yl)carbamoyl)-5-methyl-2- azabicyclo[3.1 0]hexane-2-carboxylate (269a) (0.652 g, 1.853 mmol) in DCM (10 mL) using TFA (0.999 mL, 12.97 mmol) and stirring overnight at RT. This gave after work up and purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] HC1 salt of (lR,3S,5R)-N-(6- chloropyridin-2-yl)-5-methyl-2-azabic>'clo[3.1.0]hexane-3 -carboxamide (269b) (532 mg, 100% yield); ^l H NMR (300 MHz, DMSO-tifc) δ 11.34 (s, 1H), 9.85 (s, 1H), 9.24 (s, 1H), 8.08 - 7.85 (m, 2H), 7.40 - 7.21 (m, 1H), 4.27 - 4.08 (m, 1H), 3.09 (dd, 7.0, 2.4 Hz, 1H), 2.65 (dd, J= 12.6, 7.6 Hz, 1H), 1.97 (t,J= 11.9 Hz, 1H), 1.25 (s, 3H), 1.05 - 0.94 (m, 1H), 0.82 - 0.72 (m, 1H); MS (ES+): 252.1 (M+l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5 - b]indol-9-yl)acetyl)-N-(6-chloropyridin-2-yl)-5-methyl-2-aza bicyclo[3.1 ,0]hexane-3- carboxamide (269c)

Compound 269c was prepared according to the procedure reported in step-3 of scheme- 1, from HC1 salt of ( 1 R, 3 S ,5 R)-N -(6-chloropy ridin -2-y l)-5 -methy 1-2-azabicyclo [3.1.0]hexane- 3-carboxamide (269b) (60 mg, 0.173 mmol) in DMF (1.5 mL) using HC1 salt of 2-(4-amino- 6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (lie) [(58.1 mg, 0.173 mmol), HATU (99 mg, 0.260 mmol), DIPEA (0.151 mL, 0.865 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-( 2-(4-amino-6-(trifluoromethyl)-9H-pyri mi do [4,5 - b]indol-9-yl)acetyl)-N-(6-chloropyridin-2-yl)-5-methyl-2-aza bicyclo[3.1 ,0]hexane-3- carboxamide (269c) (53 mg, 56% yield) HC1 salt as a white solid; ^! H NMR (300 MHz, DMSO-cfe) δ 10.75 (s, 1H, DzO exchangeable), 8.98 (s, 1H), 8.70 - 8.47 (m, 3H, 2H DzO exchangeable), 7.99 (d, J= 8.2 Hz, 1H), 7.90 - 7.75 (m, 3H), 7.19 (d, J= 7.7 Hz, 1H), 5.78 (d, J= 17.4 Hz, 1H), 5.43 (d, J= 17.3 Hz, 1H), 4.37 (dd,/= 9.1, 6.0 Hz, 1H), 3.70 (m, 1H), 2.49 - 2.42 (m, 1H), 1.99 (m, 1H), 1.32 (s, 3H), 1.07 - 0.98 (m, 1H), 0.98 - 0.90 (m, 1H).

MS (ES+): 544.2 (M+l); (ES-): 542.1 (M-l); Analysis calculated for C25H21CIF3N7O2.2H2O.O.75HCI: C, 49.44; H, 4.27; Cl, 10.22; N, 16.14; Found: C, 49.65; H, 4.00; Cl, 9.94; N, 16.05.

Preparation of (1 R3S,5R)-2-(2-(4-amino-6-phenyl-9H-pyrimido[4,5-b]indol-9-yl) acet _j 'l)-N- (6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (270a)

Compound 270a was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-6-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (62b) (90 mg, 0.283 mmol) in DMF (10 mL) using HC1 salt of ( 1 R,3 S, 5 R)-N-(6-bromopy ridin-2-yl)-5 -methy 1-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (8a) (113 mg, 0.339 mmol), HATU (161 mg, 0.424 mmol), DIPEA (0.197 mL, 1.131 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 5%] followed by purification using reverse phase C18 column chromatography with water (containing 0.1% HCl)/acetonitrile (1:0 to 0:1) (lR,3S,5R)-2-(2- (4-amino-6-phenyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6- bromopyridin-2-yl)-5-methyl- 2-azabicyclo[3.1.0]hexane-3-carboxamide (270a) (58 mg, 34% yield) HC1 salt as a white solid; ‘HNMR (300 MHz, DMSO-tfc) δ 10.78 (s, 1H), 8.80 (d,J= 1.6 Hz, 1H), 8.76 (s, 2H), 8.63 (s, 1H), 8.01 (d,J= 8.2 Hz, 1H), 7.92 - 7.75 (m, 4H), 7.69 (t ,J= 8.0 Hz, 1H), 7.56 - 7.47 (m, 2H), 7.43 - 7.35 (m, 1H), 7.31 (d, J= 7.7 Hz, 1H), 5.76 (d, J= 17.3 Hz, 1H), 5.40 (d,J= 17.3 Hz, 1H), 4.38 (dd, J = 9.1, 6.0 Hz, 1H), 3.71 (dd, .7= 5.5, 2.4 Hz, 1H), 2.58 - 2.41 (m, 1H), 1.99 (dd, J= 13.2, 5.9 Hz, 1H), 1.31 (s, 3H), 1.06 - 0.98 (m, 1H), 0.94 (m,

1H); MS (ES+): 596.15 & 598.15 (M+l), MS (ES-): 594.10 & 596.10 (M-l); Analysis calculated for C30H26BrN7O2.UHCl.2H2O: C, 53.57; H, 4.66; N, 14.58; Cl, 5.80. Found: C, 53.76; H, 4.48; N, 14.50.; Cl, 5.76

Scheme 271

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(m-tolyl)-9H-pyrimido[4,5-b]indol -9-yl)acetyl)- N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-caiboxam ide (271c)

Step-1: Preparation of ethyl 2-(4-amino-6-(m-tolyl)-9H-pyrimido[4,5-b]indol-9-yl)acetate (271a)

Compound 271a was prepared according to the procedure reported in step-1 of scheme-62, from ethyl 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (48a) (200 mg, 0.573 mmol) in dioxane (18 mL) using m-tolylboronic acid (117 mg, 0.859 mmol), a solution of cesium carbonate (280 mg, 0.859 mmol) in water (2.2 mL), Pd(PPh3)2Ck (80 mg, 0.115 mmol) and heating at 100 °C for 19 h under nitrogen. This gave after workup a mixture of ethyl 2-(4-amino-6-(m-tolyl)-9H-pyrimido[4,5-b]indol-9-yl)acetate (271a) and 2-(4-amino-6- m-tolyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (271b) which was used as such for the next step; MS (ES+): 361.10 & 333.15 (M+l).

Step-2: Preparation of 2-(4-amino-6-(m-tolyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (271b)

Compound 271b was prepared according to the procedure reported in step-4 of scheme- 17, from a mixture containing ethyl 2-(4-amino-6-(m-tolyl)-9H-pyrimido[4,5-b]indol-9- (271b) (207 mg, 0.573 mmol) in THF (5 mL) and methanol (5 mL) using a solution of lithium hydroxide hydrate (147 mg, 3.44 mmol) in water (5 mL) and stirring at RT for 21 h. The residue obtained after work up was used as such for tire next step; MS (ES+): 333.10 (M+l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(m-tolyl)-9H-pyrimido[4,5-b]indol -9- yl)acetyl)-N-(6-bromopyridin-2-yI)-2-azabicycIo[3.1.0]hexane -3-carboxamide (271 c)

Compound 271c was prepared according to the procedure reported in step-3 of scheme-1, from 2-(4-amino-6-(m-tolyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (271b) (0.090 mg, 0.271 mmol) in DMF (10 mL) using HC1 salt of ( 1 R,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0Jhexane-3-carboxamide (4a) (0.104 g, 0.325 mmol), HATU (0.154 g, 0.406 mmol), DIPEA ( 140 mg, 1.083 mmol) and stirring at RT for 19 h. This gave after workup and purification using flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 5%] followed by purification using reverse phase column chromatography [C18 column, eluting with ACN in water (containing 0.1% HC1) from 0-100%] (1R,3S,5R)- 2-(2-(4-amino-6-(m-tolyl)-9H-pyrimido[4,5-b]indol-9-yl)acety l)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (271c) (58 mg, 36% yield) HC1 salt as awhile solid; Ή NMR (300 MHz, DMSO-flfc) δ 10.78 (s, 1H), 8.84 - 8.70 (m, 3H), 8.64 (s, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.87 (dd, J= 8.7, 1.6 Hz, 1H), 7.81 - 7.59 (m, 4H), 7.39 (t, J= 7.6 Hz, 1H), 7.32 (d, J= 7.7 Hz, 1H), 7.20 (d, J= 7.5 Hz, 1H), 5.80 (d, J= 17.4 Hz, 1H), 5.45 (d, J= 17.3 Hz, 1H), 4.42 (dd, J= 9.0, 5.6 Hz, 1H), 3.98 - 3.89 (m, 1H), 2.42 (s, 3H), 2.41 - 2.14 (m, 2H), 2.02 - 1.82 (m, 1H), 1.16 - 0.99 (m, 1H), 0.86 - 0.72 (m, 1H); MS (ES+): 596.20 & 598.10 (M+l), (ES-): 594.10 & 596.20 (M-l); Analysis calculated for C3oH26BrN702.HC1.2.25H20: C, 53.50; H, 4.71; N, 14.56; Cl, 5.26; Found: C, 53.79; H, 4.62; N, 14.71.; Cl, 5.19.

Scheme 272

H ₂ N

CO ₂ Ό TFA

N H

I

Boc V o II °

L S Ό

259a I /M-CI 272a

O

-i"; N¾

NH ₂ 11e

N ^CF 3

H ί Ό HATU, DIPEA Λ

272b NH ₂ ^cp3 272c

Preparation of (lR,3S,5R)-2-(2-(4-ammo-6-(trifluoromethy])-9H-pyrimido[4,5- b]indol-9- yl)acetyl)-N-(pyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-cafb oxamide (272c)

Step-1: Preparation of (1 RJS,5R)-terf-butyl 3-(pyridin-2-ylcarbamoyl)-2- azabicyclo[3.1 ,0]hexane-2-carboxylate (272a)

Compound 272a was prepared according to the procedure reported in step-1 of scheme-53, from (lR,3S,5R)-2-(fer/-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane -3-carboxylic acid (259a) (2.415 g, 10.63 mmol) in DCM (10 mL) using 1 -methyl- lH-imidazole (2.181 g, 26.6 mmol), methanesulfonyl chloride (1.461 g, 12.75 mmol) in DCM (2 mL), pyridin-2-amine (1.00 g, 10.63 mmol; CAS # 504-29-0) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (80 g), eluting with EtOAc in hexane from 0 - 30%] ( 1R,3 S,5R)-ter/-butyl 3-(pyridin-2-ylcarbamoyl)-2- azabicycIo[3.1 ,0]hexane-2-carboxylate (272a) (2.54 g, 79% yield) as a sticky white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.39 (s, 1H), 8.35 - 8.22 (m, 1H), 8.08 (d, J= 8.4 Hz, 1H), 7.87 - 7.73 (m, 1H), 7.16 - 7.03 (m, 1H), 4.24 - 4.07 (m, 1H), 3.52 - 3.35 (m, 1H), 2.29 (dd, J= 13.2, 8.8 Hz, 1H), 2.18 - 2.04 (m, 1H), 1.64 - 1.51 (m, 1H), 1.32 (2bs, 9H), 0.82 - 0.70 (m, 1H), 0.43 - 0.36 (m, 1H); MS (ES+): 304.20 (M+l).

Step-2: Preparation of (lR,3S,5R)-N-(pyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3- carboxamide (272b) Compound 272b was prepared according to the procedure reported in step-2 of scheme- 1, from ( lR,3S,5R)-fc/†-butyl 3-(pyridin-2-ylcarbamoyl)-2-azabicyclo[3.1.0]hexane-2- carboxylate (272a) (2.5 g, 8.24 mmol) in DCM (30 mL) using TFA (3.15 mL, 41.2 mmol) and stirring for 16 h at RT. This gave after work up TFA salt of (lR,3S,5R)-N-(pyridin-2-yl)- 2-azabicyclo[3.1.0]hexane-3-carboxamide (272b) (6.0 g); MS (ES+): 204.10 (M+l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5 - b]indol-9-yl)acetyl)-N-(pyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (272c)

Compound 272c was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of (lR,3S,5R)-N-(pyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carb oxamide (272b) (0.127 mg, 0.4 mmol) in DMF (10 mL) using HC1 salt of 2-(4-amino-6- (trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (lie) (69.3 mg, 0.2 mmol), HATU (152 mg, 0.400 mmol), DIPEA (0.174 mL, 1.0 mmol) and stirring at RT for 19 h.

This gave after workup and purification using flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 8%] followed by purification using reverse phase column chromatography [C18 column, eluting with ACN in water (containing 0.1% HC1) from 0-50%] (lR,3S,5R)-2-(2-(4-amino-6-(trifluoromethyl)-9H-pyrimido[4,5 -b]indol-9- yl)acetyl)-N-(pyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carb oxamide (272c) (56 mg, 57% yield) HC1 as a white solid; Ή NMR (300 MHz, DMSO-cfe) δ 10.46 (s, 1H), 8.99 (s, 1H), 8.68 (s, 2H), 8.64 (s, 1H), 8.28 (d, J= 4.9 Hz, 1H), 7.99 (d, J= 8.4 Hz, 1H), 7.93 - 7.83 (m, 2H), 7.77 (t ,J= 8.3 Hz, 1H), 7.15 - 7.05 (m, 1H), 5.85 (d ,J= 17.4 Hz, 1H), 5.48 (d, J= 17.2 Hz, 1H), 4.51 - 4.41 (m, 1H), 3.95 - 3.87 (m, 1H), 2.39 - 2.19 (m, 2H), 2.00 - 1.84 (m, 1H), 1.16 - 1.04 (m, 1H), 0.87 - 0.73 (m, 1H); MS (ES+): 496.15 (M+l); (ES-): 494.10 (M-l); Analysis calculated for C24H20F3N7O2 l.8HCl.3H2O: C, 46.86; H, 4.56; Cl, 10.37; N, 15.94; Found: C, 46.80; H, 4.06; Cl, 10.11; N, 15.62.

Scheme 273

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(pyridin-3-yl)-9H-pyrimido[4,5-b] indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (273c)

Step-1: Preparation of ethyl 2-(4-amino-6-(pyridin-3 -y l)-9H-pyrimido [4,5 -b] indol-9- yl)acetate (273a)

Compound 273a was prepared according to the procedure reported in step-1 of scheme-62, from ethyl 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (48a) (200 mg, 0.573 mmol) in dioxane (18 mL) using pyridin-3-ylboronic acid (106 mg, 0.859 mmol; CAS # 1692-25-7), bis(triphenylphosphine)palladium(II) chloride (80 mg, 0.115 mmol), a solution of cesium carbonate (280 mg, 0.859 mmol) in water (2.2 mL) and heating at 100 °C for 13 h. This gave after workup a mixture of ethyl 2-(4-amino-6-(pyridin-3-yl)-9H-pyrimido[4,5- b]indol-9-yl)acetate (273a) MS (ES+): 348.15 (M+l) and 2-(4-amino-6-(pyridin-3-yl)-9H- pyrimido[4,5-b]indol-9-yl)acetic acid (273b) MS (ES+): 320.10 (M+l) which was used as such for the next step.

Step-2: Preparation of 2-(4-amino-6-(pyridin-3 -yl)-9H-pyrimido [4,5 -b] indol-9-y l)acetic acid (273b) Compound 273b was prepared according to the procedure reported in step-4 of scheme- 17, from the above mixture of ethyl 2-(4-amino-6-(pyridin-3 -y l)-9H-pyrimido [4, 5 -b] indol-9- yl)acetate (273a) and 2-(4-ammo-6-(pyridin -3 -yl )-9H-pyrimido [4,5 -b] indol-9-y l)aceti c acid (273b) (0.573 mmol) in THF (5 mL) and methanol (5 mL) using a solution of lithium hydroxide hydrate (147 mg, 3.44 mmol) in water (5 mL) and stirring at RT for 18 h. This gave after work up 2-(4-amino-6-(pyridin-3 -yl)-9H-pyrimido [4,5 -b] indol-9-y l)acetic acid (273b) which was used as such for the next step; MS (ES+): 320.10 (M+l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(pyridin-3-yl)-9H-pyrimido[4,5-b] indol- 9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (273c)

Compound 273c was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-6-(pyridin-3-yl)-9H-pyrimido[4,5-b]indol-9-yl)ace tic acid (273b) (65 mg, 0.204 mmol) in DMF (10 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (4a) (84 mg, 0.265 mmol), HATU (155 mg, 0.407 mmol), DIPEA (0.142 mL, 0.814 mmol) and stirring at RT for 21 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 8%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6-(pyridin-3-yl)-9H-pyrimido[4,5-b] indol-9-yl)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (273c) (48 mg, 40% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfe) δ 10.78 (s, 1H), 9.45 (d, J = 2.2 Hz, 1H), 9.18 (d, J= 1.7 Hz, 1H), 9.14 (bs, 3H), 9.03 - 8.96 (m, 1H), 8.86 (dd, J= 5.5, 1.3 Hz, 1H), 8.71 (s, 1H), 8.16 - 8.06 (m, 2H), 8.00 (d, J= 8.2 Hz, 1H), 7.91 (d, J= 8.7 Hz, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.31 (d, 7.7 Hz, 1H), 5.85 (d, J= 17.4 Hz, 1H), 5.48 (d, 17.2

Hz, 1H), 4.43 (dd, J= 9.0, 5.5 Hz, 1H), 4.01 - 3.87 (m, 1H), 2.43 - 2.14 (m, 2H), 2.01 - 1.83 (m, 1H), 1.18 - 1.01 (m, 1H), 0.90 - 0.71 (m, 1H); MS (ES+): 583.10 & 585.10 (M+l), MS (ES-): 581.10 & 583.10 (M-l); Analysis calculated for C28H23BrN ₈ 02.2.25HC1.4.65 HbO: C, 44.89; H, 4.65; N, 14.96; Cl, 10.65; Found: C, 45.29; H, 4.52; N, 14.35.; Cl, 10.37.

Scheme 274

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(trifluoromethoxy)-9H-pyrimido[4, 5-b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (274g)

Step-1: Preparation of2,2,2-trifluoro-N-(2-iodo-4-(trifluoromethoxy)phenyl)aceta mide (274b)

Compound 274b was prepared according to the procedure reported in step-1 of scheme-46, from 2-iodo-4-(trifluoromethoxy)aniline (274a) (10 g, 33.0 mmol; CAS # 845866-79-7) in DCM (50 mL) using triethylamine (11.50 mL, 83 mmol), trifluoroacetic acid anhydride (6.88 mL, 49.5 mmol) and stirring at RT for 15 h. This gave after workup 2,2,2-trifluoro-N-(2- iodo-4-(trifluoromethoxy)phenyl)acetamide (274b) (15.94 g) which was used as such for next step; MS (ES-): 397.90 (M-l).

Step-2: Preparation of 2-amino-5 -(trifluoromethoxy)- lH-indole-3-carbonitrile (274c)

Compound 274c was prepared according to the procedure reported in step-1 of scheme- 11, from 2,2,2-trifluoro-N-(2-iodo-4-(trifluoromethoxy)phenyl)acetami de (274b) (13.17 g, 33 mmol) in DMSO (40 mL) using malononitrile (2.62 g, 39.6 mmol), L-proline (0.760 g, 6.60 mmol), Cul (0.628 g, 3.30 mmol), a solution of K2CO3 (9.12 g, 66.0 mmol) in water (40 mL) and heating at 60 °C for 19 h under an aigon atmosphere. This gave after workup and purification using flash column chromatography [SiOzgel (120 g), eluting with EtOAc in hexane from 0-66%] 2 -amino-5 -(trifluoromethoxy)- 1 H-indole-3 -carbonitri le (274c) (4.7 g, 59% yield) as a yellow solid; Ή NMR (300 MHz, DMSO-tfc) δ 10.93 (s, 1H), 7.17 (d ,J= 8.5 Hz 1H) 703 - 698 (m 3H) 6 88 - 6 82 (m 1H); ¹⁹ F NMR (282 MHz DMSO-tfc) δ -5692; Step-3: Preparation of 6-(trifluoromethoxy)-9H-pyrimido[4,5-b]indol-4-amine (274d)

Compound 274d was prepared according to the procedure reported in step-2 of scheme-29, from 2-amino-5 -(trifl uoromethoxy )- 1 H-indole-3 -carbonitrile (274c) (4.5 g, 18.66 mmol) in ethanol (85 mL) using formamidine acetate (15.70 g, 149 mmol) and refluxing for 19 h. This gave after work up 6-(trifhioromethoxy)-9H-pyrimido[4,5-b]indol-4-amine (274d) (2.873 g) as a gray solid which was used as such for the next step; Ή NMR (300 MHz, DMSO-i/e) δ 12.06 (s, 1H), 8.42 (d, J= 2.3 Hz, 1H), 8.27 (s, 1H), 7.50 (d, 8.7 Hz, 1H), 7.39 - 7.29 (m,

3H); ¹⁹ F NMR (282 MHz, DMSO-i/e) δ -56.94; MS (ES+): 269.10 (M+l); MS (ES-): 267.00 (M-l).

Step-4: Preparation of ethyl 2-(4-amino-6-(trifluoromethoxy)-9H-pyrimido[4,5-b]indol-9- yl)acetate (274e)

Compound 274e was prepared according to the procedure reported in step-1 of scheme- 1, from 6-(trifluoromethoxy)-9H-pyrimido[4,5-b]indol-4-amine (274d) (1.2 g, 4.47 mmol) in DMF (25 mL) using ethyl 2-bromoacetate (0.546 mL, 4.92 mmol), CS2CO3 (3.64 g, 11.19 mmol) and stirring at RT for 20 h. This gave after work up ethyl 2-(4-amino-6- (trifluoromethox>')-9H-pyrimido[4,5-b]indol-9-yl)acetate (274e) (495 mg, 31% yield) as an off-white solid; Ή NMR (300 MHz, DMSO-i/e) δ 8.48 (d, J= 2.3 Hz, 1H), 8.32 (s, 1H), 7.72 (d, J= 8.9 Hz, 1H), 7.51 (s, 2H), 7.44 - 7.37 (m, 1H), 5.27 (s, 2H), 4.14 (q, J= 7.1 Hz, 2H), 1.20 (t, J= 7.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-t/e) δ -56.97; MS (ES+): 355.10 (M+l).

Step-5 : Preparation of 2-(4-amino-6-(trifluoromethoxy)-9H-pyrimidof4,5-b]indol-9-yl )acetic acid (274f)

Compound 274f was prepared according to the procedure reported in step-4 of scheme- 17, from ethyl 2-(4-amino-6-(trifluoromethoxy)-9H-pyrimido[4,5-b]indol-9-yl )acetate (274e) (400 mg, 1.129 mmol) in THF (6 mL) and MeOH (6 mL) using a solution of lithium hydroxide hydrate (290 mg, 6.77 mmol) in water (6 mL) and stirring at RT for 17 h. This gave after work up 2-(4-ammo-6-(trifhioromethoxy)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (274f) (356 mg, 97% yield); Ή NMR (300 MHz, DMSO-flfc) δ 13.09 (s, 1H), 8.49 - 8.46 (m, 1H), 8.32 (s, 1H), 7.71 (d, J= 8.9 Hz, 1H), 7.49 (s, 2H), 7.43 - 7.37 (m, 1H), 5.17 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-i/e) δ -56.96; MS (ES+): 327.10 (M+l); MS (ES-): 325.10 (M-

1). Step-6: Preparation of (lR,3S,5R)-2-(2-(4-ammo-6-(trifluoromethoxy)-9H-pyrirnido[4, 5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1.0]hexane-3-carboxamide

(274g)

Compound 274g was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-6-(trifluoromethox>')-9H-pyrimido[4,5-b]indol- 9-yl)acetic acid (274f) (75 mg, 0.230 mmol) in DMF (10 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (4a) (88 mg, 0.276 mmol), HATU (175 mg, 0.460 mmol), DIPEA (0.160 mL, 0.92 mmol) and stirring at RT for 23 h. This gave after workup and purification by flash column chromatography [silica gel (25 g), eluting with MeOH in DCM from 0 - 5%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0- 100%](lR,3S,5R)-2-(2-(4-amino-6-(trifluoromethoxy)-9H-pyrimi do[4,5-b]indol-9-yl)acetyl)- N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxam ide (274g) (87 mg, 64% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO -ck) δ 10.77 (s, 1H), 8.83 (s, 2H), 8.71 - 8.64 (m, 2H), 8.00 (d, J= 8.2 Hz, 1H), 7.82 (d, J= 9.0 Hz, 1H), 7.70 (t, J= 8.0 Hz,

1H), 7.62 - 7.54 (m, 1H), 7.32 (d, J= 7.7 Hz, 1H), 5.81 (d, J= 17.4 Hz, 1H), 5.45 (d, J= 17.3 Hz, 1H), 4.41 (dd, J= 9.1, 5.5 Hz, 1H), 3.99 - 3.84 (m, 1H), 2.41 - 2.14 (m, 2H), 2.03 - 1.77 (m, 1H), 1.16 - 0.99 (m, 1H), 0.85 - 0.71 (m, 1H); ¹⁹ FNMR(282 MHz, DMSO-zfc) δ -57.02; MS (ES+): 590.10 & 592.10 (M+l); MS (ES-): 588.00 & 590.00 (M-l); Analysis calculated for C24H19BrF3N7O3.HCl.H2O: C, 44.70; H, 3.44; N, 15.21; Cl, 5.50; Found: C, 44.48; H, 3.23; N, 15.18.; Cl, 5.42.

Scheme 275

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(furan-3-yl)-9H-pyrimido[4,5-b]in dol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (275c)

Step-1: Preparation of ethyl 2-(4-amino-6-(furan-3-yl)-9H-pyrimido [4, 5 -b]indol-9-yl)acetate (275a)

Compound 275a was prepared according to the procedure reported in step-1 of scheme-62, from ethyl 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (48a) (200 mg, 0.573 mmol) in dioxane (18 mL) using furan-3-ylboronic acid (96 mg, 0.859 mmol), bis(triphenylphosphine)palladium(II) chloride (80 mg, 0.115 mmol) a solution of cesium carbonate (280 mg, 0.859 mmol) in water (2.2 mL) and heating at 100 °C for 19 h. This gave after workup a mixture of ethyl 2-(4-amino-6-(furan-3 -yl)-9H-pyrim ido [4,5 -b] indol-9- yl)acetate (275a) and 2-(4-ammo-6-(furan-3-yl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (275b) which was used as such for the next step; MS (ES+): 337.10 (M+l) and MS (ES+): 309.10 (M+l).

Step-2: Preparation of 2-(4-amino-6-(furan-3-yl)-9H-pyrimido[4,5-b]indol-9-yl)aceti c acid (275b)

Compound 275b was prepared according to the procedure reported in step-4 of scheme- 17, yl)acetate (275a) and 2-(4-amino-6-(furan-3-yl)-9H-pyritnido[4,5-b]indol-9-yl)acet ic acid (275b) (0.573 mmol) in THE (5 mL) and methanol (5 mL) using a solution of lithium hydroxide hydrate (147 mg, 3.44 mmol) in water (5 mL) and stirring at RT for 18 h. This gave after work up 2-(4-amino-6-(furan-3-yl)-9H-pyrimido[4,5-b]indol-9-yl)aceti c acid (275b) (166 mg, 94% yield) which was used as such for the next step; MS (ES+): 309.10 (M+l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(furan-3-yl)-9H-pyrimido[4,5-b]in dol-9- yl)acet>'l)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (275c)

Compound 275c was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-6-(furan-3 -yl)-9H-pyrimido [4,5 -b] indol-9-yl)acetic acid (275b) (78 mg, 0.253 mmol) in DMF (10 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (4a) (97 mg, 0.304 mmol), HATU (192 mg, 0.506 mmol), DIPEA (0.176 mL, 1.012 mmol) and stirring at RT for 13 h. This gave after workup and purification using flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 5%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6-(fiiran-3-yl)-9H-pyrimido[4,5-b]i ndol-9-yl)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (275c) (10 mg, 7% yield) HC1 salt as a light yellow solid; Ή NMR (300 MHz, DMSCWe) δ 10.77 (s, 1H), 8.69 (s, 1H), 8.64 - 8.48 (m, 3H), 8.26 (s, 1H), 8.01 (d,./= 8.1 Hz, 1H), 7.86 - 7.81 (m, 1H), 7.79 (t,J= 1.7 Hz, 1H), 7.74 - 7.66 (m, 2H), 7.34 - 7.29 (m, 1H), 7.18 - 7.16 (m, 1H), 5.75 (d, J= 17.3 Hz, 1H), 5.42 (d, J= 17.3 Hz, 1H), 4.42 (dd, J= 9.0, 5.6 Hz, 1H), 3.98 - 3.81 (m, 1H), 2.42 - 2.13 (m, 2H), 2.00 - 1.83 (m, 1H), 1.14 - 1.01 (m, 1H), 0.83 - 0.69 (m, 1H); MS (ES+): 572.10 & 574.10 (M+l); MS (ES-): 570.10 & 572.10 (M-l).

Scheme 276

Preparation of (lR,3S,5R)-2-(2-(4-amino-6,7-dimethoxy-9H-pyrimido[4,5-b]ind ol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (276g)

Step-1: Preparation of N-(2-bromo-4,5-dimethoxyphenyl)-2,2,2-trifluoroacetamide (276b)

Compound 276b was prepared according to the procedure reported in step-1 of scheme-46, from 2-bromo-4,5-dimethoxyaniline (276a) (5 g, 21.54 mmol; CAS # 16791-41-6) in DCM (75 mL) using triethylamine (5.10 mL, 36.6 mmol), trifluoroacetic acid anhydride (4.49 mL, 32.3 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (40 g), eluting with EtOAc in hexane from 0-50%] N-(2- bromo-4,5-dimethoxyphenyl)-2,2,2-trifluoroacetamide (276b) (1.49 g, 21% yield) as a pale- yellow solid which was used as such for next step; ‘H NMR (300 MHz, DMSO-ife) δ 11.13 (s, 1H), 7.26 (s, 1H), 7.05 (s, 1H), 3.81 (s, 3H), 3.76 (s, 3H); MS (ES+): 327.90 (M+l). Step-2: Preparation of 2-amino-5,6-dimethoxy-lH-indole-3-carbonitrile (276c)

Compound 276c was prepared according to the procedure reported in step-1 of scheme- 11, from N-(2-bromo-4,5-dimethoxyphenyl)-2,2,2-trifluoroacetamide (276b) (1.45 g, 4.42 mmol) in DMSO (5 mL) using malononitrile (0334 mL 5 30 mmol) L-proline (0 102 g 0 884 and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification [silica gel (40 g), eluting with EtOAc in hexane from 0-50%] 2-amino-5,6- dimethoxy- 1 H-indole-3 -carbon itrile (276c) (457 mg, 48% yield) as a yellow solid; ‘HNMR (300 MHz, DMSO-ifc) δ 10.38 (s, 1H), 6.80 (s, 1H), 6.71 (s, 1H), 6.48 (s, 2H), 3.74 (s, 3H), 3.71 (s, 3H); MS (ES+): 218.10 (M+l).

Step-3: Preparation of 6,7-dimethoxy-9H-pyrimido[4,5-b]indol-4-amine (276d)

Compound 276d was prepared according to the procedure reported in step-2 of scheme-29, from 2-amino-5,6-dimethoxy-lH-indole-3-carbonitrile (276c) (0.45 g, 2.072 mmol) in ethanol (5 mL) using trimethyl orthoformate (2.266 mL, 20.72 mmol), NHtOAC (0.479 g, 6.21 mmol) and heating at 90 °C for 16 h. This gave after work up and purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1%HC1) from 0-100%] 6,7-dimethoxy-9H-pyrimido[4,5-b]indol-4-amine (276d) (282 mg, 49% yield) HC1 salt as a pale-yellow solid; Ή NMR (300 MHz, DMSO-tife) δ 12.87 (s, 1H), 8.70 - 8.55 (m, 2H), 8.49 (s, 1H), 8.03 (s, 1H), 7.11 (s, 1H), 3.89 (s, 3H), 3.88 (s, 3H); MS (ES+): 245.10 (M+l).

Step-4: Preparation of torf-butyl 2-(4-ami no-6,7 -dimcthoxy-9H-pyrimido [4,5 -b] indol-9- yl)acetate (276e)

Compound 276e was prepared according to the procedure reported in step-1 of scheme- 1, from HC1 salt of 6,7-dimethoxy-9H-pyrimido[4,5-b]indol-4-amine (276d) (275 mg, 0.980 mmol) in DMF (7 mL) using tort-butyl 2-bromoacetate (0.159 mL, 1.078 mmol), CszCOs (702 mg, 2.155 mmol) and stirring at RT for 16 h. This gave after work up and purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] tort-butyl 2-(4-amino-6, 7 -dimethoxy-9H- pyrimido[4,5-b]indol-9-yl)acetate (276e) (283 mg, 81% yield) as a pale yellow solid; Ή NMR (300 MHz, DMSO-ifc) δ 8.63 (s, 2H), 8.54 (s, 1H), 8.06 (s, 1H), 7.47 (s, 1H), 5.28 (s, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 1.42 (s, 9H); MS (ES+): 359.2 (M+l).

Step-5: Preparation of 2-(4-amino-6,7-dimethoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (276f)

Compound 276f was prepared according to the procedure reported in step-2 of scheme- 1, from tort-butyl 2-(4-amino-6,7-dimethoxy-9H-pyrimido[4,5-b]indol-9-yl)acetat e (276e) (270 mg, 0.753 mmol) using 20% TFA in DCM (4324 pL, 11.30 mmol) and stirring at RT for 16 9-yl)acetic acid (276f) (311 mg, 99% yield) as a pale-yellow solid; Ή NMR (300 MHz, DMSO-flfe) δ 8.50 (s, 1H), 8.47 (s, 2H), 8.03 (s, 1H), 7.51 (s, 1H), 5.27 (s, 2H), 3.89 (s, 3H), 3.89 (s, 3H); MS (ES+): 303.1 (M+l).

Step-6: Preparation of (lR,3S,5R)-2-(2-(4-amino-6,7-dimethoxy-9H-pyrimido[4,5-b]ind ol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (276g)

Compound 276g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6,7-dimethoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (276f) (65.3 mg, 0.157 mmol) in DMF (1.5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin- 2-yl)-2-azabic>'clo[3.1.0]hexane-3-carboxamide (4a) (50mg, 0.157 mmol), HATU (90 mg, 0.235 mmol), DIPEA (0.137 mL, 0.785 mmol) and stirring at RT for 16 h. This gave after work up and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6,7-dimethoxy-9H-pyrimido[4,5-b]ind ol-9-yl)acetyl)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamid e (276g) (68 mg, 76% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSOA) δ 10.73 (s, 1H, DzO exchangeable), 8.69 (s, 2H, DzO exchangeable), 8.55 (s, 1H), 8.06 (s, 1H), 8.01 (d, J= 8.2 Hz, 1H), 111 (t, J = 8.0 Hz, 1H), 7.36 - 7.29 (m, 2H), 5.72 (d, J= 17.3 Hz, 1H), 5.46 (d, J= 17.2 Hz, 1H), 4.42 (dd, J= 9.1, 5.7 Hz, 1H), 3.93 - 3.89 (m, 7H), 2.35 (dd, J= 13.4, 9.2 Hz, 1H), 2.29 - 2.14 (m, 1H), 1.98 - 1.85 (m, 1H), 1.08 (dt, J= 8.3, 5.4 Hz, 1H), 0.75 (td, J= 5.2, 2.4 Hz, 1H).

MS (ES+): 566.1/568.1 (M+l); (ES-): 564.1/566.1 (M-l); Analysis calculated for C25H24BrN ₇ 04.2.5H20.1.25HCl.:C, 45.70; H, 4.64; Cl, 6.75; N, 14.92; Found: C, 45.82; H, 4.63; Cl, 6.58; N, 14.82.

Scheme 277 Preparation of (lR,3S,5R)-2-(2-(4-amino-6,7-dimethoxy-9H-pyrimido[4,5-b]ind ol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (277a)

Compound 277a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6,7-dimethoxy-9H-pyrimido[4,5-b]mdol-9-yl)acetic acid (276f) (65.1 mg, 0.156 mmol) in DMF (1.5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin- 2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (52 mg, 0.156 mmol), HATU (89 mg, 0.234 mmol), DIPEA (0.136 mL, 0.782 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6,7-dimethoxy-9H-pyrimido[4,5-b]ind ol-9-yl)acetyl)-N- (6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-c arboxamide (277a) (51 mg, 56% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-i/e) δ 10.72 (s, 1H, D ₂ 0 exchangeable), 8.70 (s, 2H, DzO exchangeable), 8.55 (s, 1H), 8.10 - 7.91 (m, 2H), 7.71 (t, J= 8.0 Hz, 1H), 7.38 - 7.29 (m, 2H), 5.68 (d, J= 17.3 Hz, 1H), 5.40 (d, J= 17.2 Hz, 1H), 4.37 (dd, J= 9.1, 6.1 Hz, 1H), 3.89 (s, 6H), 3.69 (dd, J= 5.6, 2.4 Hz, 1H), 2.59 - 2.54 (m, 1H), 2.00 (dd, J= 13.3, 6.0 Hz, 1H), 1.32 (s, 3H), 1.08 - 0.96 (m, 1H), 0.96 - 0.82 (m, 1H). MS (ES+): 580.1/582.1 (M+l); (ES-): 578.1/580.1 (M-l); Analysis calculated for C^ifteBrNvCU 2.75H20. HCL: C, 46.86; H, 4.92; Cl, 5.32; N, 14.71; Found: C, 46.80; H, 4.88; Cl, 5.17; N, 14.55.

Scheme 278

278a 278b 278c

-*

O

NH H o r O— xv"* 1 N TFA

NH ₂ ACOH N*.r ^N o r f \ ^N

N I

Cs ₂ C0 ₃

NH ₂

H ₂ N

/°

278d /

278e

^■ :

H

0=( -N )

/* )r ^N , 4a o rV ^Br

,0· N*_

If wN A

HATU, DIPEA ^¾

H ₂ N i

NH ₂

/ /°

278f 278g

Preparation of (lR,3S,5R)-2-(2-(4-amino-6,8-dimethoxy-9H-pyrimido[4,5-b]ind ol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (278g)

Step-1: Preparation ofN-(2-bromo-4,6-dimethoxyphenyl)-2,2,2-trifluoroacetamide (278b)

Compound 278b was prepared according to the procedure reported in step-1 of scheme-46, from 2-bromo-4,6-dimethoxyaniline (278a) (1 g, 4.31 mmol; CAS # 197803-53-5) in DCM (15 mL) using triethylamine (1.021 mL, 7.33 mmol), trifluoroacetic acid anhydride (0.898 mL, 6.46 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silicagel (24 g), eluting with EtOAc in hexane from 0-50%] N-(2- bromo-4,6-dimethoxyphenyl)-2,2,2-trifluoroacetamide (278b) (0.89 g, 63% yield) as a pale yellow solid; ^l HNMR (300 MHz, DMSO-ifc) δ 10.81 (s, 1H), 6.89 (d ,J= 2.5 Hz, 1H), 6.72 (d, J= 2.6 Hz, 1H), 3.82 (s, 3H), 3.79 (s, 3H); MS (ES+): 327.91 (M+l).

Step-2: Preparation of 2-amino-5,7-dimethoxy-lH-indole-3-carbonitrile (278c) Compound 278c was prepared according to the procedure reported in step-1 of scheme- 11, from N-(2-bromo-4,6-dimethoxyphenyl)-2,2,2-trifluoroacetamide (278b) (0.87 g, 2.65 mmol) in DMSO (3 mL) and using malononitrile (0.200 mL, 3.18 mmol), L-proline (0.061 g, 0.530 mmol), Cul (51 mg, 0.265 mmol), a solution of K2CO3 (0.733 g, 5.30 mmol) in water (3 mL) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification [silica gel (40 g), eluting with EtOAc in hexane from 0-50%] 2-amino-5,7- dimethoxy-lH-indole-3-carbonitrile (278c) (279 mg, 48% yield) as a yellow solid; ‘HNMR (300 MHz, DMSO-dfc) δ 10.63 (s, 1H), 6.31 (d, ./= 2.1 Hz, 1H), 6.29 (s, 2H), 6.21 (d, J= 2.1 Hz, 1H), 3.83 (s, 3H), 3.73 (s, 3H); MS (ES+): 218.1 (M+l); (ES-): 216.0 (M-l).

Step-3: Preparation of 6,8-dimethoxy-9H-pyrimido[4,5-b]indol-4-amine (278d)

Compound 278d was prepared according to the procedure reported in step-2 of scheme-29, from 2-amino-5,7-dimethoxy-lH-indole-3-carbonitrile (278c) (0.270 g, 1.243 mmol) in ethanol (20 mL) using formamidine acetate (1046 mg, 9.94 mmol) and refluxing for 22 h. This gave after work up 6,8-dimethoxy-9H-pyrimido[4,5-b]indol-4-amine (278d) (206 mg, 68% yield) as a pale-yellow solid; ‘HNMR(300 MHz, DMSO-cfc) 5 11.72 (s, 1H), 8.18 (s, 1H), 7.43 (d, J= 2.0 Hz, 1H), 7.12 (s, 2H), 6.60 (d, J= 2.0 Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H); MS (ES+): 245.1 (M+l).

Step-4: Preparation of tort-butyl 2-(4-amino-6,8-dimethoxy-9H-pyrimido[4,5-b]indol-9- yl)acetate (278e)

Compound 278e was prepared according to the procedure reported in step-1 of scheme- 1, from 6,8-dimethoxy-9H-pyrimido[4,5-b]indol-4-amine (278d) (200 mg, 0.819 mmol) in DMF (6 mL) using tort-butyl 2-bromoacetate (0.133 mL, 0.901 mmol), CS2CO3 (400 mg, 1.228 mmol) and stirring at RT for 16 h. This gave after work up and purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1%HC1) from 0-100%] tort-butyl 2-(4-amino-6,8-dimethoxy-9H-pyrimido[4,5- b]indol-9-yl)acetate (278e) (198 mg, 68% yield) as a pale yellow solid; Ή NMR (300 MHz, DMSO-cfe) δ 8.32 (s, 1H), 7.67 (s, 2H), 7.51 (d,J = 2.0 Hz, 1H), 6.67 (d ,J= 2.0 Hz, 1H),

5.15 (s, 2H), 3.87 (s, 6H), 1.42 (s, 9H); MS (ES+): 359.1 (M+l).

Step-5: Preparation of 2-(4-amino-6,8-dimethoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (278 f)

Compound 278f was prepared according to the procedure reported in step-2 of scheme- 1, mg, 0.488 mmol) using 20% TFA in DCM (2803 pL, 7.32 mmol) and stirring at RT for 16 h. This gave after work up and purification TFA salt of 2-(4-amino-6,8-dimethoxy-9H- pyrimido[4,5-b]indol-9-yl)acetic acid (278f) (225 mg, 97% yield) as a pale-yellow solid; Ή NMR (300 MHz, DMSO-ifc) δ 8.51 (s, 1H), 8.44 (s, 2H), 7.59 (d, J= 2.0 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 5.27 (s, 2H), 3.90 (s, 3H), 3.89 (s, 3H); MS (ES+): 303.1(M+1).

Step-6: Preparation of (lR,3S,5R)-2-(2-(4-amino-6,8-dimethoxy-9H-pyrimido[4,5-b]ind ol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (278g)

Compound 278g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6,8-dimethoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (278f) (74.3 mg, 0.157 mmol) in DMF (1.5 mL) using HC1 salt of ( 1R,3 S,5R)-N-(6-bromopyridin- 2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (50 mg, 0.157 mmol), HATXJ (90 mg, 0.235 mmol), DIPEA (0.137 mL, 0.785 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6,8-dimethoxy-9H-pyrimido[4,5-b]ind ol-9-yl)acetyl)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamid e (278g) (63 mg, 71% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-tfc) δ 10.74 (s, 1H, D ₂ 0 exchangeable), 8.68 (s, 2H, D2O exchangeable), 8.57 (s, 1H), 8.02 (d, J= 8.2 Hz, 1H), 7.71 (t, J= 8.0 Hz, 1H), 7.61 (d,J= 2.0 Hz, 1H), 7.32 (d, .7= 7.7 Hz, 1H), 6.75 (d ,J= 2.0 Hz, 1H), 5.75 (d,./= 17.0 Hz, 1H), 5.53 (d,J= 16.9 Hz, 1H), 4.43 (dd,J= 8.9, 5.6 Hz, 1H), 3.91 (s, 3H), 3.88 (s, 3H), 3.86 - 3.78 (m, 1H), 2.39 - 2.14 (m, 2H), 2.00 - 1.85 (m, 1H), 1.15 - 1.05 (m, 1H), 0.71 - 0.60 (m, 1H). MS (ES+): 566.1/568.1 (M+l); (ES-): 564.1/566.1 (M-l); Analysis calculated for C25H24BrN ₇ 04.1.5H2O.1.15HC1: C, 47.26; H, 4.47; Cl, 6.42; N, 15.43; Found: C, 47.47; H, 4.81; Cl, 6.46; N, 15.10.

Scheme 279

278f 279a

Step-6: Preparation of(lR,3S,5R)-2-(2-(4-amino-6,8-dimethoxy-9H-pyrimido[4,5-b]i ndol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (279a)

Compound 279a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6,8-dimethoxy-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (278f) (74.3 mg, 0.157 mmol) in DMF (1.5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin- 2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (52.2 mg, 0.157 mmol), HATU (90 mg, 0.236 mmol), DIPEA (0.137 mL, 0.785 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6,8-dimethoxy-9H-pyrimido[4,5-b]ind ol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (279a) (53 mg, 58% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-tfc) 5 10.74 (s, 1H, D2O exchangeable), 8.68 (s, 2H, D2O exchangeable), 8.56 (s, 1H), 8.02 (d, J= 8.2 Hz, 1H), 7.71 (t, 8.0 Hz, 1H), 7.60 (s, 1H), 7.32 (d, J= 7.7 Hz, 1H), 6.75 (s, 1H), 5.70 (d, J=

17.0 Hz, 1H), 5.48 (d, J= 17.0 Hz, 1H), 4.38 (dd, J= 8.9, 5.9 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.63 - 3.58 (m, 1H), 2.48 - 2.36 (m, 1H), 1.99 (dd,J= 13.4, 5.8 Hz, 1H), 1.31 (s, 3H), 1.08 - 1.01 (m, 1H), 0.88 - 0.78 (m, 1H). MS (ES+): 580.2/582.1 (M+l); (ES-): 578.1/580.1 (M-l); Analysis calculated for C26H26BrN7O4.2H2O.UHCl: C, 47.56; H, 4.77; Cl, 5.94; N, 14.93; Found: C, 47.47; H, 4.81; Cl, 5.88; N, 14.86.

Scheme 280

280f 280g

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-fluoro-8-methoxy-9H-pyrimido[4,5- b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (280g)

Step-1: Preparation of N -(2-bromo-4-fluoro-6-methoxypheny l)-2,2,2-trifluoroacetamide (280b)

Compound 280b was prepared according to the procedure reported in step-1 of scheme-46, from 2-bromo-4-fluoro-6-methoxyaniline (280a) (1 g, 4.54 mmol; CAS # 354574-32-6) in DCM (15 mL) using triethylamine (1.077 mL, 7.73 mmol), trifluoroacetic acid anhydride (0.948 mL, 6.82 mmol) and stirring at RT for 16 h. This gave after woikup and purification using flash column chromatography [silicagel (24 g), eluting with EtOAc in hexane from 0- 50%] N-(2-bromo-4-fluoro-6-methoxyphenyl)-2,2,2-trifluoroacetamid e (280b) (1.25 g, 87% yield) as a pale yellow solid; Ή NMR (300 MHz, DMSO-cfc) δ 11.01 (s, 1H), 7.30 (dd, J= 8.2, 2.7 Hz, 1H), 7.18 (dd, J= 10.8, 2.7 Hz, 1H), 3.83 (s, 3H); MS (ES+): 315.90 (M+l). Step-2: Preparation of 2-amino-5-fluoro-7-methoxy- lH-indole-3-carbonitrile (280c)

Compound 280c was prepared according to the procedure reported in step-1 of scheme- 11, mmol) in DMSO (5 mL) using malononitrile (0.292 mL, 4.63 mmol), L-proline (0.089 g, 0.772 mmol), Cul (74 mg, 0.386 mmol), a solution of K2CO3 (1.067 g, 7.72 mmol) in water (5 mL) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification [silica gel (40 g), eluting with EtOAc in hexane from 0-50%] 2-amino-5-fluoro- 7-methoxy-lH-indole-3-carbonitrile (280c) (538 mg, 68% yield) as a yellow solid; TlNMR (300 MHz, DMSO-tifc) δ 10.90 (s, 1H), 6.60 - 6.40 (m, 4H), 3.87 (s, 3H); MS (ES+): 206.10 (M+l); (ES-): 204.10 (M-l).

Step-3: Preparation of 6-fluoro-8-methoxy-9H-pyrimido[4,5-b]indol-4-amine (280d)

Compound 280d was prepared according to the procedure reported in step-2 of scheme-29, from 2-amino-5 -fluoro-7 -methoxy- 1 H-indole-3 -carbonitrile (280c) (0.520 g, 2.53 mmol) in ethanol (30 mL) using formamidine acetate (2132 mg, 20.27 mmol) and refluxing for 22 h. This gave after work up AcOH salt of 6-fluoro-8-methoxy-9H-pyrimido[4,5-b]indol-4-amine (280d) (665 mg, 90% yield) as a pale-yellow solid; Ή NMR (300 MHz, DMSO-t/e) δ 10.00 (s, 1H), 8.22 (s, 1H), 7.81 (dd,J= 9.7, 2.2 Hz, 1H), 7.18 (s, 2H), 6.92 (dd, J= 11.5, 2.2 Hz, 1H), 3.96 (s, 3H); MS (ES+): 233.1 (M+l).

Step-4: Preparation of torf-butyl 2-(4-amino-6-fluoro-8-methoxy-9H-pyrimido[4,5-b]indol-9- yl)acetate (280e)

Compound 280e was prepared according to the procedure reported in step-1 of scheme- 1, from AcOH salt of 6-fluoro-8-methoxy-9H-pyrimido[4,5-b]indol-4-amine (280d) (650 mg, 1.576 mmol) in DMF (15 mL) using tort-butyl 2-bromoacetate (0.256 mL, 0.1.734 mmol), CszCOs (1284 mg, 3.94 mmol) and stirring at RT for 16 h. This gave after work up and purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] tort-butyl 2-(4-amino-6-fluoro-8- methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetate (280e) (546 mg, 25% yield) as a pale yellow solid; ¾NMR (300 MHz, DMSO-tife) δ 8.54 (s, 1H), 8.43 (s, 2H), 8.02 (dd, J= 9.4, 2.2 Hz, 1H), 7.11 (dd, J= 11.4, 2.2 Hz, 1H), 5.25 (s, 2H), 3.94 (s, 3H), 1.43 (s, 9H); MS (ES+): 347.1 (M+l).

Step-5 : Preparation of 2-(4-amino-6-fluoro-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)a cetic acid (2800

Compound 280f was prepared according to the procedure reported in step-2 of scheme- 1, from tort-butyl 2-(4-amino-6-fluoro-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)a cetate (280e) 16 h. This gave after work up TFA salt of 2-(4-amino-6-fluoro-8-methoxy-9H-pyrimido[4,5- b]indol-9-yl)acetic acid (280f) (171 mg, 97% yield) as a pale-yellow solid; Ή NMR (300 MHz, DMSO-Kfc) δ 8.55 (s, 1H), 8.46 (s, 2H), 8.02 (dd, J= 9.4, 2.2 Hz, 1H), 7.13 (dd, J=

11.5, 2.2 Hz, 1H), 5.30 (s, 2H), 3.94 (s, 3H); MS (ES+): 291.10 (M+l).

Step-6: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-fluoro-8-methoxy-9H-pyrimido[4,5- b]mdol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 .0]hexane-3-carboxamide (280g)

Compound 280g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-fluoro-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)a cetic acid (280f) (77 mg, 0.157 mmol) in DMF (7 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyiidin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (50 mg, 0.157 mmol), HATU (90 mg, 0.235 mmol), DIPEA (0.137 mL, 0.785 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [silica gel (12 g), DMA80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6-fluoro-8-methoxy-9H-pyrimido[4,5- b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (280g) (58 mg, 67% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfe) δ 10.75 (s, 1H, D2O exchangeable), 8.71 (s, 2H, D2O exchangeable), 8.62 (s, 1H), 8.08 - 7.91 (m, 2H), 7.71 (t,./= 8.0 Hz, 1H), 7.32 (d, J= 7.7 Hz, 1H), 7.11 (dd, ./= 11.5, 2.2 Hz, 1H), 5.78 (d, J= 17.1 Hz, 1H), 5.54 (d, J= 16.9 Hz, 1H), 4.43 (dd, J= 8.9, 5.6 Hz, 1H), 3.95 (s, 3H), 3.84 (ddd, J = 7.6, 5.3, 2.3 Hz, 1H), 2.41 - 2.14 (m, 2H), 2.00 - 1.86 (m, 1H), 1.11 (dt, J= 9.8, 5.4 Hz, 1H), 0.66 (td, J= 5.1, 2.4 Hz, 1H). ¹⁹ F NMR (282 MHz, DMSO) δ -117.06. MS (ES+): 554.1/556.1 (M+l); (ES-): 552.1/554.1 (M-l); Analysis calculated for C24H2iBrFN ₇ 0 ₃ 1.75H20. HQ.: C, 46.32; H, 4.13; Cl, 5.70; N, 15.75; Found: C, 46.24; H, 3.99; Cl, 5.70; N, 15.66.

Scheme 281 4 it·

OH HN H ny N ¾ l\

°*S O'"

8a ,N. N A rv” f Χ-Π HATU, DIPEA if * \

N¾s

F

NH ₂ NH ₂

F

280f 281a

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-fluoro-8-methoxy-9H-pyrimido[4,5- b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (281a)

Compound 281a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-fluoro-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)a cetic acid (280f) (77 mg, 0.157 mmol) in DMF (1.5 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carb oxamide (8a) (52.2 mg, 0.157 mmol), HATH (90 mg, 0.236 mmol), DIPEA (0.137 mL, 0.785 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [silica gel (12 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6-fluoro-8-methoxy-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azab icyclo[3.1 ,0]hexane-3- carboxamide (281a) (65 mg, 73% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.74 (s, 1H, D2O exchangeable), 8.65 - 8.48 (m, 3H, 2H D2O exchangeable), 8.06 - 7.95 (m, 2H), 7.71 (t, J= 8.0 Hz, 1H), 7.32 (d,J= 7.7 Hz, 1H), 7.10 (dd,J= 11.5, 2.2 Hz, 1H), 5.73 (d,./= 17.0 Hz, 1H), 5.50 (d,J= 16.9 Hz, 1H), 4.38 (dd,J= 9.0, 5.9 Hz, 1H), 3.94 (s, 3H), 3.62 (dd, J= 5.5, 2.3 Hz, 1H), 2.49 - 2.41 (m, 1H), 2.00 (dd, J= 13.2, 5.9 Hz, 1H), 1.31 (s, 3H), 1.08 - 1.00 (m, 1H), 0.89 - 0.77 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO-cfe) δ -117.27. MS (ES+): 568.1/570.1 (M+l); (ES-): 566.1/568.1 (M-l); Analysis calculated for C25H23BrFN7O3 l.75H2O.HCl.: C, 47.18; H, 4.36; Cl, 5.57; N, 15.41; Found: C, 47.11; H, 4.33; Cl, 5.23; N, 15.33

Scheme 282

257g 282a

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-hydroxy-8-methyl-9H-pyrimido[4,5- b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (282a)

Compound 282a was prepared according to the procedure reported in scheme- 164, from (lR,3S,5R)-2-(2-(4-amino-6-methoxy-8-methyl-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (257g) (64 mg, 0.116 mmol) in DCM (5 mL) using a solution of 1.0 M BBn in DCM (0.581 mL, 0.581 mmol) and stirring at RT for 16 h. This gave after work up and purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1%HC1) from 0- 100%] ( 1 R,3 S,5R)-2-(2-(4-amino-6-hydroxy-8-methyl-9H-pyrimido[4,5-b]ind ol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (282a) (29 mg, 47% yield) HCl salt as a white solid; Ή NMR (300 MHz, DMSO-cfe) (a mixture of two retainers) δ 10.89 and 10.82 (2s, 1H, DaO exchangeable), 9.39 (s, 1H, DzO exchangeable), 8.55 (s, 1H), 8.47 (s, 2H, D2O exchangeable), 8.00 and 7.95 (2d, J= 8.1 Hz, 1H), 7.71 (t, J= 7.9 Hz, 1H), 7.65 (d, J= 2.1 Hz, 1H), 7.36 - 7.26 (m, 1H), 6.81 (s, 1H), 5.84 (d, J= 17.9 Hz, 1H), 5.57 (d, J= 17.9 Hz, 1H), 4.41 (dd, J= 9.0, 5.7 Hz, 1H), 3.95 - 3.82 (m, 1H), 2.65 and 2.61 (2s, 3H), 2.40 - 2.27 (m, 1H), 2.26 - 2.11 (m, 1H), 1.98 - 1.85 (m, 1H), 1.14 - 0.99 (m, 1H), 0.73 - 0.55 (m, 1H); MS (ES+): 536/538 (M+l); (ES-): 534/536 (M-l).

Scheme 283

CF ₃

^-NH Me C HX C<¾H

H ₂ N Me NC CN M,

(CF ₃ C0) ₂ 0 I

Et ₃ N Cul, K2CO3 NC' H

— o N ⁼ ' ¾-o N ^:

283a 283b 283c r C0 ₂ 'BU

Me Br^CQ Me TFA

HC(OMe) _{3 2} ¾u [* ^N

NH4OAC CS ₂ C0 ₃

NH ₂ ^n==/ NH ₂ N¾

283d 283e

H ,N; Br

<7 </ N

^COzH N i\ N ¾ l\

H b

8a

Me Λ ⁰

N ^r JCH HATU, DIPEA

NH ₂ ^n¾/

NH ₂ ^n==/

283f 283g

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-9H-pyrido[2',3 ^, :4,5Jpyrrolo[2, 3- d]pyrimidin-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2- azabicyclo[3.1 ,0]hexane-3- carboxamide (283g)

Step-1: Preparation of N-(2-bromo-4-methylpyridin-3-yl)-2,2,2-trifluoroacetamide (283b)

Compound 283b was prepared according to the procedure reported in step-1 of scheme-46, from 2-bromo-4-methylpyridin-3-amine (283a) (5 g, 26.7 mmol; CAS # 126325-50-6) in DCM (30 mL) using triethylamine (4.60 g, 45.4 mmol), trifluoroacetic acid anhydride (8.42 g, 40.1 mmol) and stirring at RT for 1 h. This gave after workup N-(2-bromo-4- methylpyridin-3-yl)-2,2,2-trifluoroacetamide (283b) (6.85 g, 91% yield) as a plum solid; Ή NMR (300 MHz, DMSO-i/e) δ 11.51 (s, 1H), 8.30 (d, J = 4.9 Hz, 1H), 7.48 (d, J = 4.9 Hz, 1H), 2.25 (s, 3H). ¹⁹ F NMR (282 MHz, DMSO- dr) δ -74.21; MS (ES+): 283/285, (ES-): 281/283 (M-l).

