PYRROLIDINONE DERIVATIVES AS INHIBITORS OF NF KAPPA B INDUCING KINASE

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 63/364,552, filed on May 11 , 2022, which is hereby incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present disclosure relates to the field of chemistry and medicine. More particularly, the present disclosure relates to NF-KB-inducing kinase inhibitors and their use in medical treatment.

BACKGROUND

NF-KB inducing kinase (NIK) is a serine/threonine kinase transcription factor regulating the expression of various genes involved in immune response disorders. Because of this immune system regulatory role, inhibition of NIK blocks several downstream pathways that produce inflammatory molecules. Clinical validation with biologies has confirmed a key role for several NIK-dependent pathways in autoimmune diseases. See, e.g., S. V. Navarra, et al., The Lancet, 2011 ;377(9767):721-31. One way to mitigate or eliminate the adverse effects associated with NIK activity is to increase NIK inhibition.

Thus, there is a need to develop effective NIK inhibitors that can be used to treat various diseases.

SUMMARY

The present application discloses a compound of Formula I: (I), or a pharmaceutically acceptable salt thereof, wherein A, B, W, R ¹ , and R ² are as defined herein.

The present application also discloses a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The present application also discloses a method for treating a disease, disorder, or medical condition mediated by NIK activity, comprising administering to a subject in need of such treatment an effective amount of (i) a compound of Formula I, or a pharmaceutically acceptable carrier thereof, or (ii) a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the disease, disorder, or medical condition mediated by NIK activity is selected from the group consisting of inflammatory disorders, autoimmune disorders, cancers, metabolic disorders, and osteoporosis. In some embodiments, the disease, disorder, or medical condition mediated by NIK activity is selected from the group consisting of systemic lupus erythematosus (“SLE”), rheumatoid arthritis (“RA”), Sjogren’s syndrome, lupus nephritis, inflammatory bowel disease (“IBD”), ANCA associated vasculitis, myositis, lgG4 associated diseases, bullous pemphigoid, neuromyelitis optica spectrum disorders (“NMOSD”), atopic dermatitis “AD”), hidradenitis supperativa (“HS”), steatosis, nonalcoholic steatohepatitis (“NASH”), primary biliary cirrhosis, leukemias, lymphomas, pancreatic cancer, breast cancer, melanoma, obesity, diabetes, acute kidney injury, IgAN, autosomal dominant polycystic kidney disease ("ADCKD"), membranous nephropathy, osteoporosis, bone resorption (periodontitis), multiple sclerosis (“MS”), immune thrombocytopenic purpura, transplantation, myasthenia gravis, scleroderma, myositis, lgG4 associated diseases, and bullous pemphigoid.

Additional embodiments, features, and advantages of the present disclosure will be apparent from the following detailed description and through practice of the present disclosure.

DETAILED DESCRIPTION Discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is for the purpose of providing context for the present disclosure. Such discussion is not an admission that any or all of these matters form part of the prior art with respect to any inventions disclosed or claimed.

NF-KB-inducing kinase (referred to as NIK, also known as MAP3K14) is a regulator and driver of the non-canonical NIK cascade, and thus represents an attractive target for therapeutic intervention. Embodiments described herein relate to compounds that inhibit NIK and pharmaceutical compositions comprising such compounds. Compounds described herein and pharmaceutical compositions thereof are useful for preventing or treating diseases such as inflammatory disorders and autoimmune disorders.

NIK-dependent transcriptional activation is a tightly controlled signaling pathway, through sequential events including phosphorylation and protein degradation. In a NIK activation pathway, known as a non-canonical pathway, activation is accomplished by phosphorylating the catalytic complex subunit IKKa, leading to the partial proteolysis of the gene product p100, liberating DNA-binding protein p52 which then heterodimerizes with another DNA-binding protein RelB, translocates to the nucleus and mediates gene expression. The non-canonical pathway is activated by ligands such as CD40 ligands, B-cell activating factor (BAFF), lymphotoxin [3 receptor ligands, TNF-related weak inducer of apoptosis (TWEAK) cytokine, and receptor activator of nuclear factor kappa- B ligand (RANKL), also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11 ). NIK has been shown to be required for activation of the pathway by these ligands (S.-C. Sun, Nat Rev Immunol. 2017, 17(9), 545-558). Because of its role, NIK expression is tightly regulated. Under normal non-stimulated conditions NIK protein levels are very low. This is due to its interaction with baculoviral-IAP-repeat-containing-3 (BIRC3, also known as CIAP2) and a range of TNF receptor associated factors (TRAF2 and TRAF3), which are ubiquitin ligases and result in degradation of NIK. It is believed that when the non-canonical pathway is stimulated by ligands under pathological/abnormal conditions, the activated receptors now compete for TRAFs, dissociating the TRAF-BIRC3-NIK complexes and thereby increasing the levels of NIK (For a more detailed analysis of this background, see e.g., S.-C. Sun (cited above) and Thu and Richmond, Cytokine Growth F. R. 2010, 21, 213-226). NIK plays a role propitiating immune response disorders, so a NIK level increase is undesirable, and one way to mitigate or eliminate the adverse effect associated with such increase is NIK inhibition.

BAFF/BAFF-R is a clinically validated therapeutic target whose inhibition is deemed beneficial for systemic lupus erythematosus (SLE) treatment. Belimumab (anti- BAFF antibody) has been approved to treat serum positive SLE patients (S. V. Navarra, et al., The Lancet, 2011 ;377(9767):721-31 ). The CD40L/CD40 pathway plays a key role in T-dependent B cell activation, dendritic cell maturation and tissue inflammation/immunity (R. Elgueta, et al., Immunol. Rev. 2009;229(1 ): 152-72). An anti- CD40L antibody has demonstrated promising efficacy in phase 2 clinical studies in SLE patients (P.l. Sidiropoulos and D.T. Boumpas, Lupus 2004 May;13(5):391-7). Mice lacking NIK (R. Shinkura, et al., Nature Genetics 1999;22(1 ):74-7; H. D. Brightbill, et al., J Immunol. 2015;195(3):953-64) or conditional knockout of NIK (H. D. Brightbill, et al., J Immunol. 2015;195(3):953-64) or human patients carrying NIK gene mutations (K. L. Willmann, et al., Nature Comm. 2014;5:5360) showed deficiency in NIK non-canonical activation pathways such as BAFF and CD40L pathway, reduced B lymphocytes in peripheral blood, and lymphoid organs and lower T cell dependent antibody responses supporting NIK as a therapeutic target for SLE.

NIK has been characterized as being “important in the immune and bonedestructive components of inflammatory arthritis and represents a possible therapeutic target for these diseases.” K. Aya, et al. (J. Clin. Invest. 2005, 115, 1848-1854). Mice lacking functional NIK have no peripheral lymph nodes, defective B and T cells, and impaired receptor activator of NIK ligand-stimulated osteoclastogenesis. K. Aya, et al. (J. Clin. Invest. 2005, 115, 1848-1854) investigated the role of NIK in murine models of inflammatory arthritis using NIK-/- mice. The serum transfer arthritis model was initiated by preformed antibodies and required only intact neutrophil and complement systems in recipients. While NIK-/- mice had inflammation equivalent to that of NIK+/+ controls, Ada, et al., (cited above) showed significantly less periarticular osteoclastogenesis and less bone erosion. In contrast, NIK-/- mice were completely resistant to antigen-induced arthritis (AIA), which requires intact antigen presentation and lymphocyte function but not lymph nodes. Additionally, transfer of NIK+/+ splenocytes or T cells to Rag2-/- mice conferred susceptibility to AIA, while transfer of NIK-/- cells did not. NIK-/- mice were also resistant to a genetic, spontaneous form of arthritis, generated in mice expressing both the KRN T cell receptor and H-2g7. Transgenic mice were used with OC-lineage expression of NIK lacking its TRAF3 binding domain (NT3), to demonstrate that constitutive activation of NIK drives enhanced osteoclastogenesis and bone resorption, both in basal conditions and in response to inflammatory stimuli. See Aya, et al., cited above. Furthermore, constitutive activation of NIK drives enhanced osteoclastogenesis and bone resorption, both in basal conditions and in response to inflammatory stimuli. (C. Yang, et al., PLoS ONE 2010, 5(11)’. e15383, doi:10.1371/journal.pone.0015383).

NIK is also a therapeutic target for other BAFF, CD40L or lymphotoxin [3 receptor ligands driven autoimmune disorders such as Sjogren's syndrome (J. Groom, et al., J. Clin. Invest. 2002; 109(1 ):59-68) and proliferative lupus glomerulonephritis (D.T. Boumpas, et al., Arthritis & Rheumatism 2003;48(3):719-27).

Definitions

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the present disclosure pertains. Otherwise, certain terms used herein have the meanings as set forth in the specification.

In an attempt to help the reader of the application, the description has been separated in various paragraphs or sections or is directed to various embodiments of the application. These separations should not be considered as disconnecting the substance of a paragraph or section or embodiments from the substance of another paragraph or section or embodiments. To the contrary, one skilled in the art will understand that the description has broad application and encompasses all the combinations of the various sections, paragraphs and sentences that can be contemplated. The discussion of any embodiment is meant only to be exemplary and is not intended to suggest that the scope of the disclosure, including the claims, is limited to these examples. It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise.

As used herein, the terms "including," "containing," and “comprising” are used in their open, non-limiting sense.

To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about.” It is understood that, whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including equivalents and approximations due to the experimental and/or measurement conditions for such given value.

The term “administering” with respect to the methods of the present disclosure, means a method for therapeutically or prophylactically preventing, treating or ameliorating a syndrome, disorder or disease as described herein by using a compound of the disclosure, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof. Such methods include administering a therapeutically effective amount of a compound of the disclosure, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof, at different times during the course of a therapy or concurrently or sequentially as a combination therapy.

The term “subject” refers to a patient, which may be an animal, preferably a mammal, most preferably a human, whom will be or has been treated by a method according to an embodiment of the application. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, non-human primates (NHPs) such as monkeys or apes, humans, etc., more preferably a human.

The term “therapeutically effective amount” or “effective amount” means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human, that is being sought by a researcher, veterinarian, medical doctor, or other clinician, which includes preventing, treating or ameliorating the symptoms of a syndrome, disorder or disease being treated. As used herein, the term “treatment” or “treating,” is defined as the application or administration of a therapeutic agent, i.e. , a compound of the present disclosure (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has a disorder or disease as described herein, a symptom thereof; or the potential to develop such disorder or disease, where the purpose of the application or administration is to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disorder or disease, its symptoms, or the potential to develop said disorder or disease. Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.

As used herein, the term “prevent” or “prevention” means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease.

The term “C(a-b/ (where a and b are integers referring to a designated number of carbon atoms) refers, for example, to an alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl radical or to the alkyl portion of a radical in which alkyl appears as the prefix root containing from a to b carbon atoms inclusive. For example, C(1 -4) denotes a radical containing 1 , 2, 3 or 4 carbon atoms.

The term “alkyl” is a straight or branched saturated hydrocarbon. For example, an alkyl group can have 1 to 12 carbon atoms (i.e., (Ci-Ci2)alkyl), 1 to 6 carbon atoms (i.e., (Ci -Ce)alkyl), 1 to 4 carbon atoms (i.e., (Ci-C4)alkyl), or 1 to 3 carbon atoms (i.e., (Ci-C3)alkyl). Examples of alkyl groups include, but are not limited to, methyl (Me, - CH3), ethyl (Et, -CH2CH3), 1 -propyl (n-Pr, n-propyl, -CH2CH2CH3), isopropyl (/-Pr, /- propyl, -CH(CH3)2), 1 -butyl (n-bu, n-butyl, -CH2CH2CH2CH3), 2-butyl (s-bu, s-butyl, - CH(CH ₃ )CH2CH ₃ ), tert-butyl (f-bu, f-butyl, -CH(CH ₃ ) ₃ ), 1 -pentyl (n-pentyl, - CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH ₃ ) CH2CH2CH3), neopentyl (-CH ₂ C(CH3)3), 1 - hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH ₂ CH3), heptyl (- (CH ₂ )6CH ₃ ), octyl (-(CH ₂ )7CH ₃ ), 2,2,4-trimethylpentyl (-CH2C(CH3)2CH ₂ CH(CH3)2), nonyl (-(CH ₂ )8CH ₃ ), decyl (-(CH ₂ )9CH ₃ ), undecyl (-(CH ₂ )IOCH ₃ ), and dodecyl (-(CH ₂ )IICH ₃ ). In an embodiment, alkyl refers to C(1-6)alkyl. In another embodiment, alkyl refers to C(i- 4)alkyl. In another embodiment, alkyl refers to C(1-3)alkyl.

The term “halo” or “halogen” refers to bromo (-Br), chloro (-CI), fluoro (-F), or iodo (-I). In an embodiment, halo refers to fluoro.

The term “haloalkyl” refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 3 carbon atoms in the chain optionally substituting one or more H with halo. Examples of “haloalkyl” groups include trifluoromethyl (CF3), difluoromethyl (CF2H), monofluoromethyl (CH2F), pentafluoroethyl (CF2CF3), tetrafluoroethyl (CHFCF3), monofluoroethyl (CH2CH2F), trifluoroethyl (CH2CF3), tetrafluorotrifluoromethylethyl (CF(CF ₃ ) ₂ ), and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples. In an embodiment, haloalkyl refers to C(1-6)haloalkyl. In another embodiment, haloalkyl refers to C(1 -4)haloalkyl. In another embodiment, alkyl refers to C(1 -3)haloalkyl.

The term “cycloalkyl” refers to a saturated or partially unsaturated all carbon ring system having, for example, 3 to 10 carbon atoms (i.e. , C(3-10)cycloalkyl), 3 to 8 carbon atoms (i.e., C(3-8)cycloalkyl), or 3 to 6 carbon atoms (i.e., C(3-6)cycloalkyl), wherein the cycloalkyl ring system has a single ring or multiple rings in a fused, spirocyclic, or bridged configuration. Exemplary cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Some cycloalkyl groups may exist as spirocycloalkyls, wherein two cycloalkyl rings are fused through a single carbon atom; for example and without limitation, an example of a spiropentyl group is 'b ^>< 3; for example and without limitation, examples of spirohexyl groups include . In an embodiment, cycloalkyl refers to

C(3-10)cycloalkyl. In another embodiment, cycloalkyl refers to C(3-8)cycloalkyl. In another embodiment, cycloalkyl refers to C(3-6)cycloalkyl.

The term “aryl,” unless otherwise stated, refers to a polyunsaturated, typically aromatic, hydrocarbon group which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently. The term aromatic is well known to a person skilled in the art and designates cyclically conjugated systems of 4n + 2 electrons, that is with 6, 10, 14 etc. ii-electrons (rule of Huckel). Examples of aryl groups include phenyl, naphthyl, anthracenyl. In an embodiment, aryl refers to C(6-10)aryl. In another embodiment, aryl refers to phenyl.

The term “heterocyclyl” or “heterocycloalkyl” refers to a single saturated or partially unsaturated ring having 3 to 12 ring members, 3 to 10 ring members, 3 to 8 ring members, or 3 to 6 ring members and which contains carbon atoms and at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of N, 0, and S. The terms “heterocyclyl” and “heterocycloalkyl” include cyclic esters (e.g., lactones) and cyclic amides (e.g., lactams). Exemplary heterocycles include, but are not limited to oxetanyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, and thiomorpholinyl. Unless otherwise noted, the heterocyclyl group is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. In an embodiment, heterocyclyl refers to 3- to 10-membered heterocyclyl. In another embodiment, heterocyclyl refers to 3- to 8-membered heterocyclyl. In another embodiment, heterocyclyl refers to 3- to 6-membered heterocyclyl.

As used herein, the term “5- to 12-membered bi- or tricyclic ring system containing one or more heteroatoms” refers to a saturated or partially saturated bridged polycyclic, fused polycyclic, or spiro polycyclic ring system having 5 to 12 ring members (or 7 to 12 ring members or 7 to 10 ring members) and which contains carbon atoms and from 1 to 7 heteroatoms, 1 to 5 heteroatoms, 1 to 4 heteroatoms, or 1 to 3 heteroatoms, wherein the heteroatoms are independently selected from the group consisting of N, 0, and S. The ring system may include a fully unsaturated aromatic ring; however, at least one other ring in the polycyclic ring system must be saturated or partially saturated. In some embodiments, the term refers to a fused bicyclic ring system. In some embodiments, the term refers to a fused bicyclic ring system wherein one of the rings is an aromatic ring. The term includes cyclic esters (e.g., lactones) and cyclic amides (e.g., lactams). Nonlimiting examples of 5- to 12-membered bi- or tricyclic ring system containing one or more heteroatoms include 3-oxabicyclo[3.1 .0]hexyl, indolinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 4,5,6,7-tetrahydro-1 H-indazolyl, 6,7- dihydro-5H-cyclopenta[c]pyridazinyl, 4,5,6,7-tetrahydropyrazolo[1 , 5-a]pyridinyl, 4, 5,6,7- tetrahydropyrazolo[1 , 5-a]pyrim idinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, 3-methyl- 6,7-dihydro-5H-pyrazolo[5, 1 -b][ 1 ,3]oxazinyl, and 6,7-dihydropyrazolo[1 ,5-a]pyrazin- 4(5H)-onyl. Unless otherwise noted, the bi- or tricyclic ring system is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. In an embodiment, a 5- to 12-membered bi- or tricyclic ring system containing one or more heteroatoms refers to a 5- to 12-membered bicyclic ring system containing one or more heteroatoms. In another embodiment, a 5- to 12-membered bi- or tricyclic ring system containing one or more heteroatoms refers to a 7- to 12-membered bicyclic ring system containing one or more heteroatoms. In another embodiment, a 5- to 12-membered bi- or tricyclic ring system containing one or more heteroatoms refers to a 7- to 10- membered bicyclic ring system containing one or more heteroatoms.

The term “heteroaryl” refers to a monocyclic or bicyclic aryl ring system having 5 to 12 ring members, 5 to 10 ring members, or 5 to 6 ring members, and which contains carbon atoms and from 1 to 5 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms, wherein the heteroatoms are independently selected from the group consisting of N, 0, and S. Included within the term heteroaryl are aromatic rings of 5 or 6 members wherein the ring consists of carbon atoms and has at least one heteroatom member. Suitable heteroatoms include nitrogen, oxygen, and sulfur. In some embodiments, in the case of

5-membered rings, the heteroaryl ring contains one member of nitrogen, oxygen or sulfur and, in addition, up to 3 additional nitrogens. In some embodiments, in the case of

6-membered rings, the heteroaryl ring contains from 1 to 3 nitrogen atoms. For the case wherein the 6-membered ring has 3 nitrogens, at most 2 nitrogen atoms are adjacent. Examples of heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzothiadiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinazolinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Those skilled in the art will recognize that the species of heteroaryl groups listed are not exhaustive, and that additional species within the scope of these defined terms may also be selected. Unless otherwise noted, the heteroaryl is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. In an embodiment, heteroaryl refers to 5- to 10-membered heteroaryl. In another embodiment, heteroaryl refers to 5- to 8-membered heteroaryl. In another embodiment, heteroaryl refers to 5- to 6-membered heteroaryl. In another embodiment, heteroaryl refers to 5-membered heteroaryl.

The term “substituted” means that the specified group or moiety bears one or more substituents. The term "unsubstituted" means that the specified group bears no substituents. The term “optionally substituted” means that the specified group is unsubstituted or substituted by one or more substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system.

Where the compounds disclosed herein have at least one stereocenter, they may accordingly exist as enantiomers or diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present disclosure.

“Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other.

“Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A “racemic” mixture is a 1 :1 mixture of a pair of enantiomers. A “scalemic” mixture of enantiomers is mixture of enantiomers at a ratio other than 1 :1.

Where the processes for the preparation of the compounds according to the disclosure give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, a scalemic mixture, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral column vial HPLC or SFC. In some instances rotamers of compounds may exist which are observable by ¹ H NMR leading to complex multiplets and peak integration in the ¹ H NMR spectrum.

The absolute stereochemistry is specified according to the Cahn-lngold-Prelog R-S system. Chiral centers, of which the absolute configurations are known, are labelled by prefixes R and S, assigned by the standard sequence-rule procedure, and preceded when necessary by the appropriate locants (Pure & Appt. Chem. 45, 1976, 11-30). Certain pairs of enantiomers and diastereomers are presented together in the Examples. These enantiomers/diastereomers may be designated in the following synthetic method and characterized as enantiomer 1 or enantiomer 2 (or, alternately, diastereomer 1 or diastereomer 2). The presentation of stereoisomers in this manner conveys the separate preparation or isolation of the compounds as pure single enantiomers or diastereomers at the identified stereocenter(s). However, unless otherwise specified, when a pure single enantiomer (or diastereomer) is presented together with the corresponding pure single enantiomer (or diastereomer) in the Examples of the present disclosure, the order in which the chemical structures/IUPAC names are presented do not necessarily correspond to the order in which the Example numbers are listed. By way of example, where R and S enantiomers of a compound are presented side-by-side under the header “Example X and Example Y,” then Example X may be either the R enantiomer or the S enantiomer, and Example Y is the opposite enantiomer, regardless of the order in which the IIIPAC names or chemical structures of the compounds are presented, unless otherwise specified in the method and characterization that follows. During any of the processes for preparation of the compounds disclosed herein, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 . The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

Furthermore, it is intended that within the scope of the present disclosure, any element, in particular when mentioned in relation to a compound of the disclosure, or pharmaceutically acceptable salt thereof, shall comprise all isotopes and isotopic mixtures of said element, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. For example, a reference to hydrogen or “H” includes within its scope ¹ H, ² H (i.e., deuterium or D), and ³ H (i.e., tritium or T). In some embodiments, the compounds described herein include a ² H (i.e., deuterium) isotope. By way of example, the group denoted -C(1-6)alkyl includes not only -C ¹ H3, but also C ¹ HD2, C ¹ H2D, CDS and other isotopic forms; not only C ¹ H2C ¹ Hs, but also C ¹ HDC ¹ HD ₂ , C ¹ HDC ¹ H2D, C ¹ H2C ¹ H3, CD2CD3, etc. Likewise, where nonexplicit hydrogen atoms are present in a chemical structure, those hydrogen atoms may be ¹ H, ² H (i.e., deuterium or D), or ³ H (i.e., tritium or T). By way of illustration, the group . Similarly, references to carbon and oxygen include within their scope respectively ¹² C, ¹³ C and ¹⁴ C and ¹⁵ O and ¹⁶ O and ¹⁷ O and ¹⁸ O. The isotopes may be radioactive or non-radioactive. Radiolabelled compounds of the disclosure may include a radioactive isotope selected from the group comprising ³ H, ¹¹ C, ¹⁸ F, ³⁵ S, ¹²² l, ¹²³ l, ¹²⁵ l, ¹³¹ 1, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br and ⁸² Br. In some embodiments, , the radioactive isotope is selected from the group of ³ H, ¹¹ C and ¹⁸ F.

Reference to a compound herein stands for a reference to any one of: (a) the actually recited form of such compound, and (b) any of the forms of such compound in the medium in which the compound is being considered when named. For example, reference herein to a compound such as R-COOH, encompasses reference to any one of, for example, R-COOH( _S ), R-COOH(soi), and R-COO’(soi). In this example, R-COOH( _S ) refers to the solid compound, as it could be for example in a tablet or some other solid pharmaceutical composition or preparation; R-COOH(soi) refers to the undissociated form of the compound in a solvent; and R-COO’(soi) refers to the dissociated form of the compound in a solvent, such as the dissociated form of the compound in an aqueous environment, whether such dissociated form derives from R-COOH, from a salt thereof, or from any other entity that yields R-COO’ upon dissociation in the medium being considered. In another example, an expression such as “exposing an entity to compound of formula R-COOH” refers to the exposure of such entity to the form, or forms, of the compound R-COOH that exists, or exist, in the medium in which such exposure takes place. In still another example, an expression such as “reacting an entity with a compound of formula R-COOH” refers to the reacting of (a) such entity in the chemically relevant form, or forms, of such entity that exists, or exist, in the medium in which such reacting takes place, with (b) the chemically relevant form, or forms, of the compound R-COOH that exists, or exist, in the medium in which such reacting takes place. In this regard, if such entity is for example in an aqueous environment, it is understood that the compound R-COOH is in such same medium, and therefore the entity is being exposed to species such as R-COOH(aq) and/or R-COO’(aq), where the subscript “(aq)” stands for “aqueous” according to its conventional meaning in chemistry and biochemistry. A carboxylic acid functional group has been chosen in these nomenclature examples; this choice is not intended, however, as a limitation but it is merely an illustration. It is understood that analogous examples can be provided in terms of other functional groups, including but not limited to hydroxyl, basic nitrogen members, such as those in amines, and any other group that interacts or transforms according to known manners in the medium that contains the compound. Such interactions and transformations include, but are not limited to, dissociation, association, tautomerism, solvolysis, including hydrolysis, solvation, including hydration, protonation, and deprotonation. No further examples in this regard are provided herein because these interactions and transformations in a given medium are known by any one of ordinary skill in the art. The term “pharmaceutically acceptable” means approved or approvable by a regulatory agency of Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U. S. Pharmcopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

A “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound disclosed herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. It should possess the desired pharmacological activity of the parent compound. See, generally, G.S. Paulekuhn, et al., “Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database”, J. Med. Chem., 2007, 50:6665-72, S.M. Berge, et al., “Pharmaceutical Salts”, J Pharm Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley- VCH and VHCA, Zurich, 2002. Examples of pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. A compound of the disclosure may possess a sufficiently acidic group, a sufficiently basic group, or both types of functional groups, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.

Compounds of the Disclosure

The present application discloses a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein:

A is a 5-membered heteroaryl that is optionally substituted with one to three groups selected from -C(1 -4)alkyl, and -C(1 -4)haloalkyl;

B is furanyl, piperidinyl, or a group having the following structure:

W is CH ₂ , CHF, or CF ₂ ;

V is N, C-H, or C-R ^v ;

X is N, C-H, or C-R ^x ;

Y is N, C-H, or C-R ^Y ;

Z is N, C-H, or C-R ^z ;

R ^v , R ^x , R ^Y , and R ^z are each, independently, halo, -C(1 -4)alkyl, -C(1 -4)haloalkyl, or - OC(1 -4)alkyl;

R ¹ is hydrogen, -C(1-4)alkyl, or -C(1 -4)haloalkyl;

R ² is -N(H)(5- to 10-membered heteroaryl), -C(6-10)aryl, a 5- to 12-membered bi- or tricyclic ring system containing one or more heteroatoms, or 5- to 10-membered heteroaryl, wherein the -N(H)(5- to 10-membered heteroaryl), the -C(6-10)aryl, the 5- to 12-membered bi- or tricyclic ring system containing one or more heteroatoms, and the

5- to 10-membered heteroaryl are each optionally substituted with one to five R ³ groups; each R ³ is independently for each occurrence halo, -OH, -N(R ^N1 )(R ^N2 ), -CN, -C(i- 6)alkyl, -C(1-6)haloalkyl, -C(3-10)cycloalkyl, -OC(1-6)alkyl, -OC(1-6)haloalkyl, -OC(3- io)cycloalkyl, -C(1-3)alkyl-N(R ^N1 )(R ^N3 ), -C(O)OH, -C(O)N(R ^N1 )(R ^N4 ), -C(1-3)alkyl(3- to 8- membered heterocyclyl), -C(i -3)alkyl(phenyl), 3- to 8-membered heterocyclyl, or 5- to 6- membered heteroaryl, wherein the -C(1-6)alkyl, -C(1-6)haloalkyl, -C(3-10)cycloalkyl, -OC(i- 6)alkyl, -OC(1-6)haloalkyl, -OC(3-10)cycloalkyl, -C(1-3)alkyl(3- to 8-membered heterocyclyl), - C(i -3)alkyl(phenyl), 3- to 8-membered heterocyclyl, and 5- to 6-membered heteroaryl are optionally further substituted with one to five groups selected from halo, -C(1 -4)alkyl, -C(i - 4)haloalkyl, -C(3-6)cycloalkyl, -OC(1 -4)alkyl, -OC(1 -4)haloalkyl, and -C(1 -4)alkylOC(1 -4)alkyl;

R ^N1 is hydrogen or C(1 -4)alkyl;

R ^N2 , R ^N3 , and R ^N4 are each independently for each occurrence hydrogen, -C(i- 4)alkyl, -C(3-6)cycloalkyl, -C(O)C(1 -4)alkyl, -C(1 -4)alkyl(4- to 6-membered heterocyclyl), 4- to

6-membered heterocyclyl, 5- to 6-membered heteroaryl, wherein the 4- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally further substituted with one to three groups selected from -CN, -C(1 -4)alkyl, -C(1 -4)haloalkyl, -OC(1 -4)alkyl, -OC(i- 4)haloalkyl, and -C(O)C(1 -4)alkyl; provided that at least two of V, X, Y, and Z are C-H; and provided that if R ² is pyrim idinyl, then the pyrimidinyl is substituted with one group selected from -OC(1-6)alkyl and -C(O)N(R ^N1 )(R ^N4 ) and is optionally further substituted with one to two R ³ groups.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:

A is a 5-membered heteroaryl that is optionally substituted with one to three groups selected from -C(1 -4)alkyl, and -C(1 -4)haloalkyl;

B is furanyl, piperidinyl, or a group having the following structure:

W is CH ₂ or CF ₂ ;

V is N, C-H, or C-R ^v ;

X is N, C-H, or C-R ^x ;

Y is N, C-H, or C-R ^Y ;

Z is N, C-H, or C-R ^z ;

R ^v , R ^x , R ^Y , and R ^z are each, independently, halo, -C(1 -4)alkyl, -C(1 -4)haloalkyl, or - OC(1 -4)alkyl;

R ¹ is hydrogen, -C(1 -4)alkyl, or -C(1 -4)haloalkyl;

R ² is -N(H)(5- to 10-membered heteroaryl), -C(6-10)aryl, a 5- to 12-membered bi- or tricyclic ring system containing one or more heteroatoms, or 5- to 10-membered heteroaryl, wherein the -N(H)(5- to 10-membered heteroaryl), the -C(6-10)aryl, the 5- to 12-membered bi- or tricyclic ring system containing one or more heteroatoms, and the 5- to 10-membered heteroaryl are each optionally substituted with one to five R ³ groups; each R ³ is independently for each occurrence halo, -N(R ^N1 )(R ^N2 ), -C(1-6)alkyl, -C(i- 6)haloalkyl, -C(3-10)cycloalkyl, -OC(1-6)alkyl, -OC(1-6)haloalkyl, -OC(3-10)cycloalkyl, -C(i- ₃ )alkyl-N(R ^N1 )(R ^N3 ), -C(O)OH, -C(O)N(R ^N1 )(R ^N4 ), -C(1-3)alkyl(3- to 8-membered heterocyclyl), -C(i -3)alkyl(phenyl), 3- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl, wherein the -C(1-6)alkyl, -C(i -6)haloalkyl, -C(3-10)cycloalkyl, -OC(1-6)alkyl, -OC(i- 6)haloalkyl, -OC(3-10)cycloalkyl, -C(1-3)alkyl(3- to 8-membered heterocyclyl), -C(i-

3)alkyl(phenyl), 3- to 8-membered heterocyclyl, and 5- to 6-membered heteroaryl are optionally further substituted with one to five groups selected from halo, -C(1 -4)alkyl, -C(i -

4)haloalkyl, -C(3-6)cycloalkyl, -OC(1 -4)alkyl, -OC(1 -4)haloalkyl, and -C(1 -4)alkylOC(1 -4)alkyl;

R ^N1 is hydrogen or C(1 -4)alkyl;

R ^N2 is hydrogen, -C(1 -4)alkyl, -C(3-6)cycloalkyl, -C(O)C(1 -4)alkyl, -C(1 -4)alkyl(4- to 6- membered heterocyclyl), 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, wherein the 4- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally further substituted with one to three groups selected from -CN, -C(1 -4)alkyl, - C(1 -4)haloalkyl, -OC(1 -4)alkyl, -OC(1 -4)haloalkyl, and -C(O)C(1 -4)alkyl;

R ^N3 is hydrogen, -C(3-6)cycloalkyl, or 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally further substituted with one to three -C(1 -4)alkyl groups;

R ^N4 is hydrogen, -C(1 -4)alkyl, or 4- to 6-membered heterocyclyl; provided that at least two of V, X, Y, and Z are C-H; and provided that if R ² is pyrim idinyl, then the pyrimidinyl is substituted with one group selected from -OC(1-6)alkyl and -C(O)N(R ^N1 )(R ^N4 ) and is optionally further substituted with one to two R ³ groups.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:

A is a 5-membered heteroaryl that is optionally substituted with one to three -C(i- 4)alky I groups;

B is furanyl, piperidinyl, or a group having the following structure:

W is CH ₂ or CF ₂ ;

V is N, C-H, or C-R ^v ;

X is N, C-H, or C-R ^x ;

Y is N, C-H, or C-R ^Y ; Z is N, C-H, or C-R ^z ;

R ^v is halo;

R ^x , R ^Y , and R ^z are each, independently, halo, -C(1 -4)alkyl, -C(1 -4)haloalkyl, or - OC(1 -4)alkyl;

R ¹ is hydrogen, -C(1 -4)alkyl, or -C(1 -4)haloalkyl;

R ² is -N(H)(5- to 10-membered heteroaryl), -C(6-10)aryl, a 5- to 12-membered bi- or tricyclic ring system containing one or more heteroatoms, or 5- to 10-membered heteroaryl, wherein the -N(H)(5- to 10-membered heteroaryl), the -C(6-10)aryl, the 5- to 12-membered bi- or tricyclic ring system containing one or more heteroatoms, and the 5- to 10-membered heteroaryl are each optionally substituted with one to five R ³ groups; each R ³ is independently for each occurrence halo, -N(R ^N1 )(R ^N2 ), -C(1-6)alkyl, -C(i- 6)haloalkyl, -C(3-10)Cycloalkyl, -OC(1-6)alkyl, -OC(1-6)haloalkyl, -C(1-3)alkyl-N(R ^N1 )(R ^N3 ), - C(O)OH, -C(O)N(R ^N1 )(R ^N4 ), -C(1-3)alkyl(3- to 8-membered heterocyclyl), -C(1- 3)alkyl(phenyl), 3- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl, wherein the 3- to 8-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally further substituted with one to five groups selected from halo, -C(1 -4)alkyl, -C(1 -4)haloalkyl, -C(3-6)cycloalkyl, -OC(1 -4)alkyl, -OC(1 -4)haloalkyl, and -C(1 -4)alkylOC(1 -4)alkyl;

R ^N1 is hydrogen or C(1 -4)alkyl;

R ^N2 is hydrogen, -C(1 -4)alkyl, -C(3-6)cycloalkyl, -C(O)C(1 -4)alkyl, -C(1 -4)alkyl(4- to 6- membered heterocyclyl), 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, wherein the 4- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally further substituted with one to three groups selected from -CN, -C(1 -4)alkyl, - C(1 -4)haloalkyl, -OC(1 -4)alkyl, -OC(1 -4)haloalkyl, and -C(O)C(1 -4)alkyl;

R ^N3 is hydrogen, -C(3-6)cycloalkyl, or 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally further substituted with one to three -C(1 -4)alkyl groups;

R ^N4 is hydrogen, -C(1 -4)alkyl, or 4- to 6-membered heterocyclyl; provided that at least two of V, X, Y, and Z are C-H; and provided that if R ² is pyrim idinyl, then the pyrimidinyl is substituted with one group selected from -OC(1-6)alkyl and -C(O)N(R ^N1 )(R ^N4 ) and is optionally further substituted with one to two R ³ groups. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:

A is a 5-membered heteroaryl that is optionally substituted with one -C(1 -4)alkyl groups;

B is:

W is CH ₂ or CF ₂ ;

V is N, C-H, or C-F;

X is N, C-H, or C-R ^x ;

Y is N, C-H, or C-R ^Y ;

Z is N, C-H, or C-R ^z ;

R ^x , R ^Y , and R ^z are each, independently, fluorine, -CH3, or -OCH3;

R ¹ is hydrogen or -CF3;

R ² is a 5- to 12-membered bi- or tricyclic ring system containing one or more heteroatoms or 5- to 10-membered heteroaryl, wherein the 5- to 12-membered bi- or tricyclic ring system containing one or more heteroatoms and the 5- to 10-membered heteroaryl are each optionally substituted with one to five R ³ groups; each R ³ is independently for each occurrence halo, -N(R ^N1 )(R ^N2 ), -C(1-6)alkyl, -C(i- 6)haloalkyl, -C(3-10)Cycloalkyl, -OC(1-6)alkyl, -OC(1-6)haloalkyl, -C(1-3)alkyl-N(R ^N1 )(R ^N3 ), - C(O)OH, -C(O)N(R ^N1 )(R ^N4 ), -C(1-3)alkyl(3- to 8-membered heterocyclyl), -C ₍ i- 3)alkyl(phenyl), 3- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl, wherein the 3- to 8-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally further substituted with one to five groups selected from halo, -C(1 -4)alkyl, -C(1 -4)haloalkyl, -C(3-6)cycloalkyl, -OC(1 -4)alkyl, -OC(1 -4)haloalkyl, and -C(1 -4)alkylOC(1 -4)alkyl;

R ^N1 is hydrogen;

R ^N2 is hydrogen, -C(1 -4)alkyl, -C(3-6)cycloalkyl, -C(O)C(1 -4)alkyl, -C(1 -4)alkyl(4- to 6- membered heterocyclyl), 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, wherein the 4- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally further substituted with one to three groups selected from -CN, -C(1 -4)alkyl, - C(1 -4)haloalkyl, -OC(1 -4)alkyl, -OC(1 -4)haloalkyl, and -C(O)C(1 -4)alkyl;

R ^N3 is hydrogen, -C(3-6)cycloalkyl, or 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally further substituted with one to three -C(1 -4)alkyl groups;

R ^N4 is hydrogen, -C(1 -4)alkyl, or 4- to 6-membered heterocyclyl; provided that at least two of V, X, Y, and Z are C-H; and provided that if R ² is pyrim idinyl, then the pyrimidinyl is substituted with one group selected from -OC(1-6)alkyl and -C(O)N(R ^N1 )(R ^N4 ) and is optionally further substituted with one to two R ³ groups.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:

A is a 5-membered heteroaryl that is optionally substituted with one to three groups selected from -C(1 -4)alkyl and -C(1 -4)haloalkyl;

B is furanyl, piperidinyl, or a group having the following structure:

W is CH ₂ , CHF, or CF ₂ ;

V is N, C-H, or C-R ^v ;

X is N, C-H, or C-R ^x ;

Y is N, C-H, or C-R ^Y ;

Z is N, C-H, or C-R ^z ;

R ^v , R ^x , R ^Y , and R ^z are each, independently, halo, -C(1 -4)alkyl, -C(1 -4)haloalkyl, or - OC(1 -4)alkyl;

R ¹ is hydrogen, -C(1 -4)alkyl, or -C(1 -4)haloalkyl;

R ² is -N(H)(5- to 10-membered heteroaryl), -C(6-10)aryl, a 5- to 12-membered bi- or tricyclic ring system containing one or more heteroatoms, or 5- to 10-membered heteroaryl, wherein: the -N(H)(5- to 10-membered heteroaryl) is optionally substituted with one to five R ^3a groups, the -C(6-10)aryl is optionally substituted with one to five R ^3b groups, the 5- to 12-membered bi- or tricyclic ring system containing one or more heteroatoms is optionally substituted with one to five R ^3c groups, and the 5- to 10- membered heteroaryl is optionally substituted with one to five R ^3d groups;

R ^3a , R ^3b , R ^3c , and R ^3d are each independently for each occurrence halo, -OH, - N(R ^N1 )(R ^N2 ), -CN, -C(1-6)alkyl, -C(1-6)haloalkyl, -C ₍₃ -io)cycloalkyl, -OC(1-6)alkyl, -OC ₍ i- ₆ )haloalkyl, -OC ₍₃ -io)cycloalkyl, -C(i- ₃₎ alkyl-N(R ^N1 )(R ^N3 ), -C(O)OH, -C(O)N(R ^N1 )(R ^N4 ), -C ₍ i-

₃ )alkyl(3- to 8-membered heterocyclyl), -C(i- ₃ )alkyl(phenyl), 3- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl, wherein the -C(1-6)alkyl, -C(i -6)haloalkyl, - C( ₃ -io)Cycloalkyl, -OC(1-6)alkyl, -OC(1-6)haloalkyl, -OC( ₃ -io)Cycloalkyl, -C(i- ₃ )alkyl(3- to 8- membered heterocyclyl), -C(i- ₃ )alkyl(phenyl), 3- to 8-membered heterocyclyl, and 5- to 6-membered heteroaryl are optionally further substituted with one to five groups selected from halo, -C(1 -4)alkyl, -C(1 -4)haloalkyl, -C( ₃ -6)cycloalkyl, -OC(1 -4)alkyl, -OC(i-

4)haloalkyl, and -C(1 -4)alkylOC(1 -4)alkyl;

R ^N1 is hydrogen or C(1 -4)alkyl;

R ^N2 , R ^N3 , and R ^N4 are each independently for each occurrence hydrogen, -C(i- 4)alkyl, -C( ₃ -6)cycloalkyl, -C(O)C(1 -4)alkyl, -C(1 -4)alkyl(4- to 6-membered heterocyclyl), 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, wherein the 4- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally further substituted with one to three groups selected from -CN, -C(1 -4)alkyl, -C(1 -4)haloalkyl, -OC(1 -4)alkyl, -OC(i- 4)haloalkyl, and -C(O)C(1 -4)alkyl; provided that at least two of V, X, Y, and Z are C-H; and provided that if R ² is pyrim idinyl, then the pyrimidinyl is substituted with one group selected from -OC(1-6)alkyl and -C(O)N(R ^N1 )(R ^N4 ) and is optionally further substituted with one to two R ^3d groups.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:

A is a 5-membered heteroaryl that is optionally substituted with one to three groups selected from -C(1 -4)alkyl and -C(1 -4)haloalkyl;

B is furanyl, piperidinyl, or a group having the following structure: W is CH ₂ or CF ₂ ;

V is N, C-H, or C-R ^v ;

X is N, C-H, or C-R ^x ;

Y is N, C-H, or C-R ^Y ;

Z is N, C-H, or C-R ^z ;

R ^v , R ^x , R ^Y , and R ^z are each, independently, halo, -C(1 -4)alkyl, -C(1 -4)haloalkyl, or - OC(1 -4)alkyl;

R ¹ is hydrogen, -C(1 -4)alkyl, or -C(1 -4)haloalkyl;

R ² is -N(H)(5- to 10-membered heteroaryl), -C(6-10)aryl, a 5- to 12-membered bi- or tricyclic ring system containing one or more heteroatoms, or 5- to 10-membered heteroaryl, wherein: the -N(H)(5- to 10-membered heteroaryl) is optionally substituted with one to five R ^3a groups, the -C(6-10)aryl is optionally substituted with one to five R ^3b groups, the 5- to 12-membered bi- or tricyclic ring system containing one or more heteroatoms is optionally substituted with one to five R ^3c groups, and the 5- to 10- membered heteroaryl is optionally substituted with one to five R ^3d groups;

R ^3a and R ^3b are each independently for each occurrence halo, -N(R ^N1 )(R ^N2 ), -C(i- 6)alkyl, -C(1-6)haloalkyl, -OC(1-6)alkyl, -OC(1-6)haloalkyl, -C(1-3)alkyl-N(R ^N1 )(R ^N3 ), or - C(O)N(R ^N1 )(R ^N4 );

R ^3c and R ^3d are each independently for each occurrence halo, -OH, -N(R ^N1 )(R ^N2 ), -CN, -C(1-6)alkyl, -C(i -6)haloalkyl, -C(3-10)cycloalkyl, -OC(1-6)alkyl, -OC(1-6)haloalkyl, -OC(3- io)cycloalkyl, -C(1-3)alkyl-N(R ^N1 )(R ^N3 ), -C(O)OH, -C(O)N(R ^N1 )(R ^N4 ), -C(1-3)alkyl(3- to 8- membered heterocyclyl), -C(i -3)alkyl(phenyl), 3- to 8-membered heterocyclyl, or 5- to 6- membered heteroaryl, wherein the -C(1-6)alkyl, -C(1-6)haloalkyl, -C(3-10)cycloalkyl, -OC(i- 6)alkyl, -OC(1-6)haloalkyl, -OC(3-10)cycloalkyl, -C(1-3)alkyl(3- to 8-membered heterocyclyl), - C(i -3)alkyl(phenyl), 3- to 8-membered heterocyclyl, and 5- to 6-membered heteroaryl are optionally further substituted with one to five groups selected from halo, -C(1 -4)alkyl, -C(i - 4)haloalkyl, -C(3-6)cycloalkyl, -OC(1 -4)alkyl, -OC(1 -4)haloalkyl, and -C(1 -4)alkylOC(1 -4)alkyl;

R ^N1 is hydrogen or C(1 -4)alkyl;

R ^N2 , R ^N3 , and R ^N4 are each independently for each occurrence hydrogen, -C(i- 4)alkyl, -C(3-6)cycloalkyl, -C(O)C(1 -4)alkyl, -C(1 -4)alkyl(4- to 6-membered heterocyclyl), 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, wherein the 4- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally further substituted with one to three groups selected from -CN, -C(1 -4)alkyl, -C(1 -4)haloalkyl, -OC(1 -4)alkyl, -OC(i- 4)haloalkyl, and -C(O)C(1 -4)alkyl; provided that at least two of V, X, Y, and Z are C-H; and provided that if R ² is pyrim idinyl, then the pyrimidinyl is substituted with one group selected from -OC(1-6)alkyl and -C(O)N(R ^N1 )(R ^N4 ) and is optionally further substituted with one to two R ^3d groups.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:

A is a 5-membered heteroaryl that is optionally substituted with one to three groups selected from -C(1 -4)alkyl and -C(1 -4)haloalkyl;

B is furanyl, piperidinyl, or a group having the following structure:

W is CH ₂ or CF ₂ ;

V is N, C-H, or C-R ^v ;

X is N, C-H, or C-R ^x ;

Y is N, C-H, or C-R ^Y ;

Z is N, C-H, or C-R ^z ;

R ^v is halo;

R ^x , R ^Y , and R ^z are each, independently, halo, -C(1 -4)alkyl, -C(1 -4)haloalkyl, or - OC(1 -4)alkyl;

R ¹ is hydrogen, -C(1 -4)alkyl, or -C(1 -4)haloalkyl;

R ² is -N(H)(5- to 10-membered heteroaryl), -C(6-10)aryl, a 5- to 12-membered bi- or tricyclic ring system containing one or more heteroatoms, or 5- to 10-membered heteroaryl, wherein: the -N(H)(5- to 10-membered heteroaryl) is optionally substituted with one to five R ^3a groups, the -C(6-10)aryl is optionally substituted with one to five R ^3b groups, the 5- to 12-membered bi- or tricyclic ring system containing one or more heteroatoms is optionally substituted with one to five R ^3c groups, and the 5- to 10- membered heteroaryl is optionally substituted with one to five R ^3d groups; R ^3a and R ^3b are each independently for each occurrence -N(R ^N1 )(R ^N2 ) or - C(O)N(R ^N1 )(R ^N4 ); each R ^3c is independently for each occurrence halo, -N(R ^N1 )(R ^N2 ), -C(1-6)alkyl, - C(1-6)haloalkyl, -OC(1-6)alkyl, -OC(1-6)haloalkyl, -C(1-3)alkyl-N(R ^N1 )(R ^N3 ), -C(O)OH, - C(O)N(R ^N1 )(R ^N4 ), or -C(i- ₃₎ alkyl(phenyl); each R ^3d is independently for each occurrence halo, -N(R ^N1 )(R ^N2 ), -C(1-6)alkyl, - C(1-6)haloalkyl, -C(3-10)cycloalkyl, -OC(1-6)alkyl, -OC(1-6)haloalkyl, -OC(3-10)cycloalkyl, -C(i- ₃₎ alkyl-N(R ^N1 )(R ^N3 ), -C(O)N(R ^N1 )(R ^N4 ), -C ₍ i- ₃₎ alkyl(3- to 8-membered heterocyclyl), 3- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl, wherein the -C(i -ejalkyl, -C(i- 6)haloalkyl, -C(3-10)cycloalkyl, -OC(1-6)alkyl, -OC(1-6)haloalkyl, -OC(3-10)cycloalkyl, -C(i- 3)alky l(3- to 8-membered heterocyclyl), 3- to 8-membered heterocyclyl, and 5- to 6- membered heteroaryl are optionally further substituted with one to five groups selected from halo, -C(1 -4)alkyl, -C(1 -4)haloalkyl, -C(3-6)cycloalkyl, -OC(1 -4)alkyl, -OC(1 -4)haloalkyl, and -C(1 -4)alkylOC(1 -4)alkyl;

R ^N1 is hydrogen or C(1 -4)alkyl;

R ^N2 is hydrogen, -C(1 -4)alkyl, -C(3-6)cycloalkyl, -C(O)C(1 -4)alkyl, -C(1 -4)alkyl(4- to 6- membered heterocyclyl), 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, wherein the 4- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally further substituted with one to three groups selected from -CN, -C(1 -4)alkyl, - C(1 -4)haloalkyl, -OC(1 -4)alkyl, -OC(1 -4)haloalkyl, and -C(O)C(1 -4)alkyl;

R ^N3 is hydrogen, -C(3-6)cycloalkyl, or 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally further substituted with one to three -C(1 -4)alkyl groups;

R ^N4 is hydrogen, -C(1 -4)alkyl, or 4- to 6-membered heterocyclyl; provided that at least two of V, X, Y, and Z are C-H; and provided that if R ² is pyrim idinyl, then the pyrimidinyl is substituted with one group selected from -OC(1-6)alkyl and -C(O)N(R ^N1 )(R ^N4 ) and is optionally further substituted with one to two R ^3d groups.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein: A is a 5-membered heteroaryl that is optionally substituted with one to three -C(i- 4)alky I groups;

B is furanyl, piperidinyl, or a group having the following structure:

W is CH ₂ or CF ₂ ;

V is N, C-H, or C-R ^v ;

X is N, C-H, or C-R ^x ;

Y is N, C-H, or C-R ^Y ; Z is N, C-H, or C-R ^z ; R ^v is halo;

R ^x , R ^Y , and R ^z are each, independently, halo, -C(1 -4)alkyl, -C(1 -4)haloalkyl, or -

OC(1 -4)alkyl;

R ¹ is hydrogen, -C(1 -4)alkyl, or -C(1 -4)haloalkyl;

R ² is -N(H)(5- to 10-membered heteroaryl), -C(6-10)aryl, a 5- to 12-membered bi- or tricyclic ring system containing one or more heteroatoms, or 5- to 10-membered heteroaryl, wherein: the -N(H)(5- to 10-membered heteroaryl) is optionally substituted with one -N(R ^N1 )(R ^N2 ) group, the -C(6-10)aryl is optionally substituted with one - C(O)N(R ^N1 )(R ^N4 ) group, the 5- to 12-membered bi- or tricyclic ring system containing one or more heteroatoms is optionally substituted with one to five R ^3c groups, and the 5- to 10-membered heteroaryl is optionally substituted with one to five R ^3d groups; each R ^3c is independently for each occurrence -N(R ^N1 )(R ^N2 ), -C(1-6)alkyl, -C(i- ₆ )haloalkyl, -OC(1-6)alkyl, -C(O)OH, -C(O)N(R ^N1 )(R ^N4 ), or -C(i- ₃₎ alkyl(phenyl); each R ^3d is independently for each occurrence halo, -N(R ^N1 )(R ^N2 ), -C(1-6)alkyl, - C(1-6)haloalkyl, -C(3-10)Cycloalkyl, -OC(1-6)alkyl, -OC(1-6)haloalkyl, -C(1-3)alkyl-N(R ^N1 )(R ^N3 ), - C(O)N(R ^N1 )(R ^N4 ), -C(1-3)alkyl(3- to 8-membered heterocyclyl), 3- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl, wherein the 3- to 8-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally further substituted with one to five groups selected from halo, -C(1 -4)alkyl, -C(1 -4)haloalkyl, -C(3-6)cycloalkyl, -OC(i- 4)alkyl, -OC(1 -4)haloalkyl, and -C(1 -4)alkylOC(1 -4)alkyl; R ^N1 is hydrogen or C(1 -4)alkyl;

R ^N2 is hydrogen, -C(1 -4)alkyl, -C(3-6)cycloalkyl, -C(O)C(1 -4)alkyl, -C(1 -4)alkyl(4- to 6- membered heterocyclyl), 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, wherein the 4- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally further substituted with one to three groups selected from -CN, -C(1 -4)alkyl, - C(1 -4)haloalkyl, -OC(1 -4)alkyl, -OC(1 -4)haloalkyl, and -C(0)C(1 -4)alkyl;

R ^N3 is hydrogen, -C(3-6)cycloalkyl, or 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally further substituted with one to three -C(1 -4)alkyl groups;

R ^N4 is hydrogen, -C(1 -4)alkyl, or 4- to 6-membered heterocyclyl; provided that at least two of V, X, Y, and Z are C-H; and provided that if R ² is pyrim idinyl, then the pyrimidinyl is substituted with one group selected from -OC(1-6)alkyl and -C(O)N(R ^N1 )(R ^N4 ) and is optionally further substituted with one to two R ^3d groups.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:

A is a 5-membered heteroaryl that is optionally substituted with one -C(1 -4)alkyl groups;

B is:

W is CH ₂ or CF ₂ ;

V is N, C-H, or C-F;

X is N, C-H, or C-R ^x ;

Y is N, C-H, or C-R ^Y ;

Z is N, C-H, or C-R ^z ;

R ^x , R ^Y , and R ^z are each, independently, fluorine, -CH3, or -OCH3;

R ¹ is hydrogen or -CF3;

R ² is -N(H)(5- to 10-membered heteroaryl), -C(6-10)aryl, a 5- to 12-membered bi- or tricyclic ring system containing one or more heteroatoms, or 5- to 10-membered heteroaryl, wherein: the -N(H)(5- to 10-membered heteroaryl) is optionally substituted with one -NH2 group, the -C(6-10)aryl is optionally substituted with one -C(O)NH2 group, the 5- to 12-membered bi- or tricyclic ring system containing one or more heteroatoms is optionally substituted with one to five R ^3c groups, and the 5- to 10-membered heteroaryl is optionally substituted with one to five R ^3d groups; each R ^3c is independently for each occurrence -NH2, -C(1-6)alkyl, -C(i -6)haloalkyl, - OC(1-6)alkyl, -C(O)OH, -C(O)NH ₂ , or -C ₍ i- ₃₎ alkyl(phenyl); each R ^3d is independently for each occurrence halo, -N(R ^N1 )(R ^N2 ), -C(1-6)alkyl, - C(1-6)haloalkyl, -C(3-10)Cycloalkyl, -OC(1-6)alkyl, -OC(1-6)haloalkyl, -C(1-3)alkyl-N(R ^N1 )(R ^N3 ), - C(O)N(R ^N1 )(R ^N4 ), -C(1-3)alkyl(3- to 8-membered heterocyclyl), 3- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl, wherein the 3- to 8-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally further substituted with one to five groups selected from halo, -C(1 -4)alkyl, -C(1 -4)haloalkyl, -C(3-6)cycloalkyl, -OC(1- 4)alkyl, -OC(1 -4)haloalkyl, and -C(1 -4)alkylOC(1 -4)alkyl;

R ^N1 is hydrogen;

R ^N2 is hydrogen, -C(1 -4)alkyl, -C(3-6)cycloalkyl, -C(O)C(1 -4)alkyl, -C(1 -4)alkyl(4- to 6- membered heterocyclyl), 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, wherein the 4- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally further substituted with one to three groups selected from -CN, -C(1 -4)alkyl, - C(1 -4)haloalkyl, -OC(1 -4)alkyl, -OC(1 -4)haloalkyl, and -C(O)C(1 -4)alkyl;

R ^N3 is hydrogen, -C(3-6)cycloalkyl, or 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally further substituted with one to three -C(1 -4)alkyl groups;

R ^N4 is hydrogen, -C(1 -4)alkyl, or 4- to 6-membered heterocyclyl; provided that at least two of V, X, Y, and Z are C-H; and provided that if R ² is pyrim idinyl, then the pyrimidinyl is substituted with one group selected from -OC(1-6)alkyl and -C(O)N(R ^N1 )(R ^N4 ) and is optionally further substituted with one to two R ^3d groups.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula la-1 :

(la-1 ).

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula la-2:

(la-2).

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein A is a 5-membered heteroaryl, which is optionally substituted with one -C(1 -4)alkyl group. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein A is a 5-membered heteroaryl, which is optionally substituted with one methyl group. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein A is a 5-membered heteroaryl.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein A is oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, or triazolyl, each of which is optionally substituted with one -C(1 -4)alkyl group. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein A is oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, or triazolyl, each of which is optionally substituted with one methyl group. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein A is oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, or triazolyl. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein A is isoxazolyl or pyrazolyl. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein A is isoxazolyl. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein A is pyrazolyl.

In some embodiments, disclosed herein is a compound of Formula I, or a

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein A is

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein A is

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein A is

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula lb-1 :

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula lb-2:

(lb-2).

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is CH2, CHD, CD2, or CF2.ln some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is CH2 or CF2. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is CH2. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is CF2.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein B , or

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein B

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein V is N, C-H, or C-F. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein V is N. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein V is C- H. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein V is C-R ^v . In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein V is C-F. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X is N, C-H, C-F, or C-CH3. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X is C-H, C-F, or C-CH3. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X is C-H or C-R ^x . In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X is C- H. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X is C-R ^x . In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X is C-F. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X is C-CH3.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Y is N, C-H, C-F, C-CH3, or C-OCH3. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Y is C-H, C-F, C-CH3, or C-OCH3. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Y is C-H or C-R ^Y . In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Y is C-H. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Y is C-R ^Y . In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Y is C-F. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Y is C- CH3. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Y is C-OCH3.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Z is N, C-H, C-F, or C-CH3. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Z is N or C-H. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Z is N. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Z is C-H. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Z is C-R ^z . In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Z is C-F. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Z is C-CH3.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein V is C-R ^v and R ^v is halo, and wherein X, Y and Z are C-H. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein V is C-H; X, Y and Z are N or C-H, and at least one of X, Y, and Z is N. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein V is C- H, and X, Y, Z are independently selected from N, C-H, C-(halogen), C-((1 -4) alkyl), or C- (OC(1 -4)alkyl).

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein V is N or C-H; X is N or C-H; Y is N or C-H; and Z is N, C-H, or C-R ^z . In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein V is N or C-H; X is N or C-H; Y is N, C-H, or C-R ^Y ; and Z is N or C-H. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein V is N or C-H; X is N or C-H; Y is N or C-H; and Z is N or C-H; wherein that no more than one of V, X, Y, and Z are N.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ^v , R ^x , R ^Y , and R ^z are each, independently, halo, -C(1 -4)alkyl, or -OC(1 -4)alkyl. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ^v , R ^x , R ^Y , and R ^z are each, independently, halo or -C(1 -4)alkyl. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ^v , R ^x , R ^Y , and R ^z are each, independently, fluorine, -CH3, or -OCH3. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ^v , R ^x , R ^Y , and R ^z are fluorine.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ^v is halo. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ^v is fluorine.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ^x is halo or -C(1 -4)alkyl. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ^x is fluorine or -CH3.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ^Y is halo, -C(1 -4)alkyl, or -OC(1 -4)alkyl. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ^Y is fluorine, -CH3, or -OCH3.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ^z is halo or -C(1 -4)alkyl. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ^z is fluorine or -CH3.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein: V is N, C-H, or C-F; X is N, C-H, C-F, or C-CH3; Y is N, C-H, C-F, C-CH3, or C-OCH3; and Z is N, C-H, C-F, or C-CH3. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein: V is N, C-H, or C-F; X is C-H, C-F, or C-CH3; Y is C-H, C-F, C-CH3, or C-OCH3; and Z is N, C-H, C-F, or C-CH3.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein B

In some embodiments, disclosed herein is a compound of Formula I, or a

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein B

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein B

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein B

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula lc-1 :

(lc-1 ).

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula lc-2:

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula lc-3:

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen, -C(1 -4)alkyl, or -C(i- 4)haloalkyl. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen or -C(1 -4)haloalkyl. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen or -CF3. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ¹ is -CF3.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of any one of Formulas Id-1 to Id-5:

(Id-5)

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of any one of Formulas le-1 to le-6: In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is a 5- to 12-membered bi- or tricyclic ring system containing one or more heteroatoms or 5- to 10-membered heteroaryl, each of which is optionally substituted with one to five R ³ groups.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R ³ is independently for each occurrence halo, -N(R ^N1 )(R ^N2 ), -C(1-6)alkyl, -C(1-6)haloalkyl, -C(3-10)cycloalkyl, -OC(1-6)alkyl, -OC(i- ₆ )haloalkyl, -OC ₍₃ -io)cycloalkyl, -C(1-3)alkyl-N(R ^N1 )(R ^N3 ), -C(O)OH, - C(O)N(R ^N1 )(R ^N4 ), -C(1-3)alkyl(3- to 8-membered heterocyclyl), -C(1-3)alkyl(phenyl), 3- to 8- membered heterocyclyl, or 5- to 6-membered heteroaryl, wherein the -C(i -ejalkyl, -C(i - 6)haloalkyl, -C(3-10)cycloalkyl, -OC(1-6)alkyl, -OC(1-6)haloalkyl, -OC(3-10)cycloalkyl, -C(i-

3)alkyl(3- to 8-membered heterocyclyl), -C(1-3)alkyl(phenyl), 3- to 8-membered heterocyclyl, and 5- to 6-membered heteroaryl are optionally further substituted with one to five groups selected from halo, -C(1 -4)alkyl, -C(1 -4)haloalkyl, -C(3-6)cycloalkyl, -OC(i-

4)alkyl, -OC(1 -4)haloalkyl, and -C(1 -4)alkylOC(1 -4)alkyl.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R ³ is independently for each occurrence halo, -N(R ^N1 )(R ^N2 ), -C(1-6)alkyl, -C(1-6)haloalkyl, -C(3-10)cycloalkyl, -OC(1-6)alkyl, -OC(i- ₆ )haloalkyl, -C(1-3)alkyl-N(R ^N1 )(R ^N3 ), -C(O)OH, -C(O)N(R ^N1 )(R ^N4 ), -C ₍ i- ₃₎ alkyl(3- to 8-membered heterocyclyl), -C(1-3)alkyl(phenyl), 3- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl, wherein the 3- to 8-membered heterocyclyl and 5- to 6- membered heteroaryl are optionally further substituted with one to five groups selected from halo, -C(1 -4)alkyl, -C(1 -4)haloalkyl, -C(3-6)cycloalkyl, -OC(1 -4)alkyl, -OC(1 -4)haloalkyl, and -C(1 -4)alkylOC(1 -4)alkyl.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R ³ is independently for each occurrence halo, -N(R ^N1 )(R ^N2 ), -C(1-6)alkyl, -C(1-6)haloalkyl, -C(3-10)cycloalkyl, -OC(1-6)alkyl, -C(O)N(R ^N1 )(R ^N4 ), or 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl are optionally further substituted with one to five groups selected from halo, - C(1 -4)alkyl, -C(1 -4)haloalkyl, -C(3-6)cycloalkyl, -OC(1 -4)alkyl, -OC(1 -4)haloalkyl, and -C(i- 4)alkylOC(1 -4)alkyl. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R ³ is independently for each occurrence -N(R ^N1 )(R ^N2 ), -C(1-6)alkyl, -C(1-6)haloalkyl, -C(3-10)cycloalkyl, -C(O)N(R ^N1 )(R ^N4 ), or 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl are optionally further substituted with one to three groups selected from -C(1 -4)alkyl, -C(1 -4)haloalkyl, - C(3-6)cycloalkyl, and -OC(1 -4)alkyl.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R ³ is independently for each occurrence -N(R ^N1 )(R ^N2 ), -C(1-6)alkyl, -C(1-6)haloalkyl, -C(3-10)cycloalkyl, -C(O)N(R ^N1 )(R ^N4 ), or 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally further substituted with one to three -C(1 -4)alkyl groups.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is a 5- to 12-membered bi- or tricyclic ring system containing one or more heteroatoms or a 5- to 10-membered heteroaryl, wherein the 5- to 12-membered bi- or tricyclic ring system containing one or more heteroatoms is optionally substituted with one to five R ^3c groups and the 5- to 10- membered heteroaryl is optionally substituted with one to five R ^3d groups.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is -N(H)(5- to 10-membered heteroaryl), which is optionally substituted with one to five R ^3a groups. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is -N(H)(9- to 10-membered heteroaryl), which is optionally substituted with one to five R ^3a groups. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is -N(H)(thiazolopyrimidinyl), which is optionally substituted with one to five R ^3a groups.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R ^3a is independently for each occurrence halo, -N(R ^N1 )(R ^N2 ), -C(1-6)alkyl, -C(1-6)haloalkyl, -OC(1-6)alkyl, -OC(1-6)haloalkyl, -C(1-3)alkyl-N(R ^N1 )(R ^N3 ), or -C(O)N(R ^N1 )(R ^N4 ). In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R ^3a is independently for each occurrence -N(R ^N1 )(R ^N2 ) or -C(O)N(R ^N1 )(R ^N4 ). In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ^3a is -N(R ^N1 )(R ^N2 ). In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ^3a is -NH2.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is -C(6-w)aryl, which is optionally substituted with one to five R ^3b groups. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is phenyl, which is optionally substituted with one to three R ^3b groups.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R ^3b is independently for each occurrence halo, -N(R ^N1 )(R ^N2 ), -C(1-6)alkyl, -C(1-6)haloalkyl, -OC(1-6)alkyl, -OC(1-6)haloalkyl, -C(1-3)alkyl-N(R ^N1 )(R ^N3 ), or -C(O)N(R ^N1 )(R ^N4 ). In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R ^3b is independently for each occurrence -N(R ^N1 )(R ^N2 ) or -C(O)N(R ^N1 )(R ^N4 ). In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ^3b is -C(O)N(R ^N1 )(R ^N4 ). In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ^3b is -C(O)NH2.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is .

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is a 5- to 12-membered bi- or tricyclic ring system containing one or more heteroatoms, which is optionally substituted with one to five R ^3c groups. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is a 7- to 12- membered bicyclic ring system containing one or more heteroatoms, which is optionally substituted with one to three R ^3c groups. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is a 7- to 12-membered tricyclic ring system containing one or more heteroatoms, which is optionally substituted with one to three R ^3c groups.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is selected from the group consisting of: each of which is optionally substituted with one to three R ^3c groups.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is selected from the group consisting of: each of which is optionally substituted with one to three R ^3c groups.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is:

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is:

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ^3c is halo, -N(R ^N1 )(R ^N2 ), -C(1-6)alkyl, - C(1-6)haloalkyl, -OC(1-6)alkyl, -OC(1-6)haloalkyl, -C(1-3)alkyl-N(R ^N1 )(R ^N3 ), -C(O)OH, - C(O)N(R ^N1 )(R ^N4 ), or -C(1-3)alkyl(phenyl). In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ^3c is - N(R ^N1 )(R ^N2 ), -C(i- ₆ )alkyl, -C(1-6)haloalkyl, -OC(1-6)alkyl, -C(O)OH, -C(O)N(R ^N1 )(R ^N4 ), or - C(1-3)alkyl(phenyl). In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ^3c is -NH2, -C(1-6)alkyl, -C(i- 6)haloalkyl, -OC(1-6)alkyl, -C(O)OH, -C(O)NH2, or -C(1-3)alkyl(phenyl). In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is:

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is:

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is a 5- to 10-membered heteroaryl, which is optionally substituted with one to five R ^3d groups. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is a 5- to 6-membered monocyclic heteroaryl or a 9- to 10- membered bicyclic heteroaryl, each of which is optionally substituted with one to five R ^3d groups.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is a 5-membered heteroaryl, which is optionally substituted with one to three R ^3d groups. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is a 6-membered heteroaryl, which is optionally substituted with one to three R ^3d groups. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is a 9-membered heteroaryl, which is optionally substituted with one to three R ^3d groups. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is a 10-membered heteroaryl, which is optionally substituted with one to three R ^3d groups.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is pyrazolyl, imidazolyl, furanyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, indazolyl, benzimidazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, pyrrolopyridazinyl, pyrrolotriazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, triazolopyridinyl, quinazolinyl, isoquinolinonyl, quinazolinonyl, pyridopyrimidinyl, pyridopyrimidinonyl, pyrimidopyrimidinyl, benzoxazolyl, thiazolopyrimidinyl, furopyridinyl, or thienopyrimidinyl, each of which is optionally substituted with one to three R ^3d groups. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is thiazolyl, pyridinyl, pyrimidinyl, indazolyl, pyrazolopyridinyl, or imidazopyridinyl, each of which is optionally substituted with one to three R ^3d groups.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is selected from the group consisting of:

each of which is optionally substituted with one to three R ^3d groups. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is selected from the group consisting of: each of which is optionally substituted with one to three R ^3d groups.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is selected from the group consisting of: each of which is optionally substituted with one to three R ^3d groups.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is:

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is:

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R ^3d is independently for each occurrence halo, -N(R ^N1 )(R ^N2 ), -C(1-6)alkyl, -C(1-6)haloalkyl, -C(3-10)cycloalkyl, -OC(1-6)alkyl, -OC(i- ₆ )haloalkyl, -OC ₍₃ -io)cycloalkyl, -C(1-3)alkyl-N(R ^N1 )(R ^N3 ), -C(O)N(R ^N1 )(R ^N4 ), -C ₍ i- 3)alkyl(3- to 8-membered heterocyclyl), 3- to 8-membered heterocyclyl, or 5- to 6- membered heteroaryl, wherein the -C(1-6)alkyl, -C(1-6)haloalkyl, -C(3-10)cycloalkyl, -OC(i- 6)alkyl, -OC(1-6)haloalkyl, -OC(3-10)cycloalkyl, -C(1-3)alkyl(3- to 8-membered heterocyclyl), 3- to 8-membered heterocyclyl, and 5- to 6-membered heteroaryl are optionally further substituted with one to five groups selected from halo, -C(1 -4)alkyl, -C(1 -4)haloalkyl, -C(3- 6)cycloalkyl, -OC(1 -4)alkyl, -OC(1 -4)haloalkyl, and -C(1 -4)alkylOC(1 -4)alkyl.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R ^3d is independently for each occurrence halo, -N(R ^N1 )(R ^N2 ), -C(1-6)alkyl, -C(1-6)haloalkyl, -C(3-10)cycloalkyl, -OC(1-6)alkyl, -OC(i- ₆ )haloalkyl, -C(1-3)alkyl-N(R ^N1 )(R ^N3 ), -C(O)N(R ^N1 )(R ^N4 ), -C ₍ i- ₃₎ alkyl(3- to 8- membered heterocyclyl), 3- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl, wherein the 3- to 8-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally further substituted with one to five groups selected from halo, -C(1 -4)alkyl, - C(1 -4)haloalkyl, -C(3-6)cycloalkyl, -OC(1 -4)alkyl, -OC(1 -4)haloalkyl, and -C(1 -4)alkylOC(1 -4)alkyl.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R ^3d is independently for each occurrence halo, -N(R ^N1 )(R ^N2 ), -C(1-6)alkyl, -C(1-6)haloalkyl, -C(3-10)cycloalkyl, -OC(1-6)alkyl, -C(O)N(R ^N1 )(R ^N4 ), or 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl are optionally further substituted with one to five groups selected from halo, - C(1 -4)alkyl, -C(1 -4)haloalkyl, -C(3-6)cycloalkyl, -0C(1 -4)alkyl, -OC(1 -4)haloalkyl, and -C(i- 4)alkylOC(1 -4)alkyl.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R ^3d is independently for each occurrence -N(R ^N1 )(R ^N2 ), -C(1-6)alkyl, -C(1-6)haloalkyl, -C(3-10)cycloalkyl, -C(O)N(R ^N1 )(R ^N4 ), or 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl are optionally further substituted with one to three groups selected from -C(1 -4)alkyl, -C(1 -4)haloalkyl, - C(3-6)cycloalkyl, and -OC(1 -4)alkyl.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R ^3d is independently for each occurrence -N(R ^N1 )(R ^N2 ), -C(1-6)alkyl, -C(1-6)haloalkyl, -C(3-10)cycloalkyl, -C(O)N(R ^N1 )(R ^N4 ), or 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally further substituted with one to three -C(1 -4)alkyl groups.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is:

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is:

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is:

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is:

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is:

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ² is:

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ^N1 is hydrogen.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ^N2 is hydrogen, -C(1 -4)alkyl, -C(3- 6)cycloalkyl, -C(O)C(1 -4)alkyl, -C(1 -4)alkyl(4- to 6-membered heterocyclyl), 4- to 6- membered heterocyclyl, 5- to 6-membered heteroaryl, wherein the 4- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally further substituted with one to three groups selected from -CN, -C(1 -4)alkyl, -C(1 -4)haloalkyl, -OC(1 -4)alkyl, -OC(i- 4)haloalkyl, and -C(O)C(1 -4)alkyl. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ^N2 is hydrogen, - C(1 -4)alkyl, -C(3-6)cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, wherein the 4- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally further substituted with one to three groups selected from -C(1 -4)alkyl and -C(i- 4)haloalkyl. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ^N2 is hydrogen, 4- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally further substituted with one to three groups -C(1 -4)alkyl groups. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ^N2 is hydrogen. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ^N2 is 4- to 6-membered heterocyclyl. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ^N2 is 5- to 6-membered heteroaryl, which is optionally substituted with one to three groups -C(1 -4)alkyl groups.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ^N3 is hydrogen, -C(3-6)cycloalkyl, or

5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally further substituted with one to three -C(1 -4)alkyl groups.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ^N4 is hydrogen, -C(1 -4)alkyl, or 4- to

6-membered heterocyclyl. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R ^N4 is hydrogen.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein no more than one of V, X, Y, and Z is N. In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein at least three of V, X, Y, and Z are C- H.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein if R ² is pyrim idinyl, then the pyrim idinyl is substituted with one -C(O)N(R ^N1 )(R ^N4 ) group and is optionally further substituted with one to two R ^3d groups.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein if R ² is pyrim idinyl, then R ² has a structure selected from the group consisting of: wherein at least one R ^3d group is -C(O)N(R ^N1 )(R ^N4 ).

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein if R ² is pyrim idinyl, then R ² has a structure selected from the group consisting of:

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula If:

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula If: wherein:

A is a isoxazolyl;

Z is N or C-H;

R ² is 5- to 10-membered heteroaryl, which is optionally substituted with one to three R ^3d groups; each R ^3d is independently for each occurrence -N(R ^N1 )(R ^N2 ), -C(1-6)alkyl, -C(i- 6)haloalkyl, -C(3-10)cycloalkyl, -C(O)N(R ^N1 )(R ^N4 ), or 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally further substituted with one to three -C(i- 4)alky I groups;

R ^N1 is hydrogen; R ^N2 is hydrogen, 4- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally further substituted with one to three -C(1 -4)alkyl groups; and

R ^N4 is hydrogen; provided that if R ² is pyrim idinyl, then the pyrimidinyl is substituted with one - C(O)N(R ^N1 )(R ^N4 ) group and is optionally further substituted with one to two R ^3d groups.

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, having a structure as shown in any one of Tables 1A to 1 J.

Table 1A

Table 1E

Table 1H

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, having a structure as shown in any one of Tables 2A to 2J. Table 2B

Table 2E

In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

In some embodiments, disclosed herein is a compound of Formula I having the following structure: or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed herein is a compound of Formula I having the following structure: or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is a compound of Formula I having the following structure: or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed herein is a compound of Formula I having the following structure: or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed herein is a compound of Formula I having the following structure: or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed herein is a compound of Formula I having the following structure:

or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed herein is a compound of Formula I having the following structure: or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed herein is a compound of Formula I having the following structure: or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed herein is a compound of Formula I having the following structure: or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed herein is a compound of Formula I having the following structure: or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed herein is a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Therapeutic Use

The present disclosure is also directed toward a method for treating a disease, disorder, or medical condition mediated by NIK activity, comprising administering to a subject in need of such treatment an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.

The present disclosure is also directed toward a method for preventing a disease, disorder, or medical condition mediated by NIK activity, comprising administering to a subject in need of such treatment an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.

The present disclosure is also directed toward a method for improving or ameliorating a symptom of a disease, disorder, or medical condition mediated by NIK activity, comprising administering to a subject in need of such treatment an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound described herein can be administered in combination with one or more additional therapeutic agent(s).

In some embodiments of the methods of treatment disclosed herein, the disease, disorder, or medical condition is selected from the group consisting of inflammatory disorders and autoimmune disorders.

In some embodiments, the disease, disorder, or medical condition is selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis, Sjogren’s syndrome, and lupus nephritis.

In some embodiments of the methods of treatment disclosed herein, the disease, disorder, or medical condition is selected from the group consisting of inflammatory disorders, autoimmune disorders, cancers, metabolic disorders, and osteoporosis.

In some embodiments of the methods of treatment disclosed herein, the disease, disorder, or medical condition is an autoantibody associated disease. In some embodiments, the autoantibody associated diseases is selected from the group consisting of anti-neutrophil cytoplasmic antibody (“ANCA”) associated vasculitis, scleroderma, Sjogren’s disease, myositis, lgG4 associated diseases, bullous pemphigoid, and neuromyelitis optica spectrum disorders (“NMOSD”).

In some embodiments of the methods of treatment disclosed herein, the disease, disorder, or medical condition is an immune mediated dermatitis indication. In some embodiments, the immune mediated dermatitis indication is selected from the group consisting of atopic dermatitis and hidradenitis supperativa.

In some embodiments of the methods of treatment disclosed herein, the disease, disorder, or medical condition is a liver inflammation or a liver injury. In some embodiments, the liver inflammation or a liver injury is selected from the group consisting of steatosis, non-alcoholic steatohepatitis (“NASH”) and primary biliary cirrhosis.

In some embodiments of the methods of treatment disclosed herein, the disease, disorder, or medical condition is cancer. In some embodiments, the cancer is selected from the group consisting of leukemias, lymphomas, pancreatic cancer, breast cancer, and melanoma.

In some embodiments of the methods of treatment disclosed herein, the disease, disorder, or medical condition is a metabolic disorder. In some embodiments, the metabolic disorder is selected from the group consisting of obesity and diabetes. In some embodiments, the diabetes is a type 2 diabetes.

In some embodiments of the methods of treatment disclosed herein, the disease, disorder, or medical condition is a kidney disease. In some embodiments, the kidney disease is selected from the group consisting of acute kidney injury, Berger's disease (IgA nephropathy (IgAN)), autosomal dominant polycystic kidney disease ("ADCKD"), and membranous nephropathy.

In some embodiments of the methods of treatment disclosed herein, the disease, disorder, or medical condition is osteoporosis.

In some embodiments of the methods of treatment disclosed herein, the disease, disorder, or medical condition is selected from the group consisting of RA, IBD, SLE, IgAN, metabolic syndrome, multiple sclerosis, Immune thrombocytopenic purpura, primary biliary cirrhosis, transplantation, myasthenia gravis, osteoporosis, and bone resorption (periodontitis).

In some embodiments of the methods of treatment disclosed herein, the disease, disorder, or medical condition is selected from the group consisting of systemic lupus erythematosus (“SLE”), rheumatoid arthritis (“RA”), Sjogren’s syndrome, lupus nephritis, inflammatory bowel disease (“IBD”), ANCA associated vasculitis, myositis, lgG4 associated diseases, bullous pemphigoid, neuromyelitis optica spectrum disorders (“NMOSD”), atopic dermatitis “AD”), hidradenitis supperativa (“HS”), steatosis, nonalcoholic steatohepatitis (“NASH”), primary biliary cirrhosis, leukemias, lymphomas, pancreatic cancer, breast cancer, melanoma, obesity, diabetes, acute kidney injury, IgAN, autosomal dominant polycystic kidney disease ("ADCKD"), membranous nephropathy, osteoporosis, bone resorption (periodontitis), multiple sclerosis (“MS”), immune thrombocytopenic purpura, transplantation, myasthenia gravis, scleroderma, myositis, lgG4 associated diseases, and bullous pemphigoid.

In some embodiments, disclosed herein is a method for preventing or controlling an excessive inflammatory response, comprising administering to a subject in need of such treatment an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.

In some embodiments of the methods disclosed herein, the subject is a human subject.

The present disclosure also provides a method for modulating NIK activity, comprising exposing NIK to an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof.

In some embodiments, the disclosure provides a method for inhibiting NIK activity, comprising exposing NIK to an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof.

Dosing and Administration

In the methods disclosed herein, an effective amount of at least one compound according to the disclosure is administered to a subject suffering from or diagnosed as having such a disease, disorder, or medical condition. An "effective amount" means an amount or dose sufficient to generally bring about the desired therapeutic or prophylactic benefit in patients in need of such treatment for the designated disease, disorder, or medical condition. For a 70-kg human, an illustrative range for a dosage amount is from about 1 to 1000 mg/day in single or multiple dosage units.

In some embodiments, the dosage amount is about 1 mg to 500 mg of a compound of the disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage amount is about 1 , 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg of a compound of the disclosure, or pharmaceutically acceptable salt thereof. In some embodiments, the dosage amount is about 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 mg of a compound of the disclosure, or pharmaceutically acceptable salt thereof. In some embodiments, the dosage amount is about 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, or 300 mg of a compound of the disclosure, or pharmaceutically acceptable salt thereof. In some embodiments, the dosage amount is about 300, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, or 400 mg of a compound of the disclosure, or pharmaceutically acceptable salt thereof. In some embodiments, the dosage amount is about 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, or 500 mg of a compound of the disclosure, or pharmaceutically acceptable salt thereof

The dosage administered will be affected by factors such as the route of administration, the health, weight and age of the recipient, the frequency of the treatment and the presence of concurrent and unrelated treatments.

It is also apparent to one skilled in the art that the therapeutically effective dose for compounds of the present disclosure or a pharmaceutical composition thereof will vary according to the desired effect. Therefore, optimal dosages to be administered may be readily determined by one skilled in the art and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease condition. In addition, factors associated with the particular subject being treated, including subject age, weight, diet and time of administration, will result in the need to adjust the dose to an appropriate therapeutic level. The above dosages are thus exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of the present disclosure.

Once improvement of the patient's disease, disorder, or condition has occurred, the dose may be adjusted for preventive or maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a longterm basis upon any recurrence of symptoms. The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, may be formulated into pharmaceutical compositions comprising any known pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers commonly used in pharmaceutical compositions are substances that are non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle or diluent to facilitate administration of an agent and that is compatible therewith. Exemplary carriers include, but are not limited to, any suitable solvents, dispersion media, coatings, antibacterial and antifungal agents and isotonic agents. Exemplary excipients that may also be components of the formulation include fillers, binders, disintegrating agents and lubricants.