Step-2: Preparation of 2-amino-7-methyl-lH-pyrrolo[3,2-b]pyridine-3-carbonitrile (283c)

Compound 283c was prepared according to the procedure reported in step-1 of scheme- 11, from N-(2-bromo-4-methylpyridin-3-yl)-2,2,2-trifluoroacetamide (283b) (6.85 g, 24.20 4.84 mmol), Cul (0.461 g, 2.420 mmol), a solution of K2CO3 (6.69 g, 48.4 mmol) in water (30 mL) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification using flash column chromatography [silica gel (40 g), eluting with MeOH in DCM from 0-6%] 2-amino-7-methyl-lH-pyrrolo[3,2-b]pyridine-3-carbonitrile (283c) (0.39 g, 9% yield) as a yellow solid; Ή NMR (300 MHz, DMSO-i/s) δ 11.66 (s, 1H), 7.98 (d, J = 5.6 Hz, 1H), 7.48 (s, 2H), 6.93 (d, J = 5.6 Hz, 1H), 2.43 (s, 3H); MS (ES+): 173 (M+l), (ES- ): 171 (M-l).

Step-3: Preparation of 8-methyl-9H-pyrido[2',3':4,5]pynolo[2,3-d]p>Timidin-4-ami ne (283d)

Compound 283d was prepared according to the procedure reported in step-2 of scheme-29, from 2-amino-7-methyl-lH-pyrrolo[3,2-b]pyridine-3-carbonitrile (283c) (0.39 g, 2.265 mmol) in ethanol (5 mL) using NH+OAc (0.524 g, 6.79 mmol), HC(OMe)s (2.404 g, 22.65 mmol) and heating at 90 °C for 16 h. This gave after work up 8-methyl-9H- pyrido[2',3':4,5]pyrrolo[2,3-d]pyrirnidm-4-aniine (283d) (196 mg, 43% yield) as a brown solid; ΉΝΜΚ (300 MHz, DMSO-ife) δ 12.11 (s, 1H), 8.47 - 8.22 (m, 2H), 8.01 (s, 1H), 7.19 (d, J= 4.9 Hz, 1H), 6.65 (s, 1H), 2.56 (s, 3H); MS (ES+): 200 (M+l), (ES-): 198 (M-l). Step-4: Preparation of tort-butyl 2-(4-ammo-8-methyl-9H-pyrido[2',3':4,5]pyrrolo[2,3- dJpyrimidin-9-yl)acetate (283e)

Compound 283e was prepared according to the procedure reported in step-1 of scheme- 1, from 8-methyl-9H-pyrido[2',3 ^, :4,5]p> ^, rrolo[2,3-d]pyritnidin-4-amme (283d) (190 mg, 0.954 mmol) in DMF (15 mL) using tert- butyl 2-bromoacetate (205 mg, 1.049 mmol), CS2CO3 (622 mg, 1.908 mmol) and stirring at RT for 16 h. This gave after work up tort-butyl 2-(4-amino- 8-methyl-9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrirnidin-9-yl)a cetate (283e) (236 mg, 79% yield) as a white solid; Ή NMR (300 MHz, DMSO-tife) δ 8.50 - 8.31 (m, 2H), 7.90 (s, 1H), 7.20 (d, J= 5.0 Hz, 1H), 6.78 (s, 1H), 5.33 (s, 2H), 2.64 (s, 3H), 1.43 (s, 9H); MS (ES+): 314 (M+l), (ES-): 312 (M-l).

Step-5: Preparation of 2-(4-amino-8-methyl-9H-pyrido[2',3':4,5]pynOlo[2,3-dJpyrimid in-9- yl)acetic acid (283f)

Compound 283f was prepared according to the procedure reported in step-2 of scheme- 1, from tort-butyl 2-(4-amino-8-methyl-9H-pyrido[2 ^, ,3':4,5]pyrrolo[2,3-d]pyrimidin-9- yl)acetate (283e) (236 mg, 0.753 mmol) in DCM (5 mL) using TFA (859 mg, 7.53 mmol) and stirring at RT for 16 h. This gave after work up TFA salt of 2-(4-amino-8-methyl-9H- NMR (300 MHz, DMSO-cfe) δ 8.75 (s, 1H), 8.58 (s, 1H), 8.53 (d, J= 5.0 Hz, 1H), 7.93 (s, 1H), 7.37 (d, J= 5.0 Hz, 1H), 5.43 (s, 2H), 2.72 (s, 3H); MS (ES+): 258 (M+l), (ES-): 256 (M-l).

Step-6: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-9H-pyrido[2',3':4,5]pyrrol o[2,3- d]pyrimidin-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2- azabicyclo[3.1 ,0]hexane-3- carboxamide (283g)

Compound 283g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-9H-pyrido[2 ^, ,3':4,5]pyrrolo[2,3-d]pyrimidin-9- yl)acetic acid (283f) (75 mg, 0.202 mmol) in DMF (5 mL) using HC1 salt of (1R,3S,5R)-N- (6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-c arboxamide (8a) (67.2 mg, 0.202 mmol), HATU (92 mg, 0.242 mmol), DIPEA (131 mg, 1.010 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 5%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%](lR,3S,5R)-2-(2-(4-amino-8-methyl-9H- pyrido[2 ^, ,3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetyl)-N-(6-brom opyridin-2-yl)-5-methyl-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (283g) (71 mg, 66% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-flfc) δ 10.84 (s, 1H, D ₂ 0 exchangeable), 8.79 (s, 1H, D2O exchangeable), 8.61 (s, 1H), 8.53 (d ,J= 5.1 Hz, 1H), 8.34 (s, 2H, D2O exchangeable), 8.01 (d, J= 8.2 Hz, 1H), 7.72 (t, J= 8.0 Hz, 1H), 7.42 (d, ./= 5.3 Hz, 1H), 7.32 (d, J= 7.7 Hz,

1H), 5.88 (d, 18.0 Hz, 1H), 5.62 (d,J= 17.9 Hz, 1H), 4.39 (dd, J= 9.1, 6.1 Hz, 1H), 3.77

- 3.68 (m, 1H), 2.75 (s, 3H), 2.49 - 2.40 (m, 1H), 1.98 (dd, J = 13.3, 6.0 Hz, 1H), 1.31 (s, 3H), 1.03 (t, J= 5.5 Hz, 1H), 0.87 (dd, J= 5.5, 2.3 Hz, 1H); MS (ES+): 535/537 (M+l); (ES- ): 533/535 (M-l); Analysis calculated for C24H23BrN ₈ 02.1.45HC1.2.25H20: C, 45.84; H, 4.64; Cl, 8.18; N, 17.82; Found: C, 45.82; H, 4.56; Cl, 8.20; N, 17.70.

Scheme 284

283f 284a

Preparation of (lR^S _j SR^-^-^-amino-S-methyl^H-pyrido^S'^SJpyrroloP, 3- d]pyrimidin-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicycl o[3.1 ,0]hexane-3-carboxamide (284a)

Compound 284a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-9H-pyrido[2',3 ^, :4,5]pyrrolo[2,3-d]pyrimidin-9- yl)acetic acid (283f) (75 mg, 0.202 mmol) in DMF (5 mL) using HC1 salt of (1R,3S,5R)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamid e (4a) (64.4 mg, 0.202 mmol), HATU (92 mg, 0.242 mmol) DIPEA (131 mg, 1.010 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HCl) from 0-100%](lR,3S,5R)-2-(2-(4-amino-8-methyl-9H-pyrido[2',3 ^, :4,5]pyrrolo[2,3- d]pyrimidin-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabic> ;'clo[3.1 0]hexane-3-carboxamide (284a) (86 mg, 82% yield) HC1 salt as a white solid; Ή NMR (300 MHz, OMSO-de) δ 10.84 (s, 1H, DzO exchangeable), 8.91 (bs, 1H, DzO exchangeable), 8.65 (s, 1H), 8.60 (bs, 1H, DzO exchangeable), 8.55 (d, J = 5.1 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.71 (t, J = 7.9 Hz, 1H), 7.46 (d, J = 5.2 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 5.95 (d, J = 18.0 Hz, 1H), 5.68 (d, J = 17.9 Hz, 1H), 4.47 - 4.39 (m, 1H), 3.97 - 3.90 (m, 1H), 2.78 (s, 3H), 2.43 - 2.29 (m, 1H), 2.29 - 2.15 (m, 1H), 2.02 - 1.81 (m, 1H), 1.19 - 1.01 (m, 1H), 0.79 - 0.66 (m, 1H); MS (ES+): 521/523 (M+l); (ES-): 519/521 (M-l).

Scheme 285

285f

NH ₂ Me 285g

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-methyl-9H-pyrido[2',3':4,5]pyrrol o[2, 3- d]pyrimidin-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicycl o[3.1.0]hexane-3-carboxamide (285g)

Step-1: Preparation ofN-(2-bromo-6-methylpyridm-3-yl)-2,2,2-trifluoroacetamide (285b)

Compound 285b was prepared according to the procedure reported in step-1 of scheme-46, from 2-bromo-6-methylpyridin-3-amine (285a) (5 g, 26.7 mmol; CAS # 126325-53-9) in DCM (30 mL) using triethylamine (4.60 g, 45.4 mmol), trifluoroacetic acid anhydride (8.42 g, 40.1 mmol) and stirring at RT for 1 h. This gave after workup N-(2-bromo-6- methylpyridin-3-yl)-2,2,2-trifluoroacetamide (285b) (7.33 g, 97% yield) as a pale-yellow solid which was used as such for the next step; Ή NMR (300 MHz, DMSO-cfe) δ 11.42 (s, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 7.9 Hz, 1H), 2.50 (s, 3H). ^!9 F NMR (282 MHz, DMSO-isfc) δ -74.21; MS (ES+): 283/285, (ES-): 281/283 (M-l).

Step-2: Preparation of 2-amino-5-methyl- 1 H-pyrrolo(3,2-b]pyridine-3-carbonitrile (285c) Compound 285c was prepared according to the procedure reported in step-1 of scheme- 11, from N-(2-bromo-6-methylpyridin-3-yl)-2,2,2-trifluoroacetamide (285b) (7.33 g, 25.90 mmol) in DMSO (30 mL) using malononitrile (2.053 g, 31.1 mmol), L-proline (0.596 g, 5.18 mmol), Cul (0.493 g, 2.59 mmol), a solution of K2CO3 (7.16 g, 51.8 mmol) in water (30 mL) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup 2-amino-5- methyl- 1 H-pyrrolo [3 ,2-b]py ridine-3 -carbonitrile (285c) (2.27 g, 51% yield) as a pale-pink solid; ¾NMR (300 MHz, DMSO-ofe) δ 10.71 (s, 1H), 7.25 (d, J= 7.9 Hz, 1H), 7.05 (s, 2H), 6.72 (d ,J= 7.9 Hz, 1H), 2.41 (s, 3H); MS (ES+): 173 (M+l), (ES-): 171 (M-l).

Step-3: Preparation of 6-methyl-9H-pyrido[2 ^, ,3 ^, :4,5]pyrrolo[2,3-d]pyrimidin-4-amine (285d)

Compound 285d was prepared according to the procedure reported in step-2 of scheme-29, from 2-amino-5-methyl-lH-pyrrolo[3,2-b]pyridine-3-carbonitrile (285c) (1.79 g, 10.40 mmol) in ethanol (10 ttiL) using NHtOAc (2.404 g, 31.2 mmol), HC(OMe)3 (11.03 g, 104 mmol) and heating at 90 °C for 16 h. This gave after work up 6-methyl-9H- pyridoP'^M.SlpyrroloP^-dlpyrimidin^-amine (285d) (1.04 g, 50% yield) as a beige solid; Ή NMR (300 MHz, DMSO -ck) δ 11.88 (s, 1H), 8.32 (s, 1H), 7.73 (d, J= 8.2 Hz, 2H), 7.23 (d, J= 8.3 Hz, 1H), 6.53 (s, 1H), 2.63 (s, 3H); MS (ES+): 200 (M+l), (ES-): 198 (M-l). Step-4: Preparation of tort-butyl 2-(4-amino-6-methyl-9H-pyrido[2',3':4,5]pyrrolo[2,3- dJpyrimidin-9-yl)acetate (285e)

Compound 285e was prepared according to the procedure reported in step-1 of scheme- 1 , from 6-methy l-9H-pyrido [2',3 ¹ : 4,5 ]pyrrolo [2,3 -dJpyrimidin-4-amine (285d) (1.02 g, 0.5.12 mmol) in DMF (15 ttiL) using tort-butyl 2-bromoacetate (1.099 g, 5.63 mmol), CszCOs (3.34 g, 10.24 mmol) and stirring at RT for 16 h. This gave after work up tort-butyl 2-(4-amino-6- methy l-9H-pyrido [2',3 ' : 4,5 ]py rrolo [2,3 -d] py rimidin-9-y l)acetate (285e) (1.24 g, 77% yield) as a beige solid; Ή NMR (300 MHz, DMSO-i/e) δ 8.36 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.92 (s, 1H), 7.29 (d, J= 8.3 Hz, 1H), 6.58 (s, 1H), 5.13 (s, 2H), 2.65 (s, 3H), 1.39 (s, 9H); MS (ES+): 314 (M+l).

Step-5: Preparation of 2-(4-amino-6-methyl-9H-pyrido[2',3 ^, :4,5]pyrrolo[2,3-d]pyrimidin-9- yl)acetic acid (285f)

Compound 285f was prepared according to the procedure reported in step-2 of scheme- 1, from tort-butyl 2-(4-amino-6-methyl-9H-pyrido[2 ^, ,3':4,5]pyrrolo[2,3-d]pyrimidin-9- yl)acetate (285e) (1.23 g, 3.93 mmol) using TFA (4.48 g, 39.3 mmol) in DCM (5 ttiL) and pyridoP'^M.SlpyrroloP^-dlpyrimidin-g-yliacetic acid (285f) (2.28 g) as a white solid; Ή NMR (300 MHz, DMSO-ds) δ 8.87 (bs,lH), 8.59 (s, 1H), 8.27 (d, J = 8.6 Hz, 1H), 7.90 (bs, 1 H), 7.51 (d, J = 8.5 Hz, 1H), 5.28 (s, 2H), 2.73 (s, 3H). ¹⁹ F NMR (282 MHz, DMSO- d ₆ ) δ - 74.81; MS (ES+): 258 (M+l); (ES-): 256 (M-l).

Step-6: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-methyl-9H-pyrido[2 ^, ,3 ^, :4,5]pyrrolo[2,3- d]pyrimidin-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicycl o[3.1 0]hexane-3-carboxamide (285g)

Compound 285g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-methyl-9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimi din-9- yl)acetic acid (285f) (75 mg, 0.202 mmol) in DMF (5 mL) using HC1 salt of (1R,3S,5R)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamid e (4a) (64.4 mg, 0.202 mmol), HATU (92 mg, 0.242 mmol), DIPEA (131 mg, 1.010 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6-methyl-9H-pyrido[2 ^, ,3':4,5]pyrrolo[2,3- d]pyrimidin-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicycl o[3.1 ,0]hexane-3-carboxamide (285g) (69 mg, 66% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) 5 10.76 (s, 1H, DaO exchangeable), 8.86 (bs, 2H, D2O exchangeable), 8.61 (s, 1H), 8.33 (d, J = 7.7 Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 5.81 (d, J = 17.3 Hz, 1H), 5.45 (d, J = 17.3 Hz, 1H), 4.45 - 4.36 (m, 1H), 3.90 - 3.83 (m, 1H), 2.81 (s, 3H), 2.39 - 2.26 (m, 1H), 2.26 - 2.11 (m, 1H), 1.98 - 1.84 (m, 1H), 1.13 - 1.01 (m, 1H), 0.85 - 0.72 (m, 1H); MS (ES+): 521/523 (M+l); (ES-): 519/521 (M-l).

Scheme 286

285f 286a Preparation of (lR,3S,5R)-2-(2-(4-amino-6-methyl-9H-pyrido[2',3':4,5]pyrrol o[2,3- d]pyrimidin-9-yl)acet\"l)-N -(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 0]hexane-3- carboxamide (286a)

Compound 286a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-methyl-9H-pyrido[2 ^, ,3':4,5]pyrrolo[2,3-d]pyrimidin-9- yl)acetic acid (285f) (75 mg, 0.202 mmol) in DMF (5 mL) using HC1 salt of (1R,3S,5R)-N- (6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-c arboxamide (8a) (67.2 mg, 0.202 mmol), HATU (92 mg, 0.242 mmol), DIPEA (131 mg, 1.010 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%](lR,3S,5R)-2-(2-(4-amino-6-methyl-9H- pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetyl)-N-(6-b romopyridin-2-yl)-5-methyl-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (286a) (65 mg, 60% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-fifc) δ 10.77 (s, 1H, DzO exchangeable), 8.88 (bs, 2H, DzO exchangeable), 8.61 (s, 1H), 8.33 (d, J = 8.9, 2.6 Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 5.77 (d, J = 17.3 Hz, 1H), 5.41 (d, J = 17.3 Hz, 1H), 4.43 - 4.30 (m, 1H), 3.67 - 3.64 (m, 1H), 2.81 (s, 3H), 2.49 - 2.42 (m, 1H), 1.98 (dd, J = 13.3, 5.8 Hz, 1H), 1.30 (s, 3H), 1.06 - 0.98 (m, 1H), 0.98 - 0.89 (m, 1H); MS (ES+): 535/537 (M+l), (ES-): 533/535 (M-l); Analysis calculated for Cz4Hz3BrN ₈ Oz.l.95HC1.4.25HzO: C, 42.20; H, 4.94; Cl, 10.12; N, 16.40; Found: C, 42.44; H, 4.61; Cl, 9.93; N, 16.00.

Scheme 287

287a Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyr imido[4,5- b]indol-9-yl)acetyl)-N-(6-chloropyridin-2-yl)-5-methyl-2-aza bicyclo[3.1 ,0]hexane-3- carboxamide (287a)

Compound 287a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(trifluoromcthyl)-9H-pyrimido[4,5-b]in dol-9- yl)acetic acid (184f) (100 mg, 0.228 mmol) in DMF (5 mL) using HC1 salt of (1R,3S,5R)-N- (6-chloropyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3- carboxamide (269b) (65.8 mg, 0.228 mmol), HATU (130 mg, 0.342 mmol), DIPEA (147 mg, 1.141 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [silica gel ( 12 g), eluting with MeOH in DCM from 0 - 5%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1%HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-8-methyl-6- (trifhxoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6- chloropyridin-2-yl)-5-methyl-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (287a) (58 mg, 46% yield) HC1 salt as a white solid; *H NMR (300 MHz, DMSO-rik) δ 10.81 (s, 1H, DzO exchangeable), 8.79 (s, 1H), 8.64 (s,

1H), 8.64 (bs, 2H, DzO exchangeable), 7.98 (d, J = 8.2 Hz, 1H), 7.81 (t, J = 8.0 Hz, 1H), 7.60 (s, 1H), 7.18 (d, J = 7.7 Hz, 1H), 5.92 (d, J = 18.0 Hz, 1H), 5.65 (d, J = 17.9 Hz, 1H), 4.38 (dd, J = 9.1, 6.1 Hz, 1H), 3.74 - 3.69 (m, 1H), 2.76 (s, 3H), 2.49 - 2.36 (m, 1H), 1.98 (dd, J = 13.3, 6.1 Hz, 1H), 1.31 (s, 3H), 1.03 (t, J = 5.5 Hz, 1H), 0.89 - 0.82 (m, 1H); ¹⁹ FNMR(282 MHz, DMSOntfc) δ -58.77; MS (ES+): 558/560 (M+l); (ES-): 556/558 (M-l); Analysis calculated for CZ6HZ3C1F ₃ N7OZ.0.75HC1.2.25HZO: C, 49.90; H, 4.55; Cl, 9.91; N, 15.67; Found: C, 50.06; H, 4.28; Cl, 9.86; N, 15.34.

Scheme 288

HCL „OH

O C0 ₂ ¾U CO ₂ H

C0 ₂ ^f Bu r oc Me Me

Me

114c N rcs> r^ ^N v! TFA N r*.f ^IL f \ f \

Pd ₂ (dba) ₃ , XPhos NH ₂ NH ₂

NH ₂ K3PO4

Br

C\ f\

192e 288a 288b

H N. Br

Ό N

N

O

O

H 0 4a rr ^N Me

HATU, DIPEA f %

NH ₂ ίΛ

288c

Preparation of ( 1 R,3 S ,5 R)-2-( 2-(4-amino-8-methy 1 -6-(py ridin-3 -y l)-9H-pyrimido [4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1 ,0]hexane-3-carboxamide (288c)

Step-1: Preparation of /erf-butyl 2-(4-amino-8-methyl-6-(pyridin-3-yl)-9H-pyrimido[4,5- b]indol-9-yl)acetate (288a)

Compound 288a was prepared according to the procedure reported in step-1 of scheme-263, from tort-butyl 2-(4-amino-6-bromo-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)ace tate (192e) (300 mg, 0.767 mmol) in n-BuOH (4 mL) using py ridin-3 -ylboronic acid (114c) (141 mg, 1.150 mmol), a solution of 1.27 M aqueous K3PO4 (1.207 mL, 1.533 mmol), Pdj(dba)3 (70.2 mg, 0.077 mmol), XPhos (73.1 mg, 0.153 mmol) and heating at 100 °C for 16 h under nitrogen. This gave after workup and purification using flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 7%] tort-butyl 2-(4-amino-8-methyl-6- (pyridin-3-yl)-9H-pyrimido[4,5-b]indol-9-yl)acetate (288a) (260 mg, 87% yield) as a white solid; Ή NMR (300 MHz, DMSO-i/s) 59.11 (d, J = 2.4 Hz, 1H), 8.66 - 8.49 (m, 2H), 8.32 (s, 1H), 8.25 (dt, J = 8.1, 2.0 Hz, 1H), 7.58 (s, 1H), 7.56 - 7.35 (m, 3H), 5.37 (s, 2H), 2.71 (s, 3H 1 44 ( 9H) MS (ES ) 390 (M l) (ES 388 (M l) Step-2: Preparation of 2-(4-amino-8-methyl-6-(pyridin-3-yl)-9H-pyrimido[4,5-b]indol -9- yl)acetic acid (288b)

Compound 288b was prepared according to the procedure reported in step-2 of scheme- 1, from fert-butyl 2-(4-amino-8-methyl-6-(pyridin-3-yl)-9H-pyrimido[4,5-b]indol -9-yl)acetate (288a) (260 mg, 0.668 mmol) in DCM (5 mL) using TFA (761 mg, 6.68 mmol) and stirring at RT for 16 h. This gave after work up TFA salt of 2-(4-amino-8-methyl-6-(pyridin-3-yl)- 9H-pyrimido[4,5-b]indol-9-yl)acetic acid (288b) (436 mg) and used as such for the next step; Ή NMR (300 MHz, DMSO-ifc) δ 9.26 (d, J = 2.2 Hz, 1H), 8.87 - 8.71 (m, 2H), 8.68 (dd, J = 8.1, 2.2 Hz, 1H), 8.64 - 8.42 (m, 3H), 7.88 (dd, J = 8.2, 5.2 Hz, 1H), 7.81 (s, 1H), 5.48 (s, 2H), 2.78 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO -de) δ -74.60; MS (ES+): 334 (M+l); (ES-): 332 (M-l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(pyridin-3-yl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3- carboxamide (288c)

Compound 288c was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(pyridin-3-yl)-9H-pyrimido[4,5-b]indol -9-yl)acetic acid (288b) (75 mg, 0.168 mmol) in DMF (5 ml) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (53.4 mg, 0.168 mmol), HATU (76 mg, 0.201 mmol), DIPEA (108 mg, 0.838 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR3S,5R)-2-(2-(4-amino-8-methyl-6-(pyridin-3-yl)-9H-pyrimid o[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1 ,0]hexane-3-carboxamide (288c) (50 mg, 50% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfc) δ 10.84 (s, 1H, DzO exchangeable), 9.45 (d, J = 2.2 Hz, 1H), 9.12 (bs, 2H, DzO exchangeable), 8.98 (dd, J = 8.4, 1.7 Hz, 1H), 8.94 (d, J = 1.7 Hz, 1H), 8.83 (d, 1H), 8.67 (s, 1H), 8.05 (dd, J = 8.3, 5.5 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.86 (s, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 5.99 (d, J = 18.0 Hz, 1H), 5.67 (d, J = 17.9 Hz, 1H), 4.43 (dd, J = 9.1, 5.8 Hz, 1H), 4.01 - 3.94 (m, 1H), 2.80 (s, 3H), 2.37 (dd, J = 13.5, 9.1 Hz, 1H), 2.29 - 2.08 (m, 1H), 2.01 - 1.87 (m, 1H), 1.16 - 1.05 (m, 1H), 0.78 - 0.59 (m, 1H); MS (ES+): 597/599 (M+l); (ES-): 595/597 (M-l); Analysis calculated for Cz9HzsBrN ₈ 0z.2.15HC1.4.25HzO: C, 46.29; H, 4.78; Cl, 10.13; N, 14.89; Found: C, 46.42; H, 4.44; Cl, 10.13; N, 14.82.

Scheme 289

289a

Preparation of ( 1 R,3 S ,5 R)-2-( 2-(4-amino-8-methy 1 -6-(py ridin-3 -yl)-9H-pyrimido [4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azab icyclo[3.1.0]hexane-3- carboxamide (289a)

Compound 289a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(pyridin-3-yl)-9H-pyrimido[4,5-b]indol -9-yl)acetic acid (288b) (75 mg, 0.168 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-caiboxamide (8a) (55.8 mg, 0.168 mmol), HATU (76 mg, 0.201 mmol), DIPEA (108 mg, 0.838 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 5%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(pyridin-3-yl)-9H-pyrimi do[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azab icyclo[3.1 ,0]hexane-3- carboxamide (289a) (36 mg, 35% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-40 δ 10.84 (s, 1H, DzO exchangeable), 9.40 (s, 1H), 9.14 - 8.84 (m, 4H, in which 2H were DzO exchangeable), 8.84 - 8.78 (m, 1H), 8.66 (s, 1H), 8.10 - 7.95 (m, 2H), 7.85 (s, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 5.93 (d, J = 18.0 Hz, 1H), 5.64 (d, J = 17.9 Hz, 1H), 4.39 (dd, J = 9.0, 6.2 Hz, 1H), 3.73 (dd, J = 5.4, 2.4 Hz, 1H), 2.78 (s, 3H), 2.49 - 2.44 (m, 1H), 1.99 (dd, J = 13.4, 6.1 Hz, 1H), 1.32 (s, 3H), 1.04 (t, J = 5.4 Hz, 1H), 0.92 - Scheme 290

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-bromo-9H-pyrido[2 ^, ,3':4,5]pyrrolo[2,3- dJpyrimidin-9-yl)acet}'l)-N-(6-bromopyridin-2-yl)-2-azabicyc lo[3.1 ,0]hexane-3-carboxamide (290g)

Step-1: Preparation of N-(2,6-dibromopyridin-3-yl)-2,2,2-trifluoroacetamide (290b)

Compound 290b was prepared according to the procedure reported in step-1 of scheme-46, from 2,6-dibromopyridin-3-amine (290a) (10 g, 39.7 mmol; CAS # 39856-57-0) in DCM (30 mL) using triethylamine (6.83g, 67.5 mmol), trifluoroacetic acid anhydride (12.51 g, 59.5 mmol) and stirring at RT for 1 h. This gave after workup N-(2,6-dibromopyridin-3-yl)-2,2,2- trifluoroacetamide (290b) (13.78 g, 100% yield) as a pale-yellow solid and was used as such for next step; ^X H NMR (300 MHz, DMSO^ δ 11.68 (s, 1H), 8.61 (d, J = 2.4 Hz, 1H), 8.35 (d, J = 2.3 Hz, 1H); ^!9 F NMR (282 MHz, DMSO-ds) δ -74.16; MS (ES-): 345/347 (M-l).

Step-2: Preparation of 2-amino-5 -bromo- 1 H-py rrolo[3 ,2-b Jpyridine-3 -carbonitrile (290c) Compound 290c was prepared according to the procedure reported in step-1 of scheme- 11, from N-(2,6-dibromopyridin-3-yl)-2,2,2-trifluoroacetamide (290b) (13.78 g, 39.6 mmol) in DMSO (30 mL) using malononitrile (3.14 g, 47.5 mmol), L-proline (0.912 g, 7.92 mmol), Cul (0.754 g, 3.96 mmol), a solution of K2CO3 (10.95 g, 79 mmol) in water (30 mL) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and 2-amino-5- bromo- 1 H-pyrrolo [3,2-b] pyridine-3 -carbonitrile (290c) (7.03 g, 75% yield) as a beige solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.95 (s, 1H), 8.36 - 7.90 (m, 1H), 7.55 (d, J = 1.9 Hz, 1H), 7.39 (s, 2H); MS (ES+): 237/239 (M+l); (ES-): 235/237 (M-l).

Step-3: Preparation of 6-bromo-9H-pyrido[2 ^, ,3 ^, :4,5]pyrrolo[2,3-d]p>'riniidin-4-amine (290d)

Compound 290d was prepared according to the procedure reported in step-2 of scheme-29, from 2-amino-5-bromo-lH-pyrrolo[3,2-b]pyridine-3-carbonitrile (290c) (7.02 g, 29.6 mmol) in ethanol (20 mL) using NHtOAc (11.41 g, 148 mmol), formamidine acetate (9.25 g, 89 mmol), HC(OMe)3 (31.4 g, 296 mmol) and heating at 90 °C for 16 h. This gave after work up 6-bromo-9H-pyrido[2',3':4,5]pyrrolo[2,3-d]p>'rimidin-4-am ine (290d) (7.68 g, 98% yield) as a beige solid; ^! H NMR (300 MHz, DMSO-t/e) δ 12.20 (s, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.37 (s, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.87 (s, 1H), 6.75 (s, 1H); MS (ES+): 264/266 (M+l), (ES-): 262/264 (M-l).

Step-4: Preparation of tort-butyl 2-(4-amino-6-bromo-9H-pyrido[2 ^l ,3':4,5]pynOlo[2,3- d]pyrimidin-9-yl)acetate (290e)

Compound 290e was prepared according to the procedure reported in step- 1 of scheme- 1, from 6-bromo-9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-4-amine (290d) (3.00 g, 11.36 mmol) in DMF (15 mL) using tort-butyl 2-bromoacetate (2.437 g, 12.50 mmol), CszCOs (7.40 g, 22.72 mmol) and stirring at RT for 16 h. This gave after work up tort-butyl 2-(4- amino-6-bromo-9H-pyrido[2' _, 3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetate (290e) (3.20 g, 75% yield) as a beige solid; Ή NMR (300 MHz, DMSO-cfc) δ 8.61 (d, J = 1.9 Hz, 1H), 8.47 (d, J = 1.9 Hz, 1H), 8.40 (s, 1H), 7.97 (bs, 1H), 6.86 (bs, 1H), 5.16 (s, 2H), 1.41 (s, 9H); MS (ES+): 378/380 (M+l).

Step-5: Preparation of 2-(4-armno-6-bromo-9H-pyrido[2 ^, ,3 ^, :4,5]pyrrolo[2,3-d]pyrimidin-9- yl)acetic acid (290f)

Compound 290f was prepared according to the procedure reported in step-2 of scheme- 1, (290e) (300 mg, 0.793 mmol) using TFA (904 mg, 7.93 mmol) in DCM (5 mL) and stirring at RT for 16 h. This gave after work up TFA salt of 2-(4-amino-6-bromo-9H- py rido [2', 3 ' : 4,5 ]pyrrolo [2,3 -d]pyrim idi n-9-y 1 )acetic acid (290f) (346 mg) as a beige solid; *H NMR (300 MHz, DMSO-i/e) δ 8.66 (d, J = 1.9 Hz, 1H), 8.58 (d, J = 1.9 Hz, 1H), 8.56 - 8.29 (m, 2H), 7.27 (s, 1H), 5.22 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -74.62; MS (ES+): 322/324 (M+l); (ES-): 320/322 (M-l).

Step-6: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-bromo-9H-pyrido[2 ^, ,3 ^, :4,5]pyrrolo[2,3- d]pyrimidin-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicycl o[3.1 ,0]hexane-3-caiboxamide (290g)

Compound 290g was prepared according to the procedure reported in step-3 of scheme- 1, fiom 2-(4-amino-6-bromo-9H-pyrido[2 ^, ,3 ^, :4,5]pyrrolo[2,3-dJpyrimidin-9-yl)acetic acid (2900 (75 mg, 0.172 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (54.8 mg, 0.172 mmol), HATU (78 mg, 0.206 mmol), DIPEA (111 mg, 0.860 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6-bromo-9H-pyrido[2',3':4,5]pyrrolo [2,3- d]pyrimidin-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicycl o[3.1.0]hexane-3-carboxamide (290g) (73 mg, 72% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.80 (s, 1H, DzO exchangeable), 9.07 (bs, 2H, DzO exchangeable), 8.78 - 8.70 (m, 2H), 8.61 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.71 (t, J = 7.9 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 5.83 (d, J = 17.4 Hz, 1H), 5.43 (d, J = 17.3 Hz, 1H), 4.47 - 4.41 (m, 1H), 3.93 - 3.84 (m, 1H), 2.40 - 2.28 (m, 1H), 2.28 - 2.16 (m, 1H), 1.99 - 1.84 (m, 1H), 1.14 - 0.96 (m, 1H), 0.96 - 0.74 (m, 1H); MS (ES+): 585/587 (M+l), (ES-): 583/585 (M-l); Analysis calculated for C22Hi8BnN8O2.LlHCl.2H2O: C, 39.89; H, 3.52; Cl, 5.89; N, 16.92; Found: C, 39.97; H,

3.29; Cl, 5.89; N, 16.88.

Scheme 291

291a

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyr imido[4,5- b]indol-9-yl)acet>l)-N-(6-chloropyridin-2-yl)-2-azabicycl o[3.1 ,0]hexane-3-carboxamide (291a)

Compound 291a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]in dol-9- yl)acetic acid (184f) (100 mg, 0.228 mmol) in DMF (5 mL) using HC1 salt of (1R,3S,5R)-N- (6-chloropyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxami de (267b) (62.6 mg, 0.228 mmol), HATU (130 mg, 0.342 mmol), DIPEA (147 mg, 1.141 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 2%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-chloropyridin-2-yl)-2 -azabicyclo[3.1 ,0]hexane-3- carboxamide (291a) (30 mg, 24% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-flfc) δ 10.82 (s, 1H, DaO exchangeable), 8.81 (s, 1H), 8.78 (bs, 2H, D2O exchangeable), 8.66 (s, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.82 (t, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.19 (d, J = 7.7 Hz, 1H), 5.98 (d, J = 18.0 Hz, 1H), 5.70 (d, J = 18.0 Hz, 1H), 4.43 (dd, J = 9.1, 5.7 Hz, 1H), 3.98 - 3.93 (m, 1H), 2.79 (s, 3H), 2.42 - 2.30 (m, 1H), 2.30 - 2.10 (m, 1H), 2.01 - 1.84 (m, 1H), 1.20 - 1.02 (m, 1H), 0.78 - 0.58 (m, 1H); ¹⁹ FNMR(282 MHz, DMSO- de) δ -58.79; MS (ES+): 544/546 (M+l); (ES-): 542/544 (M-l); Analysis calculated for C25H21ClF3N7O2.HCl.3H2O: C, 47.33; H, 4.45; N, 15.45; Found: C, 47.40; H, 4.05; N, 15.36.

Scheme 292

290f 292a

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-bromo-9H-pyrido[2 ^, ,3':4,5]pyrrolo[2, 3- d]pyrimidin-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2- azabicyclo[3.1 ,0]hexane-3- carboxamide (292a)

Compound 292a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-bromo-9H-pyrido[2',3 ^, :4,5]pyrrolo[2,3-d]pyrimidin-9- yl)acetic acid (290f) (75 mg, 0.172 mmol) in DMF (5 mL) using HC1 salt of (1R,3S,5R)-N- (6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (8a) (57.2 mg, 0.172 mmol), HATU (78 mg, 0.206 mmol), DIPEA (111 mg, 0.860 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 5%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6-bromo-9H- pyrido[2 ^, ,3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acet>'l)-N-(6- bromopyridin-2-yl)-5-methyl-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (292a) (89 mg, 86% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-tfc) δ 10.72 (s, 1H, D ₂ 0 exchangeable), 8.70 (bs, 1H, DzO exchangeable), 8.63 (d, J = 1.9 Hz, 1H), 8.56 (s, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.14 (bs, 1H, D2O exchangeable), 7.95 (d, J = 8.2 Hz, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 5.67 (d, J = 17.4 Hz, 1H), 5.29 (d, J = 17.3 Hz, 1H), 4.32 (dd, J = 9.1, 5.8 Hz, 1H), 3.58 - 3.55 (m, 1H), 2.42 - 2.32 (m, 1H), 1.91 (dd, J = 13.3, 5.8 Hz, 1H), 1.24 (s, 3H), 1.00 - 0.83 (m, 2H); MS (ES+): 599/601 (M+l), (ES-): 597/599 (M-l); Analysis calculated for C23H20BnN8O2.HCl.2H2O: C, 41.06; H, 3.75; Cl, 5.27; N, 16.66; Found: C, 41.06; H, 3.51; Cl, 5.21; N, 16.52.

Scheme 293

(->Diastereomer-A (-)-Diastereomer-B

293A 293B

Preparation of (lS,3R,5S)-2-(l l-amino-6H-benzo[e]pyrimido[5',4':4,5]pyrrolo[l,2- c] [ 1 ,3]oxazine-6-carbonyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[ 3.1.0]hexane-3- carboxamide (293A; (-)-diastereoisomcr-A), ( 1 S,3R,5 S)-2-( 11 -amino-6H- benzo[e]pyrimido[5',4':4,5]pyrrolo[l,2-c][l,3]oxazine-6-carb onyl)-N-(6-bromopyridin-2-yl)- 2-azabicyclo[3.1.0]hexane-3-carboxamide (293B; (-)-diastereoisomer-B)

Compound (233h) was prepared according to procedure reported in scheme 233 from 11- amino-6H-benzo[e]pyrimido[5',4':4,5]pyrrolo[l,2-c][l,3]oxazi ne-6-carboxylic acid (233g) (171 mg, 0.606 mmol) and (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane - 3-carboxamide, HC1 (4a) (212 mg, 0.666 mmol) in DMF (5 mL) using HATU (346 mg, 0.909 mmol), DIPEA (0.528 mL, 3.03 mmol) and stirring at RT for 48h. This gave after workup and purification by flash column chromatography [silica (12 g), eluting with ethyl acetate/MeOH 9: 1 in hexanes from 0-100%] to afford Compound (233h) as a mixture of diastereomers. The mixture was repurified by chromatography [silica (12 g), eluting with ethyl acetate/MeOH 9:1 in DCM from 0-100%] to afford pure individual diastereoisomer 293A and 293B. The following was the order and data for the compound that was eluted

1. (lS,3R,5S)-2-(ll-amino-6H-benzo[e]pyrimido[5 ^, ,4 ^, :4,5]pyrrolo[l,2-c][l,3]oxazme-6- carbonyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane- 3-carboxamide (293A; (-)-diastereoisomer-A) as a free base; ^l H NMR (300 MHz, MeOD-t/v) δ 8.11 (s, 1H), 7.95 (d,J= 8.4 Hz, 1H), 7.68 (d, J= 7.9 Hz, 1H), 7.52 (t,J= 8.2 Hz, 1H), 7.37 (s, 1H), 7.27 (t ,J= 7.9 Hz, 1H), 7.21 - 7.03 (m, 3H), 6.92 (s, 1H), 4.33 - 4.11 (m, 2H), 2.47 - 2.19 (m, 2H), 2.05 - 1.99 (m, 1H), 1.27 - 1.23 (m, 1H), 0.79 - 0.59 (m, 1H); = -11.43 (c = 0.14, MeOH); Compound (293A; (-)-diastereoisomer-A) was further purified by reverse-phase column chromatography [EZ-PREP, C-18 column, 50 g, eluting with 0.1% aqueous HC1 in water and acetonitrile from 0-100%] to afford (lS,3R,5S)-2-(l l-amino-6H-benzo[e]pyrimido[5',4':4,5]pyrrolo[l,2-c][l,3]oxa zme-6- caibonyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (293A; (-)-diastereoisomer-A) (42mg, 13 % yield) HC1 salt as a white solid; ^! H NMR (300 MHz, DMSO-ife) δ 10.76 (s, 1H), 9.58 (s, 1H, DzO exchangeable), 8.76 (s, 1H, DzO exchangeable), 8.45 (s, 1H), 7.93 (d, ./= 8.2 Hz, 1H), 7.82 - 7.56 (m, 3H), 7.39 (d, J = 6.8 Hz, 2H), 7.33 - 7.04 (m, 3H), 4.46 - 4.26 (m, 1H), 4.26 - 4.06 (m, 1H), 2.34 - 2.18 (m, 1H), 2.18 - 2.01 (m, 1H), 2.01 - 1.81 (m, 1H), 1.36 - 1.08 (m, 1H), 0.63 - 0.32 (m, 1H); Ή NMR (300 MHz, DMSO-ifc/DzO) δ 10.71 (d, J= 4.3 Hz, 1H), 8.41 (d, J= 3.9 Hz, 1H), 7.91 (d, 8.3 Hz, 1H), 7.74 (q, J= 6.1, 4.5 Hz, 2H), 7.65 (t, J=

7.9 Hz, 1H), 7.48 - 7.31 (m, 2H), 7.31 - 7.07 (m, 3H), 4.41 - 4.22 (m, 1H), 4.22 - 4.05 (m, 1H), 2.35 - 2.17 (m, 1H), 2.17 - 2.00 (m, 1H), 2.00 - 1.82 (m, 1H), 1.21 (q, J= 6.3 Hz, 1H), 0.62 - 0.39 (m, 1H); MS (ES+): 546.1, 548.1 (M+l); (ES-): 544.1, 546.1 (M-l); LCMS, Rt = 1.96 min, (wavelength = 254 nM), 98.06%; Optical rotation [<X]D = +5.88 (c = 0.17, MeOH);

2. (lS,3R,5S)-2-(ll-amino-6H-benzo[e]pyrimido[5 ^, ,4 ^, :4,5]pyrrolo[l,2-c][l,3]oxazine-6- carbonyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane- 3-carboxamide (293B; (-)-diastereoisomer-B); Ή NMR (300 MHz, MeODntfc) δ 8.08 (s, 1H), 7.86 (d, J= 8.3 Hz, 1H), 7.67 (d, J= 7.6 Hz, 1H), 7.51 (t, J= 8.0 Hz, 1H), 7.25 - 7.14 (m, 4H), 7.12 - 7.04 (m, 1H), 6.94 (s, 1H), 4.53 - 4.38 (m, 1H), 4.23 - 4.13 (m, 1H), 2.43 - 2.25 (m, 2H), 2.03 - 1.97 (m, 1H), 1.30 - 1.22 (m, 1H), 1.02 - 0.91 (m, 1H); MS (ES+): 546.10, 548.10 (M+l); Optical rotation [a] _D = -223.88 (c = 0.135, MeOH), Compound (293B;

(-)-diastereoisomer-B) was further purified by reverse-phase column chromatography [EZ-PREP, C-18 column, 50 g, eluting with 0.1% aqueous HC1 in water and acetonitrile from 0-100%] to afford (lS,3R,5S)-2-(ll-amino-6H- benzo[e]pyrimido[5',4':4,5]pyrrolo[l,2-c][l,3]oxazine-6-carb onyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (293B; (-)- diastereoisomer-B) to afford (64mg, 19% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.79 (s, 1H), 9.60 (s, 1H, DzO exchangeable), 8.84 (s, 1H, D O h bl ) 849 ( 1H) 792 (d J 8 1 H 1H) 784 762 ( 2H) 757 7.38 (m, 3H), 7.38 - 7.16 (m, 3H), 5.21 - 4.35 (m, 1H), 4.35 - 4.10 (m, 1H), 2.44 -

2.14 (m, 2H), 2.02 (p, J= 6.8 Hz, 1H), 1.34 - 1.05 (m, 1H), 0.90 - 0.67 (m, 1H); Ή NMR(300 MHz, DMSO-tfc/DzO) δ 11.66 - 10.37 (m, 1H), 8.58 - 8.15 (m, 1H), 8.03 - 7.74 (m, 2H), 7.69 (t, J= 7.9 Hz, 1H), 7.56 - 7.14 (m, 6H), 5.14 - 4.34 (m, 1H),

4.15 (d, 6.5 Hz, 1H), 2.44 - 2.28 (m, 1H), 2.28 - 2.13 (m, 1H), 2.13 - 1.88 (m,

1H), 1.37 - 1.08 (m, 1H), 0.93 - 0.65 (m, 1H); MS (ES+): 546.1, 548.1 (M+l); (ES-): 544.1, 546.1 (M-l); LCMS, Rt = 1.98 min, (wavelength = 254 nM), 98.60%; Optical rotation [<Z]D= -256.15 (c = 0.26, MeOH);

Scheme 294

Preparation of (2S,4R)-l-(2-(4-aminoquinazolin-6-yl)acetyl)-N-(3-chloro-2-f luorobenzyl)-4- fluoropyrrolidine-2-carboxamide (294c)

Step-1: Preparation of 2-(4-aminoquinazolin-6-yl)acetic acid (294b)

Compound 294b was prepared according to the procedure reported in step-1 of scheme-2, from 6-bromoquinazolin-4-amine (294a) (1.00 g, 4.46 mmol; CAS # 21419-48-7) using zinc (1.752 g, 26.8 mmol), TMSCI (0.170 mL, 1.339 mmol) in THF (5 ttiL) and Pdz(dba) ₃ (0.204 g, 0.223 mmol) and XPhos (0.213 g, 0.446 mmol) in THF (10 mL) and heating at 60 °C under argon for 16 h. The cooled reaction mixture was diluted with H2O (30 mL) and EtOAc (30 mL), followed by addition of solid NH4CI (2 g). After 15-min stirring at rt, TFA (10 mL) was added and stirring continued for 30 min. The mixture was then filtered. The filtered cake was washed thoroughly with H2O and EtOAc and filtrate was concentrated in vacuum to provide the product TFA salt of 2-(4-aminoquinazolin-6-yl)acetic acid (294b) (475 mg, 33.5 % yield) as a brown solid. Ή NMR (300 MHz, DMSO-tfc) δ 9.70 (s, 2H), 8.75 (s, 1H), 8.24 (d, J = 1.7 Hz, 1H), 7.90 (dd, J = 8.5, 1.7 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 3.72 (s, 2H). ¹⁹ F Step-2: Preparation of (2S,4R)-l-(2-(4-aminoquinazolin-6-yl)acetyl)-N-(3-chloro-2- fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (294c)

Compound 294c was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-aminoquinazolin-6-yl)acetic acid (294b) (163 mg, 0.515 mmol) in DMF (5 mL) using (2S,4R)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrTOlidine-2-ca rboxamide (7a) (200 mg, 0.515 mmol), HATU (235 mg, 0.617 mmol), DIPEA (0.449 mL, 2.57 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography (SiCh, 12 g, eluting with 0-5% MeOH in DCM) followed by reverse phase column chromatography [C-18 column, 100 g, eluting with 0.1% aqueous HC1 in HzO and MeCN from 0-100%] (2S,4R)-l-(2-(4-aminoquinazolin-6-yl)acetyl)-N-(3-chloro-2- fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide (294c) (21 mg, 9 % yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfe) (mixture of two rotamers) δ 9.70 (bs, 2H, D20 exchangeable), 8.82 (s, 1H), 9.18 and 8.74 (2t, J= 5.9 Hz, 1H), 8.36 and 8.30 (2s, 1H), 8.02 - 7.84 (m, 1H), 7.84 - 7.72 (m, 1H), 7.53 - 7.39 (m, 1H), 7.40 - 7.25 (m, 1H), 7.23 - 7.04 (m, 1H), 5.60 - 5.21 (m, 1H), 4.51 - 3.72 (m, 6H), 3.60 - 3.46 (m, 1H), 2.76 - 2.40 (m, 1H), 2.23 - 1.86 (m, 1H); ^!9 F NMR (282 MHz, DMSO-ifc) δ -121.25, -121.65, -176.17, -176.38; MS (ES+) 460/462 (M+l).

Scheme 295

295a

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyr imido[4, 5- b]indol-9-yl)acetyl)-N-(6-bromopyrazin-2-yl)-2-azabicyclo[3. 1.0]hexane-3-carboxamide (295a)

Compound 295a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]in dol-9- (6-bromopyrazin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamid e (112a) (54.7 mg, 0.171 mmol), HATU (98 mg, 0.257 mmol), DIPEA (111 mg, 0.856 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 3%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyrazin-2-yl)-2- azabicyclo[3.1.0]hexane-3- carboxamide (295a) (66 mg, 65% yield) HC1 salt as a white solid; ‘H NMR (300 MHz, DMSO^fc) δ 11.22 (s, 1H, DzO exchangeable), 9.23 (s, 1H), 8.92 (bs, 2H, DzO exchangeable), 8.82 (s, 1H), 8.70 (s, 1H), 8.53 (s, 1H), 7.64 (s, 1H), 6.00 (d, J = 18.0 Hz,

1H), 5.71 (d, J = 17.9 Hz, 1H), 4.47 (dd, J = 9.0, 5.7 Hz, 1H), 4.00 - 3.92 (m, 1H), 2.79 (s, 3H), 2.44 - 2.31 (m, 1H), 2.31 - 2.17 (m, 1H), 2.02 - 1.88 (m, 1H), 1.19 - 1.02 (m, 1H), 0.80 - 0.64 (m, 1H); ¹⁹ FNMR(282 MHz, DMSO-de) δ -58.83; MS (ES+): 589/591 (M+l), (ES-): 587/589 (M-l).

Scheme 296

296a

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyr imido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyrazin-2-yl)-5-methyl-2-azab icyclo[3.1.0]hexane-3- carboxamide (296a)

Compound 296a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(trifluoromethyI)-9H-pyrimido[4,5-b]in doI-9- yl)acetic acid (184f) (75 mg, 0.171 mmol) in DMF (5 mL) using HC1 salt of (1R,3S,5R)-N- (6-bromopyrazin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-c arboxamide (261c) (57.1 mg, 0.171 mmol), HATU (98 mg, 0.257 mmol), DIPEA (111 mg, 0.856 mmol) and stirring at RT gel (12 g), eluting with MeOH in DCM from 0 - 2%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HCI) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyrazin-2-yl)-5- methyl-2- azabicyclo[3.1 ,0]hexane-3-caiboxamide (296a) (63 mg, 61% yield) HCI salt as a white solid; ¾ NMR (300 MHz, DMSO-flfc) δ 11.21 (s, 1H, D2O exchangeable), 9.24 (s, 1H), 8.91 (bs, 2H, DzO exchangeable), 8.85 (s, 1H), 8.69 (s, 1H), 8.53 (s, 1H), 7.62 (s, 1H), 5.94 (d, J = 18.0 Hz, 1H), 5.66 (d, J = 18.0 Hz, 1H), 4.42 (dd, J = 9.1, 6.1 Hz, 1H), 3.76 - 3.71 (m, 1H), 2.76 (s, 3H), 2.57 - 2.51 (m, 1H), 2.10 - 1.94 (m, 1H), 1.31 (s, 3H), 1.08 - 0.98 (m, 1H), 0.94 - 0.82 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-ds) δ -58.84; MS (ES+): 603/605 (M+l), (ES-): 601/603 (M-l).

Scheme 297

297c 297d

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(3-methylureido)-9H-pyrimido[4,5- b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yI)-2-azabicycIo[3.1.0]hexane -3-carboxamide (297d)

Step-1: Preparation of l-(4-amino-9H-pyrimido[4,5-b]indol-6-yl)-3-methylurea (297a) A suspension of 4-amino-9H-pyrimido[4,5-b]indole-6-caibonyl azide (225a) (111 mg, 0.438 mmol) in toluene (4 mL) was added methanamine hydrochloride (177 mg, 2.63 mmol), triethylamine (0.916 mL, 6.57 mmol) and heated at 115 °C for 2 h in a microwave. The reaction mixture was cooled to RT, triturated with dichloromethane/methanol (9: 1) (30 mL), filtered, washed with dichloromethane/methanol (9: 1). The filtrate was concentrated and purified by flash column chromatography [silica gel (40 g), eluting with dichloromethane/methanol (1:0 to 9:1)] to afford l-(4-amino-9H-pyrimido[4,5-b]indol-6-yl)- 3-methylurea (297a) (44 mg, 39% yield) as a light brown gum; MS (ES+): 257.10 (M+Na).

Step-2: Preparation of tert- butyl 2-(4-arnino-6-(3-methylureido)-9H-pyrimido[4,5-b]indol-9- yl)acetate (297b)

Compound 297b was prepared according to the procedure reported in step-1 of scheme- 1 , from l-(4-amino-9H-pyrimido[4,5-b]indol-6-yl)-3-methylurea (297a) (42 mg, 0.164 mmol) in DMF (10 mL) using tort-butyl 2-bromoacetate (0.027 mL, 0.180 mmol) and CszCOs (133 mg, 0.410 mmol) and stirring at RT for 17 h. This gave after work up tort-butyl 2-(4-amino- 6-(3-methylureido)-9H-pyrimido[4,5-b]indol-9-yl)acetate (297b) (32 mg) and was used as such for the next step; MS (ES+): 371.20 (M+l).

Step-3: Preparation of 2-(4-amino-6-(3-methylureido)-9H-pyrimido[4,5-b]indol-9-yl)a cetic acid (297c)

Compound 297c was prepared according to the procedure reported in step-2 of scheme- 1, from tort-butyl 2-(4-amino-6-(3 -methylureido) -9H-py rimido [4,5 -bj indol-9-yl)acetate (297b) (30 mg, 0.081 mmol) in DCM (10 mL) using TFA and stirring at RT. This gave after work which was used as such for the next step; MS (ES+): 315.10 (M+l).

Step-4: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(3-methylureido)-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1.0]hexane-3-carboxamide (297d)

Compound 297d was prepared according to the procedure reported in step-3 of scheme- 1 , from TFA salt of 2-(4-amino-6-(3-methylureido)-9H-pyrimido[4,5-b]indol-9-yl)a cetic acid (297c) (25.5 mg, 0.081 mmol) in DMF (10 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (4a) (51.6 mg, 0.162 mmol), HATU (61 6 mg 00 162 mmol) DIPEA (0071 mL 0405 mmol) and stirring at RT for 21 g), eluting with MeOH in DCM from 0-10%] followed by treating with acetonitrile (2 mL) and 0.1% aq. HC1 (10 mL) to afford (lR,3S,5R)-2-(2-(4-amino-6-(3-methylureido)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromop>'ridin-2-yl )-2-azabicyclo[3.1 ,0]hexane-3- carboxamide (297d) (4 mg, 9% yield) HC1 salt as a light brown solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.76 (s, 1H), 8.55 (s, 1H), 8.42 (s, 1H), 8.27 (s, 1H), 8.01 (d,J= 8.1 Hz, 1H), 7.70 (t, J= 7.9 Hz, 1H), 7.55 (s, 2H), 7.32 (d, J= 7.7 Hz, 1H), 6.19 (s, 1H), 5.71 (d,J= 17.5 Hz, 1H), 5.37 (d,J= 17.3 Hz, 1H), 4.51 - 4.33 (m, 1H), 3.98 - 3.85 (m, 1H), 2.70 - 2.63 (m, 3H), 2.40 - 2.14 (m, 2H), 1.97 - 1.83 (m, 1H), 1.14 - 0.98 (m, 1H), 0.81 - 0.71 (m, 1H); MS (ES+): 578.20 (M+l); (ES-): 576.10 (M-l).

Scheme 298

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-phenj'l-9H-pyrido[2',3':4,5]pyrro lo[2, 3- d]p>'rimidin-9-yl)acet>'l)-N-(6-bromopyridin-2-yl)-2-a zabicyclo[3.1 ,0]hexane-3-carboxamide (298c)

Step-1: Preparation of fert-butyl 2-(4-amino-6-phenyl-9H-pyrido[2',3 ^, :4,5]pyrrolo[2,3- d]pyrimidin-9-yl)acetate (298a) Compound 298a was prepared according to the procedure reported in step-lof scheme-59, from te/7-buty 12-(4-amino-6-bromo-9H-pyrido [2',3 ' : 4,5 Jpyrrolo [2,3 -d] py rimidin-9-y l)acetate (290e) (300 mg, 0.793 mmol) in dioxane (4 mL) using phenyl boronic acid (145 mg, 1.190 mmol), bis(triphenylphosphine)palladium(n) chloride (55.7 mg, 0.079 mmol) a solution of 3.3 M potassium carbonate (0.721 mL, 2.380 mmol) and heating at 100 °C for 16 h. This gave after workup and purification using flash column chromatography [silica gel (24g), eluting with MeOH in DCM from 0-3%] tert-butyl 2-(4-amino-6-phenyl-9H- pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetate (298a) (281 mg, 94% yield) as a yellow solid; TTNMR (300 MHz, DMSO-cfe) δ 8.85 (d, J= 1.8 Hz, 1H), 8.42 (d, J= 1.9 Hz, 1H), 8.39 (s, 1H), 8.15 - 7.66 (m, 3H), 7.61 - 7.50 (m, 2H), 7.49 - 7.40 (m, 1H), 6.85 (bs, 1H), 5.24 (s, 2H), 1.41 (s, 9H); MS (ES+): 376 (M+l).

Step-2: Preparation of 2-(4-amino-6-phenyl-9H-pyrido[2 ^, ,3 ^, :4,5]pyrrolo[2,3-d]pyrimidin-9- yl)acetic acid (298b)

Compound 298b was prepared according to the procedure reported in step-2 of scheme- 1, from tert-butyl 2-(4-amino-6-phenjd-9H-pyrido[2 ^, ,3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetate (298a) (280 mg, 0.746 mmol) in DCM (5 mL) using TFA (850 mg, 7.46 mmol) and stirring at RT for 16 h. This gave after work up 2-(4-amino-6-phenyl-9H-pyrido[2',3':4,5]pyrrolo[2,3- d]pyrimidin-9-yl)acetic acid (298b) (386 mg) TFA salt as a pale-yellow solid; Ή NMR (300 MHz, DMSO-<fc) δ 8.98 (d, J= 1.8 Hz, 1H), 8.80 (bs, 1H), 8.65 (d, J= 1.9 Hz, 1H), 8.60 (s, 1H), 8.10 (bs, 1H), 7.92 - 7.86 (m, 2H), 7.65 - 7.52 (m, 2H), 7.53 - 7.42 (m, 1H), 5.36 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO) δ -74.76; MS (ES+): 320 (M+l); (ES-): 318 (M-l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-phenyl-9H-pyrido[2 ^, ,3 ^, :4,5]pyrrolo[2,3- d]p>'rimidin-9-yl)acet>'l)-N-(6-bromopyridin-2-yl)-2-a zabicyclo[3.1 ,0]hexane-3-carboxamide (298c)

Compound 298c was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-phenyl-9H-pyrido[2 ^l ,3':4,5]pyrrolo[2,3-d]pyrimidin-9- yl)acetic acid (298b) (75 mg, 0.173 mmol) in DMF (5 mL) using HC1 salt of (1R,3S,5R)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamid e (4a) (55.1 mg, 0.173 mmol), HATU (79 mg, 0.208 mmol), DIPEA (112 mg, 0.865 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0 - 5%] followed by purification using reverse phase column chromatography [C18 column (100 g), eluting with ACN in water (containing 0.1% d]pyrimidin-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicycl o[3.1.0]hexane-3-carboxamide (298c) (72 mg, 71% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-flfe) δ 10.79 (s, 1H, DzO exchangeable), 9.15 - 8.85 (bs, 1H, DzO exchangeable), 8.98 (d, J = 1.8 Hz, 1H),

8.85 - 8.56 (bs, 1H, DzO exchangeable), 8.70 (s, 1H,), 8.53 (d, J = 1.9 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.90 - 7.83 (m, 2H), , 7.67 (t, J = 8.0 Hz, 1H), 7.63 - 7.55 (m, 2H), 7.54 - 7.45 (m, 1H), 7.31 (d, J = 7.7 Hz, 1H), 5.89 (d, J = 17.3 Hz, 1H), 5.54 (d, J = 17.3 Hz, 1H), 4.45 (dd, J = 9.1, 5.5 Hz, 1H), 3.98 - 3.87 (m, 1H), 2.42 - 2.28 (m, 1H), 2.28 - 2.12 (m, 1H), 2.00 -

1.86 (m, 1H), 1.19 - 0.99 (m, 1H), 0.87 - 0.72 (m, 1H); MS (ES+): 583/585 (M+l), (ES-): 581/583 (M-l).

Scheme 299

298b

299a

Preparation of(lR,3S,5R)-2-(2-(4-amino-6-phenyl-9H-pyrido[2',3 ^, :4,5]p>'rrolo[2,3- d]pyrimidin-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2- azabicyclo[3.1 ,0]hexane-3- carboxamide (299a)

Compound 299a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-phenyl-9H-pyrido[2',3':4,5jpyrrolo[2,3-d]pyrimi din-9-yl)acetic acid (298b) (75 mg, 0.173 mmol) in DMF (5 mL) using HC1 salt of ( 1 R,3 S,5R)-N-(6-bromopyridin- 2-yl)-5-methyl-2-azabic>'clo[3.1 ,0]hexane-3-carboxamide (8a) (57.6 mg, 0.173 mmol), HATU (79 mg, 0.208 mmol) DIPEA (112 mg, 0.865 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography (silica gel (12 g), eluting with MeOH in DCM from 0 - 5%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-6-phenyl-9H-pyrido[2 ^, ,3 ^, :4,5]pyrrolo[2,3-d]pyrimidin-9- (299a) (67 mg, 65% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-tfc) δ 10.79 (s, 1H, DzO exchangeable), 9.19 - 8.84 (bs, 1H, DzO exchangeable), 8.98 (d, J = 1.8 Hz, 1H), 8.84 - 8.58 (bs, 1H, DzO exchangeable), 8.70 (s, 1H), 8.53 (d, J = 1.9 Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.90 - 7.81 (m, 2H), 7.67 (t, J = 8.0 Hz, 1H), 7.63 - 7.54 (m, 2H), 7.54 - 7.46 (m, 1H), 7.30 (d, J = 7.7 Hz, 1H), 5.85 (d, J = 17.3 Hz, 1H), 5.48 (d, J = 17.3 Hz, 1H), 4.40 (dd, J = 9.1, 5.9 Hz, 1H), 3.76 - 3.61 (m, 1H), 2.48 - 2.38 (m, 1H), 1.99 (dd, J = 13.3, 5.8 Hz, 1H), 1.32 (s, 3H), 1.08 - 1.00 (m, 1H), 1.00 - 0.88 (m, 1H); MS (ES+): 597/599 (M+l); (ES-): 595/597 (M-

1).

Scheme 300

F

H N ,CI

C(¾H HN H N .

N N Me a rV N \

O

246 y _° -N. Λο

N Me

NH ₂ HATU, DIPEA if

CF ₃ N _N ^ ^¾ — y/ \

184f NH ₂

CF ₃

300a

Preparation of (2S,4R)-l-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimi do[4,5- b]indol-9-yl)acetyl)-N-(6-chloropyridin-2-yl)-4-fluoropyrroI idine-2-carboxamide (300a)

Compound 300a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]in dol-9- yl)acetic acid (184f) (61.3 mg, 0.140 mmol) in DMF (1.5 mL) using TFA salt of (2S,4R)-N- (6-chloropyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (246a) (50 mg, 0.140 mmol), HATU (80 mg, 0.210 mmol), DIPEA (0.122 mL, 0.699 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)-l-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-chloropyridin-2-yl)-4 -fluoropyrrolidine-2- carboxamide (300a) (48 mg, 62% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO fe) ( i t f t t ) δ 11 37 d 11 03 (2 1H) 8 78 ( 1H) 859 ( 1H) 8.57 - 8.46 (m, 2H), 8.15 and 7.97 (2d, J= 8.2 Hz, 1H), 7.82 (t, J= 8.0 Hz, 1H), 7.59 (s, 1H), 7.31 and 7.19 (2d, J= 7.7 Hz, 1H), 5.89 - 5.42 (m, 3H), 4.68 (t, J= 8.5 Hz, 1H), 4.32 (dd, J = 21.3, 12.6 Hz, 1H), 4.10 - 3.84 (m, 1H), 2.76 and 2.66 (2s, 3H), 2.61 - 2.53 (m, 1H), 2.28 - 2.02 (m, 1H); ¹⁹ FNMR(282 MHz, DMSO-ifc) δ -58.73, -176.50; MS (ES+): 550.1 (M+l); (ES-): 548.1 (M-l).

Scheme 301

CF ₃

184f

301a

Preparation of (2S,4R)- l-(2-(4-antino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5- b]mdol-9-yl)acetyl)-N-(6-bromopyridm-2-yl)-4-fluoropyrrolidi ne-2-carboxamide (301a)

Compound 301a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]in dol-9- yl)acetic acid (184f) (54.5 mg, 0.124 mmol) in DMF (1.5 mL) using TFA salt of (2S,4R)-N- (6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (5d) (50 mg, 0.124 mmol), HATU (70.9 mg, 0.187 mmol), DIPEA (0.108 mL, 0.622 mmol) and stirring at RT for 16 h. This gave after woikup and purification using flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (2S,4R)-l-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimi do[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-4-fluoropyrroli dine-2-carboxamide (301a) (53 mg, 72% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-flfe) (a mixture of two rotamers) δ 11.38 and 11.04 (2s, 1H, DzO exchangeable), 8.76 (s, 1H), 8.57 (s, 1H), 8.45 (s, 2H, D2O exchangeable), 8.18 and 7.99 (2d, J= 8.2 Hz, 1H), 7.84and 7.71 (2t, J= 8.0 Hz,

1H) 758 (s 1H) 744 and 732 (2d J= 77 Hz 1H) 5 86 543 (m 3H) 468 (t J = 8 5 Hz 1H), 4.31 (dd, 21.4, 12.6 Hz, 1H), 3.98 (dd, J= 38.1, 12.5 Hz, 1H), 2.75 and 2.65 (2s, 3H), 2.61 - 2.54 (m, 1H), 2.30 - 2.02 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-cfe) δ -58.70, - 176.49; MS (ES+): 594.1/596.1 (M+l); (ES-): 592.1/594.1 (M-l).

Scheme 302

302a

Preparation of ( 1 RJS,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimi do[4,5- b]indol-9-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-meth yl-2-azabicyclo[3.1.OJhexane- 3 -carboxamide (302a)

Compound 302a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]in dol-9- yl)acetic acid (184f) (63.2 mg, 0.144 mmol) in DMF (1.5 mL) using HC1 salt of (1R,3S,5R)- N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (10a) (50 mg, 0.144 mmol), HATU (82 mg, 0.216 mmol), DIPEA (0.126 mL, 0.721 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] ( 1R,3 S,5R)-2-(2-(4-amino-8-methyl-6- (trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acet>'l)-N -(6-bromo-3-methylpyridin-2-yl)-5- methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (302a) (64 mg, 72% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-tfc) δ 10.33 (s, 1H, DzO exchangeable), 8.73 (s, 1H), 8.49 (s, 1H), 8.13 (s, 2H, DzO exchangeable), 7.61 (d,J= 8.0 Hz, 1H), 7.53 (s, 1H), 7.43 (d, J= 7.9 Hz, 1H), 5.86 (d, J= 18.0 Hz, 1H), 5.65 (d, ./= 17.9 Hz, 1H), 4.37 (dd, J= 9.1, 5.6 3H), 1.33 (s, 3H), 1.07 - 1.00 (m, 1H), 0.94 - 0.85 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-tife) δ -58.58; MS (ES+): 616.2/618.1 (M+l); (ES-): 614.1/616.1 (M-l).

Scheme 303

303a

Preparation of (lR,3S,5R)-2-(2-(4-ammo-8-metbyl-6-(trifluoromethyl)-9H-pyri mido[4,5- b]indol-9-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azab icyclo[3.1 ,0]hexane-3- carboxamide (303a)

Compound 303a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]in dol-9- yl)acetic acid (184ff) (65.9 mg, 0.150 mmol) in DMF (1.5 mL) using HC1 salt of (1R,3S,5R)- N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3 -carboxamide (Id) (50 mg, 0.150 mmol), HATU (86 mg, 0.225 mmol), DIPEA (0.131 mL, 0.752 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [silica gel (24 g), eluting with DMA-80 in DCM from 0 - 100%] followed by purification using reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] (lR,3S,5R)-2-(2-(4-amino-8-methyl-6- (trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6- bromo-3-methylpyridin-2-yl)-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (303a) (45 mg, 50% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-tife) δ 10.32 (s, 1H, D ₂ 0 exchangeable), 8.78 (s, 1H), 8.63 - 8.41 (m, 3a 2H DzO exchangeable), 7.63 - 7.50 (m, 2H), 7.42 (d, J = 7.9 Hz, 1H), 5.93 (d, J= 18.3 Hz, 1H), 5.70 (d, J= 17.9 Hz, 1H), 4.38 (dd, J= 9.2, 5.5 Hz, 1H), 3.93 - 3.84 (m, 1H), 2.74 (s, 3H), 2.47 - 2.34 (m, 1H), 2.30 - 2.16 (m, 1H), 1.99 (s, 3H), 1.98 - 1.88 (m, 1H), 1.16 - 0.99 (m, 1H), 0.82 - 0.64 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-tife) δ -58.69; MS (ES+): 602.1/604.1 (M+l); (ES-): 600.1/602.1 (M-l). Scheme 304

184f 304a

Preparation of (2S,4R)- l-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridm-2-yl)-4-fluoro-4-methy lpyrrolidme-2 -carboxamide (304a)

Compound 304a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]in dol-9- yl)acetic acid (184f) (60mg, 0.137 mmol) in DMF (1.5 mL) using TFA salt of (2S,4R)-N-(6- bromopyridin-2-yl)-4-fluoro-4-methylpyrrolidine-2-carboxamid e (207a) (57.0 mg, 0.137 mmol), HATU (78 mg, 0.205 mmol), DIPEA (0.119 mL, 0.684 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-303, (2S,4R)-l-(2-(4- ammo-8-methyl-6-(trifluoromethy])-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6- bromopyridin-2-yl)-4-fluoro-4-methylpyrrolidine-2 -carboxamide (304a) (41 mg, 49% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-dk) (a mixture of two rotamers) δ 11.36 and 11.02 (2s, 1H, D2O exchangeable), 8.76 (s, 1H), 8.56 (s, 1H), 8.42 (s, 2H, D2O exchangeable), 8.18 and 7.99 (2d, ./= 8.2 Hz, 1H), 7.84 and 7.71 (2t, J= 8.0 Hz, 1H), 7.58 (s, 1H), 7.43 and 7.32 (2d ,J= 7.7 Hz, 1H), 5.76 (d, 18.0 Hz, 1H), 5.54 (d ,J= 17.9 Hz, 1H),

4.68 (t, J= 8.7 Hz, 1H), 4.41 - 4.20 (m, 1H), 3.96 - 3.81 (m, 1H), 2.75 (s, 3H), 2.62 - 2.56 (m, 1H), 2.23 - 1.95 (m, 1H), 1.62 (d ,J= 21.1 Hz, 3H); ¹⁹ F NMR(282 MHz, DMSO) δ - 58.70, -139.66; MS (ES+): 608.1/610.1 (M+l); (ES-): 606.1/608.1 (M-l); Analysis calculated for C2 ₅ H22BrF4N ₇ 022H2O. HC1 : C, 44.10; H, 4.00; Cl, 5.21; N, 14.40; Found: C, 43.75; H, 3.89; Cl, 5.56; N, 14.11.

Scheme 305

184f 305a

Preparation of (2S,4R)-l-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimi do[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyrazin-2-yl)-4-fluoro-4-meth yIpyrrolidine-2-carboxamide

(305a)

Compound 305a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]in dol-9- yl)acetic acid (184f) (60mg, 0.137 mmol) in DMF (1.5 mL) using HC1 salt of (2S,4R)-N-(6- bromopyrazin-2-yl)-4-fluoro-4-methylpyrrolidine-2-carboxamid e (213c) (46.5 mg, 0.137 mmol), HATU (78 mg, 0.205 mmol), DIPEA (0.119 mL, 0.684 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-303, (2S,4R)-l-(2-(4- amino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9 -yl)acetyl)-N-(6- bromopyrazin-2-yl)-4-fluoro-4-methylpyrrolidine-2-carboxamid e (305a) (64 mg, 77 % yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-6&) (a mixture of two retainers) δ 11.68 and 11.38 (2s, 1H, D2O exchangeable), 9.40 and 9.22 (2s, 1H), 8.78 (s, 1H), 8.70 - 8.57 (m, 3H, 2H DzO exchangeable), 8.54 (s, 1H), 7.60 (d, J= 1.7 Hz, 1H), 5.79 (d, J= 18.0 Hz, 1H), 5.57 (d,J= 18.0 Hz, 1H), 4.71 (dd, J= 9.8, 7.5 Hz, 1H), 4.30 (dd,J= 18.1, 12.1 Hz, 1H), 3.91 (dd, J= 35.3, 12.1 Hz, 1H), 2.75 (s, 3H), 2.65 - 2.55 (m, 1H), 2.25 - 1.99 (m, 1H), 1.63 (d, J= 21.0 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO) δ -58.76, -139.68; MS (ES+): 609.1/611.1 (M+l); (ES-): 607.1/609.1 (M-l); Analysis calculated for Cz^iBrF+NgCh 2H2O. HC1 : C, 42.27; H, 3.84; Cl, 5.20; N, 16.43; Found: C, 42.34; H, 3.78; Cl, 4.91; N, 16.16.

Scheme 306

Preparation of (S)-l-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4 ,5-b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)pyrrolidine-2-carboxamide (306a)

Compound 306a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]in dol-9- yl)acetic acid (184f) (60mg, 0.137 mmol) in DMF (1.5 mL) using TFA salt of (S)-N-(6- bromopyridin-2-yl)pyrrolidine-2-carboxamide (13a) (52.6 mg, 0.137 mmol), HATU (78 mg, 0.205 mmol), DIPEA (0.119 mL, 0.684 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-303, (S)-l-(2-(4-amino-8-methyl-6- (trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6- bromopyridin-2-yl)pyrrolidine- 2-carboxamide (306a) (76 mg, 96% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) (a mixture of two rotamers) 5 11.28 and 10.94 (2s, 1H, DzO exchangeable), 8.78 (s, 1H), 8.71 - 8.43 (m, 3H, 2HDzO exchangeable), 8.15 and 8.00 (2d, J= 8.1 Hz, 1H), 7.82 and 7.71 (2t ,J= 8.0 Hz, 1H), 7.60 (d, J= 1.7 Hz, 1H), 7.41 and 7.31 (2d, J= 7.7 Hz, 1H), 5.66 (s, 2H), 4.56 (dd, J= 8.4, 4.5 Hz, 1H), 3.84 (t ,J= 6.6 Hz, 2H), 2.77 (s, 3H), 2.33 - 2.16 (m, 1H), 2.13 - 2.00 (m, 2H), 2.00 - 1.85 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO) δ -58.74; MS (ES+): 576.1/578.1 (M+l); (ES-): 574.1/576.0 (M-l); Analysis calculated for Cz4HziBrF3N ₇ 0z 1.5 HzO. HC1: C, 45.05; H, 3.94; Cl, 5.54; N, 15.32; Found: C, 45.19; H, 3.98; Cl, 5.28; N, 15.22.

Scheme 307

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(pyridin-4-yl)-9H-pyrido[2',3 ^, :4,5]pyirolo[2, 3- d]pyrimidm-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicycIo [3.1 ,0]hexane-3-caiboxamide (307c)

Step-1: Preparation of tert- butyl 2-(4-ammo-6-(pyridm-4-yl)-9H-pyrido[2 ^, ,3':4,5]pyrrolo[2,3- d]pyrintidin-9-yl)acetate (307a)

Compound 307a was prepared according to the procedure reported in step-1 of scheme-263, from tert-butyl 2-(4-amino-6-bromo-9H-pyrido[2',3':4,5]pyrrolo|2,3-d]pyrimid in-9-yl)acetate (290e) (300 mg, 0.793 mmol) in n-BuOH (4 mL) using pyridin-4-ylboronic acid (146 mg, 1.190 mmol), Pdz(dba)3 (72.6 mg, 0.079 mmol), XPhos (76 mg, 0.159 mmol), a solution of 1.27 M potassium phosphate (1.249 mL, 1.586 mmol) and heating at 100 °C for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0-7%] /erf-butyl 2-(4-amino-6-(pyridin-4-yl)-9H- pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-9-y])acetate (307a) (275 mg, 92% yield) as a gray solid; Ή NMR (300 MHz, DMSO-ifc) 58.99 (d, J= 1.8 Hz, 1H), 8.73 (d, 2H), 8.61 (d, J = 1.9 Hz, 1H), 8.41 (s, 1H), 8.01 (s, 1H), 7.91 (d, 2H), 6.89 (bs, 1H), 5.25 (s, 2H), 1.41 (s, 9H); MS (ES+): 377 (M+l).

Step-2: Preparation of 2-(4-amino-6-(pyridin-4-yl)-9H-pyrido[2',3':4,5]pyrrolo[2,3- d]pyrimidin-9-yl)acetic acid (307b)

Compound 307b was prepared according to the procedure reported in step-2 of scheme- 1, yl)acetate (307a) (272 mg, 0.723 mmol) in DCM (5 mL) using TFA (824 mg, 7.23 mmol) and stirring at RT for 16 h. This gave after work up 2-(4-amino-6-(pyridin-4-yl)-9H- py rido [2', 3 ' : 4,5 ]pyrrolo [2,3 -d]pyrim idi n-9-y 1 )acetic acid (307b) (358 mg) TFA salt as a beige solid; ^! HNMR (300 MHz, DMSO -ck) δ 9.28 (d, J= 1.9 Hz, 1H), 9.13 - 9.03 (m, 3H),

8.97 (bs, 1H), 8.68 (s, 1H), 8.60 (d, 2H), 8.30 (bs, 1H), 5.39 (s, 2H); MS (ES+) 321 (M+l); (ES-): 319.10 (M-l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(pyridin-4-yl)-9H- pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetyl)-N-(6-b romopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (307c)

Compound 307c was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-(pyridin-4-yl)-9H-pyrido[2',3 ^, :4,5]pyrrolo[2,3-d]pyrimidin-9- yl)acetic acid (307b) (75 mg, 0.173 mmol) in DMF (5 mL) using HC1 salt of (1R,3S,5R)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamid e (4a) (55.0 mg, 0.173 mmol), HATU (79 mg, 0.207 mmol), DIPEA (112 mg, 0.863 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4- amino-6-(pyridin-4-yl)-9H-pyrido[2 ^, ,3 ^, :4,5]pyrrolo[2,3-d]p>rimidin-9-yl)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (307c) (52 mg, 52% yield)

HC1 salt as a white solid; ‘HNMR (300 MHz, DMSO-afe) δ 10.78 (s, 1H, D2O exchangeable), 9.20 (d, J = 1.9 Hz, 1H), 9.02 (d, J = 5.9 Hz, 2H), 8.86 - 8.68 (bs, 1H, DzO exchangeable), 8.77 (s, 1H), 8.63 (s, 1H), 8.46 (d, J = 6.0 Hz, 2H), 8.13 - 7.78 (bs, 1H, D2O exchangeable),

7.97 (d, J = 8.2 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 5.85 (d, J = 17.2 Hz, 1H), 5.53 (d, J = 17.2 Hz, 1H), 4.49 - 4.41 (m, 1H), 3.95 - 3.87 (m, 1H), 2.39 - 2.29 (m, 1H), 2.29 - 2.17 (m, 1H), 2.01 - 1.81 (m, 1H), 1.20 - 1.04 (m, 1H), 0.90 - 0.74 (m, 1H); MS (ES+): 584/586 (M+l); (ES-): 582/584 (M-l); Analysis calculated for C27H22BrN902.2.2HC1.4.5H20: C, 43.49; H, 4.49; Cl, 10.46; N, 16.90; Found: C, 43.57; H, 4.29; Cl, 10.41; N, 16.69.

Scheme 308 r C0 ₂ ^f Bu CO^u

N=\ nr" Me Me Me f % r ^N r ^N TFA f \

Pd ₂₍ dba) ₃ , XPhos,

NH _Z K ₃ PO ₄ NH ₂

Br f N= \(

192e 308a Me

Preparation of ( 1 R,3 S,5R)-2-(2-(4-amino-8-methyl-6-(2-methylpyrimidin-5-yl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1 ,0]hexane-3- carboxamide (308c)

Step-1: Preparation of torf-butyl 2-(4-amino-8-methyl-6-(2-methylpyrimidin-5-yl)-9H- pyrimido[4,5-b]indol-9-yl)acetate (308a)

Compound 308a was prepared according to the procedure reported in step-1 of scheme-263, from ferf-butyl 2-(4-amino-6-bromo-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)ace tate (192e) (500 mg, 1.278 mmol) in n-BuOH (20 mL) using (2-methylpyrimidin-5-yl)boronic acid (264 mg, 1.917 mmol), Pd2(dba)? (117 mg, 0.128 mmol), XPhos (122 mg, 0.256 mmol), a solution of 1.27 M potassium phosphate (2.012 mL, 2.56 mmol) and heating at 100 °C for 16 h. This gave after workup and purification by flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0-7%] terf-butyl 2-(4-amino-8-methyl-6-(2-methylpyrimidin-5- yl)-9H-pyrimido[4,5-b]indol-9-yl)acetate (308a) (475 mg, 92% yield) as a white solid; ^l H NMR (300 MHz, DMSO-de) δ 9.21 (s, 2H), 8.59 (d, J= 1.8 Hz, 1H), 8.33 (s, 1H), 7.64 (s, 1H), 7.49 (s, 2H), 5.37 (s, 2H), 2.71 (s, 3H), 2.68 (s, 3H), 1.44 (s, 9H); MS (ES+): 405 (M+l); (ES-): 403 (M-l).

Step-2: Preparation of 2-(4-ammo-8-methyl-6-(2-methylpyrimidin-5-yl)-9H-pyrimido[4, 5- b]indol-9-yl)acetic acid (308b) Compound 308b was prepared according to the procedure reported in step-2 of scheme- 1, from tert-butyl 2-(4-amino-8-methyl-6-(2-methylpyrimidin-5-yl)-9H-pyrimido[4 ,5-b]indol-9- yl)acetate (308a) (475 mg, 1.174 mmol) in DCM (20 mL) using TFA (1339 mg, 11.74 mmol) and stirring at RT for 16 h. This gave after work up TFA salt 2-(4-amino-8-methyl-6-(2- methylpyiimidin-5-yl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (308b) (715 mg) as a pale yellow solid; Ή NMR (300 MHz, DMSO-afc) δ 9.21 (s, 2H), 8.82 (bs, 2H), 8.73 (d, J = 1.8 Hz, 1H), 8.65 (s, 1H), 7.80 (s, 1H), 5.48 (s, 2H), 2.77 (s, 3H), 2.70 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-de) δ -74.78; MS (ES+): 349 (M+l); (ES-): 347 (M-l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(2-methylpyrimidin-5-yl) -9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1 ,0]hexane-3- carboxamide (308c)

Compound 308c was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(2-methylpyrimidin-5-yl)-9H-pyrimido[4 ,5- b]indol-9-yl)acetic acid (308b) (75 mg, 0.162 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (4a) (51.7 mg, 0.162 mmol), HATU (74.0 mg, 0.195 mmol), DIPEA (105 mg, 0.81 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(2-methylpyrimidin-5-yl) -9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (308c) (70 mg, 71% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-de) δ 10.84 (s, 1H,

D2O exchangeable), 9.23 (s, 2H), 9.06 (bs, 2H, DzO exchangeable), 8.77 (d, J = 1.7 Hz, 1H), 8.69 (s, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.79 (s, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 5.97 (d, J = 18.0 Hz, 1H), 5.67 (d, J = 17.9 Hz, 1H), 4.43 (dd, J = 9.1, 5.7 Hz, 1H), 3.98 - 3.91 (m, 1H), 2.78 (s, 3H), 2.69 (s, 3H), 2.42 - 2.29 (m, 1H), 2.29 - 2.10 (m, 1H), 2.02 - 1.87 (m, 1H), 1.17 - 1.02 (m, 1H), 0.79 - 0.62 (m, 1H); MS (ES+): 612/614 (M+l); (ES-): 610/612 (M-l); Analysis calculated for C29H26BrN9O2.i 5HCl.4H2O: C, 47.12; H, 4.84; Cl, 7.19; N, 17.05; Found: C, 47.26; H, 4.67; Cl, 7.17; N, 17.07.

Scheme 309

308b 309a

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(2-methylpyrimidin-5-yl) -9H- pyrimido[4,5-b]indol-9-yI)acetyl)-N-(6-bromopyridin-2-yl)-5- methyI-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (309a)

Compound 309a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(2-methylpyrimidin-5-yl)-9H-pyrimido[4 ,5- b]indol-9-yl)acetic acid (308b) (75 mg, 0.162 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (8a) (54 mg, 0.162 mmol), HATU (74.0 mg, 0.195 mmol), DIPEA (105 mg, 0.811 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme- 299, (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(2-methylpyrimidin-5-yl) -9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azab icyclo[3.1.0Jhexane-3- carboxamide (309a) (64 mg, 63% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-de) δ 10.84 (s, 1H, DzO exchangeable), 9.23 (s, 1H), 9.21 (s, 1H), 9.01 (bs, 1H, DzO exchangeable), 8.89 (bs, 1H, DzO exchangeable), 8.76 (s, 1H), 8.71 - 8.64 (m, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.79 (s, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 5.92 (d, J = 18.0 Hz, 1H), 5.63 (d, J = 17.8 Hz, 1H), 4.39 (dd, J = 9.0, 6.2 Hz, 1H), 3.75 - 3.70 (m, 1H), 2.77 (s, 3H), 2.69 (s, 3H), 2.49 - 2.44 (m, 1H), 1.99 (dd, J = 13.3, 6.1 Hz, 1H), 1.32 (s, 3H), 1.11 - 0.99 (m, 1H), 0.92 - 0.81 (m, 1H); MS (ES+) 626/628 (M+l); (ES-) 624/626 (M-l); Analysis calculated for CzoHzsBrN-tOz.1.6HC1.4HzO: C, 47.60; H, 5.01; Cl, 7.49; N, 16.65; Found: C, 47.59; H, 4.89; Cl, 7.36; N, 16.44.

Scheme 310

308b 310a

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(2-methylpyrimidin-5-yl) -9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromo-3-methylpyridin -2-yl)-2- azabicyclo[3.1.0jhexane-3-carboxamide (310a)

Compound 310a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(2-methylpyrimidin-5-yl)-9H-pyrimido[4 ,5- b]indol-9-yl)acetic acid (308b) (75 mg, 0.162 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1 .0]hexane-3-carboxamide (Id) (54 mg, 0.162 mmol), HATU (74 mg, 0.195 mmol), DIPEA (105 mg, 0.811 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4-amino-8-meth _j 'l-6-(2-methylpyrimidin-5-yl)-9H-pyrimido[4,5-b]indol- 9- yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (310a) (41 mg, 40% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-i/d) δ 10.35 (s, 1H, DzO exchangeable), 9.26 (s, 2H), 9.11 (bs, 2H, DzO exchangeable), 8.80 (s, 1H), 8.70 (s, 1H), 7.79 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 7.9 Hz, 1H), 5.96 (d, J = 18.0 Hz, 1H), 5.68 (d, J = 17.8 Hz, 1H), 4.41 (dd, J = 9.2, 5.6 Hz, 1H), 3.95 - 3.93 (m, 1H), 2.76 (s, 3H), 2.71 (s, 3H), 2.48 - 2.36 (m, 1H), 2.32 - 2.19 (m, 1H), 2.00 (s, 3H), 1.98 - 1.91 (m, 1H), 1.19 - 0.98 (m, 1H), 0.89 - 0.65 (m, 1H); MS (ES+) 626/628 (M+l); (ES-) 624/626 (M-l); Analysis calculated for C3oHz8BrN90z.l.5HC1.5.25HzO: C, 46.45; H, 5.20; N, 16.25; Found: C, 46.48; H, 4.98; N, 16.02.

Scheme 311

308b 311a

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(2-methylpyrimidin-5-yl) -9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromo-3-methylpyridin -2-yl)-5-methyl-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (311a)

Compound 311a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(2-methylpyrimidin-5-yl)-9H-pyrimido[4 ,5- b]indol-9-yl)acetic acid (308b) (75 mg, 0.162 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabi cyclo[3.1.0]hexane-3- carboxamide (10a) (56.2 mg, 0.162 mmol), HATU (74.0 mg, 0.195 mmol), DIPEA (105 mg, 0.811 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(2-methylpyrimidin-5-yl) -9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromo-3-methylpyridin -2-yl)-5-methyl-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (311a) (61 mg, 59% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-dk) δ 10.37 (s, 1H, DzO exchangeable), 9.24 (s, 2H), 9.04 (bs, 2H, DzO exchangeable), 8.78 (d, J = 1.7 Hz, 1H), 8.68 (s, 1H), 7.78 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 7.9 Hz, 1H), 5.90 (d, J = 18.0 Hz, 1H), 5.63 (d, J = 17.9 Hz, 1H), 4.39 (dd, J = 9.1, 5.7 Hz, 1H), 3.71 - 3.68 (m, 1H), 2.74 (s, 3H), 2.70 (s, 3H), 2.63 - 2.53 (m, 1H), 2.13 - 2.04 (m, 1H), 2.02 (s, 3H), 1.34 (s, 3H), 1.10 - 0.97 (m, 1H), 0.98 - 0.85 (m, 1H); MS (ES+): 640/642 (M+l), (ES-): 638/640 (M-l); Analysis calculated for C ₃ iH3oBrN90z.l.5HC1.3.5HzO: C, 49.10; H, 5.12; Cl, 7.01; N, 16.62; Found: C, 48.93; H, 4.95; Cl, 7.05; N, 16.39.

Scheme 312

Preparation of (2S,4R)- l-(2-(4-amino-8-methyl-6-(2-methylpyrimidin-5-yl)-9H- pyrimido[4,5-b]indol-9-yl)acetYl)-N-(6-bromopyridin-2-yl)-4- fluoropynolidine-2- carboxamide (312a)

Compound 312a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(2-methylpyrimidin-5-yl)-9H-pyrimido[4 ,5- b]indol-9-yl)acetic acid (308b) (75 mg, 0.162 mmol) in DMF (5 mL) using HC1 salt of (2S,4R)-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carbox amide (5d) (52.6 mg, 0.162 mmol), HATU (74.0 mg, 0.195 mmol), DIPEA (105 mg, 0.811 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-299, (2S,4R)-l-(2-(4- amino-8-methvi-6-(2-methylpyrimidin-5-yl)-9H-pyrimido[4,5-b] indol-9-yl)acetyl)-N-(6- bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (312a) (26 mg, 26% yield) HC1 salt as a white solid; ^! H NMR (300 MHz, DMSO-tifc) δ (a mixture of two retainers) 11.39 and 11.05 (2s, 1H, DzO exchangeable), 9.23 and 9.21 (2s, 2H), 8.94 (s, 2H, DzO exchangeable), 8.76 (d, .7= 1.7 Hz, 1H), 8.67 and 8.65 (2s, 1H), 8.18 and 7.99 (2d, J= 8.2 Hz, 1H), 7.82 and 7.70 (2t, 8.0 Hz, 1H), 7.79 (s, 1H), 7.44 and 7.31 (d, J= 7.7 Hz, 1H), 5.91 - 5.09 (m, 3H),

4.69 (t, J= 8.5 Hz, 1H), 4.42 - 4.22 (m, 1H), 4.10 - 3.93 (m, 1H), 2.77 (s, 3H), 2.69 (s, 3H), 2.32 - 2.16 (m, 1H), 2.16 - 2.01 (m, 1H); ^!9 FNMR (282 MHz, DMSO-ifc) δ -176.18; MS (ES+): 618/620 (M+l); (ES-): 616/618 (M-l).

Scheme 313

184f 313b

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyr imido[4,5- b] indol-9-y l)acetyl )-N-(6-bromo-5 -methy lpyrazin-2-yl)-2-azabicyclo [3.1 ,0]hexane-3- carboxamide (313b)

Compound 313b was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]in dol-9- yl)acetic acid (184f) (75 mg, 0.171 mmol) in DMF (5 mL) using HC1 salt of (1R,3S,5R)-N- (6-bromo-5-methylpyrazin-2-yl)-2-azabicyclo[3.1.0]hexane-3-c arboxamide (313a) (57.1 mg, 0.171 mmol; CAS # 2086190-99-8), HATU (98 mg, 0.257 mmol), DIPEA (111 mg, 0.856 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyr imido[4,5- b]indol-9-yl)acetyl)-N-(6-bromo-5-methylpyrazin-2-yl)-2-azab icyclo[3.1.0]hexane-3- carboxamide (313b) (52 mg, 50% yield) HC1 salt as a white solid; *H NMR (300 MHz, DMSOnifc) δ 11.08 (s, 1H, D2O exchangeable), 9.10 (s, 1H), 8.80 (s, 1H), 8.71 (bs, 2H, D2O exchangeable), 8.65 (s, 1H), 7.61 (s, 1H), 5.98 (d, J = 18.1 Hz, 1H), 5.70 (d, J = 17.9 Hz, 1H), 4.44 (dd, J = 9.1, 5.6 Hz, 1H), 3.98 - 3.90 (m, 1H), 2.77 (s, 3H), 2.52 (s, 3H), 2.43 - 2.29 (m, 1H), 2.29 - 2.14 (m, 1H), 2.01 - 1.87 (m, 1H), 1.17 - 0.99 (m, 1H), 0.82 - 0.62 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-tfc) δ -58.78; MS (ES+): 603/605 (M+l), (ES-): 601/603 (M-l); Analysis calculated for C25H22BrF ₃ Ng02.1.4HC1.1.5H20: C, 44.06; H, 3.90; N, 16.44; Found: C, 44.02; H, 3.55; N, 16.44.

Scheme 314

189f 314a

Preparation of (lR,3S,5R)-2-(2-(4-amino-6,8-dimethyl-9H-pyrimido[4,5-b]indo l-9- yl)acetyl)-N-(6-bromopyrazin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (314a)

Compound 314a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6,8-dimethyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (189f) (75 mg, 0.195 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyrazin-2- yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (261c) (65.1 mg, 0.195 mmol), HATU (111 mg, 0.293 mmol), DIPEA (126 mg, 0.976 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4- amino-6,8-dimethyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6 -bromopyrazin-2-yl)-5- methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (314a) (66 mg, 62% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-tfc) 5 11.20 (s, 1H, DzO exchangeable), 9.24 (s, 1H), 8.64 (bs, 2H, DzO exchangeable), 8.61 (s, 1H), 8.54 (s, 1H), 8.17 (s, 1H), 7.12 (s, 1H), 5.86 (d, J = 18.0 Hz, 1H), 5.58 (d, J = 17.9 Hz, 1H), 4.41 (dd, J = 9.1, 6.1 Hz, 1H), 3.74 - 3.69 (m, 1H), 2.65 (s, 3H), 2.50 - 2.45 (m, 1H), 2.43 (s, 3H), 2.12 - 1.98 (m, 1H), 1.31 (s, 3H), 1.09 - 0.95 (m, 1H), 0.92 - 0.81 (m, 1H); MS (ES+): 549/551 (M+l); (ES-): 547/549 (M-l); Analysis calculated for CzsHzsBrNsOz.UHCl. 2HzO: C, 48.00; H, 4.85; Cl, 6.23; N, 17.91; Found: C, 47.84; H, 4.67; Cl, 6.10; N, 17.90.

Scheme 315

308b 315a

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(2-methylpyrimidin-5-yl) -9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-chloropyridin-2-yl)-5 -methyl-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (315a)

Compound 315a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(2-methylpyrimidin-5-yl)-9H-pyrimido[4 ,5-b]indol- 9-yl)acetic acid (308b) (75 mg, 0.162 mmol) in DMF (5 mL) using HC1 salt of (1R,3S,5R)- N-(6-chloropyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (269b) (46.7 mg, 0.162 mmol), HATU (74.0 mg, 0.195 mmol), DIPEA (105 mg, 0.811 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4-ammo-8-methyl-6-(2-methylpyrimidin-5-yl)- 9H-pyrimido[4,5-b]indol-9- yl)acetyI)-N-(6-chloropyridin-2-yl)-5-methyl-2-azabicyclo[3. 1 ,0]hexane-3-carboxamide (315a) (47 mg, 50% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-de) δ 10.83 (s, 1H, DzO exchangeable), 9.24 (s, 2H), 9.06 (bs, 2H, D2O exchangeable), 8.77 (d, J = 1.7 Hz, 1H), 8.69 (s, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.87 - 7.74 (m, 2H), 7.18 (d, J = 7.7 Hz, 1H), 5.92 (d, J = 18.0 Hz, 1H), 5.62 (d, J = 17.9 Hz, 1H), 4.40 (dd, J = 9.0, 6.2 Hz, 1H), 3.76 - 3.70 (m, 1H), 2.76 (s, 3H), 2.70 (s, 3H), 2.49 - 2.43 (m, 1H), 1.99 (dd, J = 13.3, 6.1 Hz, 1H), 1.32 (s, 3H), 1.08 - 0.95 (m, 1H), 0.94 - 0.76 (m, 1H); MS (ES+): 582/584 (M+l); (ES-): 580/582 (M-l); Analysis calculated for C30H28CIN9O2.1 SHCUHbO: C, 52.72; H, 5.21; Cl, 11.93; N, 18.44; Found: C, 52.74; H, 5.19; Cl, 11.84; N, 18.36.

Scheme 316

Preparation of (2S,4R)-l-(2-(4-amino-8-methyl-6-(2-methylpyrimidin-5-yl)-9H - pyrimido[4,5-b]indol-9-yI)acetyl)-N-(6-bromopyridin-2-yl)-4- fluoro-4-methylpyrrolidine-2- carboxamide (316a)

Compound 316a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(2-mcthylpyrimidin-5-yl)-9H-pyrimido[4 ,5-b]indol- 9-yl)acetic acid (308b) (75 mg, 0.162 mmol) in DMF (5 mL) using TFA salt of (2S,4R)-N- (6-bromopyridm-2-yl)-4-fluoro-4-methylpyrrolidine-2-carboxam ide (207a) (67.5 mg, 0.162 mmol), HATU (74.0 mg, 0.195 mmol), DIPEA (105 mg, 0.811 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-299, (2S,4R)-l-(2-(4- amino-8-methyl-6-(2-methylpyrimidin-5-yl)-9H-pyrimido[4,5-b] indol-9-yl)acetyl)-N-(6- bromopyridin-2-yl)-4-fluoro-4-methylpyrrolidine-2-carboxamid e (316a) (60 mg, 59% yield) HC1 salt as a white solid; *H NMR (300 MHz, DMSO-ofc) δ (a mixture of two rotamers) 11.37 and 11.03 (2s, 1H, D2O exchangeable), 9.22 (s, 2H), 8.93 (bs, 2H, D2O exchangeable), 8.77 (s, 1H), 8.67 and 8.65 (2s, 1H), 8.19 and 7.99 (2d, J = 8.2 Hz, 1H), 7.79 (d, J = 1.6 Hz, 1H), 7.85 and 7.70 (2t, J = 8.0 Hz, 1H), 7.44 and 7.32 (2d, J = 7.7 Hz, 1H), 5.77 (d, J = 18.0 Hz, 1H), 5.56 (d, J = 17.9 Hz, 1H), 4.70 (dd, J = 9.7, 7.5 Hz, 1H), 4.29 (dd, J = 18.2, 12.3 Hz,

1H), 3.99 - 3.81 (m, 1H), 2.77 (s, 3H), 2.69 (s, 3H), 2.63 - 2.55 (m, 1H), 2.24 - 1.96 (m, 1H), 1.63 (d, J = 21.1 Hz, 3H); ¹⁹ FNMR(282 MHz, DMSO -de) δ -139.89; MS (ES+): 632/634 (M+l); (ES-): 630/632 (M-l); Analysis calculated for C29H27BrFN9C>2.1 55HC1.2.5H20: C, 47.45; H, 4.61; Cl, 7.49; N, 17.17; Found: C, 47.48; H, 4.71; Cl, 7.45; N, 17.11.

Scheme 317

Preparation of ( 1 R,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrim ido[4,5- b]indol-9-yl)acetyl)-N-(6-bromo-3-fluoropyridin-2-yl)-2-azab icyclo[3.1.0]hexane-3- carboxamide (317c)

Step-1: Preparation of (lR,3S,5R)-tor/-butyl 3-((6-bromo-3-fluoropyridin-2-yl)carbamoyl)-2- azabicyclo[3.1.0]hexane-2-carboxylate (317a)

Compound 317a was prepared according to the procedure reported in step-1 of scheme-53, from (lR,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hcxane -3-carboxylic acid (259a) (0.5 g, 2.2mmol) and 6-bromo-3 -fl uoropyridi n -2-amine (0.42 g, 2.2 mmol; CAS # 1379457-78-9) to afford after purification using flash column chromatography [silica gel (24 g), EtOAc in hexane from 0 - 50%] (lR,3S,5R)-terf-butyl 3 -((6-bromo-3 -fluoropyridin-2- yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (317a) (180 mg, 20% yield) as a white solid; MS (ES+): 400.1/402.1(M+1).

Step-2: Preparation of (lR,3S,5R)-N-(6-bromo-3-fluoropyridin-2-yl)-2- azabicyclo[3.1.OJhexane-3-carboxamide (317b)

Compound 317b was prepared according to the procedure reported in step-2 of scheme- 1, from (lR,3S,5R)-tert-butyl 3-((6-bromo-3-fluoropyridin-2-yl)carbamoyl)-2- azabicyclo[3.1.0]hexane-2-caiboxylate (317a) (0.18 g, 0.450 mmol) in DCM (2.5 mL) using TFA (0.243 mL, 3.15 mmol). This gave after work up TFA salt of ( lR,3S,5R)-N-(6-bromo- 3-fluoropyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamid e (317b) (180 mg, 97% yield); Ή NMR (300 MHz DMSO cfc) δ 1095 (d J= 13 0 Hz 1H) 8 50 (dd J= 45 25 Hz 1H) 8.32 (d, 5.7 Hz, 1H), 4.30 - 4.18 (m, 1H), 3.41 - 3.31 (m, 1H), 2.66 - 2.57 (m, 1H), 2.34

- 2.09 (m, 1H), 1.92 - 1.70 (m, 1H), 0.92 - 0.73 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-i/e) δ -73.77, -142.14; MS (ES+): 300.0/302.0 (M+l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromo-3-fluoropyridin -2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (317c)

Compound 317c was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of (lR,3S,5R)-N-(6-bromo-3-fluoropyridin-2-yl)-2-azabicyclo[3.1 .0]hexane- 3 -carboxamide (317b) (56.7 mg, 0.137 mmol) in DMF (1.5 mL) using TFA salt of 2-(4- amino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9 -yl)acetic acid (184f) (60mg, 0.137 mmol), HATU (78 mg, 0.205 mmol), DIPEA (0.119 mL, 0.684 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-303, (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyr imido[4,5-b]indol-9- yl)acetyl)-N-(6-bromo-3-fluoropyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (317c) (47mg, 57% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-i/e) δ 10.49 (s, 1H, DzO exchangeable), 8.78 (s, 1H), 8.59 (s, 1H), 8.50 (s, 2H, DzO exchangeable), 8.37 (d, J= 2.5 Hz, 1H), 8.34 (d ,J= 5.7 Hz, 1H), 7.61 (s, 1H), 5.97 (d, J= 18.0 Hz, 1H), 5.70 (d, J= 18.0 Hz, 1H), 4.59 (dd, J= 8.9, 5.8 Hz, 1H), 4.01 - 3.89 (m, 1H), 2.78 (s, 3H), 2.42 - 2.20 (m, 2H), 2.02 - 1.86 (m, 1H), 1.15 - 1.05 (m, 1H), 0.77 - 0.68 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-i/e) δ -58.71, -142.98; MS (ES+): 606.1/608.1 (M+l); (ES-): 604.1/606.1 (M- 1); Analysis calculated for CzsHzolMuNzOz 2HzO. HC1.: C, 44.23; H, 3.71; Cl, 5.22; N, 14.44; Found: C, 44.06; H, 3.73; Cl, 4.96; N, 14.31.

Scheme 318

Preparation of ( 1 R ₁ 3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-p yrimido[4,5- b]indol-9-yl)acetyl)-N-(6-chloro-3-methylpyridin-2-yl)-2-aza bicyclo[3.1 ,0]hexane-3- carboxamide (318c)

Step-1: Preparation of ( 1R,3 S,5R)-te/7-butyl 3-((6-chloro-3-methylpyridin-2-yl)carbamoyl)- 2-azabicyclo [3.1 ,0]hexane-2-carboxylate (318a)

Compound 318a was prepared according to the procedure reported in step-1 of scheme-53, from (lR,3S,5R)-2-(terf-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane -3-carboxylic acid (259a) (0.5 g, 2.2 mmol) in DCM (15 mL) and 6-chloro-3 -methyl pyridin-2 -amine (0.314 g, 2.200 mmol; CAS # 442128-86-1) to afford after purification as described in step-1 of scheme-317 ( 1R,3 S,5R)-terf-butyl 3-((6-chloro-3-methylpyridin-2-yl)carbamoyl)-2- azabicyclo[3.1 ,0]hexane-2-carboxylate (318a) (0.46 g, 59% yield) as a white solid; MS (ES+): 352.1(M+1).

Step-2: Preparation of (lR,3S,5R)-N-(6-chloro-3-methylpyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (318b)

Compound 318b was prepared according to the procedure reported in step-2 of scheme- 1, from (lR,3S,5R)-fert-butyl 3-((6-chloro-3-methylpyridin-2-yl)carbamoyl)-2- azabicyclo[3.1 ,0]hexane-2-carboxylate (318a) (0.45 g, 1.279 mmol) in DCM (7 mL) using TFA (0.690 mL, 8.95 mmol). This gave after work up TFA salt of (lR,3S,5R)-N-(6-chloro-3- methylpyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (318b) (0.47 g); ¹ HNMR (300 MHz, DMSO-ifc) δ 10.79 (s, 1H), 9.86 (s, 1H), 9.23 (s, 1H), 7.83 (d, J= 8.0 Hz, 1H), 7.42 (d, J= 8.0 Hz, 1H), 4.34 - 4.15 (m, 1H), 3.37 - 3.26 (m, 1H), 2.68 - 2.58 (m, 1H), 2.15 (s, 3H), 2.15 - 2.05 (m, 1H), 1.95 - 1.75 (m, 1H), 0.97 - 0.78 (m, 2H); MS (ES+): 252.0 (M+l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyrimido[4,5-b]indol-9-yl)acet _\ l)-N-(6-chloro-3-methylpyridin-2-vi)-2- azabicyclo[3.1.0]hexane-3-carboxamide (318c)

Compound 318c was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of (lR,3S,5R)-N-(6-chloro-3-methylpyridin-2-yl)-2-azabicyclo[3. 1.0]hexane- 3 -carboxamide (318b) (50.1 mg, 0.137 mmol) in DMF (1.5 mL) using TFA salt of 2-(4- amino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9 -yl)acetic acid (1841) (60mg, 0.137 mmol), HATU (78 mg, 0.205 mmol), DIPEA (0.119 mL, 0.684 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-303, (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyr imido[4,5-b]indol-9- yl)acetyl)-N-(6-chloro-3-methylpyridin-2-yl)-2-azabicyclo[3. 1 ,0]hexane-3-carboxamide (318c) (19 mg, 25% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-rib) δ 10.30 (s, 1H, DzO exchangeable), 8.82 (s, 1H), 8.73 (s, 2H, DzO exchangeable), 8.65 (d, ./= 1.7 Hz, 1H), 7.71 (d, 8.0 Hz, 1H), 7.61 (d, J= 1.7 Hz, 1H), 7.30 (d, J= 7.9 Hz, 1H), 5.96 (d, J=

18.0 Hz, 1H), 5.72 (d, J= 17.9 Hz, 1H), 4.40 (dd, J= 9.2, 5.5 Hz, 1H), 3.99 - 3.88 (m, 1H), 2.76 (s, 3H), 2.42 (dd, J= 13.4, 9.3 Hz, 1H), 2.33 - 2.19 (m, 1H), 2.02 (s, 3H), 2.01 - 1.90 (m, 1H), 1.17 - 1.03 (m, 1H), 0.82 - 0.66 (m, 1H); ¹⁹ FNMR(282 MHz, DMSO) δ -58.69; MS (ES+): 558.2 (M+l); (ES-): 556.1 (M-l).

Scheme 319 Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyr imido[4,5- b]indol-9-yl)acetyl)-N-(6-chloro-3-fluoropyridin-2-yl)-2-aza bicyclo[3.1.0]hexane-3- carboxamide (319c)

Step-1: Preparation of ( lR,3S,5R)-terf-butyl 3-((6-chloro-3-fluoropyridin-2-yl)carbamoyl)-2- azabicyclo[3.1 ,0]hexane-2-carboxylate (319a)

Compound 319a was prepared according to the procedure reported in step-1 of scheme-53, from (lR,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hcxane -3-carboxylic acid (259a) (0.25 g, 1.1 mmol) and 6-chloro-3-fl uoropyridi n -2-amine (0.161 g, 1.1 mmol; CAS # 1260672-14-7) to afford after purification as described in step-1 of scheme-317 (1R,3S,5R)- tert-butyl 3-((6-chloro-3-fluoropyridin-2-yl)carbamoyl)-2-azabicyclo[3. 1 ,0]hexane-2- carboxylate (319a) (0.187 g, 48% yield) as a white solid; MS (ES+): 356.1 (M+l); 378.1 (M+Na).

Step-2: Preparation of (lR,3S,5R)-N-(6-chloro-3-fluoropyridin-2-yl)-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (319b)

Compound 319b was prepared according to the procedure reported in step-2 of scheme- 1, from (lR,3S,5R)-tert-butyl 3-((6-chloro-3-fhioropyridin-2-yl)carbamoyl)-2- azabicyclo[3.1 0]hexane-2-carboxylate (319a) (0.18 g, 0.506 mmol) in DCM (2.7 mL) using TFA (0.273 mL, 3.54 mmol). This gave after work up and purification using reverse phase column chromatography [C18 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%] TFA/HC1 salt of (lR,3S,5R)-N-(6-chloro-3-fluoropyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (319b) (0.19 g); Ή NMR (300 MHz, DMSO-cfe) δ 11.11 (s, 1H), 9.82 (s, 1H), 9.29 (s, 1H), 7.99 (t ,J= 8.9 Hz, 1H), 7.56 (dd, J= 8.6, 3.0 Hz, 1H), 4.30 - 4.23 (m, 1H), 3.38 - 3.28 (m, 1H), 2.70 - 2.56 (m, 1H), 2.15 - 2.02 (m, 1H), 1.94 - 1.71 (m, 1H), 1.04 - 0.70 (m, 2H); MS (ES+): 256.1 (M+l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-chloro-3-fluoropyridi n-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (319c)

Compound 319c was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of (lR,3S,5R)-N-(6-chloro-3-fluoropyridin-2-yl)-2-azabicyclo[3. 1.0]hexane-3- carboxamide (319b) (50.6 mg, 0.137 mmol) in DMF (1.5 mL) using TFA salt of 2-(4-amino- 8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (184f) (60mg, 0.137 mmol), HATU (78 mg, 0.205 mmol), DIPEA (0.119 mL, 0.684 mmol) and stirring at RT for 16 h This gave after workup and purification as described in scheme-303 (lR3S 5R)-2-(2- fluoropyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-caiboxamide (319c) (27 mg, 35.1 % yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-i/e) δ 10.56 (s, 1H, DzO exchangeable), 8.81 (s, 1H), 8.68 (s, 2H, DzO exchangeable), 8.64 (s, 1H), 7.86 (t ,J= 8.9 Hz, 1H), 7.60 (s, 1H), 7.43 (dd, J= 8.5, 2.9 Hz, 1H), 5.96 (d, J= 18.0 Hz, 1H), 5.70 (d, J= 17.9 Hz, 1H), 4.44 (dd, 9.3, 5.3 Hz, 1H), 3.95 - 3.90 (m, 1H), 2.76 (s, 3H), 2.42 (dd, J= 13.5, 9.4 Hz, 1H), 2.30 - 2.16 (m, 1H), 2.03 - 1.90 (m, 1H), 1.19 - 1.04 (m, 1H), 0.77 - 0.69 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO) δ -58.75, -125.59; MS (ES+): 562.2 (M+l); (ES-): 560.1 (M-l).

Scheme 320

Preparation of (2S,4R)- l-(2-(4-antino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-chloropyridin-2-yl)-4-fluoro-4-met hylpyrrolidine-2-carboxamide

(320c)

Step-1: Preparation of (2S,4R)-terf-butyl 2-(( 6-chloropyridi n -2-yl )carbamoyl )-4-fluoro-4- methylpy rrolidine- 1 -caiboxylate (320a)

Compound 320a was prepared according to the procedure reported in step-1 of scheme-53, from (2S,4R)-l-(tort-butoxycarbonyl)-4-fluoro-4-methylpyrrolidine -2-carbox>'lic acid (213a) (0.35 g, 1.415 mmol) and 6-chloropyridin-2-amine (0.182 g, 1.415 mmol; CAS # 45644-21- 1) to afford after purification as described in step-1 of scheme-317, (2S,4R)-ter/-butyl 2-((6- chloropyridin-2-yl)carbamoyl)-4-fluoro-4-methylpyrrolidine- 1 -carboxylate (320a) (0.362 g, 72% yield) as a white solid; MS (ES+): 358.2 (M+l); 380.1 (M+Na).

Step-2: Preparation of (2S,4R)-N-(6-chloropyridin-2-yl)-4-fluoro-4-methylpyrrolidin e-2- carboxamide (320b) Compound 320b was prepared according to the procedure reported in step-2 of scheme- 1, from (2S,4R)-/er/-butyl 2-((6-chloropyridin-2-yl)carbamoyl)-4-fluoro-4-methylpyrroli dine- 1 - carboxylate (320a) (0.36 g, 1.006 mmol) in DCM (5.5 mL) using TFA (0.543 mL, 7.04 mmol) to afford after work up TFA salt of (2S,4R)-N-(6-chloropyridin-2-yl)-4-fluoro-4- methylpyrrolidine-2-carboxamide (320b) (0.375 g); ΉΝΜΚ (300 MHz, DMSO-ifc) δ 11.45 (s, 1H), 9.99 (s, 1H), 9.12 (s, 1H), 8.05 (d, J= 8.2 Hz, 1H), 7.95 (t,J= 7.9 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 4.76 - 4.51 (m, 1H), 3.68 - 3.29 (m, 2H), 2.88 - 2.67 (m, 1H), 2.35 - 2.11 (m, 1H), 1.55 (dd, J= 21.3, 5.8 Hz, 3H); MS (ES+): 258.1 (M+l).