Delivery forms of the pharmaceutical compositions containing one or more compounds of the disclosure may be prepared using pharmaceutically acceptable excipients and compounding techniques known or that become available to those of ordinary skill in the art. The compositions may be administered in the presently disclosed methods by a suitable route of delivery, e.g., oral, parenteral, rectal, topical, or ocular routes, or by inhalation.

The preparation may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories. The compositions may be formulated for any one of a plurality of administration routes, such as intravenous infusion, subcutaneous injection, topical administration, or oral administration.

For oral administration, the compounds of the present disclosure can be provided in the form of tablets, capsules, or beads, or as a solution, emulsion, or suspension. To prepare the oral compositions, the active agents may be formulated to yield a dosage of, e.g., for a 70-kg human, from about 1 to 1000 mg/day in single or multiple dosage units as an illustrative range.

Oral tablets may include a compound of the disclosure mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Illustrative examples of liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are examples of disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract or may be coated with an enteric coating. Additional coatings that may be used include coatings that are designed to release the compound or active agent as a function of time, pH or bacterial content.

Capsules for oral administration include hard and soft gelatin or (hydroxypropyl)methyl cellulose capsules. To prepare hard gelatin capsules, active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the active ingredient with an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol. Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.

The compounds of the present disclosure may also be administered by non-oral routes. For example, compositions may be formulated for rectal administration as a suppository, enema or foam. For parenteral use, including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the compounds of the disclosure may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit-dose form such as ampules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses range from about 1 to 1000 pg/kg/m inute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.

For topical administration, the compounds of the disclosure may be mixed with a pharmaceutical carrier. Another mode of administering the compounds of the disclosure may utilize a patch formulation to effect transdermal delivery.

Compounds of the disclosure may alternatively be administered in methods of the present disclosure by inhalation, via the nasal or oral routes, e.g., in a spray formulation also containing a suitable carrier.

Although the present embodiments have been described in connection with certain specific embodiments for instructional purposes, the present embodiments are not limited thereto. Accordingly, various modifications, adaptations, and combinations of various features of the described embodiments can be practiced without departing from the scope of the invention as set forth in the claims. Furthermore, the following examples are illustrative, but not limiting, of the compounds, compositions and methods described herein. Other suitable modifications and adaptations known to those skilled in the art are within the scope of the following embodiments. Any and all journal articles, patent applications, issued patents, or other cited references are incorporated by reference in their entirety

EXAMPLES

The following specific examples are provided to further illustrate embodiments within the scope of the present disclosure.

Abbreviations

In some embodiments, provided herein are processes and intermediates disclosed herein that are useful for preparing a compound of the disclosure or pharmaceutically acceptable salts thereof.

By way of illustration, but not as limitation, compounds of the present disclosure are prepared according to the following general preparation procedures given by Schemes 1-7. One of ordinary skill in the art will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternately, in the place of the ultimately desired substituent, a suitable group may be carried through the reaction scheme and replaced, as appropriate, with the desired substituent. Unless otherwise specified, the variables in Schemes 1-7 are as defined above in reference to Formula I. Scheme 1

The compounds of Formula I of the present disclosure can be prepared, for example, as shown in Scheme 1. When substituent B ¹ in compound XI is a boron-based coupling agent such as a boronic acid or a boronic ester and when substituent B ² in compound XII is a halide such as Cl, Br, or I, this coupling is achieved by reaction under Suzuki conditions. One having skill in the art would recognize that coupling under Suzuki conditions also provides a compound of Formula I when B ¹ in compound XI is a halide and B ² in compound XII is a boron-based coupling agent. Typical Suzuki coupling conditions involve the use of a palladium catalyst, a base, a suitable solvent, and other optional reagents including ligands (e.g., tri-tert-butylphosphine or butyldi(1 - adamantanyl)phosphine). Examples of suitable palladium catalysts include, but are not limited to, Pd(t-Bu3P)2, Pd(PPh3)4, Pd(dtbpf)Cl2, Pd2(dba)3, RuPhos Pd G4, and Pd(dppf)Cl2. Suitable bases include, but are not limited to, K3PO4, KF, CS2CO3, NaHCOs, Na2CO3, and mixtures thereof Suitable solvents include, but are not limited to, 1 ,4-dioxane, 1 ,2-dioxane, DMF, THF, water, and mixtures thereof. The reaction may be heated to a temperature of about 65 °C to about 170 °C for a time period of about 1 to 20 hours, employing microwave or conventional heating to provide the compound of Formula I.

Alternately, Stille coupling conditions can be used to couple compound XI to compound XII when B ¹ is a halide such as Cl, Br, or I, and when B ² is a stannyl group (e.g., Sn(Me)3 or Sn(n-Bu)s). One having skill in the art would recognize that coupling under Stille conditions also provides a compound of Formula I when B ¹ is a stannyl group and when B ² is a halide. Typical Stille coupling conditions involve the use of a catalyst (usually palladium, but sometimes nickel), a suitable solvent, and other optional reagents including ligands, TEA, or Cui. Examples of suitable catalysts include, but are not limited to Pd(PPhs)4 and PdCl2(PPh3)2. Suitable solvents include, but are not limited to, DMF, toluene, and mixtures thereof. The reaction may be heated to a temperature from about 120 °C to about 160 °C for a time period of about 1 to 16 hours, employing microwave or conventional heating to provide the compound of Formula I.

Where a protecting or masking group is present on a compound of Formula XI or XII, a final deprotection step is added, employing conditions known to one skilled in the art, to provide the compound of Formula I. For example, if a methyl or ethyl ester is used to mask a primary amide, it may be unmasked using a reagent such as ammonia in a solvent such as MeOH or EtOH. Alternately, if a nitrile group is used to mask a primary amide, it may be converted to the amide using a reagent such as NaOMe in a solvent such as MeOH. Alternately still, if a carboxylic acid is used to mask a primary amide, it may be converted to the amide using reagents such as NH4CI, HATLI, and TEA in a solvent such as DMF.

By way of further example, if a tosyl or phthalimide group is used to protect an amino group, it can be removed using a reagent such as ammonia in a solvent such as MeOH or EtOH. Alternately, if a tert-butyloxycarbonyl (Boc) or tetrayhydropyran (THP) group is used to protect an amino group, it can be removed using a reagent such as HCI in a solvent such as dioxane and/or MeOH. Alternately still, if a 2- (trimethylsilyl)ethoxymethyl (SEM) group is used to protect an amino group, it can be removed using a reagent such as TBAF in a solvent such as MeOH. Alternately still, if a para-methoxybenzyl (PMB) group is used to protect an amino group, it can be removed using a reagent such as TFA.

By way of further example, if a nitro group is used to mask a primary amine, it may be converted to the amine using reagents such as porous nickel-aluminum alloy (e.g., Raney Nickel) and hydrazine hydrate in a solvent such as ethanol and/or 1 ,2- dichloroethane. Alternately, the nitro group may be converted to the anime using reagents such as zinc dust and NH4CI in a solvent such as MeOH and/or water.

Scheme 2

The compounds of Formula I of the present disclosure can be prepared, for example, as shown in Scheme 2. When substituent B ³ in compound XIII is a boron- based coupling agent such as a boronic acid or a boronic ester and when substituent B ⁴ in compound XIV is a halide such as Cl, Br, or I, this coupling is achieved by reaction under Suzuki conditions. One having skill in the art would recognize that coupling under Suzuki conditions also provides a compound of Formula I when B ³ in compound XIII is a halide and B ⁴ in compound XIV is a boron-based coupling agent. Typical Suzuki coupling conditions involve the use of a palladium catalyst, a base, a suitable solvent, and other optional reagents including ligands (e.g., tri-tert-butylphosphine or butyldi(1 - adamantanyl)phosphine). Examples of suitable palladium catalysts include, but are not limited to, Pd(t-Bu3P)2, Pd(PPh3)4, Pd(dtbpf)Cl2, Pd2(dba)3, RuPhos Pd G4, and Pd(dppf)Cl2. Suitable bases include, but are not limited to, K3PO4, KF, CS2CO3, NaHCOs, Na2CO3, and mixtures thereof Suitable solvents include, but are not limited to, 1 ,4-dioxane, 1 ,2-dioxane, DMF, THF, water, and mixtures thereof. The reaction may be heated to a temperature of about 65 °C to about 170 °C for a time period of about 1 to 20 hours, employing microwave or conventional heating to provide the compound of Formula I.

Alternately, Stille coupling conditions can be used to couple compound XIII to compound XIV when B ³ is a halide such as Cl, Br, or I, and when B ⁴ is a stannyl group (e.g., Sn(Me)3 or Sn(n-Bu)s). One having skill in the art would recognize that coupling under Stille conditions also provides a compound of Formula I when B ³ is a stannyl group and when B ⁴ is a halide. Typical Stille coupling conditions involve the use of a catalyst (usually palladium, but sometimes nickel), a suitable solvent, and other optional reagents including ligands, TEA, or Cui. Examples of suitable catalysts include, but are not limited to Pd(PPhs)4 and PdCl2(PPh3)2. Suitable solvents include, but are not limited to, DMF, toluene, and mixtures thereof. The reaction may be heated to a temperature from about 120 °C to about 160 °C for a time period of about 1 to 16 hours, employing microwave or conventional heating to provide the compound of Formula I.

Where a protecting or masking group is present on a compound of Formula XIII or XIV, a final deprotection step is added, employing conditions known to one skilled in the art, to provide the compound of Formula I. For example, if a 2- (trimethylsilyl)ethoxymethyl (SEM) group is used to protect an amino group, it can be removed using a reagent such as TBAF in a solvent such as MeOH.

Scheme 3

The compounds of Formula I of the present disclosure can be prepared, for example, as shown in Scheme 3 when the bond between B and R ² is between a carbon atom and a nitrogen atom. In some embodiments, substituent B ⁵ is a halide, and substituent B ⁶ is a hydrogen atom covalently bonded to a nitrogen atom of R ² . Alternately, substituent B ⁵ is a hydrogen atom covalently bonded to a nitrogen atom of B, and B ⁶ is a halide. Compounds XV and XVI may be combined with a suitable catalyst (e.g., a palladium or copper catalyst), a suitable base, a suitable solvent, and other optional reagents including ligands. Suitable catalysts include, but are not limited to, Pd2(dba)3 and Cui. Suitable bases include, but are not limited to, f-BuONa and K3PO4. Suitable solvents include, but are not limited to, DMF and toluene. Suitable ligands include, but are not limited to BINAP and frans-N,N’-dimethylcyclohexane-1 ,2-diamine. The reaction may be heated to a temperature from about 85 °C to about 100 °C for a time period of about 16 hours to provide the compound of Formula I.

Alternately, compounds XV and XVI may be combined with a suitable base and a suitable solvent. Suitable bases include, but are note limited to, CS2CO3 and TEA. Suitable solvents include, but are not limited to DMF and DMA. The reaction may be heated to a temperature from about 100 °C to about 140 °C for a time period of about 3 to 24 hours, employing microwave or conventional heating to provide the compound of Formula I.

Where a protecting or masking group is present on a compound of Formula XV or XVI, a final deprotection step is added, employing conditions known to one skilled in the art, to provide the compound of Formula I. For example, if a methyl or ethyl ester is used to mask a primary amide, it may be unmasked using a reagent such as ammonia in a solvent such as MeOH or EtOH.

Scheme 4

The compounds of Formula I of the present disclosure can be prepared, for example, as shown in Scheme 4. In some embodiments, substituent B ⁷ is a boron- based coupling agent such as a boronic acid or a boronic ester, and substituent B ⁸ is a hydrogen atom covalently bonded to a nitrogen atom of R ² . Compounds XVII and XVIII may be combined with a suitable catalyst (e.g., Cu(0Ac)2), a suitable base (e.g., pyridine), a suitable solvent, and other optional reagents (e.g., molecular seives). Suitable solvents include, but are not limited to, DMF and chloroform. The reaction may be heated to a temperature from about 40 °C to about 120 °C for a time period of about 3 to 72 hours to provide the compound of Formula I.

Where a protecting or masking group is present on a compound of Formula XVII or XVIII, a final deprotection step is added, employing conditions known to one skilled in the art, to provide the compound of Formula I. For example, if a methyl or ethyl ester is used to mask a primary amide, it may be unmasked using a reagent such as ammonia in a solvent such as MeOH or EtOH.

Scheme 5

The compounds of Formula XXI of the present disclosure can be prepared, for example, as shown in Scheme 5. Substituent B ⁹ in compound XX is, for example, a halide such as Cl. Compounds XIX and XX may be combined with a suitable base (e.g., TEA) and a suitable solvent (e.g., DCM). The reaction may be heated to a temperature from about 25 °C to about 40 °C for a time period of about 3 to 16 hours to provide the compound of Formula XXI.

Scheme 6

The compounds of Formula XXIII of the present disclosure can be prepared, for example, as shown in Scheme 6. Substituent B ¹⁰ in compound XXII is, for example, a halide such as I. Compounds XIX and XXII may be combined with a copper catalyst (e.g., Cui), a ligand (e.g., frans-N,N’-dimethylcyclohexane-1 ,2-diamine), and NaNs in a solvent (e.g., DMSO and/or water). An additive, such as sodium ascorbate may also be included. The reaction may be allowed to progress at room temperature for about 16 hours to provide the compound of Formula XXIII.

Where a protecting or masking group is present on a compound of Formula XXII, a final deprotection step is added, employing conditions known to one skilled in the art, to provide the compound of Formula XXIII. For example, if a methyl or ethyl ester is used to mask a primary amide, it may be unmasked using a reagent such as ammonia in a solvent such as MeOH or EtOH. Scheme 7

The compounds of Formula XXV of the present disclosure can be prepared, for example, as shown in Scheme 7. Compound XXIV may be combined with p- toluenesulfonyl hydrazide and a suitable solvent (e.g., ACN), and the reaction mixture may be allowed to progress at room temperature for about 3 hours. A suitable base (e.g., NaOH) and the compound of Formula XIX may then be added to the reaction mixture. The reaction may subsequently be heated to a temperature of about 50 °C for about 16 hours to provide the compound of Formula XXV.

In obtaining the compounds described in the examples below and the corresponding analytical data, the following experimental and analytical protocols were followed unless otherwise indicated.

Unless otherwise specified, reaction solutions were stirred at room temperature under a N2(g) or Ar<g) atmosphere. When solutions were “concentrated to dryness”, they were concentrated using a rotary evaporator under reduced pressure. When solutions were dried, they are typically dried over a drying agent such as MgSO4 or Na2SO4. Normal phase flash column chromatography (FCC) was performed on silica gel with prepackaged silica gel columns, such as RediSep®, using ethyl acetate (EtOAc)Zhexanes, CH2Cl2/MeOH, or CH2Cl2/10% 2N NH3 in MeOH, as eluent, unless otherwise indicated.

Thin-layer chromatography was performed using silica gel plates, such as Merck silica gel 60 F2542.5 cm x 7.5 cm 250 mm or 5.0 cm x 10.0 cm 250 pm pre-coated silica gel plates. Preparative thin-layer chromatography was performed using silica gel plates such as EM Science silica gel 60 F254 20 cm x 20 cm 0.5 mm pre-coated plates with a 20 cm x 4 cm concentrating zone. Microwave reactions were carried out in a microwave reactor, such as a CEM Discover®, a Biotage Initiator™ or Optimizer™ microwave, at specified temperatures. Mass spectra were obtained on a mass spectrometer, such as Agilent series 1100 MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. Calculated mass corresponds to the exact mass. NMR spectra were obtained on an NMR spectrometer, such as a Bruker model DPX400 (400 MHz), DPX500 (500 MHz), DRX600 (600 MHz) spectrometer. The format of the ¹ H NMR data below is as follows: Chemical shift in ppm down field of the tetramethylsilane reference (multiplicity, coupling constant J in Hz, integration).

Whenever a yield is given as a percentage, such yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Reagent concentrations that are given as percentages refer to mass ratios, unless indicated differently. Whether expressly indicated or not, yields given in the following examples are computed with respect to the dried form of the compound for which any such yield is given.

Chemical names were generated using ChemDraw Ultra 17.1 (CambridgeSoft Corp., Cambridge, MA) or OEMetaChem V1 .4.0.4 (Open Eye).

Intermediate 1 : (R)-3-Ethynyl-3-hydroxy-1 -methylpyrrolidin-2-one.

Step A: te/t-Butyl 3-(methylamino)propanoate. A 2 L round-bottomed flask equipped with an overhead stirrer was charged with methylamine (500 mL, 3.48 mol, 30 wt % in EtOH) and EtOH (500 mL) followed by dropwise addition of te/t-butyl acrylate (100 g, 0.78 mol) over 3 h at 20-25 °C. The resultant mixture was stirred at rt for 3 h and then concentrated to dryness to give te/t-butyl 3-(methylamino)propanoate (124 g) as a colorless oil. MS (ESI): Mass calcd. for C8H17NO2, 159.1 ; m/z found, 160.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCI3) δ 2.79 (t, J = 6.5 Hz, 2H), 2.43 (s, 3H), 2.41 (t, J = 6.5 Hz, 2H),1.44 (s, 9H).

Step B: te/t-Butyl 4-hydroxy-1 -methyl-5-oxo-2,5-dihydro-1 /-/-pyrrole-3- carboxylate. A 50 L glass-lined reactor equipped with an overhead stirrer was charged with te/t-butyl 3-(methylamino)propanoate (900 g, 5.65 mol), diethyl oxalate (827 g, 5.65 mol) and THF (18 L). The resultant mixture was warmed to 50-55 °C followed by addition of f-BuOK (633 g, 5.65 mol) batch-wise. After stirring for 1 h, the mixture was cooled to 20 °C, concentrated to dryness, and water (5.00 L) was added which resulted in the formation of a suspension. The pH was adjusted to 1-2 with aqueous HCI and the resultant mixture was stirred at 20-25 °C for 1 h followed by filtration and drying to give te/Y-butyl 4-hydroxy-1 -methyl-5-oxo-2,5-dihydro-1 /-/-pyrrole-3-carboxylate (940 g, 78%) as an off-white solid. ¹ H NMR (300 MHz, CDCh) δ 8.99 (s, 1 H), 3.94 (s, 2H), 3.10 (s, 3H), 1.56 (s, 9H).

Step C: 4-Hydroxy-1 -methyl-5-oxo-2,5-dihydro-1 /-/-pyrrole-3-carboxylic acid. A 5 L round-bottomed flask equipped with an overhead stirrer was charged with fe/Y-butyl 4- hydroxy-1 -methyl-5-oxo-2,5-dihydro-1 /-/-pyrrole-3-carboxylate (500 g, 2.34 mol) and TFA (2.00 L). The resultant mixture was stirred at 20-25 °C for 3 h and then concentrated to dryness. To the residue was added acetonitrile (1 .50 L) with stirring at 20-25 °C for 1 h. The product was isolated by filtration and dried to give 4-hydroxy-1 - methyl-5-oxo-2,5-dihydro-1 /-/-pyrrole-3-carboxylic acid (357 g, 97%) as an off-white solid. ¹ H NMR (300 MHz, CD3OD) δ 4.04-3.98 (m, 2H), 3.08 (s, 3H).

Step D: 1-Methylpyrrolidine-2, 3-dione. A 20 L round-bottomed flask equipped with an overhead stirrer was charged with 4-hydroxy-1 -methyl-5-oxo-2,5-dihydro-1 /-/- pyrrole-3-carboxylic acid (1000 g, 6.4 mol) and THF (15 L). The resultant mixture was heated to 65 °C. After 4 h, the mixture was concentrated to dryness to give 1 - methylpyrrolidine-2, 3-dione (712 g, 99%) as a yellow solid. ¹ H NMR (400 MHz, CDCh) 8 3.70 (t, J = 5.7 Hz, 2H), 3.13 (s, 3H), 2.72 (t, J = 5.7 Hz, 2H).

Step E: (R,S)-3-Ethynyl-3-hydroxy-1 -methylpyrrolidin-2-one. A 10 L round- bottomed flask equipped with an overhead stirrer was charged with ethynylmagnesiumbromide (3.50 L, 0.5 M in THF). The flask was purged with nitrogen and cooled to - 10 °C before adding 1-methylpyrrolidine-2, 3-dione (120 g, 1.06 mol) over the course of 20 min. The resultant mixture was warmed to 20 - 25 °C and stirred for 16h. The resulting mixture was quenched with aqueous NH4CI solution (120 g in 360 mL H2O) followed by dilution with DCM (3.50 L). After being slurried for 1 h, the suspension was filtered, and the filtrate was dried over anhydrous Na2SO4 (500 g) and treated with activated charcoal (24 g). The activated charcoal was removed by filtration and the filtrate was concentrated under vacuum to dryness. The residue was slurried in MTBE (360 mL) at 20-25 °C for 1 h. The product was isolated by filtration followed by drying to give (F?,S)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (81 g, 55%) as a yellow solid. MS (ESI): Mass calcd. for C7H9NO2, 139.1 ; m/z found, 140.1 [M+H] ⁺ . ¹ H NMR (300 MHz, CD3OD) 5 3.40 (dd, J = 7.7, 5.3 Hz, 2H), 3.03 (s, 1 H), 2.88 (s, 3H), 2.52-2.41 (m, 1 H), 2.21 (dt, J = 12.7, 7.7 Hz, 1 H).

Step F: (R)-3-Ethynyl-3-hydroxy-1-methylpyrrolidin-2-one and (S)-3-Ethynyl-3- hydroxy-1-methylpyrrolidin-2-one. The enantiomers of (R,S)-3-ethynyl-3-hydroxy-1- methylpyrrolidin-2-one were separated by chiral preparative SFC using an SFC column, such as a CHIRALPAK® AS-H 5 pm, 5 x 25 cm column, mobile phase (80% CO2, 20% IPA (0.1 % DEA). Detection, UV at 25 °C = 220-254 nM) to yield (R)-3-ethynyl-3- hydroxy-1-methylpyrrolidin-2-one (40%) and (S)-3-ethynyl-3-hydroxy-1-methylpyrrolidin- 2-one (Intermediate 2, 40%). Data for (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one: MS (ESI): Mass calcd. for C7H9NO2, 139.1 ; m/z found, 140.1 [M+H] ⁺ . ¹ H NMR (300 MHz, CD3OD) 53.40 (dd, J = 7.7, 5.3 Hz, 2H), 3.03 (s, 1 H), 2.88 (s, 3H), 2.52-2.41 (m, 1 H), 2.21 (dt, J = 12.7, 7.7 Hz, 1 H). [O] ²⁰ D = -100.1 (c = 1.01 in MeOH).

Intermediate 2: (S)-3-Ethynyl-3-hydroxy-1 -methylpyrrolidin-2-one.

The chiral separation described in Intermediate 1 , Step F also provided (S)-3- ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (40%). MS (ESI): Mass calcd. for C7H9NO2, 139.1 ; m/z found, 140.1 [M+H] ⁺ . ¹ H NMR (300 MHz, CD3OD) 53.40 (dd, J = 7.7, 5.3 Hz, 2H), 3.03 (s, 1 H), 2.88 (s, 3H), 2.52-2.41 (m, 1 H), 2.21 (dt, J = 12.7, 7.7 Hz, 1 H). [O] ²⁰ D = +90.5 (c = 1.19 in MeOH).

Intermediate 3: (R)-3-(3-(3-Bromophenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2- one.

Step A: 3-Bromobenzaldehyde oxime. To a solution of 3-bromobenzaldehyde (3.0 g, 16 mmol) in EtOH (40 mL) was added NH2OH (50% in water, 1.1 mL, 19 mmol). The reaction was stirred at 25 °C for 4 h. The reaction mixture was then concentrated under reduced pressure to afford (3.2 g, 98%) of 3-bromobenzaldehyde oxime as a white solid. MS (ESI): Mass calcd. for CyHeBrNO, 199.0; m/z found, 200.1 [M+H] ⁺ .

Step B: 3-Bromo-/V-hydroxybenzimidoyl chloride. To a solution of 3- bromobenzaldehyde oxime (3.20 g, 16.0 mmol) in anhydrous DCM (20 mL) was added /V-chlorosuccinimide (2.56 g, 19.2 mmol), portion wise. The reaction mixture was stirred at 25°C for 2 h and filtered. The filtrate was concentrated to afford 3-bromo-/V- hydroxybenzimidoyl chloride (3.0 g, 95%) as a yellow solid. MS (ESI): Mass calcd. For CyHsBrCINO, 234.5; m/z found, 235.2 [M+H] ⁺ .

Step C: (R)-3-(3-(3-Bromophenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2- one. To a solution of 3-bromo-/V-hydroxybenzimidoyl chloride (1 .50 g, 3.20 mmol) in DCM (20 mL) was added (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 1 , 4.45 g, 3.20 mmol) followed by TEA (1 .24 mL, 9.60 mmol). The reaction mixture was stirred at 25 °C for 16 h, diluted with DCM (30 mL), washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether/ethyl acetate = 1/1 ) to afford (R)-3-(3-(3-bromophenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyr rolidin-2-one (0.6 g, 55%) as a yellow oil. MS (ESI): Mass calcd. for CuHisBrlXhCh, 336.0; m/z found, 337.1 [M+H] ⁺ .

Intermediate 4: (R)-3-Hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one.

A flask containing (R)-3-(3-(3-bromophenyl)isoxazol-5-yl)-3-hydroxy-1- methylpyrrolidin-2-one (Intermediate 3, 0.60 g, 1.8 mmol) in 1 ,4-dioxane (10 mL) was charged with bis(pinacolato)diboron (0.90 g, 3.56 mmol), Pd(dppf)Cl2*CH2Cl2 (130 mg, 0.180 mmol) and KOAc (540 mg, 5.34 mmol). The reaction mixture was heated at 85 °C for 16 h under an Ar atmosphere. The mixture was concentrated and the residue was purified by preparative TLC (DCM/MeOH = 20/1 ) to afford (R)-3-hydroxy-1-methyl-3-(3- (3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (0.62 g, 77%) as a brown solid. MS (ESI): Mass calcd. for C20H25BN2O5, 384.2; m/z found, 385.2 [M+H] ⁺ .

Intermediate 5: (R)-3-Hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one.

Step A: (R)-3-(3-(3-Bromophenyl)-3-oxoprop-1-ynyl)-3-hydroxy-1- methylpyrrolidin-2-one. A solution of (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 1 , 3.00 g, 21 .6 mmol) in THF (150 mL) was cooled to -20 °C and PdCl2(PPh ₃ )2 (0.61 g, 0.86 mmol), Cui (0.21 g, 1 .08 mmol) and TEA (4.47 mL, 34.1 mmol) were added. A solution of 3-bromobenzoyl chloride (4.73 g, 21 .6 mmol) in THF (10 mL) was added dropwise. The reaction mixture was slowly warmed to 0 °C, stirred for 2 h, diluted with water (80 mL) and extracted with EtOAc (3 x 60 mL). The combined organic solvent extracts were washed with brine (60 mL), dried over Na2SO4, and filtered. The filtrate was concentrated and purified by FCC (DCM/MeOH = 100/1 ) to afford (R)-3-(3-(3-bromophenyl)-3-oxoprop-1 -ynyl)-3-hydroxy-1 -methylpyrrolidin-2-one (1 .6 g, 23%) as a yellow solid. MS (ESI): Mass calcd. for Ci4Hi2BrNO3, 321 .0; m/z found, 322.0 [M+H] ⁺ .

Step B: (R)-3-(5-(3-Bromophenyl)isoxazol-3-yl)-3-hydroxy-1 -methylpyrrolidin-2- one. To a solution of (R)-3-(3-(3-bromophenyl)-3-oxoprop-1 -ynyl)-3-hydroxy-1- methylpyrrolidin-2-one (1.60 g, 4.37 mmol) in DCM (100 mL) was added NaNs (1.42 g, 21 .8 mmol). The mixture was cooled to 0 °C and AcOH (1 .31 g, 21 .85 mmol) was added dropwise, followed by TEA (1 .21 mL, 0.87 mmol). The reaction mixture was stirred at rt for 2 days. Saturated aqueous NaHCOs solution (100 mL) was added and the mixture was stirred for 10 min. The organic solvent portion was separated, and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organic solvent extracts were washed with brine (2 x 100 mL), dried over Na2SO4 and filtered. The filtrate was concentrated by blowing a continuous stream of N2 over the filtrate and the residue was purified by FCC (DCM/MeOH = 50/1 ) to afford (R)-3-(5-(3- bromophenyl)isoxazol-3-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (0.6 g, 41 %) as a grey oil. MS (ESI): Mass calcd. for CuHisBrlXkCh, 336.0; m/z found, 337.0 [M+H] ⁺ .

Step C: (R)-3-Hydroxy-1 -methyl-3-(5-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one. A flask containing (R)-3-(5-(3- bromophenyl)isoxazol-3-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (85 mg, 0.252 mmol) in 1 ,4-dioxane (5 mL) was charged with bis(pinacolato)diboron (128.0 mg, 0.50 mmol), Pd(dppf)Cl2«CH2Cl2 (18.4 mg, 0.025 mmol) and KOAc (74.2 mg, 0.76 mmol). The mixture was heated at 65 °C for 4 h under Ar. The reaction mixture was filtered and concentrated to afford (R)-3-hydroxy-1 -methyl-3-(5-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one (0.10 g, 87%) as a brown oil which was used in the next step without further purification. MS (ESI): Mass calcd. for C20H25BN2O5, 384.2; m/z found, 385.2 [M+H] ⁺ .

Intermediate 6: (R, S)-3-(5-(3-Bromophenyl)isoxazol-3-yl)-3-hydroxy-1 -methylpyrrolidin- 2-one.

(R _; S)-3-(5-(3-Bromophenyl)isoxazol-3-yl)-3-hydroxy-1-meth ylpyrrolidin-2-one (1 .4 g) was prepared using analogous conditions to those described in the preparation of Intermediate 5 ((R)-3-hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one) using (R, S)-3-ethynyl-3-hydroxy-1 - methylpyrrolidin-2-one (prepared in Intermediate 1 , step E) instead of (R)-3-ethynyl-3- hydroxy-1-methylpyrrolidin-2-one. MS (ESI): Mass calcd. for CuHisBrlXkCh, 336.0; m/z found, 337.0 [M+H] ⁺ .

Intermediate 7 : (R)-3-(3-(2-Bromopyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1 - methylpyrrolidin-2-one.

Step A: 2-Bromoisonicotinaldehyde oxime. To a solution of 2- bromoisonicotinaldehyde (250 mg, 1.3 mmol) in EtOH (10 mL) was added hydroxylamine (0.095 mL, 50% in water, 1 .6 mmol). The reaction mixture was stirred at rt for 16 h and concentrated to dryness to afford 2-bromoisonicotinaldehyde oxime (240 mg, 89%) as a colorless solid. MS (ESI): Mass calcd. for CeHsBrlShO, 200.0; m/z found, 201.1 [M+H] ⁺ .

Step B: 2-Bromo-/V-hydroxyisonicotinimidoyl chloride. To a solution of 2- bromoisonicotinaldehyde oxime (140 mg, 0.60 mmol) in DCM (5 mL) was added N- chlorosuccinimide (120 mg, 0.90 mmol) portion-wise at rt. The reaction mixture was stirred for 2 h at rt, then DMF (1 mL) was added, and the reaction mixture was stirred for an additional 2 h. The mixture was diluted with EtOAc (20 mL) and washed with brine (3 x 20 mL). The organic extracts were dried over Na2SO4, filtered and concentrated to dryness to afford 2-bromo-/V-hydroxyisonicotinimidoyl chloride (140 mg, 80%) as a white solid. MS (ESI): Mass calcd. for CeHUBrCIlS^O, 235.5; m/z found, 199.0 [M-HCI +1 ] ⁺ .

Step C: (R)-3-(3-(2-Bromopyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1 - methylpyrrolidin-2-one. To a solution of bromo-M-hydroxyisonicotinimidoyl chloride (2.80 g, 11.9 mmol), and (R)-3-ethynyl-3-hydroxy-1 -methylpyrrolidin-2-one (Intermediate 1 , 1.64 g, 11.9 mmol) in f-BuOH:H2O (10 mL 1 :1 ) was added a solution of sodium ascorbate (0.24 g, 1 .2 mmol) in H2O (1 mL). A solution of CuSO4*5H2O (0.89 g, 3.6 mmol) in H2O (2 mL) was then added followed by the addition of KHCO3 (3.57 g, 1.19 mmol). The reaction mixture was stirred for 16 h at rt, diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic solvent extracts were dried, filtered, concentrated to dryness and purified by preparative TLC (DCM/MeOH = 20/1 ) to afford (R)-3-(3-(2-bromopyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (1 .8 g, 45%) as a yellow solid. MS (ESI): Mass calcd. for CnH^BrNsOs, 337.0, m/z found, 338.3 [M+H] ⁺ .

Intermediate 8: (R)-3-Hydroxy-1 -methyl-3-(1 -(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)phenyl)-1 H-1 ,2,3-triazol-4-yl)pyrrolidin-2-one.

Step A: (R)-3-(1 -(3-Bromophenyl)-1 H-1 ,2,3-triazol-4-yl)-3-hydroxy-1 - methylpyrrolidin-2-one. To a suspension of 1 -bromo-3-iodobenzene (281 mg, 0.99 mmol) in DMSO (2 mL) was added (R)-3-ethynyl-3-hydroxy-1 -methylpyrrolidin-2-one (Intermediate 1 , 138 mg, 0.993 mmol), sodium azide (71 mg, 1.1 mmol), (1S,2S)- /\H,/V2-dimethylcyclohexane-1 ,2-diamine (28 mg, 0.20 mmol) and copper(l) iodide (38 mg, 0.20 mmol), successively. A solution of sodium ascorbate (39 mg, 0.20 mmol) in water (0.5 mL) was slowly added and the reaction mixture was stirred at rt for 16 h under an Ar atmosphere. The mixture was diluted with EtOAc (20 mL), the organic phase was washed with brine (3 x 15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (DCM\MeOH = 20/1 ) to afford (R)-3-(1 -(3-bromophenyl)-1 H-1 ,2,3-triazol-4-yl)-3-hydroxy-1 -methylpyrrolidin-2- one (200 mg, 76%) as a yellow solid. MS (ESI): Mass calcd. for CisHnBrlSUCte, 336.0; m/z found, 337.0 [M+H],

Step B: (R)-3-Hydroxy-1 -methyl-3-(1 -(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)phenyl)-1 H-1 ,2,3-triazol-4-yl)pyrrolidin-2-one. To a solution of (R)-3-(1-(3- bromophenyl)-1 /-/-1 ,2,3-triazol-4-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (200 mg, 0.593 mmol) in dioxane (10 mL) was added bis(pinacolato)diboron (301 mg, 1.19 mmol), followed by [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (45 mg, 0.059 mmol) and KOAc (175 mg, 1.78 mmol). The reaction mixture was heated at 65 °C for 2 h under an Ar atmosphere. The reaction mixture was then filtered and concentrated under reduced pressure. The residue was purified by FCC (DCM/MeOH = 20/1 ) to afford (R)-3-hydroxy-1 -methyl-3-(1 -(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)-1 H-1 ,2,3-triazol-4-yl)pyrrolidin-2-one (260 mg, 68%) as a yellow solid. MS (ESI): Mass calcd. for C19H25BN4O4, 384.2; m/z found, 385.2 [M+H] ⁺ .

Intermediate 9: (R _; S)-3-Hydroxy-1 -methyl-3-(1 -(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)-1 /-/-imidazol-4-yl)pyrrolidin-2-one.

Step A: 1 -(3-Bromophenyl)-4-iodo-1 /-/-imidazole. A mixture of 4-iodoimidazole (3.68 g, 19.0 mmol) in THF (100 mL), 3-bromophenylboronic acid (7.6 g, 38 mmol), di-p- hydroxo-bis[(/V,/V,/V(/V'-tetramethylethylenediamine)copper( ll)] chloride (9.7 g, 20.869 mmol) and molecular sieves (250 mg) was stirred at 30 °C under an O2 atmosphere for 16 h. The reaction mixture was then filtered through diatomaceous earth, washed with EtOAc (200 mL) and concentrated under reduced pressure. The residue was purified by FCC (petroleum ether/EA=2/1 ) to afford 1 -(3-bromophenyl)-4-iodo-1 /-/-imidazole (3.2 g, 48%) as a brown solid. MS (ESI): Mass calcd. for CoHeBrl N2, 347.9; m/z found, 349.0 [M+H] ⁺ .

Step B: 3-(1 -(3-Bromophenyl)-1 H-imidazol-4-yl)-3-hydroxy-1 -methylpyrrolidin-2- one. A solution of isopropylmagnesium chloride-lithium chloride (3.6 mL, 1.3 M in THF) was added dropwise to a solution of 1 -(3-bromophenyl)-4-iodo-1 /-/-imidazole (1.35 g, 3.87 mmol) in THF (30 mL) that had been cooled to 0 °C. After one hour, a solution of 1 - methylpyrrolidine-2, 3-dione (0.87 g, 7.74 mmol) in THF (10 mL) was added and the mixture was stirred at 0 °C for 2 h. The reaction mixture was allowed to warm to rt and stirred overnight. The reaction mixture was then cooled to 0 °C, quenched with ice water (6 mL) and MeOH (10 mL) and concentrated under reduced pressure. The residue was purified using preparative TLC (DCM/MeOH=15/1 ) to afford 3-(1 -(3-bromophenyl)-1 /-/- imidazol-4-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (0.29 mg, 22%) as a brown solid. MS (ESI): Mass calcd. for Ci4Hi4BrN3O2, 336.2; m/z found, 336.0 [M+H] ⁺ .

Step C: 3-Hydroxy-1 -methyl-3-(1-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)-1 /-/-imidazol-4-yl)pyrrolidin-2-one. A mixture of bis(pinacolato)diboron (242 mg, 0.95 mmol), 3-(1 -(3-bromophenyl)-1 /-/-imidazol-4-yl) -3-hydroxy-1-methylpyrrolidin - 2-one (160 mg, 0.48 mmol), Pd(dppf)Cl2*CH2Cl2 (36.3 mg, 0.048 mmol) and KOAc (140.1 mg, 1 .428 mmol) in dioxane (10 mL) was heated at 80 °C for 16 h under an Ar atmosphere. The reaction mixture was used directly in subsequent reactions. MS (ESI): Mass calcd. for C20H26BN3O4, 383.3; m/z found, 384.0 [M+H] ⁺ .

Intermediate 10: (R)-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenylboronic acid.

To a suspension of (R)-3-(3-(3-bromophenyl)isoxazol-5-yl)-3-hydroxy-1 - methylpyrrolidin-2-one (Intermediate 3, 500 mg, 1.5 mmol) in MeOH (15 mL) was added tetrakis(dimethylaminio)diboron (881 mg, 4.45 mmol) followed by chloro(2- dicyclohexylphosphino-2',4',6'-triisopropyl-1 , 1 '-biphenyl)[2-(2'-amino-1 , 1 '- biphenyl)]palladium(l I) (43.4 mg, 59.3 mmol) and the reaction was heated at 60 °C for 16 h under an argon atmosphere. The mixture was concentrated to dryness and purified by FCC (8% MeOH I DCM) to afford (R)-(3-(5-(3-hydroxy-1-methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)boronic acid (160 mg, 36%) as a yellow solid. MS (ESI): Mass calcd. for C14H15BN2O5, 302.11 ; m/z found, 303.2 [M+H] ⁺ .

Intermediate 11 : 5-Chloro-3-nitro-1/-/-pyrazolo[4,3-b]pyridine.

To a flask containing 5-chloro-1/-/-pyrazolo[4,3-b]pyridine (5.0 g, 32.56 mmol) was added H2SO4 (10 mL), followed by KNO3 (8.2 g, 81.397 mmol) at 0 °C. The mixture was stirred at rt for 3 h and then heated at 115 °C for 8 h. The reaction mixture was then poured into ice water and the pH was adjusted to pH 9 using aqueous NH4OH. A precipitate formed and was collected by filtration. The filter cake was dried to afford 5- chloro-3-nitro-1/-/-pyrazolo[4,3-b]pyridine (5.2 g, 80%) as a yellow solid. MS (ESI): calcd. for C6H3CIN4O2, 198.6; m/z found, 199.0 [M+H] ⁺ .

Intermediate 12: 5-Chloro-1-methyl-3-nitro-1/-/-pyrazolo[4,3-b]pyridine.

To a solution of 5-chloro-3-nitro-1/-/-pyrazolo[4,3-b]pyridine (Intermediate 11 , 500 mg, 2.5 mmol) and iodomethane (357 mg, 2.52 mmol) in DMF (4 mL) was added potassium carbonate (348 mg, 2.52 mmol). The reaction was heated at 50 °C for 2 h, then diluted with EtOAc (30 mL), and washed with brine (3 x 10 mL). The organic layers were combined and concentrated to dryness and the resulting residue was purified by preparative TLC (100% EtOAc) to afford 5-chloro-1-methyl-3-nitro-1/-/-pyrazolo[4,3- b]pyridine (200 mg, 37%) as a yellow solid. MS (ESI): Mass calcd. for C7H5CIN4O2, 212.0; m/z found, 213.0 [M+H] ⁺ . Intermediate 13: 8-Chloro-2-(methylthio)pyrido[3,4-c/]pynmidine.

Step A: Methyl (E)-5-(2-ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxylate . A mixture of methyl-5-bromo-2-(methylthio)pyrimidine-4-carboxylate (3.00 g, 11.4 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (2.26 g, 11.40 mmol), Pd(dppf)Cl2 (0.43 g, 0.57 mmol), water (10 mL) and Na2COs (3.63 g, 34.2 mmol) in THF (70 mL) was heated at 65 °C for 16 h under an Ar atmosphere. The reaction mixture was concentrated to dryness and the residue was purified by FCC eluting with petroleum ether/ethyl acetate (20/1 to 8/1 , gradient elution) to afford methyl (E)-5-(2- ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxylate (1.2 g, 41 %) as a yellow solid. MS (ESI): Mass calcd. for C11 H14N2O3S, 254.1 ; m/z found, 255.1 [M+H] ⁺ .

Step B: (E)-5-(2-Ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxamide . A mixture of methyl (E)-5-(2-ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxylate (1.2 g, 4.7 mmol) in a solution of NH3 in MeOH (7 M, 12 mL, 84 mmol) was heated at 80 °C for 16 h in a sealed tube. The reaction mixture was cooled to rt and then concentrated under reduced pressure to afford (E)-5-(2-ethoxyvinyl)-2-(methylthio)pyrimidine-4- carboxamide (950 mg, 84%) as a yellow solid, which was used in the next step without further purification. MS (ESI): Mass calcd. for C10H13N3O2S, 239.1 ; m/z found, 240.1 [M+H] ⁺ .

Step C: 2-(Methylthio)pyrido[3,4-c(]pyrimidin-8-ol. To a solution of (E)-5-(2- ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxamide (950 mg, 3.97 mmol) in toluene (25 mL), was added p-toluenesulfonic acid monohydrate (113 mg, 0.60 mmol). The resulting mixture was heated at 90 °C for 2 h, cooled to rt and then concentrated under reduced pressure to afford 2-(methylthio)pyrido[3,4-c/]pynmidin-8-ol (700 mg, 91 %) as a yellow solid, which was used in the next step without further purification. MS (ESI): Mass calcd. for CsHyNsOS, 193.0; m/z found, 194.1 [M+H] ⁺ .

Step D: 8-Chloro-2-(methylthio)pyrido[3,4-c/]pyrimidine. A mixture of 2- (methylthio)pyrido[3,4-c/]pynmidin-8-ol (700 mg, 3.62 mmol) in POCI3 (25 mL, 269 mmol) was heated at 70 °C for 16 h. The mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc (20 mL) and saturated aqueous NaHCOs solution (20 mL). The aqueous layer was extracted with EtOAc (2 x 10 mL) and the combined organic solvent extracts were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (petroleum ether/ethyl acetate = 3/1 , Rf =0.4) to afford 8-chloro-2- (methylthio)pyrido[3,4-c/]pynmidine (500 mg, 65%) as white solid. MS (ESI): Mass calcd. for CsHeCINsS, 211.0; m/z found, 212.1 [M+H] ⁺ .

Intermediate 14: Methyl 6-(3-iodophenyl)picolinate.

A mixture of methyl 6-bromopicolinate (1 .0 g, 4.63 mmol), (3-iodophenyl) boronic acid (1.0 g, 4.21 mmol), KF (733 mg, 12.6 mmol), PdCI ₂ (dppf) (128 mg, 0.17 mmol), 1 ,4- dioxane (15 mL) and water (2 mL) was heated at 80 °C under a N ₂ atmosphere for 15 h. The mixture was concentrated, diluted with water (35 mL) and extracted with EtOAc (4 x 35 mL). The combined organic solvent extracts were washed with brine (20 mL), dried over Na ₂ SO4, filtered and concentrated. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=5/1 ) to afford methyl 6-(3-iodophenyl)picolinate (89 mg, 6.2%) as a yellow oil. MS (ESI): Mass calcd. for Ci3HwlNO ₂ , 339.1 ; m/z found, 340.0 [M+H] ⁺ .

Intermediate 15: 6-Chloro-4-methoxypicolinamide.

To a solution of 6-chloro-4-methoxypicolinic acid (200 mg, 1.07 mmol) in DCM (3 mL) and DMF (3 mL) was added ammonium chloride (160 mg, 2.99 mmol), followed by DIEA (689 mg, 5.33 mmol) and HATU (567 mg, 1 .49 mmol). The reaction mixture was stirred at rt overnight and then diluted with water (20 mL). The aqueous phase was extracted with EtOAc (3 x 15 mL), concentrated to dryness and purified by FCC (petroleum ether/ethyl acetate = 1 :1 ) to afford 6-chloro-4-methoxypicolinamide (130 mg, 65%) as a yellow solid. MS (ESI): Mass calcd. for C7H7CIN2O2, 186.0; m/z found, 187.0 [M+H] ⁺ .

Intermediate 16: 6-Chloro-2-methylpyrido[3,2-c/]pyrimidin-4-amine.

A vial containing 3-amino-6-chloropicolinonitrile (100 mg, 0.65 mmol) was charged with ethanimidamide hydrochloride salt (57.0 mg, 0.98 mmol), potassium phosphate tribasic (553 mg, 2.6 mmol), and THF (3 mL). The vial was sealed and heated at 80 °C for 16 h. The resulting mixture was cooled to rt and concentrated to dryness. To this residue was added water (3 mL) and the resulting mixture was heated at 70 °C. After stirring for 30 min, the resulting mixture was cooled to rt and stirred for an additional 30 min. The resulting solid was isolated by filtration and washed sequentially with water (3 mL) and Et20 (10 mL) to afford 6-chloro-2-methylpyrido[3,2-d]pyrimidin-4- amine (70 mg, 55%) as a pale yellow solid. MS (ESI): Mass calcd. for C8H7CIN4, 194.0; m/z found, 195.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCI3) δ 8.00 (d, J = 8.7 Hz, 1 H), 7.62 (d, J = 8.7 Hz, 1 H), 6.76 (s, 2H), 2.63 (s, 3H).

Intermediate 17: 6-Chloropyrido[3,2-c/]pynmidin-2-c/-4-amine.

A 1 L round-bottomed flask was charged with 3-amino-6-chloropicolinonitrile (22.0 g, 0.14 mol), formamide-cfe (20.6 g, 0.43 mol), KsPO4 (122 g, 0.57 mol), and cyclopentylmethyl ether (440 mL). The resultant mixture was heated at 65 °C for 16 h before cooling to rt. Then the reaction mixture was filtered and the filter cake was slurried in water (100 mL) at 20 °C for 3 h. The solid was isolated by filtration and dried to give 6-chloropyrido[3,2-c/]pynmidin-2-c/-4-amine (23.9 g, 94%) as a yellow solid. MS (ESI): Mass calcd. for C7H4DCIN4, 181 .0; m/z found, 182.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-cfe) δ 8.15 (d, J = 8.8 Hz, 1 H), 8.05 (br s, 1 H), 7.95 (br s, 1 H), 7.88 (d, J = 8.8 Hz, 1 H).

Intermediate 18: 6-(3-lodophenyl)pyndo[3,2-c/]pyrimidin-2-c/-4-amine.

Step A: 6-(3-(Trimethylsilyl)phenyl)pyrido[3,2-c/]pynmidin-2-c/-4-am ine. A 1 L flask equipped with an overhead stirrer containing 6-chloropyrido[3,2-c(]pyrimidin-2-c/-4-amine (Intermediate 17, 31 g, 0.14 mol) was charged with 4-(trimethylsilyl) phenylboronic acid (32 g, 0.17 mol), Pd(dppf)Cl2 (10.2 g, 13.8 mmol), CH3CN (500 mL) and aqueous CS2CO3 solution (1 M, 125 mL) under at atmosphere of N2, successively. The resulting mixture was heated at 75 °C for 3 h. Water (375 mL) was added and the reaction mixture was further heated at 65 °C for 0.5 h. The resultant mixture was then allowed to cool to rt gradually and stirred for 1 h. The product was isolated by filtration and dried to afford 6-(3-(trimethylsilyl)phenyl)pyrido[3,2-c/]pyrimidin-2-c/-4-a mine (39 g, 94%) as a brown solid. MS (ESI): Mass calcd. for CwHiyDISUSi, 295.1 ; m/z found, 296.1 [M+H] ⁺ . ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.46 (t, J = 8.9 Hz, 2H), 8.39 (s, 1 H), 8.15 (d, J = 8.8 Hz, 1 H), 8.04 (d, J = 10.3 Hz, 2H), 7.65 (d, J = 7.1 Hz, 1 H), 7.54 (t, J = 7.6 Hz, 1 H), 0.35 (s, 9H).

Step B: 6-(3-lodophenyl)pyndo[3,2-c/]pyrimidin-2-c/-4-amine. A 10-L round-bottom flask equipped with overhead stirrer was charged with 6-(3-(trimethylsi lyl) phenyl) pyrido[3,2-c/]pynmidin-2-c/-4-amine (49.0 g, 0.17 mol) and DCM (980 mL). A solution of ICI (134 g, 0.830 mol) in CH2CI2 (735 mL) was then added dropwise at -5 °C, the reaction mixture was warmed to 15 °C and stirred for 1 h. A precipitate formed and was isolated by filtration and dried under vacuum at 50 °C. The resultant solid was combined with several additional batches of this material and was dissolved in DMSO (800 mL). Then an aqueous solution of K2HPO4 (10 wt %) was added dropwise to the above solution and stirring was continued at 20 °C for 2 h. The precipitate was isolated by filtration followed by slurrying in water (1600 mL) at 20 °C for 4 h. The solid was isolated and dried to afford 6-(3-iodophenyl)pyrido[3,2-c/]pyrimidin-2-c/-4-amine as light-brown solid (135 g). MS (ESI): Mass calcd. for C13H8DIN4, 349.0; m/z found, 350.0 [M+H] ⁺ . ¹ H- NMR (400 MHz, DMSO-d ₆ ) δ 8.84 (m, 1 H), 8.47 (m, 1 H), 8.40 (m, 2H), 8.12 (m, 2H), 7.86 (m, 1 H), 7.34 (m, 1 H).

Intermediate 19: 3-Amino-6-(3-iodophenyl)picolinamide.

Step A: 3-Amino-6-(3-(trimethylsilyl)phenyl)picolinamide. To an N2 purged solution of 3-amino-6-chloropicolinamide (1.00 g, 5.83 mmol) and (3-(trimethylsilyl)phenyl)boronic acid (1.11 g, 5.83 mmol) in dioxane (58 mL) and water (15 mL), was added (2- dicyclohexylphosphino-2’,6’-diisopropoxy-1 ,1 ’-biphenyl)[2-(2’-amino-T- biphenyl)]palladium(l I) methanesulfonate (0.48 g, 0.58 mmol) followed by CS2CO3 (5.70 g, 17.5 mmol). The reaction mixture was heated at 80 °C for 1 h, partitioned between EtOAc (40 mL) and water (60 mL), and the organic layers were separated, concentrated to dryness and purified by FCC (0-40% EtOAc: hexanes) to afford 3-amino-6-(3- (trimethylsilyl)phenyl)picolinamide (1 .2 g, 73%) as an orange solid. MS (ESI): Mass calcd. for CisHigNsOSi, 285.1 ; m/z found, 286.1 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.12 - 8.03 (m, 2H), 8.02 (s, 1 H), 7.87 (d, J = 8.7 Hz, 1 H), 7.49 - 7.44 (m, 1 H), 7.43 - 7.37 (m, 2H), 7.25 (d, J = 8.7 Hz, 1 H), 6.95 (s, 2H), 0.30 (s, 9H).

Step B: 3-Amino-6-(3-iodophenyl)picolinamide. To a solution of 3-amino-6-(3- (trimethylsilyl)phenyl)picolinamide (0.20 g, 0.70 mmol) in DCM (7 mL) at 0 °C was added a solution of ICI (3.5 mL, 2 M in DCM, 3.50 mmol) dropwise. The reaction mixture was allowed to warm to rt and stirred for 1 h. A solution of saturated aqueous Na2S20s (25 mL) was added and the solid was isolated by filtration. The solid was purified by FCC (0-10% MeOH:DCM) to afford 3-amino-6-(3-iodophenyl)picolinamide (133 mg, 56%) as a beige solid. MS (ESI): Mass calcd. for C12H10IN3O, 339.0; m/z found, 340.0 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.45 - 8.39 (m, 1 H), 8.16 (s, 1 H), 8.12 - 8.01 (m, 1 H), 7.87 (d, J = 8.7 Hz, 1 H), 7.70 - 7.62 (m, 1 H), 7.40 (s, 1 H), 7.25 - 7.17 (m, 2H), 7.03 (s, 2H).

Intermediate 20: 2-(5-lodo-2-methylphenyl)thiazolo[5,4-c/]pyrimidin-7-amine.

Step A: A/-(4-Amino-6-oxo-1 ,6-dihydropyrimidin-5-yl)-5-iodo-2-methylbenzamide.

A 2 L round-bottomed flask equipped with an overhead stirrer was charged with 5,6- diaminopyrimidin-4(3/-/)-one (47.3 g, 375 mmol), 5-iodo-2-methylbenzoic acid (108 g, 412 mmol), DMF (710 mL), and DIEA (153 g, 1.18 mol), successively. The flask was purged with nitrogen and cooled to 0 - 10 °C before adding 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (148 g, 390 mmol). The resultant mixture was stirred for 1 h at 0 - 10 °C before warming to rt with stirring for 18 h. The mixture was diluted with acetonitrile (709 mL) with continued stirring for 30 min. The resulting solid was filtered and washed with CH3CN (190 mL x 3). The filter cake was collected and dried under vacuum at 50 - 55 °C to afford A/-(4-amino-6-oxo-1 ,6-dihydropyrimidin-5-yl)-5-iodo-2-methylbenzamide (108 g, 78.0%) as a light brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.68 (s, 1 H), 8.89 (s, 1 H), 8.01 (s, 1 H), 7.78 (s, 1 H), 7.66 (d, J = 8.0 Hz, 1 H), 7.05 (d, J = 8.0 Hz, 1 H), 6.39 (s, 2H), 2.35 (s, 3H).

Step B: 2-(5-lodo-2-methylphenyl)thiazolo[5,4-c(]pyrimidin-7-amine. A 2 L round- bottomed flask equipped with an overhead stirrer was charged with A/-(4-amino-6-oxo- 1 ,6-dihydropyrimidin-5-yl)-5-iodo-2-methylbenzamide (110 g, 297 mmol), pyridine (1.10 L), and P2S5 (165 g, 742 mmol). The resultant mixture was heated at 100 °C for 1 h before cooling to rt. The mixture was concentrated to dryness, diluted with acetonitrile (550 mL), and neutralized with 1 N aqueous HCI (1.20 L). The resulting mixture was stirred for 1 h, the suspension was filtered, washed with MeOH (110 mL x 3) and dried under vacuum at 50-55 °C. The resulting solid was further purified by adding MeOH (1150 mL) at 60 °C and stirring for 1 h. The solid was collected by filtration and dried under vacuum at 50-55 °C to afford 2-(5-iodo-2-methylphenyl)thiazolo[5,4-d]pyrimidin- 7 -amine (88.4 g, 80.8%) as a light yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.33 (s, 1 H), 8.15 (d, J = 1.9 Hz, 1 H), 7.81 (d, J = 2.0 Hz, 2H), 7.78 (d, J = 1.9 Hz, 1 H), 7.23 (d, J = 8.1 Hz, 1 H), 2.57 (s, 3H).

Intermediate 21 : 2-(3-lodophenyl)thiazolo[5,4-c(]pyrimidin-7-amine.

Step A: A/-(4-Amino-6-oxo-1 ,6-dihydropyrimidin-5-yl)-3-iodobenzamide. To a solution of 5,6-diaminopyrimidin-4-ol and NaOH (2 M, 50 mL, 100 mmol) at 0°C, was added 3-iodobenzoyl chloride (4.23 g, 15.9 mmol). The reaction mixture was stirred for 4 h at 0°C, allowed to warm to rt and then stirred overnight. The solid was removed by filtration and the pH of the filtrate was was adjusted to pH 4-5 with acetic acid. The resulting precipitate was filtered, washed with water (50 mL), and the resulting solid was suspended in EtOH (100 mL) and stirred for 10 min and filtered. The filter cake was washed with EtOH (30 mL) and then dried to afford A/-(4-amino-6-oxo-1 ,6- dihydropyrimidin-5-yl)-3-iodobenzamide (0.64 g, 23%) as a brown solid. MS (ESI): Mass calcd. for C11H9IN4O2, 356.0; m/z found, 357 [M+H] ⁺ .

Step B: 2-(3-lodophenyl)thiazolo[5,4-d]pyrimidin-7-amine. A solution of A/-(4- amino-6-oxo-1 ,6-dihydropyrimidin-5-yl)-3-iodobenzamide (640 mg, 1.80 mmol), 2,4- bis(4-methoxyphenyl)-2,4-dithioxo-1 ,3,2,4-dithiadiphosphetane, (727 mg, 1.80 mmol in toluene (15 mL) was heated to reflux for 16 h, cooled to rt and the solid was isolated by filtration. The filter cake was washed with toluene (5 mL), the solid was suspended in MeOH (3 mL), stirred for 2 min and isolated by filtration to afford 2-(3- iodophenyl)thiazolo[5,4-d]pyrimidin-7-amine (420 mg, 66%) as a white solid. MS (ESI): Mass calcd for C11 H7IN4S, 353.9; m/z found, 355.0 [M+H] ⁺ .

Intermediate 22: 4-(Azetidin-1 -yl)-6-chloropyrido[3,2-c/]pynmidine.

To a mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (250 mg, 1.25 mmol), DIPEA (0.87 mL, 5.00 mmol), and DMF (2.5 mL), was added azetidine (71.3 mg, 1.25 mmol) and the resulting mixture was stirred at rt. After 1 .5 h, the mixture was filtered and the filter cake was dried under reduced pressure to afford 4-(azetidin-1-yl)-6- chloropyrido[3,2-c(]pyrimidine (200 mg, 73%). As a white solid. MS (ESI): Mass calcd. for C10H9CIN4, 220.1 ; m/z found, 221 .1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD3OD) 5 8.34 (s, 1 H), 7.97 (d, J = 8.8 Hz, 1 H), 7.69 (d, J = 8.8 Hz, 1 H), 4.88 (t, J = 7.7 Hz, 2H), 4.36 (t, J = 7.7 Hz, 2H), 2.82 - 2.21 (m, 2H).

Intermediate 23: (R)-3-Hydroxy-3-(3-(3-iodophenyl)isoxazol-5-yl)-1 -methylpyrrolidin-2- one.

Step A: 3-lodobenzaldehyde oxime. To a solution of 3-iodobenzaldehyde (1 .5 g, 6.5 mmol) in EtOH (20 mL) was added NH2OH (50% in water) (0.46 mL, 7.8 mmol). The mixture was stirred at 25 °C for 16 h, then concentrated to dryness to give 3- iodobenzaldehyde oxime (1500 mg, 6.072 mmol) as a pale yellow solid, which was used in the next step without further purification. MS (ESI): Mass calcd. for CyHelNO, 247.0; m/z found, 248.1 [M+H] ⁺ .

Step B: /V-Hydroxy-3-iodobenzimidoyl chloride. /V-chlorosuccinimide (973 mg, 7.29 mmol) was added portion-wise to a solution of 3-iodobenzaldehyde oxime (1.5 g, 6.1 mmol) in dry DCM (30 mL). The reaction mixture was stirred at 25 °C for 2 h. The mixture was then concentrated to give A/-hydroxy-3-iodobenzimidoyl chloride (1450 mg, 5.151 mmol) as a pale yellow oil which was used in the next step without further purification. MS (ESI): Mass calcd. for C7H5CIINO, 280.9; m/z found, 282.3 [M+H] ⁺ .

Step C: (R)-3-Hydroxy-3-(3-(3-iodophenyl)isoxazol-5-yl)-1 -methylpyrrolidin-2- one. To a solution of ZV-hydroxy-3-iodobenzimidoyl chloride (650 mg, 2.31 mmol) in DCM (15 mL) were added (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 1 , 385 mg, 2.77 mmol) and TEA (934 mg, 9.24 mmol). The mixture was heated at 50 °C for 4 h. The mixture was then cooled to rt, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH = 20/1 , Rf =0.4) to give (R)-3-hydroxy-3-(3-(3-iodophenyl)isoxazol-5- yl)-1 -methylpyrrolidin-2-one (110 mg, 0.266 mmol) as a yellow solid. MS (ESI): Mass calcd. for C14H13IN2O3, 384.0; m/z found, 385.0 [M+H] ⁺ .

Intermediate 24: te/t-Butyl 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/- pyrrolo[2,3-b]pyridine-1 -carboxylate.

Step A: 3-lodo-1 /-/-pyrrolo[2,3-b]pyridine. To a solution of 1 /-/-pyrrolo[2,3- b]pyridine (5 g, 42.324 mmol) in MeCN (60 mL) was added /V-iodosuccinimide (11 .427 g, 50.789 mmol), portion-wise. The mixture was stirred at 25 °C for 2 h, then the solid from the reaction mixture was collected by vacuum filtration. This solid was washed with MeCN (30 mL) and the filtrate was concentrated to give 3-iodo-1 /-/-pyrrolo[2,3- b]pyridine (8.0 g, 31 mmol) as a yellow solid. MS (ESI): Mass calcd. for C7H5IN2, 244.0; m/z found, 245.1 [M+H] ⁺ .

Step B: te/t-Butyl-3-iodo-1 /-/-pyrrolo[2,3-b]pyridine-1 -carboxylate. To a solution of 3-iodo-1 H-pyrrolo[2,3-b]pyridine (8.00 g, 32.8 mmol), DMAP (0.40 g, 3.28 mmol) and TEA (13.2 g, 131 mmol) in DCM (130 mL) was added di-te/Y-butyl dicarbonate (8.58 g,

39.3 mmol) dropwise. The mixture was stirred at 25 °C for 2 h. The reaction mixture was then diluted with DCM (130 mL) and washed with saturated aqueous Na2SO3 solution (100 mL) and then with brine (120 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether/EtOAc (8/1 ) to give te/Y-butyl 3-iodo-1 /-/-pyrrolo[2,3-b]pyridine-1- carboxylate (11 .8 g) as a yellow oil. MS (ESI): Mass calcd. for C12H13IN2O2, 344.0; m/z found, 345.1 [M+H] ⁺ .

Step C: te/Y-Butyl 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrrolo[2,3- b]pyridine-1 -carboxylate. To a solution of te/Y-butyl 3-iodo-1 /-/-pyrrolo[2,3-£>]pyridine-1 - carboxylate (11 .8 g, 34.3 mmol) in 1 ,4-dioxane (50 mL) was added b/s(pinacolato)diboron (17.4 g, 68.6 mmol), PdCl2(dppf) (0.78 g, 1.03 mmol) and KOAc (10.1 g, 103 mmol). The mixture was heated at 85 °C for 16 h under an argon atmosphere. The mixture was cooled to room temperature, diluted with EtOAc (50 mL) and washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography eluting with petroleum ether/EtOAc (gradient from 20/1 to 8/1 ) to give te/Y-butyl 3-(4,4,5,5- tetramethyl-1 , 3, 2-dioxaborolan-2-yl)-1 /-/-pyrrolo[2,3-b]pyridine-1 -carboxylate (8 g, 9 mmol) as a pale yellow solid. MS (ESI): Mass calcd. for C18H25BN2O4, 344.2; m/z found,

345.3 [M+H] ⁺ .

Intermediate 25: 6-(3-Chlorophenyl)pyrido[3,2-c(]pynmidin-2-c/-4-amine.

1 ,1'-Bis(di-te/Y butylphosphino)ferrocene palladium dichloride (144 mg, 0.22 mmol) was added to a mixture of 6-chloropyrido[3,2-c/]pyrimidin-2-c/-4-amine (Intermediate 17, 400 mg, 2.20 mmol), (3-chlorophenyl)boronic acid (413 mg, 2.64 mmol), K3PO4 (1.4 g, 6.6 mmol), 1 ,4-dioxane (6.4 mL), and H2O (1.6 mL). The resultant mixture was sparged with Ar for 5 minutes and then subjected to microwave irradiation at 90 °C for 1 .5 hours. The mixture was then cooled to room temperature and concentrated to dryness under reduced pressure to give the product, which was purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 1 :1 ) to afford 6-(3- chlorophenyl)pyrido[3,2-c(]pyrimidin-2-c/-4-amine (300 mg, 51 %) as a yellow solid. MS (ESI): Mass calcd. for Ci3H ₈ CIDN ₄ 257.7 m/z found, 258.1 [M+1 ] ⁺ .

Intermediate 26: (S)-3-(3-(3-Bromophenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2- one.

The title compound was prepared using analogous conditions described in Intermediate 3 using Intermediate 2 instead of Intermediate 1 in Step C. MS (ESI): Mass calcd. for Ci4Hi ₃ BrN ₂ O3, 336.0; m/z found, 337.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) 58.01 (t, J = 1 .8 Hz, 1 H), 7.81 (td, J = 7.8, 1 .2 Hz, 1 H), 7.67 - 7.61 (m, 1 H), 7.41 (t, J = 7.9 Hz, 1 H), 6.92 - 6.89 (m, 1 H), 3.62 - 3.49 (m, 2H), 2.95 (s, 3H), 2.72 (ddd, J = 13.5, 6.8, 5.1 Hz, 1 H), 2.45 - 2.33 (m, 1 H).

Intermediate 27: (S)-3-Hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one.

The title compound was prepared in a manner analogous to (R)-3-(3-(3- bromophenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (Steps A-C) using (S)-3- ethynyl-3-hydroxy-1 -methylpyrrolidin-2-one in Step C and the borylation reaction was analogous to (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. MS (ESI): Mass calcd. for C20H25BN2O5, 384.2; m/z found, 385.2 [M+H] ⁺ .

Intermediate 28: (R)-3-Hydroxy-1 -methyl-3-(3-(3-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one.

Step A: 3-Bromo-5-methylbenzaldehyde oxime. To a solution of 3-bromo-5- methylbenzaldehyde (2 g, 10.05 mmol) in EtOH (20 mL) was added NH2OH (50% in water) (0.71 mL, 12.06 mmol). The mixture was stirred at 25 °C for 16 h and concentrated under reduced pressure to afford 3-bromo-5-methylbenzaldehyde oxime (2.1 g, 97%) as a white solid. MS (ESI): Mass calcd. for CsH8BrNO, 214.1 ; m/z found, 214.1 [M+H] ⁺ .

Step B: 3-Bromo-/V-hydroxy-5-methylbenzimidoyl chloride. To a solution of 3- bromo-5-methylbenzaldehyde oxime (600 mg, 2.80 mmol) in anhydrous DCM (20 mL) was added /V-chlorosuccinimide (450 mg, 3.36 mmol) portion wise. The reaction mixture was stirred at 25 °C for 2 h, filtered, and the filtrate was concentrated under reduced pressure to afford 3-bromo-/V-hydroxy-5-methylbenzimidoyl chloride (0.6 g, 86%) as a yellow solid. MS (ESI): Mass calcd. for CsH7BrCINO, 248.5; m/z found, 249.1 [M+H] ⁺ .

Step C: (R)-3-(3-(3-Bromo-5-methylphenyl)isoxazol-5-yl)-3-hydroxy-1 - methylpyrrolidin-2-one. A solution of (R)-3-ethynyl-3-hydroxy-1 -methylpyrrolidin-2-one (Intermediate 1 , 336 mg, 2.41 mmol), 3-bromo-/V-hydroxy-5-methylbenzimidoyl chloride (600 mg, 2.41 mmol), and TEA (0.99 mL, 7.24 mmol) in DCM (20 mL) was stirred at 25 °C for 16 h. The reaction mixture was diluted with DCM (80 mL), washed with brine (60 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (DCM/MeOH=20/1 ) to afford (R)-3-(3-(3-bromo-5-methylphenyl)isoxazol-5- yl)-3-hydroxy-1 -methylpyrrolidin-2-one (0.3 g, 35%) as a yellow oil. MS (ESI): Mass calcd. for CisHisBrtoOs, 351 .2; m/z found, 351 .0 [M+H] ⁺ .

Step D: (R)-3-Hydroxy-1-methyl-3-(3-(3-methyl-5-(4,4,5,5-tetramethyl -1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. A mixture of bis(pinacolato)diboron (398 mg, 1.57 mmol), (R)-3-(3-(3-bromo-5- methylphenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-o ne (275 mg, 0.78 mmol) Pd(dppf)Cl2 CH ₂ Cl2 (59.6 mg, 0.078 mmol), KOAc (230.5 mg, 2.35 mmol) and 1 ,4- dioxane (8 mL) was heated at 80°C for 2h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by FCC (DCM/MeOH=60/1) to afford (R)-3-hydroxy-1-methyl-3-(3-(3-methyl-5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (0.3 g, 96%) as a yellow solid. MS (ESI): Mass calcd. for C ₂ I H ₂ 7BN ₂ O5, 398.3; m/z found, 399.3 [M+H] ⁺ .

Intermediate 29: (R)-3-hydroxy-1 -methyl-3-(3-(2-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one.

The title compound was prepared in a manner analogous to (R)-3-hydroxy-1 - methyl-3-(3-(3-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5- yl)pyrrolidin-2-one Steps A-D using 5-bromo-2-methylbenzaldehyde in place of 3- bromo-5-methylbenzaldehyde in Step A. MS (ESI): Mass calcd. for C ₂ I H ₂ 7BN ₂ O5, 398.3; m/z found, 399 [M+H] ⁺ .

Intermediate 30: (R)-3-Hydroxy-1-methyl-3-(3-(4-methyl-3-(4,4,5,5-tetramethyl -1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one

The title compound was prepared in a manner analogous to (R)-3-hydroxy-1 - methyl-3-(3-(3-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5- yl)pyrrolidin-2-one Steps A-D using 3-bromo-4-methylbenzaldehyde in place of 3- bromo-5-methylbenzaldehyde in Step A. MS (ESI): Mass calcd. for C21 H27BN2O5, 398.3; m/z found, 399 [M+H] ⁺ .

Intermediate 31 : (R)-3-Hydroxy-3-(3-(3-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-5-yl)-1 -methylpyrrolidin-2-one.

The title compound was prepared in a manner analogous to (R)-3-hydroxy-1 - methyl-3-(3-(3-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5- yl)pyrrolidin-2-one Steps A-D using 3-bromo-5-methoxybenzaldehyde in place of 3- bromo-5-methylbenzaldehyde in Step A. MS (ESI): Mass calcd. for C21 H27BN2O6, 414.2; m/z found, 415.2 [M+H] ⁺ .

Intermediate 32: (R)-3-Hydroxy-1 -methyl-3-(3-(5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)furan-2-yl)isoxazol-5-yl)pyrrolidin-2-one.

The title compound was prepared in a manner analogous to (R)-3-hydroxy-1 - methyl-3-(3-(3-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5- yl)pyrrolidin-2-one Steps A-D using 5-bromofuran-2-carbaldehyde in place of 3-bromo- 5-methylbenzaldehyde in Step A. MS (ESI): Mass calcd. for C18H23BN2O6, 374.2; m/z found, 293 [M - C ₆ HI ₂ ] ⁺ .

Intermediate 33: (R)-3-(3-(5-(6-Chloropyridin-2-yl)furan-2-yl)isoxazol-5-yl)- 3-hydroxy-1 - methylpyrrolidin-2-one.

Step A: 5-(6-Chloropyridin-2-yl)furan-2-carbaldehyde. To a solution of 2-chloro-6- (furan-2-yl)pyridine (1.8 g, 10 mmol) in THF (40 mL) was added LDA (2 N, 6 mL, 12 mmol) and the reaction mixture was stirred at -78 °C for 1 h. A solution of DMF (1 .5 g, 20 mmol) in THF (5 mL) was added dropwise and the reaction was stirred at -78 °C for 2 h and then diluted with water (50 mL). The mixture was allowed to warm to rt and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over Na2SO4 and filtered. The filtrate was concentrated to dryness and then stirred with petroleum ether (50 mL) and EtOAc (5 mL) for 10 min. The solid was isolated by filtration to afford 5-(6-chloropyridin-2-yl)furan-2-carbaldehyde (1.5 g, 72.0%) as a yellow solid. MS (ESI): Mass calcd. for C10H6CINO2, 207.6; m/z found, 208 [M+H] ⁺ .

Step B: 5-(6-Chloropyridin-2-yl)furan-2-carbaldehyde oxime. To a solution of 5- (6-chloropyridin-2-yl)furan-2-carbaldehyde (1.3 g, 6.26 mmol) in EtOH (100 mL) was added hydroxylamine (50% in water, 827 mg, 12.52 mmol). The mixture was stirred at 25 °C for 6 h and then concentrated to afford 5-(6-chloropyridin-2-yl)furan-2- carbaldehyde oxime (1.3 g, 93%) as a yellow solid. MS (ESI): Mass calcd. for C10H7CIN2O2, 222.6; m/z found, 223.1 [M+H] ⁺ .

Step C: 5-(6-Chloropyridin-2-yl)-N-hydroxyfuran-2-carbimidoyl chloride. To a solution of 5-(6-chloropyridin-2-yl)furan-2-carbaldehyde oxime (500 mg, 2 mmol)) in dry DMF (8 mL) was added N-chlorosuccinimide (360 mg, 2.7 mmol) portion wise and the reaction was stirred at 30 °C for 4 hr. The reaction mixture was concentrated to dryness to afford 5-(6-chloropyridin-2-yl)-N-hydroxyfuran-2-carbimidoyl chloride (550 mg, 95%) as a yellow solid which was used in the next step without further purification. MS (ESI): Mass calcd. for C10H6CI2N2O2, 257.1 ; m/z found, 257 [M+H] ⁺ .

Step D: (R)-3-(3-(5-(6-Chloropyridin-2-yl)furan-2-yl)isoxazol-5-yl)- 3-hydroxy-1 - methylpyrrolidin-2-one. To a solution of 5-(6-chloropyridin-2-yl)-N-hydroxyfuran-2- carbimidoyl chloride (550 mg, 2.14 mmol) in DCM (30 mL) were added (R)-3-ethynyl-3- hydroxy-1-methylpyrrolidin-2-one (Intermediate 1 , 298 mg, 2.14 mmol) and TEA (648 mg, 6.42 mmol). The mixture was stirred at 25 °C for 16 h. The mixture was washed with brine (2 x 50 mL), dried with Na2SO4 and filtered. The filtrate was concentrated and the residue was purified by Prep-TLC (UV-254, silica, DCM:MeOH / 20: 1 ) to afford (R)-3-(3-(5-(6-chloropyridin-2-yl)furan-2-yl)isoxazol-5-yl)- 3-hydroxy-1-methylpyrrolidin-2- one (110 mg, 14%) as a brown oil. MS (ESI): Mass calcd. for C17H14CIN3O4, 359.8; m/z found, 360 [M+H] ⁺ .

Intermediate 34: (R, S,)-3-(3-(2-Bromopyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1 - methylpyrrolidin-2-one.

The title compound (Step A: 700 mg, 30%; Step B: 1 .4 g, 69%) was prepared using analogous conditions described in (R)-3-hydroxy-1-methyl-3-(5-(3-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one Steps A-B using (R _; S)-3-ethynyl-3-hydroxy-1 -methylpyrrolidin-2-one in place of (R)-3-ethynyl-3- hydroxy-1-methylpyrrolidin-2-one in Step A. MS (ESI): Mass calcd. for Ci4Hi3BrN2O3, 337.2; m/z found, 337 [M+H] ⁺ .

Intermediate 35: (R,S,)-3-(5-(3-Aminophenyl)isoxazol-3-yl)-3-hydroxy-1 -rnethylpyrrolidin-

2-one.

Step A: (R _; S _> )-3-(5-(3-((Diphenylmethylene)amino)phenyl)isoxazol-3- yl)-3- hydroxy-1-methylpyrrolidin-2-one. A solution of (R,S,)-3-(3-(2-bromopyridin-4-yl)isoxazol- 5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (Intermediate 34, 260 mg, 0.77 mmol), diphenylmethanimine (210 mg, 0.16 mmol), cesium carbonate (502 mg, 1.54 mmol), BINAP (72 mg, 0.12 mmol) and palladium^ I) acetate (17 mg, 0.12 mmol) in dioxane (8 mL) was heated to 100 °C for 16 h. The reaction mixture was cooled to rt, concentrated to dryness and purified by FCC (DCM:MeOH, 20:1 ) to afford (R,S _> )-3-(5-(3- ((diphenylmethylene)amino)phenyl)isoxazol-3-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (200 mg, 59% yield) as a yellow oil. MS (ESI): Mass calcd. for C27H23N3O3, 437.5; m/z found, 438 [M+H] ⁺ .

Step B: (R,S,)-3-(5-(3-Aminophenyl)isoxazol-3-yl)-3-hydroxy-1-methyl pyrrolidin-2- one. A solution of (R,S,)-3-(5-(3-((diphenylmethylene)amino)phenyl)isoxazol-3-y l)-3- hydroxy-1 -methylpyrrolidin-2-one (210 mg, 0.48 mmol) in EtOH (10 mL) was treated with aq. HCI (2.7 mL, 1 M, 2.7 mmol) and the reaction was stirred at rt for 1 h. The reaction mixture was diluted with sat. aq. NaHCOs (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried (Na2SO4), filtered, concentrated and purified by prep TLC (DCM:MeOH, 15:1 ) to afford (R,S,)-3-(5-(3-aminophenyl)isoxazol- 3-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (95 mg, 72% yield) as a colorless solid. MS (ESI): Mass calcd. for C14H15N3O3, 273.1 ; m/z found, 274.2 [M+H] ⁺ . Intermediate 36: (R, S,)-(3-(3-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-5- yl)phenyl)boronic acid.

Step A: (R,S)-3-Hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one. The title compound was prepared in a manner analogous to Step C of (R)-3-hydroxy-1 -methyl-3-(5-(3-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one using (R _; S)-3- (3-(2-bromopyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (Intermediate 34) in place of (R)-3-(5-(3-bromophenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyr rolidin-2- one to afford (R _; S)-3-hydroxy-1 -methyl-3-(5-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-

2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one (200 mg, 88% yield) as a yellow solid. MS (ESI): Mass calcd. for C20H25BN2O5, 384.2; m/z found, 385.2 [M+H] ⁺ .

Step B: (R, S _> )-(3-(3-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol- 5yl)phenyl)boronic acid. The title compound was synthesized analogous to (R)-3-(5-(3- hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenylbo ronic acid using (R,S)-3- hydroxy-1 -methyl-3-(5-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-

3-yl)pyrrolidin-2-one to afford (R,S _> )-(3-(3-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-5yl)phenyl)boronic acid (40 mg, 61 % yield) as a pale yellow solid. MS (ESI): Mass calcd. for C14H15BN2O5, 302.1 ; m/z found, 303.1 [M+H] ⁺ .

Intermediate 37: (5R,8S)-2-(3-Formylphenyl)-6,7,8,9-tetrahydro-5/-/-5,8- epoxycyclohepta[d]pyrimidine-4-carboxamide. Step A: (5R,8S)-2-(3-Vinylphenyl)-6,7,8,9-tetrahydro-5/-/-5,8- epoxycyclohepta[d]pyrimidine-4-carboxamide. A mixture of (5R,8S)-2-(3-iodophenyl)- 6,7,8,9-tetrahydro-5/-/-5,8-epoxycyclohepta[c/]pynmidine-4-c arboxamide (350 mg, 0.86 mmol), potassium trifluoro(vinyl) borate (173 mg, 1.23 mmol), tetrakis(triphenylphosphine) palladium(O) (99 mg, 0.086 mmol), Na2COs (274 mg, 2.58 mmol), 1 ,4-dioxane (10 mL) and water (1 mL) was stirred under nitrogen at 85 °C for 16 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3 X 20 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The product was purified by prep-TLC (DCM/MeOH=40/1 , silica, UV=254 nm) to afford (5R,8S)-2-(3-vinylphenyl)-6,7,8,9-tetrahydro-5/-/-5,8- epoxycyclohepta[c/]pyrimidine-4-carboxamide (250 mg, 82.5 %) as a yellow solid. MS (ESI): Mass calcd. for C18H17N3O2, 307.3; m/z found, 308 [M+H] ⁺ .

Step B: (5R,8S)-2-(3-formylphenyl)-6,7,8,9-tetrahydro-5/-/-5,8- epoxycyclohepta[d]pyrimidine-4-carboxamide. To a solution of (5R,8S)-2-(3- vinylphenyl)-6,7,8,9-tetrahydro-5/-/-5,8-epoxycyclohepta[c/] pyrimidine-4-carboxamide (250 mg, 0.81 mmol) in t-BuOH (4.5 mL), THF (3.0 mL) and H2O (1 .5 mL) was added N- methylmorpholine N-oxide (114.4 mg, 0.98 mmol) followed by OsCM (10 mg, 0.041 mmol). The reaction mixture was stirred at rt for 7 h and subsequently NaHCOs (820 mg, 9.76 mmol), NalCM (557 mg, 2.60 mmol) and H2O (3 mL) were added. The mixture was stirred for 45 min and then poured into aq. sat. Na2SOs. The mixture was extracted with diethyl ether. The organic layer was dried with MgSCM, filtered and concentrated. The residue was purified by prep-TLC (DCM/MeOH=40/1 , silica, UV=254 nm) to afford (5R,8S)-2-(3-formylphenyl)-6,7,8,9-tetrahydro-5/-/-5,8-epoxy cyclohepta[c(]pyrimidine-4- carboxamide (200 mg, 80%). MS (ESI): Mass calcd. for C17H15N3O3, 309; m/z found, 309.8 [M+H] ⁺ .