Step-3: Preparation of (2S,4R)-l-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimi do[4,5- b]indol-9-yl)acetyl)-N-(6-chloropyridin-2-yl)-4-fluoro-4-met hylpyrrolidine-2-carboxamide

(320c)

Compound 320c was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of (2S,4R)-N-(6-chloropyridin-2-yl)-4-fluoro-4-methylpyrrolidin e-2- carboxamide (320b) (50.9 mg, 0.137 mmol) in DMF (1.5 mL) using TFA salt of 2-(4-amino- 8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (184f) (60 mg, 0.137 mmol), HATU (78 mg, 0.205 mmol), DIPEA (0.119 mL, 0.684 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-303, (2S,4R)-l-(2-(4- amino-8-methyl-6-(trifhioromethyl)-9H-pyrimido[4,5-b]indol-9 -yl)acetyl)-N-(6- chloropyridin-2-yl)-4-fluoro-4-methylpyrrolidine-2-carboxami de (320c) (46mg, 60% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfe) (a mixture of two rotamers) δ 11.34 and 11.00 (2s, 1H, DzO exchangeable), 8.76 (s, 1H), 8.57 (s, 1H), 8.45 (s, 2H, DzO exchangeable), 8.16 and 7.97 (2d, J= 8.2 Hz, 1H), 7.82 (t, J= 8.0 Hz, 1H), 7.58 (s, 1H), 7.30 and 7.19 (2d, J= 7.7 Hz, 1H), 5.76 (d, 18.0 Hz, 1H), 5.54 (d, J= 17.9 Hz, 1H), 4.68 (t, J

= 8.6 Hz, 1H), 4.28 (dd, J= 18.0, 12.0 Hz, 1H), 3.88 (dd, J= 35.2, 12.0 Hz, 1H), 2.75 (s,

3H), 2.62-2.54 (m, 1H), 2.23 - 1.94 (m, 1H), 1.63 (d, J= 21.1 Hz, 3H); ¹⁹ FNMR (282 MHz, DMSO-ifc) δ -58.71, -139.94; MS (ES+): 564.2 (M+l); (ES-): 562.1 (M-l); Analysis calculated for CZ5HZZC1F4N ₇ OZ2HZO. 0.9HC1.: C, 47.45; H, 4.28; Cl, 10.65; N, 15.49; Found: C, 47.18; H, 3.93; Cl, 10.40; N, 15.20.

Scheme 321

321d

Preparation of (2S,4R)- l-(2-(4-antino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyrazin-2-yl)-4-fluoropyrroli dine-2-cafboxamide (321 d) Step-1: Preparation of (2S,4R)-te/f-butyl 2-((6-bromopyrazin-2-yl)carbamoyl)-4- fluoropyrrolidine- 1 -caiboxylate (321b)

Compound 321b was prepared according to the procedure reported in step-1 of scheme-53, from (2S,4R)-l-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carbox ylic acid (321a) (0.5 g, 2.144 mmol; CAS # 203866-14-2) and 6-bromopyrazin-2-amine (0.373 g, 2.144 mmol; CAS # 54237-53-5) to afford after purification as described in step-1 of scheme-317, (2S,4R)-terf- butyl 2-((6-bromopyrazin-2-y l)carbamoyl)-4-fluoropyrrolidine- 1 -caiboxylate (321b) (0.452 g, 54% yield) as a white solid; MS (ES+): 389.1/391.1(M+1).

Step-2: Preparation of (2S,4R)-N-(6-bromopyrazin-2-yl)-4-fluoropyrrolidine-2-carbox amide (321c)

Compound 321c was prepared according to the procedure reported in step-2 of scheme- 1, from (2S,4R)-tert-butyl 2-((6-bromopyrazin-2-yl)carbamoyl)-4-fluoropyrrolidine- 1 - caiboxylate (321b) (0.45 g, 1.156 mmol) in DCM (6 mL) using TFA (0.624 mL, 8.09 mmol) to afford after work up TFA salt of (2S,4R)-N-(6-bromopyrazin-2-yl)-4-fluoropyrrolidine-2- carboxamide (321c) (0.569 g); ‘HNMR (300 MHz, DMSO-flk) 5 11.80 (s, 1H), 9.30 (s, 1H), 8.67 (s, 1H), 5.65 - 5.37 (m, 1H), 4.66 (dd, J= 10.8, 7.4 Hz, 1H), 3.71 - 3.47 (m, 2H), 2.88 - 2.66 (m, 1H), 2.44 - 2.18 (m, 1H); MS (ES+): 289.0/290.9 (M+l).

Step-3: Preparation of (2S,4R)-l-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimi do[4,5- Compound 321 d was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of (2S,4R)-N-(6-bromopyrazin-2-yl)-4-fluoropyrrolidine-2-carbox amide (321c) (70.8 mg, 0.137 mmol) in DMF (1.5 mL) using TFA salt of 2-(4-amino-8-methyl-6- (trifluoromethy 1 )-9H-pyrimido [4,5 -b] indol -9-yl)acetic acid (184f) (60 mg, 0.137 mmol), HATU (78 mg, 0.205 mmol), DIPEA (0.119 mL, 0.684 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-303, (2S,4R)-l-(2-(4-amino- 8-me1hyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)ac etyl)-N-(6-bromopyrazin-2- yl)-4-fluoropyrrolidine-2-carboxamide (321 d) (45 mg, 55% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-tife) (a mixture of two rotamers) δ 11.69 and 11.39 (2s, 1H, D2O exchangeable), 9.40 and 9.22 (2s, 1H), 8.77 (s, 1H), 8.65 and 8.58 (2s, 1H), 8.54 (s, 1H), 8.48 (s, 2H, D2O exchangeable), 7.59 (s, 1H), 6.00 - 5.45 (m, 3H), 4.70 (t, J= 8.5 Hz, 1H), 4.33 (dd, J= 21.4, 12.6 Hz, 1H), 4.15 - 3.88 (m, 1H), 2.75 (s, 3H), 2.67 - 2.57 (m, 1H), 2.38 - 2.07 (m, 1H); ¹⁹ FNMR(282 MHz, DMSO-de) δ -58.72, -176.42; MS (ES+): 595.1/597.1 (M+l); (ES-): 593.1/595.1 (M-l); Analysis calculated for CzsHislMuNsOa 1 JSHzO. HC1.:

C, 41.65; H, 3.57; Cl, 5.34; N, 16.89; Found: C, 41.92; H, 3.47; Cl, 5.35; N, 16.51.

Scheme 322

Preparation of ( lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyri mido[4,5- bJindol-9-yl)acetyl)-N-(6-bromo-5-fluoro-3-methylpyridin-2-y l)-2-azabicyclo[3. l.Ojhexane- 3 -carboxamide (322c)

Step-1: Preparation of ( 1 R,3 S,5R)-terf-butyl 3-((6-bromo-5-fluoro-3-methylpyridin-2- yl)carbamoyl)-2-azabicyclo[3.1 ,0]hexane-2-carboxylate (322a)

Compound 322a was prepared according to the procedure reported in step-1 of scheme-53, (259a) (0.322 g, 1.415 mmol) in DCM (12 mL) and 6-bromo-5-fluoro-3-methylpyridin-2- amine (0.290 g, 1.415 mmol; CAS # 2086189-45-7) to afford after purification as described in step-1 of scheme-317, (lR,3S,5R)-ft?rr-butyl 3 -((6-bromo-5 -fluoro-3 -methylpyridin-2- yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-caiboxylate (322a) (0.463 g, 79% yield) as a white solid; MS (ES+): 414.1/416.1(M+1).

Step-2: Preparation of (lR,3S,5R)-N-(6-bromo-5-fluoro-3-methylpyridin-2-yl)-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (322b)

Compound 322b was prepared according to the procedure reported in step-2 of scheme- 1, from (lR,3S,5R)-te/7-butyl 3-((6-bromo-5-fluoro-3-methylpyridin-2-yl)carbamoyl)-2- azabicyclo[3.1 0]hexane-2-carboxylate (322a) (0.46 g, 1.110 mmol) in DCM (6 mL) using TFA (0.599 mL, 7.77 mmol) to afford after purification as described in step-2 of scheme-319 TFA salt of (lR,3S,5R)-N-(6-bromo-5-fluoro-3-methylpyridin-2-yl)-2- azabicyclo[3.1.OJhexane-3-carboxamide (322b) (0.54 g, 100% yield); Ή NMR (300 MHz, OMSO-ck ) δ 10.81 (s, 1H), 9.88 (s, 1H), 9.21 (s, 1H), 7.93 (d, J= 8.4 Hz, 1H), 4.48 - 3.96 (m, 1H), 3.46 - 3.19 (m, 1H), 2.67 - 2.54 (m, 1H), 2.23 - 2.05 (m, 4H), 1.91 - 1.80 (m, 1H), 1.02 - 0.87 (m, 1H), 0.88 - 0.74 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-cfe) δ -74.31, -117.92; MS (ES+): 314.0/316.0 (M+l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromo-5-fluoro-3-meth ylpyridin-2-yl)-2- azabicyclo[3.1.OJhexane-3-carboxamide (322c)

Compound 322c was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of (lR,3S,5R)-N-(6-bromo-5-fluoro-3-methylpyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (322b) (66.4 mg, 0.137 mmol) in DMF (1.5 mL) using TFA salt of 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]in dol-9- yl)acetic acid (184f) (60 mg, 0.137 mmol), HATU (78 mg, 0.205 mmol), DIPEA (0.119 mL, 0.684 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-303, (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyr imido[4,5- b]indol-9-yl)acetyl)-N-(6-bromo-5-fluoro-3-methylpyridin-2-y l)-2-azabicyclo[3.1.OJhexane- 3-carboxamide (322c) (45 mg, 55% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfe) δ 10.34 (s, 1H, DzO exchangeable), 8.80 (s, 1H), 8.60 (s, 1H), 8.56 (s, 2H, DzO exchangeable), 7.82 (d, J = 8.4 Hz, 1H), 7.59 (s, 1H), 5.94 (d, J= 18.0 Hz, 1H), 5.71 (d,J= 17.9 Hz, 1H), 4.37 (dd, J= 9.2, 5.5 Hz, 1H), 3.97 - 3.86 (m, 1H), 2.75 (s, 3H), 2.42 (dd, J= 134 94 Hz 1H) 233 - 2 17 (m 1H) 202 (s 3H) 200 - 1 88 (m 1H) 1 21 - 1 05 (m 620.1/622.1 (M+l); (ES-): 618.0/620.0 (M-l); Analysis calculated for C26H22BrF4N7O2.H2O.HCl: C, 46.27; H, 3.73; Cl, 5.25; N, 14.53; Found: C, 46.1; H, 4.02; Cl, 5.16; N, 14.25.

Scheme 323

F,

F*J H ,Br

N N.

HN H

CC½H N i\ rV α> N A O

Me

Me 209a * N¾ y*

HATU, DIPEA

NH ₂ r>

CF ₃ CF

NH _{2 3}

184f 323a

Preparation of (2S,4R)-l-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimi do[4,5- b]indol-9-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-4-fluo ro-4-methylpyrrolidme-2- carboxamide (323a)

Compound 323a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]in dol-9- yl)acetic acid (184f) (60 mg, 0.137 mmol) in DMF (1.5 mL) using HC1 salt of (2S,4R)-N-(6- bromo-3-methylpyridin-2-yl)-4-fluoro-4-methylpyrroUdme-2-car boxamide (209a) (48.3 mg, 0.137 mmol), HATU (78 mg, 0.205 mmol), DiPEA (0.119 mL, 0.684 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-303, (2S,4R)-1- (2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]i ndol-9-yl)acetyl)-N-(6-bromo- 3-methylpyridin-2-yl)-4-fluoro-4-methylpyrrolidine-2-carboxa mide (323a) (45 mg, 53% yield) HC1 salt as a white solid; *H NMR (300 MHz, DMSO-de) (a mixture of two retainers) δ 10.83 and 10.50 (2s, 1H, D ₂ 0 exchangeable), 8.72 (s, 1H), 8.48 and 8.46 (2s, 1H), 8.14 (s, 2H, DzO exchangeable), 7.73 and, 7.59 (2d, J= 8.0 Hz, 1H), 7.55 and 7.51 (2s, 1H), 7.41 (d, J= 7.9 Hz, 1H), 5.74 (d,J= 18.0 Hz, 1H), 5.49 (d, J= 17.9 Hz, 1H), 4.62 (dd,J= 9.8, 7.5 Hz, 1H), 4.27 (dd,J= 18.1, 12.0 Hz, 1H), 3.89 (dd,J= 35.2, 12.0 Hz, 1H), 2.71 (s, 3H), 2.61 - 2.54 (m, 1H), 2.21 - 2.00 (m, 1H), 1.95 (s, 3H), 1.65 (d, J= 21.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-cfc) δ -58.59, -139.97. MS (ES+): 622.1/624.1(M+1); (ES-): 620.1/622.1 (M- 1).; Analysis calculated for C26H24BrF4N ₇ 02.1 JSH-OHCl: C, 45.23; H, 4.16; Cl, 5.14; N, 14.20; Found: C, 45.34; H, 4.07; Cl, 4.99; N, 14.15

Scheme 324 / — S H N~V'^

HN-C H ^r coaH o ^Γ^" ^ΒΓ

N N Me W O

171a

N \ N; _Λ Me

N. /

HATU, DIPEA

NH ₂ N--/

CF _a r>

CF

NH _{2 3}

324a

184f

Preparation of (S)-3-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4 ,5-b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yI)thiazolidine-2-carboxamide (324a)

Compound 324a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]in dol-9- yl)acetic acid (184f) (60 mg, 0.137 mmol) in DMF (1.5 mL) using TFA salt of (S)-N-(6- bromopyridin-2-yl)thiazolidine-2-carboxamide (171a) (55.1 mg, 0.137 mmol), HATU (78 mg, 0.205 mmol), DIPEA (0.119 mL, 0.684 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-303, (S)-3-(2-(4-amino-8-methyl-6- (trifhxoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6- bromopyridin-2-yl)thiazolidine- 2-carboxamide (324a)(75 mg, 92% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-flfe) (a mixture of two rotamers) δ 11.30and 11.08 (2s, 1H, D2O exchangeable), 8.78 (s, 1H), 8.59 (s, 1H), 8.51 (s, 2H, DzO exchangeable), 8.07and 7.97 (2d, J= 8.2 Hz, 1H), 7.82 and 7.74 (2t, J= 8.0 Hz, 1H), 7.59 (s, 1H), 7.42 and 7.35 (2d, J= 7.7 Hz, 1H), 5.86 - 5.54 (m, 3H), 4.42 - 4.28 (m, 1H), 4.18 - 4.05 (m, 1H), 3.44 - 3.31 (m, 2H), 2.75 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-fife) δ -58.74; MS (ES+): 594.1/596.1 (M+l); (ES-): 592.0/594.0 (M-l); Analysis calculated for C23Hi9BrF ₃ N702S.1.25H20.1.15HCl: C, 41.93; H, 3.47; Cl, 6.19; N, 14.88; Found: C, 41.81; H, 3.38; Cl, 5.92; N, 14.71.

Scheme 325

325c

Preparation of (2S,4R)-l-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimi do[4,5- b]indoI-9-yl)acetyl)-N-(6-chloropyrazin-2-yl)-4-fluoropyrrol idine-2-carboxamide (325c) Step-1: Preparation of (2S,4R)-fer/-butyl 2-((6-chloropyrazin-2-yl)carbamoyl)-4- fluoropyrrolidine- 1 -carboxylate (325a)

Compound 325a was prepared according to the procedure reported in step-1 of scheme-53, from (2S,4R)-l-(/£Tf-butoxycarbonyl)-4-fluoropyrrolidine-2-carbo xylic acid (321a) (0.466 g, 2 mmol) in DCM (15 mL) and 6-chloropyrazin-2-amine (0.259 g, 2.00 mmol; CAS # 33332- 28-4) to afford after purification as described in step-1 of scheme-317, (2S,4R)-/ei7-butyl 2- ((6-chloropyrazin-2-yl)carbamoyl)-4-fluoropyrrolidine- 1 -carboxylate (325a) (0.36 g, 52% yield) as a clear gel; MS (ES+): 345.1(M+1).

Step-2: Preparation of (2S,4R)-N-(6-chloropyrazin-2-yl)-4-fluoropyrrolidine-2-carbo xamide (325b)

Compound 325b was prepared according to the procedure reported in step-2 of scheme- 1, from (2S,4R)-tert-butyl 2-((6-chloropyrazin-2-yl)carbamoyl)-4-fluoropyTrolidine- 1 - carboxylate (325a) (0.35 g, 1.015 mmol) in DCM (5.5 mL) using TFA (0.547 mL, 7.11 mmol) to afford after purification as described in step-2 of scheme-319, HC1 salt of (2S,4R)- N-(6-chloropyrazin-2-yl)-4-fluoropyrrolidine-2 -carboxamide (325b) (0.220 g, 77% yield); Ή NMR (300 MHz, DMSO-de) δ 11.77 (s, 1H), 9.29 (s, 1H), 8.62 (s, 1H), 5.51 (d, J= 52.4 Hz, 1H), 4.64 (dd, J= 10.9, 7.3 Hz, 1H), 3.67 - 3.61 (m, 1H), 3.59 - 3.47 (m, 1H), 2.93 - 2.67 (m, 1H), 2.45 - 2.17 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-i/e) δ -175.30; MS (ES+): 245.0 (M+l).

Step-3: Preparation of (2S,4R)-l-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimi do[4,5- b]indol-9-yl)acetyl)-N-(6-chloropyrazin-2-yl)-4-fluoropyrrol idine-2-carboxamide (325c)

Compound 325c was prepared according to the procedure reported in step-3 of scheme- 1, from HC1 salt of (2S,4R)-N-(6-chloropyrazin-2-yl)-4-fluoropyrrolidine-2-carbo xamide (325b) (38.5 mg, 0.137 mmol) in DMF (1.5 mL) using TFA salt of 2-(4-amino-8-methyl-6- (trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (184f) (60 mg, 0.137 mmol), HATU (78 mg, 0.205 mmol), DIPEA (0.119 mL, 0.684 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-303, (2S,4R)-l-(2-(4-amino- 8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)ac etyl)-N-(6-chloropyrazin-2- yl)-4-fhioropyrrohdine-2-carboxamide (325c) (69 mg, 91% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-i/e) (a mixture of two rotamers) δ 11.68 and 11.37 (2s, 1H, DzO exchangeable), 9.38 and 9.21 (2s, 1H), 8.78 (s, 1H), 8.67 - 8.50 (m, 3H, 2H DzO exchangeable), 8.48 (s, 1H), 7.60 (s, 1H), 5.93 - 5.46 (m, 3H), 4.70 (t, J= 8.5 Hz, 1H), 4.34 (dd, J= 21.4, 12.6 Hz, 1H), 4.01 (dd, J= 38.1, 12.5 Hz, 1H), 2.75 (s, 3H), 2.64 - 2.55 (m, 1H), 2.35 - 2.06 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-tife) δ -58.74, -176.51. MS (ES+): 551.2 (M+l); (ES-): 549.1 (M-l); Analysis calculated for CuHuCIFiNsOz 1.75 HzO. 0.85HC1.: C, 45.03; H, 3.84; Cl, 10.69; N, 18.27; Found: C, 45.06; H, 3.84; Cl, 10.59; N, 18.07.

Scheme 326

326b 326c

Preparation of ( lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyri mido[4,5- b]indol-9-yl)acetyl)-N-(6-chloropyrazin-2-yl)-2-azabicyclo[3 .1 ,0]hexane-3-carboxamide (326c)

Step-1: Preparation of ( 1 R,3 S,5R)-tert-butyl 3-((6-chloropyrazin-2-yI)carbamoyl)-2- azabicyclo[3.1 ,0]hexane-2-carboxylate (326a)

Compound 326a was prepared according to the procedure reported in step-1 of scheme-53, from ( 1 R,3 S,5R)-2-(/er/-butoxycarbonyl)-2-azabicyclo[3.1 ,0]hexane-3-carboxylic acid (259a) (0.455 g, 2 mmol) and 6-chloropyrazin-2-amine (0.259 g, 2 mmol; CAS # 33332-28- 4) to afford after purification as described in step-1 of scheme-317 ( 1R,3 S,5R)-/erf-butyl 3- ((6-chloropyrazin-2-yl)carbamoyl)-2-azabicyclo[3.1.Ojhexane- 2-carboxylate (326a) (0.245 g, 36% yield) as a clear gel; MS (ES+): 339.1 (M+l).

Step-2: Preparation of (1 R,3S,5R)-N-(6-chloropyrazin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3- carboxamide (326b)

Compound 326b was prepared according to the procedure reported in step-2 of scheme- 1 , from ( 1 R,3S,5R)-te/t-butyl 3-((6-chloropyrazin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan e- 2-carboxylate (326a) (0.24 g, 0.708 mmol) in DCM (4 mL) using TFA (0.382 mL, 4.96 mmol) to afford after purification as described in step-2 of scheme-319, (lR,3S,5R)-N-(6- chloropyraan-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (326b) (0.14 g, 72% yield) HCl salt; ¾NMR(300 MHz, DMSO-ffc) δ 11.66 (s, 1H), 9.26 (s, 1H), 8.61 (s, 1H), 4.21 (dd, J= 10.9, 7.8 Hz, 1H), 3.32 - 3.26 (m, 1H), 2.62 (dd, J= 12.8, 7.8 Hz, 1H), 2.22 - 1.99 (m, Step-3: Preparation of ( 1 R,3 S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-chloropyrazin-2-yl)-2 -azabicyclo[3.1.0] hexane-3 - carboxamide (326c)

Compound 326c was prepared according to the procedure reported in step-3 of scheme- 1, from HC1 salt of (lR,3S,5R)-N-(6-chloropyrazin-2-yl)-2-azabicyclo[3.1.0]hexan e-3- carboxamide (326b) (37.7 mg, 0.137 mmol) in DMF (1.5 mL) using TFA salt of 2-(4-amino- 8-me1hyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (184f) (60 mg, 0.137 mmol), HATU (78 mg, 0.205 mmol), DIPEA (0.119 mL, 0.684 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-303, (lR,3S,5R)-2-(2- (4-amino-8-methyl-6-(trifluoromcthyl)-9H-pyrimido[4,5-b]indo l-9-yl)acety])-N-(6- chloropyrazin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (326c) (67 mg, 90 % yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-c/e) δ 11.19 (s, 1H, D ₂ 0 exchangeable), 9.23 (s, 1H), 8.79 (s, 1H), 8.63 (s, 3H, 2H DzO exchangeable), 8.48 (s, 1H), 7.62 (s, 1H), 5.99 (d, J= 18.0 Hz, 1H), 5.71 (d, J= 18.0 Hz, 1H), 4.46 (dd,J= 9.1, 5.7 Hz, 1H), 4.03 - 3.80 (m, 1H), 2.78 (s, 3H), 2.38 (dd,J= 13.5, 9.2 Hz, 1H), 2.32 - 2.18 (m, 1H), 2.02 - 1.87 (m, 1H), 1.21 - 1.01 (m, 1H), 0.78 - 0.67 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-cfe) δ -58.76; MS (ES+): 545.2 (M+l); (ES-): 543.1 (M-l); Analysis calculated for C24H20CIF3N8O2.2H2O. 0.75HC1.: C, 47.39; H, 4.10; Cl, 10.20; N, 18.42; Found: C, 47.57; H, 3.92; Cl, 10.02; N, 18.31.

Scheme 327 Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyr imido[4,5- b]indol-9-yl)acetyl)-N-(6-diloropyrazin-2-yl)-5-methyl-2-aza bicyclo[3.1.0]hexane-3- carboxamide (327c)

Step-1: Preparation of ( lR,3S,5R)-terf-butyl 3-((6-chloropyrazin-2-\i)carbamo\i)-5-methyl- 2-azabicyclo[3.1 ,0]hexane-2-carboxylate (327a)

Compound 327a was prepared according to the procedure reported in step-1 of scheme-53, from ( 1 R, 3 S,5 R)-2-(tert-butoxycarbonyl)-5 -methyl -2-azabicyclo [3.1 ,0]hexane-3-carboxylic acid (261a) (0.483 g, 2 mmol) and 6-chloropyrazin-2-amine (0.259 g, 2 mmol) to afford after purification as described in step-1 of scheme-317, ( 1 R,3 S, 5 R)-te/†-buty 13-((6-chloropyrazin-

2-yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexane-2-carb oxylate (327a) (0.091 g, 13% yield) as a clear gel; MS (ES+): 353.1 (M+l).

Step-2: Preparation of (lR,3S,5R)-N-(6-chloropyrazin-2-yl)-5-methyl-2- azabicyclo[3.1.OJhexane-3-carboxamide (327b)

Compound 327b was prepared according to the procedure reported in step-2 of scheme- 1, from (lR,3S,5R)-terf-butyl 3-((6-chloropyrazin-2-yl)carbamoyl)-5-methyl-2- azabicyclo[3.1.0]hexane-2-carboxylate (327a)(0.085 g, 0.241 mmol) in DCM (1.5 mL) using TFA (0.130 mL, 1.686 mmol) to afford after purification as described in step-2 of scheme- 319, (1 R,3S,5R)-N-(6-chloropyrazin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3- carboxamide (327b) (0.055 g, 79% yield) HC1 salt; Ή NMR (300 MHz, DMSO-tife) δ 11.68 (s, 1H), 9.26 (s, 1H), 8.61 (s, 1H), 4.24 (dd, J= 11.1, 7.7 Hz, 1H), 3.10 (dd, J= 6.9, 2.4 Hz, 1H), 2.74 - 2.60 (m, 1H), 2.00 (t, J= 11.8 Hz, 1H), 1.26 (s, 3H), 1.03 (dd, J= 7.2, 2.5 Hz, 1H), 0.79 (t, J= 7.0 Hz, 1H); MS (ES+): 253.1 (M+l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyrimido[4,5-b]indol-9-yl)acet>l)-N-(6-chloropyrazin-2-yl )-5-methyl-2- azabicyclo[3.1.0]hexane-3-carboxamide (327c)

Compound 327c was prepared according to the procedure reported in step-3 of scheme- 1, from HC1 salt of (lR,3S,5R)-N-(6-chloropyrazin-2-yl)-5-methyl-2-azabicyclo[3. 1.0]hexane-

3-carboxamide (327b) (39.6 mg, 0.137 mmol) in DMF (1.5 mL) using TFA salt of 2-(4- amino-8-methvi-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9 -yl)acetic acid (184f) (60 mg, 0.137 mmol), HATU (78 mg, 0.205 mmol), DIPEA (0.119 mL, 0.684 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-303, (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifhioromethyl)-9H-pyr imido[4,5-b]indol-9- yl)acetyl)-N-(6-chloropyrazin-2-yl)-5-methyl-2-azabicyclo[3 1 0]hexane-3-carboxamide (s, 1H, DzO exchangeable), 9.23 (s, 1H), 8.78 (s, 1H), 8.60 (s, 1H), 8.53 (s, 2H, DzO exchangeable), 8.48 (s, 1H), 7.60 (s, 1H), 5.93 (d, J= 18.0 Hz, 1H), 5.66 (d, J= 17.9 Hz,

1H), 4.41 (dd,J= 9.1, 6.1 Hz, 1H), 3.73 (dd,J= 5.5, 2.3 Hz, 1H), 2.76 (s, 3H), 2.56 - 2.52 (m, 1H), 2.03 (dd, ./= 13.3, 6.0 Hz, 1H), 1.32 (s, 3H), 1.08 - 0.99 (m, 1H), 0.92 - 0.83 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-t/e) δ -58.73; MS (ES+): 559.1 (M+l); (ES-): 557.1 (M-l); Analysis calculated for C25H22CIF3N8O22.25H20. 0.75HC1.: C, 47.90; H, 4.38; Cl, 9.90; N, 17.88; Found: C, 47.92; H, 4.18; Cl, 9.91; N, 17.77.

Scheme 328

Preparation of (lR,3S,5R)-2-(2-(4-amino-7-methoxy-6-methyl-9H-pyrimido[4,5- b]indol-9- yl)acet}'l)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (328f)

Step-1: Preparation of 2-amino-6-methoxy-5 -methyl- 1 H-indole-3 -carbonitrile (328b) Compound 328b was prepared according to the procedure reported in step-1 of scheme- 11, from N-(2-bromo-5-methoxy-4-methylphenyl)-2,2,2-trifluoroacetamid e (328a) (7.4 g, 23.71 mmol; CAS # 1262881-27-5) in DMSO (30 mL) using malononitrile (1.792 mL, 28.5 mmol), L-proline (0.546 g, 4.74 mmol), Cul (452 mg, 2.371 mmol), a solution of K2CO3 (6.55 g,

47.4 mmol) in water (30 mL) and heating at 60 °C for 16 h under an argon atmosphere. This gave after workup and purification [SiCkgel (80 g), EtOAc/methanol (9: 1) in hexane from 0 - 50%] 2-amino-6-methoxy-5-methyl-lH-indole-3-carbonitrile (328b) (1.95 g, 41% yield) as a grey solid; ^! HNMR (300 MHz, DMSO-ife) δ 10.43 (s, 1H), 6.89 (s, 1H), 6.75 (s, 1H), 6.49 (s, 2H), 3.73 (s, 3H), 2.21 - 2.07 (m, 3H); MS (ES+): 202.1 (M+l); (ES-): 200.1 (M-l). Step-2: Preparation of 7-methoxy-6-methyl-9H-pyrimido[4,5-b]indol-4-amine (328c) Compound 328c was prepared according to the procedure reported in step-2 of scheme-29, ethanol (60 mL) using foimamidine acetate (7.94 g, 76 mmol) to afford after workup AcOH salt of 7-methoxy-6-methyl-9H-pyrimido[4,5-b]indol-4-amine (328c) (2.72 g, 81% yield) as a pale-yellow solid; Ή NMR (300 MHz, DMSO-i/e) δ 8.53 (s, 1H), 8.45 (s, 1H), 8.32 (s, 1H), 7.46 (s, 1H), 5.29 (s, 2H), 3.92 (s, 3H), 2.32 (s, 3H); MS (ES+): 229.1 (M+l).

Step-3: Preparation of te/7-butyl 2-(4-amino-7-methoxy-6-methyl-9H-pyrimido[4,5-b]indol- 9-yl)acetate (328d)

To a mixture of 7-methoxy-6-metbyl-9H-pyrimido[4,5-b]indol-4-amine (328c) AcOH salt (2 g, 6.94 mmol) in DMF (50 mL) was added cesium carbonate (6.78 g, 20.81 mmol) at 0 °C under N2 and stirred at the same temperature for 20 min. To this mixture was added terl- butyl 2-bromoacetate (1.128 mL, 7.63 mmol) and allowed to RT over a period of 16 h at RT. The reaction mixture was quenched by adding water. The solid separated was filtered and purified by reverse phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0 - 100%] to afford tert-butyl 2-(4-amino-7-methoxy-6- methyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (328d) (0.2g, 8% yield) as a pale yellow solid; Ή NMR (300 MHz, DMSO-cfc) δ 8.24 (s, 1H), 8.15 (s, 1H), 7.19 (s, 3H), 5.12 (s, 2H), 3.88 (s, 3H), 2.29 (s, 3H), 1.41 (s, 9H); MS (ES+): 343.2 (M+l).

Step-4: Preparation of 2-(4-amino-7-methoxy-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)a cetic acid (328e)

Compound 328e was prepared according to the procedure reported in step-2 of scheme- 1, from /erf-butyl 2-(4-amino-7-methoxy-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)a cetate (328d) (0.19 g, 0.555 mmol) using 20% TFA in DCM (3.18 mL, 8.32 mmol) to afford the TFA salt of 2-(4-amino-7-methoxy-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)a cetic acid (328e) (285 mg) as a pale-yellow solid; Ή NMR (300 MHz, DMSO-cfe) δ 8.53 (s, 1H), 8.45 (s, 1H), 8.32 (s, 1H), 7.46 (s, 1H), 5.29 (s, 2H), 3.92 (s, 3H), 2.32 (s, 3H); MS (ES+): 287.10 (M+l).

Step-5: Preparation of (lR,3S,5R)-2-(2-(4-amino-7-methoxy-6-methyl-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1.0]hexane-3-carboxamide

(328f)

Compound 328f was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-7 -methoxy-6-methyl-9H-pyrimido [4,5 -b] indol-9-y l)acetic acid (328e) (81 mg, 0.157 mmol) in DMF (2 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (50mg, 0.157 mmol), HATU (90 mg 0235 mmol) DIPEA (0 137 mL 0785 mmol) and stirring at RT for 16 h This gave after workup and purification as described in scheme-303, (lR,3S,5R)-2-(2-(4- amino-7-methox _} '-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-b romopyridin-2-yl)- 2-azabicyclo[3.1.0]hexane-3-carboxamide (328f) (51 mg, 59% yield) HC1 salt as a white solid; ^! HNMR (300 MHz, DMSO-ifc) δ 10.73 (s, 1H, DzO exchangeable), 8.54 (s, 1H), 8.43 (s, 2H, D2O exchangeable), 8.31 (s, 1H), 8.01 (d, J= 8.2 Hz, 1H), 7.72 (t 8.0 Hz, 1H), 7.33 (d, J= 7.7 Hz, 1H), 7.25 (s, 1H), 5.71 (d, J= 17.2 Hz, 1H), 5.46 (d, J= 17.2 Hz, 1H), 4.41 (dd, J= 9.1, 5.6 Hz, 1H), 4.00 - 3.86 (m, 4H), 2.46 - 2.12 (m, 5H), 2.00 - 1.88 (m, 1H), 1.12 - 1.01 (m, 1H), 0.79 - 0.65 (m, 1H). MS (ES+): 550.1/552.1 (M+l); (ES-): 548.1/550.1 (M-l); Analysis calculated for C25H24BrN ₇ 03 2H ₂ 0. HCL: C, 48.20; H, 4.69; Cl, 5.69; N, 15.74; Found: C, 48.19; H, 4.35; Cl, 5.70; N, 15.69.

Scheme 329

328e 329a

Preparation of ( lR,3S,5R)-2-(2-(4-amino-7-methoxy-6-methyl-9H-pyrirnido[4,5- b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (329a)

Compound 329a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-7-methoxy-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)a cetic acid (328e) (81 mg, 0.157 mmol) in DMF (2 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.OJhexane-3-carb oxamide (8a) (52.2 mg, 0.157 mmol), HATU (90 mg, 0.236 mmol), DIPEA (0.137 mL, 0.785 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-303, (lR,3S,5R)-2-(2- (4-amino-7-methoxy-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)ace tyl)-N-(6-bromopyridin-2- yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (329a) (56 mg, 63% yield) HC1 salt as a white solid; ^! HNMR (300 MHz, DMSO-tife) δ 10.72 (s, 1H, DzO exchangeable), 8.53 (s, 1H), 8.40 (s, 2H, D2O exchangeable), 8.30 (s, 1H), 8.02 (d,J= 8.2 Hz, 1H), 7.72 (t ,J= 8.0 Hz, 1H), 4.37 (dd, J= 9.1, 6.1 Hz, 1H), 3.92 (s, 3H), 3.70 (dd, J= 5.6, 2.3 Hz, 1H), 2.50 - 2.43 (m, 1H), 2.30 (s, 3H), 2.00 (dd, J= 13.2, 6.0 Hz, 1H), 1.32 (s, 3H), 1.10 - 0.97 (m, 1H), 0.97 - 0.82 (m, 1H); MS (ES+): 564.1/566.1 (M+l); (ES-): 562.1/564.0 (M-l); Analysis calculated for CaJfceBrNrOs 1.75H20. 1.15HCL: C, 48.95; H, 4.84; Cl, 6.39; N, 15.37; Found: C, 48.93; H, 4.87; Cl, 6.37; N, 15.47.

Scheme 330

Preparation of (lR,3S,5R)-2-(2-(4-amino-7-fluoro-6-methoxy-9H-pyrimido[4,5- b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (330f)

Step-1: Preparation of 2-amino-6-fluoro-5-methoxy-lH-indole-3-carbonitrile (330b) Compound 330b was prepared according to the procedure reported in step-1 of scheme- 11, from N-(2-bromo-5-fluoro-4-methoxyphenyl)-2,2,2-trifluoroacetamid e (330a) (3.5 g, 11.07 mmol; CAS # 1262881-29-7) in DMSO (15mL) using malononitrile (0.837 mL, 13.29 mmol), L-proline (0.255 g, 2.215 mmol), Cul (211 mg, 1.107 mmol), a solution of K2CO3 (3.06 g, 22.15 mmol) in water (15 mL) to afford after workup and purification as described in step-1 of scheme-328, 2-amino-6-fluoro-5-methoxy-lH-indole-3-carbonitrile (330b)(0.95 g, 42% yield) as a yellow solid; MS (ES+): 206.1 (M+l); (ES-): 204.0 (M-l).

Step-2: Preparation of 7-fluoro-6-methoxy-9H-pyrimido[4,5-b]indol-4-amine (330c) Compound 330c was prepared according to tire procedure reported in step-2 of scheme-29, from 2-amino-6-fluoro-5-methoxy-lH-indole-3-carbonitrile (330b) (0.9 g, 4.39 mmol) in ethanol (30 mL) using formamidine acetate (3.69 g, 35.1 mmol) to afford after workup AcOH salt of 7-fluoro-6-methoxy-9H-pyrimido[45-b]indol-4-amme (330c) (098 g 85% yield) as a pale-yellow solid; Ή NMR (300 MHz, DMSO -de) δ 11.74 (s, 1H), 8.20 (s, 1H), 8.04 (d,J= 8.4 Hz, 1H), 7.35 - 7.16 (m, 3H), 3.93 (s, 3H); MS (ES+): 233.1 (M+l).

Step-3: Preparation of tort-butyl 2-(4-amino-7-fluoro-6-methoxy-9H-pyrimido[4,5-b]indol- 9-yl)acetate (330d)

Compound 330d was prepared according to the procedure reported in step-1 of scheme-1/ step-3 of scheme-328, from AcOH salt of 7-fluoro-6-methoxy-9H-pyrimido[4,5-b]indol-4- amine (330c) (950 mg, 3.62 mmol) in DMF (25 mL) using tort-butyl 2-bromoacetate (0.589 mL, 3.98 mmol) and CS2CO3 (2.95 g, 9.06 mmol) to afford after workup and purification as described in step-3 of scheme-328, tert- butyl 2-(4-amino-7-fluoro-6-methoxy-9H- pyiimido[4,5-b]indol-9-yl)acetate (330d) (0.89 g, 71% yield) as a pale yellow solid; MS (ES+): 347.2 (M+l).

Step-4: Preparation of 2-(4-amino-7-fluoro-6-methoxy-9H-pyrimido[4,5-b]indol-9-yl)a cetic acid (330e)

Compound 330e was prepared according to the procedure reported in step-2 of scheme- 1, from tort-butyl 2-(4-amino-7-fluoro-6-methoxy-9H-pyrimido[4,5-b]indol-9-yl)a cetate (330d) (0.87 g, 2.51 mmol) using 20% TFA in DCM (14.42 mL, 37.7 mmol) to afford after workup TFA salt of 2-(4-amino-7-fluoro-6-methoxy-9H-pyrimido[4,5-b]indol-9-yl)a cetic acid (330e) (1.3 g) as a pale-yellow solid; Ή NMR (300 MHz, DMSO-i/e) δ 8.73 (s, 2H), 8.58 (s, 1H), 8.24 (d, J= 8.2 Hz, 1H), 7.91 (d ,J= 11.7 Hz, 1H), 5.24 (s, 2H), 3.98 (s, 3H); MS (ES+): 291.1 (M+l).

Step-5: Preparation of (lR,3S,5R)-2-(2-(4-ammo-7-fluoro-6-methoxy-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1 ,0]hexane-3-carboxamide (330f)

Compound 330f was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-7-fluoro-6-methoxy-9H-pyrimido[4,5-b]indol-9-yl)a cetic acid (330e) (81 mg, 0.157 mmol) in DMF (2 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0Jhexane-3-carboxamide (4a) (50mg, 0.157 mmol), HATU (90 mg, 0.235 mmol), DIPEA (0.137 mL, 0.785 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-303, (lR,3S,5R)-2-(2-(4- amino-7-fluoro-6-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetyl )-N-(6-bromopyridin-2-yl)- 2-azabicyclo[3.1.0]hexane-3-carboxamide (330f) (56 mg, 64.4 % yield) HC1 salt as a white solid; 'HNMR (300 MHz, DMSO-ife) δ 10.77 (s, 1H, D2O exchangeable), 8.54 (s, 3H, 2H D2O exchangeable) 824 (d J= 82 Hz 1H) 801 (d J= 8 1 Hz 1H) 777 - 763 (m 2H) 9.0, 5.4 Hz, 1H), 3.97 (s, 3H), 3.93 - 3.81 (m, 1H), 2.39 - 2.27 (m, 1H), 2.27 - 2.14 (m, 1H), 2.00 - 1.82 (m, 1H), 1.19 - 0.96 (m, 1H), 0.84 - 0.75 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO- ifc) δ -133.52. MS (ES+): 554.1/556.1 (M+l); (ES-): 552.1/554.1 (M-l); Analysis calculated for C ₂ 4H2iBrFN ₇ 03 2H*0. 0.9HC1.: C, 46.25; H, 4.19; Cl, 5.12; N, 15.73; Found: C, 46.18; H, 3.92; Cl, 5.08; N, 15.62.

Scheme 331

Preparation of (lR,3S,5R)-2-(2-(4-amino-7-fluoro-6-methoxy-9H-pyrimido[4,5- b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (331a)

Compound 331a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-7-fluoro-6-methoxy-9H-pyrimido[4,5-b]indol-9-yl)a cetic acid (330e) (78 mg, 0.150 mmol) in DMF (2 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.OJhexane-3-carb oxamide (8a) (50 mg, 0.150 mmol), HATU (86 mg, 0.225 mmol), DIPEA (0.131 mL, 0.752 mmol) and stirring atRT for 16 h. This gave after workup and purification using as described in scheme-303, ( 1R,3S,5R)- 2-(2-(4-amino-7-fluoro-6-methoxy-9H-pyrimido[4,5-b]indol-9-y l)acetyl)-N-(6- bromopyiidin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (331a) (48mg, 56% yield) HC1 salt as a white solid; 'HNMR (300 MHz, DMSO-ifc) δ 10.77 (s, 1H, DzO exchangeable), 8.64 - 8.28 (m, 3H, 2H D2O exchangeable), 8.21 (d, J= 8.2 Hz, 1H), 8.02 (d, J= 8.1 Hz, 1H), 7.80 - 7.58 (m, 2H), 7.32 (d,J= 7.7 Hz, 1H), 5.66 (d, J= 17.4 Hz, 1H), 5.30 (d,J= 17.3 Hz, 1H), 4.37 (dd, .7= 9.1, 5.9 Hz, 1H), 3.96 (s, 3H), 3.70 - 3.64 (m, 1H), 2.48 - 2.41 (m, 1H), 1.98 (dd, J= 13.3, 5.8 Hz, 1H), 1.31 (s, 3H), 1.06 - 0.90 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -133.30. MS (ES+): 568.1/570.1 (M+l); (ES-): 566.1/568.1 (M-l); Analysis calculated for CzsHyBrHSbOs ZHzO. l.lHCL: C, 46.59; H, 4.39; Cl, 6.05; N, 15.21; Found: C, 46.52; H, 4.33; Cl, 6.12; N, 15.15.

332c

Preparation of ( 1 RJS,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimi do[4,5- b]indol-9-yl)acetyl)-N-(6-chloro-3-methylpyridin-2-yl)-5-met hyl-2-azabicyclo[3.1.0]hexane- 3 -carboxamide (332c)

Step-1: Preparation of ( 1R,3 S,5R)-ter/-butyl 3-((6-chloro-3-methylpyridin-2-yl)carbamoyl)- 5-methyl-2-azabicyclo[3.1 ,0]hexane-2-carboxylale (332a)

Compound 332a was prepared according to the procedure reported in step-1 of scheme-53, from (lR,3S,5R)-2-(terf-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxylic acid (261a) (0.35 g, 1.451 mmol) and 6-chloro-3-methylpyridin-2-amine (0.207 g, 1.451 mmol) to afford after purification as described in step-1 of scheme-317, ( 1R,3 S,5R)-tert-butyl 3 -((6-chloro-3 -methylpyridin-2-y l)carbamoy l)-5 -methyl-2-azabicy clo [3.1 ,0]hexane-2- carbox>'late (332a) (0.196 g, 37% yield) as a white solid; MS (ES+): 366.2 (M+l).

Step-2: Preparation of (lR,3S,5R)-N-(6-chloro-3-methylpyridin-2-yl)-5-methyl-2- azabicyclo[3.1.0]hexane-3-carboxamide (332b)

Compound 332b was prepared according to the procedure reported in step-2 of scheme- 1, from (lR,3S,5R)-tert-butyl 3-((6-chloro-3-methylpyridin-2-yl)carbamoyl)-5-methyl-2- azabicyclo[3.1.0]hexane-2-carbo¾ylate (332a) (0.19 g, 0.519 mmol) in DCM (2.8 mL) using TFA (0.280 mL, 3.64 mmol) to afford after purification as described in step-2 of scheme-319, (lR,3S,5R)-N-(6-chloro-3-methylpyridin-2-yl)-5-methyl-2-azab icyclo[3.1 ,0]hexane-3- carboxamide (332b) (137 mg, 99% yield); ‘HNMR (300 MHz, DMSO-i/e) δ 10.89 (s, 1H), 10.12 (s, 1H), 9.19 (d,J= 10.0 Hz, 1H), 7.82 (d, J= 8.0 Hz, 1H), 7.41 (d ,J= 8.0 Hz, 1H), 436 422 ( 1H) 3 11 3 04 ( 1H) 265 (dd J 126 76 H 1H) 2 16 ( 3H) 205 1.95 (m, 1H), 1.27 (s, 3H), 1.13 - 1.03 (m, 1H), 0.84 - 0.72 (m, 1H); MS (ES+): 266.1 (M+l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyrimido[4,5-b]indol-9-yl)acet _\ 'l)-N-(6-chloro-3-methylpyridin-2-yl)-5-methyl-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (332c)

Compound 332c was prepared according to the procedure reported in step-3 of scheme- 1, from HC1 salt of (lR,3S,5R)-N-(6-chloro-3-methylpyridin-2-yl)-5-methyl-2- azabicyclo[3.1.0]hexane-3-carboxamide (332b) (41.4 mg, 0.137 mmol) in DMF (1.5 mL) using TFA salt of 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]in dol-9- yl)acetic acid (184f) (60 mg, 0.137 mmol), HATU (78 mg, 0.205 mmol), DIPEA (0.119 mL, 0.684 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-303, (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyr imido[4,5- b]indol-9-yl)acetyl)-N-(6-chloro-3-methylpyridin-2-yl)-5-met hyl-2-azabicyclo[3. i OJhexane-

3-carboxamide (332c) (55 mg, 70% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.31 (s, 1H, DzO exchangeable), 8.79 (s, 1H), 8.59 (s, 1H), 8.53 (s, 2H, DzO exchangeable), 7.72 (d, J= 8.0 Hz, 1H), 7.58 (s, 1H), 7.31 (d, J= 7.9 Hz, 1H), 5.90 (d ,J = 18.0 Hz, 1H), 5.66 (d, J= 17.9 Hz, 1H), 4.38 (dd, J= 9.1, 5.6 Hz, 1H), 3.69 (dd, J= 5.6, 2.4 Hz, 1H), 2.74 (s, 3H), 2.62 - 2.56 (m, 1H), 2.10 - 1.94 (m, 4H), 1.33 (s, 3H), 1.12 - 0.98 (m, 1H), 0.96 - 0.78 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO-i/e) δ -58.70; MS (ES+): 572.2 (M+l); (ES-): 570.1 (M-l); Analysis calculated for C27H25CIF3N7O22.25H2O.0.75HC1: C, 50.68; H, 4.77; Cl, 9.70; N, 15.32; Found: C, 50.55; H, 4.68; Cl, 9.70; N, 15.18.

Scheme 333

JU iy

6γ OH

Me F Ν-χ Η TFA HI H ο=< I Boc V-N. _Μ N,

N ο \ " Br

O

^L I -N ^T Χ,Χχ* Me o a

\ F

2618 333a 333b

C0 ₂ H

Γ rV ^N H Br

Me <7 ,N;

N

N y~ ^* F

O

NH ₂ Αθ Me

184f CFj

N i J*

HATU, DIPEA < rs

N~y

CF

NH _{2 3} Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyr imido[4,5- b]indol-9-yl)acetyl)-N-(6-bromo-5-fluoro-3-methylpyridin-2-y l)-5-methyl-2- azabicyclo[3.1 ,0]hexane-3-caiboxamide (333c)

Step-1: Preparation of (lR,3S,5R)-terf-butyl 3-((6-bromo-5-fhioro-3-methylpyridin-2- yl)carbamoyl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-2-carboxylate (333a)

Compound 333a was prepared according to the procedure reported in step-1 of scheme-53, from (lR,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxylic acid (261a) (0.35 g, 1.451 mmol) and 6-bromo-5-fluoro-3-methylpyridin-2-amine (0.297 g, 1.451 mmol) to afford after purification as described in step- 1 of scheme-317, (1R,3S,5R)- tert-butyl 3-((6-bromo-5-fluoro-3-methylpyridin-2-yl)carbamoyl)-5-methy l-2- azabicyclo[3.1.0]hexane-2-caiboxylate (333a) (0.560 g, 90% yield) as a white solid; MS (ES+): 428.1/430.1(M+1).

Step-2: Preparation of (lR,3S,5R)-N-(6-bromo-5-fluoro-3-methylpyridin-2-yl)-5-methy l-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (333b)

Compound 333b was prepared according to the procedure reported in step-2 of scheme- 1, from ( lR,3S,5R)-/ert-butyl 3-((6-bromo-5-fluoro-3-methylpyridin-2-yl)carbamoyl)-5-methy l- 2-azabicyclo[3.1.0]hexane-2-carboxylate (333a) (0.550 g, 1.284 mmol) in DCM (7 mL) using TFA (0.693 mL, 8.99 mmol) to afford after purification as described in step-2 of scheme-319, (lR,3S,5R)-N-(6-bromo-5-fluoro-3-methylpyridin-2-yl)-5-methy l-2- azabicyclo[3.1.OJhexane-3-carboxamide (333b) (408 mg, 97% yield); Ή NMR (300 MHz, DMSO-^fc) δ 10.92 (s, 1H), 10.08 (s, 1H), 9.27 - 9.11 (m, 1H), 7.93 (d, J= 8.4 Hz, 1H), 4.38 - 4.21 (m, 1H), 3.07 (d, J= 6.6 Hz, 1H), 2.65 (dd,J= 12.6, 7.6 Hz, lH), 2.17 (s, 3H), 1.99 (t, J= 11.8 Hz, 1H), 1.27 (s, 3H), 1.15 - 1.01 (m, 1H), 0.81 - 0.71 (m, 1H); MS (ES+):

328.1/330.1(M+1).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromo-5-fluoro-3-meth ylpyridin-2-yl)-5-methyl-2- azabicyclo[3.1.OJhexane-3-carboxamide (333c)

Compound 333c was prepared according to the procedure reported in step-3 of scheme- 1, from HC1 salt of (lR,3S,5R)-N-(6-bromo-5-fluoro-3-methylpyridin-2-yl)-5-methy l-2- azabicyclo[3.1.0]hexane-3-carboxamide (333b) (49.9 mg, 0.137 mmol) in DMF (1.5 mL) using TFA salt of 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]in dol-9- yl)acetic acid (184f) (60 mg, 0.137 mmol), HATU (78 mg, 0.205 mmol), DIPEA (0.119 mL, 0684 mmol) and stirring at RT for 16 h This gave after workup and purification as described b]mdol-9-yl)acetyl)-N-(6-bromo-5-fluoro-3-methylpyridin-2-yl )-5-methyl-2- azabicyclo[3.1.0]hexane-3-carboxamide (333c) (68 mg, 78 % yield) HC1 salt as a white solid; ΉΝΜΚ (300 MHz, DMSCMs) δ 10.36 (s, 1H, DzO exchangeable), 8.80 (s, 1H), 8.74 - 8.44 (m, 3H, 2H D2O exchangeable), 7.82 (d, ./= 8.5 Hz, 1H), 7.59 (s, 1H), 5.90 (d,./= 18.0 Hz, 1H), 5.66 (d 17.9 Hz, 1H), 4.35 (dd,J= 9.2, 5.7 Hz, 1H), 3.69 (dd, J= 5.6, 2.4 Hz, 1H), 2.74 (s, 3H), 2.62 - 2.54 (m, 1H), 2.08 - 1.97 (m, 4H), 1.33 (s, 3H), 1.09 - 0.96 (m, 1H), 0.94 - 0.86 (m, 1H). ¹⁹ F NMR (282 MHz, DMSOK/ ₆ ) δ -58.72, -119.20. MS (ES+): 634.1/636.1 (M+l); (ES-): 632.1/634.1 (M-l); Analysis calculated for C27H24BrF4N?02 H2O.HCI: C, 47.07; H, 3.95; Cl, 5.15; N, 14.23; Found: C, 47.00; H, 3.75; Cl, 4.92; N, 14.06.

Scheme 334

274f 334a

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(trifluoromethoxy)-9H-pyrimido[4, 5-b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (334a)

Compound 334a was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-6-(trifluoromethoxy)-9H-pyrimido[4,5-b]indol-9-yl )acetic acid (274f) (75 mg, 0.23 mmol) in DMF (10 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-5- methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (92 mg, 0.276 mmol), HATU (175 mg, 0.460 mmol), DIPEA (0.160 mL, 0.920 mmol) and stirring at RT for 20 h. This gave after workup and purification as described in scheme-299, ( 1 R,3 S,5R)-2-(2-(4-amino-6- (trifluoromethoxy)-9H-pyrimido[4,5-b]mdol-9-yl)acetyl)-N-(6- bromopyridin-2-yl)-5-methyl- 2-azabicyclo[3.1 ,0]hexane-3-carboxamide (334a) (109 mg, 78% yield) HC1 salt as a white solid; ’HNMR (300 MHz, DMSO -ek) δ 10.76 (s, 1H, D2O exchangeable), 8.64 - 8.59 (m, 1H), 8.56 (s, 1H), 8.44 (s, 2H, D2O exchangeable), 8.01 (d ,J= 8.2 Hz, 1H), 7.76 (d,J= 9.0 Hz, 1H), 7.70 (t ,J= 8.0 Hz, 1H), 7.57 - 7.48 (m, 1H), 7.32 (d, J= 7.7 Hz, 1H), 5.72 (d ,J= 174 Hz 1H) 5 38 (d J= 173 Hz 1H) 436 (dd J= 90 60 Hz 1H) 3 71 3 64 (m 1H) 2.56 - 2.41 (m, 1H), 1.98 (dd ,J= 13.3, 5.9 Hz, 1H), 1.30 (s, 3H), 1.05 - 0.97 (m, 1H), 0.97 - 0.90 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-flfe) δ -57.00; MS (ES+): 604.10 & 606.10 (M+l); MS (ES-): 602.00 & 604.00 (M-l); Analysis calculated for CisHbiBrFaNvOs HCl.1 25H20:

C, 45.26; H, 3.72; N, 14.78; Cl, 5.34; Found: C, 45.13; H, 3.83; N, 14.66; Cl, 5.08.

Scheme 335

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(4-fluorophenyl)-9H-pyrimido[4,5- b]indol-9- yl)acet\l)-N -(6-bromopyridin-2-yl)-2-azabicyclo [3.1.0Jhexane-3-carboxamide (335c)

Step-1: Preparation of ethyl 2-(4-amino-6-(4-fluorophenyl)-9H-pyrimido[4,5-b]indol-9- yl)acetate (335a)

Compound 335a was prepared and purified according to the procedure reported in step-1 of scheme-62, from ethyl 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (48a) (200 mg, 0.573 mmol) in dioxane (18 mL) using (4-fluorophenyl)boronic acid (120 mg, 0.859 mmol), cesium carbonate (280 mg, 0.859 mmol) in water (2.2 mL), Pd(PPh3)2Ck (80 mg,

0.115 mmol) and heating at 100 °C for 18 h to give a mixture of ethyl 2-(4-amino-6-(4- fluorophenyl)-9H-pyrimido[4,5-b]indol-9-yl)acetate (335a) and 2-(4-amino-6-(4- fluorophenyl)-9H-pyrimido [4,5 -b] indol-9-y l)acetic acid (335b) which was used as such for the next step; MS (ES+): 337.10 & 365.10 (M+l).

Step-2: Preparation of 2-(4-amino-6-(4-f]uorophenyl)-9H-pyrimido[4,5-b]indol-9-yl)a cetic acid (335b)

Compound 335b was prepared according to the procedure reported in step-4 of scheme- 17, f i t f th l 2 (4 i 6 (4 fl h l) 9H i id [45 b]i d l 9 l) t t (335a) and 2-(4-amino-6-(4-fluorophenyl)-9H-pyrimido[4,5-b]indol-9-yl)a cetic acid (335b) obtained in step-1 of this scheme (0.573 mmol) in THF (5 mL) and methanol (5 mL) using a solution of lithium hydroxide hydrate (147 mg, 3.44 mmol) in water (5 mL) and stirring at RT for 12 h. The reaction mixture was concentrated to dryness diluted with water (12 mL), acidified with 4 N HC1 to pH about 6 followed by filtration, washing with water, and drying under vacuum to afford a gray solid of 2-(4-amino-6-(4-fluorophenyl)-9H-pyrimido[4,5- b]indol-9-yl)acetic acid (335b) (120 mg) which was used as such for the next step; MS (ES+): 337.10 (M+l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(4-fluorophenyl)-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1.0] hexane-3 -carboxam ide (335c)

Compound 335c was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-6-(4-fluorophenyl)-9H-pyrimido[4,5-b]indol-9-yl)a cetic acid (335b) (60 mg, 0.178 mmol) in DMF (10 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (4a) (68.2 mg, 0.214 mmol), HATU (136 mg, 0.357 mmol), DIPEA (0.124 mL, 0.714 mmol) and stirring at RT for 20 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4-amino-6-(4-fluorophenyl)- 9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl) -2-azabicyclo[3.1 ,0]hexane-3- carboxamide (335c) (52 mg, 49% yield) HC1 salt as a white solid; ^! H NMR (300 MHz, DMSO-cfe) δ 10.77 (s, 1H, DzO exchangeable), 8.78 (d, 1H), 8.67 (s, 3H, DzO exchangeable), 8.62 (s, 1H), 8.01 (d, J= 8.2 Hz, 1H), 7.92 - 7.83 (m, 3H), 7.77 (d, J= 8.7 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.40 - 7.28 (m, 3H), 5.79 (d, J= 17.4 Hz, 1H), 5.45 (d, J= 17.3 Hz, 1H), 4.42 (dd, J= 9.0, 5.6 Hz, 1H), 4.05 - 3.81 (m, 1H), 2.44 - 2.14 (m, 2H), 2.02 - 1.84 (m, 1H), 1.17 - 1.01 (m, 1H), 0.85 - 0.69 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-tife) δ -116.03; MS (ES+): 600.10 & 602.15 (M+l); MS (ES-): 598.10 & 600.05 (M-l); Analysis calculated for CzpHzzBrFNzOz.1.15HC1.1 ,75HzO: C, 51.69; H, 4.14; N, 14.55; Cl, 6.05; Found: C, 51.71; H, 4.14; N, 14.42; Cl, 5.91.