Intermediate 38: 2-Chloro-7-fluoroquinazoline-4-carboxamide. Step A: 7-Fluoroquinazoline-2,4(1 H,3H)-dione. An aqueous solution of potassium nitrate (10 mL, 4.8 M, 48.3 mmol) was added dropwise to a mixture of 2-amino-4- fluorobenzoic acid (5.0 g, 32.2 mmol) in AcOH (3.5 g, 58.0 mmol) and water (20 mL). The reaction mixture was heated to 50 °C for 16 h and then NaOH (5.1 g, 129 mmol) was added portionwise. The stirring was continued at 50 °C for 4 h, then the pH was slowly adjusted to pH <1 with cone. HCI(aq). The precipitate was isolated by filtration and washed with water to afford 7-fluoroquinazoline-2,4(1 H,3H)-dione (2.8 g, 48% yield) as a yellow solid. MS (ESI): Mass ealed. for C8H5FN2O2, 180.0; m/z found, 212.1 [M+H] ⁺ .

Step B: 2,4-Dichloro-7-fluoroquinazoline. A mixture of 7-fluoroquinazoline- 2,4(1 H,3H)-dione (2.8 g, 15.5 mmol), POCI ₃ (10 mL, 107.6 mmol), and DIEA (5.36 mL, 31 .1 mmol) was heated to reflux for 4 h. The reaction mixture was concentrated in vacuo and treated with ice water. The precipitate was isolated by filtration, washed with water, and dried under reduced pressure to afford 2,4-dichloro-7-fluoroquinazoline (3.0 g, 89% yield) as a brown solid. MS (ESI): Mass ealed. for C8H3CI2FN2, 217; m/z found, 217 [M+H],

Step C: 2-Chloro-4-(1 -ethoxyvinyl)-7-fluoroquinazoline. To a solution of 2,4- dichloro-7-fluoroquinazoline (3.0 g, 13.8 mmol) in DMF (26 mL) was added tributyl(1 - ethoxyvinyl)stannane (5.0 g, 13.8 mmol), followed by dichlorobis(triphenylphosphine)palladium(ll) (0.48 g, 0.69 mmol). The reaction mixture was heated to 60 °C for 16 h, cooled to rt and quenched with KF(aq). EtOAc was added, the mixture was filtered, and the filtrate was washed with water, followed by brine. The product was purified by FCC (ether: EtOAc, 10:1 ) to afford 2-chloro-4-(1 -ethoxyvinyl)-7- fluoroquinazoline (2.2 g, 63% yield) as a yellow solid. MS (ESI): Mass ealed. for C12H10CIFN2O, 252.1 ; m/z found, 253 [M+H] ⁺ .

Step D: 2-Chloro-7-fluoroquinazoline-4-carboxylic acid. A solution of 2-chloro-4- (1-ethoxyvinyl)-7-fluoroquinazoline (2.2 g, 8.7 mmol) in dioxane (20 mL) was treated with a solution of sodium periodate (3.7 g, 17.4 mmol) in water (2 mL), followed by KMnO4 (0.69 g, 4.4 mmol) and the mixture was stirred at rt 16 h. The pH was adjusted to 7-8 with sat. aq. K2CO3, and the precipitate was removed by filtration and washed with DCM. The filtrate was washed with water and the organic layer was isolated, dried, and concentrated under reduced pressure. The product was purified by prep TLC (ether: EtOAc, 3:1 ) to afford ethyl 2-chloro-7-fluoroquinazoline-4-carboxylate (900 mg, 41 %). The pH of the aqueous layer was adjusted to pH 1 -3 with aq 2 M HCI and extracted with DCM (2 x 20 mL). The organic layer was concentrated to afford 2-chloro- 7-fluoroquinazoline-4-carboxylic acid (0.26 g, 13% yield) as a yellow solid. MS (ESI): Mass calcd. for C9H4CIFN2O2, 226; m/z found, 226 [M+H] ⁺ .

Step E: 2-Chloro-7-fluoroquinazoline-4-carboxamide. A solution of 2-chloro-7- fluoroquinazoline-4-carboxylic acid (150 mg, 0.66 mmol) in DCM (2 mL) was treated with oxalyl chloride (0.17 mL, 1.98 mmol) and DMF (0.036 mL, 0.47 mmol) at 0 °C. The solution was stirred for 0.5 h and then treated with 28% NH3 in water (0.15 mL, 2.29 mmol) and continued stirring at 0 °C for 0.5 h. The mixture was diluted with water (10 mL) and extracted with DCM (3 x 5 mL). The combined organic extracts were concentrated to afford 2-chloro-7-fluoroquinazoline-4-carboxamide (60 mg, 40% yield) as a yellow solid. MS (ESI): Mass calcd. for C9H5CIFN3O, 225.0; m/z found, 226 [M+H] ⁺ .

Intermediate 39: Ethyl 2-chloro-7-fluoroquinazoline-4-carboxylate.

The title compound was prepared in a manner analogous to Steps A-D of 2- chloro-7-fluoroquinazoline-4-carboxamide to afford ethyl 2-chloro-7-fluoroquinazoline-4- carboxylate (900 mg, 41 %). MS (ESI): Mass calcd. for C11H8CIFN2O2, 254.7; m/z found, 255 [M+H] ⁺ .

Intermediate 40: 6-(Tributylstannyl)picolinamide. To a solution of 6-bromopicolinamide (0.50 g, 2.49 mmol) in toluene (10 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.14 g, 0.12 mmol) followed by bis(tributyltin) (2.89 g, 4.96 mmol) and the mixture was heated at 100 °C for 16 h. The reaction mixture was cooled to rt, concentrated to dryness and purified by prep-TLC (DCM:EtOAC 4:1 ) to afford 6-(tributylstannyl)picolinamide (0.80 g, 78% yield) as a colorless oil. MS (ESI): Mass calcd. for CisH32N2OSn, 412.2; m/z found, 413 [M+H] ⁺ .

Intermediate 41 : 3-Amino-6-(tributylstannyl)picolinamide.

The title compound was synthesized using analogous conditions to 6- (tributylstannyl)picolinamide using 3-amino-6-bromopicolinamide in place of 6- bromopicolinamide to afford 3-amino-6-(tributylstannyl)picolinamide (0.11 g, 46% yield) as a colorless oil. MS (ESI): Mass calcd. for CwHssNsOSn, 427.2; m/z found, 427.0 [M+H] ⁺ .

Intermediate 42: (R)-3-Hydroxy-1 -methyl-3-(3-(2-(tributylstannyl)pyridin-4-yl)isoxazol-5- yl)pyrrolidin-2-one.

The title compound was synthesized using analogous conditions to 6- (tributylstannyl)picolinamide using (R)-3-(3-(2-bromopyridin-4-yl)isoxazol-5-yl)-3- hydroxy-1-methylpyrrolidin-2-one (Intermediate 7) in place of 6-bromopicolinamide to afford (R)-3-hydroxy-1 -methyl-3-(3-(2-(tributylstannyl)pyridin-4-yl)isoxazol-5- yl)pyrrolidin-2-one (0.25 g, 22% yield) as a brown oil. MS (ESI): Mass calcd. for C25H ₃ 9N ₃ O3Sn, 549.2; m/z found, 550.0 [M+H] ⁺ .

Intermediate 43: (R)-3-(3-(6-bromopyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1 - methylpyrrolidin-2-one.

Step A. (E)-6-Bromopicolinaldehyde oxime. Into a 1 L 3-necked round-bottom flask was added 6-bromopyridine-2-carbaldehyde (40 g, 215 mmol), EtOH (600 mL) and NH2OH*HCI (17.93 g, 258.05 mmol) at room temperature. To the above mixture was added sodium acetate (35.28 g, 430.09 mmol) in portions at 0 °C. The resulting mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The mixture was acidified to pH=7 with saturated aqueous NaHCOs (100 mL). The resulting mixture was extracted with EtOAc (2x100 mL). The combined organic extracts were washed with brine (1x150 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to a residue. The residue was purified by trituration with hexane (80 mL). The precipitated solids were collected by filtration and washed with hexanes to afford the title compound as a white solid (39 g, 90%).

Step B. (Z)-6-Bromo-N-hydroxypicolinimidoyl chloride. Into a 2 L 4-necked roundbottom flask was added (E)-N-[(6-bromopyridin-2-yl)methylidene]hydroxylamine (39 g, 194 mmol) and DMF (1 L) at room temperature. To the above mixture was added NCS (31 .09 g, 232.8 mmol) at room temperature. The resulting mixture was stirred overnight at room temperature. Then the pH of the mixture was adjusted to pH=7 with TFA (5 L, 1 M). The resulting mixture was extracted with MTBE (2x1 L). The combined organic extracts were washed with brine (1x1 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide a residue. The residue was purified by trituration with hexanes (80 mL). The precipitated solids were collected by filtration and washed with hexane to afford the title compound as a white solid (41.2607 g, 90.19%). LC-MS (ESI): Mass calcd. for C6H ₄ BrCIN ₂ O 233.9 m/z found 235 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.89 (s, 1 H), 7.91 (d, J = 7.7, 1 .2 Hz, 1 H), 7.85 (t, J = 7.6 Hz, 1 H), 7.76 (d, J = 7.6, 1 .2 Hz, 1 H).

Step C. fR _> )-3-(3-(6-Bromopyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1 - methylpyrrolidin-2-one. To a solution of (R)-3-ethynyl-3-hydroxy-1 -methylpyrrolidin-2- one (90.0 g, 646.78 mmol, Intermediate 1 ) and (Z)-6-bromo-N-hydroxypicolinimidoyl chloride (609 g, 2.59 mol) in EtOAc (900 mL) and H2O (450 mL) was added NaHCOs (326 g, 3.88 mol, in 150 mL H2O). The mixture was stirred at 25 °C for 24 h and then filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ ethyl acetate = 1/ 0 to 0/ 1 ). The product was triturated with EtOH (4000 mL) at 25 °C for 12 hr. The above procedure was repeated 4 times. This resulting product was triturated with petroleum ether: ethyl acetate = 1 :1 (2000 mL) at 25 °C for 12 h and repeated twice to afford the title compound as a white solid (490 g, 50.4%). LC-MS (ESI): Mass calcd. for CnH^BrNsOs, 337.01 ; m/z found, 340.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.04 (d, J = 7.5 Hz, 1 H), 7.92 (t, J = 7.8 Hz, 1 H), 7.79 (d, J = 7.9 Hz, 1 H), 6.94 (s, 1 H), 6.77 (s, 1 H), 3.52 - 3.38 (m, 2H), 2.83 (s, 3H), 2.59 (ddd, J = 4.9, 7.8, 13.2 Hz, 1 H), 2.27 (ddd, J = 5.8, 7.9, 13.5 Hz, 1 H).

Intermediate 44: (R)-3-Ethynyl-4,4-difluoro-3-hydroxy-1 -methylpyrrolidin-2-one.

Step A. (3E)-1 -Methyl-3-[(1 -phenylethyl)imino]pyrrolidin-2-one. Into a 20 L 4- necked round-bottom flask was added 1 -methylpyrrolidine-2, 3-dione (346 g, 3060 mmol), MgSCM (368 g, 3060 mmol) and DCM (7 L). To this was added (+/-)-a- methylbenzylamine (389.21 g, 3211 .74 mmol) and TFA (0.2 mL). The resulting mixture was stirred overnight at 40 °C under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The solids were filtered out and washed with DCM (1x1 L). The filtrate was collected and concentrated under reduced pressure. The product was slurried with ether (1.5 L). The solids were collected by filtration to afford (3E)-1 -methyl- 3-[(1 -phenylethyl)imino]pyrrolidin-2-one (540 g) as a purple solid. ¹ H NMR (300 MHz, DMSO-cfe) δ 7.39-7.08 (m, 5H), 5.41 (d, J = 7.0 Hz, 1 H), 4.88 (t, J = 2.4 Hz, 1 H), 4.30- 4.13 (m,1 H), 3.76-3.52 (m, 2H), 2.89 (s, 3H), 1.40 (d, J = 6.8 Hz, 3H).

Step B. 4,4-Difluoro-3,3-dihydroxy-1 -methylpyrrolidin-2-one. Into a 10 L 4-necked round-bottom flask were added (3E)-1 -methyl-3-[(1 -phenylethyl)imino]pyrrolidin-2-one (540 g, 2496.71 mmol), Na2SO4 (511 g, 3600 mmol) and acetonitrile (5.4 L). To this was added Select-F (1946 g, 5493 mmol) in portions at 0 °C. The reaction mixture was stirred overnight at room temperature and then acetonitrile (5.4 L) was added. To the mixture was added HCI in 1 ,4-dioxane (4 N, 936 mL) dropwise at 0 °C. The resulting mixture was stirred for an additional 1 h at room temperature. The resulting precipitate was filtered and washed with acetonitrile (1x2 L). The filtrate was concentrated under vacuum. This filtration and concentration were repeated 2 times again. The residue was purified by DAC using a C18 column (CH3CN/H2O (0.1 % NH ₄ HCO ₃ )=1 % to 15% in 17 min) to afford 4,4-difluoro-3,3-dihydroxy-1 -methylpyrrolidin-2-one (122 g, 23.9% Steps A and B) as an off-white solid. ¹ H NMR (300 MHz, DMSO-cfe) δ 7.29 (s, 2H), 3.65 (t, J = 12.0 Hz, 2H), 2.80 (s, 3H).

Step C. (3R)-3-Ethynyl-4,4-difluoro-3-hydroxy-1 -methylpyrrolidin-2-one. Into a 5 L

4-necked round-bottom flask were added 4,4-difluoro-3,3-dihydroxy-1 -methylpyrrolidin- 2 -one (122 g, 730.04 mmol), DMF (2440 mL), K2CO3 (10.09 g, 73.00 mmol), trimethylsilylacetylene (143 g, 1460 mmol) and Cu(OAc)2 (26.52 g, 146.01 mmol) at room temperature under N2 atmosphere. The resulting mixture was stirred for overnight at 50 °C. The mixture was allowed to cool down to room temperature, quenched by the addition of MeOH (500 mL) at room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (10:1 to 1 :1 ) to afford (R,S)-3-ethynyl-4,4-difluoro-3-hydroxy-1 -methylpyrrolidin- 2-one (97 g, 75%) as a yellow solid. The (R) and (S) enantiomers of 3-ethynyl-4,4- difluoro-3-hydroxy-1-methylpyrrolidin-2-one (97 g and 6.2 g from a separate synthesis) were separated by Chiral-Prep-SFC (CHIRALPAK® IC-3 (50x4.6 mm), 80% hexanes with 0.1 % DEA : 20% EtOH) which provided as the first eluting enantiomer, (3R)-3- ethynyl-4,4-difluoro-3-hydroxy-1 -methylpyrrolidin-2-one (45.6 g, 88%), as an off-white solid. LC-MS (ESI): Mass calcd. for C7H7F2NO2 175.0 m/z found 176 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-cfe) δ 7.43 (s, 1 H), 3.84-3.80 (m, 3H), 2.82 (s, 3H).

Intermediate 45: (3R,5S)-3-ethynyl-3-hydroxy-1 -methyl-5-(trifluoromethyl)pyrrolidin-2- one.

Step A. Ethyl 4,4,4-trifluoro-3-(methylamino)butanoate. To a solution of ethyl (E)- 4,4,4-trifluorobut-2-enoate (4400 g, 26.17 mol, 3.89 L) in THF (18.0 L), was added MeNH2 (3330 g, 32.17 mol, 30% purity). The light yellow solution was stirred at 25 °C for 3 hrs. The reaction mixture was concentrated under reduced pressure to provide the product as a yellow liquid (4.64 kg, 89%) which was used in the next step without further purification. ¹ H NMR (400 MHz, chloroform-d) 84.08-4.26 (m, 2H), 3.40-3.56 (m, 1 H), 2.61-2.68 (m, 1 H), 2.51-2.55 (m, 3H), 2.41-2.50 (m, 1 H), 1.22-1.29 (m, 3H).

Step B. Ethyl 4-hydroxy-1-methyl-5-oxo-2-(trifluoromethyl)-2,5-dihydro-1 H- pyrrole-3-carboxylate. To a solution of ethyl 4,4,4-trifluoro-3-(methylamino)butanoate (2400 g, 12.05 mol) in 2-MeTHF (24000 mL) was added f-BuOK (1.35 kg, 12.05 mol) and diethyl oxalate (1 .76 kg, 12.05 mol, 1 .65 L) at 25 °C under N2 atmosphere. The reaction mixture was heated at 60 °C for 3 h under a N2 atmosphere. The reaction mixture was quenched by the addition of NH4CI (saturated aqueous, 10.0 L) at 25 °C. Then, the pH of the mixture was adjusted to pH = 2-3 with 1 M aqueous HCI (9.00 L), and the resulting mixture was extracted with EtOAc (5.00 L) twice. The combined organic extracts were washed with brine (15.0 L), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (DCM/MeOH 0% to 3%) to afford the title compound as a brown oil (4.20 kg, 16.59 mol, 68.8%). ¹ H NMR (400 MHz, chloroform-d) 84.63 (q, J = 5.0 Hz, 1 H), 4.24-4.42 (m, 4H), 3.10-3.14 (m, 3H), 1.19-1.26 (m, 2H). Step C. 1 -Methyl-5-(trifluoromethyl)pyrrolidine-2, 3-dione. A mixture of ethyl 4- hydroxy-1 -methyl-5-oxo-2-(trifluoromethyl)-2,5-dihydro-1 H-pyrrole-3-carboxylate (2000 g, 7.90 mol) in HCI (10.96 kg, 108.23 mol, 10.75 L, 36% solution) was heated at 110 °C for 16 hrs. The reaction mixture was cooled to 20 °C and extracted with isopropylacetate (5000 mL x 8). The combined organic extracts were washed with brine (10000 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with MTBE (5000 mL) at 25 °C for 3 hrs. The solid was filtered, washed with MTBE (1000 mL) and dried under high vacuum to afford the title compound as a yellow solid (1 .15 kg, 6.35 mol, 40.2%). ¹ H NMR (400 MHz, chloroform-cf) δ 4.28-4.42 (m, 1 H), 3.28 (s, 3H), 2.87-3.01 (m, 1 H), 2.71 -2.83 (m, 1 H).

Step D. 3-Hydroxy-1 -methyl-5-(trifluoromethyl)-3- ((trimethylsilyl)ethynyl)pyrrolidin-2-one. To a solution of trimethylsilylacetylene (1.21 kg, 12.3 mol, 1.71 L) in THF (5400 mL) was added dropwise, n-BuLi (2.5 M, 4.95 L) at -70 to -60 °C over 30 mins and the mixture was stirred at -70 to -60 °C for 1 hr. 1 -Methyl-5- (trifluoromethyl)pyrrolidine-2, 3-dione (1120 g, 6.18 mol) in THF (9000 mL) was added dropwise to the mixture at -70 to -60 °C over 30 mins. The black solution was stirred at -70 to -60 °C for 2 hrs. The reaction mixture was added into NH4CI (aqueous saturated, 10000 mL) drop wise at 0 °C, then the pH of the mixture was adjusted to pH = 5 with 2 M aqueous HCI (5000 mL) and the aqueous solution was extracted with EtOAc (5000 mL x 3). The combined organic extracts were washed with 5000 mL brine, dried over Na2SO4, filtered and evaporated to dryness. The title compound was obtained as a red solid (1 .50 kg, 86%) and was used without further purification. ¹ H NMR (400 MHz, chloroform-cf) δ 4.08-4.16 (m, 1 H), 2.96-3.06 (m, 3H), 2.72-2.82 (m, 1 H), 2.22-2.35 (m, 1 H), 0.08-0.21 (m, 8H).

Step E. (3R,5S)-3-Ethynyl-3-hydroxy-1 -methyl-5-(trifluoromethyl)pyrrolidin-2-one. 3-Hydroxy-1 -methyl-5-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)pyrro lidin-2-one (1500 g, 5.37 mol) was dissolved in MeOH (10.0 L), then K2CO3 (742 g, 5.37 mol) was added. The black mixture was stirred at 25 °C for 1 hr. The reaction mixture was filtered and the filter cake was washed with CH2CI2 (4000 mL) and poured into water (3000 mL). The organic phase was separated, the aqueous phase was extracted with CH2CI2 (3000 mL x 2), the combined organic extracts were washed with water (2000 mL) and brine (2000 mL), dried over Na2SO4, and concentrated to dryness under reduced pressure to afford a mixture of (3R,5S)-3-ethynyl-3-hydroxy-1 -methyl-5-(trifluoromethyl)pyrrolidin-2-one and (3S,5R)-3-ethynyl-3-hydroxy-1 -methyl-5-(trifluoromethyl)pyrrolidin-2-one This mixture was purified by column chromatography (PE: EA = 10:1 to 3:1 ) to afford a mixture of diastereomers (635 g, 55%, 97.8% purity). (3R,5S)-3-Ethynyl-3-hydroxy-1 - methyl-5-(trifluoromethyl)pyrrolidin-2-one and (3S,5R)-3-ethynyl-3-hydroxy-1 -methyl-5- (trifluoromethyl)pyrrolidin-2-one were then separated by SFC (column: DAICEL CHIRALPAK® AD (250 mm x 50 mm, 10 pm); mobile phase: [0.1 % NH3.H2O EtOH]; B%: 20% - 20%, min) to afford the title compound, (3R,5S)-3-ethynyl-3-hydroxy-1 - methyl-5-(trifluoromethyl)pyrrolidin-2-one, the first eluting peak, as a yellow solid (95.0 g, 45.7%). ¹ H NMR (400 MHz, chloroform-d) 5 3.97-4.08 (m, 1 H), 3.03 (d, J = 1.0 Hz, 3H), 2.80 (dd, J = 13.6, 7.5 Hz, 1 H), 2.62 (s, 1 H), 2.33 (dd, J = 13.7, 7.2 Hz, 1 H), 1.23- 1.28 (m, 1 H).

Intermediate 46:(R)-3-Ethynyl-3-hydroxy-1 -methylpyrrolidin-2-one-4,4,5,5-ck

Step A: 1 -Methylpyrrolidin-2-one-3,3,4,4,5,5-c/6. Into a 1000-mL, 3-necked round-bottom flask, purged and maintained with an atmosphere of nitrogen, was placed NaH (60% in mineral oil, 52 g, 1302 mmol). THF (400 mL) was added and the mixture was then cooled to 0 °C. To this was added pyrrolidin-2-one-3,3,4,4,5,5-cfe (39.5 g, 434 mmol) at 0 °C. The resulting solution was stirred at 0 °C for 20 min, then iodomethane (184 g, 1302 mmol) was added dropwise at 0 °C. The resulting solution was slowly warmed to room temperature and stirred for 3.5 hours. The resulting solution was poured into ice-water (800 mL), extracted with DCM (15 x 400 mL), the organic extracts combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford 1-methylpyrrolidin-2-one-3,3,4,4,5,5-cfe as a yellow oil (67.6 g) of LC-MS (ESI): Mass calcd. for CsHsDeNO 105.1 m/z found 106 [M+H] ⁺ .

Step B: 3-Benzoyl-1 -methylpyrrolidin-2-one-4,4,5,5-c/4. Into a 2000-mL, 3- necked round-bottom flask, purged and maintained with an atmosphere of nitrogen, was added NaH (60% in mineral oil, 26 g, 651 mmol), toluene (900 mL) and methanol (1.82 mL). To this was added a mixture solution of 1-methylpyrrolidin-2-one-3,3,4,4,5,5-c/6 (67.6 g, 434 mmol) and methyl benzoate (65 g, 477 mmol) dropwise at room temperature. The resulting solution was heated at 110 °C overnight. After this time, the reaction mixture was cooled to 0 °C and HOAc (39 g, 651 mmol) and water (24 g, 1302 mmol), were added. After 10 min water was added and the reaction mixture was extracted with 3x600 mL of DCM. The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was purified by silica gel chromatography (eluent: PE/EtOAc from 10/1 to 3/1 ). This resulted in 70.5 g (steps A and B, 78%) of 3-benzoyl-1-methylpyrrolidin-2-one-4,4,5,5-c/4as a yellow oil. LC-MS (ESI): Mass calcd. for C12H9D4NO2 207.1 m/z found 208 [M+H] ⁺ .

Step C: 3-Benzoyl-3-ethynyl-1-methylpyrrolidin-2-one-4,4,5,5-c/4. Into a 2000 mL, 4-necked round-bottom flask with a mechanical agitator, purged and maintained with an atmosphere of nitrogen, was placed 3-benzoyl-1-methylpyrrolidin-2 -one-4, 4,5,5- d4 (70.5 g, 340 mmol) and THF (dry, 1200 mL). The resulting mixture was cooled to -78 °C, and 1-((trimethylsilyl)ethynyl)-1X3-benzo[d][1 ,2]iodaoxol-3(1/-/)-one (175 g, 510 mmol) was added in one portion and the reaction mixture was stirred at -78 °C for 10 min. TBAF (1 M in THF, 510 mL, 510 mmol) was added dropwise at -78 °C. The resulting solution was stirred at -70 °C for 2 hours, and then warmed to room temperature for another 2 hours. The resulting mixture was quenched with saturated aqueous NH4CI solution, extracted with 3x600 mL of EtOAc and the organic extracts combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by silica gel chromatography (PE/EtOAc from 10/1 to 5/1) to afford 53.8 g (62%) of 3-benzoyl-3-ethynyl-1-methylpyrrolidin-2-one- 4, 4, 5, 5-d4 as a yellow oil. LC-MS (ESI): Mass calcd. for C14H9D4NO2231.1 m/z found 232 [M+H] ⁺ .

Step D: 3-Ethynyl-1 -methyl-2 -oxopyrrolidin-3-yl-4, 4, 5, 5-C/4 benzoate. Into a 5000-mL 4-necked round-bottom flask with mechanical agitator, was placed 3-benzoyl- 3-ethynyl-1-methylpyrrolidin-2-one-4,4,5,5-c/4 (53.8 g, 233 mmol), DCM (3000 mL), KHCO3 (116 g, 1165 mmol), and m-CPBA (236 g, 1165 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was then quenched with saturated aqueous NaHCOs solution, stirred for 1 hour, extracted with 2x1000 mL of DCM and the organic extracts combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was purified by silica gel chromatography (PE/EtOAc from 10/1 to 3/1 ) to provide 27 g (47%) of 3-ethynyl-1 - methyl-2-oxopyrrolidin-3-yl-4,4,5,5-c/4 benzoate as a yellow solid. LC-MS (ESI): Mass calcd. for C14H9D4NO3 247.1 m/z found 248 [M+H] ⁺ .

Step E: 3-Ethynyl-3-hydroxy-1 -methylpyrrolidin-2-one-4,4,5,5-c/4. Into a 1000- mL, 4-necked round-bottom flask, was placed 3-ethynyl-1-methyl-2-oxopyrrolidin-3-yl- 4,4,5,5-C/4 benzoate (27g, 109 mmol) and THF (270 mL) and the mixture was cooled to 0 °C. A solution of UOH-H2O (13.8 g, 327 mmol) in H2O (270 mL) at 0 °C-10 °C was added and the reaction mixture was stirred at room temperature for 5 hours. The mixture was then cooled to 0 °C, the pH was adjusted to pH=7 with 1 M aqueous HCI, and the reaction mixture was concentrated under reduced pressure. The product was purified by silica gel chromatography (DCM/MeOH from 300/1 to 100/1 ) to afford 15.1 g (87%) of 3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-c/4 as a yellow solid. LC- MS (ESI): Mass calcd. for C7H5D4NO2 143.1 m/z found 144 [M+H] ⁺ .

Step F: (7?)-3-Ethynyl-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-cU The (R) and (S) enantiomers of 3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one-4,4,5,5-c/4 were separated with SFC (Column: CHIRALPAK® IH, 3 x 25 cm, 5 pm ; Mobile Phase A:CO ₂ , Mobile Phase B:IPA (0.5% 2 M NH ₃ -MeOH); Flow rate: 100 mL/min;

Gradient: 10% B; Column Temperature: 35 °C; Back Pressure: 100 bar; 220 nm; RT1 :3.62; RT2:4.82). The first eluting peak was (S)-3-ethynyl-3-hydroxy-1 - methylpyrrolidin-2-one-4,4,5,5-c/4and the second eluting peak was (R)-3-ethynyl-3- hydroxy-1 -methylpyrrolidin-2-one-4,4,5,5-c/4. (R)-3-Ethynyl-3-hydroxy-1 -methylpyrrolidin- 2-one-4,4,5,5-c/4was then slurried with MTBE (60 mL) and the solids were filtered off and collected. The filter cake was washed with MTBE and the filtrate was concentrated to afford 6.46 g (79%) of fR)-3-ethynyl-3-hydroxy-1 -methylpyrrolidin-2-one-4,4,5,5-c/4 as white solid. LC-MS (ESI): Mass calcd. for C7H5D4NO2 143.1 m/z found 144 [M+H] ⁺ .

Intermediate 47: (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one-4,4, 5,5-c/4.

Step A. (R)-3-(3-(3-Bromophenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2- one-4,4,5,5-ck To a microwave vial containing (R)-3-ethynyl-3-hydroxy-1- methylpyrrolidin-2-one-4,4,5,5-c/4 (Intermediate 46, 250 mg, 1.75 mmol) and (Z)-3- bromo-N-hydroxybenzimidoyl chloride (409 mg, 1.75 mmol) was added DCM (11 mL) followed by EtsN (0.73 mL). The vial was sealed, and the resulting homogeneous mixture was stirred at room temperature. After ~10 min, a white suspension resulted and after 3.5 h, the reaction was judged to be complete by TLC. The contents were filtered through a pad of diatomaceous earth and rinsed with DCM. The colorless eluent was concentrated to give the product as an off-white solid. The material was redissolved in CHCh-MeOH and diatomaceous earth (3 g) was added and concentrated to dryness. The material was purified by FCC (using 100% DCM increasing to 5% MeOH-DCM) to give the title compound (405 mg, 67%) as a yellowish solid after drying. MS (ESI): Mass calcd. for Ci4Hi ₃ BrN ₂ O3 341.2 m/z found 342.2 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d) 5 7.87 (t, J = 1 .8 Hz, 1 H), 7.63 (dt, J = 7.9, 1 .3 Hz, 1 H), 7.54 (ddd, J = 8.0, 2.0, 1 .0 Hz, 1 H), 7.29 (d, J = 7.9 Hz, 1 H), 6.64 (s, 1 H), 4.25 (s, 1 H), 2.99 (s, 3H).

Step B. (R)-3-Hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one-4,4,5,5-c/4. To a microwave vial was added (R)-3-(3-(3-bromophenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyr rolidin-2-one-4,4,5,5-cf4 (400 mg, 1.17 mmol), bis(pinacolato)diboron (416.8 mg, 1.64 mmol), chloro(2- dicyclohexylphosphino-2',4',6'-triisopropyl-1 ,1'-biphenyl)[2-(2'-amino-1 ,T- biphenyl)]palladium(l I) (92.2 mg, 0.12 mmol), KOAc (460 mg, 4.69 mmol) and 1 ,4- dioxane (21 mL, degassed with nitrogen for 20 min prior to use). The vial was sealed and evacuated/purged with nitrogen and then placed in an aluminum heating mantle at 110 °C. After 2.5 h, the reaction mixture was filtered through a pad of diatomaceous earth (while still warm) and rinsed with EtOAc and THF and the effluent was concentrated to give an orange viscous oil. The material was dissolved in EtOAc and purified by FCC (using 100% hexanes increasing to 100% EtOAc) to give the titled compound as an off-white solid (223 mg, 49%). MS (ESI): Mass calcd. for C20H25BN2O5 388.3 m/z found 339.3 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d) 5 8.15 (t, J = 1.5 Hz, 1 H), 7.89 (ddt, J = 18.6, 7.4, 1 .4 Hz, 2H), 7.44 (t, J = 7.6 Hz, 1 H), 6.74 (s, 1 H), 3.72 (d, J = 12.3 Hz, 1 H), 2.99 (s, 3H), 1.36 (s, 12H).

Intermediate 48: (3R,5S)-3-Hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-5-yl)-5-(trifluoromethyl)p yrrolidin-2-one.

Step A. (3R,5S)-3-(3-(3-Bromophenyl)isoxazol-5-yl)-3-hydroxy-1 -methyl-5- (trifluoromethyl)pyrrolidin-2-one. To a 50 mL flask containing (3R,5S)-3-ethynyl-3- hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one (Intermediate 45, 500 mg, 2.41 mmol) and (Z)-3-bromo-N-hydroxybenzimidoyl chloride (566 mg, 2.41 mmol) was added DCM (15 mL) followed by EtsN (1 mL). The flask kept under nitrogen and the resulting homogeneous mixture was stirred at room temperature. After 24 h, the reaction was judged to be complete by TLC. The contents were filtered through a pad of diatomaceous earth and rinsed with DCM. The colorless eluent was concentrated to give the product as an off-white solid. The product was dissolved in CHCh-MeOH with diatomaceous earth (3 g), concentrated and purified by FCC (100% hexanes increasing to 100% EtOAc) to give the titled compound (815 mg, 83.0%) as a an off-white amorphous solid after drying. MS (ESI): Mass calcd. for CisHi2BrF3N2O3 405.2 m/z found 406.0 [M+H] ⁺ . ¹ H NMR (500 MHz, Chloroform-d) 5 7.88 (t, J = 1.8 Hz, 1 H), 7.65 (ddd, J = 7.8, 1.6, 1.0 Hz, 1 H), 7.57 (ddd, J = 8.1 , 2.0, 1.0 Hz, 1 H), 7.30 (t, J = 7.9 Hz, 1 H), 6.70 (s, 1 H), 4.35 - 4.20 (m, 1 H), 4.10 - 3.98 (m, 1 H), 3.09 (q, J = 1 .2 Hz, 3H), 3.06 - 2.93 (m, 2H), 2.48 (dd, J = 14.2, 6.8 Hz, 1 H).

Step B. (3R,5S)-3-Hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-5-yl)-5-(trifluoromethyl)p yrrolidin-2-one. To a microwave vial was added (3R,5S)-3-(3-(3-bromophenyl)isoxazol-5-yl)-3-hydroxy-1 - methyl-5-(trifluoromethyl)pyrrolidin-2-one (400 mg, 0.99 mmol), bis(pinacolato)diboron (351 mg, 1.38 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1 ,1'- biphenyl)[2-(2'-amino-1 ,1'-biphenyl)]palladium(ll) (77 mg, 0.099 mmol), KOAc (387.5 mg, 3.95 mmol) and 1 ,4-dioxane (18 mL, degassed with nitrogen for 20 min prior to use). The vial was sealed and evacuated/purged with nitrogen and then placed in an aluminum heating mantle at 110 °C. After 4 h, The reaction mixture was filtered through a pad of diatomaceous earth (while still warm) and rinsed with EtOAc and THF and the mixture was concentrated to give a brownish viscous oil. The material was dissolved in EtOAc and purified by FCC (using 100% hexanes increasing to 100% EtOAc) to give the title compound (404 mg, 90.0 %) initially as a viscous amber gum which solidifies to an amorphous solid under vacuum but was not completely pure by HPLC analysis and was used as is. MS (ESI): Mass calcd. for C21H24BF3N2O5452.2 m/z found 453.3 [M+H] ⁺ .

Intermediate 49: (R)-3-Ethynyl-3-hydroxy-1 -(methyl-c/3)pyrrolidin-2-one.

Step A: 4-((fe/t-Butoxycarbonyl)amino)-2-hydroxybutanoic acid. Into a 5 L 3- necked round-bottomed flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-amino-2-hydroxybutanoic acid (200 g, 1.67 mol) in water (1 L). This was followed by the addition of K2CO3 (695 g, 4.99 mol) in several batches at 0 °C. To this mixture was added a solution of di-te/Y-butyl dicarbonate (436 g, 2 mol) in dioxane (1 L) dropwise with stirring at 0 °C. The resulting solution was stirred for 24 h at 20-25 °C. The resulting mixture was washed with petroleum ether (1 L x 2). The combined aqueous phase was cooled to 0 °C with a water/ice bath and adjusted to pH = 4-5 with aqueous HCI (6 N). The resulting solution was extracted with ethyl acetate (1 L x 4). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to afford 4-((fe/Y-butoxycarbonyl)amino)-2- hydroxybutanoic acid (260 g, 71 %) as a yellow oil. Step B: Methyl 4-((fe/Y-butoxycarbonyl)amino)-2-hydroxybutanoate. Into a 5 L 3- necked round-bottomed flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-[[(fe/Y-butoxy)carbonyl]amino]-2-hydroxybutanoic acid (260 g, 1.19 mol) in /V,/V-dimethylformamide (2.5 L) and CS2CO3 (503 g, 1.54 mol). After 10 min, iodomethane (202 g, 1 .42 mol) was added dropwise to the mixture with stirring at rt. After 4.5 h, the mixture was poured into water/ice (2 L) and extracted with ethyl acetate (2 L x 2). The combined organic extracts were washed with brine (1 L x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. This afforded methyl 4-((fe/t-butoxycarbonyl)amino)-2-hydroxybutanoate (180 g, 65%) as a yellow oil.

Step C: Methyl 4-((fe/Y-butoxycarbonyl)amino)-2-((te/Y- butyldimethylsilyl)oxy)butanoate. Into a 5 L 3-necked round-bottomed flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 4- [[(tert-butoxy)carbonyl]amino]-2-hydroxybutanoate (180 g, 0.77 mol) in dichloromethane (1.8 L) and imidazole (108 g, 1 .54 mol). This was followed by the addition of tert- butyl(chloro)dimethylsilane (231 g, 1.53 mol) in several batches at 0 °C. The resulting solution was warmed to rt and stirred for 16 h. After which time, the mixture was poured into water/ice (1 L) and extracted with dichloromethane (1.5 L x 3). The combined organic extracts were washed with brine (1 L), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was purified by FCC (1 :10, ethyl acetate I petroleum ether) to afford methyl 4-((fe/Y-butoxycarbonyl)amino)-2-((fe/Y- butyldimethylsilyl)oxy)butanoate (200 g, 75%) as a light yellow oil.

Step D: Methyl 4-((terf-butoxycarbonyl)(methyl-c/3)amino)-2-((te/Y- butyldimethylsilyl)oxy)butanoate. Into a 1 L 3-necked round-bottomed flask, purged and maintained with an inert atmosphere of nitrogen, was placed methyl 4-[[(fe/t- butoxy)carbonyl]amino]-2-[(fe/Y-butyldimethylsilyl)oxy]butan oate (50.0 g, 144 mmol), N,N-dimethylformamide (500 mL), and CD3I (62.6 g, 432 mmol). The resulting solution was cooled to 0 °C and sodium hydride (8.60 g, 358 mmol, 60% in mineral oil) was added in several batches at 0 °C. After 2 h at 0 °C, the mixture was poured into saturated aqueous NH4CI (250 mL). The resulting mixture was extracted with ethyl acetate (500 mL x 2). The combined organic extracts were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The above procedure (Step D) was repeated 3x and afforded methyl 4-((tert- butoxycarbonyl)(methyl-c/3)amino)-2-((fe/t-butyldimethylsily l)oxy)butanoate (200 g, 95%) as a light yellow oil.

Step E: Methyl 4-((ferf-butoxycarbonyl)(methyl-c/3)amino)-2-hydroxybutanoat e. Into a 3 L 3-necked round-bottomed flask, purged and maintained with an inert atmosphere of nitrogen, was placed methyl 4-((fe/t-butoxycarbonyl)(methyl-c/3)amino)-2- ((te/Y-butyldimethylsilyl)oxy)butanoate (200 g, 549 mmol), methanol (2 L), and amine hydrofluoride (204 g, 5.51 mol). The resulting solution was heated at 50 °C. After 12 h, the resulting solution was cooled to rt, concentrated to dryness, and diluted with water (1 L). The resulting mixture was extracted with ethyl acetate (1 L x 3). The combined organic extracts were washed with brine (1 L), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. This afforded methyl 4-((tert- butoxycarbonyl)(methyl-c/3)amino)-2-hydroxybutanoate (137 g) as a light yellow oil which was used directly in the next step without further purification.

Step F: Methyl 4-((ferf-butoxycarbonyl)(methyl-c/3)amino)-2-oxobutanoate. A 3 L 3-necked round-bottomed flask, purged and maintained with an inert atmosphere of nitrogen, was charged with methyl 4-((ferf-butoxycarbonyl)(methyl-c/3)amino)-2- hydroxybutanoate (137 g, 547 mmol), dichloromethane (1.4 L), and 1 ,1 ,1- tris(acetyloxy)-1 ,1 -dihydro-1 ,2-benziodoxol-3-(1 H)-one, (Dess-Martin periodinane, 348 g, 821 mmol) at 5 °C. The resulting mixture was stirred for 3 h at rt. After which time the mixture was poured into aqueous sodium bicarbonate (2 L). The resulting solids were filtered off and filtrate was extracted with dichloromethane (1 .5 L x 3). The combined organic extracts were washed with brine (1 L), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was purified by FCC (1 :3, ethyl acetate I petroleum ether) to afford methyl 4-((fe/Y-butoxycarbonyl)(methyl- c/3)amino)-2-oxobutanoate (81 g, 60%) as a yellow oil. ¹ H NMR (300 MHz, CDCI3) 8 3.90 (s, 3H), 3.56 (t, J = 6.6 Hz, 2H), 3.08 (t, J = 6.6 Hz, 2H), 1 .48 (s, 9H).

Step G: Methyl 2-(2-((terf-butoxycarbonyl)(methyl-c/3)amino)ethyl)-2-hydrox ybut- 3-ynoate. Into a 1 L 3-necked round-bottomed flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 4-((tert- butoxycarbonyl)(methyl-c/3)amino)-2-oxobutanoate (20 g, 81 mmol) in THF (0.2 L). The solution was cooled to -78 °C, followed by dropwise addition of bromo(ethynyl)magnesium (274 mL, 138 mmol). The resulting solution was stirred at - 40 °C. After 2 h, saturated aqueous NH4CI (100 mL) was added dropwise at -70 °C. The resulting mixture was warmed slowly to rt and extracted with ethyl acetate (800 mL x 3). The combined organic extracts were washed with brine (800 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The above procedure (Step G) was repeated 3x and the combined residues afforded methyl 2-(2-((tert- butoxycarbonyl)(methyl-c/3)amino)ethyl)-2-hydroxybut-3-ynoat e (82 g) as a yellow oil.