Scheme 336

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(furan-2-yl)-9H-pyrimido[4,5-b]in dol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (336c)

Step-1: Preparation of ethyl 2-(4-amino-6-(furan-2-yl)-9H-pyiimido[4,5-b]indol-9-yl)aceta te (336a)

Compound 336a was prepared and purified according to the procedure reported in step-1 of scheme-62, from ethyl 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (48a) (200 mg, 0.573 mmol) in dioxane (18 mL) using furan-2-ylboronic acid (96 mg, 0.859 mmol), cesium carbonate (280 mg, 0.859 mmol) in water (2.2 mL), Pd(PPh3)2Ch (80 mg, 0.115 mmol) to give a mixture of ethyl 2-(4-amino-6-(furan-2-yl)-9H-pyrimido[4,5-b]indol-9- yl)acetate (336a) and 2-(4-amino-6-(furan-2-yl)-9H-pyrimido[4,5-b]indol-9-yl)aceti c acid (336b) and this was used as such for the next step; MS (ES+): 309.10 & 337.20.

Step-2: Preparation of 2-(4-amino-6-(furan-2-yl)-9H-pyrimido[4,5-b]indol-9-yl)aceti c acid (336b)

Compound 336b was prepared according to the procedure reported in step-4 of scheme- 17, from a mixture of ethyl 2-(4-amino-6-(furan-2-yl)-9H-pyrimido[4,5-b]indol-9-yl)aceta te (336a) and 2-(4-amino-6-(furan-2-yl)-9H-pyrimido[4,5-b]indol-9-yl)aceti c acid (336b) from step-1 above (0.573 mmol) in THF (5 mL) and methanol (5 mL) using a solution of lithium hydroxide hydrate (147 mg, 3.44 mmol) in water (5 mL) and stirring at RT for 23 h. This gave after workup a dark brown solid (190 mg) which was used as such for the next step; MS (ES+): 309.10 (M+l) Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(furan-2-yl)-9H-pyrimido[4,5-b]in dol-9- yl)acet\l)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (336c)

Compound 336c was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-6-(furan-2-yl)-9H-pytimido[4,5-b]indol-9-yl)aceti c acid (336b) (90 mg, 0.292 mmol) in DMF (10 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-5- methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (97 mg, 0.292 mmol), HATU (222 mg, 0.584 mmol), DIPEA (0.203 mL, 1.168 mmol) and stirring at RT for 20 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4-amino-6- (furan-2-yl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromo pyridin-2-yl)-5-methyl-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (336c) (29 mg, 17% yield foro three steps) HC1 salt as a light brown solid. Ή NMR (300 MHz, DMSO-cfe) δ 10.77 (s, 1H, DzO exchangeable), 8.83 (d, J= 1.6 Hz, 1H), 8.67 (s, 2H, DzO exchangeable), 8.60 (s, 1H), 8.01 (d,7= 8.2 Hz, 1H), 7.90 (dd, J= 8.6, 1.5 Hz, 1H), 7.80 - 7.78 (m, 1H), 7.73 (d, J= 8.5 Hz, 1H), 7.68 (d, J= 8.0 Hz, 1H), 7.31 (d, J= 7.7 Hz, 1H), 7.04 (d, ./= 3.4 Hz, 1H), 6.65 (dd, J= 3.4, 1.8 Hz, 1H), 5.72 (d ,J= 17.3 Hz, 1H), 5.37 (d, J= 17.3 Hz, 1H), 4.37 (dd, 9.2, 5.8 Hz, 1H), 3.69 (dd, J= 5.6, 2.3 Hz, 1H), 2.60 - 2.38 (m, 1H), 1.98 (dd, J= 13.4, 5.9 Hz, 1H), 1.31 (s, 3H), 1.06 - 0.97 (m, 1H), 0.97 - 0.87 (m, 1H); MS (ES+): 586.10 & 588.20 (M+l); MS (ES-): 584.10 & 586.05 (M-l); Analysis calculated for C28H2*BrN ₇ 03.1 0HC1.2.25H2O: C, 50.69; H, 4.48; N, 14.78; Cl, 5.34; Found: C, 50.60; H, 4.34; N, 14.64; Cl, 5.09.

Scheme 337

Preparation of ( lR,3S,5R)-2-(2-(4-arnino-6-(4-fluorophenyl)-9H-pyrimido[4,5- b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (337a)

Compound 337a was prepared according to the procedure reported in step-3 of scheme- 1, mg, 0.178 mmol) in DMF (10 mL) using HC1 salt of ( lR,3S,5R)-N-(6-bromopyridin-2-yl)-5- methyl-2-azabicyclo[3.1.0Jhexane-3-carboxamide (8a) (71.2 mg, 0.214 mmol), HATU (136 mg, 0.357 mmol), DIPEA (0.124 mL, 0.714 mmol) and stirring at RT for 20 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4-amino-6-(4- fluorophenyl)-9H-pyrimido[4,5-b]indol-9-yl)ace1yl)-N-(6-brom opyridin-2-yl)-5-methyl-2- azabicyclo[3.1.0]hexane-3-carboxamide (337a) (48 mg, 44% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-flk) δ 10.78 (s, 1H, D2O exchangeable), 8.77 (d,J= 1.7 Hz, 1H), 8.66 (s, 3H, D2O exchangeable), 8.61 (s, 1H), 8.01 (d, J= 8.2 Hz, 1H), 7.92 - 7.82 (m, 3H), 7.76 (d ,J= 8.7 Hz, 1H), 7.69 (t ,J= 7.9 Hz, 1H), 7.39 - 7.29 (m, 3H), 5.75 (d ,J= 17.3 Hz, 1H), 5.40 (d, J= 17.3 Hz, 1H), 4.37 (dd,J= 9.1, 6.0 Hz, 1H), 3.71 (dd,J= 5.6, 2.4 Hz, 1H), 2.63 - 2.37 (m, 1H), 1.99 (dd,J= 13.1, 5.9 Hz, 1H), 1.31 (s, 3H), 1.07 - 0.98 (m, 1H), 0.98 - 0.89 (m, 1H).; ¹⁹ F NMR (282 MHz, DMSO-cfe) δ -116.03; MS (ES+): 614.10 & 616.15 (M+l); MS (ES-): 612.10 & 614.10 (M-l); Analysis calculated for C30H25BrFN7O2.UHCU.6H2O: C, 52.72; H, 4.32; N, 14.35; Cl, 5.71; Found: C, 52.79; H, 4.25; N, 14.28; Cl, 5.52.

Scheme 338

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-cyclopentyl-9H-pyrimido[4,5-b]ind ol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (338e)

Step-1: Preparation of ethyl 2-(4-amino-6-(cyclopent-l-en-l-yl)-9H-pyrimido[4,5-b]indol-9 - yl)acetate (338a) and 2-(4-amino-6-(cyclopent-l-en-l-yl)-9H-pyrimido[4,5-b]indol-9 - yl)acetic acid (338b) Compound 338a was prepared and purified according to the procedure reported in step-1 of scheme-62, from ethyl 2-(4-amino-6-bromo-9H-pyrimido[4,5-b]indol-9-yl)acetate (48a) (200 mg, 0.573 mmol) in dioxane (18 mL) using cyclopent-l-en-l-ylboronic acid (96 mg, 0.859 mmol), cesium carbonate (280 mg, 0.859 mmol) in water (2.2 mL), Pd(PPh3)2Ch (80 mg,

0.115 mmol) to give a mixture of ethyl 2-(4-amino-6-(cyclopent-l-en-l-yl)-9H-pyrimido[4,5- b]indol-9-yl)acetate (338a) and 2-(4-amino-6-(cyclopent-l-en-l-yl)-9H-pyrimido[4,5- b]indol-9-yl)acetic acid (338b) which was used as such for tire next step; MS (ES+): 309.10 & 337.20 (M+l).

Step-2: ethyl 2-(4-amino-6-cyclopentyl-9H-pyrimido[4,5-b]indol-9-yl)acetat e (338c) and 2- (4-amino-6-cyclopentyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (338d)

To a solution of mixture of ethyl 2-(4-amino-6-(cyclopent-l-en-l-yl)-9H-pyrimido[4,5- b]indol-9-yl)acetate (338a) and 2-(4-amino-6-(cyclopent-l-en-l-yl)-9H-pyrimido[4,5- bJindol-9-yl)acetic acid (338b) from step-1 above (0.097 g, 0.287 mmol) in ethyl acetate (5 mL), ethanol (5 mL) and MeOH (5 mL) was treated with palladium (0.046 g, 0.043 mmol) and hydrogenated for 29 h. Reaction mixture was filtered, washed with ethyl acetate/methanol (9: 1), and concentrated to obtained residue containing mixture of Ethyl 2- (4-amino-6-cyclopentyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (338c) and 2-(4-amino-6- cyclopenty 1 -9H-pyrimido [4,5 -b] indol -9-yl)acetic acid (338d) (206 mg) which was used as such for next step; MS (ES+): 311.10 & 339.20 (M+l).

Step-3: Preparation of 2-(4-amino-6-cyclopentyl-9H-pyrimido[4,5-bJindol-9-yl)acetic acid (338d)

Compound 338d was prepared according to the procedure reported in step-4 of scheme- 17, from mixture of Ethyl 2-(4-amino-6-cyclopentyl-9H-pyrimido[4,5-b]indol-9-yl)acetat e (338c) and 2-(4-amino-6-cyclopentyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (338d) (97 mg, 0.287 mmol) in THE (3 mL) and methanol (3 mL) using a solution of lithium hydroxide hydrate (73.7 mg, 1.722 mmol) in water (3 mL) and stirring at RT for 32 h. This gave after workup 2-(4-amino-6-cyclopentyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (338d) as a gray- solid (56 mg) which was used as such for the next step; MS (ES+): 311.20 (M+l).

Step-4: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-cyclopentyl-9H-pyrimido[4,5-b]ind ol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (338e)

Compound 338e was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-6-cyclopentyl-9H-pyrimido[45-b]indol-9-yl)acetic acid (338d) (52 mg methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (66.9 mg, 0.201 mmol), HATU (127 mg, 0.335 mmol), DIPEA (0.117 mL, 0.670 mmol) and stirring at RT for 19 h. This gave after workup as described in scheme-299, ( 1R,3 S,5R)-2-(2-(4-amino-6-cyclopentyl-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5- methyl-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (338e) (22 mg, 22% yield) HC1 salt as a light brown solid; ¾ NMR (300 MHz, DMSO-cfe) δ 10.76 (s, 1H, D2O exchangeable), 8.61 (s, 3H, DzO exchangeable), 8.59 (s, 1H), 8.37 (s, 1H), 8.01 (d, J= 8.2 Hz, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.59 (d, J= 8.5 Hz, 1H), 7.48 - 7.43 (m, 1H), 7.32 (d, J= 7.7 Hz, 1H), 5.69 (d, J= 17.3 Hz, 1H), 5.35 (d, 17.3 Hz, 1H), 4.35 (dd,J= 9.0, 6.0 Hz, 1H), 3.69 (dd,J= 5.6, 2.4 Hz, 1H),

3.20 - 3.03 (m, 1H), 2.59 - 2.38 (m, 1H), 2.19 - 1.55 (m, 9H), 1.30 (s, 3H), 1.05 - 0.97 (m, 1H), 0.95 - 0.88 (m, 1H); MS (ES+): 588.20 & 590.20 (M+l); MS (ES-): 586.10 & 588.10 (M-l).

Scheme 339

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(methoxymethyl)-9H-pyrimido[4,5-b ]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (339g)

Step-1: Preparation of 2,2,2-trifluoro-N-(2-iodo-4-(methoxymetityl)phenyl)acetamide (339b) Compound 339b was prepared according to the procedure reported in step-1 of scheme-46, from 2-iodo-4-(methoxymethyl)aniline (339a)(6.538 g, 24.85 mmol; CAS # 1697458-72-2) in DCM (40 mL) using triethylamine (8.66 mL, 62.1 mmol), trifluoroacetic acid anhydride (5.18 mL, 37.3 mmol) and stirring at RT for 20 h. This gave after workup 2,2,2-trifluoro-N- (2-iodo-4-(methoxymethyl)phenyl)acetamide (339b) (10.39 g) as a yellow solid and was used as such for next step; MS (ES-): 358.00 (M-l).

Step-2: Preparation of 2-amino-5 -(methoxy methyl)- lH-indole-3-carbonitrile (339c) Compound 339c was prepared according to the procedure reported in step-1 of scheme- 11, from 2,2,2-trifluoro-N-(2-iodo-4-(methoxymethyl)phenyl)acetamide (339b) (8.92 g, 24.85 mmol) in DMSO (30 mL) using malononitrile (1.970 g, 29.8 mmol), L-proline (0.572 g, 4.97 mmol), Cul (0.473 g, 2.485 mmol), and K2CO3 (6.87 g, 49.7 mmol) in water (30 mL) to afford after workup and purification as described in step-1 of scheme-328, 2-amino-5- (methoxymethyl)-lH-indole-3-carbonitrile (339c) (2.68 g, 54% yield) as a yellow solid; ¾ NMR (300 MHz, DMSO-rfe) δ 10.69 (s, 1H), 7.11 - 7.04 (m, 2H), 6.88 - 6.82 (m, 1H), 6.75 (s, 2H), 4.38 (s, 2H), 3.24 (s, 3H); MS (ES+): 202.10 (M+l).

Step-3: Preparation of 6-(methoxymethyl)-9H-pyrimido[4,5-b]indol-4-amine (339d) Compound 339d was prepared according to the procedure reported in step-2 of scheme-29, from 2-amino-5-(methoxymethyl)-lH-indole-3-carbonitrile (339c)(2.55 g, 12.67 mmol) in ethanol (60 mL) using formamidine acetate (10.66 g, 101 mmol) and refluxing for 19 h. This gave after workup 6-(methoxymethyl)-9H-pyrimido[4,5-b]indol-4-amine (339d) (910 mg) as a light brown solid which was used as such for the next step; Ή NMR (300 MHz, DMSO-ofe) δ 11.81 (s, 1H), 8.27 (s, 1H), 8.23 (s, 1H), 7.40 (d, J= 8.2 Hz, 1H), 7.32 (dd ,J= 8.2, 1.5 Hz, 1H), 7.14 (s, 2H), 4.51 (s, 2H), 3.29 (s, 3H); MS (ES+): 229.10 (M+l).

Step-4: Preparation of ethyl 2-(4-amino-6-(methoxymethvT)-9H-pyrimido [4,5 -bj indol-9- yl)acetate (339e)

Compound 339e was prepared according to the procedure reported in step-1 of scheme- 1, from 6-(methoxymethyl)-9H-pyrimido[4,5-b]indol-4-amine (339d) (850 mg, 3.72 mmol) in DMF (20 mL) using ethyl 2-bromoacetate (0.454 mL, 4.10 mmol), CS2CO3 (3033 mg, 9.31 mmol) and stirring at RT for 26 h. This gave after workup ethyl 2-(4-amino-6- (methoxymethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetate (339e) (780 mg) as a light-yellow solid; ¾ NMR (300 MHz, DMSO-cfe) δ 8.35 - 8.32 (m, 1H), 8.28 (s, 1H), 7.56 (d, J= 8.3 Hz, 1H), 7.38 (dd, J= 8.4, 1.5 Hz, 1H), 7.30 (s, 2H), 5.23 (s, 2H), 4.53 (s, 2H), 4.14 (q, J= 7.1 Hz, 2H), 3.30 (s, 3H), 1.20 (t, J= 7.1 Hz, 3H); MS (ES+): 315.15 (M+l).

Step-5: Preparation of 2-(4-amino-6-(methoxymethyl)-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (339f)

Compound 339f was prepared according to the procedure reported in step-4 of scheme- 17, from ethyl 2-(4-amino-6-(methoxymethyl)-9H-pyrimido[4,5-b]indol-9-yl)ac etate (339e) (600 mg, 1.909 mmol) in THF (8 mL) and methanol (8 mL) using a solution of lithium hydroxide hydrate (490 mg, 11.45 mmol) in water (8 mL) and stirring at RT for 19 h. This gave after workup 2-(4-amino-6-(methoxymethyl)-9H-pyrimido[45-b]indol-9-yl)ace tic acid (339f) Step-6: Preparation of(lR,3S,5R)-2-(2-(4-amino-6-(methoxymethyl)-9H-pyrimido[4,5 - b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1.0]hexane-3-carboxamide (339g)

Compound 339g was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-6-(methoxymethyl)-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (339f) (0.23 mmol) in DMF (10 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (4a) (0.088 g, 0.276 mmol), HATU (0.175 g, 0.460 mmol), DIPEA (0.160 mL, 0.92 mmol) and stirring at RT overnight. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4-amino-6-(methoxymethyl)- 9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl) -2-azabicyclo[3.1 ,0]hexane-3- carboxamide (339g) (83 mg, 66% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.76 (s, 1H, D2O exchangeable), 8.75 (s, 2H, DzO exchangeable), 8.64 (s, 1H), 8.52 (s, 1H), 8.00 (d,J= 8.2 Hz, 1H), 7.80 - 7.63 (m, 2H), 7.54 (d, J= 8.4 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 5.77 (d,J= 17.4 Hz, 1H), 5.42 (d ,J= 17.3 Hz, 1H), 4.56 (s, 2H), 4.47 - 4.35 (m, 1H), 3.98 - 3.83 (m, 1H), 3.32 (s, 3H), 2.40 - 2.10 (m, 2H), 1.99 - 1.82 (m, 1H), 1.19 - 0.96 (m, 1H), 0.89 - 0.65 (m, 1H); MS (ES+): 550.10 & 552.15 (M+l); MS (ES-): 548.10 & 550.10 (M-l); Analysis calculated for C25H24BrN ₇ 03.1.15HC1.1.OH2O: C, 49.20; H, 4.48; N, 16.06; Cl, 6.68; Found: C, 49.30; H, 4.44; N, 15.99; Cl, 6.56.

Scheme 340

339f 340a

Preparation of ( lR,3S,5R)-2-(2-(4-amino-6-(methoxymethyl)-9H-pyrimido[4,5-b] indol-9- yI)acetyl)-N-(6-bromopyridin-2-yl)-5-methyI-2-azabicyclo[3.1 .0]hexane-3-carboxamide (340a)

Compound 340a was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-ammo-6-(methoxymethyl)-9H-pyrimido[4,5-b]indol-9-yl)ace tic acid (339f) (0.23 mmol) in DMF (10 mL) using HC1 salt of ( 1 R 3 S 5R)-N-(6-bromopyridin-2-yl)-5-methyl-2- mmol), DIPEA (0.160 mL, 0.920 mmol) and stirring at RT overnight. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4-amino-6-(methoxymethyl)- 9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl) -5-methyl-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (340a) (80 mg, 62% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfe) δ 10.77 (s, 1H, DzOexchangeable), 8.69 (s, 2H, DzOexchangeable), 8.62 (s, 1H), 8.50 (s, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.75 - 7.64 (m, 2H), 7.53 (dd, J= 8.5, 1.5 Hz, 1H), 7.31 (d, J= 7.7 Hz, 1H), 5.72 (d, J= 17.4 Hz, 1H), 5.37 (d, J= 17.3 Hz, 1H), 4.56 (s, 2H), 4.37 (dd, J= 9.1, 6.0 Hz, 1H), 3.69 (dd, J= 5.5, 2.4 Hz, 1H), 3.31 (s, 3H), 2.55 - 2.41 (m, 1H), 1.98 (dd, 13.2, 5.9 Hz, 1H), 1.30 (s, 3H), 1.01 (t, J= 5.5 Hz, 1H), 0.93 (dd, J= 5.4, 2.4 Hz, 1H); MS (ES+): 564.10 & 566.10 (M+l); MS (ES-): 562.10 & 564.10 (M-l); Analysis calculated for CzeHzeBrNzOz.1 0HC1.1 SHzO: C, 49.73; H, 4.82; N, 15.61; Cl, 5.65; Found: C, 49.79; H, 4.86; N, 15.71; Cl, 5.38.

Scheme 341

341b 341c

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(3-methoxyphenyl)-8-methyl-9H-pyr imido[4,5- bJindol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1.0]hexane-3-carboxamide (341c)

Step-1: Preparation of tert- butyl 2-(4-amino-6-(3-methoxyphenyl)-8-methyl-9H- pyrimido[4,5-b]indol-9-yl)acetate (341a)

Compound 341a was prepared and purified according to the procedure reported in step-1 of yl)acetate (192 e) (200 mg, 0.511 mmol) in dioxane (18 mL) using (3-methoxyphenyl)boronic acid (117 mg, 0.767 mmol), cesium carbonate (250 mg, 0.767 mmol) in water (2.2 mL), Pd(PPh3)2Ch (71.8 mg, 0.102 mmol) to afford tert-butyl 2-(4-amino-6-(3-methoxyphenyl)-8- methyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (341a) (110 mg, 51% yield) as a white solid; MS (ES+): 419.20 (M+l).

Step-2: Preparation of 2-(4-amino-6-(3-methox\phenyl)-8-methyl-9H-pyrimido[4,5-b]in dol- 9-yl)acetic acid (341b)

Compound 341b was prepared according to the procedure reported in step-2 of scheme- 1, from tert-butyl 2-(4-amino-6-(3-methoxyphenyl)-8-methyl-9H-pyrimido[4,5-b]in dol-9- yl)acetate (341a) (105 mg, 0.251 mmol) in DCM (10 mL) using TFA (0.483 mL, 6.27 mmol) and stirring at RT for 27 h. This gave after workup 2-(4-amino-6-(3-methoxyphenyl)-8- methyl-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (341b) and was used as such for the next step; MS (ES+): 363.10 (M+l).

Step-3: Preparation of ( 1 R,3S,5R)-2-(2-(4-amino-6-(3-mcthoxyphenyl)-8-methyl-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3- carboxamide (341c)

Compound 341c was prepared according to tire procedure reported in step-3 of scheme- 1, from 2-(4-amino-6-(3-methoxyphenyl)-8-methyl-9H-pyrimido[4,5-b]in dol-9-yl)acetic acid (341b) (0.125 mmol) in DMF (8 mL) using HC1 salt of ( 1 R,3 S,5R)-N-(6-bromopyridin-2-yl)- 2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (0.048 g, 0.150 mmol), HATU (0.095 g,

0.250 mmol), DIPEA (0.109 mL, 0.625 mmol) and stirring at RT for 22 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4-amino-6-(3- methoxyphenyl)-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl) -N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (341c) (26 mg, 33% yield) HC1 salt as a white solid; 'HNMR (300 MHz, DMSO-de) δ 10.83 (s, 1H, DzO exchangeable), 8.69 (s, 2H, D2O exchangeable), 8.62 (s, 1H), 8.59 - 8.56 (m, 1H), 8.01 (d, J= 8.2 Hz, 1H), 7.71 (t ,J= 8.0 Hz, 1H), 7.64 (s, 1H), 7.45 - 7.35 (m, 3H), 7.31 (d, J= 7.7 Hz, 1H), 7.01 - 6.90 (m, 1H), 5.94 (d, J= 18.0 Hz, 1H), 5.66 (d, J= 17.9 Hz, 1H), 4.43 (dd, J= 9.0, 5.7 Hz, 1H), 3.98 - 3.89 (m, 1H), 3.85 (s, 3H), 2.77 (s, 3H), 2.45 - 2.29 (m, 1H), 2.28 - 2.14 (m, 1H), 2.01 - 1.86 (m, 1H), 1.15 - 1.03 (m, 1H), 0.78 - 0.56 (m, 1H); MS (ES+): 626.10 & 628.20 (M+l); MS (ES-): 624.10 & 626.10 (M-l); Analysis calculated for CaiH-eBrNzOa.1.OHCI.2.OH2O: C, 53.27; H, 4.76; N, 14.03; Found: C, 53.14; H, 4.60; N, 13.87.

Scheme 342

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(3-methoxyphenyl)-8-methyl-9H-pyr imido[4, 5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azab icyclo[3.1 ,0]hexane-3- carboxamide (342a)

Compound 342a was prepared according to the procedure reported in step-3 of scheme- 1, from 2-(4-amino-6-(3-methoxyphenyl)-8-methyl-9H-pyrimido[4,5-b]in dol-9-yl)acetic acid (341b) (0.125 mmol) in DMF (8 mL) using HC1 salt of ( 1 R,3 S,5R)-N-(6-bromopyridin-2-yl)- 5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (49.9 mg, 0.150 mmol), HATU (95 mg, 0.250 mmol), DIPEA (0.109 mL, 0.625 mmol) and stirring at RT for 22 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4-amino-6-(3- methoxyphenyl)-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl) -N-(6-bromopyridin-2-yl)-5- methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (342a) (27 mg, 34% yield) HC1 salt as a white solid; ‘HNMR (300 MHz, DMSO-tife) δ 10.82 (s, 1H, D ₂ 0 exchangeable), 8.57 (s, 1H), 8.56 - 8.48 (m, 4H, 3H D2O exchangeable ), 8.01 (d ,J= 8.2 Hz, 1H), 7.70 (t ,J= 8.0 Hz,

1H), 7.61 (s, 1H), 7.43 - 7.35 (m, 3H), 7.31 (d, J= 7.7 Hz, 1H), 7.01 - 6.89 (m, 1H), 5.88 (d, J= 17.9 Hz, 1H), 5.61 (d, J= 17.8 Hz, 1H), 4.39 (dd, J= 8.9, 6.2 Hz, 1H), 3.85 (s, 3H), 3.74 - 3.68 (m, 1H), 2.74 (s, 3H), 2.58 - 2.42 (m, 1H), 1.98 (dd, J= 13.2, 6.1 Hz, 1H), 1.31 (s, 3H), 1.02 (t, J= 5.4 Hz, 1H), 0.87 - 0.82 (m, 1H); MS (ES+): 640.20 & 642.15 (M+l); MS (ES-): 638.10 & 640.10 (M-l); Analysis calculated for C32H3oBrN ₇ 03.1.OHCl.1.75H2O: C, 54.25; H, 4.91; N, 13.84; Found: C, 54.21; H, 4.81; N, 13.72.

Scheme 343

308b 343a

Preparation of (2S,4R)- l-(2-(4-amino-8-methyl-6-(2-methylpyrimidin-5-yl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-chloropyridin-2-yl)-4 -fluoro-4-methylpyrrolidine-2- carboxamide (343a)

Compound 343a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(2-methylpyrimidin-5-yl)-9H-pyrimido[4 ,5-b]indol- 9-yl)acetic acid (308b) (75 mg, 0.162 mmol) in DMF (5 mL) using TFA salt of (2S,4R)-N- (6-chloropyridin-2-yl)-4-fluoro-4-methylpyrrolidine-2-carbox amide (320b) (60.3 mg, 0.162 mmol), HATU (74.0 mg, 0.195 mmol), DIPEA (105 mg, 0.811 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-299, (2S,4R)-l-(2-(4- amino-8-methyl-6-(2-methy lpyrimidin-5 -y l)-9H-py rimido [4,5-b] indol-9-yl)acetyl)-N -(6- chloropyridin-2-y])-4-fluoro-4-methy]pyrrolidine-2-carboxami de (343a) (43 mg, 45% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfc) 5 (a mixture of two rotamers)

11.37 and 11.01 (2s, 1H, DzO exchangeable), 9.24 and 9.23 (2s, 2H), 9.04 (bs, 2H, D ₂ 0 exchangeable), 8.80 and 8.77 (2s, 1H), 8.68 (s, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.87 - 7.75 (m, 2H), 7.18 (d, J = 7.7 Hz, 1H), 5.77 (d, J = 18.0 Hz, 1H), 5.56 (d, J = 17.7 Hz, 1H), 4.70 (dd, J = 9.7, 7.5 Hz, 1H), 4.37 - 4.22 (m, 1H), 3.98 - 3.93 (m, 1H), 2.77 (s, 3H), 2.70 (s, 3H), 2.65 - 2.56 (m, 1H), 2.22 - 1.97 (m, 1H), 1.64 (d, J = 21.1 Hz, 3H); ¹⁹ F NMR (282 MHz, DMSO-tfc) δ -139.90; MS (ES+): 588/590 (M+l); (ES-): 586/588 (M-l); Analysis calculated for C29H27CIFN9O2.I.35HCI.3.25H2O: C, 50.06; H, 5.05; Cl, 11.97; N, 18.12; Found: C, 50.03; H, 4.93; Cl, 12.07; N, 17.91.

Scheme 344

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyr imido[4,5- b]indol-9-yl)acetyl)-N-(6-bromo-4-methoxypyridin-2-yl)-2-aza bicyclo[3.1.0]hexane-3- carboxamide (344c)

Step-1: Preparation of (lR,3S,5R)-/er/-butyl 3-((6-bromo-4-methoxypyridin-2- yl)carbamoyl)-2-azabicyclo[3.1 0]hexane-2-carboxylate (344a)

An aliquot of 1 -chIoro-N,N,2-trimethylprop- 1 -en- 1 -amine (0.090 mL, 0.677 mmol) was added drop wise to a solution of (lR,3S,5R)-2-(fer/-butoxycarbonyl)-2- azabicyclo[3.1.0]hexane-3-carboxylic acid (259a) (140 mg, 0.616 mmol) in DCM (10 mL) at 0 °C and the mixture was stirred at 0 °C for 1 h, followed by addition of 6-bromo-4- methoxypyridin-2-amine (125 mg, 0.616 mmol), DIPEA (159 mg, 1.231 mmol) and stirring at RT for 16 h. The reaction mixture was diluted with DCM (15 mL), washed with H2O (20 mLx2), brine (20 mL) dried, filtered, concentrated and the residue obtained was purified using flash column chromatography [S1O2 gel, eluting with EtOAc in hexane from 0-20%] to provide (lR,3S,5R)-terf-butyl 3-((6-bromo-4-methoxypyridin-2-yl)carbamoyl)-2- azabicyclo[3.1.0]hexane-2-carboxylate (344a) (155 mg, 61% yield) as a pale-yellow solid; Ή NMR (300 MHz, DMSO-fife) δ 10.74 (s, 1H), 7.69 (s, 1H), 6.99 (d, J= 2.0 Hz, 1H), 4.26 - 4.01 (m, 1H), 3.85 (s, 3H), 3.47 - 3.35 (m, 1H), 2.37 - 2.18 (m, 1H), 2.18 - 2.01 (m, 1H),

1.68 - 1.49 (m, 1H), 1.33 (d,/ = 46.4 Hz, 9H), 0.83 - 0.65 (m, 1H), 0.47 - 0.31 (m, 1H); MS (ES+): 412/414 (M+l); (ES-): 410/412 (M-l). Step-2: Preparation of (lR,3S,5R)-N-(6-bromo-4-methoxypyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-caiboxamide (344b)

A mixture of (lR,3S,5R)-tor/-butyl 3-((6-bromo-4-methoxypyridin-2-yl)carbamoyl)-2- azabicyclo[3.1 ,0]hexane-2-carboxvlate (344a) (155 mg, 0.376 mmol), 4 M HC1 in dioxane (0.94 mL, 3.76 mmol) were suspended in DCM (5 mL), stirred at RT for 16 h and concentrated in vacuum to dryness. The residue was triturated with ether and the solid obtained was collected by filtration to provide the HC1 salt of (lR,3S,5R)-N-(6-bromo-4- methoxypyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (344b) (130 mg, 99 % yield) as a white solid; ¾ NMR (300 MHz, DMSO-cfe) δ 11.32 (s, 1H), 10.51 (bs, .7= 6.9 Hz, 1H), 9.18 (bs, 1H), 7.60 (d, J= 2.0 Hz, 1H), 7.09 (d, J= 2.0 Hz, 1H), 4.29 - 4.04 (m, 1H), 3.87 (s, 3H), 3.39 - 3.25 (m, 1H), 2.69 - 2.54 (m, 1H), 2.16 - 1.96 (m, 1H), 1.90 - 1.73 (m, 1H), 0.95 - 0.65 (m, 2H); MS (ES+): 312/314 (M+l); (ES-): 310/312 (M-l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromo-4-methoxypyridi n-2-yl)-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (344c)

Compound 344c was prepared according to the procedure reported in step-3 of scheme- 1, from HC1 salt of ( 1 R, 3 S,5 R)-N -(6-bromo-4-methoxypyridi n -2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (344b) (59.7 mg, 0.171 mmol) in DMF (5 mL) using HC1 salt of 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]in dol-9-yl)acetic acid (184f) (75 mg, 0.171 mmol), HATH (98 mg, 0.257 mmol), DIPEA (111 mg, 0.856 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyr imido[4,5- b]indol-9-yl)acetyl)-N-(6-bromo-4-methoxypyridin-2-yl)-2-aza bicyclo[3.1.0]hexane-3- carboxamide (344c) (27 mg, 34% yield) HC1 salt as a white solid; ^! H NMR (300 MHz, DMSO-flk) δ 10.77 (s, 1H, D2O exchangeable), 9.03 (bs, 2H, D2O exchangeable), 8.83 (s,

1H), 8.72 (s, 1H), 7.64 (d, J = 1.7 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 6.95 (d, J = 2.0 Hz, 1H), 5.98 (d, J = 18.1 Hz, 1H), 5.69 (d, J = 18.0 Hz, 1H), 4.49 - 4.37 (m, 1H), 3.96 - 3.90 (m, 1H), 3.82 (s, 3H), 2.78 (s, 3H), 2.41 - 2.27 (m, 1H), 2.26 - 2.13 (m, 1H), 2.02 - 1.83 (m, 1H), 1.15 - 1.01 (m, 1H), 0.78 - 0.59 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -58.86; MS (ES+): 618/620 (M+l); (ES-): 616/618 (M-l); Analysis calculated for

C26H23BrF3N ₇ 03.1.1HC1.1.75H20: C, 45.26; H, 4.03; Cl, 5.65; N, 14.21; Found: C, 45.34; H, 3.95; Cl, 5.74; N, 14.16.

Scheme 345

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyr imido[4, 5- bJindol-9-yl)acetyl)-N-(6-(difluoromethoxy)pyridin-2-yl)-2-a zabicyclo[3. l.OJhexane-3- carboxamide (345c)

Step-1: Preparation of ( 1 R,3 S,5R)-/erf-butyl 3-((6-(difluoromethoxy)pyridin-2- yl)carbamoyl)-2-azabicyclo[3.1 ,0]hexane-2-carboxylate (345a)

Compound 345a was prepared and purified according to the procedure reported in step-1 of scheme-344, from (lR,3S,5R)-2-(tm-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3 - carboxylic acid (259a) (177 mg, 0.781 mmol) in DCM (5 mL) using l-chloro-N,N,2- trimethylprop- 1 -en- 1 -amine (0.114 mL, 0.859 mmol), 6-(difhioromethoxy)pyridin-2-amine (125 mg, 0.781 mmol) and DIPEA (202 mg, 1.561 mmol) to afford ( 1R,3 S,5R)-tert-butyl 3- (6-(difluoromethoxy)pyridin-2-ylcarbamoyl)-2-azabicyclo[3.1 ,0]hexane-2-carboxylate (345a) (170 mg, 59% yield) as a pale-yellow solid; Ή NMR (300 MHz, DMSO-cfe) δ 10.44 (s, 1H), 8.04 - 7.85 (m, 2H), 7.57 (s, 1H), 6.88 - 6.64 (m, 1H), 4.34 - 4.05 (m, 1H), 3.35 (s, 1H), 2.38 - 2.21 (m, 1H), 2.21 - 2.02 (m, 1H), 1.71 - 1.53 (m, 1H), 1.32 (s, 9H), 0.84 - 0.64 (m, 1H), 0.50 - 0.33 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO -de) δ -86.36; MS (ES+): 370 (M+l); (ES-): 368 (M-l).

Step-2: Preparation of ( 1 R,3 S,5R)-N-(6-(difluoromethoxy)pyridin-2-yl)-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (345b)

Compound 345b was prepared according to the procedure reported in step-2 of scheme-344, from (lR,3S,5R)-terf-butyl 3-((6-(difluoromethoxy)pyridin-2-yl)carbamoyl)-2- azabicyclo[3.1 0]hexane-2-carboxyIate (345a) (165 mg, 0.447 mmol) in DCM (5 mL) using 4 up HC1 salt of (lR,3S,5R)-N-(6-(difluoromethoxy)pyridin-2-yl)-2-azabicyclo[ 3.1.0]hexane- 3 -carboxamide (345b) (123 mg, 90% yield) as a white solid ¹ !! NMR (300 MHz, DMSO-flfe) 5 11.08 (s, 1H), 7.98 (t, J= 8.0 Hz, 1H), 7.86 (d, J= 8.1 Hz, 1H), 7.58 (t, J= 72.8 Hz, 1H),

6.88 (d, J= 7.9 Hz, 1H), 4.34 - 4.08 (m, 1H), 3.33 - 3.18 (m, 1H), 2.66 - 2.54 (m, 1H), 2.19 - 1.98 (m, 1H), 1.91 - 1.62 (m, 1H), 0.91 - 0.76 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-cfe) δ -86.32; MS (ES+): 270 (M+l); (ES-): 268 (M-l)

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-(difluoromethoxy)pyri din-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (345c)

Compound 345c was prepared according to the procedure reported in step-3 of scheme- 1, from HCl salt of (lR,3S,5R)-N-(6-(difluoromethoxy)pyiidin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (345b) (52.3 mg, 0.171 mmol) in DMF (5 mL) using TEA salt of 2-(4-amino-8-methyl-6-(trifluoromethy 1) -9H-pyrimido [4,5 -bj indol-9-y l)acetic acid (184f) (75 mg, 0.171 mmol), HATU (98 mg, 0.257 mmol), DIPEA (111 mg, 0.856 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyr imido[4,5- b]indol-9-yl)acetyl)-N-(6-(difluoromethoxy)pyridin-2-yl)-2-a zabicyclo[3.1.0]hexane-3- carboxamide (345c) (56 mg, 57% yield) HCl salt as a white solid; Ή NMR (300 MHz, DMSO-tifc) δ 10.54 (s, 1H, D2O exchangeable), 8.86 (bs, 2H, DzO exchangeable), 8.82 (s,

1H), 8.68 (s, 1H), 7.91 - 7.80 (m, 2H), 7.63 (d, J = 1.7 Hz, 1H), 7.50 (t, J = 73.0 Hz, 1H),

6.82 - 6.67 (m, 1H), 5.99 (d, J = 18.0 Hz, 1H), 5.70 (d, J = 18.0 Hz, 1H), 4.49 (dd, J = 9.0, 5.7 Hz, 1H), 3.99 - 3.91 (m, 1H), 2.79 (s, 3H), 2.42 - 2.30 (m, 1H), 2.28 - 2.14 (m, 1H), 2.03 - 1.87 (m, 1H), 1.17 - 1.04 (m, 1H), 0.70 (m, J = 5.2, 2.4 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSOtifc) δ -58.82, -86.30, -86.40; MS (ES+): 576 (M+l); (ES-): 574 (M-l); Analysis calculated for C26H22F5N7O3.HCl l.5H2O: C, 48.87; a 4.10; Cl, 5.55; N, 15.34; Found: C, 48.78; ¾ 4.12; Cl, 5.53; N, 15.26.

Scheme 346

Preparation of ( lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyrido[4\3^4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetyl)-N-(6-bro mopyridin-2-yl)-2- azabicydo[3.1.0]hexane-3-caiboxamide (346g)

Step-1 : Preparation ofN-(4-bromo-2-methyl-6-(trifluoromethyl)pyridin-3-yl)-2,2,2 - trifluoroacetamide (346b)

Compound 346b was prepared according to the procedure reported in step-1 of scheme-46, from 4-bromo-2-methyl-6-(trifluoromethyl)pyridin-3-amine (346a)(6.16 g, 24.15 mmol; CAS # 1990462-02-6) in DCM (25 mL) using triethylamine (4.15 g, 41.1 mmol), trifluoroacetic acid anhydride (7.61 g, 36.2 mmol) to afford after workup N-(4-bromo-2-methyl-6- (trifluoromethyl)p>Tidin-3-yl)-2,2,2-trifluoroacetamide (346b) (8.08 g, 95% yield) as a pale- yellow solid and was used as such for next step; Ή NMR (300 MHz, DMSO-cfc) δ 11.84 (s, 1H), 8.32 (s, 1H), 2.51 (s, 3H); ¹⁹ FNMR(282 MHz, DMSO-cf ₆ ) δ -66.43, -74.09; MS (ES+): 351/353 (M+l); (ES-): 349/351 (M-l).

Step-2: Preparation of 2-amino-7-methyl-5-(trifluoromethyl)- 1 H-pyrrolo [2,3 -c]py ridine-3 - carbonitrile (346c)

Compound 346c was prepared and purified according to the procedure reported in step-1 of scheme-11, from N-(4-bromo-2-methyl-6-(trifluoromethyl)pyridin-3-yl)-2,2,2- trifluoroacetamide (346b) (8.08 g, 23.02 mmol) in DMSO (30 mL) using malononitrile (1.825 g, 27.6 mmol), L-proline (0.530 g, 4.60 mmol), Cul (0.438 g, 2.302 mmol), a solution of K2CO3 (6.36 g, 46.0 mmol) in water (30 mL) to afford 2-amino-7 -methyl-5 - (trifhxoromethyl)-lH-pyrrolo[2,3-c]pyridine-3-carbonitrile (346c) (3.76 g, 68% yield) as a yellow solid; Ή NMR (300 MHz, DMSO-ifc) δ 11.68 (s, 1H), 7.40 (s, 1H), 7.27 (s, 2H), 2.57 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -64.65; MS (ES+): 241 (M+l); (ES-): 239 (M-l). Step-3: Preparation of 8-methyl-6-(trifluoromethyl)-9H-pyrido[4 ^, ,3 ^, :4,5]p>Trolo[2,3- d]pyrimidin-4-amine (346d)

Compound 346d was prepared according to the procedure reported in step-2 of scheme-29, from 2-amino-7-methyl-5-(trifluoromethyl)-lH-pyrrolo[2,3-c]pyridi ne-3-carbonitrile (346c) (3.76 g, 15.65 mmol) in ethanol (10 mL) using trimethoxymethane (16.61 g, 157 mmol), NHtOAc (3.62 g, 47.0 mmol) and heating at 90 °C for 16 h. This gave after workup 8- methyl-6-(trifluoromethyl)-9H-p> ^, rido[4 ^, ,3 ^, :4,5]pyrrolo[2,3-d]pyrimidin-4-amine (346d) (3.53 g, 84% yield) as a pale-yellow solid; Ή NMR (300 MHz, DMSO^) δ 12.66 (s, 1H), 8.78 (s, 1H), 8.40 (s, 1H), 7.72 (bs, 2H), 2.79 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO) -de δ -63.78; MS (ES+): 268 (M+l); (ES-): 266 (M-l).

Step-4: Preparation of tert-butyl 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyrido[4',3':4,5]pyiTolo[2,3-d]pyrimidin-9-yl)acetate (346e)

Compound 346e was prepared according to the procedure reported in step-1 of scheme- 1, from 8-methyl-6-(trifluoromethyl)-9H-pyrido[4 ^l ,3 ^l :4,5]pyrrolo[2,3-d]pyrimidin-4-amine (346d) (3.53 g, 13.21 mmol) in DMF (20 mL) using fe/7-butyl 2-bromoacetate (3.09 g, 15.85 mmol), CszCOs (8.61 g, 26.4 mmol) and stirring at RT for 16 h. This gave after workup tert- butyl 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrido [4',3 ¹ : 4,5 Jpyrrolo [2,3 -d]py rimidin- 9-yl)acetate (346e) (3.46 g, 69% yield) as a pale-yellow solid; Ή NMR (300 MHz, DMSO- de) δ 8.86 (s, 1H), 8.45 (s, 1H), 7.91 (bs, 2H), 5.44 (s, 2H), 2.88 (s, 3H), 1.44 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-de) δ -64.14; MS (ES+): 382 (M+l); (ES-): 380 (M-l).

Step-5: Preparation of 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyrido[4',3':4,5]pyirolo[2,3-d]pyrimidin-9-yl)acetic acid (346f)

Compound 346f was prepared according to the procedure reported in step-2 of scheme- 1, from tert-butyl 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrido[4 ^, ,3 ^, :4,5]pyrrolo[2,3- d]pyrimidin-9-yl)acetate (346e) (366 mg, 0.960 mmol) using TFA (1094 mg, 9.60 mmol) in DCM (5 mL) to afford after workup TFA salt of 2-(4-amino-8-methyl-6-(trifluoromethyl)- 9H-pyrido[4 ^, ,3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetic acid (346f) (0.280 g, 66% yield) as a pale-yellow solid; Ή NMR (300 MHz, DMSO-ifc) δ 8.88 (s, 1H), 8.48 (s, 1H), 8.04 (bs, 2H), 5.47 (s, 2H), 2.91 (s, 3H); ^!9 F NMR (282 MHz, DMSO-Je) δ -64.16, -74.52; MS (ES+): 326 (M+l), (ES-): 324 (M-l).

Step-6: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyrido[4 ^, ,3 ^, :4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetyl)-N-(6-bromopy ridin-2-yl)-2- azabicyclo[3 1 0]hexane-3-carboxamide (346g) Compound 346g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methjd-6-(trifluoromethyl)-9H-pyrido[4',3 ^, :4,5]pyrrolo[2,3- d]pyrimidin-9-yl)acetic acid (346f) (60 mg, 0.137 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (4a) (43.5 mg, 0.137 mmol), HATU (62.3 mg, 0.164 mmol), DIPEA (88 mg, 0.683 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-p&g t; ^, rido[4 ^, ,3 ^, :4,5]pyrrolo[2,3- d]pyrimidin-9-yl)acetyl)-N-(6-hromopyridin-2-yl)-2-azabicycl o[3.1.0]hexane-3-carboxamide (346g) (72 mg, 89% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-de) δ 10.85 (s, 1H, DzO exchangeable), 8.99 (s, 1H), 8.95 (bs, 2H, D2O exchangeable), 8.71 (s, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 6.03 (d, J = 18.0 Hz, 1H), 5.73 (d, J = 17.9 Hz, 1H), 4.46 - 4.40 (m, 1H), 4.00 - 3.92 (m, 1H), 2.43 - 2.30 (m, 1H), 2.28 - 2.12 (m, 1H), 2.04 - 1.82 (m, 1H), 1.10 (m, J = 8.8, 5.4 Hz, 1H), 0.80 - 0.59 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-de) δ -64.39; MS (ES+): 589/591 (M+l); (ES-): 587/589 (M-l); Analysis calculated for C24H20BrF3N8O2.UHCl.2H2O: C, 43.31; H, 3.80; Cl, 5.86; N, 16.84; Found: C, 43.24; H, 3.73; Cl, 5.97; N, 16.73.

Scheme 347

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetyl)-N-(6-b romopyridin-2-yl)-5-methyl-2- azabicyclo[3.1.0Jhexane-3-carboxamide (347a)

Compound 347a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrido[4 ^, ,3':4,5]pyrrolo[2,3- d]pyrimidin-9-yl)acetic acid (346f) (60 mg, 0.137 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (8a) (45.4 mg, 0.137 mmol), HATU (62.3 mg, 0.164 mmol), DIPEA (88 mg, 0.683 mmol) and stirring at RT for 16 h This gave after workup and purification as described in scheme 299, (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyr ido[4',3':4,5]pyrrolo[2,3- d]pyrimidin-9-yl)acetyl)-N -(6-bromopy ridin-2-y l)-5 -methyl-2-azabicyclo [3.1 0]hexane-3- carboxamide (347a) (63 mg, 76 % yield) HCI salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.84 (s, 1H, D ₂ 0 exchangeable), 8.95 (s, 1H), 8.66 (bs, 2H, D2O exchangeable), 8.63 (s, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 5.95 (d, J = 18.0 Hz, 1H), 5.68 (d, J = 17.9 Hz, 1H), 4.39 (dd, J = 9.1, 6.2 Hz, 1H), 3.77 - 3.73 (m, 1H), 2.93 (s, 3H), 2.50 - 2.41 (m, 1H), 1.99 (dd, J = 13.3, 6.1 Hz, 1H), 1.32 (s, 3H), 1.07 - 0.98 (m, 1H), 0.96 - 0.82 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-<¾) δ -64.32; MS (ES+): 603/605 (M+l); (ES-): 601/603 (M-l); Analysis calculated for C2sH22BrF3N ₈ O2.0.95HC1.1.75H2O: C, 44.85; H, 3.98; Cl, 5.03; N, 16.74; Found: C, 44.76;

H, 3.80; Cl, 5.06; N, 16.60.

Scheme 348

Preparation of ( 1 R,3S,5R)-2-(2-(4-ammo-8-methyl-6-(trifluoromethy])-9H-pyrimi do[4,5- b]indol-9-yl)acetyl)-N-(6-(trifluoromethyl)pyrazin-2-yl)-2-a zabicyclo[3.1.0]hexane-3- carboxamide (348c)

Step-1: Preparation of ( 1R,3 S,5R)-ferf-butyl 3-((6-(trifluoromethyl)pyrazin-2-yl)carbamoyl)- 2-azabicyclo [3.1 ,0]hexane-2-carboxylate (348a)

Compound 348a was prepared and purified according to the procedure reported in step-1 of scheme-344, from (lR,3S,5R)-2-(te/7-butoxycarbonyl)-2-azabicyclo[3.1 ,0]hexane-3- carboxylic acid (259a) (174 mg, 0.766 mmol) in DCM (10 mL) using l-chloro-N,N,2- trimethylprop- 1 -en- 1 -amine (0.112 mL, 0.843 mmol), 6-(trifluoromethyl)pyrazin-2-amine (125 0766 l) DIPEA (198 1 533 l) t ff d (lR 3S 5R) b l 3 ((6 (trifluoromethyl)pyrazin-2-yl)carbamoyl)-2-azabicyclo[3.1 ,0]hexane-2-carboxylate (348a)

(63 mg, 22% yield) as a pale-yellow solid; MS (ES+): 373 (M+l); (ES-): 371 (M-l).

Step-2: Preparation of (lR,3S,5R)-N-(6-(trifluoromethyl)pyrazin-2-yl)-2- azabicyclo[3.1.0]hexane-3-caiboxamide (348b)

Compound 348b was prepared according to the procedure reported in step-2 of scheme-344, from (lR,3S,5R)-tert-butyl 3-((6-(trifhioromethyl)pyrazin-2-yl)carbamoyl)-2- azabicyclo[3.1.0]hexane-2-carboxylate (348a) (63 mg, 0.169 mmol) in DCM (5 mL) using 4 M HC1 in dioxane (0.423 mL, 1.692 mmol) to afford HC1 salt of (lR,3S,5R)-N-(6- (trifluoromethyl)pyrazin-2-yl)-2-azabicyclo[3.1.OJhexane-3-c arboxamide (348b) (42 mg,

80% yield) as a white solid; Ή NMR (300 MHz, DMSO-ife) 5 11.88 (s, 1H), 9.58 (s, 1H), 8.98 (s, 1H), 4.25 (dd, J= 10.8, 7.8 Hz, 1H), 3.40 - 3.30 (m, 1H), 2.64 (dd, J= 12.8, 7.8 Hz, 1H), 2.23 - 2.04 (m, 1H), 1.90 - 1.74 (m, 1H), 0.93 - 0.76 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-ί/ή) 5 -66.42; MS (ES+): 273 (M+l); (ES-): 271 (M-l).

Step-3: Preparation of ( 1 R,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-(trifluoromethyl)pyra zin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (348c)

Compound 348c was prepared according to the procedure reported in step-3 of scheme- 1, from HC1 salt of (lR,3S,5R)-N-(6-(trifluoromethyl)pyrazin-2-yl)-2-azabicyclo[ 3.1.0]hexane- 3-carboxamide (348b) (42.3 mg, 0.137 mmol) in DMF (5 mL) using TFA salt of 2-(4-amino- 8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (184f) (60 mg, 0.137 mmol), HATU (78 mg, 0.205 mmol), DIPEA (88 mg, 0.684 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4- amino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9 -yl)acetyl)-N-(6- (trifluoromethyl)pyrazin-2-yl)-2-azabicyclo[3.1.0]hexane-3-c arboxamide (348c) (58 mg,

73% yield) HC1 salt as a white solid; ^! H NMR (300 MHz, DMSO-tife) δ 11.38 (s, 1H, DzO exchangeable), 9.55 (s, 1H), 8.85 (s, 1H), 8.80 (s, 1H), 8.70 (bs, 2H, DzO exchangeable), 8.64 (s, 1H), 7.61 (d, J = 1.7 Hz, 1H), 5.99 (d, J = 18.0 Hz, 1H), 5.71 (d, J = 17.9 Hz, 1H), 4.51 (dd, J = 9.0, 5.8 Hz, 1H), 4.01 - 3.91 (m, 1H), 2.79 (s, 3H), 2.46 - 2.34 (m, 1H), 2.34 - 2.22 (m, 1H), 2.03 - 1.89 (m, 1H), 1.16 - 1.03 (m, 1H), 0.81 - 0.66 (m, 1H); ¹⁹ FNMR(282 MHz, DMSO-ife) 5 -58.78, -66.52; MS (ES+): 579 (M+l), (ES-): 577 (M-l); Analysis calculated for CzsHzoFeNsOz.1. lHCLHzO: C, 47.17; H, 3.66; Cl, 6.13; N, 17.60; Found: C, 47.00; H, 3.61; Cl, 6.09; N, 17.45.

Scheme 349 H ₂ N N CF ₃

C0 XJ DIPEA

N ₂ H

Boc Cl

259a ΎΥ 349a 349b

CO ₂ H

L Me

Preparation of ( 1 R,3S,5R)-2-(2-(4-ammo-8-methyl-6-(trifluoromethy])-9H-pyrimi do[4,5- b]indol-9-yl)acetyl)-N-(6-(trifluoromethyl)pyiidin-2-yl)-2-a zabicyclo[3.1.0]hexane-3- carboxamide (349c)

Step-1: Preparation of (lR,3S,5R)-ter/-butyl 3-((6-(trifluoromethyl)pyridin-2-yl)caibamoyl)- 2-azabicyclo [3.1 ,0]hexane-2-carboxylate (349a)

Compound 349a was prepared according to the procedure reported in step-1 of scheme-345, from (lR,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicycIo[3.1.0]hexane -3-carboxylic acid (259a) (350 mg, 1.542 mmol) in DCM (5 mL) using 1 -chloro-N,N,2-trimethylprop- 1 -en- 1 - amine (0.224 mL, 1.696 mmol), 6-(trifluoromethyl)pyridin-2-amine (250 mg, 1.542 mmol), DIPEA (399 mg, 3.08 mmol) to afford after work up and purification using flash column chromatography [SiChgel, eluting with EtOAc in hexane from 0-15%] followed by purification using reverse phase column chromatography [Cl 8 column (100 g), eluting with ACN in water (containing 0.1% HCl) from 0-100%] ( 1R,3 S,5R)-/ert-butyl 3-((6- (trifluoromethyl)pyridin-2-yl)carbamoyl)-2-azabicyclo[3.1 ,0]hexane-2-carboxylate (349a) (280 mg, 49% yield) as a white solid; Ή NMR (300 MHz, DMSO-tfc) δ 10.92 (s, 1H), 8.38 (d, J= 8.4 Hz, 1H), 8.09 (t, 8.1 Hz, 1H), 7.61 (d, J= 7.5 Hz, 1H), 4.36 - 4.03 (m, 1H),

3.53 - 3.37 (m, 1H), 2.39 - 2.23 (m, 1H), 2.23 - 2.02 (m, 1H), 1.74 - 1.52 (m, 1H), 1.37 (d, 9H), 0.89 - 0.65 (m, 1H), 0.53 - 0.31 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -66.61; MS (ES+): 394 (M+Na); (ES-): 370 (M-l).

Step-2: Preparation of (lR,3S,5R)-N-(6-(trifluoromethyl)pyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (349b) Compound 349b was prepared according to the procedure reported in step-2 of scheme-344, from ( lR,3S,5R)-fc/i-butyl 3-((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)-2- azabicyclo[3.1 0]hexane-2-carboxylate (349a) (280 mg, 0.754 mmol) in DCM (5 mL) using 4 M HC1 in dioxane (1.885 mL, 7.54 mmol) to afford HC1 salt of (lR,3S,5R)-N-(6- (trifluoromethyl)pyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-c afboxamide (349b) (230 mg, 99% yield) as a white solid; Ή NMR (300 MHz, DMSO-afc) δ 11.48 (s, 1H), 8.32 (d,7= 8.5 Hz, 1H), 8.17 (t, J= 8.0 Hz, 1H), 7.71 (d, J= 7.5 Hz, 1H), 4.38 - 4.07 (m, 1H), 3.41 - 3.29 (m, 1H), 2.62 (dd, J= 12.8, 7.7 Hz, 1H), 2.27 - 2.05 (m, 1H), 1.98 - 1.72 (m, 1H), 0.98 - 0.58 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-ds) δ -66.61; MS (ES+): 272 (M+l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-(trifluoromethyl)pyri din-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (349c)

Compound 349c was prepared according to the procedure reported in step-3 of scheme- 1, from HC1 salt of (lR,3S,5R)-N-(6-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[ 3.1.0]hexane- 3-carboxamide (349b) (42.1 mg, 0.137 mmol) in DMF (5 mL) using TFA salt of 2-(4-amino- 8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (184f) (60 mg, 0.137 mmol), HATU (78 mg, 0.205 mmol), DIPEA (88 mg, 0.684 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4- amino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9 -yl)acetyl)-N-(6- (trifluoromethyl)pyridin-2-yl)-2-azabicyclo[3.1.0Jhexane-3-c arboxamide (349c) (54 mg, 68% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.96 (s, 1H, DzO exchangeable), 8.80 (s, 1H), 8.77 (bs, 2H, DzO exchangeable), 8.66 (s, 1H), 8.29 (d, J = 8.5 Hz, 1H), 8.05 (t, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.58 (d, J = 7.6 Hz, 1H), 5.99 (d, J = 18.0 Hz, 1H), 5.70 (d, J = 18.0 Hz, 1H), 4.49 (dd, J = 9.0, 5.7 Hz, 1H), 4.01 - 3.90 (m, 1H), 2.79 (s, 3H), 2.44 - 2.31 (m, 1H), 2.30 - 2.16 (m, 1H), 2.03 - 1.86 (m, 1H), 1.18 - 0.98 (m, 1H), 0.78 - 0.62 (m, 1H); ¹⁹ FNMR(282 MHz, DMSO-i/s) δ -58.80, -66.65; MS (ES+): 578 (M+l), (ES- ): 576 (M-l); Analysis calculated for CZ6HZIF ₆ N70Z.1.1HC1.1.25HZ0: C, 48.79; H, 3.87; Cl, 6.09; N, 15.32; Found: C, 48.59; H, 3.85; Cl, 5.97; N, 15.33.

Scheme 350 *»·]

CO ₂ H Ν l\ /

Η O Ν N

Me 261c

N r si ¹ T ^{1 N} Λ r \ Me

HATU, DIPEA

NH ₂

CF ₃ N-s _s JCi f \

NH ₂

346f ^CFa 350a

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyrido[4 ^, ,3':4,5jpyrrolo[2,3-d]pyrimidin-9-yl)acet>'l)-N-(6- bromopyrazin-2-yl)-5-methyl-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (350a)

Compound 350a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methjd-6-(trifluoromethyl)-9H-pyrido[4',3 ^, :4,5]pyrrolo[2,3- d]pyrimidin-9-yl)acetic acid (346f) (60 mg, 0.137 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyrazin-2-y])-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (261c) (45.6 mg, 0.137 mmol), HATU (62.3 mg, 0.164 mmol), DIPEA (88 mg, 0.683 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme- 299, (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyr ido[4',3':4,5]pyrrolo[2,3- d]pyrimidin-9-yl)acetyl)-N-(6-bromopyrazin-2-yl)-5-methyl-2- azabicyclo[3.1 ,0]hexane-3- carboxamide (350a) (57 mg, 69% yield) HC1 salt as a white solid; *H NMR (300 MHz, DMSO^fc) δ 11.21 (s, 1H, D2O exchangeable), 9.24 (s, 1H), 8.95 (s, 1H), 8.68 (bs, 2H, D2O exchangeable), 8.64 (s, 1H), 8.53 (s, 1H), 5.96 (d, J = 18.0 Hz, 1H), 5.68 (d, J = 17.9 Hz, 1H), 4.41 (dd, J = 9.1, 6.2 Hz, 1H), 3.80 - 3.70 (m, 1H), 2.92 (s, 3H), 2.60 - 2.52 (m, 1H), 2.03 (dd, J = 13.2, 6.1 Hz, 1H), 1.32 (s, 3H), 1.09 - 0.99 (m, 1H), 0.96 - 0.86 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO-tife) δ -64.34; MS (ES+): 604/606 (M+l); (ES-): 602/604 (M-l); Analysis calculated for C24H21BrF3N9O2 l.45HCl.2H2O: C, 41.58; H, 3.85; Cl, 7.42; N, 18.18; Found: C, 41.70; H, 3.67; Cl, 7.44; N, 18.08.

Scheme 351

346f 351a

Preparation of (lR,3S,5R)-2-(2-(4-ammo-8-methyl-6-(tiifluoromethyl)-9H- pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetyl)-N-(6-c hloropyridin-2-yl)-5-methyl-2- azabicyclo[3.1.0]hexane-3-caiboxamide (351a)

Compound 351a was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrido[4 ^, ,3':4,5]pyrrolo[2,3- d]pyrimidin-9-yl)acetic acid (346f) (55 mg, 0.125 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-chloropyridin-2-yl)-5-methyl-2-azabicyclo[3. 1.0]hexane-3-carboxamide (269b) (36.1 mg, 0.125 mmol), HATU (57.1 mg, 0.150 mmol), DIPEA (81 mg, 0.626 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme- 299, (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyr ido[4 ^l ,3 ^, :4,5Jpyrrolo[2,3- d]pyrimidin-9-yl)acet>'l)-N-(6-chloropyridin-2-yl)-5-me1h yl-2-azabicyclo[3.1 ,0]hexane-3- carboxamide (351a) (56 mg, 80% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-tifc) δ 10.82 (s, 1H, D ₂ 0 exchangeable), 8.97 (s, 1H), 8.81 (bs, 2H, DzO exchangeable), 8.67 (s, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.81 (t, J = 8.0 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 5.96 (d, J = 18.1 Hz, 1H), 5.68 (d, J = 17.9 Hz, 1H), 4.39 (dd, J = 9.1, 6.2 Hz, 1H), 3.78 - 3.69 (m, 1H), 2.93 (s, 3H), 2.49 - 2.43 (m, 1H), 1.99 (dd, J = 13.3, 6.1 Hz, 1H), 1.31 (s, 3H), 1.08 - 0.98 (m, 1H), 0.92 - 0.81 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-tifc) δ -64.37; MS (ES+): 559/561 (M+l); (ES-): 557/559 (M-l); Analysis calculated for C25H22CIF3N8O2.O.95HCI.2H2O: C, 47.69; H, 4.31; Cl, 10.98; N, 17.80; Found: C, 47.78; H, 4.27; Cl, 10.90; N, 17.77.

Scheme 352 (HO) ₂ B

COJ'BU C0 ₂ 'BU

Γ r oc rV Me Me

Me TFA

N f * r*V.

PdtPPhakClz f *

NH _{2 2} C0 ₃ NH ₂ NH ₂

K

Br

Vo Vo

Preparation of ( 1 R,3 S,5 R)-2-(2-(4-amino-6-(furan-3 -yl)-8-methyl-9H-pyrimido [4,5 -bj indol- 9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexa ne-3-carboxamide (352c) Step-1: Preparation of terf-butyl 2-(4-amino-6-(furan-3-yl)-8-methyl-9H-pyrimido(4,5- b]indol-9-yl)acetate (352a)

Compound 352a was prepared according to the procedure reported in step-lof scheme-62, from /erf-butyl 2-(4-amino-6-bromo-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)ace tate (192e) (200 mg, 0.511 mmol) in dioxane (4 mL) using furan-3-ylboronic acid (57.2 mg, 0.511 mmol), bis(triphenylphosphine)palladium(H) chloride (35.9 mg, 0.051 mmol), a solution of 3.3 M potassium carbonate (0.465 mL, 1.533 mmol) and heating at 100 °C for 16 h. This gave after workup and purification using flash column chromatography [silica gel (24 g), eluting with MeOH in DCM from 0-3%] te/7-butyl 2-(4-amino-6-(furan-3-yl)-8-methyl-9H- pyrimido[4,5-b]indol-9-yl)acetate (352a) (74 mg, 38% yield) as a yellow solid; Ή NMR (300 MHz, DMSOK/6) δ 8.35 (s, 1H), 8.30 (s, 1H), 8.23 (s, 1H), 7.76 (t, J= 1.7 Hz, 1H), 7.47 (s, 1H), 7.40 (bs, 2H), 7.19 (d, ./= 1.9 Hz, 1H), 5.33 (s, 2H), 2.64 (s, 3H), 1.43 (s, 9H); MS (ES+): 379 (M+l); (ES-): 377 (M-l).

Step-2: Preparation of 2-(4-amino-6-(furan-3-y])-8-methyl-9H-pyrimido[4,5-b]indol-9 - yl)acetic acid (352b)

Compound 352b was prepared according to the procedure reported in step-2 of scheme- 1, (352a) (72 mg, 0.190 mmol) in DCM (5 mL) using TFA (217 mg, 1.903 mmol) to afford TFA salt of 2-(4-amino-6-(furan-3-yl)-8-methyl-9H-pyrimido[4,5-b]indol-9 -yl)acetic acid (352b) (105 mg) as a brown solid; MS (ES+): 323 (M+l); (ES-): 321 (M-l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(futan-3-yl)-8-methyl-9H-pyrimido [4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1 ,0]hexane-3-carboxamide (352c)

Compound 352c was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-(furan-3-yl)-8-methyl-9H-pyrimido[4,5-b]indol-9 -yl)acetic acid (352b) (50 mg, 0.115 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (4a) (36.5 mg, 0.115 mmol), HATU (52.3 mg, 0.138 mmol), DIPEA (74.0 mg, 0.573 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-299, ( 1 R,3 S,5R)-2-(2-(4- amino-6-(furan-3-yl)-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)a cetyl)-N-(6-bromopyridm-2- yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (352c) (34 mg, 51% yield) HC1 salt as a white solid; ¾ NMR (300 MHz, DMSO-ifc) δ 10.84 (s, 1H, DzO exchangeable), 8.74 (bs, 2H, D ₂ 0 exchangeable), 8.61 (s, 1H), 8.52 (s, 1H), 8.27 (s, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.78 (t, J = 1.7 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.60 (s, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.19 (d, J = 1.9 Hz, 1H), 5.91 (d, J = 17.9 Hz, 1H), 5.63 (d, J = 17.9 Hz, 1H), 4.43 (dd, J = 9.1, 5.7 Hz, 1H), 3.98 - 3.89 (m, 1H), 2.73 (s, 3H), 2.42 - 2.29 (m, 1H), 2.30 - 2.12 (m, 1H), 2.01 - 1.84 (m, 1H), 1.22 - 0.95 (m, 1H), 0.77 - 0.60 (m, 1H); MS (ES+): 586/588 (M+l), (ES-): 584/586 (M-l); Analysis calculated for CzeHMBr^Cb HClJTSHzO: C, 50.01; H, 4.57; Cl, 5.27; N, 14.58; Found: C, 49.94; H, 4.36; Cl, 5.41; N, 14.67.

Scheme 353 Preparation of(lR,3S,5R)-2-(2-(4-amino-6-(furan-3-yl)-8-methyl-9H-pyrimi do[4,5-b]indol- 9-yl)acet>’l)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabic yclo[3.1 ,0]hexane-3-carboxamide (353a)

Compound 353a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-(furan-3-yl)-8-methyl-9H-pyrimido[4,5-b]indol-9 -yl)acetic acid (352b) (50 mg, 0.115 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6- btomopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (8a) (38.1 mg, 0.115 mmol), HATU (52.3 mg, 0.138 mmol), DIPEA (74.0 mg, 0.573 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2- (4-amino-6-(furan-3-yl)-8-me1hyl-9H-pyrimido[4,5-b]indol-9-y l)acetyl)-N-(6-bromopyridin- 2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (353a) (37 mg, 54% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-dis) δ 10.83 (s, 1H, D2O exchangeable),

8.71 (bs, 2a D2O exchangeable), 8.59 (s, 1H), 8.51 (s, 1H), 8.28 (s, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.81 - 7.76 (m, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.59 (s, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.19 (d, J = 1.9 Hz, 1H), 5.83 (d, J = 18.0 Hz, 1H), 5.56 (d, J = 17.9 Hz, 1H), 4.39 (dd, J = 9.0, 6.2 Hz, 1H), 3.70 - 3.64 (m, 1H), 2.69 (s, 3H), 2.49 - 2.43 (m, 1H), 1.98 (dd, J = 13.3, 6.0 Hz, 1H), 1.31 (s, 3H), 1.08 - 0.94 (m, 1H), 0.92 - 0.79 (m, 1H); MS (ES+): 600/602 (M+l); (ES-): 598/600 (M-l); Analysis calculated for C29H2 ₆ BrN7O3.1.05HC1.2.75H2O: C, 50.61; H, 4.77; Cl, 5.41; N, 14.24; Found: C, 50.69; H, 4.66; Cl, 5.31; N, 14.36.

Scheme 354

Preparation of(lR,3S,5R)-2-(2-(4-ammo-8-methyl-6-(2-(trifluoromethyl)pyr idm-4-yl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1 ,0]hexane-3- carboxamide (354c)

Step-1: Preparation of tert-butyl 2-(4-amino-8-methyl-6-(2-(trifluoromethyl)pyridm-4-yl)- 9H-pyrimido[4,5-b]indol-9-yl)acetate (354a)

Compound 354a was prepared according to the procedure reported in scheme-263, from tert- butyl 2-(4-amino-6-bromo-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)ace tate (192e) (200 mg, 0.511 mmol) in n-BuOH (4 mL) using (2-(trifluoromethyl)pyridin-4-yl)boronic acid (146 mg, 0.767 mmol), Pdb(dba)3 (46.8 mg, 0.051 mmol), XPhos (48.7 mg, 0.102 mmol), a solution of 1.27 M potassium phosphate (0.805 mL, 1.022 mmol) and heating at 100 °C for 16 h. This gave after workup and purification using flash column chromatography [silica gel (12 g), eluting with MeOH in DCM from 0-7%] tert-butyl 2-(4-amino-8-methyl-6-(2- (trifluoromethyl)pyridin-4-yl)-9H-pyrimido[4,5-b]indol-9-yl) acetate (354a) (169 mg, 72% yield); ΉΝΜΚ (300 MHz, DMSO-ifc) δ 8.82 (d, J= 5.2 Hz, 1H), 8.76 - 8.66 (m, 1H), 8.42 (d ,J= 1.6 Hz, 1H), 8.35 (s, 1H), 8.26 (dt,J= 5.6, 1.2 Hz, 1H), 7.82 (d,J= 1.7 Hz, 1H), 7.58 (bs, 2H), 5.39 (s, 2H), 2.74 (s, 3H), 1.44 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-t/e) δ -66.17; MS (ES+): 458 (M+l); (ES-): 456 (M-l). Step-2: Preparation of 2-(4-amino-8-methyi-6-(2-(trifluoromethyl)pyridin-4-yl)-9H- pyrimido[4,5-b]indol-9-yl)acetic acid (354b)

Compound 354b was prepared according to the procedure reported in step-2 of scheme- 1 , from tert- butyl 2-(4-amino-8-methyl-6-(2-(trifluoromethyl)pyridin-4-yl)-9H-p yrimido[4,5- b]indol-9-yl)acetate (354a) (167 mg, 0.365 mmol) in DCM (5 mL) using TFA (416 mg, 3.65 mmol) to afford after workup TFA salt of 2-(4-amino-8-methyl-6-(2- (trifluoromethyi)pyridin-4-yl)-9H-pyrimido[4,5-b]indol-9-yl) acetic acid (354b) (233 mg) as a pale-yellow solid; Ή NMR (300 MHz, DMSCWe) δ 8.86 (d, J= 5.2 Hz, 1H), 8.81 (d, ./= 1.8 Hz, 1H), 8.57 (s, 1H), 8.45 (s, 2H), 8.41 (d, J= 1.7 Hz, 1H), 8.26 (dd, J= 5.2, 1.7 Hz, 1H), 7.93 (d, J= 1.6 Hz, 1H), 5.48 (s, 2H), 2.79 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-tife) δ -66.19, -74.61; MS (ES+): 402 (M+l); (ES-): 400 (M-l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(2-(trifluoromethyl)pyri din-4- yl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2 -yl)-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (354c)

Compound 354c was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(2-(trifluoromethyl)pyridin-4-yl)-9H-p yrimido[4,5- b]indol-9-yl)acetic acid (354b) (60 mg, 0.116 mmol) in DMF (5 ttiL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (4a) (37.1 mg, 0.116 mmol), HATU (53.1 mg, 0.140 mmol), DIPEA (75 mg, 0.582 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-299, (lR3S,5R)-2-(2-(4-amino-8-methyi-6-(2-(trifluoromethyi)pyrid in-4-yl)-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1.0]hexane-3-carboxamide (354c) (52 mg, 67% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.84 (s, 1H, D2O exchangeable), 8.85 (d, J = 5.6 Hz, 1H), 8.84 (s, 1H), 8.79 (bs, 2H, D2O exchangeable), 8.65 (s, 1H), 8.40 (d, J = 1.7 Hz, 1H), 8.26 (dd, J = 5.3, 1.7 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.93 (s, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 5.97 (d, J =

18.0 Hz, 1H), 5.68 (d, J = 17.9 Hz, 1H), 4.44 (dd, J = 9.0, 5.7 Hz, 1H), 4.00 - 3.92 (m, 1H), 2.81 (s, 3H), 2.43 - 2.30 (m, 1H), 2.30 - 2.11 (m, 1H), 2.05 - 1.85 (m, 1H), 1.18 - 1.00 (m, 1H), 0.81 - 0.60 (m, 1H); ¹⁹ FNMR(282 MHz, DMSO-tifc) δ -66.18; MS (ES+): 665/667 (M+l), (ES-): 663/665 (M-l); Analysis calculated for C3oH24BrF3N ₈ 02.1.3HC1.1.75H20: C, 48.40; H, 3.90; Cl, 6.19; N, 15.05; Found: C, 48.48; H, 3.70; Cl, 6.30; N, 14.97.

Scheme 355

354b 355a

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(2-(trifluoromethyl)pyri din-4-yl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5- methyl-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (355a)

Compound 355a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(2-(trifluoromethyl)pyridin-4-yl)-9H-p yrimido[4,5- b]indol-9-yl)acetic acid (354b) (60 mg, 0.116 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (8a) (38.7 mg, 0.116 mmol), HATU (53.1 mg, 0.140 mmol), DIPEA (75 mg, 0.582 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme- 299, (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(2-(trifluoromethyl)pyri din-4-yl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5- methyl-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (355a) (55 mg, 70% yield) HC1 salt as a white solid; >H NMR (300 MHz, DMSO-tfc) δ 10.84 (s, 1H, DzO exchangeable), 8.99 - 8.69 (m, 4H, in which 2H were DzO exchangeable), 8.65 (s, 1H), 8.39 (d, J = 1.7 Hz, 1H), 8.26 (dd, J = 5.2, 1.7 Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 1.7 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 5.91 (d, J = 18.0 Hz, 1H), 5.63 (d, J = 17.9 Hz, 1H), 4.40 (dd, J = 9.0, 6.1 Hz, 1H), 3.74 - 3.69 (m, 1H), 2.79 (s, 3H), 2.49 - 2.44 (m, 1H), 1.99 (dd, J = 13.2, 6.0 Hz,

1H), 1.32 (s, 3H), 1.08 - 0.96 (m, 1H), 0.93 - 0.81 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-C/Λ) δ -66.18; MS (ES+): 679/681 (M+l); (ES-): 677/679 (M-l); Analysis calculated for C31H26BrF3N8O2 O.25HCl.4H2O: C, 48.95; H, 4.54; Cl, 1.17; N, 14.73; Found: C, 48.94; H, 3.99; Cl, 1.07; N, 14.73.

Scheme 356 B(OH) ₂

Preparation of(lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(6-(trifluoromethyl)py ridin-3-yl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1 ,0]hexane-3- carboxamide (356c)

Step-1: Preparation of ten-butyl 2-(4-amino-8-methyl-6-(6-(trifluoromethyl)pyridm-3-yl)- 9H-pyrimido[4,5-b]indol-9-yl)acetate (356a)

Compound 356a was prepared according to the procedure reported in scheme-263 and step-1 of scheme-354, from fen-butyl 2-(4-amino-6-bromo-8-methyl-9H-pyrimido[4,5-b]indol-9- yl)acetate (192e) (200 mg, 0.511 mmol) and (6-(trifluoromethyl)pyridin-3-yl)boronic acid (146 mg, 0.767 mmol) to afford ten-butyl 2-(4-amino-8-methyl-6-(6- (trifluoromethyl)pyridin-3-yl)-9H-pjTimido[4,5-b]indol-9-yl) acetate (356a) (214 mg, 92% yield) as a white solid; Ή NMR (300 MHz, DMSO-cfe) δ 9.30 (d, J= 2.4 Hz, 1H), 8.66 (s, 1H), 8.54 (d,./= 8.3 Hz, 1H), 8.34 (d,J= 1.8 Hz, 1H), 8.01 (dd,./= 8.3, 1.8 Hz, 1H), 7.70 (s, 1H), 7.52 (bs, 2H), 5.38 (s, 2H), 2.73 (s, 3H), 1.45 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO d ₆ ) δ -66.02; MS (ES+): 458 (M+l); (ES-): 456 (M-l).

Step-2: Preparation of 2-(4-antino-8-methyl-6-(6-(trifluoromethyl)pyridin-3-yl)-9H- pyrimido[4,5-b]indol-9-yl)acetic acid (356b)

Compound 356b was prepared according to the procedure reported in step-2 of scheme- 1, b]indol-9-yl)acetate (356a) (210 mg, 0.459 mmol) in DCM (5 mL) using TFA (523 mg, 4.59 mmol) to afford TFA salt of 2-(4-amino-8-methyl-6-(6-(trifluoromethyl)pyridin-3-yl)-9H- pyrimido[4,5-b]indol-9-yl)acetic acid (356b) (298 mg) as a pale-yellow solid; Ή NMR (300 MHz, DMSO-ifc) δ 9.30 (d, J= 2.2 Hz, 1H), 8.77 (d,./= 1.8 Hz, 1H), 8.58 (s, 1H), 8.55 (dd, J = 8.4, 2.2 Hz, 1H), 8.49 (s, 1H), 8.05 (d, J= 8.3 Hz, 1H), 7.82 (d, 1.7 Hz, 1H), 5.48 (s,

2H), 2.78 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -66.07, -74.59; MS (ES+): 402 (M+l); (ES-): 400 (M-l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(6-(trifluoromethyl)pyri din-3- yl)-9H-pyrimido[4,5-b]indol-9-yl)acet>i)-N-(6-bromopyridi n-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (356c)

Compound 356c was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(6-(trifluoromethyl)pyridin-3-yl)-9H-p yrimido[4,5- b]indol-9-yl)acetic acid (356b) (60 mg, 0.116 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (4a) (37.1 mg, 0.116 mmol), HATU (53.1 mg, 0.140 mmol), DIPEA (75 mg, 0.582 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-299,

( 1 R,3 S, 5 R)-2-(2-(4-amino-8-methyl-6-(6-(trifluoromethy l)pyridin-3 -y 1) -9H-py rimido [4,5 - b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1.0]hexane-3-carboxamide (356c) (47 mg, 61% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.84 (s, 1H, DzO exchangeable), 9.29 (d, J = 2.2 Hz, 1H), 8.78 (d, J = 1.8 Hz, 1H), 8.68 (bs, 2H, DzO exchangeable), 8.62 (s, 1H), 8.54 (dd, J = 8.1, 2.2 Hz, 1H), 8.10 - 7.97 (m, 2H), 7.80 (s, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 5.96 (d, J = 18.0 Hz, 1H), 5.68 (d, J = 17.9 Hz, 1H), 4.44 (dd, J = 9.0, 5.7 Hz, 1H), 4.01 - 3.90 (m, 1H), 2.80 (s, 3H), 2.44 - 2.30 (m, 1H), 2.30 - 2.13 (m, 1H), 2.03 - 1.86 (m, 1H), 1.18 - 1.04 (m, 1H), 0.80 - 0.63 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -66.08; MS (ES+): 665/667 (M+l); (ES-): 663/665 (M-l); Analysis calculated for C3oHz4BrF3N ₈ Oz.UHC1.2.5HzO: C, 48.00; H, 4.04; Cl, 5.20; N, 14.93; Found: C, 48.10; H, 3.54; Cl, 5.27; N, 14.93.

Scheme 357

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(6-(trifluoromethyl)pyri din-3-yl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5- methyl-2- azabicyclo[3.1.0]hexane-3-carboxamide (357a)

Compound 357a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(6-(trifluoromethyl)pyridin-3-yl)-9H-p yrimido[4,5- b]indol-9-yl)acetic acid (356b) (60 mg, 0.116 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (8a) (38.7 mg, 0.116 mmol), HATU (53.1 mg, 0.140 mmol), DIPEA (75 mg, 0.582 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme- 299, (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(6-(trifluoromethyl)pyri din-3-yl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5- methyl-2- azabicyclo[3.1.0]hexane-3-carboxamide (357a) (50 mg, 63% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifo) δ 10.84 (s, 1H, D ₂ 0 exchangeable), 9.29 (d, J = 2.2 Hz, 1H), 8.99 - 8.69 (m, 3H, in which 2H were D2O exchangeable), 8.63 (s, 1H), 8.54 (dd, J = 8.0, 2.3 Hz, 1H), 8.04 (d, J = 3.0 Hz, 1H), 8.01 (d, J = 3.0 Hz, 1H), 7.79 (s, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 5.90 (d, J = 18.0 Hz, 1H), 5.61 (d, J = 17.8 Hz, 1H), 4.40 (dd, J = 9.0, 6.2 Hz, 1H), 3.75 - 3.68 (m, 1H), 2.77 (s, 3H), 2.49 - 2.39 (m, 1H), 1.99 (dd, J = 13.3, 6.0 Hz, 1H), 1.32 (s, 3H), 1.07 - 0.96 (m, 1H), 0.90 - 0.74 (m, 1H); ¹⁹ F NMR (282 MHz, DMSOtty δ -66.09; MS (ES+): 679/681 (M+l); (ES-): 677/679 (M-l); Analysis calculated for C31H26BrF3NeO2.U5HCl.2H2O: C, 49.16; H, 4.15; Cl, 5.38; N, 14.79; Found: C, 49.25; H, 3.91; Cl, 5.37; N, 14.83.

Scheme 358

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(2-(trifluoromethyl)pyri din-3-yl)-9H- pyrimido[4,5-bjindol-9-yl)acetyl)-N-(6-bromop _} Tidin-2-yl)-5-methyl-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (358c)

Step-1: Preparation of terf-butyl 2-(4-amino-8-methyl-6-(2-(trifluoromethyl)pyridin-3-yl)- 9H-pyrimido[4,5-b]indol-9-yl)acetate (358a)

Compound 358a was prepared according to the procedure reported in scheme-263 and step-1 of scheme-354, from /erf-butyl 2-(4-amino-6-bromo-8-methyl-9H-pyrimido[4,5-b]indol-9- yl)acetate (192e) (200 mg, 0.511 mmol) and (2-(trifluoromethyl)pyridin-3-yl)boronic acid (98 mg, 0.511 mmol) to afford tert- butyl 2-(4-amino-8-methyl-6-(2-(trifluoromethyl)pyridin- 3-yl)-9H-pyrimido[4,5-b]indol-9-yl)acetate (358a) (21 mg, 9% yield); MS (ES+): 458 (M+l); (ES-): 456 (M-l).

Step-2: Preparation of 2-(4-amino-8-methyl-6-(2-(trifluoromethyl)pyridin-3-yl)-9H- pyrimido[4,5-b]indol-9-yl)acetic acid (358b)

Compound 358b was prepared according to the procedure reported in step-2 of scheme- 1 , from /erf-butyl 2-(4-amino-8-methyl-6-(2-(trifIuoromethyl)pyiidin-3-yI)-9H-p yrimido[4,5- bJindol-9-yl)acetate (358a) (21 mg, 0.456 mmol) in DCM (5 mL) using TFA (52.3 mg, 0.459 mmol) to afford TFA salt of 2-(4-amino-8-methyl-6-(2-(trifluoromethyl)pyridin-3-yl)-9H- pyrimido[4,5-b]indol-9-yl)acetic acid (358b) (26 mg) as a pale-yellow solid; MS (ES+): 402 (M+l); (ES-): 400 (M-l). Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(2-(trifluoromethyl)pyri din-3- yl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2 -yl)-5-methyl-2- azabicyclo[3.1 ,0]hexane-3-caiboxamide (358c)

Compound 358c was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(2-(trifluoromethyl)pyridin-3-yl)-9H-p yrimido[4,5- b]indol-9-yl)acetic acid (358b) (26 mg, 0.050 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (8a) (16.78 mg, 0.050 mmol), HATU (23.02 mg, 0.061 mmol), DIPEA (32.6 mg, 0.252 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-299, ( 1 R,3 S,5R)-2-(2-(4-amino-8-methyl-6-(2-(trifluoromethyl)pyridin-3 -yl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5- methyl-2- azabicyclo[3.1.0]hexane-3-carboxamide (358c) (21 mg, 0.031 mmol, 61.3 % yield) HC1 salt as a pale-yellow solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.85 (s, 1H, D ₂ 0 exchangeable), 8.81 (d, J = 4.7 Hz, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.42 (bs, 2H, DzO exchangeable), 8.38 (s, 1H), 8.12 - 7.95 (m, 2H), 7.83 (dd, J = 7.8, 4.7 Hz, 1H), 7.71 (t, J = 7.9 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.26 (s, 1H), 5.92 (d, J = 17.9 Hz, 1H), 5.65 (d, J = 18.0 Hz, 1H), 4.49 - 4.33 (m, 1H), 3.74 - 3.69 (m, 1H), 2.73 (s, 3H), 2.49 - 2.45 (m, 1H), 1.99 (dd, J = 13.2, 6.1 Hz, 1H), 1.32 (s, 3H), 1.10 - 0.97 (m, 1H), 0.93 - 0.80 (m, 1H); ¹⁹ F NMR(282 MHz, DMSO-tife) δ - 59.64; MS (ES+): 679/681 (M+l); (ES-): 677/679 (M-l).

Scheme 359 Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(furan-2-yl)-8-methyl-9H-pyrimido [4,5-b]indol- 9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3 .1 ,0]hexane-3-carboxamide (359c)

Step-1: Preparation of ter/-butyl 2-(4-amino-6-(furan-2-yl)-8-methyl-9H-pyrimido[4,5- b]indol-9-yl)acetate (359a)

Compound 359a was prepared according to the procedure reported in scheme-263 and step-1 of scheme-354, from /erf-butyl 2-(4-amino-6-bromo-8-methyl-9H-pyrimido[4,5-b]indol-9- yl)acetate (192e) (180 mg, 0.460 mmol) and furan-2-ylboronic acid (103 mg, 0.920 mmol), to afford tort-butyl 2-(4-amino-6-(furan-2-yl)-8-methyl-9H-pyrimido[4,5-b]indol-9 -yl)acetate (359a) (158 mg, 91% yield)as a pale-yellow solid; Ή NMR (300 MHz, DMSO-afe) δ 8.49 (d, J= 1.7 Hz, 1H), 8.31 (s, 1H), 7.74 (d, J= 1.8 Hz, 1H), 7.54 (s, 1H), 7.42 (bs, 2H), 7.03 (d, J = 3.3 Hz, 1H), 6.62 (dd, J= 3.4, 1.8 Hz, 1H), 5.34 (s, 2H), 2.67 (s, 3H), 1.43 (s, 9H); MS (ES+): 379 (M+l); (ES-): 377 (M-l).

Step-2: Preparation of 2-(4-ammo-6-(furan-2-yl)-8-methyl-9H-pyrimido[4,5-b]indol-9- yl)acetic acid (359b)

Compound 359b was prepared according to the procedure reported in step-2 of scheme- 1 , from fcrf-butyl 2-(4-amino-6-(furan-2-yl)-8-methyI-9H-pyrimido[4,5-b]indol-9 -yl)acetate (359a) (158 mg, 0.418 mmol) in DCM (5 mL) using TFA (476 mg, 4.18 mmol) to afford TFA salt of 2-(4-amino-6-(furan-2-yl)-8-methyl-9H-pyrimido[4,5-b]indol-9 -yl)acetic acid (359b) (196 mg) as a green solid; Ή NMR (300 MHz, DMSO-i/e) δ 8.54 (d, J= 1.6 Hz, 1H), 8.52 - 8.45 (m, 3H), 7.70 (d, J= 1.8 Hz, 1H), 7.58 (s, 1H), 6.96 (d, J= 3.3 Hz, 1H), 6.57 (dd, J= 3.4, 1.8 Hz, 1H), 5.36 (s, 2H), 2.64 (s, 3H); MS (ES+): 323 (M+l), (ES-): 321 (M-l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(furan-2-yl)-8-methyl-9H-pyrimido [4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azab icyclo[3.1.0]hexane-3- carboxamide (359c)

Compound 359c was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-(furan-2-yl)-8-methyl-9H-pyrimido[4,5-b]indol-9 -yl)acetic acid (359b) (60 mg, 0.138 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyiidin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carb oxamide (8a) (45.7 mg, 0.138 mmol), HATH (62.7 mg, 0.165 mmol), DIPEA (89 mg, 0.688 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2- (4 amino 6 (furan 2 yl) 8 methyl 9H pyrimido[45 b]indol 9 yl)acetyl) N (6 bromopyridin 2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (359c) (27 mg, 33% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-r/i) δ 10.83 (s, 1H, D ₂ 0 exchangeable), 8.60 (s, 1H), 8.55 (s, 1H), 8.46 (bs, 2H, DzO exchangeable), 8.02 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 1.7 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.63 (s, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 3.4 Hz, 1H), 6.69 - 6.59 (m, 1H), 5.86 (d, J = 17.8 Hz, 1H), 5.59 (d, J = 17.8 Hz, 1H), 4.39 (dd, J = 9.1, 6.2 Hz, 1H), 3.73 - 3.67 (m, 1H), 2.72 (s, 3H), 2.49 - 2.42 (m, 1H), 1.99 (dd, J = 13.3, 6.1 Hz, 1H), 1.31 (s, 3H), 1.09 - 0.96 (m, 1H), 0.91 - 0.73 (m, 1H); MS (ES+): 600/602 (M+l); (ES-): 598/600 (M-l).

Scheme 360

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-cyclopropyl-8-methyl-9H-pyrimido[ 4,5-b]indol- 9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexa ne-3-carboxamide (360c) Step-1: Preparation of /erf-butyl 2-(4-amino-6-cyclopropyl-8-methyl-9H-pyrimido[4,5- b]indol-9-yl)acetate (360a)

Compound 360a was prepared according to the procedure reported in step-1 of scheme-59 and step-1 of scheme-354, from te/7-butyl 2-(4-amino-6-bromo-8-methyl-9H-pyrimido[4,5- b]indol-9-yl)acetate (192e) (180 mg, 0.460 mmol) and cyclopropyl boronic acid (79 mg, 0.920 mmol) to afford tert- butyl 2-(4-amino-6-cyclopropyl-8-methyl-9H-pyrimido[4,5- b]indol-9-yl)acetate (360a) (157 mg, 97% yield); Ή NMR (300 MHz, DMSO-tfc) δ 8.80 (bs, 2H), 8.63 (s, 1H), 8.00 (d, J= 1.7 Hz, 1H), 7.11 (d, J= 1.6 Hz, 1H), 5.41 (s, 2H), 2.63 (s, 3H), 2.13 - 1.91 (m, 1H), 1.44 (s, 9H), 1.07 - 0.95 (m, 2H), 0.89 - 0.73 (m, 2H); MS (ES+): Step-2: Preparation of 2-(4-amino-6-cyclopropyl-8-methyl-9H-pyrimido[4,5-b]indol-9- yl)acetic acid (360b)

Compound 360b was prepared according to the procedure reported in step-2 of scheme- 1 , from fcrf-butyl 2-(4-amino-6-cyclopropyl-8-methyl-9H-pyrimido[4,5-b]indol-9- yl)acetate (360a) (151 mg, 0.428 mmol) in DCM (5 mL) using TFA (489 mg, 4.28 mmol) to afford TFA salt of 2-(4-amino-6-cyclopropyl-8-methyl-9H-pyrimido[4,5-b]indol-9- yl)acetic acid (360b) (186 mg) as a white solid; Ή NMR (300 MHz, DMSO-i/e) δ 8.63 (bs, 2H), 8.59 (s, 1H), 7.96 (d, J= 1.7 Hz, 1H), 7.10 (s, 1H), 5.41 (s, 2H), 2.65 (s, 3H), 2.13 - 1.94 (m, 1H), 1.09 - 0.93 (m, 2H), 0.88 - 0.72 (m, 2H); MS (ES+): 297 (M+l); (ES-): 295 (M-l).

Step-3: Preparation of ( lR,3S,5R)-2-(2-(4-amino-6-cyclopropyl-8-methyl-9H-pyrimido[4 ,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1 ,0]hexane-3-carboxamide (360c)

Compound 360c was prepared according to the procedure reported in step-3 of scheme- 1 , from TFA salt of 2-(4-amino-6-cyclopropyl-8-methyl-9H-pyrimido[4,5-b]indol-9- yl)acetic acid (360b) (66 mg, 0.161 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (51.2 mg, 0.161 mmol), HATU (73.4 mg, 0.193 mmol), DIPEA (104 mg, 0.804 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4- amino-6-cyclopropyl-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)ac etyl)-N-(6-bromopyridin-2- yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (360c) (39 mg, 43% yield) HC1 salt as a white solid; 'HNMR (300 MHz, DMSO-ifc) δ 10.82 (s, 1H, DzO exchangeable), 8.89 - 8.33 (m, 3H, in which 2H were DzO exchangeable), 8.01 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 1.7 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 7.06 (s, 1H), 5.88 (d, J = 17.9 Hz, 1H), 5.61 (d, J = 17.9 Hz, 1H), 4.42 (dd, J = 9.1, 5.7 Hz, 1H), 3.98 - 3.86 (m, 1H), 2.66 (s, 3H), 2.42 - 2.28 (m, 1H), 2.27 - 2.13 (m, 1H), 2.08 - 1.97 (m, 1H), 1.96 - 1.86 (m, 1H), 1.14 - 1.02 (m, 1H), 1.02 - 0.92 (m, 2H), 0.87 - 0.77 (m, 2H), 0.73 - 0.64 (m, 1H); MS (ES+): 560/562 (M+l); (ES-): 558/560 (M-l); Analysis calculated for Cz7Hz ₆ BrN ₇ Oz.l.35HC1.2.75HzO: C, 49.19; H, 5.02; Cl, 7.26; N, 14.87; Found: C, 49.09; H, 4.77; Cl, 7.30; N, 14.93.

Scheme 361

Preparation of ( 1 RJS,5R)-2-(2-(4-amino-6-cyclopropyl-8-methyl-9H-pyrimido[4,5 -b]indol- 9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3 .1.0]hexane-3-carboxamide (361a)

Compound 361a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-cyclopropyl-8-methyI-9H-pyrimido[4,5-b]indol-9- yl)acetic acid (360b) (60 mg, 0.146 mmol) in DMF (5 ml) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (8a) (48.6 mg, 0.146 mmol), HATU (66.7 mg, 0.175 mmol), DIPEA (94 mg, 0.731 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2- (4-amino-6-cyclopropyl-8-methyl-9H-pyrimido[4,5-b]indol-9-yl )acetyl)-N-(6-bromopyridin- 2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-caiboxamide (361a) (49 mg, 58% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.82 (s, 1H, D2O exchangeable), 8.73 (bs, 2H, D2O exchangeable), 8.61 (s, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 1.7 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 7.06 (d, J = 1.6 Hz, 1H), 5.83 (d, J = 17.9 Hz, 1H), 5.56 (d, J = 17.9 Hz, 1H), 4.38 (dd, J = 9.0, 6.1 Hz, 1H), 3.72 - 3.66 (m, 1H), 2.64 (s, 3H), 2.49 - 2.36 (m, 1H), 2.07 - 1.89 (m, 2H), 1.31 (s, 3H), 1.06 - 0.91 (m, 3H), 0.89 - 0.76 (m, 3H); MS (ES+): 574/576 (M+l); (ES-): 572/574 (M-l); Analysis calculated for C28H28BrN7O2.HCl.2H2O: C, 51.98; H, 5.14; Cl, 5.48; N, 15.15; Found: C, 51.82; H, 5.01;

Cl, 5.44; N, 15.22.

Scheme 362

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-9-y])acetyl)-N-(6-b romopyridm-2-yl)-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (362f)

Step-1 : Preparation of 2-amino-7-methyl-5-(trifluoromethyl)-lH-pyrrolo[3,2-b]pyridi ne-3- carbonitrile (362b)

Compound 362b was prepared according to the procedure reported in step-1 of scheme- 11, from N-(2-bromo-4-methyl-6-(trifluoromethyl)pyridin-3-yl)-2,2,2-t rifluoroacetamide (362a) (4.87 g, 13.87 mmol; CAS # 2055497-18-0) in DMSO (30 mL) using malononitrile (1.100 g, 16.65 mmol), L-proline (0.319 g, 2.77 mmol), Cul (0.264 g, 1.387 mmol), a solution of K2CO3 (3.83 g, 27.7 mmol) in water (10 mL) to afford after purification [S1O2 gel (80 g), MeOH in DCM from 0-10%] 2-amino-7-methyl-5 -(trifluoromethy 1)- 1 H-pyrrolo [3,2- b]pyridine-3-carbonitrile (362b) (3.38 g) as a pale-yellow solid; ^! H NMR (300 MHz, DMSO- ek) δ 11.52 (s, 1H), 7.31 (s, 2H), 7.22 (s, 1H), 2.43 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO) δ - 64.38; MS (ES+): 241 (M+l); (ES-): 239 (M-l).

Step-2: Preparation of 8-methyl-6-(trifluoromethyl)-9H-p>Tido[2',3 ^, :4,5]pyrrolo[2,3- d]pyrimidin-4-amine (362c)

Compound 362c was prepared according to the procedure reported in step-2 of scheme-29, from 2-amino-7-methyl-5-(trifluoromethyl)-lH-pyrrolo[3,2-bJpyridi ne-3-carbonitrile (362b) (3.38 g, 14.07 mmol) using trimethoxymethane (7.47 g, 70.4 mmol) and NHtOAc (3.25 g, 42.2 mmol) to afford 8-methyl-6-(trifluoromethyl)-9H-pyrido[2',3':4,5]pyrrolo|2,3 - d] i idi 4 i (362 ) (328 87% i ld) lid *H NMR (300 MH DMSO-cfe) δ 12.57 (s, 1H), 8.43 (s, 1H), 7.99 (s, 1H), 7.72 (s, 1H), 6.46 (s, 1H), 2.66 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-i/e) δ -64.00; MS (ES+): 268 (M+l); (ES-): 266 (M-l).

Step-3: Preparation of tert-butyl 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyrido[2',3':4,5jp3'rrolo[2,3-d]pyrimidin-9-yl)acetate (362d)

Compound 362d was prepared according to the procedure reported in step-1 of scheme- 1, from 8-methyl-6-(trifluoromethyl)-9H-pyrido[2 ^, ,3 ^, :4,5]pyrrolo[2,3-d]pyrimidin-4-amine (362c) (3.28 g, 12.27 mmol) in DMF (15 mL) using tert-butyl 2-bromoacetate (2.63 g, 13.50 mmol) and CszCOs (8.0 g, 24.55 mmol) to afford tert- butyl 2-(4-amino-8-methyl-6- (trifluoromethyl)-9H-pyrido[2 ^, ,3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetate (362d) (3.21 g, 69% yield) as a pale-yellow solid; Ή NMR (300 MHz, DMSO-t/e) δ 8.48 (s, 1H), 8.20 (s, 1H), 7.75 (s, 1H), 6.64 (s, 1H), 5.39 (s, 2H), 2.74 (s, 3H), 1.43 (s, 9H); ¹⁹ F NMR (282 MHz, DMSO-ί/ό) δ -64.31; MS (ES+) 382 (M+l).

Step-4: Preparation of 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- py rido [2', 3 ¹ : 4,5 ]pyrrolo [2,3 -dJpyrimidin-9-y l)acetic acid (362e)

Compound 362e was prepared according to the procedure reported in step-2 of scheme- 1, from tert- butyl 2-(4-amino-8-methyl-6-(trifhxoromethyl)-9H-pyrido[2 ^, ,3 ^, :4,5]pyrrolo[2,3- d]pyrimidin-9-yl)acetate (362d) (3.21 g, 8.42 mmol) using TFA (9.6 g, 84 mmol) in DCM (10 mL) to afford TFA salt of 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyridoP'^M^lpyrroloP^-dlpyrimidin-g-yOacetic acid (362e) (3.16 g, 85% yield) as a pale- yellow solid; Ή NMR (300 MHz, DMSO-ifc) δ 8.57 (s, 2H), 7.80 (s, 1H), 7.09 (bs, 1H), 5.43 (s, 2H), 2.78 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO) δ -64.34, -74.87; MS (ES+): 326 (M+l); (ES-): 324 (M-l).

Step-5: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyrido[2 ^, ,3':4,5]pyrrolo[2,3-d]py ^, rimidin-9-yl)acety'l)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (362f)

Compound 362f was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrido[2',3':4,5] pyrrolo[2,3- d]pyrimidin-9-yl)acetic acid (362e) (75 mg, 0.171 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (4a) (54.4 mg, 0.171 mmol), HATU (78 mg, 0.205 mmol), DIPEA (110 mg, 0.854 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-299, (lR 3S 5R) 2 (2 (4 amino 8 methyl 6 (trifluoromethyl) 9H py'rido[2 ^, 3 ^, :45]pyrrolo[23 d]pyrimidin-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicycl o[3.1.0]hexane-3-carboxamide (362f) (76 mg, 76% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) 5 10.77 (s, 1H, D2O exchangeable), 8.52 (bs, 2H, in which 1H was D2O exchangeable), 7.93 (d, J = 8.2 Hz, 1H), 7.71 (s, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 7.13 (bs, 1H, D2O exchangeable), 5.84 (d, J = 18.0 Hz, 1H), 5.59 (d, J = 17.9 Hz, 1H), 4.36 (dd, J = 9.1, 5.7 Hz, 1H), 3.91 - 3.83 (m, 1H), 2.72 (s, 3H), 2.36 - 2.22 (m, 1H), 2.19 - 2.08 (m, 1H), 1.93 - 1.77 (m, 1H), 1.09 - 0.94 (m, 1H), 0.71 - 0.58 (m, 1H); ^!9 F NMR (282 MHz, DMSCMe) δ -64.32; MS (ES+): 589/591 (M+l); (ES-): 587/589 (M-l).

Scheme 363

362e 363a

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)acetyl)-N-(6-b romopyridm-2-yl)-5-methyl-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (363a)

Compound 363a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-methjd-6-(trifluoromethyl)-9H-pyrido[2',3 ^, :4,5]pyrrolo[2,3- d]pyrimidin-9-yl)acetic acid (362e) (75 mg, 0.171 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (8a) (56.8 mg, 0.171 mmol), HATU (78 mg, 0.205 mmol), DIPEA (110 mg, 0.854 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme- 299, (lR,3S,5R)-2-(2-(4-ammo-8-methy]-6-(trifluoromethyl)-9H-pyri do[2 ^, ,3 ^, :4,5]pyrrolo[2,3- d]pyrimidin-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2- azabicyclo[3.1 ,0]hexane-3- carboxamide (363a) (71 mg, 69% yield) HC1 salt as a white solid; *H NMR (300 MHz, DMSO-flk) δ 10.84 (s, 1H, D2O exchangeable), 8.82 (bs, 1H, DzO exchangeable), 8.63 (s,

1H), 8.01 (d, J = 8.1 Hz, 1H), 7.80 (s, 1H), 7.71 (t, J = 7.9 Hz, 1H), 7.41 (bs, 1H, D2O exchangeable), 7.32 (d, J = 7.7 Hz, 1H), 5.88 (d, J = 18.0 Hz, 1H), 5.62 (d, J = 17.9 Hz, 1H), 439 (dd J = 9 1 6 1 Hz 1H) 3 76 - 3 67 (m 1H) 278 (s 3H) 250 - 2 38 (m 1H) 1 98 (dd, J = 13.3, 6.0 Hz, 1H), 1.31 (s, 3H), 1.08 - 0.98 (m, 1H), 0.93 - 0.78 (m, 1H); ¹⁹ FNMR (282 MHz, DMSO-dk) δ -64.34; MS (ES+): 603/605 (M+l); (ES-): 601/603 (M-l).

Scheme 364

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyr imido[4,5- b]indol-9-yl)acetyl)-N-(6-chloro-5-methylpyrazin-2-yl)-5-met hyl-2-azabicyclo[3.1.0]hexane- 3 -carboxamide (364e) and ( I R,3 S,5R)-2-(2-(4-amino-8-methyl-6-(trijluoromethyl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromo-5-methylpyrazin -2-yl)-5-methyl-2- azabicyclo[3.1.0]hexane-3-caiboxamide (364d)

Step-1: Preparation of (lR,3S,5R)-ter/-butyl 3 -((6-bromo-5 -methy lpyrazin -2-yl)carbamoyl)- 5-methyl-2-azabicyclo[3.1 ,0]hexane-2-carbox>'late (364a)

Compound 364a was prepared according to the procedure reported in step-1 of scheme-53 and step-1 of scheme-317, from ( 1 R,3 S,5 R)-2-(to/7-butoxycarbonyl)-5 -methy 1-2- azabicyclo[3.1.0]hexane-3-carbox>'hc acid (261a) (0.321 g, 1.330 mmol) and 6-bromo-5- methylpyrazin-2 -amine (0.25 g, 1.330 mmol) to afford ( 1R,3 S,5R)-tert-butyl 3-((6-bromo-5- methylpyrazin-2-yl)carbamoyl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-2-carboxylate (364a) (0.36 g, 66% yield) as a white crystalline solid; ^! HNMR (300 MHz, DMSCMs) δ 11.13 - 10.84 (m, 1H), 9.33 - 9.08 (m, 1H), 4.23 - 4.03 (m, 1H), 3.24 - 3.09 (m, 1H), 2.56 (s, 3H), 2.40 (dd,J= 12.9, 8.8 Hz, 1H), 1.98 - 1.77 (m, 1H), 1.32 (d, 9H), 1.19 (s, 3H), 0.75 - 0.55 (m, 2H); MS (ES+): 411/413 (M+l); (ES-): 409/411 (M-l).

Step-2: Preparation of (lR,3S,5R)-N-(6-bromo-5-methylpyrazin-2-yl)-5-methyl-2- azabicyclo[3.1.0]hexane-3-carboxamide (364b) and (lR,3S,5R)-N-(6-chloro-5- Compounds 364b and 364c were prepared according to the procedure reported in step-2 of scheme-344, from (lR,3S,5R)-tert-butyl 3-((6-bromo-5-methylpyrazin-2-yl)carbamoyl)-5- methyl-2-azabicyclo[3.1.0]hexane-2-carboxylate (364a) (360 mg, 0.875 mmol) in DCM (5 mL) using 4 M HC1 in dioxane (2.188 mL, 8.75 mmol) to afford 318 mg HC1 salt of a mixture of two products (lR,3S,5R)-N-(6-bromo-5-methylpyrazin-2-yl)-5-methyl-2- azabicyclo[3.1.0]hexane-3-carboxamide (364b); MS (ES+): 311/313 (M+l); (ES-): 309/311 (M-l), and (lR,3S,5R)-N-(6-chloro-5-methylpyrazin-2-yl)-5-methyl-2- azabicyclo[3.1.0]hexane-3-carboxamide (364c); MS (ES+): 267/269 (M+l); (ES-): 265/267 (M-l) as white sohds.

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-chloro-5-methylpyrazi n-2-yl)-5-methyl-2- azabicyclo[3.1.0]hexane-3-carboxamide (364e) and (lR,3S,5R)-2-(2-(4-amino-8-methyl-6- (trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6- bromo-5-methylpyrazin-2-yl)- 5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (364d)

Compounds 364d and 364e were prepared according to the procedure reported in step-3 of scheme- 1, from above mixture of (lR,3S,5R)-N-(6-bromo-5-methylpyiazin-2-yl)-5-methyl- 2-azabicyclo[3.1.0]hexane-3-carboxamide (364b) and (lR,3S,5R)-N-(6-chloro-5- methylpyrazin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-car boxamide (364c) (99 mg, 0.285 mmol) in DMF (5 mL) using HC1 salt of 2-(4-amino-8-methyl-6-(trifluoromethyl)-9H- pyrimido[4,5-b]indol-9-yl)acetic acid (184f) (125 mg, 0.285 mmol), HATU (163 mg, 0.428 mmol), DIPEA (184 mg, 1.426 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4-amino-8-methyl-6- (trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6- chloro-5-methylpyrazin-2-yl)- 5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (364e) (10 mg, 6% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 11.05 (s, 1H, D2O exchangeable), 9.10 (s, 1H),

8.79 (s, 1H), 8.65 (bs, 2H, DzO exchangeable), 8.63 (s, 1H), 7.60 (d, J = 1.7 Hz, 1H), 5.93 (d, J = 18.0 Hz, 1H), 5.65 (d, J = 18.0 Hz, 1H), 4.40 (dd, J = 9.1, 6.1 Hz, 1H), 3.74 - 3.69 (m,

1H), 2.76 (s, 3H), 2.51 (s, 3H), 2.49 - 2.44 (m, 1H), 2.01 (dd, J = 13.3, 6.0 Hz, 1H), 1.32 (s, 3H), 1.08 - 0.97 (m, 1H), 0.94 - 0.81 (m, 1H); ¹⁹ F NMR (282 MHz, DMSOntfc) δ -58.76; MS (ES+): 573/575 (M+l); (ES-): 571/573 (M-l); and (lR,3S,5R)-2-(2-(4-amino-8-methyl-6- (trifluoromethy l)-9H-pyrimido [4,5 -b] indol-9-yl)acetyl)-N -(6-bromo-5 -methylpyrazin-2-yl)- 5-methyl-2-azabicyclo[3.1.0]hexane-3-caiboxamide (364d) (77 mg, 44% yield) HC1 salt as a white solid; Ή NMR (300 MHz DMSO-tife) δ 11 08 (s 1H D2O exchangeable) 9 11 (s 1H) 18.0 Hz, 1H), 5.66 (d, J = 18.0 Hz, 1H), 4.40 (dd, J = 9.1, 6.1 Hz, 1H), 3.75 - 3.69 (m, 1H), 2.76 (s, 3H), 2.52 (s, 3H), 2.50 - 2.45 (m, 1H), 2.01 (dd, J = 13.2, 6.0 Hz, 1H), 1.32 (s, 3H), 1.11- 0.98 (m, 1H), 0.98 - 0.78 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-<fc) δ -58.80; MS (ES+): 617/619 (M+l); (ES-): 615/617 (M-l); Analysis calculated for C2 ₆ H2*BrF3N ₈ 02.1.25HC1.2.5H20: C, 44.10; H, 4.31; Cl, 6.26; N, 15.83; Found: C, 43.91; H, 4.15; Cl, 6.31; N, 15.93

Scheme 365

365b 365c

Preparation of (2S,4R)- l-^-^-amino-S-methyl-e-itrifluoromethylJ^H-pyrimido^S-

^indol-y-ylJacetyO-NKe-chloro-S-methylpyridin^-yl^-fluoro pynOlidine^-carboxamide

(365c)

Step-1: Preparation of (2S,4R)-ferf-butyl 2-((6-chloro-3-methylpyridin-2-yl)carbamoyl)-4- fluoropyrrolidine- 1 -carboxylate (365a)

Compound 365a was prepared according to the procedure reported in step-1 of scheme-53, from (2S,4R)-l-(terr-butoxycarbonyl)-4-fluoropyrrolidine-2-carbox ylic acid (321a) (0.340 g, 1.458 mmol) and 6-chloro-3-methylpyridin-2-amine (0.208 g, 1.458 mmol) to afford after purification as reported in step-1 of scheme-317, (2S,4R)-/ert-butyl 2-((6-chloro-3- methylpyridin-2-yl)carbamoyl)-4-fluoropyrrolidine- 1 -carboxylate (365a) (0.150 g, 29% yield) as a white solid; MS (ES+): 358.1(M+1); 380.1 (M+Na); (ES-): 356.1(M-1).

Step-2: Preparation of (2S,4R)-N-(6-chloro-3-methylpyridin-2-yl)-4-fluoropyrrolidin e-2- carboxamide (365b) Compound 365b was prepared according to the procedure reported in step-2 of scheme- 1, from (2S,4R)-/er/-butyl 2-((6-chloro-3-methylpyridin-2-yl)carbamoyl)-4-fluoropyrroli dine-l- carboxylate (365a) (0.145 g, 0.405 mmol) in DCM (2.2 mL) using TFA (0.219 mL, 2.84 mmol) to afford after purification as repotted in step-2 of scheme-319, HC1 salt of (2S,4R)-N- (6-chloro-3-methylpyridin-2-yl)-4-fluoropyrrolidine-2-carbox amide (365b) (0.086 mg, 82% yield); ‘HNMR(300 MHz, DMSO -de) 5 10.96 (s, 1H), 10.22 (s, 1H), 9.05 (s, 1H), 7.83 (d ,J = 8.0 Hz, 1H), 7.42 (d, 8.0 Hz, 1H), 5.69 - 5.34 (m, 1H), 4.66 (s, 1H), 3.59 (d,J= 28.5

Hz, 2H), 2.87 - 2.72 (m, 1H), 2.40 - 2.22 (m, 1H), 2.18 (s, 3H); MS (ES+): 258.0 (M+l).

Step-3: Preparation of (2S,4R)-l-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimi do[4,5- b]indol-9-yl)acetyl)-N-(6-chloro-3-methylpyridin-2-yl)-4-flu oropyrrolidine-2 -carboxamide (365c)

Compound 365c was prepared according to the procedure reported in step-3 of scheme- 1 , from HC1 salt of (2S,4R)-N-(6-chloro-3-methylpyridin-2-yl)-4-fluoropyrrolidin e-2- carboxamide (365b) (40.3 mg, 0.137 mmol) in DMF (1.5 mL) using TFA salt of 2-(4-amino- 8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (184f) (60 mg, 0.137 mmol), HATU (78 mg, 0.205 mmol), DIPEA (0.119 mL, 0.684 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-303, (2S,4R)-l-(2-(4- ammo-8-methyl-6-(trifIuoromethyl)-9H-pyrimido[4,5-b]indol-9- yl)acetyl)-N-(6-chloro-3- methylpyridm-2-yl)-4-fluoropyrrolidine-2-carboxamide (365c) (37mg, 48% yield) HC1 salt as a white solid; ^l HNMR (300 MHz, DMSO-tifc) (a mixture of two rotamers) 5 10.99 and 10.52 (2s, 1H, D2O exchangeable), 8.92 (s, 2H, D2O exchangeable), 8.83 (s, 1H), 8.68 (s, 1H), 7.83 and 7.69 (2d, J= 8.0 Hz, 1H), 7.64 and 7.61 (2s, 1H), 7.40 and 7.29 (2d, J= 7.9 Hz, 1H),

5.83 (d, J= 18.1 Hz, 1H), 5.69 - 5.41 (m, 2H), 4.63 (t, J= 8.5 Hz, 1H), 4.37 - 4.26 (m, 1H), 4.08-3.92 (m, 1H), 2.74 (s, 3H), 2.66 - 2.55 (m, 1H), 2.32 - 2.08 (m, 1H), 1.97 (s, 3H); ¹⁹ F NMR (282 MHz, DMSO-de) δ -58.82, -176.22; MS (ES+): 564.2 (M+l);586.1 (M+Na); (ES- ): 562.1 (M-l); Analysis calculated for C25H22CIF4N7O22H2O.0.85HC1: C, 47.59; H, 4.29;

Cl, 10.40; N, 15.54; Found: C, 47.87; H, 4.01; Cl, 10.51; N, 15.43.

Scheme 366

Preparation of (2S,4R)-l-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimi do[4,5- b]indol-9-yl)acetyl)-N-(6-bromo-5-fluoro-3-methylpyridin-2-y l)-4-fluoropyrrolidine-2- carboxamide (366c)

Step-1: Preparation of (2S,4R)-te/T-butyl 2-((6-bromo-5-fluoro-3-methylpyridin-2- yl)carbamoyl)-4-fluoropyrrolidine- 1 -carboxylate (366a)

Compound 366a was prepared according to the procedure reported in step-1 of scheme-53, from (2S,4R)-l-(/er/-butoxycarbonyl)-4-fluoropyrrolidine-2-carbox ylic acid (321a) (0.340 g, 1.458 mmol) and 6-bromo-5-fluoro-3-methylpyridin-2-amine (0.299 g, 1.458 mmol) to afford after purification as reported in step-1 of scheme-317, (2S,4R)-ter/-butyI 2-((6-bromo-5- fluoro-3-methylpyridin-2-yl)carbamoyl)-4-fluoropyrrolidine-l -caiboxylate (366a) (0.445 g, 73% yield) as a white solid; MS (ES+): 420.1/422.1 (M+l); 442.0/444.0 (M+Na).