Step H: Methyl 2-hydroxy-2-(2-((methyl-c/3)amino)ethyl)but-3-ynoate as a trifluoroacetate salt. Into a 1 L 3-necked round-bottomed flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 2-(2-((tert- butoxycarbonyl)(methyl-c/3)amino)ethyl)-2-hydroxybut-3-ynoat e (70.0 g, 255 mmol), dichloromethane (420 mL), and trifluoroacetic acid (140 mL). The resulting solution was stirred for 1 h at rt. The resulting mixture was concentrated to dryness and used directly in the next step without further purification.

Step I: (R)-3-Ethynyl-3-hydroxy-1-(methyl-c/3)pyrrolidin-2-one. Into a 1 L 3- necked round-bottomed flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 2-hydroxy-2-(2-((methyl-c/3)amino)ethyl)but-3- ynoate as a trifluoroacetate salt (70.0 g, 243 mmol), methanol (700 mL), and potassium carbonate (133 g, 964 mmol). The resulting solution was stirred for 3 h at rt. The resulting solids were filtered off and the filtrate was concentrated to dryness. The resulting residue was purified by FCC (1 :5, ethyl acetate I petroleum ether) and then recrystallized from diethyl ether (100 mL) to afford racemic 3-ethynyl-3-hydroxy-1 - (methyl-c/3)pyrrolidin-2-one (16 g, 46%) as a yellow solid. This material was further purified by preparative chiral SFC (CHIRALPAK®AS-H, 5 x 25 cm, 5 pm; mobile phase, CO2 (80%) and IPA (0.1 % DEA) (20%); Detector, UV at 25 °C = 220 nm) to afford (R)-3- ethynyl-3-hydroxy-1 -(methyl-c/3)pyrrolidin-2-one (5.4 g, 34%, >97% ee) as a brown solid and (S)-3-ethynyl-3-hydroxy-1 -(methyl-c/3)pyrrolidin-2-one (5.2 g, 33%, >97% ee) as a brown solid. Data for (R)-3-ethynyl-3-hydroxy-1 -(methyl-c/3)pyrrolidin-2-one: MS (ESI): Mass calcd. for C7H6D3NO2, 142.1 ; m/z found, 143.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD3OD) 5 3.41-3.38 (t, J = 5.2 Hz, 2H), 3.03 (s, 1 H), 2.48-2.43 (m, 1 H), 2.24-2.17 (m, 1 H). Data for (S)-3-ethynyl-3-hydroxy-1 -(methyl-d3)pyrrolidin-2-one: MS (ESI): Mass calcd. for C7H6D3NO2, 142.08; m/z found, 143.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD3OD) 5 3.41-3.38 (t, J = 5.2 Hz, 2H), 3.03 (s, 1 H), 2.48-2.43 (m, 1 H), 2.24-2.17 (m, 1 H).

Intermediate 50: (R)-3-Hydroxy-1-(methyl-c/3)-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one.

Step A. (R)-3-(3-(3-Bromophenyl)isoxazol-5-yl)-3-hydroxy-1 -(methyl- c/3)pyrrolidin-2-one. To a vial containing (R)-3-ethynyl-3-hydroxy-1-(methyl-c/3)pyrrolidin- 2-one (Intermediate 49, 500 mg, 3.52 mmol) and (Z)-3-bromo-N-hydroxybenzimidoyl chloride (800 mg, 3.41 mmol) was added DCM (22 mL) followed by EtsN (1.5 mL). The flask was sealed, and the homogeneous mixture was stirred at room temp. After 24 h, the contents were filtered through a pad of diatomaceous earth and rinsed with DCM. The mixture was concentrated to give the product as a viscous orange gum. The product was dissolved in DCM (40 mL), water (20 mL) was added and the layers were separated. The aqueous portion was back-extracted 3 times with CHCI3 (10 mL) and the combined organic extracts were dried over MgSCM, filtered and concentrated to give an orange oil which was purified by FCC (100% DCM increasing to 5% MeOH-DCM) to give the title compound (810 mg, 67%) as a hygroscopic semi-solid MS (ESI): Mass calcd. for Ci4Hi ₃ BrN ₂ O3 340.2 m/z found 341 .7 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d) 5 7.87 (t, J = 1 .8 Hz, 1 H), 7.69 - 7.47 (m, 2H), 7.27 (t, J = 7.9 Hz, 2H), 6.67 (s, 1 H), 4.66 (s, 1 H), 3.76 (s, 1 H), 3.60-3.67 (m, 1 H), 3.57 - 3.27 (m, 2H), 2.72-2.77 (m, 1 H), 2.59 - 2.38 (m, 2H), 2.25-2.33 (m,1 H).

Step B. (R)-3-Hydroxy-1-(methyl-c/3)-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. To a 50 mL flask containing (R)-3-(3-(3-bromophenyl)isoxazol-5-yl)-3-hydroxy-1-(methyl-c /3)pyrrolidin-2-one (800 mg, 2.35 mmol) was added bis(pinacolato)diboron (836 mg, 3.29 mmol), chloro(2- dicyclohexylphosphino-2',4',6'-triisopropyl-1 ,1 '-biphenyl)[2-(2'-amino-1 ,T- bipheny l)]pallad ium ( 11 ) (185 mg, 0.24 mmol ), KOAc (923 mg, 9.41 mmol) and 1 ,4- dioxane (42 mL, degassed with nitrogen for 20 min prior to use). The flask was fitted with a reflux condenser and evacuated/purged with nitrogen and then placed in an aluminum heating mantle at 105 °C. After 4.5 h, TLC (20% EtOAc-DCM) indicated the reaction was complete. The mixture was filtered through a pad of diatomaceous earth (while still warm) and rinsed with EtOAc and THF and the filtrate was concentrated to a brownish viscous oil. The material was dissolved in EtOAc and purified by FCC (100% hexanes increasing to 100% EtOAc) to give the title product (211 mg, 23 %) as an amber amorphous solid. MS (ESI): Mass calcd. for C20H25BN2O5 387.3 m/z found 388.3 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d) 5 8.15 (d, J = 1 .6 Hz, 1 H), 7.85-7.94 (m, 2H), 7.44 (t, J = 7.6 Hz, 1 H), 6.74 (s, 1 H), 3.68-3.74 (m, 1 H), 3.58-3.66 (m, 1 H), 3.42-3.47 (m, 1 H), 2.77-2.81 (m, 1 H), 2.41 -2.50 (m, 1 H), 1.36 (s, 12H).

Intermediate 51 : 4-Bromo-6-chloropicolinamide

To a 25 mL round-bottom flask containing 4-bromo-6-chloropicolinonitrile (360 mg, 1 .7 mmol) was added acetone (8.3 mL), water (2.8 mL), and K2CO3 (114 mg, 0.8 mmol). To this stirring mixture was then added urea-hydrogen peroxide (1.6 g, 16.6 mmol) and the resulting mixture was stirred at room temperature. After 90 minutes, the resulting solution was diluted with water and extracted with ethyl acetate. The resulting organic solution was then dried over MgSCM, filtered, and evaporated to dryness, to yield a white solid (320 mg, 82%) that was used without further purification. LC-MS (ESI): Mass calcd. for C6H ₄ BrCIN ₂ O 233.9 m/z found 234.9 [M+H] ⁺ .

Intermediate 52: 6-Chloro-4-(1-methyl-1 /-/-pyrazol-5-yl)picolinamide

A mixture consisting of 4-bromo-6-chloropicolinamide (100 mg, 0.43 mmol), 1- methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrazole (132 mg, 0.63 mmol), K3PO4 (276 mg, 1.27 mmol), 1 ,4-dioxane (1.1 mL), and water (0.2 mL) was subsequently evacuated and refilled with N2 for 3 times, treated with Pd(dppf)Cl2 (46 mg, 0.064 mmol), and heated at 100 °C for 3 h under N2. The reaction vessel was removed from the heating mantle and allowed to gradually cool to rt. The resulting mixture was diluted with water and extracted with ethyl acetate. The resulting organic solution was then dried over MgSCk, filtered, and evaporated to dryness. The residue was subjected to flash column chromatography, with a gradient of 0% to 10% MeOH in DCM over 15 minutes, to afford an orange oil (100 mg). MS (ESI): Mass calcd. for C10H9CIN4O 236.1 m/z, found 237.0 [M+H] ⁺ .

Intermediate 53: 6-chloro-4-(isothiazol-5-yl)picolinamide

The title compound (60 mg, 59%) was prepared with analogous conditions to those described in Intermediate 52 using 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)isothiazole in place of 1 -methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/- pyrazole. MS (ESI): Mass calcd. for C9H6CIN3OS 239.0 m/z, found 240.0 [M+H] ⁺ . Intermediate 54: 6-chloro-4-(thiazol-5-yl)picolinamide

The title compound (60 mg, 59%) was prepared with analogous conditions to those described in Intermediate 52 using 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)thiazole in place of 1 -methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/- pyrazole. MS (ESI): Mass calcd. for C9H6CIN3OS 239.0 m/z, found 239.9 [M+H] ⁺ .

Intermediate 55: (R)-4-chloro-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol- 3-yl)phenyl)picolinic acid

To a mixture of (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 10.0 g, 26.0 mmol) and methyl 4,6-dichloropicolinate (10.7 g, 52.1 mmol) in 1 ,4-dioxane (75.0 mL) and water (25.0 mL) were added K2CO3 (7.19 g, 52.1 mmol) and Pd(PPh3)4 (1 .50 g, 1 .30 mmol) and the resulting mixture was degassed and purged with N2 for 3 times, and then the mixture was heated at 90 °C for 4 hr under N2 atmosphere. The reaction mixture was diluted with water (40 mL), the pH of the mixture was adjusted to pH 3, and the mixture was extracted with ethyl acetate (50.0 mL x 3). The combined organic layers were washed with brine (50.0 mL x 1 ), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The product was triturated with ethyl acetate (15 mL) at 25 °C for 15 mins. The title compound was obtained as a white solid (8.50 g, 19.3 mmol, 74.2%). MS (ESI): Mass calcd. for C20H16CIN3O5 413.1 m/z, found 414.1 [M+H] ⁺ . Intermediate 56: Methyl (R)-4-chloro-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)picolinate

To a solution of (R)-4-chloro-6-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)picolinic acid (16.0 g, 38.7 mmol, Intermediate 55) in MeOH (35.0 mL) and THF (35.0 mL) was slowly added trimethylsilyl-diazomethane (2 M, 58.00 mL) at 0 °C under N2. The mixture was stirred slowly warming from 0-25 °C over 2 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (petroleum ether: ethyl acetate = 1 : 0 to 0: 1 ) to yield product. The product was triturated with MTBE (60 mL at 25 °C for 48 hrs). Compound was obtained as a white solid (11 .8 g, 26.3 mmol, 68.0%). MS (ESI): Mass calcd. for C21 H18CIN3O5 427.1 m/z, found 428.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.53 - 8.66 (m, 2H), 8.31 (br d, J = 7.88 Hz, 1 H), 7.99 - 8.10 (m, 2H), 7.69 (t, J = 7.75 Hz, 1 H), 7.19 (s, 1 H), 6.75 (s, 1 H), 3.95 (s, 3H), 3.38 - 3.55 (m, 2H), 2.85 (s, 3H), 2.53 - 2.64 (m, 1 H), 2.29 (ddd, J = 13.38, 7.63, 6.00 Hz, 1 H).

Intermediate 57: (R)-4-Chloro-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol- 3-yl)phenyl)picolinamide

A solution of ammonia (11 .7 mL, 2 M in MeOH) and methyl (R)-4-chloro-6-(3-(5- (3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinate (Intermediate 56, 1 g, 2.3 mmol) was stirred in a microwave at 100 °C for 80 minutes. The resulting solution was evaporated to dryness to yield a white solid (1 g) which was used as-is.

MS (ESI): Mass calcd. for C20H17CIN4O4412.1 m/z, found 413.1 [M+H] ⁺ .

Intermediate 58: 6,8-Dichloropyrido[3,2-c/]pyrimidin-4-amine.

A flask was charged with a solution of 3-amino-4,6-dichloropicolinonitrile (1 .21 g, 6.34 mmol), K3PO4 (13.6 g, 64.0 mmol), and 1 ,4-dioxane (50 mL) followed by formimidamide acetate (3.87 g, 37.1 mmol). The resulting mixture was heated at 100 °C for 16 h. The resulting mixture was cooled to rt and concentrated to dryness. The residue was diluted with H2O (50 mL) and stirred at rt for 16 h. The resulting mixture was filtered, the filter cake was washed with water (200 mL), and the solid was collected. The resulting solid was added to DCM (50 mL) and the mixture was stirred at rt for 40 min. The resulting solids were collected by filtration and dried to afford 6,8- dichloropyrido[3,2-c(]pyrimidin-4-amine (1 .35 g, 97.5%) as a white solid. MS (ESI): Mass calcd. for C7H4CI2N4, 214.0; m/z found, 215.0 [M+H] ⁺ . ¹ H NMR (500 MHz, CDCI3) 5 8.72 (s, 1 H), 7.81 (s, 1 H), 5.95 - 5.48 (m, 2H).

Intermediate 59: 6-Chloropyrido[3,2-d]pyrimidin-4-amine

Formimidamide acetate (25.0 g, 240 mmol) was added into a solution of 3- amino-6-chloropicolinonitrile (8.80 g, 57.3 mmol) and K3PO4 (78.0 g, 367 mmol) in 1 ,4- dioxane (400 mL). The reaction was heated at 100 °C for 2 h. After the reaction mixture was cooled to room temperature, the reaction mixture was concentrated to dryness in vacuo to give the product, which was poured into H2O (500 mL), and stirred at roomtemperature for 16 hours. The suspension was filtered. The filter cake was washed with H2O (100 mL) and the filtrate was poured into CHCI3 (70 mL). The mixture was heated at 50 °C for 30 min. The suspension was isolated via filtration before cooling to roomtemperature, and the filter cake was washed with CHCh (30 mL). Then the filter cake was dried in vacuo to afford the product (7.8 g, 75%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-cfe) 88.41 (s, 1 H), 8.10 (d, J = 8.8 Hz, 1 H), 8.04 - 7.90 (m, 2H), 7.84 (d, J = 8.6 Hz, 1 H).

Intermediate 60: tert-Butyl 3-((hydroxyimino)methyl)piperidine-1 -carboxylate

A mixture of fe/Y-butyl 3-formylpiperidine-1 -carboxylate (3.50 g, 16.4 mmol), hydroxylamine hydrochloride (1.71 g, 24.6 mmol) and Na2COs (2.61 g, 24.6 mmol) in EtOH (50 mL) and water (5 mL) was heated to 80 °C for 16 h. The reaction vessel was removed from the oil bath and allowed to gradually cool to room temperature. The mixture was concentrated in vacuo, diluted with water (40 mL), and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give te/Y-butyl 3-((hydroxyimino)methyl)piperidine- 1 -carboxylate as a solid (3.2 g,), which was used directly in the next step without purification. ¹ H NMR (400 MHz, CDCI3) 8 7.36 (d, J = 5.5 Hz, 1 H), 4.12 - 3.70 (m, 3H), 2.90 - 2.79 (m, 2H), 2.44 - 2.33 (m, 1 H), 1.98 - 1.76 (m, 2H), 1.46 (s, 9H). ¹ H NMR (400 MHz, MeOD) 87.26 (d, J = 5.7 Hz, 1 H), 4.01 - 3.64 (m, 3H), 3.06 - 2.87 (m, 2H), 2.34 - 2.24 (m, 1 H), 1.91 - 1.81 (m, 1 H), 1 .75 - 1 .62 (m, 2H), 1 .43 (s, 9H).

Intermediate 61 : tert-Butyl 3-(chloro(hydroxyimino)methyl)piperidine-1 -carboxylate

NCS (1 .87 g, 14.0 mmol) was added to a solution consisting of fe/t-butyl 3- ((hydroxyimino)methyl)piperidine-1 -carboxylate (Intermediate 60, 3.2 g, 14 mmol) and /V,/V-dimethylfonriamide (100 mL) and the resulting mixture was stirred for 16 h at room temperature under nitrogen. After this time, the mixture was diluted with ethyl acetate (200 mL) and washed with water (50 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was subjected to silica gel chromatography (0-30% EtOAc/petroleum ether) to afford tertbutyl 3-(chloro(hydroxyimino)methyl)piperidine-1 -carboxylate as a colorless oil (1.36 g, 29%). MS (ESI): Mass calcd. for C11H19CIN2O3 262.1 m/z found 207.1 [M-55] ⁺ .

Intermediate 62: te/t-Butyl 3-(5-((R)-3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- y l)piperid ine-1 -carboxylate

(R)-3-Ethynyl-3-hydroxy-1 -methylpyrrolidin-2-one (Intermediate 1 , 500 mg, 3.59 mmol), te/t-butyl 3-(chloro(hydroxyimino)methyl)piperidine-1 -carboxylate (Intermediate 61 , 1.3 g, 4.9 mmol), and NaHCOs (604 mg, 7.19 mmol) in EtOAc (20 mL) was stirred at room temperature for 16 h. After this time, the mixture was concentrated to dryness in vacuo. The residue was subjected to silica gel chromatography (10-100% EtOAc/petroleum ether) to afford te/Y-butyl 3-(5-((R)-3-hydroxy-1 -methyl-2-oxopyrrolidin- 3-yl)isoxazol-3-yl)piperidine-1 -carboxylate (1.32 g, 99.8%) as a white solid. MS (ESI): Mass calcd. for C18H27N3O5 365.2 m/z found 266.2 [M-99] ⁺ . Intermediate 63: (3R)-3-Hydroxy-1 -methyl-3-(3-(piperidin-3-yl)isoxazol-5-yl)pyrrolidin-2-

TFA (3.6 mL, 48 mmol) was added to a solution of tert-butyl 3-(5-((R)-3-hydroxy- 1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)piperidine-1 -carboxylate (Intermediate 62, 1 .2 g, 3.3 mmol) in DCM (36 mL) at room temperature. The resulting mixture was stirred for 2 h at room temperature. After this time, the mixture was treated with sat. aqueous NaHCOs (50 mL) to pH 8-9 and lyophilized to dryness. The residue was triturated with DCM/EtOAc/MeOH (200 mL, 10:10:1 ), filtered, and the filtrate concentrated to dryness in vacuo to afford (3R)-3-hydroxy-1-methyl-3-(3-(piperidin-3-yl)isoxazol-5-yl)p yrrolidin-2- one as a sticky solid (4 g). The product was used for next step directly without purification. MS (ESI): Mass calcd. for C13H19N3O3 265.1 m/z found 266.0 [M+1]+.

Intermediate 64: Ethyl 3-bromo-5, 6, 7, 8-tetrahydroimidazo[1 ,5-a]pyrazine-1 -carboxylate

Ethyl 5, 6, 7, 8-tetrahydroimidazo[1 ,5-a]pyrazine-1 -carboxylate hydrochloride (1.0 g, 4.3 mmol) and MeCN (10 mL) were added to a 40 mL flask, and charged with NBS (768 mg, 4.32 mmol). The resulting mixture stirred for 2 h at room temperature, quenched with sat. aq. Na2S20s (20 mL) and stirred for 15 min at room temperature. After this time, the mixture was basified with sat. aq. NaHCOs to pH = 8 and concentrated to dryness in vacuo to give a yellow solid. The yellow solid was then subjected to silica gel chromatography (0-10% MeOH/DCM) to give ethyl 3-bromo- 5, 6, 7, 8-tetrahydroimidazo[1 ,5-a]pyrazine-1 -carboxylate as a yellow solid (290 mg, 21 %). LCMS (ESI): Mass calcd. for C ₉ Hi2BrN ₃ O2273.0 m/z, found 276.0 [M+H] ⁺ . Intermediate 65: (R)-3-(3-(2-chloropyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1 - methylpyrrolidin-2-one.

(R)-3-(3-(2-Chloropyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (512 mg) was prepared in a manner analogous to Intermediate 7: (R)-3-(3-(2- Bromopyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one. using 2- chloroisonicotinaldehyde instead of 2-bromoisonicotinaldehyde. MS (ESI): Mass calcd. for C13H12CIN3O3, 293.1 ; m/z found, 293.9 [M+H] ⁺ .

Example 1 : (R)-3-(3-(3-(4-Amino-2-methylpyrido[3,2-c/]pyrimidin-6-yl)ph enyl)isoxazol-5- yl)-3-hydroxy-1 -methylpyrrolidin-2-one.

To a solution of (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 150 mg, 0.39 mmol) in 1 ,4-dioxane (8 mL) and H2O (1 mL) was added 6-chloro-2-methylpyrido[3,2- d]pyrimidin-4-amine (Intermediate 16, 152 mg, 0.780 mmol), followed by bis(tri-tert- butylphosphine)palladium(O) (20 mg, 0.04 mmol) and KF (68 mg, 1.2 mmol). The mixture was heated at 85 °C for 3 h, under a N2 atmosphere, cooled to rt and then concentrated. The resulting residue was purified by reverse phase HPLC using an HPLC column, such as an Xtimate C18 10 pm, 21 .2 x 250 mm column using a 5% to 38% gradient of CH3CN/H2O (10 mM NH4HCO3 and 0.025% NH ₄ OH) to afford (R)-3-(3- (3-(4-amino-2-methylpyrido[3,2-c/]pyrimidin-6-yl)phenyl)isox azol-5-yl)-3-hydroxy-1 - methylpyrrolidin-2-one (5.9 mg, 4%) as a white solid. MS (ESI): Mass calcd. for C22H20N6O3, 416.4; m/z found, 417.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.75 (s, 1 H), 8.52 - 8.56 (m, 2H), 8.30 (s, 1 H), 8.13 (s, 1 H), 8.08 (d, J = 8.0 Hz, 1 H), 8.01 (d, J = 8.0 Hz, 1 H), 7.93 (s, 1 H), 7.67 (t, J = 7.6 Hz, 1 H), 7.32 (s, 1 H), 3.41 - 3.53 (m, 2H), 2.85 (s, 3H), 2.55 - 2.61 (m, 1 H), 2.47 (s, 3H), 2.26 -2.33 (m, 1 H).

Example 2: (R)-3-(3-(3-(4-Aminopyrido[3,2-d]pyrimidin-6-yl-2-c/)phenyl) isoxazol-5-yl)-3- hydroxy-1 -methylpyrrolidin-2-one.

To a solution of (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 15 mg, 0.39 mmol) in 1 ,2-dioxane (2 mL) and H2O (0.2 mL) was added 6-chloropyrido[3,2- d]pyrimidin-2-c/-4-amine (Intermediate 17, 71 mg, 0.39 mmol), followed by bis(tri-tert- butylphosphine)palladium(O) (20 mg, 0.04 mmol) and K3PO4 (249 mg, 1.17 mmol). The mixture was heated at 90 °C for 16 h under a N2 atmosphere, cooled to rt, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC using an HPLC column, such as an Xtimate 10 pm, 150 A, 21.2 x 250 mm column using a 20 to 35% gradient of CH3CN/ H2O (10 mM NH4HCO3 and 0.025% NH4OH) to afford (R)-3-(3-(3-(4-aminopyrido[3,2-d]pyrimidin-6-yl-2-c/)phenyl) isoxazol-5- yl)-3-hydroxy-1 -methylpyrrolidin-2-one (28 mg, 18%) as a brown solid. MS (ESI): Mass calcd. for C21 H17DN6O3, 403.1 ; m/z found, 404.0 [M+H] ⁺ . ¹ HNMR (400 MHz, DMSO-d ₆ ) 5 8.78 (s, 1 H), 8.59 (d, J = 7.2 Hz, 2H), 8.28 (s, 1 H), 8.17 (d, J = 8.8 Hz, 1 H), 8.00-8.10 (m, 2H), 7.68 (t, J = 8.0 Hz, 1 H), 7.34 (s, 1 H), 6.78 (s, 1 H), 3.40-3.60 (m, 2H), 2.86 (s, 3H), 2.50-2.60 (m, 1 H), 2.20-2.40 (m, 1 H).

Example 3: (R)-3-(5-(3-(4-Amino-2-methylpyrido[3,2-c/]pyrimidin-6-yl)ph enyl)isoxazol-3- yl)-3-hydroxy-1 -methylpyrrolidin-2-one.

(R)-3-(5-(3-(4-Amino-2-methylpyrido[3,2-c/]pynmidin-6-yl) phenyl)isoxazol-3-yl)-3- hydroxy-1 -methylpyrrolidin-2 -one (57.8 mg, 53%) was prepared using analogous conditions to those described in Example 1 using (R)-3-hydroxy-1 -methyl-3-(5-(3- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one (Intermediate 5) in place of (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. MS (ESI): Mass calcd. for C22H20N6O3, 416.4; m/z found, 417.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.83 (s, 1 H), 8.53-8.56 (m, 2H), 8.17 (s, 1 H), 8.08 (d, J = 8.8 Hz, 1 H), 7.94-7.97 (m, 2H), 7.69 (t, J = 8.0 Hz, 1 H), 7.39 (s, 1 H), 6.52 (s, 1 H), 3.37-3.49 (m, 2H), 2.85 (s, 3H), 2.63-2.71 (m, 1 H), 2.47 (s, 3H), 2.22-2.29 (m, 1 H).

Example 4: (R)-3-(3-(3-(3-Amino-1 /-/-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)-3- hydroxy-1 -methylpyrrolidin-2 -one.

Step A: (R)-3-Hydroxy-1 -methyl-3-(3-(3-(3-nitro-1 /-/-pyrazolo[4,3-b]pyridin-5- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. To a solution of (R)-3-hydroxy-1 -methyl-3-(3- (3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 50 mg, 0.1 mmol) in dioxane (2 mL) and DMF (1 mL) was added 5- chloro-3-nitro-1 /-/-pyrazolo[4,3-b]pyridine (26 mg, 0.13 mmol), followed by Pd(f-BusP)2 (7.0 mg, 0.013 mmol) and K3PO4 (83 mg, 0.39 mmol). The mixture was heated at 95 °C for 16 h under a N2 atmosphere, then cooled to rt and diluted with water (20 mL). The resulting aqueous mixture was extracted with DCM (4 x 15 mL). The combined organic solvent extracts were concentrated and purified using preparative TLC (DCM/MeOH = 20/1 ) to afford (R)-3-hydroxy-1 -methyl-3-(3-(3-(3-nitro-1/-/-pyrazolo[4,3-b]pyridin-5- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (8 mg, 15%) as a brown solid. MS (ESI): Mass calcd. for C20H16N6O5, 420.4; m/z found, 421.0 [M+H] ⁺ .

Step B: (R)-3-(3-(3-(3-Amino-1 /-/-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)- 3-hydroxy-1 -methylpyrrolidin-2-one. To a solution of (R)-3-hydroxy-1 -methyl-3-(3-(3-(3- nitro-1 /-/-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)pyrroli din-2-one (15 mg, 0.036 mmol) in ethanol (2 mL) and 1 ,2-dichloroethane (1 mL) was added a porous nickel - aluminum alloy (nickel aluminide) such as Raney Ni (50 mg), followed by hydrazine hydrate (71 mg, 1 .4 mmol). The mixture was stirred at 20 °C for 1 h and then filtered and concentrated. The resulting residue was purified by reverse phase HPLC using an HPLC column, such as an Xtimate C18 10 pm, 21.2 x 250 mm column using a 5 to 35% gradient of CH3CN/H2O (10 mM NH4HCO3 and 0.025% NH ₄ OH) to afford (R)-3-(3-(3-(3- amino-1 /-/-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)-3-hydr oxy-1 -methylpyrrolidin- 2-one (5 mg, 36%) as an off-white solid. MS (ESI): Mass calcd. for C20H18N6O3, 390.4; m/z found, 391 .0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 11 .7 (s, 1 H), 8.60 (s, 1 H), 8.26 (d, J = 8.0 Hz, 1 H), 8.00 (d, J = 8.8 Hz, 1 H), 7.90 (d, J = 8.0 Hz, 1 H), 7.81 (d, J = 8.8 Hz, 1 H), 7.63 (t, J = 8.0 Hz, 1 H), 7.15 (s, 1 H), 6.74 (s, 1 H), 5.49 (s, 2H), 3.40-3.50 (m, 2H), 2.86 (s, 3H), 2.50-2.60 (m, 1 H), 2.26-2.33 (m, 1 H).

Example 5: (R)-3-(3-(3-(3-Amino-1 -methyl-1/-/-pyrazolo[4,3-b]pyridin-5- yl)phenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one.

Step A: (R)-3-Hydroxy-1 -methyl-3-(3-(3-(1 -methyl-3-nitro-1 /-/-pyrazolo[4,3- b]pyridin-5-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. To a solution of (R)-3-hydroxy-1 - methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5- yl)pyrrolidin-2-one (Intermediate 4, 271 mg, 0.710 mmol) in DMF (2 mL) and H2O (0.2 mL) was added 5-chloro-1 -methyl-3-nitro-1 /-/-pyrazolo[4,3-b]pyridine (26 mg, 0.13 mmol), followed by Pd(f-BusP)2 (36 mg, 0.071 mmol) and K3PO4 (449 mg, 2.12 mmol). The mixture was heated at 90 °C for 16 h under a N2 atmosphere. The mixture was cooled to rt, filtered and purified by reverse phase HPLC using an HPLC column, such as an Xtimate C18 10 pm, 21.2 x 250 mm column using an 18% to 35% gradient of CH3CN/H2O (10 mM NH4HCO3 and 0.025% NH ₄ OH) to yield (R)-3-hydroxy-1 -methyl- 3-(3-(3-(1 -methyl-3-nitro-1 /-/-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)pyrroli din-2- one (37 mg, 12%). MS (ESI): Mass calcd. for C21 H18N6O5, 434.4; m/z found, 435.0 [M+H] ⁺ .

Step B: (R)-3-(3-(3-(3-Amino-1 -methyl-1 /-/-pyrazolo[4,3-b]pyridin-5- yl)phenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one. A solution of (R)-3-hydroxy- 1 -methyl-3-(3-(3-(1 -methyl-3-nitro-1 /-/-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5- yl)pyrrolidin-2-one (30 mg, 0.07 mmol), saturated aqueous NH4CI solution (10 mL), and zinc dust (45 mg, 0.69 mmol) in MeOH (10 mL) was heated at 37 °C for 16 h. The reaction mixture was concentrated to dryness and purified by reverse phase HPLC using an HPLC column, such as an Xtimate C18 10 pm, 21 .2 x 250 mm column using a 5% gradient of CH3CN/H2O (10 mM NH4HCO3 and 0.025% NH4OH) for 3 min then a 27-35% gradient of CH3CN/H2O (10 mM NH4HCO3 and 0.025% NH ₄ OH) to afford (R)-3-(3-(3-(3-amino-1 -methyl-1 /-/-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5- yl)-3-hydroxy-1 -methylpyrrolidin-2-one (8.6 mg, 31 %) as a yellow solid. MS (ESI): Mass calcd. for C21 H20N6O3, 404.2; m/z found, 405.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 9.06 (s, 1 H), 8.85 (d, J = 5.2 Hz, 1 H), 8.68 (s, 1 H), 8.13 (d, J = 2.8 Hz, 1 H), 7.98 (dd, J = 1 .2, 5.2 Hz, 1 H), 7.84 (s, 1 H), 7.65 (d, J = 2.4 Hz, 1 H), 7.48 (s, 1 H), 6.83 (s, 1 H), 4.00 (s, 3H), 3.43-3.52 (m, 2H), 2.86 (s, 3H), 2.56-2.62 (m, 1 H), 2.29-2.34 (m, 1 H).

Example 6: (R)-3-(5-(3-(3-Amino-1 -methyl-1 /-/-pyrazolo[4, 3-b]pyridin-5- yl)phenyl)isoxazol-3-yl)-3-hydroxy-1 -methylpyrrolidin-2-one.

(R)-3-(5-(3-(3-Amino-1 -methyl-1 /-/-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-3- yl)-3-hydroxy-1 -methylpyrrolidin-2-one was prepared using analogous conditions as described in Example 5 using (R)-3-hydroxy-1 -methyl-3-(5-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one (Intermediate 5) in place of (R)- 3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. MS (ESI): Mass calcd. for C21 H20N6O3, 404.2; m/z found, 405.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 12.30 (s, 1 H), 8.70 (s, 1 H), 8.61 (s, 1 H), 8.55 (d, J = 2.8 Hz, 1 H), 8.42 (d, J = 8.0 Hz, 1 H), 8.34 (d, J = 2.8 Hz, 1 H), 7.73 (d, J = 8.0 Hz, 1 H), 7.57 (t, J = 8.0 Hz, 1 H), 7.07 (s, 1 H), 6.75 (s, 1 H), 3.52-3.41 (m, 2H), 2.85 (s, 3H), 2.62-2.55 (m, 1 H), 2.32-2.25 (m, 1 H).

Example 7: (R)-3-Amino-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)picolinamide.

To a solution of (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 105 mg, 0.270 mmol) in DMF (2 mL) and H2O (0.2 mL) was added 3-amino-6-bromopicolinamide (70 mg, 0.4 mmol), followed by Pd(f-Bu3P)2 (14 mg, 0.026 mmol) and K3PO4 (174 mg, 0.820 mmol). The mixture was heated at 90 °C for 16 h under a N2 atmosphere. The mixture was then cooled to rt and concentrated. The residue was purified by reverse phase HPLC using an HPLC column, such as an Xtimate 10 pm, 150 A, 21.2 x 250 mm column using a 20 to 35% gradient of CH3CN/ H2O (10 mM NH4HCO3 and 0.025% NH4OH) to afford (R)-3-amino-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol- 3-yl)phenyl)picolinamide as a brown solid (5.2 mg, 5%). MS (ESI): Mass calcd. for C20H19N5O4, 393.1 ; m/z found, 394.0 [M+H] ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.44 (s, 1 H), 8.26 (d, J = 8.0 Hz, 1 H), 8.20 (s, 1 H), 8.00 (d, J = 8.8 Hz, 1 H), 7.83 (d, J = 8.0 Hz, 1 H), 7.55 (t, J = 8.0 Hz, 1 H), 7.47 (s, 1 H), 7.26 (d, J = 8.8 Hz, 1 H), 7.22 (s, 2H), 7.04 (s, 1 H), 6.73 (s, 1 H), 3.51 -3.44 (m, 2H), 2.85 (s, 3H), 2.55-2.48 (m, 1 H), 2.35-2.25 (m, 1 H).

Example 8: (R)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-4- methoxypicolinamide.

(R)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-4- methoxypicolinamide (2 mg, 2%) was prepared using analogous conditions to those described in Example 7 using 6-chloro-4-methoxypicolinamide (Intermediate 15) in place of 3-amino-6-bromopicolinamide. MS (ESI): Mass calcd. for C21 H20N4O5, 408.1 ; m/z found, 409.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.63 (s, 1 H), 8.46 (d, J = 8.0 Hz, 1 H), 8.41 (s, 1 H), 7.99 (d, J = 8.0 Hz, 1 H), 7.83 (s, 1 H), 7.78 (s, 1 H), 7.64 (t, J = 8.0 Hz, 1 H), 7.56 (s, 1 H), 7.30 (s, 1 H), 6.77 (s, 1 H), 4.00 (s, 3H), 3.60-3.40 (m, 2H), 2.85 (s, 3H), 2.62-2.52 (m, 1 H), 2.36-2.23 (m, 1 H).

Example 9: (R,S)-3-(5-(3-(1 /-/-Pyrrolo[2,3-b]pyridin-3-yl)phenyl)isoxazol-3-yl)-3-hydro xy- 1 -methylpyrrolidin-2-one. Step A: te/t-Butyl 3-(3-(3-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-5- yl)phenyl)-1 /-/-pyrrolo[2, 3-£>]pyrid ine-1 -carboxylate. te/t-Butyl 3-(3-(3-(3-hydroxy-1 - methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)-1 /-/-pyrrolo[2,3-b]pyridine-1 -carboxylate (80 mg, 76%) was prepared using analogous conditions to those described in Example 7 using (R, S)-3-(5-(3-bromophenyl)isoxazol-3-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (Intermediate 6) in place of (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one and fe/Y-butyl 3-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrrolo[2 ,3-£>]pyrid ine-1 -carboxylate (Intermediate 24) in place of 3-amino-6-bromopicolinamide. MS (ESI): Mass calcd. for C26H26N4O5, 474.2; m/z found, 475.2 [M+H] ⁺ .

Step: B: (R,S)-3-(5-(3-(1 /-/-Pyrrolo[2,3-b]pyridin-3-yl)phenyl)isoxazol-3-yl)-3- hydroxy-1-methylpyrrolidin-2-one. A solution of fe/Y-butyl 3-(3-(3-(3-hydroxy-1-methyl-2- oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)-1 H-py rrolo[2 , 3-b]py rid ine-1 -carboxylate (80 mg, 0.17 mmol) in 4 M HCI in 1 ,4-dioxane (15 mL, 60 mmol) was stirred at rt for 16 h and then concentrated to dryness. The residue was diluted with saturated aqueous NaHCOs solution and extracted with EtOAc (2 x 15 mL). The organic solvent extracts were combined, concentrated to dryness and purified by reverse phase HPLC using an HPLC column, such as an Agela Durashell C18 10 pm, 21 .2 x 250 mm column using a 18 to 35% gradient of CH3CN/ H2O (10 mM NH4HCO3 and 0.025% NH ₄ OH) to afford (R,S)-3-(5-(3-(1 /-/-pyrrolo[2,3-b]pyridin-3-yl)phenyl)isoxazol-3-yl)-3-hydro xy-1- methylpyrrolidin-2-one (42 mg, 67%) as a white solid. MS (ESI): Mass calcd. for C21 H18N4O3, 374.1 ; m/z found, 375.2 [M+H] ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 12.05 (s, 1 H), 8.35 (d, J = 8.0 Hz, 1 H), 8.30 (d, J = 4.0 Hz, 1 H), 8.18 (s, 1 H), 8.08 (s, 1 H), 7.88 (t, J = 8.0 Hz, 1 H), 7.74 (d, J = 8.0 Hz, 1 H), 7.60 (t, J = 8.0 Hz, 1 H), 7.21 (s, 1 H), 7.19 (t, J = 4.0 Hz, 1 H), 6.50 (s, 1 H), 3.45-3.38 (m, 2H), 2.81 (s, 3H), 2.70-2.64 (m, 1 H), 2.28- 2.23 (m, 1 H).

Example 10: (R)-3-(3-(3-(8-Aminopyrido[3,4-d]pyrimidin-2-yl)phenyl)isoxa zol-5-yl)-3- hydroxy-1 -methylpyrrolidin-2-one.

Step A: (R)-3-(3-(3-(8-Chloropyrido[3,4-c/]pyrimidin-2-yl)phenyl)iso xazol-5-yl)-3- hydroxy-1-methylpyrrolidin-2-one. To a suspension of 8-chloro-2-(methylthio)pyrido[3,4- c/]pyrimidine (Intermediate 13, 90.0 mg, 0.43 mmol), (R)-(3-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)boronic acid (Intermediate 10, 154 mg, 0.51 mmol) and copper(l) thiophene-2-carboxylate (162 mg, 0.85 mmol) in THF (2 mL) was added Pd(PPh3)4 (49 mg, 0.04 mmol). The mixture was heated at 105 °C under a nitrogen atmosphere for 2 h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/MeOH = 20/1 , Rf = 0.4) to afford (R)-3-(3-(3-(8-chloropyrido[3,4-c/]pyrimidin-2-yl)phenyl)iso xazol-5-yl)-3- hydroxy-1-methylpyrrolidin-2-one (40 mg, 22%) as a yellow solid. MS (ESI): Mass calcd. for C21 H16CIN5O3, 421.1 ; m/z found, 422.1 [M+H1 ⁺ .

Step B: (R)-3-(3-(3-(8-Aminopyrido[3,4-c/]pyrimidin-2-yl)phenyl)isox azol-5-yl)-3- hydroxy-1-methylpyrrolidin-2-one. To a solution of (R)-3-(3-(3-(8-chloropyrido[3,4- c/]pyrimidin-2-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (50 mg, 0.1 mmol) in dioxane (1 mL) was added aqueous ammonium hydroxide (12 N, 5 mL, 60 mmol). The mixture was heated at 70 °C for 16 h in a sealed tube and then concentrated under reduced pressure. The residue was purified by reverse phase HPLC using an HPLC column, such as a Boston pHlex ODS 10 pm, 21 .2 x 250 mm column using a 30 to 54% gradient of CH3CN and H2O (0.1 % FA) to afford (R)-3-(3-(3- (8-aminopyrido[3,4-c(]pyrimidin-2-yl)phenyl)isoxazol-5-yl)-3 -hydroxy-1 -methylpyrrolidin- 2-one (1 mg, 2%) as a yellow solid. MS (ESI): Mass calcd. for C21 H18N6O3, 402.1 ; m/z found, 403.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD3OD) 8 9.48 (s, 1 H), 9.14-9.16 (m, 1 H), 8.78 (d, J = 8.0 Hz, 1 H), 8.03 (d, J = 8.0 Hz, 1 H), 7.96 (d, J = 5.6 Hz, 1 H), 7.70 (d, J = 8.0 Hz, 1 H), 7.10 (s, 1 H), 7.09 (d, J = 5.6 Hz, 1 H), 3.63-3.60 (m, 2H), 3.00 (s, 3H), 2.80- 2.76 (m, 1 H), 2.46-2.42 (m, 1 H). Example 11 : (R)-3-(3-(3-(4-(Azetidin-1-yl)pyrido[3,2-c/]pynmidin-6-yl)ph enyl)isoxazol-5- yl)-3-hydroxy-1 -methylpyrrolidin-2-one.

To a solution of (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 140 mg, 0.36 mmol) in DMF (3 mL) and H2O (0.3 mL) was added 4-(azetidin-1 -yl)-6-chloropyrido[3,2- d]pyrimidine (80 mg, 0.4 mmol), followed by Pd(f-Bu3P)2 (18 mg, 0.04 mmol) and K2CO3 (151 mg, 1 .09 mmol). The mixture was heated at 105 °C for 16 h under a N2 atmosphere and then cooled to rt and concentrated. The resulting compound was purified using reverse phase HPLC using an HPLC column, such as an Xtimate C18 10 pm, 21 .2 x 250 mm column using a 36 to 41 % gradient of CH3CN/H2O (10 mM NH4HCO3 and 0.025% NH ₄ OH) to afford (R)-3-(3-(3-(4-(azetidin-1-yl)pyrido[3,2- c/]pyrimidin-6-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (37 mg, 23%) as an off-white solid. MS (ESI): Mass calcd. for C24H22N6O3, 442.47; m/z found, 443.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.68 (s, 1 H), 8.56 (d, J = 8.8 Hz, 1 H), 8.45 (s, 1 H), 8.34 (d, J = 7.6, 1 H), 8.17 (d, J = 8.8 Hz, 1 H), 8.01 (d, J = 7.6, 1 H), 7.17 (t, J = 7.6, 1 H), 7.19 (s, 1 H), 6.77 (s, 1 H), 5.04 (t, J = 7.2, 2H), 4.34 (t, J = 7.2, 2H), 3.50-3.44 (m, 2H), 2.86 (s, 3H), 2.62-2.57 (m, 2H), 2.33-2.27 (m, 2H).

Example 12: (R)-3-(3-(3-(7-Aminothiazolo[5,4-d]pyrimidin-2-yl)-4-methylp henyl)isoxazol- 5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one. Step A: 3-(7-Aminothiazolo[5,4-c/]pyrimidin-2-yl)-4-methylbenzaldehy de. A mixture of 2-(5-iodo-2-methylphenyl)thiazolo[5,4-c/]pyrimidin-7-amine (Intermediate 20, 400 mg, 1 mmol), 1 ,T-bis(diphenylphosphino)ferrocene-palladium(ll)dichloride DCM complex (44 mg, 0.054 mmol), triethylsilane (379 mg, 3.26 mmol) and Na2COs (138 mg, 1 .30 mmol) in DMF (8 mL) were heated at 80 °C for 24 h under a CO atmosphere. The reaction mixture was cooled, diluted with EtOAc (20 mL) and washed with brine (3 x 10 mL). The organic solvent portion was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH=20/1 ) to afford 3-(7-aminothiazolo[5,4-c/]pyrimidin-2-yl)-4-methylbenzaldehy de (0.22 g, 75%) as a yellow solid. MS (ESI): Mass calcd. for C13H10N4OS, 270.3; m/z found, 271 .1 [M+H] ⁺ .

Step B: 3-(7-Aminothiazolo[5,4-c/]pyrimidin-2-yl)-4-methylbenzaldehy de oxime. To a solution of 3-(7-aminothiazolo[5,4-c/]pyrimidin-2-yl)-4-methylbenzaldehy de (220 mg, 0.81 mmol) in EtOH (10 mL) was added hydroxylamine (50% in water) (0.24 mL, 4.07 mmol). The mixture was stirred at 25 °C for 2 h and then concentrated to afford 3- (7-aminothiazolo[5,4-c/]pyrimidin-2-yl)-4-methylbenzaldehyde oxime (200 mg, 86%) as a white solid. MS (ESI): Mass calcd. for C13H11 N5OS, 285.3; m/z found, 286.1 [M+H] ⁺ .

Step C: 3-(7-Aminothiazolo[5,4-c/]pyrimidin-2-yl)-N-hydroxy-4-methyl benzimidoyl chloride. To a solution of 3-(7-aminothiazolo[5,4-d]pyrimidin-2-yl)-4- methylbenzaldehyde oxime (200 mg, 0.7 mmol) in DCM (10 mL) and DMF (15 mL) was added N-chlorosuccinimide (281 mg, 2.10 mmol) portion-wise. The reaction mixture was stirred at 25 °C for 5 h, then diluted with EtOAc (50 mL) and washed with brine (3 x 60 mL). The organic solvent portion was dried over Na2SO4, filtered and concentrated to afford 3-(7-aminothiazolo[5,4-d]pyrimidin-2-yl)-N-hydroxy-4-methylb enzimidoyl chloride (0.18 g, 80%) as a yellow solid. MS (ESI): Mass calcd. for C13H10CIN5OS, 319.8; m/z found, 284.1 [M-HCI] ⁺ .

Step D: (R)-3-(3-(3-(7-Aminothiazolo[5,4-d]pyrimidin-2-yl)-4- methylphenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-o ne. To a solution of 3-(7- aminothiazolo[5,4-c/]pyrimidin-2-yl)-/\/-hydroxy-4-methylben zimidoyl chloride (180 mg, 0.28 mmol) in DCM (15 mL) was added (R)-3-ethynyl-3-hydroxy-1 -methylpyrrolidin-2- one (Intermediate 1 , 39.2 mg, 0.28 mmol), followed by triethylamine (0.12 mL, 0.84 mmol). The reaction mixture was stirred at 25 °C for 16 h, diluted with DCM (30 mL) and washed with brine (20 mL). The organic solvent portion was dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase HPLC using an HPLC column, such as a Boston pHlex ODS 10 pm, 21 .2 x 250 mm column using a 20% to 60% gradient of CH3CN/H2O (0.1 % FA) to afford (R)-3-(3-(3-(7- aminothiazolo[5,4-d]pyrimidin-2-yl)-4-methylphenyl)isoxazol- 5-yl)-3-hydroxy-1 - methylpyrrolidin-2-one (1 .9 mg, 1 %) as a yellow oil. MS (ESI): Mass calcd. for C20H18N6O3S, 422.1 ; m/z found, 423.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.43 (s, 4H), 8.29 (s, 1 H), 8.20 (d, J = 1 .2 Hz, 1 H), 7.87 (dd, J = 8.0, 1 .6 Hz, 1 H), 8.51 (d, J = 8.0 Hz, 1 H), 6.96 (s, 1 H), 3.41 -3.47 (m, 2H), 2.84 (s, 3H), 2.66 (s, 3H), 2.54-2.61 (m, 1 H), 2.26-2.32 (m, 1 H).

Example 13: (R)-3-(3-(3-(7-Aminothiazolo[5,4-c/]pyrimidin-2-yl)phenyl)is oxazol-5-yl)-3- hydroxy-1 -methylpyrrolidin-2-one.

(R)-3-(3-(3-(7-Aminothiazolo[5,4-c/]pynmidin-2-yl)phenyl) isoxazol-5-yl)-3-hydroxy- 1 -methylpyrrolidin-2-one was prepared using analogous conditions to those described in Example 1 using 2-(3-iodophenyl)thiazolo[5,4-d]pyrimidin-7-amine (Intermediate 21 ) in place of 6-chloro-2-methylpyrido[3,2-c(]pyrimidin-4-amine (Intermediate 16). MS (ESI): Mass calcd. for CwHieNeOsS, 408.1 ; m/z found, 409 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-c/e) 8 8.56 (s, 1 H), 8.33 (s, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 8.08 (d, J = 8.0 Hz, 1 H), 7.85 (s, 2H), 7.74 (t, J = 8.0 Hz, 1 H), 7.15 (s, 1 H), 6.78 (s, 1 H), 3.53-3.44 (m, 2H), 2.85 (s, 3H), 2.62-2.55 (m, 1 H), 2.33-2.26 (m, 1 H).

Example 14: (R)-6-(3-(4-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 /-/-1 ,2,3-triazol-1 - yl)phenyl)picolinamide.

Step A: Methyl (R)-6-(3-(4-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 /-/-1 ,2,3- triazol-1 -yl)phenyl)picolinate. To a mixture of methyl 6-(3-iodophenyl)picolinate (64 mg, 0.19 mmol), (R)-3-ethynyl-3-hydroxy-1 -methylpyrrolidin-2-one (Intermediate 1 , 32 mg, 0.23 mmol), NaNs (13.5 mg, 0.210 mmol), Cui (7 mg, 0.04 mmol) and trans-/V, N'~ dimethyl-cyclohexane-1 ,2-diamine (5.4 mg, 0.038 mmol) in DMSO (2 mL) was added water (0.5 mL) followed by sodium ascorbate (7.5 mg, 0.038 mmol). The mixture was stirred at rt under a N2 atmosphere for 16 h, poured into water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (2 x 20 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative TLC (EA/ petroleum ether = 2/1 , Rf = 0.5) to afford methyl (R)-6-(3-(4-(3- hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 H-1 , 2, 3-triazol-1 -yl)phenyl)picolinate (70 mg, 94%) as a white solid. MS (ESI): Mass calcd. for C20H19N5O4, 393.4; m/z found, 394 [M+H] ⁺ .

Step B: (R)-6-(3-(4-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 /-/-1 ,2,3-triazol-1 - yl)phenyl)picolinamide. A mixture of methyl (R)-6-(3-(4-(3-hydroxy-1-methyl-2- oxopyrrolidin-3-yl)-1 /-/-1 ,2,3-triazol-1-yl)phenyl)picolinate (60 mg, 0.15 mmol) and ammonia in MeOH (7 N, 5 mL) was heated at 75 °C for 16 h. The solution was concentrated and purified by reverse phase HPLC using an HPLC column, such as an Xtimate 10 pm 150 A, 21.2 x 250 mm column using a 5% to 33% gradient of CH3CN/H2O (10 mM NH4HCO3 and 0.025% NH ₄ OH) to afford (R)-6-(3-(4-(3-hydroxy-1 - methyl-2-oxopyrrolidin-3-yl)-1 /-/-1 ,2,3-triazol-1 -yl)phenyl)picolinamide (19 mg, 33%) as a white solid. MS (ESI): Mass calcd. for C19H18N6O3, 378.4; m/z found, 379.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.96 (s, 1 H), 8.73 (s, 1 H), 8.52 (s, 1 H), 8.43 (d, J =7.6 Hz, 1 H), 8.37 (d, J =8.0, 1 H), 8.12 (t, J =7.6 Hz, 1 H), 8.05 (d, J =7.6 Hz, 2H), 7.80-7.70 (m, 2H), 6.28 (s, 1 H), 3.55-3.45 (m, 2H), 2.83 (s, 3H), 2.80-2.65 (m, 1 H), 2.35-2.25 (m, 1 H). Example 15: (R)-1 -(3-(4-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 H-1 , 2, 3-triazol-1 - yl)phenyl)imidazo[1 ,5-a]pyridine-3-carboxamide.

To a solution of (R)-3-hydroxy-1 -methyl-3-(1-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)-1 /-/-1 ,2,3-triazol-4-yl)pyrrolidin-2-one (Intermediate 8, 100 mg, 0.26) in DMF (10 mL) and water (1 mL) was added 1 -bromoimidazo[1 ,5-a]pyridine-3- carboxamide (62 mg, 0.26 mmol), followed by Pd(f-Bu3P)2 (13 mg, 0.026 mmol) and K3PO4 (166 mg, 0.78 mmol). The mixture was heated at 90 °C for 16 h under a nitrogen atmosphere, cooled to rt, and then concentrated under reduced pressure. The residue was purified by preparative HPLC to afford (R)-1 -(3-(4-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)-1 H-1 , 2, 3-triazol-1 -yl)phenyl)imidazo[1 ,5-a]pyridine-3-carboxamide (19.4 mg, 18%) as a yellow solid. MS (ESI): Mass calcd. for C21 H19N7O3, 417.2; m/z found, 418.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 9.51 (d, J = 7.6 Hz, 1 H), 8.79 (s, 1 H), 8.45 (t, J = 2 Hz, 1 H), 8.24 (d, J = 9.2 Hz, 1 H), 8.10 (d, J = 8.4 Hz, 2H), 7.88-7.85 (m, 1 H), 7.74-7.65 (m, 2H), 7.29-7.26 (m, 1 H), 7.09 (t, J = 6.8 Hz, 1 H), 6.28 (s, 1 H), 3.51 -3.47 (m, 2H), 2.83 (s, 3H), 2.77-2.66 (m, 1 H), 2.34-2.26 (m, 1 H).

Example 16: (R)-3-(5-(3-(4-Aminopyrido[3,2-d]pyrimidin-6-yl-2-c/)phenyl) isoxazol-3-yl)-3- hydroxy-1-methylpyrrolidin-2-one.

A mixture of 6-chloropyrido[3,2-c/]pyrimidin-2-c/-4-amine (Intermediate 17, 78 mg, 0.43 mmol), (R)-3-hydroxy-1 -methyl-3-(5-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one (Intermediate 5, 110 mg, 0.29 mmol), bis(tri-tert- butylphosphine)palladium(O) (15 mg, 0.029 mmol), K3PO4 (182 mg, 0.86 mmol), 1 ,4- dioxane (10 mL) and water (1 mL) was heated at 65 °C for 16 h under an argon atmosphere. The reaction mixture was filtered and concentrated. The residue was purified by reverse phase HPLC using an HPLC column, such as an Xtimate C18 10 pm, 21.2 x 250 mm column using a 20% to 35% gradient of CH3CN/H2O (10 mM NH4HCO3 and 0.025% NH4OH) to afford (R)-3-(5-(3-(4-aminopyrido[3,2-c/]pynmidin-6- yl-2-c/)phenyl)isoxazol-3-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (51 mg, 44%) as a white solid. MS (ESI): Mass calcd. for C21 H17DN6O3, 403.4; m/z found, 404.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-cfe) 8 8.86 (s, 1 H), 8.61 (d, J = 4.8 Hz, 1 H), 8.57 (d, J = 8 Hz, 1 H), 8.31 (s, 1 H), 8.17 (d, J = 4.8 Hz, 1 H), 8.05 (s, 1 H), 7.98 (d, J = 8 Hz, 1 H), 7.71 (t, J = 8 Hz, 1 H), 7.40 (s, 1 H), 6.53 (s, 1 H), 3.49-3.38 (m, 2H), 2.82 (s, 3H), 2.72-2.65 (m, 1 H), 2.31 -2.23 (m, 1 H).

Example 17: (R)-3-(5-(3-(3-Amino-1 /-/-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-3-yl)- 3-hydroxy-1 -methylpyrrolidin-2-one.

Step A: (R)-3-(5-(3-(3-Nitro-1 /-/-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-3-yl)- 3-hydroxy-1 -methylpyrrolidin-2-one. To a solution of (R)-3-hydroxy-1 -methyl-3-(5-(3- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one (Intermediate 5, 100 mg, 0.26 mmol) in 1 ,4-dioxane (4 mL), H2O (1 mL) and DMF (5 mL) were added 5-chloro-3-nitro-1 /-/-pyrazolo[4,3-b]pyridine (103 mg, 0.52 mmol), Pd(f- BUSP)2 (13 mg, 0.026 mmol) and K3PO4 (166 mg, 0.78 mmol). The mixture was heated at 80 °C for 16 h under an Ar atmosphere, cooled to rt, and then concentrated. The residue was purified by reverse phase HPLC using an HPLC column, such as an Xtimate C18 10 pm, 21.2 x 250 mm column using a 15% to 35% gradient of CH3CN/H2O (10 mM NH4HCO3 and 0.025% NH ₄ OH) to afford (R)-3-(5-(3-(3-nitro-1 H- pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-3-yl)-3-hydroxy- 1 -methylpyrrolidin-2-one (20 mg, 18%) as a white solid. MS (ESI): Mass calcd. for C20H16N6O5, 420.4; m/z found, 421.2 [M+H] ⁺ .

Step B: (R)-3-(5-(3-(3-Amino-1 /-/-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-3-yl)- 3-hydroxy-1 -methylpyrrolidin-2-one. To a solution of (R)-3-(5-(3-(3-nitro-1 /-/- pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-3-yl)-3-hydroxy- 1 -methylpyrrolidin-2-one (20 mg, 0.05 mmol) in saturated aqueous NH4CI solution (2 mL) and MeOH (2 mL) was added zinc dust (200 mg, 3.06 mmol). The mixture was stirred at 30 °C for 1 h, filtered and the filtrate was concentrated. The residue was purified by reverse phase HPLC using an HPLC column, such as an Xtimate C18 10 pm, 21 .2 x 250 mm column using a 5% to 40% gradient of CH3CN/H2O (10 mM NH4HCO3 and 0.025% NH4OH) to afford (R)-3-(5-(3-(3-amino-1 /-/-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-3- yl)-3-hydroxy-1 -methylpyrrolidin-2-one (1 mg, 5%) as a pale yellow solid. MS (ESI): Mass calcd. for C20H18N6O3, 390.4; m/z found, 391.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD3OD) 8 8.54 (s, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 7.95-7.88 (m, 3H), 7.66 (t, J = 8.0 Hz, 1 H), 7.07 (s, 1 H), 3.58-3.55 (m, 2H), 2.95 (s, 3H), 2.88-2.80 (m, 1 H), 2.41-2.37 (m, 1 H).

Example 18: (R)-6-(3-(3-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-5- yl)phenyl)picolinamide.

Step A: Methyl (R)-6-(3-(3-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-5- yl)phenyl)picolinate. A mixture of methyl 6-bromopicolinate (76 mg, 0.35 mmol), (R)-3- hydroxy-1 -methyl-3-(5-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol- 3-yl)pyrrolidin-2-one (Intermediate 5, 90 mg, 0.23 mmol), bis(tri-tert- butylphosphine)palladium(O) (11.9 mg, 0.02 mmol) and K3PO4 (149 mg, 0.70 mmol) in 1 ,4-dioxane (8 mL) and water (1 mL) was heated at 75 °C for 16 h under an Ar atmosphere. The reaction mixture was filtered, concentrated and the residue was purified by preparative TLC (DCM:MeOH = 20:1 ) to afford methyl (R)-6-(3-(3-(3- hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)p icolinate (87 mg, 94%) as a white solid. MS (ESI): Mass calcd. for C21 H19N3O5, 393.1 ; m/z found, 394.1 [M+H] ⁺ .

Step B: (R)-6-(3-(3-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-5- yl)phenyl)picolinamide. A solution of methyl (R)-6-(3-(3-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)picolinate (75.9 mg, 0.35 mmol) in NH3 (7 N, in EtOH, 5 mL) was heated at 75 °C for 16 h. The reaction mixture was concentrated and the residue was purified by reverse phase HPLC using an HPLC column, such as an Xtimate 10 pm, 21 .2 x 250 mm column using a 15 to 45% gradient of CH3CN/ H2O (10 mM NH4HCO3 and 0.025% NH ₄ OH) to afford (R)-6-(3-(3-(3-hydroxy-1-methyl-2- oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)picolinamide (18 mg, 23%) as a white solid. MS (ESI): Mass calcd. for C20H18N4O4, 378.1 ; m/z found, 379.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 8 8.73 (s, 1 H), 8.47 (s, 1 H), 8.45 (s, 1 H), 8.35 (d, J = 7.6 Hz, 1 H), 8.11 (t, J = 7.6 Hz, 1 H), 8.03 (d, J = 8.0 Hz, 1 H), 7.95 (d, J = 7.6 Hz, 1 H), 7.76 (s, 1 H), 7.68 (t, J = 8.0 Hz, 1 H), 7.36 (s, 1 H), 6.52 (s, 1 H), 3.49-3.37 (m, 2H), 2.82 (s, 3H), 2.71-2.65 (m, 1 H), 2.29-2.22 (m, 1 H).

Example 19: (R,S)-2-(3-(4-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)-1 /-/-imidazol-1 - yl)phenyl)quinazoline-4-carboxamide.

Step A: (R,S)-Ethyl 2-(3-(4-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 /-/- imidazol-1 -yl)phenyl)quinazoline-4-carboxylate. To a solution of (R,S)-3-hydroxy-1 - methyl-3-(1 -(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-1 /-/-imidazol-4- yl)pyrrolidin-2-one (Intermediate 9, 180 mg, 0.47 mmol) in 1 ,4-dioxane (2 mL) and H2O (0.2 mL) was added ethyl 2-chloroquinazoline-4-carboxylate (222 mg, 0.94 mmol) followed by Pd(f-BusP)2 (24.0 mg, 0.05 mmol) and KF (82 mg, 1.41 mmol). The mixture was heated at 85 °C overnight under a N2 atmosphere. The mixture was concentrated and purified using preparative TLC (DCM/MeOH=15/1 ) to afford ethyl (R,S)-2-(3-(4-(3- hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 /-/-im idazol-1 -yl)phenyl)quinazoline-4- carboxylate (150 mg, 69.8%) as a yellow solid. MS (ESI): Mass calcd. for C25H23N5O4, 457.5; m/z found, 458.0 [M+H] ⁺ .

Step B: (R,S)-2-(3-(4-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 /-/-imidazol-1 - yl)phenyl)quinazoline-4-carboxamide. A solution of (R,S)-ethyl 2-(3-(4-(3-hydroxy-1 - methyl-2-oxopyrrolidin-3-yl)-1 /-/-im idazol-1 -yl)phenyl) quinazoline-4-carboxylate (140 mg, 0.31 mmol) in NH3 in MeOH (7 N, 5 mL) was heated at 75 °C for 16 h. The reaction mixture was concentrated and the residue was purified by HPLC using an HPLC column, such as an Xtimate 10 pm 150A, 21.2 x 250 mm column using a 15 to 45% gradient of CH3CN/ H2O (10 mM NH4HCO3 and 0.025% NH ₄ OH) to afford (R,S)-2-(3-(4- (3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 H-im idazol-1 -yl)phenyl)quinazoline-4- carboxamide (40 mg, 31 %) as a white solid. MS (ESI): Mass calcd. for C23H20N6O3, 428.4; m/z found, 429.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.91 (d, J = 8.4 Hz ,1 H), 8.79 (s,2H), 8.64 (d, J = 8.4 Hz ,1 H), 8.31 (s, 1 H), 8.10-8.30 (m, 3H), 8.00-7.70 (m, 4H), 5.89 (s, 1 H), 3.50-3.30 (m, 2H), 2.80 (s, 3H), 2.70-2.50 (m, 1 H), 2.20-2.10 (m, 1 H).

Example 20: (R)-3-(3-(2-(8-Amino-3,4-dihydro-2,7-naphthyridin-2(1 H)-y l)pyrid in-4- yl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one.

To a solution of (R)-3-(3-(2-bromopyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1 - methylpyrrolidin-2-one (Intermediate 7, 560 mg, 1.66 mmol) and 5,6,7,8-tetrahydro-2,7- naphthyridin-1 -amine (247 mg, 1.66 mmol) in DMF (9 mL) was added Pd2(dba)3 (75.8 mg, 0.08 mmol), followed by BINAP (155 mg, 0.25 mmol) and f-BuONa (477 mg, 4.97 mmol). The reaction mixture was heated at 85 °C for 16 h under an Ar atmosphere, then diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic solvent extracts were concentrated to dryness and purified subsequently by preparative TLC (DCM:MeOH 10:1 ) and reverse phase HPLC to afford (R)-3-(5-(3-(8- amino-3,4-dihydro-2,7-naphthyridin-2(1 /-/)-yl)phenyl)isoxazol-3-yl)-3-hydroxy-1- methylpyrrolidin-2-on (2.5 mg, 0.4%) as a pale yellow solid. MS (ESI): Mass calcd. for C21 H22N6O3, 406.2; m/z found, 407.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.27 (d, J = 5.2 Hz, 1 H), 7.75 (d, J = 5.2 Hz, 1 H), 7.35 (s, 1 H), 7.18 (s, 1 H), 7.11 (d, J = 5.2 Hz, 1 H), 6.78 (s, 1 H), 6.41 (d, J = 5.2 Hz, 1 H), 5.92 (s, 2H), 4.31 (s, 2H), 3.94 (t, J = 5.2 Hz, 2H), 3.50-3.40 (m, 2H), 2.85 (s, 3H), 2.75 (t, J = 5.2 Hz, 2H), 2.60-2.54 (m, 1 H), 2.33- 2.25 (m, 1 H).

Example 21 : (R)-4'-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)-4- methoxy-[2,2'-bipyridine]-6-carboxamide.

Step A: 4-Methoxy-6-(tributylstannyl)picolinamide. To a solution of 6-bromo-4- methoxypicolinamide (400.0 mg, 1.730 mmol) in toluene (10 mL), was added bis(tributyltin) (2 g, 3.5 mmol), followed by Pd(Ph3P)4 (100 mg, 0.09 mmol) and the reaction mixture was heated at 90 °C for 16 h under a N2 atmosphere. A solution of saturated aqueous KF (20 mL) was added and stirring was continued at rt for 2 h. The mixture was extracted with EtOAc (3 x 20 mL), then the combined organic solvent extracts were washed with brine (3 x 20 mL) and concentrated to dryness. The residue was purified by FCC (DCM:MeOH, 20:1 ) to afford 4-methoxy-6- (tributylstannyl)picolinamide (185 mg, 18%) as a yellow solid. MS (ESI): Mass calcd. for Ci9H ₃ 4N2O ₂ Sn, 442.2; m/z found, 443.1 [M+H] ⁺ .

Step B: (R)-4'-(3-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)-4- methoxy-[2,2'-bipyridine]-6-carboxamide. A solution of 4-methoxy-6- (tributylstannyl)picolinamide (185 mg, 0.42 mmol), (R)-3-(3-(2-bromopyridin-4- yl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (Intermediate 7, 212 mg, 0.06 mmol), and Pd(PhsP)4 (48.5 mg, 0.04 mmol) in DMF (3 mL) was heated at 125 °C for 16 h under N2. The reaction mixture was cooled to rt, diluted with EtOAc (20 mL) and washed with brine (3 x 15 mL). The organic layer wasconcentrated to dryness and purified by reverse phase HPLC using an HPLC column, such an Xtimate 10 pm 150A, 21.2 x 250 mm column using a 5% to 36% gradient of CH3CN/H2O (10 mM NH4HCO3 and 0.025% NH4OH) to afford (R)-4'-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)-4-methoxy-[2,2'-bipyridine]-6-carboxamide (12 mg, 7%) as a white solid. MS (ESI): Mass calcd. for C20H19N5O5, 409.2; m/z found, 410.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 8 8.63 (s, 1 H), 8.46 (d, J = 8.0 Hz, 1 H), 8.41 (s, 1 H), 7.99 (d, J = 8.0 Hz, 1 H), 7.83 (s, 1 H), 7.78 (s, 1 H), 7.64 (t, J = 8.0 Hz, 1 H), 7.56 (s, 1 H), 7.30 (s, 1 H), 4.00 (s, 3H), 3.60-3.40 (m, 2H), 2.85 (s, 3H), 2.62-2.52 (m, 1 H), 2.36-2.23 (m, 1 H).

Example 22: (R)-1 -(4-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)pyridin- 2-yl)-1 /-/-indazole-3-carboxamide.

Step A: Methyl (R)-1 -(4-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)pyridin-2-yl)-1 /-/-indazole-3-carboxylate. To a solution of methyl 1 /-/-indazole-3- carboxylate (65 mg, 0.67 mmol) in toluene (5 mL), was added (R)-3-(3-(2-bromopyridin- 4-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 7, 124 mg, 0.37 mmol), followed by (1 S,2S)-/V^/V ² -dimethylcyclohexane-1 ,2-diamine (10.5 mg, 0.074 mmol), Cui (3.5 mg, 0.02 mmol), and K3PO4 (165 mg, 0.78 mmol). The reaction mixture was heated at 100 °C for 16 h under a N2 atmosphere, then concentrated to dryness and purified by FCC (DCM:MeOH, 20:1 ) to afford methyl (R)-1 -(4-(5-(3-hydroxy-1 - methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)pyridin-2-yl)-1 /-/-indazole-3-carboxylate (60 mg, 77%) as a yellow solid. MS (ESI): Mass calcd. for C22H19N5O5, 433.1 ; m/z found, 434.1 [M+H] ⁺ .

Step B: (R)-1 -(4-(3-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-5- yl)pyridin-2-yl)-1 /-/-indazole-3-carboxamide. A solution of methyl (R)-1 -(4-(5-(3-hydroxy- 1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)pyridin-2-yl)-1 H-indazole-3-carboxylate (60 mg, 0.14 mmol) in NH3 (7 N, in MeOH, 5 mL, 35 mmol) was heated at 75 °C for 16 h. The mixture was cooled to rt, concentrated to dryness and purified by reverse phase HPLC using an HPLC column, such as Xtimate 10 pm 150A, 21 .2 x 250 mm column using a 40 to 45% gradient of CH ₃ CN/(10 mM NH4HCO3 and 0.025% NH ₄ OH in H2O) to afford (R)-1 -(4-(5-(3-ydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)pyridin-2-yl)-1 H- indazole-3-carboxamide (33 mg, 55%) as a white solid. MS (ESI): Mass calcd. for C21 H18N6O4, 418.1 ; m/z found, 419.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.84 (d, J = 8.8 Hz, 1 H), 8.76 (d, J = 5.2 Hz, 1 H), 8.69 (s, 1 H), 8.35-8.32 (m, 2H), 7.88-7.86 (m, 1 H), 7.74 (s, 1 H), 7.65 (t, J = 7.2 Hz, 1 H), 7.46 (t, J = 7.2 Hz, 1 H), 7.30 (s, 1 H), 6.85 (s, 1 H), 3.52-3.45 (m, 2H), 2.86 (s, 3H), 2.62-2.57 (m, 1 H), 2.35-2.30 (m, 1 H).

Example 23: (R)-1 -(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)imidazo[1 ,5-a]pyridine-3-carboxamide.

To a large vial was added (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 200 mg, 0.52 mmol), 1 -bromoimidazo[1 ,5-a]pyridine-3-carboxamide (190 mg, 0.79 mmol) and Pd(PPh ₃ )4 (61 mg, 0.05 mmol). Then, a mixture of 1 ,4-dioxane (20 mL) and 2 M K2CO3 (1 .2 mL, 2.4 mmol) were degassed together with N2 for 20 min and added to the reaction mixture. The vial was sealed and evacuated/purged with nitrogen 3 times, and then placed in an aluminum heating mantle at 100 °C. After 2 h, the mixture was heated at 80 °C overnight. After 18 h, the reaction mixture was filtered through a diatomaceous earth pad (while still warm) and rinsed further with EtOAc and THF and the eluent was concentrated to give a tan viscous oil. The material was re-dissolved in CHCI3 and purified by FCC with a gradient of 0-90% EtOAc in DCM to give (R)-1 -(3-(5- (3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)imidazo[1 ,5-a]pyridine-3- carboxamide (151 mg, 70%) as an off-white fluffy solid. MS (ESI): Mass calcd. for C19H16N6O2, 417.4; m/z found, 418.1 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 8 9.48 (dt, J = 7.2, 1.1 Hz, 1 H), 8.46 - 8.32 (m, 1 H), 8.11 - 7.99 (m, 2H), 7.81 -7.77 (m, 1 H), 7.67 - 7.51 (m, 1 H), 7.21 - 7.18 (m, 1 H), 7.01 - 6.91 (m, 2H), 3.65 - 3.47 (m, 2H), 2.96 (s, 3H), 2.78-2.72 (m, 1 H), 2.43-2.37 (m, 1 H).

Example 24: (R)-3-(3-(3-(1 /-/-Pyrrolo[2,3-b]pyridin-3-yl)phenyl)isoxazol-5-yl)-3-hydro xy- 1 -methylpyrrolidin-2-one.

Step A: fe/t-Butyl (R)-3-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-1 /-/-pyrrolo[2,3-b]pyridine-1 -carboxylate. To a solution of (R)-3-hydroxy-3-(3- (3-iodophenyl)isoxazol-5-yl)-1 -methylpyrrolidin-2-one (Intermediate 23, 90 mg, 0.234 mmol) in 1 ,4-dioxane (10 mL) and water (1.5 mL) were added te/Y-butyl 3-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrrolo[2, 3-£>]pyrid ine-1 -carboxylate (Intermediate 24, 604 mg, 0.70 mmol), b/s(tri-fe/Y-butylphosphine)palladium(0) (12 mg, 0.02 mmol) and K3PO4 (149 mg, 0.70 mmol). The mixture was heated at 75 °C for 16 h, then diluted with H2O (20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic solvent extracts were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by preparative TLC (DCM/MeOH=20/1 ) to give fe/Y-butyl (R)-3-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)-1 /-/-pyrrolo[2,3-b]pyridine-1 -carboxylate (50 mg, 0.086 mmol) as a yellow solid. MS (ESI): Mass calcd. for C26H26N4O5, 474.2; m/z found, 475.2 [M+H] ⁺ .

Step B: (R)-3-(3-(3-(1 /-/-Pyrrolo[2,3-b]pyridin-3-yl)phenyl)isoxazol-5-yl)-3- hydroxy-1-methylpyrrolidin-2-one. A solution of fe/Y-butyl (R)-3-(3-(5-(3-hydroxy-1 - methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-1 /-/-pyrrolo[2,3-b]pyridine-1 -carboxylate (50.0 mg, 0.11 mmol) in HCI solution (8 mL, 7 M in 1 ,4-dioxane) was stirred at 25 °C for 2 h, then concentrated to dryness. The residue was dissolved in H2O (10 mL) and the pH of the solution was adjusted to pH > 7 with saturated aqueous NaHCOs. The solution was then extracted with DCM//-PrOH (3 x 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (DCM/MeOH=20/1 , Rf =0.35) to give (R)-3-(3-(3-(1 /-/-pyrrolo[2,3- b]pyridin-3-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (9 mg, 22%) as a white solid. MS (ESI): Mass calcd. for C21 H18N4O3, 374.1 ; m/z found, 375.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 12.01 (s, 1 H), 8.29 - 8.33 (m, 2H), 8.16 (s, 1 H), 8.04 (s, 1 H), 7.86 (d, J = 7.6 Hz, 1 H), 7.75 (d, J = 7.6 Hz, 1 H), 7.57 (t, J = 8.0 Hz, 1 H), 7.20 - 7.17 (m, 1 H), 7.13 (s, 1 H), 6.71 (s, 1 H), 3.49 - 3.40 (m, 2H), 2.84 (s, 3H), 2.60 - 2.54 (m, 1 H), 2.32 - 2.25 (m, 1 H).

Example 25: (R)-3-Hydroxy-1-methyl-3-(3-(3-(4-methylpyrido[3,2-c/]pyrimi din-6- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one.

Step A: 6-Chloro-4-methylpyrido[3,2-c/]pyrimidine. Trimethylaluminium (1.25 mL, 2 M in THF, 3.00 mmol) was added to a mixture of 4,6-dichloropyndo[3,2-c/]pyrimidine (500 mg, 2.50 mmol) and THF (20 mL) that had been cooled to 0 °C. The mixture was purged with N2 for 5 minutes, treated with Pd(PPh3)4 (144 mg, 0.13 mmol), purged with N2 for another 5 minutes, and then heated at 80 °C under a N2 atmosphere for 8 h. The mixture was then cooled to room temperature, diluted with saturated aqueous NH4CI solution (20 mL), and extracted with ethyl acetate (100 mL). The organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC over silica gel (eluent: petroleum ether: ethyl acetate = 1 :0 to 3:1 ) to afford 6-chloro-4- methylpyrido[3,2-c/]pyrimidine (270 mg, 60%) as a pale yellow solid. ¹ H NMR (400 MHz, CDCI3) 89.24 (s, 1 H), 8.27 (d, J = 8.8 Hz, 1 H), 7.78 (d, J = 8.8 Hz, 1 H), 3.06 (s, 3H).

Step B: (R)-3-Hydroxy-1 -methyl-3-(3-(3-(4-methylpyrido[3,2-c/]pyrimidin-6- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. A mixture of (R)-3-hydroxy-1 -methyl-3-(3-(3- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 360 mg, 0.94 mmol), 6-chloro-4-methylpyrido[3,2-c/]pyrimidine (168 mg, 0.935 mmol), K3PO4 (597 mg, 2.81 mmol), 1 ,4-dioxane (4 mL), and H2O (1 mL) was purged with Ar for 5 minutes, then treated with 1 , 1'-bis(di-te/t butylphosphino)ferrocene palladium dichloride (61 mg, 0.09 mmol), and purged with Ar for another 5 minutes. The resultant mixture was subjected to microwave irradiation for 1 h at 90 °C. The mixture was then cooled to room temperature and concentrated under reduced pressure. The product was purified by preparative HPLC using an HPLC column, such a Phenomenex Gemini-NX, 150 mm x 30 mm x 5 pm column (eluent: 27% to 51 %, water (0.04% NH4OH + 10 mM NH4HCO3)-CH3CN). The product was suspended in water (10 mL), the mixture was frozen by insertion into a -78 °C bath, and then lyophilized to dryness to afford (R)-3-hydroxy-1 -methyl-3-(3-(3-(4-methylpyrido[3,2-c(]pyrimidin-6- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (99 mg, 26%) as a red solid. MS (ESI): Mass calcd. for C22H19N5O3, 401.2; m/z found, 402.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 9.21 (s, 1 H), 8.83 - 8.69 (m, 2H), 8.54 - 8.44 (m, 2H), 8.11 - 8.03 (m, 1 H), 7.79 - 7.69 (m, 1 H), 7.22 (s, 1 H), 6.78 (s, 1 H), 3.52 - 3.44 (m, 2H), 3.09 (s, 3H), 2.86 (s, 3H), 2.64 - 2.57 (m, 1 H), 2.37 - 2.26 (m, 1 H).

Example 26: (R)-3-(3-(3-(4-Amino-8-methylpyrido[3,2-c/]pyrimidin-6-yl)ph enyl)isoxazol- 5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one.

Step A: 3-Amino-4-bromo-6-chloropicolinonitrile. /V-Bromosuccinimide (3.4 g, 19 mmol) was added to a solution of 3-amino-6-chloropicolinonitrile (2.7 g, 18 mmol) and DMF (50 mL). The resultant mixture was heated at 90 °C for 2 h. The mixture was then cooled to room temperature, treated with saturated aqueous Na2SOs solution (100 mL) and stirred for 1 h. The resultant mixture was treated with saturated aqueous NaHCOs solution (100 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The resulting residue was purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 1 :1 ) to afford 3-amino-4-bromo-6- chloropicolinonitrile (1.3 g, 30%) as a yellow solid. MS (ESI): Mass calcd. for CeHsBrCINs 230.9; m/z found 233.7 [M+H] ⁺ .

Step B: 3-Amino-6-chloro-4-methylpicolinonitrile. 3-Amino-4-bromo-6- chloropicolinonitrile (1.2 g, 5.2 mmol), 2,4,6-trimethyl-1 ,3,5,2,4,6-trioxatriborinane (0.8 mL, 5.7 mmol), K2CO3 (13 mL, 2.0 M in water, 26 mmol), and 1 ,4-dioxane (30 mL) were added to a 100 mL round bottom flask. The mixture was sparged with Ar for 5 minutes and then treated with PdCl2(dppf)*CH2Cl2 (0.5 g, 0.5 mmol). The mixture was sparged with Ar for another 5 minutes and the resultant mixture was heated at 80 °C for 2 h. The mixture was then cooled to room temperature, diluted with H2O (100 mL), and extracted with ethyl acetate (60 mL x 3). The combined organic extracts were washed with brine (10 mL), dried with anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The resulting residue was purified by FCC (eluent: petroleum ether: ethyl acetate = 5:1 to 1 :1 ) to afford 3-amino-6-chloro-4-methylpicolinonitrile (600 mg, 69%) as a yellow solid.

Step C: 6-Chloro-8-methylpyrido[3,2-d]pyrimidin-4-amine. 3-Amino-6-chloro-4- methylpicolinonitrile (1.05 g, 6.27 mmol), formimidamide acetate (5.22 g, 50.1 mmol), K3PO4 (13.3 g, 62.7 mmol), and 1 ,4-dioxane (30 mL) were added to 100 mL round- bottomed flask. The reaction mixture was heated at 90 °C for 2 h. The mixture was then cooled to room temperature, diluted with H2O (100 mL), and extracted with ethyl acetate (60 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give the product which was purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 1 :1 ) to afford 6-chloro-8-methylpyrido[3,2-c/]pynmidin-4-amine (1.0 g, 82%) as a yellow solid. MS (ESI): Mass calcd. for C8H7CIN4, 194.0; m/z found, 195.1 [M+H] ⁺ .

Step D: (R)-3-(3-(3-(4-Amino-8-methylpyrido[3,2-c/]pyrimidin-6-yl)ph enyl)isoxazol- 5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one. A mixture of (R)-3-hydroxy-1-methyl-3-(3-(3- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 250 mg, 0.651 mmol), 6-chloro-8-methylpyrido[3,2-c(]pyrimidin-4-amine (152 mg, 0.781 mmol), K3PO4 (414 mg, 1 .95 mmol), 1 ,4-dioxane (4 mL), and H2O (1 mL) was sparged with Ar for 5 minutes, treated with 1 ,1 '-bis(di-tert butylphosphino)ferrocene palladium dichloride (42 mg, 0.064 mmol), and sparged with Ar for another 5 minutes. The resultant mixture was subjected to microwave irradiation at 90 °C for 1 h. The resulting mixture was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC using an HPLC column, such an Welch Xtimate C18, 150 mm x 25 mm x 5 pm column (eluent: 20% to 50%, water (0.04% NFWHj-CHsCN) to afford the product. The product was suspended in water (10 mL), the mixture was frozen by insertion into a -78 °C bath, and then lyophilized to dryness to afford (R)-3-(3-(3-(4- amino-8-methylpyrido[3,2-c/]pyrimidin-6-yl)phenyl)isoxazol-5 -yl)-3-hydroxy-1 - methylpyrrolidin-2-one (100 mg, 35%) as a yellow solid. MS (ESI): Mass calcd. for C22H20N6O3, 416.2; m/z found, 417.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.73 (s, 1 H), 8.57 (d, J = 7.9 Hz, 1 H), 8.50 - 8.39 (m, 2H), 8.17 (br s, 1 H), 8.06 - 7.88 (m, 2H), 7.72 - 7.61 (m, 1 H), 7.31 (s, 1 H), 6.99 - 6.50 (m, 1 H), 3.52 - 3.40 (m, 2H), 2.85 (s, 3H), 2.68 (s, 3H), 2.62 - 2.55 (m, 1 H), 2.36 - 2.22 (m, 1 H).