Step-2: Preparation of (2S,4R)-N-(6-bromo-5-fluoro-3-methylpyridin-2-yl)-4- fluoropyrrolidine-2-carboxamide (366b)

Compound 366b was prepared according to the procedure reported in step-2 of scheme- 1, from (2 S ,4R) -to/7-butyl 2-((6-bromo-5-fluoro-3-methylpyiidin-2-yl)carbamoyl)-4- fluoropyrrolidine- 1 -carboxylate (366a) (0.435 g, 1.035 mmol) in DCM (5.6 mL) using TFA (0.558 mL, 7.25 mmol) to afford after purification as reported in step-2 of scheme-319, HC1 salt of (2S,4R)-N-(6-bromo-5-fluoro-3-methylpyridin-2-yl)-4-fluoropy rrolidine-2- carboxamide (366b) (0.324 mg, 98% yield); ¹ HNMR(300 MHz, DMSO-i/e) δ 10.98 (s, 1H), 10.18 (s, 1H), 9.06 (s, 1H), 7.94 (d, J= 8.4 Hz, 1H), 5.53 (dd, J= 53.5, 3.5 Hz, 1H), 4.64 (t, J = 9.2 Hz, 1H), 3.68 - 3.60 (m, 1H), 3.57 - 3.51 (m, 1H), 2.88 - 2.69 (m, 1H), 2.42 - 2.23 (m, Step-3: Preparation of (2S,4R)-l-(2-(4-amino-8-methyl-6-(trifluoromethyl)-9H-pyrimi do[4,5- b]indol-9-yl)acetyl)-N-(6-bromo-5-fluoro-3-methylpyridin-2-y l)-4-fluoropyrrotidine-2- carboxamide (366c)

Compound 366c was prepared according to the procedure reported in step-3 of scheme- 1, from HC1 salt of (2S,4R)-N-(6-bromo-5-fluoro-3-methylpyridin-2-yl)-4-fluoropy rrolidine-2- carboxamide (366b) (48.8 mg, 0.137 mmol) in DMF (1.5 mL) using TFA salt of 2-(4-amino- 8-metiiyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9-yl)a cetic acid (184f) (60 mg, 0.137 mmol), HATU (78 mg, 0.205 mmol), DIPEA (0.119 mL, 0.684 mmol) and stirring at RT for 16 h. Ibis gave after workup and purification as described in scheme-303, (2S,4R)-l-(2-(4- amino-8-methyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-9 -yl)acetyl)-N-(6-bromo-5- fluoro-3-methylpyridin-2-yl)-4-fluoropyrrolidine-2-carboxami de (366c) (63mg, 74% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-de) (a mixture of two retainers) δ 10.88 and 10.54 (2s, 1H, DzO exchangeable), 8.78 (s, 1H), 8.57 (s, 1H), 8.48 (s, 2H, DzO exchangeable), 7.94 and 7.80 (2d, J= 8.5 Hz, 1H), 7.59 and 7.56 (2s, 1H), 5.80 (d, J= 18.0 Hz, 1H), 5.69 - 5.46 (m, 2H), 4.60 (t, J= 8.5 Hz, 1H), 4.31 (dd, J= 21.4, 12.7 Hz, 1H), 4.07 - 3.90 (m, 1H), 2.72 (s, 3H), 2.68 - 2.58 (m, 1H), 2.32 - 2.07 (m, 1H), 1.98 (s, 3H). ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -58.69, -119.17, -176.67. MS (ES+): 626.1/628.1 (M+l); (ES-): 624.0/626.0 (M-l); Analysis calculated for CzsHziBrFsNzOz 1.5HzO.HCl: C, 43.53; H, 3.65; Cl, 5.14; N, 14.21; Found: C, 43.65; H, 3.48; Cl, 5.01; N, 14.04.

Scheme 367

Preparation of (lR,3S,5R)-2-(2-(4-amino-7-methoxy-6-(trifluoromethyl)-9H-py rimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1.0] hexane-3 -carboxami de (367g)

Step-1: Preparation of N-(2-bromo-5-methoxy-4-(trifluoromethyl)phenyl)-2, 2, 2- trifluoroacetamide (367b)

Compound 367b was prepared according to the procedure reported in step-1 of scheme-46, from 2-bromo-5-methoxy-4-(trifhioromethyl)aniline (367a)(l g, 3.70 mmol; CAS # 694514- 19-7) in DCM (15 mL) using triethylamine (0.877 mL, 6.30 mmol), trifluoroacetic acid anhydride (0.772 mL, 5.55 mmol) and stirring at RT for 16 h. This gave after workup and purification using flash column chromatography [silica gel (24 g), eluting with EtOAc in hexane from 0 to 50 %] N-(2-bromo-5-methoxy-4-(trifluoromethyl)phenyl)-2,2,2- trifluoroacetamide (367b) (1.35 g, 100% yield) as a pale yellow solid; ^! H NMR (300 MHz, DMSO-afe) δ 11.57 (s, 1H), 7.96 (s, 1H), 7.47 (s, 1H), 3.91 (s, 3H); ¹⁹ FNMR(282 MHz, DMSO-ifc) δ -61.15, -74.02; MS (ES-): 363.9 (M-l).

Step-2: Preparation of 2-amino-6-methoxy-5-(trifluoromethyl)- 1 H-i ndole-3 -carbonitrile (367c) Compound 367c was prepared according to the procedure reported in step-1 of scheme- 11, from N-(2-bromo-5-methoxy-4-(trifluoromethyl)phenyl)-2,2,2-triflu oroacetamide (367b) (1.3 g, 3.55 mmol) in DMSO (5 mL) and using malononitrile (0.268 mL, 4.26 mmol), L- proline (0.082 g, 0.710 mmol), Cul (0.068 g, 0.355 mmol) and K2CO3 (0.982 g, 7.10 mmol) to afford after workup and purification as described in step-1 of scheme-328, 2-amino-6- methoxy-5 -(trifluoromethyl)- lH-indole -3 -carbonitrile (367c) (0.106 g, 12% yield) as a yellow solid; Ή NMR (300 MHz, DMSO-de) δ 10.98 (s, 1H), 7.31 (s, 1H), 7.07 (s, 1H), 6.99 (s, 2H), 3.89 (s, 3H); ¹⁹ FNMR(282 MHz, DMSO) δ -59.05; MS (ES+): 256.1 (M+l); (ES-): 254.0 (M-l).

Step-3: Preparation of 7-methoxy-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-4-amin e (367d)

Compound 367d was prepared according to the procedure reported in step-2 of scheme-29, from 2-amino-6-methoxy-5-(trifhioromethyl)-lH-mdole-3-carbonitril e (367c) (0.1 g, 0.392 mmol) in ethanol (10 mL) using formamidine acetate (0.33 g, 3.13 mmol) and refluxing for 22 h. The mixture was purified using reverse-phase column chromatography [Cl 8 column (50 g), eluting with ACN in water (containing 0.1% HC1) from 0-100%]] to afford 7- methoxy-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-4-amine (367d) (80 mg, 72% yield) HC1 salt as a pale yellow solid; Ή NMR (300 MHz, DMSO-cfe) δ 13.07 (s, 1H), 8.81 (s, 1H), 8.59 - 8.42 (m, 3H), 7.27 (s, 1H), 3.99 (s, 3H); MS (ES+): 283.1(M+1).

Step-4: Preparation of /erf-butyl 2-(4-amino-7-methoxy-6-(trifluoromethyl)-9H- pyrimido[4,5-b]indol-9-yl)acetate (367e)

Compound 367e was prepared according to the procedure reported in step-2 of scheme- 16, from HCl salt of 7-methoxy-6-(trifhxoromethyl)-9H-pyrimido[4,5-b]indol-4-amin e (367d) (75 mg, 0.235 mmol) in DMF (3 mL) using terf-butyl 2-bromoacetate (0.038 mL, 0.259 mmol), CS2CO3 (192 mg, 0.588 mmol) and stirring at RT for 16 h. The solid separated was collected by filtration to give tert-butyl 2-(4-amino-7-methoxy-6-(trifluoromethyl)-9H- pyrimido[4,5-b]indol-9-yl)acetate (367e) (85 mg, 91% yield) as a pale yellow solid; MS (ES+): 397.1 (M+l).

Step-5: Preparation of 2-(4-ami no-7 -methoxy-6-(tri fluoromethyl )-9H-py rimido [4,5 -b] indol - 9-yl)acetic acid (367f)

Compound 367f was prepared according to the procedure reported in step-2 of scheme- 1, from fert-butyl 2-(4-amino-7-methoxy-6-(trifluoromethyl)-9H-pyrimido[4,5-b]i ndol-9- afford TFA salt of 2-(4-amino-7-methoxy-6-(trifluoromethyl)-9H-pyrimido[4,5-b]i ndol-9- yl)acetic acid (367f) (70 mg, 98% yield) as a pale-yellow solid; Ή NMR (300 MHz, DMSO- ek) δ 8.75 (s, 1H), 8.45 (s, 1H), 8.01 (d, J= 31.6 Hz, 1H), 7.67 (s, 1H), 5.27 (s, 2H), 3.99 (s, 3H); MS (ES+): 341.1 (M+l).

Step-6: Preparation of ( 1 R,3S,5R)-2-(2-(4-amino-7-methoxy-6-(trifluoromethyl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3- carboxamide (367g)

Compound 367g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-7-methoxy-6-(trifIuoromethyl)-9H-pyrimido[4,5-b]i ndol-9- yl)acetic acid (367f) (45.4 mg, 0.1 mmol) in DMF (1 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (31.9 mg, 0.100 mmol), HATH (57.0 mg, 0.150 mmol), DIPEA (0.087 mL, 0.500 mmol) and stirring at RT for 1 h. This gave after workup and purification as described in scheme-303, (lR,3S,5R)-2-(2-(4- amino-7-methoxy-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol- 9-yl)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (367g) (48 mg, 79% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-tife) δ 10.73 (s, 1H, DzO exchangeable), 8.84 (s, 1H), 8.71 - 8.52 (m, 3H, 2H D ₂ 0 exchangeable), 8.02 (d, J= 8.1 Hz, 1H), 7.72 (t, J= 8.0 Hz, 1H), 7.52 (s, 1H), 7.33 (d ,J= 7.7 Hz, 1H), 5.77 (d ,J= 17.3 Hz, 1H), 5.51 (d ,J=

17.2 Hz, 1H), 4.42 (dd,J= 9.1, 5.7 Hz, 1H), 4.01 (s, 3H), 3.93 (td, J= 6.2, 5.3, 2.3 Hz, 1H), 2.36 (dd, J= 13.4, 9.2 Hz, 1H), 2.31 - 2.16 (m, 1H), 2.00 - 1.88 (m, 1H), 1.17 - 1.02 (m,

1H), 0.82 - 0.73 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -59.20; MS (ES+): 604.1/606.1 (M+l); (ES-): 602.0/604.1 (M-l); Analysis calculated for C25H2iBrF3N ₇ O3.3.5H2O.0.65HCl: C, 43.45; H, 4.18; Cl, 3.33; N, 14.19; Found: C, 43.07; H, 3.76; Cl, 3.04; N, 13.78.

Scheme 368 Preparation of (lR,3S,5R)-2-(2-(4-amino-7-methoxy-6-(trifluoromethyl)-9H-py rimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azab icyclo[3.1.0]hexane-3- carboxamide (368a)

Compound 368a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-7-methoxy-6-(trifluoromethyl)-9H-pyrimido[4,5-b]i ndol-9- yl)acetic acid (367f) (45.4 mg, 0.1 mmol) in DMF (1 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carb oxamide (8a) (33.3 mg, 0.100 mmol), HATU (57.0 mg, 0.150 mmol), DIPEA (0.087 mL, 0.500 mmol) and stirring at RT for 1 h. This gave after workup and purification as described in scheme-303, (lR,3S,5R)-2- (2-(4-amino-7-methoxy-6-(trifluoromethyl)-9H-pyrimido[4,5-b] indol-9-yl)acetyl)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carb oxamide (368a) (44 mg, 71% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO^fe) δ 10.72 (s, 1H, DzO exchangeable), 8.85 (s, 1H), 8.70 (s, 2H, DzO exchangeable), 8.61 (s, 1H), 8.02 (d, J= 8.2 Hz, 1H), 7.72 (t, J= 8.0 Hz, 1H), 7.53 (s, 1H), 7.33 (d, J= 7.7 Hz, 1H), 5.74 (d, J= 17.3 Hz, 1H), 5.46 (d, J= 17.2 Hz, 1H), 4.38 (dd, J= 9.1, 6.1 Hz, 1H), 4.00 (s, 3H), 3.70 (dd, J= 5.5, 2.4 Hz, 1H), 2.57 - 2.53 (m, 1H), 2.01 (dd, 13.3, 6.0 Hz, 1H), 1.33 (s, 3H), 1.09 - 0.97 (m, 1H), 0.97 - 0.88 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -59.24; MS (ES+):

618.1/620.1 (M+l); (ES-): 616.1/618.0 (M-l); Analysis calculated for CzeHzzBrFsNzOz 2Hz0.1.2HCl: C, 44.73; H, 4.07; Cl, 6.09; N, 14.04; Found: C, 44.79; H, 4.07; Cl, 5.87; N, 13.85.

Scheme 369

369f 369g

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-fluoro-6-(trifluoromethyl)-9H-pyr imido[4, 5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1.0]hexane-3-carboxamide (369g)

Step-1: Preparation ofN-(2-bromo-6-fluoro-4-(trifluoromethyl)phenyl)-2,2,2- trifluoroacetamide (369b)

Compound 369b was prepared according to the procedure reported in step-1 of scheme-46, from 2-bromo-6-fluoro-4-(trifluoromethyl)aniline (369a) (1 g, 3.88 mmol; CAS # 1034325- 63-7) in DCM (15 mL) using triethylamine (0.918 mL, 6.59 mmol), trifluoroacetic acid anhydride (0.808 mL, 5.81 mmol) to afford after purification as reported in step-1 of scheme- 367 N-(2-bromo-6-fluoro-4-(trifluoromethyl)phenyl)-2,2,2-trifluo roacetamide (369b) (1.276 g, 93% yield) as a pale yellow solid; Ή NMR (300 MHz, DMSO-cfe) 5 11.84 (s, 1H), 8.13 (s, 1H), 8.04 (dd, J= 9.4, 1.9 Hz, 1H); MS (ES-): 351.9/353.9 (M-l).

Step-2: Preparation of 2-amino-7 -fluoro-5 -(trifluoromethyl)- 1 H-indole-3 -carbonitrile (369c) Compound 369c was prepared according to the procedure reported in step-1 of scheme- 11, from N-(2-bromo-6-fluoro-4-(trifluoromethyl)phenyl)-2,2,2-trifluo roacetamide (369b) (1.25 g 3 53 mmol) in DMSO (5 mL) using malononitrile (0267 mL 424 mmol) L-proline in water (5 mL) to afford after purification as reported in step-2 of scheme-367, 2-amino-7- fluoro-5 -(trifluoromethyl)- 1 H-indole-3 -carbonitrile (369c)(0.125 g, 15% yield) as a yellow solid; Ή NMR (300 MHz, DMSO-ife) δ 11.89 (s, 1H), 7.26 (s, 1H), 7.17 (d ,J= 11.0 Hz, 1H), 7.11 (s, 2H); MS (ES+): 244.0 (M+l); (ES-): 242.0 (M-l).

Step-3: Preparation of 8-fhioro-6-(trifhxoromethyl)-9H-pyrimido[4,5-b]indol-4-amine (369d) Compound 369d was prepared according to the procedure reported in step-2 of scheme-29, from 2 -amino-7 -fluoro-5-(trifluoromethyl)-lH-indole-3-carbonitrile (369c) (0.120 g, 0.494 mmol) in ethanol (10 mL) using formamidine acetate (0.415 g, 3.95 mmol) to afford after purification as reported in step-3 of scheme-367, 8-fluoro-6-(trifluoromethyl)-9H- pyrimido[4,5-b]indol-4-amine (369d) (61 mg, 46% yield) HC1 salt as a pale yellow solid; Ή NMR (300 MHz, DMSO-ifc) δ 13.69 (s, 1H), 8.83 (s, 1H), 8.67 (s, 2H), 8.60 (s, 1H), 7.79 (dd, J= 11.0, 1.4 Hz, 1H); MS (ES+): 271.1(M+1).

Step-4: Preparation of terf-butyl 2-(4-amino-8-fluoro-6-(trifluoromethyl)-9H-pyrimido[4,5- b]indol-9-yl)acetate (369e)

Compound 369e was prepared according to the procedure reported in step-2 of scheme- 16, from HC1 salt of 8-fluoro-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indol-4-amine (369d) (60 mg, 0.196 mmol) in DMF (3 mL) using tert-butyl 2-bromoacetate (0.032 mL, 0.215 mmol), CS2CO3 (159 mg, 0.489 mmol) and stirring at RT for 16 h. The solid separated was collected by filtration to give te/7-butyl 2-(4-amino-8-fluoro-6-(trifluoromethyl)-9H-pyrimido[4,5- b]indol-9-yl)acetate (369e) (30 mg, 40% yield) as a pale yellow solid; MS (ES+): 385.1(M+1).

Step-5: Preparation of 2-(4-amino-8-fluoro-6-(trifluoromethyl)-9H-pyrimido[4,5-b]in dol-9- yl)acetic acid (369f)

Compound 369f was prepared according to the procedure reported in step-2 of scheme- 1, from tert- butyl 2-(4-amino-8-fluoro-6-(trifluoromethyl)-9H-pyrimido[4,5-b]in dol-9- yl)acetate (369e) (28 mg, 0.073 mmol) using 20% TFA in DCM (418 pL, 1.093 mmol)) to afford 2-(4-amino-8-fluoro-6-(trifluoromethyl)-9H-pyrimido[4,5-b]md ol-9-yl)acetic acid (369f) (23 mg, 96% yield) TFA salt as a pale-yellow solid; Ή NMR (300 MHz, DMSO-ffc) δ 8.73 (s, 1H), 8.41 (s, 1H), 7.80 (s, 2H), 7.70 (d, J= 12.3 Hz, 1H), 5.25 (s, 2H); MS (ES+): 329.0(M+1).

Step-6: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-fluoro-6-(trifluoromethyl)-9H- pyrimido[4,5-bJindol-9-yl)acetyl)-N-(6-bromop _} Tidin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3- Compound 369g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-fluoro-6-(trifluoromethyl)-9H-pyrimido[4,5-b]in dol-9- yl)acetic acid (369f) (31.0 mg, 0.07 mmol) in DMF (1 mL) using HC1 salt of (1R,3S,5R)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamid e (4a) (22.30 mg, 0.070 mmol), HATU (39.9 mg, 0.105 mmol), DIPEA (0.061 mL, 0.350 mmol) and stirring at RT for 16 h. This gave after workup and purification as described in scheme-303, (lR,3S,5R)-2- (2-(4-amino-8-fluoro-6-(trifluoromethyl)-9H-pyrimido[4,5-b]i ndol-9-yl)acetyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (369g) (35 mg, 84 % yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-dk) δ 10.78 (s, 1H, DzO exchangeable), 8.81 (s, 1H), 8.60 (s, 1H), 8.48 (s, 2H, DzO exchangeable), 8.01 (d, J= 8.2 Hz, 1H), 7.81 - 7.65 (m, 2H), 7.32 (d,J= 7.7 Hz, 1H), 5.90 - 5.73 (m, 1H), 5.50 (dd,./= 17.3, 2.0 Hz, 1H), 4.43 (dd, J= 9.0, 5.6 Hz, 1H), 3.91 - 3.83 (m, 1H), 2.34 (dd ,J= 13.4, 9.1 Hz, 1H), 2.30 - 2.15 (m, 1H), 2.00 - 1.86 (m, 1H), 1.16 - 1.05 (m, 1H), 0.70 - 0.58 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-tife) δ -58.66, -132.55; MS (ES+): 592.1/594.1 (M+l); (ES-): 590.0/592.0 (M- 1); Analysis calculated for CziHieBrF+NzOz 2HzO.HCl: C, 43.36; H, 3.49; Cl, 5.33; N, 14.75; Found: C, 43.40; H, 3.46; Cl, 5.47; N, 14.64.

Scheme 370

359b 370a

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(furan-2-yl)-8-methyl-9H-pyrimido [4,5-b]indol- 9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexa ne-3-carboxamide (370a) Compound 370a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-(furan-2-yl)-8-methyl-9H-pyrimido[4,5-b]indol-9 -yl)acetic acid (359b) (100 mg, 0.182 mmol) in DMF (8 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (4a) (69.5 mg, 0.218 mmol), HATU (138 mg, 0.363 mmol), DIPEA (0.158 mL, 0.908 mmol) and stirring at RT for 18 h. amino-6-(furan-2-yl)-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)a cetyl)-N-(6-bromopyridin-2- yl)-2-azabic\clo[3.1 ,0]hexane-3-caiboxamide (370a) (9 mg, 8% yield) HC1 salt as a white solid; ΉΝΜΚ(300 MHz, DMSO-c/&) δ 10.83 (s, 1H), 8.61 (s, 1H), 8.57 (s, 1H), 8.52 (s, 2H, D2O exchangeable), 8.01 (d, J= 8.1 Hz, 1H), 7.77 (d, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.64 (s, 1H), 7.31 (d, J= 7.7 Hz, 1H), 7.03 (d,J= 3.4 Hz, 1H), 6.65 - 6.62 (m, 1H), 5.91 (d ,J= 18.0 Hz, 1H), 5.64 (d, J= 17.9 Hz, 1H), 4.43 (dd, J= 9.1, 5.8 Hz, 1H), 3.99 - 3.84 (m, 1H), 2.74 (s, 3H), 2.43 - 2.12 (m, 2H), 2.01 - 1.81 (m, 1H), 1.18 - 0.98 (m, 1H), 0.75 - 0.63 (m, 1H); MS (ES+): 586.1 (M+l); (ES-): 584.0 (M-l).

Scheme 371

371b 371c

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(pyridin-3-yl)-9H-pyrido[2 ^, ,3 ^, :4,5]pynolo[2, 3- d]pyrimidin-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicycl o[3.1 ,0]hexane-3-carboxamide (371c)

Step-1: Preparation of terf-butyl 2-(4-anMno-6-(pyridin-3-yl)-9H-pyiido[2 ^, ,3 ^, :4,5]pyrroIo[2,3- d]pyrimidin-9-yl)acetate (371a)

Compound 371a was prepared according to the procedure reported in in scheme-263 and step-1 of scheme-354, from /erf-butyl 2-(4-amino-6-bromo-9H-pyrido[2 ^, ,3 ^, :4,5]pyrrolo[2,3- d]pyrimidin-9-yl)acetate (290e) (300 mg, 0.793 mmol) and pyridin-3-ylboronic acid (146 mg, 1.190 mmol) to afford ter/-butyl 2-(4-amino-6-(pyridin-3-yl)-9H-pyrido[2 ^, ,3 ^, :4,5]pyrrolo[2,3- d]pyrimidin-9-yl)acetate (371a) (260 mg, 87% yield); ¾ NMR (300 MHz, DMSO-dfi) δ 9.08 Hz, 1H), 8.41 (s, 1H), 8.26 (dt, J = 8.1, 1.9 Hz, 1H), 8.03 (bs, 1H), 7.70 - 7.46 (m, 1H), 6.86 (bs, 1H), 5.23 (s, 2H), 1.41 (s, 9H); MS (ES+): 377 (M+l).

Step-2: Preparation of 2-(4-ammo-6-(pyridin-3-yl)-9H-pyrido[2 ^, ,3 ^, :4,5]pyiTolo[2,3- d]pyrimidin-9-yl)acetic acid (371b)

Compound 371b was prepared according to the procedure reported in step-2 of scheme- 1, from fer/-butyl 2-(4-ammo-6-(pyridm-3-yl)-9H-pyrido[2',3 ^, :4,5]pyrrolo[2,3-d]pyrimidin-9- yl)acetate (371a) (260 mg, 0.691 mmol) in DCM (5 mL) using TFA (788 mg, 6.91 mmol) to afford TFA salt of 2-(4-amino-6-(pyridin-3-yl)-9H-pyrido[2 ^, ,3 ^, :4,5]pyrrolo[2.3-d]pyrimidin- 9-yl)acetic acid (371b) (344 mg) as a pale-yellow solid; Ή NMR (300 MHz, DMSO-de) δ 9.18 (s, 1H), 9.01 (d, J = 3.3 Hz, 1H), 8.71 (d, J = 11.4 Hz, 2H), 8.58 - 8.26 (m, 3H), 7.74 (s, 1H), 7.52 (s, 1H), 5.29 (s, 2H); MS (ES+): 321 (M+l), (ES-): 319 (M-l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(pyridin-3-yl)-9H- pyrido[2 ^, ,3':4,5Jpyrrolo[2,3-d]pyrimidin-9-yl)acet>'l)-N-(6- bromopyridin-2-yl)-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (371c)

Compound 371c was prepared according to the procedure reported in step-3 of scheme- 1 , from TFA salt of 2-(4-amino-6-(pyridm-3-yl)-9H-pyrido[2',3 ^, :4,5]pyrrolo[2,3-d]pyrimidin-9- yl)acetic acid (371b) (75 mg, 0.173 mmol) in DMF (8 mL) using HC1 salt of (1R,3S,5R)-N- (6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamid e (4a) (66 mg, 0.207 mmol), HATU (131 mg, 0.345 mmol), DIPEA (0.150 mL, 0.863 mmol) and stirring at RT for 18 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4- ammo-6-(pyridin-3-yl)-9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyri midin-9-yl)acctyl)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (371c) (47 mg, 47% yield) HC1 salt as a pale-yellow solid; Ή NMR (300 MHz, DMSO-cfc) δ 10.78 (s, 1H, D ₂ 0 exchangeable), 9.45 (d, J = 2.0 Hz, 1H), 9.22 (s, 2H, D2O exchangeable), 9.15 (d ,J= 1.9 Hz, 1H), 9.00 - 8.93 (m, 2H), 8.83 (d, J= 1.9 Hz, 1H), 8.77 (s, 1H), 8.16 (dd, J= 7.9, 5.8 Hz, 1H), 7.95 (d, J= 8.2 Hz, 1H), 7.67 (t, J= 8.0 Hz, 1H), 7.29 (d, 7.7 Hz, 1H), 5.91 (d, J=

17.3 Hz, 1H), 5.55 (d, J= 17.2 Hz, 1H), 4.45 (dd, J= 9.0, 5.5 Hz, 1H), 3.97 - 3.89 (m, 1H), 2.42 - 2.15 (m, 2H), 2.00 - 1.85 (m, 1H), 1.17 - 1.03 (m, 1H), 0.88 - 0.76 (m, 1H); MS (ES+): 584.10 (M+l); (ES-): 582.00 (M-l).

Scheme 372

371b 372a

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(pyridin-3-yl)-9H-pyrido[2 ^, ,3 ^, :4,5]pynx)lo[2, 3- d]pyrimidin-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2- azabicyclo[3.1 ,0]hexane-3- carboxamide (372a)

Compound 372a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-(pyridin-3-yl)-9H-pyrido[2',3 ^, :4,5]pyrrolo[2,3-d]pyrimidin-9- yl)acetic acid (371b) (75 mg, 0.234 mmol) in DMF (8 mL) using HC1 salt of (1R,3S,5R)-N- (6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-c arboxamide (8a) (93 mg, 0.281 mmol), HATU (178 mg, 0.468 mmol), DIPEA (0.204 mL, 1.171 mmol) and stirring at RT for 18 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4-amino-6-(pyridin-3-yl)-9H-pyrido[2 ^, ,3 ^, :4,5]pyrrolo[2,3-d]pyrimidin-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (372a) (48 mg, 34% yield) HC1 salt as a pale-yellow solid; Ή NMR (300 MHz, DMSO-efe) δ 10.78 (s, 1H, D2O exchangeable), 9.33 (s, 1H), 9.10 (d, J= 2.8 Hz, 1H), 8.89 (s, 1H), 8.81 - 8.63 (m, 3H), 8.09 - 7.89 (m, 2H), 7.67 (t, J= 8.0 Hz, 1H), 7.29 (d, .7= 7.7 Hz, 1H), 5.83 (d, J= 17.4 Hz, 1H), 5.48 (d, J= 17.3 Hz, 1H), 4.40 (dd, J= 9.0, 5.9 Hz, 1H), 3.73 - 3.63 (m, 1H), 2.50 - 2.41 (m, 1H), 1.99 (dd,./= 13.3, 5.8 Hz, 1H), 1.09 - 1.00 (m, 1H), 1.00 - 0.92 (m, 1H); MS (ES+): 598.1 (M+l); (ES-): 596.1 (M-l).

Scheme 373

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-(pyridin-4-yl)-9H-pyrido[2 ^, ,3 ^, :4,5]pyirolo[2, 3- d]pyrirnidin-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2 -azabicyclo[3.1 ,0]hexane-3- carboxamide (373a)

Compound 373a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-(pyridin-4-yl)-9H-pyrido[2 ^, ,3':4,5]pyrrolo[2,3-d]pyrimidin-9- yl)acetic acid (307b) (80 mg, 0.250 mmol) in DMF (8 mL) using HC1 salt of (1R,3S,5R)-N- (6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 0]hexane-3-carboxamide (8a) (100 mg, 0.300 mmol), HATU (190 mg, 0.500 mmol), DIPEA (0.218 mL, 1.249 mmol) and stirring at RT for 18 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4-amino-6-(pyridm-4-yl)-9H-pyrido[2',3 ^, :4,5]pyrrolo[2,3-d]pyrimidin-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (373a) (72 mg, 48% yield) HC1 salt as a pale-yellow solid; Ή NMR (300 MHz, DMSO-i/e) δ 10.77 (s, 1H, DzO exchangeable), 9.23 (d, J= 1.9 Hz, 1H), 9.09 - 9.02 (m, 2H), 8.96 (s, 2H, D2O exchangeable), 8.84 (d, J= 2.0 Hz, 1H), 8.68 (s, 1H), 8.56 - 8.48 (m, 2H), 8.26 (s, 1H, D2O exchangeable), 7.97 (d, J= 8.1 Hz, 1H), 7.67 (t ,J= 8.0 Hz, 1H), 7.29 (d ,J= 7.7 Hz, 1H), 5.84 (d, J= 17.3 Hz, 1H), 5.50 (d,J= 17.2 Hz, 1H), 4.40 (dd, J = 9.1, 5.9 Hz, 1H), 3.69 (dd, J= 5.6, 2.4 Hz, 1H), 2.55 - 2.40 (m, 1H), 1.99 (dd,J= 13.2, 5.8 Hz, 1H), 1.32 (s, 3H), 1.08 - 1.01 (m, 1H), 1.00 - 0.94 (m, 1H); MS (ES+): 598.10 (M+l); (ES-): 596.0 (M-l).

Scheme 374

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-bromo-7-methoxy-9H-pyrimido[4,5-b ]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (374g)

Step-1: Preparation ofN-(2,4-dibromo-5-methoxyphenyl)-2,2,2-trifluoroacetamide (374b) Compound 374b was prepared according to the procedure reported in step-1 of scheme-46, from 2,4-dibromo-5-methoxyaniline (374a) (5.0 g, 17.80 mmol; CAS # 35736-52-8) in DCM (50 mL) using trifluoroacetic acid anhydride (3.78 mL, 26.68 mmol) and stirring at RT for 1 h. This gave after workup N-(2,4-dibromo-5-methoxyphenyl)-2,2,2-trifluoroacetamide (374b) (6.5 g, 97% yield) as a pale yellow solid; Ή NMR (300 MHz, DMSO-cfe) δ 11.37 (s, 1H), 7.99 (s, 1H), 7.27 (s, 1H), 3.86 (s, 3H).

Step-2: Preparation of 2-amino-5-bromo-6-methoxy- lH-indole-3-carbonitrile (374c) Compound 374c was prepared according to the procedure reported in step-1 of scheme- 11, from N-(2,4-dibromo-5-methoxyphenyl)-2,2,2-trifluoroacetamide (374b) (6.1 g, 16.18 mmol) in DMSO (24.4 mL) using malononitrile (1.28 g, 19.41 mmol), L-proline (0.37 g, 3.23 mmol), Cul (0.31 g , 1.61 mmol), a solution of K2CO3 (2.80 g, 20.22 mmol) in water (3.05 mL) and heating at 65 °C for 16 h under an argon atmosphere This gave after workup and purification by flash column chromatography [SiOzgel, eluting with EtOAc in n-heptane from 0 - 100%] 2-amino-5 -bromo-6-methoxy- 1 H-indole -3 -carbonitrile (374c) (1.48 g, 34% yield) as a reddish solid; Ή NMR (300 MHz, DMSO-tfe) δ 10.69 (s, 1H), 7.24 - 7.19 (m, 1H), 6.95 - 6.89 (m, 1H), 6.79 (s, 2H), 3.79 (s, 3H).

Step-3: Preparation of 6-bromo-7-methoxy-9H-pyrimido[4,5-b]indol-4-amine (374d) Compound 374d was prepared according to the procedure reported in step-1 of scheme-6, from 2-amino-5-bromo-6-methoxy-lH-indole-3-carbonitrile (374c) (1.6 g, 6.01 mmol) using trimethyl orthoformate (19.73 mL, 180.3 mmol), AcOH (1.72 mL, 30.05 mmol) and NEUOAc (2.32 g, 30.05) at RT. This gave after workup AcOH salt of 6-bromo-7-methoxy- 9H-pyrimido[4,5-b]indol-4-amine (374d) (1.65 g, 78% yield) as a greenish solid; MS (ES-) 291.3 (M-l).

Step-4: Preparation of tert- butyl 2-(4-amino-6-bromo-7-methoxy-9H-pyrimido[4,5-b]indol-9- yl)acetate (374e)

Compound 374e was prepared according to the procedure reported in step-2 of scheme- 16, from AcOH salt of 6-bromo-7-methoxy-9H-pyrimido[4,5-b]indol-4-amine (374d) (1.65 g, 4.67 mmol) in DMF (66 mL) using tert-butyl 2-bromoacetate (0.83 mL, 5.62 mmol) and CszCOa (3.67 g, 11.24 mmol) and stirring at RT for 16 h. This gave after workup and purification by flash column chromatography [SiOz gel, eluting with MeOH in DCM from 0 - 10%] te/7-butyl 2-(4-amino-6-bromo-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)ac etate (374e) (0.97 g, 51% yield ) as an off white solid; Ή NMR (300 MHz, DMSO-cfe) δ 8.62 (s, 1H), 8.24 (s, 1H), 7.40 (s, 1H), 7.27 (s, 2H), 5.14 (s, 2H), 3.92 (s, 3H), 1.40 (s, 9H).

Step-5 : Preparation of 2-(4-amino-6-bromo-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (374f)

Compound 374f was prepared according to the procedure reported in step-2 of scheme- 1, from tert-butyl 2-(4-amino-6-bromo-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)ac etate (374e) (0.97 g, 2.38 mmol) in DCM (4.0 mL) using TFA (4.0 mL, 52.36 mmol) in DCM (11.60 mL) to afford 2-(4-amino-6-bromo-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (374f) (1.1 g, 99% yield) UFA salt as an off white solid; ‘H NMR (300 MHz, DMSO-ifc) δ 8.80 (s, 1H), 8.52 (s, 1H), 8.44 (s, 2H), 7.62 (s, 1H), 5.27 (s, 2H), 3.96 (s, 3H).

Step-6: Preparation of ( 1 R,3S,5R)-2-(2-(4-amino-6-bromo-7-methoxy-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1 ,0]hexane-3-carboxamide Compound 374g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-bromo-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (374f) (87 mg, 0.15 mmol) in DMF (8 mL) using HC1 salt of ( 1 R,3 S,5R)-N-(6-bromopyridin- 2-yl)-2-azabic>'clo[3.1.0]hexane-3-carboxamide (4a) (57.3 mg, 0.180 mmol), HATU (114 mg, 0.300 mmol), DIPEA (0.131 mL, 0.750 mmol) and stirring at RT for 18 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4-amino-6- bromo-7 -methoxy-9H-pyrimido [4,5-b] indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (374g) (67 mg, 73% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-tife) δ 10.71 (s, 1H, DzO exchangeable), 8.82 (s, 1H), 8.56 (s,

1H), 8.53 (s, 3H, D2O exchangeable), 8.00 (d, J= 8.2 Hz, 1H), 7.71 (t, J= 8.0 Hz, 1H), 7.42 (s, 1H), 7.32 (d, ./= 7.7 Hz, 1H), 5.72 (d, J= 17.3 Hz, 1H), 5.46 (d,J= l 7.2 Hz, 1H), 4.41 (dd, 9.1, 5.7 Hz, 1H), 3.97 (s, 3H), 3.94 - 3.86 (m, 1H), 2.42 - 2.15 (m, 2H), 2.01 - 1.79 (m, 1H), 1.13 - 0.97 (m, 1H), 0.82 - 0.67 (m, 1H); MS (ES+): 614/616 (M+l).

Scheme 375

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-bromo-7-methoxy-9H-pyrimido[4,5-b ]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (375a)

Compound 375a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-bromo-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (374f) (87 mg, 0.15 mmol) in DMF (8 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin- 2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (59.9 mg, 0.1800 mmol), HATU (114 mg, 0.300 mmol), DIPEA (0.131 mL, 0.750 mmol) and stirring at RT for 18 h. This gave after workup and purification as described in scheme-299, ( 1 R,3 S,5R)-2-(2-(4- amino-6-bromo-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetyl) -N-(6-bromopyridin-2-yl)-

5-metiiyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (375a) (47 mg, 50% yield) HC1 salt as a 8.55 (s, 1H), 8.51 (s, 2H, D2O exchangeable), 8.01 (d ,J= 8.2 Hz, 1H), 7.71 (t, J= 8.0 Hz, 1H), 7.42 (s, 1H), 7.32 (d, J= 7.7 Hz, 1H), 5.68 (d, J= 17.4 Hz, 1H), 5.41 (d, J= 17.2 Hz, 1H), 4.36 (dd, J= 9.1, 6.0 Hz, 1H), 3.96 (s, 3H), 3.73 - 3.63 (m, 1H), 2.56 - 2.40 (m, 1H), 1.99 (dd, ./= 13.1, 6.1 Hz, 1H), 1.32 (s, 3H), 1.07 - 0.96 (m, 1H), 0.94 - 0.87 (m, 1H); MS (ES+): 628/630 (M+l).

Scheme 376

C0 ₂ H

NH ₂

H f H "="4 F

Br.

^F (CF.COUO ^CF3 NC CN

Ύ YS NC‘ ri

Cul, K2CO3

°Br' ^A ^Br

Br Br

376a 376b 376c

O

H o f

Nf»V XV'B' , o f*

N II 1 N TFA

HC(OMe) _3l NH ₄ OAC f % F

Cs ₂ C0

AcOH ₃

NH ₂

Br H ₂ N

376d Br

376e

J ·":

O H .

O N N-< H

H

HO

F 4a rxj °=<

Br

^N _x

I* V-N > _{° f} wV f ^N v HATU, DIPEA N \ _ , ^F

N¾ _n 1

B H ₂ N

NH ₂ r

Br

376f 376g

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-bromo-8-fluoro-9H-pyrimido[4,5-b] indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane -3-carboxamide (376g)

Step-1: Preparation of N-(2,4-dibromo-6-fluorophenj4)-2,2,2-trifluoroacetamide (376b)

Compound 376b was prepared according to the procedure reported in step-1 of scheme-46, from 2,4-dibromo-6-fluoroaniline (376a) (10.0 g, 37.19 mmol; CAS # 141474-37-5) in DCM (100 tnL) using trifluoroacetic acid anhydride (8.4 mL, 55.78 mmol) to afford N-(2,4- dibromo-6-fluorophenyl)-2,2,2-trifluoroacetamide (376b) (13.27 g, 98% yield) as an off white solid; Ή NMR (300 MHz DMSO-tife) δ 11 55 (s 1H) 797 (t J = 1 9 Hz 1H) 787 Step-2: Preparation of 2-amino-5-bromo-7-fluoro-lH-indole-3-carbonitrile (376c)

Compound 376c was prepared according to the procedure reported in step-1 of scheme- 11 and step-2 of scheme-374, from N-(2,4-dibromo-6-fluorophenyl)-2,2,2-trifluoroacetamide (376b) (7.40 g, 20.28 mmol) in DMSO (20.0 mL) using malononitrile (1.35 mL, 24.32 mmol), L-proline (0.47 mg, 4.06 mmol), Cul (386 mg, 2.03 mmol), a solution of K2CO3 (3.50 g, 25.34 mmol) in water (1.4 mL) to afford 2-amino-5-bromo-7-fluoro-lH-indole-3- carbonitrile (376c) (1.84 g, 36% yield) as abrown solid; ^l HNMR (300 MHz, DMSO-c/e) δ 11.57 (s, 1H), 7.14 - 7.07 (m, 1H), 7.06 - 7.00 (m, 1H), 6.97 (s, 2H).

Step-3: Preparation of 6-bromo-8-fluoro-9H-pyrimido[4,5-b]indol-4-amine (376d)

Compound 376d was prepared according to the procedure reported in step-1 of scheme-6 and step-3 of scheme-374, from 2-amino-5-bromo-7-fluoro-lH-indole-3-carbonitrile (376c) (3.40 g, 13.38 mmol) using trimethyl orthoformate (42.61 g, 401.47 mmol), AcOH (4.017 g, 66.9 mmol), NIHUOAc (5.156 g, 66.9 mmol) to afford AcOH salt of 6-bromo-8-fluoro-9H- pyrimido[4,5-b]indol-4-amine (376d) (3.50 g, 93% yield) as an off white solid; Ή NMR (300 MHz, DMSO-i/e) δ 12.54 (s, 1H), 8.46 (d ,J= 1.6 Hz, 1H), 8.30 (s, 1H), 7.50 (dd, J= 10.4,

1.5 Hz, 1H), 7.42 (s, 2H).

Step-4: Preparation of fen-butyl 2-(4-amino-6-bromo-8-fluoro-9H-pyrimido[4,5-b]indol-9- yl)acetate (376e)

Compound 376e was prepared according to the procedure reported in step-2 of scheme- 16 and step-4 of scheme-374, from AcOH salt of 6-bromo-8-fluoro-9H-pyrimido[4,5-b]indol-4- amine (376d) (3.50 g, 12.45 mmol) in DMF (140 mL) using fen-butyl 2-bromoacetate (2.43 g, 12.45 mmol), CS2CO3 (8.11 g, 24.90 mmol) to afford fen-butyl 2-(4-amino-6-bromo-8- fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetate (376e) (3.10 g, 63 % yield) as an off white solid; Ή NMR (300 MHz, DMSO-i/e) δ 8.51 (d, J= 1.6 Hz, 1H), 8.35 (s, 1H), 7.68 - 7.46 (m, 3H), 5.25 - 5.07 (m, 2H), 1.40 (s, 9H).

Step-5: Preparation of 2-(4-amino-6-bromo-8-fluoro-9H-pyrimido[4,5-b]indol-9-yl)ace tic acid (376f)

Compound 376f was prepared according to the procedure reported in step-2 of scheme- 1, from fen-butyl 2-(4-amino-6-bromo-8-fluoro-9H-pyrimido[4,5-b]indol-9-yl)ace tate (376e) (3.0 g, 7.59 mmol) in DCM (50 mL) using TFA (12.77 mL, 166.99 mmol) to afford 2-(4- an off white solid; Ή NMR (300 MHz, DMSO-c/e) δ 8.60 (d, 1.7 Hz, 1H), 8.49 (s, 1H),

8.16 (s, 2H), 7.64 (dd ,J= 11.7, 1.6 Hz, 1H), 5.22 (d ,J= 1.9 Hz, 2H).

Step-6: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-bromo-8-fluoro-9H-pyrimido[4,5- bJindol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1.0]hexane-3-carboxamide (376g)

Compound 376g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-bromo-8-fluoro-9H-pyrimido[4,5-b]indol-9-yl)ace tic acid (376f) (85 mg, 0.15 mmol) in DMF (8 mL) using HC1 salt of ( 1 R,3 S,5R)-N-(6-bromopyridin- 2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (57.3 mg, 0.180 mmol), HATU (114 mg, 0.300 mmol), DIPEA (0.131 mL, 0.750 mmol) and stirring at RT for 18 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4-amino-6- bromo-8-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bro mopyridin-2-yl)-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (376g) (52 mg, 58% yield) HC1 salt as a white solid; ¾ NMR (300 MHz, DMSO-rik) δ 10.76 (s, 1H), 8.61 (s, 1H), 8.55 (s, 1H), 8.32 (s, 2H, D2O exchangeable), 8.08 - 7.92 (m, 1H), 7.79 - 7.56 (m, 2H), 7.39 - 7.22 (m, 1H), 5.76 (d, J= 17.7 Hz, 1H), 5.42 (d, J= 17.4 Hz, 1H), 4.53 - 4.26 (m, 1H), 3.95 - 3.77 (m, 1H), 2.43 - 2.13 (m, 2H), 2.02 - 1.81 (m, 1H), 1.14 - 1.01 (m, 1H), 0.72 - 0.50 (m, 1H); MS (ES+): 602.00 & 604.00 (M+l).

Scheme 377

H

Br 0 o=( NV YV N l\

-Λ ) Γ V-N

N _, F "J u

HATU, DIPEA ^« V ,

H ₂ N f N¾X-Pi

Br Br

NH ₂

376f 377a

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-bromo-8-fluoro-9H-pyrimido[4,5-b] indol-9- yl)acetyl)-N-(6-bromopyridin-2-yI)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (377a)

Compound 377a was prepared according to the procedure reported in step-3 of scheme- 1, fr TFA lt f 2 (4 i 6 b 8 fl 9H i id [45 b]i d l 9 l) ti id (376f) (85 mg, 0.15 mmol) in DMF (8 mL) using HC1 salt of ( 1R,3 S,5R)-N-(6-bromopyridin- 2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (59.9 mg, 0.180 mmol), HATU (114 mg, 0.300 mmol), DIPEA (0.131 mL, 0.750 mmol) and stirring at RT for 18 h. This gave after workup and purification as described in scheme-299, ( 1 R,3 S,5R)-2-(2-(4- amino-6-bromo-8-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetyl)- N-(6-bromopyridin-2-yl)-5- methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (377a) (84 mg, 91% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ife) δ 10.77 (s, 1H), 8.70 - 8.49 (m, 4H, 2H D2O exchangeable), 8.05 - 7.96 (m, 1H), 7.78 - 7.55 (m, 2H), 7.37 - 7.23 (m, 1H), 5.72 (d, J= 17.5 Hz, 1H), 5.38 (d,J= 17.5 Hz, 1H), 4.43 - 4.32 (m, 1H), 3.13 - 2.98 (m, 1H), 2.61 - 2.32 (m, 1H), 2.17 - 1.76 (m, 1H), 1.29 (s, 3H), 1.08 - 0.95 (m, 1H), 0.83 - 0.70 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-A) δ -131.77; MS (ES+): 616.00 & 618.00 (M+l).

Scheme 378

Br

Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(pyridin-2-yl)-9H-pyrirn ido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azab ic>'clo[3.1 ,0]hexane-3- carboxamide (378c)

Step-1: Preparation of tert-butyl 2-(4-amino-8-methyl-6-(pyridin-2-yl)-9H-pyrimido(4,5- A mixture of tort-butyl 2-(4-amino-6-bromo-8-methyl-9H-pyrimido[4,5-b]indol-9-yl)ace tate (192e) (300 mg, 0.767 mmol), B ₂ (pin)2 (292 mg, 1.150 mmol), PdidppQClz.CHzCh (62.6 mg, 0.077 mmol), KOAc (226 mg, 2.300 mmol) in anhydrous dioxane (15 mL) was heated at 100 °C for 16 h under nitrogen. To this mixture 2-bromopyridine (182 mg, 1.150 mmol), Pd(PPh3)iCk (53.8 mg, 0.077 mmol) and 3.3 M aqueous K2CO3 (0.697 mL, 2.300 mmol) were added and the mixture was stirred at 100 °C for 16 h under nitrogen. The resulting mixture was diluted with EtOAc (50 mL) and filtered. The filtrate was washed with H2O (25 mL x 3), brine (25 mL), dried, filtered and concentrated in vacuum. The residue obtained was purified using flash column chromatography [SiOz gel (12 g), eluting with DMA-80 in DCM from 0-20%] to provide tort-butyl 2-(4-amino-8-methyl-6-(pyridin-2-yl)-9H-pyrimido[4,5- b]indol-9-yl)acetate (378a) (60 mg, 20% yield) as a yellow semi-solid; Ή NMR (300 MHz, DMSO-ifc) δ 8.75 (d, .7= 3.7 Hz, 1H), 8.66 (s, 1H), 8.43 - 8.21 (m, 2H), 8.08 (s, 1H), 7.92 (t, J= 8.7 Hz, 1H), 7.48 (s, 2H), 7.32 (d, J= 6.6 Hz, 1H), 5.37 (s, 2H), 2.71 (s, 3H), 1.44 (s,

9H); MS (ES+): 390 (M+l), (ES-): 388 (M-l).

Step-2: Preparation of 2-(4-amino-8-methyl-6-(pyridin-2-yl)-9H-pyrimido[4,5-b]indol -9- yl)acetic acid (378b)

Compound 378b was prepared according to the procedure reported in step-2 of scheme- 1, from tort-butyl 2-(4-amino-8-methyl-6-(pyridin-2-yl)-9H-pyrimido[4,5-b]indol -9-yl)acetate (378a) (60 mg, 0.154 mmol) in DCM (5 mL) using TEA (176 mg, 1.541 mmol) to afford after purification as reported in step-2 of scheme-319, 2-(4-amino-8 -methyl-6-(pyridin-2-y 1) - 9H-pyrimido[4,5-b]indol-9-yl)acetic acid (378b) (33 mg, 58% yield) HC1 salt as a white solid; ΉΝΜΚ (300 MHz, DMSO-ife) δ 9.23 (s, 1H), 9.15 (bs, 2H), 8.81 (dd, J= 5.5, 1.7 Hz, 1H), 8.71 (s, 1H), 8.57 (d,./= 8.2 Hz, 1H), 8.38 (t, J= 7.8 Hz, 1H), 8.21 (s, 1H), 7.84 - 7.66 (m, 1H), 5.52 (s, 2H), 2.79 (s, 3H); MS (ES+): 334 (M+l), (ES-): 332 (M-l).

Step-3: Preparation of (lR,3S,5R)-2-(2-(4-amino-8-methyl-6-(pyridin-2-yl)-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-5- methyl-2- azabicyclo[3.1.0]hexane-3-carboxamide (378c)

Compound 378c was prepared according to the procedure reported in step-3 of scheme- 1, from HC1 salt of 2-(4-amino-8-methyl-6-(pyridin-2-yl)-9H-pyrimido[4,5-b]indol -9-yl)acetic acid (378b) (30 mg, 0.081 mmol) in DMF (5 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carb oxamide (8a) (32.4 mg, 0.097 for 18 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2- (2-(4-amino-8-methyl-6-(pyridin-2-yl)-9H-pyrimido[4,5-b]indo l-9-yl)acetyl)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (378c) (32 mg, 65% yield) HC1 salt as a white solid; >HNMR (300 MHz, DMSCM _> ) δ 10.84 (s, 1H), 9.08 (s, 1H), 8.95 (s, 2H, DzO exchangeable), 8.80 - 8.74 (m, 1H), 8.68 (s, 1H), 8.43 (d, J= 8.1 Hz, 1H), 8.24 (t, J= 7.8 Hz, 1H), 8.14 (s, 1H), 8.01 (d, J= 8.2 Hz, 1H), 7.70 (t ,J= 8.0 Hz, 1H), 7.66 - 7.58 (m, 1H), 7.31 (d, J= 7.7 Hz, 1H), 5.94 (d ,J= 18.0 Hz, 1H), 5.65 (d,J= 17.9 Hz, 1H), 4.40 (dd, J= 9.0, 6.2 Hz, 1H), 3.72 (dd, ./= 5.5, 2.4 Hz, 1H), 2.79 (s, 3H), 2.56 - 2.42 (m, 1H), 1.99 (dd, 13.2, 6.0 Hz, 1H), 1.31 (s, 3H), 1.08 - 0.99 (m, 1H), 0.89 - 0.83 (m, 1H); MS (ES+): 611.10 (M+l); (ES-): 609.10 (M-l).

Scheme 379

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-bromo-7-methyl-9H-pyrimido[4,5-b] indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (379h)

Step-1: Preparation ofN-(4-bromo-3-methylphenyl)-2,2,2-trifluoroacetamide (379b) Compound 379b was prepared according to the procedure reported in step-1 of scheme-46, from 4-bromo-3-methylaniline (379a) ( 15.0 g, 80.62 mmol; CAS # 6933-10-4) in DCM (30 mL) using trifluoroacetic acid anhydride (25.40 g, 120.93 mmol) and stirring at RT for 30 min. This gave after workup N-(4-bromo-3-methylphenyl)-2,2,2-trifluoroacetamide (379b) (22.8 g) as a brown solid; Ή NMR (300 MHz, DMSO-i/e) δ 11.31 (s, 1H), 7.88 - 7.54 (m, 2H), 7.45 (dd, J= 8.6, 2.6 Hz, 1H), 2.35 (s, 3H).

Step-2: Preparation ofN-(4-bromo-2-iodo-5-methylphenyl)-2,2,2-trifluoroacetamide (379c)

To a stirred solution of N-(4-bromo-3-methylphenyl)-2,2,2-trifluoroacetamide (379b) (22.8 g, 80.83 mmol) in acetonitrile (228 mL) was added at RTNIS (18.18 g, 80.83 mmol), triflic acid (0.6 g, 4.05 mmol) and stirred overnight at RT. Reaction quenched with water (250.0 mL), extracted with ethyl acetate (2 X 250 mL). The combined organic layers were washed with brine (150 mL), dried, filtered and concentrated to give N-(4-bromo-2-iodo-5- methylphenyl)-2,2,2-trifluoroacetamide (379c) (31.4 g, 95% yield) as a brown solid; Ή NMR (300 MHz, DMSO-ifc) δ 11.29 (s, 1H), 8.13 (s, 1H), 7.41 (s, 1H), 2.31 (s, 3H).

Step-3: Preparation of 2-amino-5 -bromo-6-methyl- 1 H-indole-3 -carbonitrile (379d)

Compound 379d was prepared according to the procedure reported in step-1 of scheme- 11 and step-2 of scheme-374, from N-(4-bromo-2-iodo-5-methylphenyl)-2,2,2- trifluoroacetamide (379c) (10.0 g, 24.51 mmol) in DMSO (40.0 mL) using malononitrile (1.94 g, 29.41 mmol), L-proline (0.569 g, 4.92 mmol), Cul (0.47 g , 2.45 mmol), a solution of K2CO3 (4.064 g, 29.41 mmol) in water (0.5 mL) to afford 2-amino-5-bromo-6-methyl- 1 H- indole-3-carbonitrile (379d) (4.0 g, 65% yield) as a yellow solid; Ή NMR (300 MHz, DMSO-i/e) δ 10.77 (s, 1H), 7.25 - 7.23 (m, 1H), 7.09 (s, 1H), 6.88 (s, 2H), 2.35 - 2.31 (m,

3H).

Step-4: Preparation of 6-bromo-7-methyl-9H-pyrimido[4,5-b]indol-4-amine (379e)

Compound 379e was prepared according to the procedure reported in step- 1 of scheme-6, from 2-amino-5-bromo-6-methyl-lH-indole-3-carbonitrile (379d)( 4.0 g, 15.99 mmol) using trimethyl orthoformate (50.90 g, 479.7 mmol), AcOH (4.80 g) and NEUOAc (6.16 g, 79.96 mmol) at 100 °C for 16 h. This gave after workup AcOH salt of 6-bromo-7-methyl-9H- pyrimido[4,5-b]indol-4-amine (379e) (3.13 g, 58% yield) as a gray solid; MS (ES+): 277.1 (M+l). Step-5: Preparation of /erf-butyl 2-(4-amino-6-bromo-7-methyl-9H-pyrimido[4,5-b]indol-9- yl)acetate (379f)

Compound 379f was prepared according to the procedure reported in step-2 of scheme- 16 and step-4 of scheme-374, from AcOH salt of 6-bromo-7-methyl-9H-pyrimido[4,5-b]indol-4- amine (379e) (3.13 g, 9.28 mmol) in DMF (125.2 mL) using tert-butyl 2-bromoacetate (2.2 g, 11.29 mmol), CS2CO3 (7.35 g, 22.59 mmol) to afford tert- butyl 2-(4-amino-6-bromo-7- methyl-9H-pyrimido[4,5-b]indol-9-yl)acetate (379f) (1.32 g, 36% yield) as a yellow solid; Ή NMR (300 MHz, DMSO-flfe) δ 8.64 (s, 1H), 8.27 (d, J= 0.8 Hz, 1H), 7.60 (s, 1H), 7.36 (s, 2H), 5.07 (s, 2H), 2.49 (s, 3H), 1.57 - 1.30 (m, 9H).

Step-6: Preparation of 2-(4-amino-6-bromo-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)ace tic acid (379g)

Compound 379g was prepared according to the procedure reported in step-2 of scheme- 1, from /erf-butyl 2-(4-amino-6-bromo-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)ace tate (379f) (1.3 g, 3.32 mmol) in DCM (10 mL) using TFA (8.33 g, 73.10 mmol) in DCM (15 mL) to afford 2-(4-amino-6-bromo-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)ace tic acid (379g) (1.35 g, 91% yield) TFA salt as an off white solid; Ή NMR (300 MHz, DMSO-flfe) 58.60 (s, 1H), 8.45 (s, 1H), 7.62 (s, 1H), 5.16 (s, 2H), 2.45 (s, 3H).

Step-7: Preparation of ( lR,3S,5R)-2-(2-(4-amino-6-bromo-7-methyl-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1.0] hexane-3 -carboxam ide (379h)

Compound 379h was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-bromo-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)ace tic acid (379g) (84 mg, 0.15 mmol) in DMF (8 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (4a) (57.3 mg, 0.180 mmol), HATU (114 mg, 0.300 mmol), DIPEA (0.131 mL, 0.750 mmol) and stirring at RT for 18 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4- amino-6-bromo-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)- N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (379h) (45 mg, 50% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-flfe) δ 10.76 (s, 1H), 8.80 (s, 1H), 8.56 (s, 1H), 8.48 (s, 3H, DzO exchangeable), 8.06 - 7.93 (m, 1H), 7.76 - 7.62 (m, 2H), 7.36 - 7.25 (m, 1H), 5.70 (d, ./= 17.6 Hz, 1H), 5.37 (d, J= 17.9 Hz, 1H), 4.52 - 4.31 (m, 1H), 3.99 - 3.82 (m, 1H), 2.41 - 2.13 (m, 2H), 2.00 - 1.81 (m, 1H), 1.11 - 0.97 (m, 1H), 0.88 - 0.62 (m, 1H); MS (ES+): 598.00 (M+l); (ES-): 595.95 (M-l).

Scheme 380

379g 380a

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-bromo-7-methyl-9H-pyrimido[4,5-b] indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (380a)

Compound 380a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-bromo-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)ace tic acid (379g) (84 mg, 0.15 mmol) in DMF (8 mL) using HC1 salt of (lR,3S,5R)-N-(6- bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (8a) (59.9 mg, 0.180 mmol), HATU (114 mg, 0.300 mmol), DIPEA (0.131 mL, 0.750 mmol) and stirring at RT for 18 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2- (4-amino-6-bromo-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)acety l)-N-(6-bromopyridin-2-yl)- 5-me1hyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (380a) (73 mg, 79% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-tfc) δ 10.76 (s, 1H, D20 exchangeable), 8.80 (s,

1H), 8.70 - 8.47 (m, 3H, 2H D20 exchangeable), 8.06 - 7.94 (m, 1H), 7.77 - 7.58 (m, 2H), 7.35 - 7.25 (m, 1H), 5.65 (d,J= 17.2, 3.8 Hz, 1H), 5.31 (d, J= 17.4 Hz, 1H), 4.42 - 4.30 (m, 1H), 3.70 - 3.61 (m, 1H), 2.65 - 2.33 (m, 4H), 2.09 - 1.89 (m, 1H), 1.30 (s, 3H), 1.07 - 0.87 (m, 2H); MS (ES+): 612.00 (M+l); (ES-): 609.90 (M-l).

Scheme 381 CO ₂ H

NH ₂ CF ₃

H

Br- H ₂ N β

(CF ₃ C0½0 NC CN

Cul, K ₂ C0 ₃ NC'

F F F

381a 381b 381c

-Y

O

H (OMe) ₃ , NH ₄ OAC XV o "* 1 N

HC r"

N

N

AcOH n<s r ^N II f \ Cs ₂ C0 ₃

NH ₂ H ₂ N \

F

F

381 d 381e

381f F 381 g

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-fluoro-7-methyl-9H-pyrimido[4,5-b ]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yI)-2-azabicycIo[3.1.0]hexane -3-carboxamide (381 g)

Step-1: Preparation ofN-(2-bromo-4-fluoro-5-methylphenyl)-2,2,2-trifluoroacetami de (381b)

Compound 381b was prepared according to the procedure reported in step-1 of scheme-46, from 2-bromo-4-fluoro-5-methylaniline (381a)( 4.0 g, 19.60 mmol; CAS # 1065076-39-2) in DCM (20 mL) using trifluoroacetic acid anhydride (6.17g, 29.40 mmol) and stirring at RT for 1 h. This gave after workup N-(2-bromo-4-fluoro-5-methylphenyl)-2,2,2-trifluoroacetamide (381b) (6.25 g) as a tight violet color solid; Ή NMR (300 MHz, DMSO-^β) δ 11.26 (s, 1H), 7.66 (d, J= 9.1 Hz, 1H), 7.43 (d, J= 7.6 Hz, 1H), 2.22 (d, J= 2.1 Hz, 3H).

Step-2: Preparation of 2-amino-5 -fluoro-6-methyl- 1 H-indole-3 -carbonitrile (381c)

Compound 381c was prepared according to the procedure reported in step-1 of scheme- 11 and step-2 of scheme-374, from N-(2-bromo-4-fluoro-5-methylphenyl)-2,2,2- g, 24.99 mmol), L-proline (0.48 g, 4.16 mmol), Cul (0.40 g , 2.08 mmol), a solution of K2CO.3 (5.75 g, 41.64 mmol) in water (16 mL) to afford 2-amino-5-fluoro-6-methyl- 1H- indole-3-carbonitrile (381c) (1.4 g, 36% yield) as a gray solid; Ή NMR (300 MHz, DMSO- ek) δ 10.64 (s, 1H), 6.97 (d, J= 6.5 Hz, 1H), 6.82 (d, ./= 10.2 Hz, 1H), 6.77 (s, 2H), 2.21 (d, J = 2.2 Hz, 3H).

Step-3: Preparation of 6-fluoro-7-methyl-9H-pyrimido[4,5-b]indol-4-amine (381d)

Compound 381d was prepared according to the procedure reported in step-1 of scheme-6 and step-3 of scheme-374, from 2-amino-5-fluoro-6-methyl-lH-indole-3-caibonitrile (381c) (1.35 g, 7.14 mmol) using trimethyl orthoformate (22.69 g, 213.9 mmol), AcOH (2.03 mL) NHtOAc (2.75 g, 35.67 mmol) to afford AcOH salt of 6-fluoro-7 -methyl-9H-pyrimido [4,5 - b]indol-4-amine (381d) (1.0 g, 65% yield) as a gray solid; Ή NMR (300 MHz, DMSO-tfe) δ 11.77 (s, 1H), 8.22 (s, 1H), 8.15 (d,./= 10.9 Hz, 1H), 7.29 (d, J= 6.6 Hz, 1H), 7.16 (s, 2H), 2.37 (d, 2.2 Hz, 3H).

Step-4: Preparation of tert-butyl 2-(4-amino-6-fluoro-7-methyl-9H-pyrimido[4,5-b]indol-9- yl)acetate (381e)

Compound 381e was prepared according to the procedure reported in step-2 of scheme-16 and step-2 of scheme-374, from AcOH salt of 6-fluoro-7-methyl-9H-pyrimido[4,5-b]indol-4- amine (381d) (1.0 g, 3.82 mmol) in DMF (40 mL) using te/7-butyl 2-bromoacetate (0.745 g, 3.82 mmol), CS2CO3 (2.49 g, 7.65 mmol) to afford tert-butyl 2-(4-amino-6-fluoro-7-methyl- 9H-pyrimido[4,5-b]indol-9-yl)acetate (381 e) (1.21 g, 80% yield) as an off white solid; Ή NMR (300 MHz, DMSO-ifc) δ 8.26 (s, 1H), 8.21 (d, J= 10.7 Hz, 1H), 7.47 (d, J= 6.4 Hz, 1H), 7.29 (s, 2H), 5.07 (s, 2H), 2.39 (d, J= 2.2 Hz, 3H), 1.40 (s, 9H).

Step-5 : Preparation of 2-(4-amino-6-fluoro-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (381f)

Compound 381f was prepared according to the procedure reported in step-2 of scheme- 1, from fer/-butyl 2-(4-amino-6-fluoro-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)ac etate (381e) (1.44 g, 4.36 mmol) in DCM (6 mL) using TFA (10.93 g, 95.90 mmol) in DCM (18 mL) to afford 2-(4-amino-6-fluoro-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (381f) (1.62 g, 96% yield) TFA salt as an off white solid; Ή NMR (300 MHz, DMSO-Je) δ 8.71 (s, 2H), 8.60 (s, 1H), 8.37 (d, J= 10.5 Hz, 1H), 7.74 (d, J= 6.3 Hz, 1H), 5.23 (s, 2H), 2.42 (d, J= 2.2 Step-6: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-fluoro-7-methyl-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1.0]hexane-3-carboxamide

(381g)

Compound 381g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-fluoro-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (381f) (75 mg, 0.15 mmol) in DMF (8 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin- 2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (57.3 mg, 0.180 mmol), HATU (114 mg, 0.300 mmol), DIPEA (0.131 mL, 0.750 mmol) and stirring at RT for 22 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4-amino-6- fluoro-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)acet\i)-N-(6-br omopyridin-2-yl)-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (381g) (36 mg, 45% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-flfc) δ 10.77 (s, 1H), 8.66 (s, 2H), 8.61 (s, 1H), 8.41 (d, J= 10.4 Hz, 1H), 8.01 (d, ./= 8.2 Hz, 1H), 7.71 (t ,J= 8.0 Hz, 1H), 7.64 (d, J= 6.3 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 5.73 (d, J= 17.3 Hz, 1H), 5.39 (d, J= 17.3 Hz, 1H), 4.42 (dd,/= 9.1, 5.6 Hz, 1H), 3.97 - 3.83 (m, 1H), 2.42 (s, 3H), 2.39 - 2.16 (m, 2H), 1.99 - 1.85 (m, 1H), 1.13 - 1.00 (m, 1H), 0.84 - 0.75 (m, 1H); MS (ES+): 538.1 (M+l); (ES-): 536.0 (M-l).

Scheme 382

1

H ₂ N

381 f F 382a

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-fluoro-7-methyl-9H-pyrimido[4,5-b ]indol-9- yl)acet>'l)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo [3.1 ,0]hexane-3-carboxamide (382a)

Compound 382a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-fluoro-7-methyl-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (381f) (75 mg, 0.15 mmol) in DMF (8 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin- 2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (59.9 mg, 0.180 mmol), HATU (114 mg, 0.3 mmol), DIPEA (0.131 mL, 0.750 mmol) and stirring at RT for 18 h. amino-6-fluoro-7-methyl-9H-pyTimido[4,5-b]indol-9-yl)acetyl) -N-(6-bromopyridin-2-yl)-5- methyl-2-azabicyclo[3.1.0Jhexane-3-carboxamide (382a) (77 mg, 93% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-i/e) δ 10.77 (s, 1H), 8.67 (s, 2H, D2O exchangeable), 8.60 (s, 1H), 8.41 (d,J= 10.4 Hz, 1H), 8.01 (d, J= 8.2 Hz, 1H), 7.70 (t, ./= 8.0 Hz, 1H), 7.64 (d, 6.4 Hz, 1H), 7.32 (d, 7.7 Hz, 1H), 5.69 (d ,J= 17.4 Hz, 1H), 5.34 (d, J= 17.3 Hz,

1H), 4.42 - 4.31 (m, 1H), 3.67 (d, J= 6.1 Hz, 1H), 2.47 - 2.43 (m, 1H), 2.42 (s, 3H), 2.04 - 1.91 (m, 1H), 1.31 (s, 3H), 1.06 - 0.87 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -123.40; MS (ES+): 552.10 (M+l); (ES-): 550.0 (M-l).

Scheme 383

383f 383g

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-fluoro-7-methoxy-9H-pyrimido[4,5- b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (383g)

Step-1: Preparation ofN-(2-bromo-4-fluoro-5-methoxyphenyl)-2,2,2-trifluoroacetam ide (383b)

Compound 383b was prepared according to the procedure reported in step-1 of scheme-46, DCM (50 mL) using trifluoroacetic acid anhydride (4.80 mL, 34.08 mmol) and stirring at RT for 1 h. This gave after workup N-(2-bromo-4-fluoro-5-methoxyphenyl)-2,2,2- trifluoroacetamide (383b) (7.0 g, 97% yield) as a light purple solid; Ή NMR (300 MHz, DMSO-ifc) δ 11.29 (s, 1H), 7.73 (dd ,J= 10.8, 1.2 Hz, 1H), 7.34 (dd,./= 8.5, 1.2 Hz, 1H), 3.84 (d, 1.3 Hz, 3H).

Step-2: Preparation of 2-amino-5-fluoro-6-methoxy- lH-indole-3-carbonitrile (383c)

Compound 383c was prepared according to the procedure reported in step-1 of scheme- 11 and step-2 of scheme-374, from N-(2-bromo-4-fluoro-5-methoxyphenyl)-2,2,2- trifluoroacetamide (383b) (6.5 g, 20.57 mmol) in DMSO (26 mL) using malononitrile (1.63 g, 24.67 mmol), L-proline (0.47 g, 4.11 mmol), Cul (0.39 g , 2.05 mmol), a solution of K2CO3 (4.26 g, 30.84 mmol) in water (6.5 mL) to afford 2-amino-5 -fluoro-6-methoxy- 1 H- indole-3-cafbonitrile (383c) (1.42 g, 34% yield) as a black solid; Ή NMR (300 MHz, DMSO-cfe) δ 10.58 (s, 1H), 6.94 (s, 1H), 6.91 (d, J= 4.3 Hz, 1H), 6.68 (s, 2H), 3.78 (s, 3H).

Step-3: Preparation of 6-fluoro-7-methox>'-9H-pyrimido[4,5-b]indol-4-amine (383d)

Compound 383d was prepared according to the procedure reported in step-1 of scheme-6 and step-3 of scheme-374, from 2-amino-5-fluoro-6-methoxy- 1 H-indole-3-carbonitrile (383c) (1.48 g, 7.21 mmol) using trimethyl orthoformate (23.67 mL, 216.3 mmol), AcOH (2.06 mL, 36.05 mmol), NHtOAc (2.78 g, 36.05 mmol) to afford 6-fluoro-7-methoxy-9H-pyrimido[4,5- b]indol-4-amine (383d) (1.20 g, 72% yield) as a light brown solid; Ή NMR (300 MHz, DMSO-ifc) δ 11.80 (s, 1H), 8.40 - 8.10 (m, 2H), 7.22-6.98 (m, 3H), 3.91 (s, 3H).

Step-4: Preparation of terf-butyl 2-(4-am ino-6-fluoro-7 -methoxy-9H-pyrim ido [4,5 -b] indol-9- yl)acetate (383e)

Compound 383e was prepared according to the procedure reported in step-2 of scheme- 16 and step-4 of scheme-374, from 6-fluoro-7-methoxy-9H-pyrimido[4,5-b]indol-4-amine (383d) (1.20 g, 5.17 mmol,) in DMF (48 mL) using tert- butyl 2-bromoacetate (0.95 mL, 6.19 mmol), CS2CO3 (3.86 g, 11.35 mmol) to afford tert- butyl 2-(4-amino-6-fluoro-7-methoxy- 9H-pyrimido[4,5-b]indol-9-yl)acetate (383e) (0.95 g, 53% yield) as an off white solid; Ή NMR (300 MHz, DMSO -ck) δ 8.28 (d, J= 12.1 Hz, 1H), 8.23 (s, 1H), 7.44 (d, J= 7.4 Hz, 1H), 7.22 (s, 2H), 5.13 (s, 2H), 3.92 (s, 3H), 1.40 (s, 10H).

Step-5 : Preparation of 2-(4-amino-6-fluoro-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)a cetic Compound 383f was prepared according to the procedure reported in step-2 of scheme- 1, from tert-butyl 2-(4-amino-6-fluoro-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)a cetate (383e) (0.95 g, 2.74 mmol) in DCM (4.75 mL) using TFA (4.62 mL, 60.28 mmol) in DCM (10.45 mL) to afford 2-(4-amino-6-fluoro-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)a cetic acid (383f) (1.10 g, 99.2% yield) TFA salt as an off white solid; ΉΝΜΕ (300 MHz, DMSO-c/e) δ 8.62 - 8.51 (m, 3H), 8.47 (d,J= 11.9 Hz, 1H), 7.71 (d, J= 7.3 Hz, 1H), 5.29 (s, 2H), 3.96 (s,

3H).

Step-6: Preparation of (lR,3S,5R)-2-(2-(4-amino-6-fluoro-7-methoxy-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromop>ridin-2-yl)-2-azabic> 'clo[3.1.0] hexane-3 -carboxam ide (383g)

Compound 383g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-fluoro-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)a cetic acid (383f) (78 mg, 0.15 mmol) in DMF (8 mL) using HC1 salt of ( 1R,3 S,5R)-N-(6-bromopyridin- 2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (57.3 mg, 0.180 mmol), HATU (114 mg, 0.300 mmol), DIPEA (0.131 mL, 0.750 mmol) and stirring at RT for 18 h. This gave after workup and purification as described in scheme-299, ( 1R,3 S,5R)-2-(2-(4-amino-6- fluoro-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-b romopyridin-2-yl)-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (383g) (36 mg, 43% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfe) δ 10.72 (s, 1H), 8.55 (s, 1H), 8.52 - 8.43 (m, 3H, 2H DzO exchangeable), 8.00 (d, J = 8.2 Hz, 1H), 7.71 (t, J = 7.9 Hz, 1H), 7.49 (d,J= 7.2 Hz, 1H), 7.33 (d, .7= 7.7 Hz, 1H), 5.72 (d, J= 17.3 Hz, 1H), 5.46 (d, J= 17.3 Hz, 1H), 4.48 - 4.37 (m, 1H), 3.97 (s, 3H), 3.93 - 3.82 (m, 1H), 2.40 - 2.13 (m, 2H), 2.00 - 1.83 (m, 1H), 1.15 - 0.96 (m, 1H), 0.85 - 0.66 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -140.13; MS (ES+):554.10 (M+l); (ES-):552.0 (M-l).

Scheme 384

Preparation of ( lR,3S,5R)-2-(2-(4-amino-7-fIuoro-6-methyl-9H-pyrimido[4,5-b] indoI-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (384g)

Step-1: Preparation of N-(2-bromo-5-fluoro-4-methylphenyl)-2,2,2-trifluoroacetamide (384b)

Compound 384b was prepared according to the procedure reported in step-1 of scheme-46, from 2-bromo-5 -fluoro-4-methylan iline (384a) ( 3.0 g, 14.70 mmol; CAS # 202865-78-9) in DCM (30 rtiL) using trifluoroacetic acid anhydride (4.63 g, 22.05 mmol) and stirring at RT for 1 h. This gave after workup N-(2-bromo-5-fluoro-4-methylphenyl)-2,2,2- trifluoroacetamide (384b) (3.5 g, 79% yield) as a dark brown solid; Ή NMR (300 MHz, DMSO-ifc) 5 11.33 (s, 1H), 7.73 (d, J= 7.7 Hz, 1H), 7.39 (d, J= 10.0 Hz, 1H), 2.26 (d, J= 2.0 Hz, 3H).

Step-2: Preparation of 2-amino-6-fluoro-5-methyl-lH-indole-3-carbonitrile (384c)

Compound 384c was prepared according to the procedure reported in step-1 of scheme- 11 and step-2 of scheme-374, from N-(2-bromo-5-fluoro-4-methylphenyl)-2,2,2- trifluoroacetamide (384b) (5.0 g, 16.66 mmol) in DMSO (15 mL) using malononitrile (1.32 g, 19.98 mmol), L-proline (0.38 g, 3.32 mmol), Cul (0.31 g , 1.66 mmol), a solution of K2CO3 (4.60 g, 33.35 mmol) in water (15 mL) to afford 2-amino-6-fluoro-5 -methyl- 1 H- indole-3-carbonitrile (384c) (1.5 g, 48% yield) as a white solid; Ή NMR (300 MHz, DMSO- ck) 5 10.62 (s, 1H), 6.96 (d ,J= 7.1 Hz, 1H), 6.91 (d, J= 10.3 Hz, 1H), 6.73 (s, 2H), 2.22 (s.

3H).

St 3 P ti f 7 fl 6 th l 9H i id [45 b]i d l 4 i (384d) Compound 384d was prepared according to the procedure reported in step-1 of scheme-6 and step-3 of scheme-374, from 2-amino-6-fluoro-5-methyl-lH-indole-3-carbonitrile (384c) (1.5 g, 7.93 mmol) using trimethyl orthofoimate (25.24 g, 237.85 mmol), AcOH (7.5 mL), NHiOAc (3.05 g, 39.65 mmol) to afford 7-fluoro-6-methyl-9H-pyrimi do [4,5 -b] indol-4-am ine (384d) ( 1.2 g, 70% yield) as an off-white solid.

Step-4: Preparation of tert- butyl 2-(4-amino-7-fluoro-6-methyl-9H-pyrimido[4,5-b]indoI-9- yl)acetate (384e)

Compound 384e was prepared according to the procedure reported in step-2 of scheme- 16 and step-4 of scheme-374, from 7-fluoro-6-methyl-9H-pyrimido[4,5-b]indol-4-amine (384d) (1.2 g, 5.55 mmol) in DMF (36.0 mL) using tert- butyl 2-bromoacetate (1.07 g, 5.55 mmol), CS2CO3 (3.60 g, 11.09 mmol) to afford tert-butyl 2-(4-amino-7 -fl uoro-6-mcthyl-9H- pyrimido[4,5-b]indol-9-yl)acetate (384e) (500.0 mg, 27% yield ) as an off-white solid; ^! H NMR (300 MHz, DMSO-cfe) δ 8.30 - 8.24 (m, 2H), 7.47 (d, 7= 10.7 Hz, 1H), 7.25 (s, 2H), 5.08 (s, 2H), 2.37 (d,7= 2.2 Hz, 3H), 1.40 (s, 9H).

Step-5 : Preparation of 2-(4-amino-7-fluoro-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (384f)

Compound 384f was prepared according to the procedure reported in step-2 of scheme- 1, from tert-butyl 2-(4-amino-7 -fluoro-6-methy l-9H-py rimido [4,5 -b] indol-9-y l)acetate (384e) (700.0 mg, 2.12 mmol) in DCM (7.0 mL) using TFA (5.3 lg, 46.6 mmol) in DCM (10 mL) to afford 2-(4-amino-7-fluoro-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (384f) (590.0 mg, 72% yield) TFA salt as an off white solid; Ή NMR (300 MHz, DMSO-ifc) δ 8.52 (s,

1H), 8.47 - 8.29 (m, 3H), 7.70 (d, 7= 10.6 Hz, 1H), 5.21 (s, 2H), 2.40 (d, 7 = 2.1 Hz, 3H).

Step-6: Preparation of (lR,3S,5R)-2-(2-(4-amino-7-fluoro-6-methyl-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1.0]hexane-3-carboxamide

(384g)

Compound 384g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-7-fluoro-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (384f) (75 mg, 0.15 mmol) in DMF (8 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin- 2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (57.3 mg, 0.180 mmol), HATU (114 mg, 0.300 mmol), DIPEA (97 mg, 0.750 mmol) and stirring at RT for 18 h. This gave after methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridi n-2-yl)-2- azabicyclo[3.1.0]hexane-3-carboxamide (384g) (50 mg, 62% yield) HC1 salt as a white solid; ΉΝΜΚ (300 MHz, DMSCMs) δ 10.76 (s, 1H), 8.58 (s, 1H), 8.55 (s, 2H, D ₂ 0 exchangeable), 8.46 (d, ./= 7.3 Hz, 1H), 8.00 (d ,J= 8.2 Hz, 1H), 7.70 (t,J= 8.0 Hz, 1H), 7.62 (d, J= 10.5 Hz, 1H), 7.31 (d, 7.7 Hz, 1H), 5.73 (d, J= 17.4 Hz, 1H), 5.37 (d, J=

17.3 Hz, 1H), 4.42 (dd,J= 9.0, 5.6 Hz, 1H), 3.92 - 3.83 (m, 1H), 2.39 (s, 3H), 2.37 - 2.14 (m, 2H), 1.98 - 1.84 (m, 1H), 1.13 - 0.97 (m, 1H), 0.85 - 0.74 (m, 1H); ^!9 FNMR (282 MHz, DMSO-ifc) δ -117.36; MS (ES+): 538.10 (M+l); (ES-): 536.10 (M-l).

Scheme 385

384f 385a

Preparation of (lR,3S,5R)-2-(2-(4-amino-7-fluoro-6-methyl-9H-pyrimido[4,5-b ]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 .0]hexane-3-carboxamide (385a)

Compound 385a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-7-fluoro-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (384f) (75 mg, 0.15 mmol) in DMF (8 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromop>Tidin- 2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (60 mg, 0.180 mmol), HATU (114 mg, 0.300 mmol), DIPEA (97 mg, 0.750 mmol) and stirring at RT for 18 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4-amino-7- fluoro-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-br omopyridin-2-yl)-5-methyl-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (385a) (75 mg, 82 % yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.77 (s, 1H), 8.71 (s, 2H, DzO exchangeable), 8.61 (s,

1H), 8.48 (d, J= 7.2 Hz, 1H), 8.01 (d, J= 8.2 Hz, 1H), 7.69 (t, J= 8.0 Hz, 1H), 7.62 (d, J= 10.4 Hz, 1H), 7.31 (d ,J= 7.7 Hz, 1H), 5.69 (d,J= 17.4 Hz, 1H), 5.32 (d,J= 17.3 Hz, 1H), 4.37 (dd, J = 9.0, 5.9 Hz, 1H), 3.71 - 3.63 (m, 1H), 2.47 - 2.41 (m, 1H), 2.39 (s, 3H), 1.97 (dd, J= 13.3, 5.8 Hz, 1H), 1.30 (s, 3H), 1.06 - 0.89 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-cfe) 5 -116.70; MS (ES+): 552.10 (M+l); (ES-): 550.0 (M-l).

Scheme 386

Preparation of ( lR,3S,5R)-2-(2-(4-amino-6,7-difluoro-9H-pyrimido[4,5-b]indol -9-yl)acetyl)- N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxam ide (386g)

Step-1: Preparation ofN-(2-bromo-4,5-difluorophenyl)-2,2,2-trifluoroacetamide (386b)

Compound 386b was prepared according to the procedure reported in step-1 of scheme-46, from 2-bromo-4,5-difluoroaniline (386a)( 3.0 g, 14.70 mmol; CAS # 64695-79-0 ) in DCM (30 mL) using trifluoroacetic acid anhydride (4.54 g, 21.62 mmol) and stirring at RT for 1 h. This gave after workup N-(2-bromo-4,5-difluorophenyl)-2,2,2-trifluoroacetamide (386b) (3.5 g, 79% yield) as a dark brown solid; Ή NMR (300 MHz, DMSO-tfc) 5 11.43 (s, 1H), 8.11 - 7.98 (m, 1H), 7.78 (dd, J= 11.2, 7.9 Hz, 1H).

Step-2: Preparation of 2-amino-5 ,6-difluoro- 1 H-indole-3 -carbonitrile (386c)

Compound 386c was prepared according to the procedure reported in step-1 of scheme- 11 (386b) (4.5 g, 14.80 mmol) in DMSO (13.5 mL) using malononitrile (1.17 g, 17.71 mmol), L-proline (0.34 g, 2.95 mmol), Cul (0.28 g , 1.47 mmol), a solution of K2CO3 (4.09 g, 29.60 mmol) in water (13.5 mL) to afford 2-amino-5,6-difluoro-lH-indole-3-carbonitrile (386c) (

1.4 g, 49% yield) as a white solid; Ή NMR (300 MHz, DMSO-ffc) δ 10.80 (s, 1H), 7.12 (ddd, J= 20.0, 10.9, 7.3 Hz, 2H), 6.93 (s, 2H).

Step-3: Preparation of 6,7-difluoro-9H-pyrimido[4,5-b]indol-4-amine (386d)

Compound 386d was prepared according to the procedure reported in step-1 of scheme-6 and step-3 of scheme-374, from 2-amino-5,6-difluoro-lH-indole-3-carbonitrile (386c) (1.4 g,

7.25 mmol) using trimethyl orthoformate (23.07 g, 217.43 mmol), AcOH (7 mL), NHtOAc (2.79 g, 36.23 mmol) to afford 6,7-difhioro-9H-pyrimido[4,5-b]indol-4-amine (386d) (500 mg, 32% yield) as a brown solid.

Step-4: Preparation of lert- butyl 2-(4-amino-6,7-difluoro-9H-pyrimido[4,5-b]indol-9- yl)acetate (386e)

Compound 386e was prepared according to the procedure reported in step-2 of scheme- 16 and step-4 of scheme-374, from 6,7-difluoro-9H-pyrimido[4,5-b]indol-4-amine (386d) (500 mg, 2.27 mmol) in DMF (6.5 mL) using tort-butyl 2-bromoacetate (443.0 mg, 2.27 mmol), CS2CO3 (1.48 g, 4.54 mmol) to afford tort-butyl 2-(4-amino-6,7-difluoro-9H-pyrimido[4,5- b]indol-9-yl)acetate (386e) (220.0 mg, 29% yield ) as an off-white solid.

Step-5: Preparation of 2-(4-ami no-6, 7-difluoro-9H-pyrimido [4,5 -b] indol-9-vi)acetic acid (386f)

Compound 386f was prepared according to the procedure reported in step-2 of scheme- 1, from tort-butyl 2-(4-amino-6,7-difluoro-9H-pyrimido[4,5-b]indol-9-yl)acetate (386e) (500.0 mg, 1.50 mmol) in DCM (5.0 mL) using TFA (3.75 g, 32.90 mmol) in DCM (10 mL) to afford 2-(4-amino-6,7-difluoro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (386f) (360.0 mg, 61% yield) TFA salt as a white solid; Ή NMR (300 MHz, DMSO-i/e) δ 8.60 (dd, ./= 11.5, 7.9 Hz, 1H), 8.46 (s, 1H), 8.09 (s, 2H), 7.99 (dd, J= 11.3, 6.9 Hz, 1H), 5.20 (s, 2H).

Step-6: Preparation of (lR,3S,5R)-2-(2-(4-amino-6,7-difluoro-9H-pyrimido[4,5-b]indo l-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (386g)

Compound 386g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2 (4 amino 67 difluoro 9H pyrimido[45 b]indol 9 yl)acetic acid (3861) (76 mg, 0.15 mmol) in DMF (8 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)- 2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (52 mg, 0.180 mmol), HATU (114 mg, 0.300 mmol), DIPEA (97 mg, 0.750 mmol) and stirring at RT for 18 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4-amino-6,7-difluoro-9H- pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2- azabicyclo[3.1 ,0]hexane-3- carboxamide (386g) (57 mg, 64% yield) HC1 salt as a white solid; *H NMR (300 MHz, DMSO-ifc) δ 10.76 (s, 1H), 8.82 - 8.54 (m, 4H, 2H exchangeable), 8.06 - 7.87 (m, 2H), 7.70 (t, ./= 7.9 Hz, 1H), 7.32 (d, J= 7.7 Hz, 1H), 5.76 (d, ./= 17.4 Hz, 1H), 5.39 (d, J= 17.4 Hz, 1H), 4.42 (dd, J= 9.0, 5.5 Hz, 1H), 3.94 - 3.83 (m, 1H), 2.41 - 2.11 (m, 2H), 2.00 - 1.82 (m, 1H), 1.14 - 0.99 (m, 1H), 0.90 - 0.74 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -138.00, - 144.42; MS (ES+): 542.10 (M+l); (ES-): 540.0 (M-l).

Scheme 387

386f 387a

Preparation of(lR,3S,5R)-2-(2-(4-ammo-6,7-difluorio-9H-pyrimido[4,5-b]in dol-9-yl)acetyl)- N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (387a)

Compound 387a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-ammo-6,7-difluoro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (386f) (76 mg, 0.15 mmol) in DMF (8 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin-2-yl)- 5-me1hyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (60 mg, 0.180 mmol), HATU (114 mg, 0.300 mmol), DIPEA (97 mg, 0.750 mmol) and stirring at RT for 18 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4-amino-6,7-difluoro- 9H-pyrimido [4, 5 -b] indol-9-y l)acetyl)-N -(6-bromopyridin-2-yl)-5 -methyl-2- azabicyclo[3.1 ,0]hexane-3-caiboxamide (387a) (55 mg, 60% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-cfc) δ 10.77 (s, 1H), 8.76 - 8.63 (m, 1H), 8.62 - 8.50 (m, 3H, 2H DzO exchangeable), 8.01 (d, J= 8.2 Hz, 1H), 7.93 (dd, J= 11.2, 6.9 Hz, 1H), 7.71 (t, J= 8.0 (t ,J= 7.5 Hz, 1H), 3.71 - 3.62 (m, 1H), 2.51 - 2.39 (m, 1H), 1.99 (dd,J = 13.1, 5.8 Hz, 1H), 1.31 (s, 3H), 1.08 - 0.90 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-dk) δ -138.26, -144.69; MS (ES+): 556.10 (M+l); (ES-): 554.0 (M-l).

Scheme 388

^■ £'·*

H

O f* V-N : ^H J U

\ HATU, DIPEA

H ₂ N OMe _^ rP cy-

H ₂ N OMe

F

F

383f 388a

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-fluoro-7-methoxy-9H-pyrimido[4,5- b]indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (388a)

Compound 388a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-fluoro-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)a cetic acid (383f) (78 mg, 0.15 mmol) in DMF (8 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin- 2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (59.9 mg, 0.180 mmol), HATU (114 mg, 0.300 mmol), DIPEA (0.131 mL, 0.750 mmol) and stirring at RT for 18 h. This gave after workup and purification as described in scheme-299, ( 1 R,3 S,5R)-2-(2-(4- amino-6-fluoro-7-methoxy-9H-pyrimido[4,5-b]indol-9-yl)acetyl )-N-(6-bromopyridin-2-yl)- 5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (388a) (40 mg, 47% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.71 (s, 1H), 8.65 (s, 2H, D ₂ 0 exchangeable), 8.58 (s, 1H), 8.50 (d,J= 11.9 Hz, 1H), 8.01 (d ,J= 8.2 Hz, 1H), 7.71 (t ,J= 8.0 Hz, 1H), 7.51 (d, J= 7.4 Hz, 1H), 7.32 (d,J= 7.7 Hz, 1H), 5.70 (d ,J= 17.3 Hz, 1H), 5.42 (d, J= 17.3 Hz, 1H), 4.37 (t, J= 7.5 Hz, 1H), 3.96 (s, 3H), 3.72 - 3.66 (m, 1H), 2.52 - 2.42 (m, 1H), 2.00 (dd, J= 13.4, 5.9 Hz, 1H), 1.32 (s, 3H), 1.06 - 0.87 (m, 2H); ¹⁹ F NMR (282 MHz, DMSO-ifc) δ - 139.92; MS (ES+): 568.10 (M+l); (ES-): 566.0 (M-l).

Scheme 389

389f Br 389g

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-bromo-7-fluoro-9H-pyrimido[4,5-b] indol-9- yl)acet}'l)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (389g)

Step-1: Preparation ofN-(2,4-dibromo-5-fluorophenyl)-2,2,2-trifluoroacetamide (389b)

Compound 389b was prepared according to the procedure reported in step-1 of scheme-46, from 2,4-dibromo-5-fluoroaniline (389a)(5 g, 18.59 mmol; CAS # 1000578-04-0) in DCM (25 mL) using trifluoroacetic acid anhydride (5.86 g, 27.89 mmol) and stirring at RT for 1 h. This gave after workup N-(2,4-dibromo-5-fluorophenyl)-2,2,2-trifluoroacetamide (389b) ( 6.4 g, 94% yield) as an off-white solid; Ή NMR (300 MHz, DMSO-ffc) 5 11.47 (s, 1H), 8.22 (dd, J= 7.1, 2.1 Hz, 1H), 7.69 (dd, J= 9.2, 2.0 Hz, 1H).

Step-2: Preparation of 2-amino-5-bromo-6-fluoro-lH-indole-3-carbonitrile (389c)

Compound 389c was prepared according to the procedure reported in step-1 of scheme- 11 and step-2 of scheme-374, from N-(2,4-dibromo-5-fluorophenyl)-2,2,2-trifluoroacetamide proline (0.404 g, 3.51 mmol), Cul (0.334 g, 1.75 mmol), a solution of K2CO3 (3.647 g , 26.31 mmol) in DMW (6.4 mL) to afford 2-amino-5 -bromo-6-fluoro- 1 H-indole-3 -carbonitrile (389c) (1.7 g, 38% yield) as a yellow solid; Ή NMR (300 MHz, DMSO-ifc) δ 10.93 (s, 1H), 7.27 (d, J= 6.4 Hz, 1H), 7.13 (d, J= 9.2 Hz, 1H), 7.01 (s, 2H).

Step-3: Preparation of 6-bromo-7-fluoro-9H-pyrimido[4,5-b]indol-4-amine (389d)

Compound 389d was prepared according to the procedure reported in step-1 of scheme-6 and step-3 of scheme-374, from 2-amino-5 -bromo-6-fluoro- 1 H-indole-3 -carbonitrile (389c) (1.8 g, 7.08 mmol) using trimethyl orthoformate (22.55 g, 212.55 mmol), AcOH (2.127 g, 35.425 mmol), NH»OAc (2.731 g, 35.425 mmol) to afford 6-bromo-7-fluoro-9H-pyrimido[4,5- bJindol-4-amine (389d)(1.52 g, 76% yield) as a brown solid; Ή NMR (300 MHz, DMSO-ifc) δ 12.12 (s, 1H), 8.70 (d, J= 6.8 Hz, 1H), 8.26 (s, 1H), 7.39 (d, J= 9.4 Hz, 1H), 7.34 (s, 2H).

Step-4: Preparation of tort-butyl 2-(4-amino-6-bromo-7-fluoro-9H-pyrimido[4,5-b]indol-9- yl)acetate (389e)

Compound 389e was prepared according to the procedure reported in step-2 of scheme- 16 and step-4 of scheme-374, from 6-bromo-7-fluoro-9H-pyrimido[4,5-b]indol-4-amine (389d) (1.5 g, 5.34 mmol) in DMF (60 mL) using tort-butyl 2-bromoacetate (1.15 g, 5.87 mmol), CszCOs (3.65 g, 11.21 mmol) to afford tort-butyl 2-(4-amino-6-bromo-7-fluoro-9H- pyrimido[4,5-b]indol-9-yl)acetate (389e) (1.5 g, 71% yield) as a brown solid; Ή NMR (300 MHz, DMSO-<fc) δ 8.78 - 8.72 (m, 1H), 8.30 (d, J= 1.0 Hz, 1H), 7.82 - 7.76 (m, 1H), 7.46 (s, 2H), 5.12 (s, 2H), 1.42 - 1.37 (m, 9H).

Step-5 : Preparation of 2-(4-amino-6-bromo-7 -fl uoro-9H-pyrim ido [4,5 -b] indol-9-yl)acetic acid (389f)

Compound 389f was prepared according to the procedure reported in step-2 of scheme- 1, from /erf-butyl 2-(4-amino-6-bromo-7-fluoro-9H-pyrimido[4,5-b]indol-9-yl)ace tate (389 e) (1.5 g, 3.80 mmol) in DCM (24 mL) using TFA (9.52 g, 83.50 mmol) to afford 2-(4-amino-6- bromo-7-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetic acid (389f) (1.8 g) TFA salt as an off- white solid; Ή NMR (300 MHz, DMSO-ifc) δ 8.86 (d, J= 6.7 Hz, 1H), 8.48 (s, 1H), 8.18 (s, 2H), 7.95 (d, J= 9.8 Hz, 1H), 5.20 (s, 2H).

Step-6: Preparation of (lR,3S,5R)-2-(2-(4-ammo-6-bromo-7-fluoro-9H-pyrimido[4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1.0]hexane-3-carboxamide Compound 389g was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-bromo-7-fluoro-9H-pyrimido[4,5-b]indol-9-yl)ace tic acid (389f) (85 mg, 0.15 mmol) in DMF (8 mL) using HC1 salt of ( 1 R,3 S,5R)-N-(6-bromopyridin- 2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (4a) (57.3 mg, 0.180 mmol), HATU (114 mg, 0.300 mmol), DIPEA (97 mg, 0.75 mmol) and stirring at RT for 18 h. This gave after workup and purification as described in scheme-299, ( 1 R, 3 S,5 R)-2-(2-(4-amino-6-bromo-7 - fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bromopyridi n-2-yl)-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (389g) (62 mg, 69% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-tfc) δ 10.76 (s, 1H), 8.88 (d, J= 6.7 Hz, 1H), 8.52 (s, 1H), 8.28 (s, 2H, DzO exchangeable), 8.00 (d, J= 8.2 Hz, 1H), 7.83 (d, J= 9.7 Hz, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.32 (d, J= 7.7 Hz, 1H), 5.71 (d, ./= 17.4 Hz, 1H), 5.35 (d, J= 17.4 Hz, 1H), 4.41 (dd, J= 9.3, 5.5 Hz, 1H), 3.90 - 3.80 (m, 1H), 2.39 - 2.12 (m, 2H), 1.98 - 1.84 (m, 1H), 1.11 - 0.98 (m, 1H), 0.87 - 0.75 (m, 1H); MS (ES+): 601.90 (M+l).

Scheme 390

^■ £'·>

OH \ H

° N N ^Bf

N /». _s Vi H 1 < : i u

HATU, DIPEA

H ₂ N N*J

F P

H ₂ N \ ^V

F

Br

389f ^Br 390a

Preparation of (lR,3S,5R)-2-(2-(4-amino-6-bromo-7-fluoro-9H-pyrimido[4,5-b] indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (390a)

Compound 390a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-6-bromo-7-fluoro-9H-pyrimido[4,5-b]indol-9-yl)ace tic acid (389f) (85 mg, 0.15 mmol) in DMF (8 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin- 2-yl)-5-methyl-2-azabic>'clo[3.1 ,0]hexane-3-carboxamide (8a) (60 mg, 0.180 mmol), HATU (114 mg, 0.300 mmol), DIPEA (97 mg, 0.750 mmol) and stirring at RT for 18 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4-amino-6- bromo-7-fluoro-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-bro mopyridin-2-yl)-5-methyl-2- azabicyclo[3 1 0]hexane 3 carboxamide (390a) (85 mg 84% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-dk) δ 10.76 (s, 1H), 8.89 (d, J= 6.6 Hz, 1H), 8.53 (s, 1H), 8.35 (s, 2H, D2O exchangeable), 8.01 (d, J= 8.2 Hz, 1H), 7.83 (d,J= 9.6 Hz, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.31 (d, J= 7.7 Hz, 1H), 5.68 (d, J= 17.4 Hz, 1H), 5.31 (d, J= 17.2 Hz, 1H), 4.42 - 4.27 (m, 1H), 3.68 - 3.61 (m, 1H), 2.49 - 2.40 (m, 1H), 1.99 - 1.89 (m, 1H), 1.30 (s, 3H), 1.04 - 0.90 (m, 2H); MS (ES+): 616.00 (M+l); (ES-): 613.85 (M-l).

Scheme 391

Preparation of ( lR,3S,5R)-2-(2-(4-amino-8-fluoro-6-methyl-9H-pyrimido[4,5-b] indol-9- yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (391g)

Step-1: Preparation of N-(2-bromo-6-fluoro-4-methylphenyl)-2,2,2-trifluoroacetamide (391b)

Compound 391b was prepared according to the procedure reported in step-1 of scheme-46, from 2-bromo-6-fluoro-4-methylaniline (391a) (5 g, 24.50 mmol; CAS # 18349-09-2) in DCM (25 mL) using trifluoroacetic acid anhydride (7.72 g, 36.76 mmol) in DCM (25 mL) and stirring at RT for 1 h. This gave after workup N-(2-bromo-6-fluoro-4-methylphenyl)- 2,2,2-trifluoroacetamide (391b) (6.8 g, 93% yield) as a black sohd; Ή NMR (300 MHz, DMSO-flfe) δ 11.35 (s, 1H), 7.48 (s, 1H), 7.35 - 7.24 (m, 1H), 2.35 (s, 3H).

Step-2: Preparation of 2-amino-7-fluoro-5-methyl- lH-indole-3-carbonitrile (391c)

Compound 391c was prepared according to the procedure reported in step-1 of scheme- 11 and step-2 of scheme-374, from N-(2-bromo-6-fluoro-4-methylphenyl)-2,2,2- trifluoroacetamide (391b) (6.2 g, 20.66 mmol) in DMSO (19.3 mL) using malononitrile (1.64 g, 24.80 mmol), L-proline (0.476 g, 4.13 mmol), Cul (0.393 g, 2.07 mmol), a solution of K2CO3 (4.28 g, 30.99 mmol) in DMW (6.2 mL) to afford 2-amino-7-fluoro-5-methyl-lH- indole-3-carbonitrile (391c) (1.55 g, 40% yield) as a brown solid; 'HNMR (300 MHz, DMSO-de) δ 11.16 (s, 1H), 6.77 (s, 1H), 6.68 (s, 2H), 6.63 - 6.53 (m, 1H), 2.31 (s, 3H).

Step-3: Preparation of 8-fluoro-6-methyl-9H-pyrimido[4,5-b]indol-4-amine (391d)

Compound 391d was prepared according to the procedure reported in step-1 of scheme-6 and step-3 of scheme-374, from 2-amino-7-fluoro-5-methyl-lH-indole-3-caibonitrile (391c) (1.6 g, 8.46 mmol) using trimethyl orthoformate (26.92 g, 253.71 mmol), AcOH (2.54 g, 42.29 mmol), NH*OAc (3.26 g, 42.29 mmol) to afford 8-fluoro-6-methyl-9H-pyrimido[4,5-b]indol- 4-amine (391d) (1.45 g, 79% yield) as an off-white solid; Ή NMR (300 MHz, DMSO-ifc) δ 12.19 (s, 1H), 8.26 (d ,J= 1.0 Hz, 1H), 8.03 - 7.93 (m, 1H), 7.21 (s, 2H), 7.06 (d ,J= 12.0 Hz, 1H), 2.46 (s, 3H).

Step-4: Preparation of tort-butyl 2-(4-amino-8-fluoro-6-methyl-9H-pyrimido[4,5-b]indol-9- yl)acetate (391e)

Compound 391 e was prepared according to the procedure reported in step-2 of scheme- 16 and step-4 of scheme-374, from 8-fluoro-6-methyl-9H-pyrimido[4,5-b]indol-4-amine (391 d) (1.45 g, 6.71 mmol) in DMF (58 mL) using tort-butyl 2-bromoacetate (1.44 g, 7.38 mmol), CS2CO3 (4.588 g, 14.08 mmol) to afford tort-butyl 2-(4-amino-8-fluoro-6-methyl-9H- pyrimido[4,5-b]indol-9-yl)acetate (391e) (1.6 g, 72% yield) as an off-white solid; 'HNMR (300 MHz, DMSO-tik) δ 8.30 (s, 1H), 8.08 - 8.01 (m, 1H), 7.37 (s, 2H), 7.09 (d ,J= 13.1 Hz, 1H), 5.12 (d, J= 1.8 Hz, 2H), 2.46 (s, 3H), 1.40 (s, 9H).

Step-5 : Preparation of 2-(4-amino-8-fluoro-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (391f) Compound 391f was prepared according to the procedure reported in step-2 of scheme-1, from /erf-butyl 2-(4-amino-8 -fluoro-6-methy l-9H-py rimido [4,5 -b] indol-9-y l)acetate (391e) (1.6 g, 4.84 mmol) in DCM (25.6 mL) using TFA (12.15 g, 106.55 mmol) to afford 2-(4- amino-8-fluoro-6-methyl-9H-pyrim ido [4,5 -b] indol -9-y 1 )acetic acid (391f) (1.85 g, 98% yield) TFA salt as a cream color solid; Ή NMR (300 MHz, DMSO-de) 58.56 (d, J- 0.9 Hz, 1H), 8.46 (s, 2H), 8.15 (s, 1H), 7.23 (d, J= 13.3 Hz, 1H), 5.25 - 5.21 (m, 2H), 2.49 (s, 3H).

Step-6: Preparation of ( 1 R,3 S,5 R) -2-(2-(4-amino-8 -fluoro-6-methy l-9H-pyrimido [4,5- b]indol-9-yl)acetyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3. 1.0Jhexane-3-carboxamide

(391g)

Compound 391g was prepared according to the procedure reported in step-3 of scheme-1, from TFA salt of 2-(4-amino-8-fluoro-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (391f) (75 mg, 0.15 mmol) in DMF (8 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin- 2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4a) (57.3 mg, 0.180 mmol), HATU (114 mg, 0.300 mmol), DIPEA (97 mg, 0.750 mmol) and stirring at RT for 18 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4-amino-8-fluoro-6- methyl-9H-pyrimido[4,5-b]mdol-9-yl)acetyl)-N-(6-bromopyridin -2-yl)-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (391g) (56 mg, 69% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-afc) δ 10.76 (s, 1H, D ₂ 0 exchangeable), 8.61 (s, 1H), 8.58 (s, 2H, D2O exchangeable), 8.18 (s, 1H), 8.01 (d, .7= 8.2 Hz, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.31 (d,./ = 7.7 Hz, 1H), 7.22 (d, J= 13.2 Hz, 1H), 5.77 (d ,J= 17.4 Hz, 1H), 5.48 - 5.38 (m, 1H), 4.42 (dd, J= 9.1, 5.6 Hz, 1H), 3.91 - 3.81 (m, 1H), 2.48 (s, 3H), 2.39 - 2.14 (m, 2H), 2.02 - 1.83 (m, 1H), 1.16 - 0.97 (m, 1H), 0.68 - 0.53 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-i/e) δ - 135.24; MS (ES+): 538.10 (M+l); (ES-): 536.10 (M-l).

Scheme 392

391f Me 392a Preparation of (lR,3S,5R)-2-(2-(4-amino-8-fluoro-6-methyl-9H-pyrimido[4,5-b ]indol-9- yl)acetyl)-N-(6-bromopyiidin-2-yl)-5-methyl-2-azabicyclo[3.1 ,0]hexane-3-carboxamide (392a)

Compound 392a was prepared according to the procedure reported in step-3 of scheme- 1, from TFA salt of 2-(4-amino-8-fluoro-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)ac etic acid (391f) (75 mg, 0.15 mmol) in DMF (8 mL) using HC1 salt of (lR,3S,5R)-N-(6-bromopyridin- 2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (8a) (59.9 mg, 0.180 mmol), HATU (114 mg, 0.300 mmol), DIPEA (97 mg, 0.750 mmol) and stirring at RT for 18 h. This gave after workup and purification as described in scheme-299, (lR,3S,5R)-2-(2-(4-amino-8- fluoro-6-methyl-9H-pyrimido[4,5-b]indol-9-yl)acetyl)-N-(6-br omopyridin-2-yl)-5-methyl-2- azabicyclo[3.1 ,0]hexane-3-carboxamide (392a) (31 mg, 37% yield) HC1 salt as a white solid; Ή NMR (300 MHz, DMSO-flfc) δ 10.76 (s, 1H, DiO exchangeable), 8.59 (s, 1H), 8.51 (s, 2H, D2O exchangeable), 8.17 (s, 1H), 8.01 (d, .7= 8.2 Hz, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.31 (d,./ = 7.7 Hz, 1H), 7.21 (d, J= 13.1 Hz, 1H), 5.72 (d ,J = 17.5 Hz, 1H), 5.38 (d, J= 17.5 Hz, 1H), 4.37 (dd, J = 9.0, 5.9 Hz, 1H), 3.64 (dd, J= 5.5, 2.3 Hz, 1H), 2.49 - 2.42 (m, 4H), 1.98 (dd, J = 13.3, 5.9 Hz, 1H), 1.29 (s, 3H), 1.06 - 0.97 (m, 1H), 0.83 - 0.74 (m, 1H); ¹⁹ F NMR (282 MHz, DMSO-ifc) δ -135.26; MS (ES+): 552.10 (M+l); (ES-): 549.95 (M-l).

Example 393

The IC50 value of a compound (i.e., the concentration of the compound that inhibits 50% of the enzymatic activity) was calculated according to the procedure reported in US patent 6,653,340 Bl, e.g., column 74 (incorporated by reference).

Specifically, the compounds were dissolved in a stock solution of DMSO at 10.0 or 100 mM. A portion of this stock solution was added to assay buffer in a final volume of 50 fiL. Controls included buffer alone and enzyme solutions to which DMSO was added. Substrate was added to the reaction wells immediately or after incubation at room temperature. The reaction rates were measured spectrophotometrically by the generation of product at 405 nm for 600 sec. Background absorbance at 690 nm was measured and subtracted from the absorbance at 405 nm for each well.

The reaction rate for enzyme alone was compared to the rate of enzyme in the presence of inhibitor and the percent inhibition was calculated as shown below:

Percent Inhibition = [Rate without inhibitor-Rate with inhibitor)/(Rate without i hibi )] 100 Factor D Esterolytic Assay:

An established esterolytic assay for the measurement of Factor D activity and inhibition of Factor D activity was used (Kam, C. M.; McRae, B. J.; Harper, J. W.; Niemann, M. A.; Volanakis, J. E.; Powers, J. C. Human complement proteins D, C2, and B Active site mapping with peptide thioester substrates. J Biol. Chem. 1987, 262, 3444-3451). For this assay Z-Lys-SBzl, 1.29 mM (Kim, S.; Narayana, S. V. L; Volanakis, J. E. Mutational analysis of the substrate binding site of human complement Factor D. Biochemistry. 1994,

33, 14393-14399.) was used as the substrate for Factor D (104 mM). Hydrolysis of this compound by Factor D liberated a free sulfhydiyl group which is then reacted with 5,5'- dithiobis(2nitrobenzoic acid) producing an intense yellow color (Habeeb, A. F. S. A.

Reaction of protein sulfhydryl groups with Ellman's Reagent. Methods in Enzymol. 1976, 25, 457-464.). The assays were performed in 96 well microtiter plates and rates of hydrolysis were monitored at 405 nmona Biotek Synergy HI plate reader. Hydrolysis rates were reported as change in mOD/min. The assay was conducted in 100 mM HEPES, 500 mM NaCl, pH 7.5 containing 10% DMSO in a final volume of 50 pL per well.

An ICso, a compound concentration which inhibits 50% of the enzymatic activity, was calculated. Compounds in the examples were tested a minimum of three times. In the table below, three plus symbols (+++) are used to indicate compounds with an ICso value of greater than 1 micromolar (>1000 nM) concentration; Two (++) indicate compounds with an ICso value between 1 and 0.1 micromolar (1000-100 nM) concentration; One (+) indicate compounds with an ICso value less than 0.1 micromolar (<100 nM) concentration.

Table 1. Measured Ki (ICso) Value for Compounds.

Three (+++) is used to denote compounds with an ICso value of greater than 1 micromolar (>1000 nM) concentration; Two (++) indicate compounds with an ICso value between 1 and 0.1 micromolar (1000-100 nM) concentration; One (+) indicate compounds with an ICso value less than 0.1 micromolar (<100 nM) concentration. Compound ICso Compound IC50 Compound ICso

75d +++ 93a ++ 106b +++

76b +++ 94b +++ 112b +

77b +++ 95c +++ 119a ++

78a ++ 96e +++ 120c +++

79a ++ 97b 4-H- 12 Id +++

80a + 98b ++ 122c ++

82a +++ 100b +++ 118a +++

83d ++ 101b -H- 117d ++

84a ++ 102b -H- 116b ++

85b +++ 103b ++ 115e ++

86b ++ 104a + 114f +

87f +++ 105b ++ 113a ++

88f +++ 111b ++ 66b ++

89b ++ 107b 4-H- 124b +++

90d +++ 108b +++ 68a ++

91a + 109e -H- 67c ++

92b +++ 110(1 +++ 65a +

Compound ICso Compound ICso Compound ICso

64a + 144g 44 151a 44

130c 44 145a 44 152d 44

131c 44 146a 444 le 4

132d 444 235a 444 6e 4

133b 4 147a 444 7b 4

20a 4 148d 44 21a 4

134b 4 19a 4 73a 4

135a 44 3b 4 74a 44

136a +++ 149b 44 153a +++

137b + 4b 4 27a +

140a +4+ 5e 44 25a +

141a +++ 150d 44 26a +

138d ++ 69a 44 8b +

139b + 70a 44 28a +

125d ++ 2d 444 10b +

126f ++ 71a 44 Ilf +

142d +++ 72a 44 12a +

143d ++ 9a 4 127d +4+

Compound ICso Compound ICso Compound ICso

128a +++ 50f ++ 49c +

154e ++ 157a ++ 58c +

34c + 158c ++ 59c +

13b ++ 32f + 17f +

14a + 43a + 18a +

15a + 35f + 3 If +

155f +++ 30f + 60c +

156e ++ 47g + 61a +

45d + 48(1 + 129f ++

41f + 38e + 46g ++

37a + 51g + 62c +

42a + 52f + 63d +

16e + S4g + 53d ++

36e + 44a + 55a +

39f + 29f + 56g ++

23f + 22c +++ 57g +

40a + 22d +++ 159a +

24a + 33e + 160a +

Compound lCso Compound lCso Compound IC50

171b + 167a + 204a +

172a + 168g + 184g +

173a + 187c + 185a +

161a + 188g + 186a +

174g +-H- 195e + 206c ++

175a +++ 198a + 209b +

176a ++ 199a + 210d ++

169f + 200a + 189g +

177d ++ 194a + 193a +

178d ++ 20 le ++ 190a +

162g + 21 le ++ 191a +

163g + 212e ++ 192g +

164a + 181a + 196d +

165a + 182a + 197c +

170c + 183a + 214b +

179d +++ 207b + 213d +

180e ++ 208d + 215g +

166a + 203a + 216g +

Compound ICs* Compound ICso Compound IC$o

217a 4 224b 44-4 271c +

220a 44- 225e 4 249a +

202a + 226c + 252a +

205c + 219a 4 253a +

221c + 227c + 254a +

236f + 228a 4 263c +

237a + 25 If ++ 272c ++

238g + 233h 4 255c +

239a + 229c + 256a +

222a 444 230a 4 273c +

240g + 231g + 257g +

241a + 246b 4 258a +

242g + 247d 4-4 259d 44

243a + 248(1 444 260a +

244d + 232a + 261d +

245a + 234a 4 262a +

218a + 250b 44-4 264a +

223a + 270a 4 265a +

Compound ICso Compound ICso

266b + 288c +

267c + 289a +

268b + 290g +

269c + 291a +

274g + 292a +

275c + 293a ++

276g + 293b +

277a + 294c +++

278g + 295a +

279a + 296a +

280g + 297d +

281a + 298c +

282a + 299a +

283g + 300a +

284a + 301a +

285g + 302a +

286a + 303a +

287a +

Compound ICso Compound ICso Compound ICso

307c + 313b + 315a +

304a + 314a + 316a +

305a + 312a + 343a +

308c + 323a + 344c +

309a + 324a + 345c +

310a + 306a + 346g +

311a + 325c + 347a +

317c ++ 326c + 338e +

318c + 327c + 339g +

319c + 328f + 348c +

320c + 329a + 349c +

32 Id + 330f + 350a +

322c + 331a + 351a +

334a + 336c + 332c +

335c + 337a + 333c +

Compound ICso Compound ICs. Compound ICso

365c + 367g + 389g +

366c + 368a + 390a +

352c + 369g + 376g +

353a + 362f + 377a +

354c + 363a + 379H +

355a + 364d + 380a +

340a + 364e + 374g +

341c + 381g + 375a +

342a + 382a + 391g +

356c + 385a + 392a +

357a + 384g + 370a +

358c ++ 386g + 378c +

359c + 387a + 371c ++

360c + 383g + 372a ++

361a + 388a + 373a ++

INCORPORATION BY REFERENCE

All of the U.S. patents and U.S. and PCT published patent applications cited herein are hereby incorporated by reference.

EQUIVALENTS

The foregoing written specification is considered to be sufficient to enable one skilled in the art to practice the invention. The present invention is not to be limited in scope by examples provided, since the examples are intended as a single illustration of one aspect of the invention and other functionally equivalent embodiments are within the scope of the invention. Various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and fall within the scope of the appended clams. The advantages and objects of the invention are not necessarily encompassed by each embodiment of the invention.