Example 27: (S)-3-(3-(3-(4-Amino-8-methylpyrido[3,2-c/]pynmidin-6-yl)phe nyl)isoxazol- 5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one.

Step A: (S)-3-Hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. 4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi(1 ,3,2- dioxaborolane) (300 mg, 1.18 mmol) was added to (S)-3-(3-(3-bromophenyl)isoxazol-5- yl)-3-hydroxy-1 -methylpyrrolidin-2-one (Intermediate 26, 200 mg, 0.6 mmol) and KOAc (380 mg, 1 .79 mmol) in 1 ,4-dioxane (5 mL). The resultant mixture was sparged with Ar for 5 minutes and then treated with PdCl2(dppf) (43.0 mg, 0.06 mmol) to provide a reaction mixture. The reaction mixture was sparged with Ar for another 5 minutes and then subjected to microwave irradiation at 100 °C for 1 h. After this time, the reaction mixture was cooled to room temperature, and filtered through a pad of diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure to afford the product, which was purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 0:1 ) to afford (S)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (156 mg, 62%) as a yellow oil. MS (ESI): Mass calcd. for C20H25BN2O5, 384.2; m/z found, 385.2 [M+H] ⁺ .

Step B: (S)-3-(3-(3-(4-Amino-8-methylpyrido[3,2-c(]pynmidin-6-yl)phe nyl)isoxazol- 5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one. 6-Chloro-8-methylpyrido[3,2-c/]pynmidin-4- amine (Example 26 Step C, 51 mg, 0.26 mmol), (S)-3-hydroxy-1 -methyl-3-(3-(3- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (100 mg, 0.26 mmol), K3PO4 (166 mg, 0.78 mmol), 1 ,4-dioxane (2 mL), and H2O (0.5 mL) were added to a 5 mL microwave tube. The resultant mixture was sparged with Ar for 5 minutes, treated with Pd(dtbpf)Cl2 (17 mg, 0.03 mmol), and sparged with Ar for another 5 minutes to provide a reaction mixture. This reaction mixture was subjected to microwave irradiation at 90 °C for 1 h. After this time, the reaction mixture was cooled to room temperature and filtered through a pad of diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure to afford the product, which was purified by preparative HPLC using a HPLC column such as a Welch Xtimate C18 150 x 25 mm x 5 pm column (eluent: 23% to 43% CH3CN and H2O with (0.04% NH4OH +10 mM NH4HCO3)), and further purified by SFC using an SFC column, such as a DAICEL CHIRALPAK® AS 250 mm x 30 mm, 10 pm column (isocratic elution: EtOH (containing 0.1 % of 25% NH3): supercritical CO2, 45%: 55%). The product containing fractions were collected and concentrated under reduced pressure. The product was suspended in water (10 mL), the mixture was frozen by insertion into a -78 °C bath, and then lyophilized to dryness to afford (S)-3-(3-(3-(4-amino-8-methylpyrido[3,2-c/]pyrimidin-6- yl)phenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (36.1 mg, 33%) as a colorless solid. MS (ESI): Mass calcd. for C22H20N6O3, 416.2; m/z found, 417.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.70 (s, 1 H), 8.53 (d, J = 7.8 Hz, 1 H), 8.47 - 8.37 (m, 2H), 8.13 (br s, 1 H), 8.02 - 7.85 (m, 2H), 7.68 - 7.57 (m, 1 H), 7.26 (s, 1 H), 6.72 (br s, 1 H), 3.47 - 3.37 (m, 2H), 2.82 (s, 3H), 2.64 (s, 3H), 2.57 - 2.52 (m, 1 H), 2.30 - 2.22 (m, 1 H).

Example 28: (R)-6-(3-(2-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)thiazol-5- yl)phenyl)picolinamide.

Step A: 5-(3-Bromophenyl)thiazole. Tricyclohexylphosphine tetrafluoroborate (4.3 g, 12 mmol) was added to a mixture of thiazole (5.0 g, 59 mmol), 1 ,3- dibromobenzene (10.7 mL, 88.1 mmol), PivOH (1.80 g, 17.6 mmol), K2CO3 (12.2 g, 88.1 mmol), and DMA (100 mL). The mixture was purged with Ar three times and then treated with Pd(OAc)2 (1.32 mg, 5.87 mmol). The resultant mixture was heated at 100 °C for 2 h. After this time, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to afford the product, which was purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 10:1 ) to provide 5-(3- bromophenyl)thiazole (1.9 g, 13%) as an orange oil. MS (ESI): Mass calcd. for CgHeBrNS 240.1 ; m/z found, 242.0 [M+H] ⁺ .

Step B: (R, S)-3-(5-(3-Bromophenyl)thiazol-2-yl)-3-hydroxy-1 -methylpyrrolidin-2- one. Lithium diisopropylamide (5.94 mL, 11.9 mmol, 2.0 M in hexanes) was added to a solution of 5-(3-bromophenyl)thiazole (1 .9 g, 7.9 mmol) in THF (10 mL) that had been cooled to -72 °C. The resultant mixture was stirred at -72 °C for 30 minutes, treated with a solution of 1-methylpyrrolidine-2, 3-dione (1.07 g, 9.50 mmol) in THF (10 mL), and stirred at -72 °C for 1 hour. After this time, the reaction mixture was quenched with H2O (50 mL) and extracted with DCM/MeOH (10:1 ) (50 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The resulting residue was purified by FCC (eluent: methylene chloride : methanol = 1 :0 to 10:1 ) to afford (R,S)-3-(5-(3- bromophenyl)thiazol-2-yl)-3-hydroxy-1-methylpyrrolidin-2-one (741 mg, 25%) as a brown oil. MS (ESI): Mass calcd. for CuHisBrIShChS, 350.0; m/z found, 353.1 [M+H] ⁺ .

Step C: (R _; S)-3-Hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)thiazol-2-yl)pyrrolidin-2-one. (R,S)-3-(5-(3- Bromophenyl)thiazol-2-yl)-3-hydroxy-1-methylpyrrolidin-2-one (641 mg, 1.82 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (691 mg, 2.72 mmol), and KOAc (534 mg, 5.44 mmol) and 1 ,4-dioxane (5 mL) were added to a microwave tube. The resultant mixture was purged with Ar for 5 minutes and then treated with Pd(dppf)Cl2 (133 mg, 0.181 mmol). The mixture was purged with Ar for another 5 minutes and then subjected to microwave irradiation at 90 °C for 1 h. After this time, the mixture was poured into H2O (15 mL), and extracted with EtOAc (15 mL x 2). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The resulting residue was purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 1 :2) to afford (R,S)-3-hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1 ,3,2-c/ioxaborolan-2- yl)phenyl)thiazol-2-yl)pyrrolidin-2-one (425 mg, 48%) as a brown solid. MS (ESI): Mass calcd. for C20H25BN2O4S 400.3; m/z found, 401 .3 [M+H] ⁺ .

Step D: (R, S)-6-(3-(2-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)thiazol-5- yl)phenyl)picolinamide. 6-Chloropicolinamide (191 mg, 1.22 mmol), (R,S)-3-hydroxy-1- methyl-3-(5-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)thiazol-2- yl)pyrrolidin-2-one (325 mg, 0.812 mmol), and K3PO4 (517 mg, 2.44 mmol) were added to a microwave tube and the resultant mixture dissolved in 1 ,4-dioxane (1.6 mL) and H2O (0.4 mL). The resultant mixture was purged with Ar for 5 minutes and then treated with Pd(dtbpf)Cl2 (53 mg, 0.081 mmol). The resultant mixture was purged with Ar for another 5 minutes and then subjected to microwave irradiation at 100 °C for 1 hour. After this time, the mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give the product which was purified by FCC (eluent: methylene chloride : methanol = 1 :0 to 10:1 ) to afford (F?,S)-6-(3-(2-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)thia zol-5- yl)phenyl)picolinamide (200 mg, 52%) as a brown solid. MS (ESI): Mass calcd. for C20H18N4O3S 394.1 ; m/z found 395.1 [M+H] ⁺ .

Step E: (R)-6-(3-(2-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)thiazol-5- yl)phenyl)picolinamide. The (R) and (S) enantiomers of (R,S)-6-(3-(2-(3-Hydroxy-1 - methyl-2-oxopyrrolidin-3-yl)thiazol-5-yl)phenyl)picolinamide (300 mg, 0.76 mmol) were separated by SFC using an SFC column, such as a DAICEL CHIRALCEL® OD 250 mm x 30 mm, 10 pm column (isocratic elution: EtOH (containing 0.1 % of 25% aqueous NH3 solution): supercritical CO2, 45%: 55%). The second eluting product was (R)-6-(3-(2-(3- hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)thiazol-5-yl)phenyl)picolinamid e. The fractions containing this enantiomer were collected and concentrated under reduced pressure. The product was suspended in water (10 mL), the mixture was frozen by insertion into a -78 °C bath, and then lyophilized to dryness to afford (R)-6-(3-(2-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)thiazol-5-yl)phenyl)picolinamide, which was further purified with preparative HPLC using an HPLC column, such a Phenomenex Gemini NX-C18 75 x 30 mm x 3 pm column (eluent: 25% to 55%, CH3CN and H2O (with 0.05% NH4OH and 10 mM NH4HCO3)). The product was suspended in water (10 mL), the mixture was frozen by insertion into a -72 °C bath, and then lyophilized to dryness to afford (R)-6-(3-(2-(3- hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)thiazol-5-yl)phenyl)picolinamid e (48 mg, 16%) as a colorless solid. MS (ESI): Mass calcd. for C20H18N4O3S, 394.1 ; m/z found, 395.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.54 - 8.41 (m, 2H), 8.33 - 8.27 (m, 3H), 8.15 - 8.02 (m, 2H), 7.80 - 7.71 (m, 2H), 7.64 - 7.56 (m, 1 H), 6.99 (s, 1 H), 3.57 - 3.52 (m, 2H), 2.84 (s, 3H), 2.79 - 2.71 (m, 1 H), 2.34 - 2.24 (m, 1 H).

Example 29: (R)-6-(3-(4-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 /-/-pyrazol-1 - yl)phenyl)picolinamide. Step A: 4-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1/-/-pyrazole. Sodium hydride (5.99 g, 60% in mineral oil, 150 mmol) was added to a solution of 4-bromo-1 H- pyrazole (20.0 g, 136 mmol) and THF (100 mL) that had been cooled to 0 °C. The resultant mixture was stirred at 0 °C for 1 h, treated with 2-(trimethylsilyl)ethoxymethyl chloride (27.2 g, 163 mmol) dropwise, and stirred for 16 h with gradual warming to room temperature. The resulting mixture was poured into a saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic extracts were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford the product, which was purified by FCC (eluent: petroleum ether: methylene chloride = 3:1 to 1 :1) to afford 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)- 1 H-pyrazole (32 g, 82%) as a colorless oil. ¹ H NMR (400 MHz, CDCh) 8 7.61 (s, 1 H), 7.51 (s, 1 H), 5.40 (s, 2H), 3.61 - 3.52 (m, 2H), 0.95 - 0.90 (m, 2H), 0.00 (s, 9H).

Step B: (R _; S)-3-Hydroxy-1-methyl-3-(1-((2-(trimethylsilyl)ethoxy) methyl)-1/-/- pyrazol-4-yl)pyrrolidin-2-one. n-Butyllithium (8.7 mL, 2.5 M in hexanes, 1.4 mmol) was added dropwise to a solution of 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1/-/- pyrazole (5.0 g, 18 mmol) in anhydrous THF (50.0 mL) that had been cooled to -72 °C. The resultant mixture was stirred at -72 °C for 30 minutes before it was treated with 1- methylpyrrolidine-2, 3-dione (4.1 g, 36 mmol). The resultant mixture was stirred at -72 °C for 5 minutes, and then stirred for 15 minutes with gradual warming to room temperature. After this time, the mixture was poured into a saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The product was purified by preparative HPLC using an HPLC column, such an Xtimate C18 150 x 40 mm, 10 pm column (eluent: 25 % to 55%, water (0.04% NH4OH + 10 mM NH4HCO3)-CH3CN). The fractions containg the product were collected and concentrated under vacuum. The residue was suspended in water (10 mL), the mixture was frozen by insertion into a -78 °C bath, and then lyophilized to dryness to afford (R,S)-3-hydroxy-1-methyl-3-(1-((2-(trimethylsilyl)ethoxy)met hyl)-1/-/- pyrazol-4-yl)pyrrolidin-2-one (720 mg, 13%) as a yellow oil. MS (ESI): Mass calcd. for Ci4H ₂ 5N ₃ O3Si, 311.2; m/z found, 312.2 [M+H] ⁺ .

Step C: (R,S)-3-Hydroxy-1-methyl-3-(1/-/-pyrazol-4-yl)pyrrolidin-2-o ne. Tetrabutylammonium fluoride (11 .6 mL, 1 .0 M in THF, 11 .6 mmol) was added to a mixture of (R _; S)-3-hydroxy-1-methyl-3-(1-((2-(trimethylsilyl)ethoxy) methyl)-1/-/-pyrazol-4- yl)pyrrolidin-2-one (0.7 g, 2.3 mmol) and THF (10.0 mL) at room temperature. The resultant reaction mixture was heated at 90 °C for 16 h. The mixture was then concentrated under reduced pressure to afford the product, which was purified by FCC (eluent: methylene chloride: methanol = 1 :0 to 9:1) to afford (R,S)-3-hydroxy-1-methyl-3- (1/-/-pyrazol-4-yl)pyrrolidin-2-one (418 mg, 88%) as a yellow oil. MS (ESI): Mass calcd. for C8H11N3O2 181.2; m/z found, 182.2 [M+H] ⁺ .

Step D: (R, S)-3-(1 -(3-Bromophenyl)-1 /-/-pyrazol-4-yl)-3-hydroxy-1 - methylpyrrolidin-2-one. Pyridine (365 mg, 4.61 mmol) was added to a mixture of (R,S)~ 3-hydroxy-1 -methyl-3-(1 H-pyrazol-4-yl)pyrrolidin-2-one (418 mg, 2.31 mmol), (3- bromophenyl)boronic acid (927 mg, 4.61 mmol), copper diacetate (419 mg, 2.31 mmol), and DMF (10 mL). The resultant mixture was heated at 90 °C for 5 hours under an air atmosphere. The mixture was then poured into water (30 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic extracts were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The product was purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 0:1 ) to yield (R,S)-3-(1- (3-bromophenyl)-1/-/-pyrazol-4-yl)-3-hydroxy-1-methylpyrroli din-2-one (120 mg, 15%) as a colorless oil. MS (ESI): Mass calcd. for CuHuBrNsO? 336.2 m/z found, 337.1 [M+H] ⁺ .

Step E: (R _; S)-3-Hydroxy-1-methyl-3-(1-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)-1 /-/-pyrazol-4-yl)pyrrolidin-2-one. [1 , T- bis(Diphenylphosphino)ferrocene]dichloropalladium(ll) (65 mg, 0.089 mmol) was added to a mixture of (F?,S)-3-(1-(3-bromophenyl)-1/-/-pyrazol-4-yl)-3-hydroxy-1- methylpyrrolidin-2-one (300 mg, 0.9 mmol), bis(pinacolato)diboron (272 mg, 1.07 mmol), KOAc (175 mg, 1 .79 mmol), and 1 ,4-dioxane (5 mL) under a N2 atmosphere. The resultant mixture was subjected to microwave irradiation at 90 °C for 2 h. The mixture was then poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic extracts were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The product was purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 0:1 ) to afford (R,S)-3-hydroxy-1-methyl-3-(1-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)-1 /-/-pyrazol-4-yl)pyrrolidin-2-one (200 mg) as a colorless oil. MS (ESI): Mass calcd. for C20H26BN3O4, 383.2; m/z found, 384.3 [M+H] ⁺ .

Step F: (R,S)-6-(3-(4-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 /-/-pyrazol-1 - yl)phenyl)picolinamide. (R _; S)-3-Hydroxy-1-methyl-3-(1 -(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)-1 /-/-pyrazol-4-yl)pyrrolidin-2-one (180 mg, 0.47 mmol), 6- chloropicolinamide (110 mg, 0.705 mmol) and 1 ,4-dioxane/H2O (10 mL, 4/1 ) were added to a microwave tube. The mixture was sparged with N2 for 5 minutes. [1 ,T- bis(Diphenylphosphino)ferrocene]dichloropalladium(ll) (31 mg, 0.047 mmol) and K3PO4 (299 mg, 1 .41 mmol) were added and the mixture was sparged with N2 for another 5 minutes. The resultant mixture was subjected to microwave irradiation at 100 °C for 1 hour. The mixture was then poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic extracts were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The product was initially purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 0:1 ), and then further purified by preparative HPLC using an HPLC column, such as a Phenomenex Gemini NX-C18 75 x 30 mm, 3 pm column (eluent: 15 % to 45%, water (0.04% NH4OH +10 mM NFUHCOsj-CHsCN). The fractions containing the product were collected and concentrated under vacuum. The residue was suspended in water (10 mL), the mixture was frozen by insertion into a -78 °C bath, and then lyophilized to dryness to afford (R, S)-6-(3-(4-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 /-/-pyrazol-1 - yl)phenyl)picolinamide (70 mg, 39%) as a colorless solid. MS (ESI): Mass calcd. for C20H19N5O3, 377.4; m/z found, 378.3 [M+H] ⁺ .

Step G: (R)-6-(3-(4-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 /-/-pyrazol-1 - yl)phenyl)picolinamide. The (R) and (S) enantiomers of (R,S)-6-(3-(4-(3-Hydroxy-1 - methyl-2-oxopyrrolidin-3-yl)-1 /-/-pyrazol-1 -yl)phenyl)picolinam ide (70.0 mg, 0.185 mmol) were separated by SFC using an SFC column, such as a DAICEL CHIRALPAK® AS 250 mm x 30 mm, 10 pm column (isocratic elution: EtOH (containing 0.1 % of 25% aqueous NH3 solution): supercritical CO2, 50 %: 50%). The second eluting compound was (R)-6-(3-(4-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 /-/-pyrazol-1 - yl)phenyl)picolinamide. The fractions containing the product were collected and concentrated under reduced pressure. The product was suspended in water (10 mL), the mixture was frozen by insertion into a -78 °C bath, and then lyophilized to dryness to afford (R)-6-(3-(4-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 /-/-pyrazol-1 - yl)phenyl)picolinamide (22.3 mg, 32%) as a colorless solid. MS (ESI): Mass calcd. for C20H19N5O3 377.4 m/z found, 378.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.66 (s, 1 H), 8.59 - 8.56 (m, 1 H), 8.42 (s, 1 H), 8.33 - 8.29 (m, 1 H), 8.27 - 8.22 (m, 1 H), 8.15 - 8.08 (m, 1 H), 8.06 - 8.00 (m, 1 H), 7.98 - 7.91 (m, 1 H), 7.81 - 7.73 (m, 2H), 7.66 - 7.58 (m, 1 H), 6.34 - 5.33 (m, 1 H), 3.46 - 3.40 (m, 2H), 2.80 (s, 3H), 2.57 - 2.53 (m, 1 H), 2.29 - 2.22 (m, 1 H).

Example 30: (R)-6-(3-(3-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 -methyl-1 H-pyrazol- 5-yl)phenyl)picolinamide.

Step A: 3, 5-Dibromo-1 -methyl-1 H-pyrazole. Sodium hydride (2.5 g, 60% purity, 63 mmol) was added to a solution of 3, 5-dibromo-1 H-pyrazole (7.0 g, 31 mmol) in THF (80 mL) that had been cooled to 0 °C under a N2 atmosphere. The reaction mixture was stirred at 0 °C for 1 hour before it was treated with methyl iodide (11 g, 75 mmol) dropwise. The resultant mixture was stirred for 2 h and was gradually warmed to room temperature. The reaction mixture was then quenched with saturated aqueous NH4CI solution (100 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The product was purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 1 :1 ) to afford 3, 5-dibromo-1 -methyl-1 H- pyrazole (7.0 g, 94%) as a yellow oil. MS (ESI): Mass calcd. for C4H4Br2N2, 237.9; m/z found 238.9 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCI3) 8 6.35 - 6.29 (m, 1 H), 3.87 (s, 3H), 6.35 - 6.29 (m, 1 H), 3.87 (s, 3H). Step B: 3-Bromo-5-(3-chlorophenyl)-1-methyl-1/-/-pyrazole. 3,5-Dibromo-1- methyl-1/-/-pyrazole (6.0 g, 25 mmol), (3-chlorophenyl)boronic acid (3.32 g, 21.2 mmol), and K2CO3 (10.4 g, 75.3 mmol) were added to a solution of 1 ,4-dioxane (80 mL) and H2O (20 mL). The mixture was sparged with Ar for 5 minutes and then treated with Pd(dppf)Cl2 (1 .83 g, 2.50 mmol). The mixture was sparged with Ar for another 5 minutes and heated at 105 °C for 16 h. This reaction mixture combined with another reaction mixture batch of 3-bromo-5-(3-chlorophenyl)-1-methyl-1/-/-pyrazole (200 mg, 0.5 mmol). These combined batches were then poured into H2O (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic solvent extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The product was initially purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 3:1 ). The product was further purified by preparative HPLC using an HPLC column, such as a YMC-Triart Prep C18 150 x 40 mm x 7 pm column (eluent: 47% to 77%, CH3CN and H2O with (0.04% NH4OH + 10 mM NH4HCO3)) to afford 3-bromo-5-(3-chlorophenyl)-1 -methyl-1 /-/- pyrazole (2.5 g) as a white solid. MS (ESI): Mass calcd. for CioHsBrCIN2, 270.0; m/z found 273.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 87.67 - 7.64 (m, 1 H), 7.58 - 7.52 (m, 3H), 6.66 (s, 1 H), 3.83 (s, 3H).

Step C: (R, S)-3-(5-(3-Chlorophenyl)-1 -methyl-1 /-/-pyrazol-3-yl)-3-hydroxy-1 - methylpyrrolidin-2-one. n-Butyllithium (3.2 mL, 8.0 mmol, 2.5 M in hexanes) was added dropwise to a solution of 3-bromo-5-(3-chlorophenyl)-1 -methyl-1 H-pyrazole (2.00 g, 7.36 mmol) and DCM (30 mL) that had been cooled to -72 °C, under a N2 atmosphere. The resultant mixture was stirred at -72 °C for 0.5 hours before treating with a solution of 1-methylpyrrolidine-2, 3-dione (1 .00 g, 8.84 mmol) and DCM (10 mL) under a N2 atmosphere. The mixture was stirred at -72 °C for 1 hour under a N2 atmosphere. The reaction mixture was then quenched with saturated aqueous NH4CI solution (50 mL) and extracted with DCM (100 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The product was purified by FCC. The initial eluent was a gradient of 100% petroleum ether/0% EtOAc to 0% petroleum ether/100% EtOAc, and then the eluent was changed to 100% EtOAc/0% MeOH to 80% EtOAc/20% MeOH to afford 3-(5-(3-chlorophenyl)-1 -methyl-1 H-pyrazol- 3-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (1.2 g, 45%) as a yellow solid. MS (ESI): Mass calcd. for C15H16CIN3O2, 305.1 ; m/z found 306.1 [M+H] ⁺ .

Step D: (R _; S)-3-Hydroxy-1 -methyl-3-(1-methyl-5-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)-1 /-/-pyrazol-3-yl)pyrrolidin-2-one. Chloro(2- dicyclohexylphosphino-2',4',6'-triisopropyl-1 , 1 '-biphenyl)[2-(2'-amino-1 , 1 '- biphenyl)]palladium(l I) (267 mg, 0.339 mmol) was added to a mixture of 3-(5-(3- chlorophenyl)-1 -methyl-1 /-/-pyrazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-one (1 .00 g, 3.27 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (1.67 g, 6.58 mmol), KOAc (966 mg, 9.84 mmol), and 1 ,4-dioxane (60 mL) under a N2 atmosphere. The mixture was heated at 110 °C for 6 h under a N2 atmosphere. The reaction mixture was concentrated to dryness. The resulting residue was purified by FCC using 100% petroleum ether/0% EtOAc to 0% petroleum ether/100% EtOAc. The eluent was then changed to 0% MeOH/100% EtOAc to 20% MeOH / 80% EtOAc to afford (R,S)-3- hydroxy-1 -methyl-3-(1 -methyl-5-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)- 1 /-/-pyrazol-3-yl)pyrrolidin-2-one (1.2 g) as a brown oil. MS (ESI): Mass calcd. for C21 H28BN3O4, 397.2; m/z found 398.1 [M+H] ⁺ .

Step E: (R, S)-6-(3-(3-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 -methyl-1 H- pyrazol-5-yl)phenyl)picolinamide. [1 ,T-Bis(di-te/t- butylphosphino)ferrocene]dichloropalladium(ll) (197 mg, 0.302 mmol) was added to a mixture of (R _; S)-3-hydroxy-1 -methyl-3-(1 -methyl-5-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)-1 /-/-pyrazol-3-yl)pyrrolidin-2-one (1.2 g, 3.02 mmol), 6- chloropicolinamide (525 mg, 3.02 mmol), K3PO4 (1.90 g, 8.95 mmol), 1 ,4-dioxane (50 mL), and H2O (12.5 mL) under a N2 atmosphere. The mixture was heated at 100 °C for 16 h under a N2 atmosphere. The combined mixture was concentrated to dryness under reduced pressure to give the product, which was purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 0:1 , then ethyl acetate: methanol =1 :0 to 5:1 ) to afford (R, S)-6-(3-(3-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 -methyl-1 /-/-pyrazol-5- yl)phenyl)picolinamide (800 mg) as a brown solid. MS (ESI): Mass calcd. for C21 H21 N5O3, 391.2; m/z found 392.2 [M+H] ⁺ .

Step F: (R)-6-(3-(3-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 -methyl-1 H- pyrazol-5-yl)phenyl)picolinamide. The (R) and (S) enantiomers of (R,S)-6-(3-(3-(3- hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 -methyl-1 H-pyrazol-5-yl)phenyl)picolinamide (300 mg, 0.77 mmol ) was further purified by SFC using an SFC column, such as a DAICEL CHIRALPAK® IC column (250 mm x 30 mm x 5 pm (isocratic elution: EtOH (containing 0.1 % of 25% aqueous NH3 solution): supercritical CO2, 55%: 45%). The second eluting product was (R)-6-(3-(3-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1- methyl-1 /-/-pyrazol-5-yl)phenyl)picolinamide, which was further purified by preparative HPLC using an HPLC column, such as a Phenomenex Gemini NX-C18 75 mm x 30 mm x 3 pm column (eluent: 15% to 45%,CH3CN and H2O (with 0.05% NH4OH +10 mM NH4HCO3)) to afford the product. The product was suspended in water (10 mL), the mixture was frozen by insertion into a -78 °C bath, and then lyophilized to dryness to afford (R)-6-(3-(3-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 -methyl-1 H-pyrazol-5- yl)phenyl)picolinamide (86.5 mg, 29%) as a white solid. LCMS (ESI): Mass calcd. For C21 H21 N5O3 391 .2 m/z found 392.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.45 - 8.39 (m, 2H), 8.35 (d, J = 7.7 Hz, 1 H), 8.27 (d, J = 7.7 Hz, 1 H), 8.11 - 8.06 (m, 1 H), 8.04 - 8.00 (m, 1 H), 7.71 (s, 1 H), 7.67 - 7.62 (m, 1 H), 7.61 - 7.56 (m, 1 H), 6.57 (s, 1 H), 5.89 (s, 1 H), 3.86 (s, 3H), 3.42 - 3.38 (m, 2H), 2.78 (s, 3H), 2.73 - 2.67 (m, 1 H), 2.20 - 2.09 (m, 1 H).

Example 31 : (R)-6-(3-(3-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 H-pyrazol-5- yl)phenyl)picolinamide.

Step A: 3,5-Dibromo-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-pyrazole. 2- (Trimethylsilyl)ethoxymethyl chloride (6.66 mL, 37.6 mmol) was added to a solution of 3, 5-dibromo-1 H-pyrazole (5.00 g, 22.1 mmol), EtsN (4.62 mL, 33.2 mmol), and methylene chloride (60 mL). This mixture was stirred at room temperature for 30 minutes and then concentrated to dryness under reduced pressure. The product was purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 3:1 ) to yield 3,5- dibromo-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-pyrazole (4.7 g, 46%) as a colorless oil. ¹ H NMR (400 MHz, CDCh) 86.40 - 6.32 (m, 1 H), 5.45 - 5.41 (m, 2H), 3.65 - 3.59 (m, 2H), 0.93 - 0.87 (m, 2H), -0.02 (s, 9H).

Step B: (R, S)-3-(3-Bromo-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-pyrazol-5-yl)-3- hydroxy-1-methylpyrrolidin-2-one. n-Butyllithium (4.15 mL, 10.4 mmol, 2.5 M in hexanes) was added to a solution of 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)- 1 H-pyrazole (4.20 g, 9.40 mmol) in THF (10 mL) that had been cooled to -72 °C. The resultant mixture was stirred at -72 °C for 30 minutes, treated with a solution of 1- methylpyrrolidine-2, 3-dione (1 .28 g, 11.3 mmol) in THF (20 mL), and then stirred at - 72 °C for 1 h. The reaction mixture was then quenched with H2O (50 mL) and extracted with DCM/MeOH (10:1 , 50 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The resulting residue was purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 1 :1 ) to yield (R,S)-3-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (1.1 g, 27%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 86.52 - 6.45 (m, 1 H), 6.34 - 6.26 (m, 1 H), 5.95 - 5.85 (m, 1 H), 5.31 - 5.21 (m, 1 H), 3.69 - 3.55 (m, 2H), 3.41 - 3.36 (m, 2H), 3.27 - 3.19 (m, 1 H), 2.79 (s, 3H), 2.28 - 2.17 (m, 1 H), 0.94 - 0.73 (m, 2H), 0.03 (s, 9H).

Step C: (R, S)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 -((2- (trimethylsilyl)ethoxy)methyl)-1 H-pyrazol-3-yl)phenyl)picolinamide. (R,S)-3-(3-Bromo-1 - ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-3-hydrox y-1-methylpyrrolidin-2-one (400 mg, 1.02 mmol), (3-(6-carbamoylpyridin-2-yl)phenyl)boronic acid (248 mg, 1.02 mmol), and K3PO4 (653 mg, 3.07 mmol) were added to a microwave tube and the resultant mixture dissolved in 1 ,4-dioxane (1 .6 mL) and H2O (0.4 mL). This mixture was purged with Ar for 5 minutes and then treated with Pd(dtbpf)Cl2 (67 mg, 0.10 mmol). The resultant mixture was purged with Ar for another 5 minutes and then subjected to microwave irradiation at 80 °C for 1 hour. After this time, the mixture was poured into H2O (10 mL), and extracted with EtOAc (10 mL x 2). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The product was purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 0:1 ) to afford (R,S)-6-(3-(5-(3-hydroxy-1- methyl-2-oxopyrrolidin-3-yl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 /-/-pyrazol-3- yl)phenyl)picolinamide (300 mg, 52%) as a yellow solid. MS (ESI): Mass calcd. for C26H33N ₅ O4Si, 507.2; m/z found 508.3 [M+H] ⁺ .

Step D: (R,S)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 /-/-pyrazol-3- yl)phenyl)picolinamide. (R,S)-6-(3-(5-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)-1 -((2- (trimethylsilyl)ethoxy)methyl)-1 /-/-pyrazol-3-yl)phenyl)picolinamide (270 mg, 0.532 mmol) was added to a solution of TBAF (1 .60 mL, 1 .0 M in THF, 1 .60 mmol). The resultant mixture was heated at 90 °C for 16 h. The mixture was concentrated to dryness under reduced pressure and the product was purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 0:1 ) to yield (R,S)-6-(3-(5-(3-hydroxy-1-methyl-2- oxopyrrolidin-3-yl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 /-/-pyrazol-3- yl)phenyl)picolinamide (130 mg, 60%) as a yellow solid. MS (ESI): Mass calcd. for C20H19N5O3, 377.4; m/z found 378.2 [M+H] ⁺ .

Step E: (R)-6-(3-(3-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 /-/-pyrazol-5- yl)phenyl)picolinamide. The (R) and (S) enantiomers of (R,S)-6-(3-(5-(3-Hydroxy-1 - methyl-2-oxopyrrolidin-3-yl)-1 /-/-pyrazol-3-yl)phenyl)picolinamide (130 mg, 0.344 mmol) were separated by SFC using an SFC column, such as a DAICEL CHIRALCEL® OD-H 250 mm x 30 mm, 5 μm column (isocratic elution of EtOH : supercritical CO2, 45% : 55%). The second eluting product was (R)-6-(3-(3-(3-hydroxy-1 -methyl-2-oxopyrrolidin- 3-yl)-1 /-/-pyrazol-5-yl)phenyl)picolinamide. The fractions containing (R)-6-(3-(3-(3- hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 /-/-pyrazol-5-yl)phenyl)picolinamide were collected and concentrated under reduced pressure. This product was then suspended in water (10 mL), the mixture was frozen by insertion into a -78 °C bath, and then lyophilized to dryness to afford (R)-6-(3-(3-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 /-/- pyrazol-5-yl)phenyl)picolinamide (32.6 mg, 25.0%) as a colorless solid. MS (ESI): Mass calcd. for C20H19N5O3, 377.2; m/z found, 378.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 13.41 - 12.72 (m, 1 H), 8.66 - 8.50 (m, 1 H), 8.47 - 8.33 (m, 1 H), 8.30 - 8.21 (m, 2H), 8.13 - 8.07 (m, 1 H), 8.05 - 8.00 (m, 1 H), 7.90 - 7.75 (m, 2H), 7.62 - 7.51 (m, 1 H), 6.87 (s, 1 H), 6.40 - 5.79 (m, 1 H), 3.41 - 3.41 (m, 2H), 2.79 (s, 3H), 2.53 - 2.53 (m, 1 H), 2.30 - 2.08 (m, 1 H). Example 32: (R)-3-(5-(3-(4-Aminopyrido[3,2-d]pyrimidin-6-yl-2-c/)phenyl) thiazol-2-yl)-3- hydroxy-1 -methylpyrrolidin-2-one.

Step A: (R,S)-3-(5-(3-(4-Aminopyrido[3,2-c/]pyrimidin-6-yl-2-c/)phen yl)thiazol-2- yl)-3-hydroxy-1-methylpyrrolidin-2-one. (R,S)-3-Hydroxy-1 -methyl-3-(5-(3-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)thiazol-2-yl)pyrrolidin-2-one (obtained from Example 28, Step C, 0.4 g, 0.9 mmol), 6-chloropyrido[3,2-c(]pyrimidin-2-cM-amine (Intermediate 17, 0.26 g, 1.5 mmol), and K3PO4 (0.62 g, 2.9 mmol) were added to a microwave tube and the resultant mixture was dissolved in 1 ,4-dioxane (2.4 mL) and H2O (0.6 mL). This mixture was purged with N2 for 5 minutes and then treated with Pd(dtbpf)Cl2 (63 mg, 0.1 mmol). The resultant mixture was purged with N2 for another 5 minutes and then subjected to microwave irradiation for 1 hour at 100 °C before cooling to room temperature. The mixture was then concentrated to dryness under reduced pressure. The product was purified by preparative HPLC using an HPLC column, such as a Phenomenex Gemini-NX, 150 x 30 mm x 5 pm column (eluent: 20% to 50%,CH3CN-water (with 0.04% NH4OH + 10 mM NH4HCO3)). The product was then suspended in water (10 mL), the mixture was frozen by insertion into a -72 °C bath, and then lyophilized to dryness to afford (R,S)-3-(5-(3-(4-aminopyrido[3,2-c/]pyrimidin-6-yl-2- d)phenyl)thiazol-2-yl)-3-hydroxy-1-methylpyrrolidin-2-one (100 mg, 24%) as a colorless solid. MS (ESI): Mass calcd. for C21 H17DN6O2S, 419.1 ; m/z found, 420.1 [M+H] ⁺ .

Step B: (R)-3-(5-(3-(4-Aminopyrido[3,2-c(]pyrimidin-6-yl-2-c/)phenyl )thiazol-2-yl)- 3-hydroxy-1 -methylpyrrolidin-2-one. The (R) and (S) enantiomers of (R,S)-3-(5-(3-(4- aminopyrido[3,2-c(]pyrimidin-6-yl-2-c/)phenyl)thiazol-2-yl)- 3-hydroxy-1-methylpyrrolidin-2- one (100 mg, 0.238 mmol) were separated by SFC using an SFC column, such as a DAICEL CHIRALCEL® OD-H 250 x 30 mm x 5 pm column (isocratic elution of EtOH : supercritical CO2, 45% : 55%). The second eluting product was (R)-3-(5-(3-(4- aminopyrido[3,2-c/]pyrimidin-6-yl-2-c/)phenyl)thiazol-2-yl)- 3-hydroxy-1-methylpyrrolidin-2- one. The fractions of (R)-3-(5-(3-(4-aminopyrido[3,2-c/]pyrimidin-6-yl-2-c/)phenyl )thiazol- 2-yl)-3-hydroxy-1 -methylpyrrolidin-2-one were collected and concentrated under reduced pressure. This product was suspended in water (10 mL), the mixture was frozen by insertion into a -78 °C bath and then lyophilized to dryness to afford (R)-3-(5- (3-(4-aminopyrido[3,2-d]pyrimidin-6-yl-2-c/)phenyl)thiazol-2 -yl)-3-hydroxy-1 - methylpyrrolidin-2-one (38.1 mg, 38%) as a colorless solid. MS (ESI): Mass calcd. for C21 H17DN6O2S, 419.1 ; m/z found, 420.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.66 - 8.63 (m, 1 H), 8.56 (d, J = 9.0 Hz, 1 H), 8.41 - 8.37 (m, 1 H), 8.34 (s, 1 H), 8.25 (br s, 1 H), 8.17 (d, J = 8.8 Hz, 1 H), 8.03 (br s, 1 H), 7.76 - 7.71 (m, 1 H), 7.64 - 7.58 (m, 1 H), 6.96 (s, 1 H), 3.59 - 3.43 (m, 2H), 2.83 (s, 3H), 2.78 - 2.71 (m, 1 H), 2.32 - 2.24 (m, 1 H).

Example 33: (R)-3-(2-(3-(4-Amino-2-c/-pyrido[3,2-c/]pynmidin-6-yl)phenyl )thiazol-4-yl)-3- hydroxy-1 -methylpyrrolidin-2-one.

Step A: (R,S)-3-(1 -Ethoxyvinyl)-3-hydroxy-1 -methylpyrrolidin-2-one. tert- Butyllithium (10.2 mL, 13.3 mmol, 1.3 M in pentane) was added dropwise to a solution of ethoxyethene (3.00 mL, 31.0 mmol) and anhydrous THF (40 mL) that had been cooled to -72 °C. The resultant mixture was warmed to 0 °C, and stirred until the color of the solution turned pale yellow. The mixture was then cooled to -72 °C, treated with a solution of 1 -methylpyrrolidine-2, 3-dione (500 mg) and anhydrous THF (10 mL), and stirred at -72 °C for 1 h. The mixture was then treated with saturated aqueous NaHCOs solution (5 mL) and water (15 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The product was purified by preparative HPLC using an HPLC column, such as a C18 column (eluent: 5% to 50%,CH3CN and H2O) to afford (R,S)-3-(1 -ethoxyvinyl)-3-hydroxy-1 -methylpyrrolidin-2- one (160 mg, 17%) as a colorless oil. MS (ESI): Mass calcd. for C9H15NO3, 185.1 , m/z found, 186.1 [M+H] ⁺ .

Step B: (R,S)-3-(2-Bromoacetyl)-3-hydroxy-1-methylpyrrolidin-2-one. /V- Bromosuccinimide (778 mg, 4.37 mmol) was added in portions to a solution of (R,S)-3- (1-ethoxyvinyl)-3-hydroxy-1-methylpyrrolidin-2-one (810 mg, 4.37 mmol) and acetone/water (9:1 , 12 mL) that had been cooled to 0 °C. The resultant mixture was stirred at room temperature for 1 hour. The mixture was then partitioned between ethyl acetate (30 mL) and water (30 mL). The organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give (R,S)-3-(2-bromoacetyl)-3-hydroxy-1-methylpyrrolidin-2-one (1.19 g) as a colorless oil which was used for the next reaction without further purification. MS (ESI): Mass calcd. for CzHioBrNOs 235.0 m/z found, 236.0 [M+H] ⁺ .

Step C: (R, S)-3-(2-(3-Chlorophenyl)thiazol-4-yl)-3-hydroxy-1 -methylpyrrolidin-2- one. (R,S)-3-(2-Bromoacetyl)-3-hydroxy-1-methylpyrrolidin-2-one (550 mg, 2.33 mmol),,

3-chlorobenzothioamide (400 mg, 2.33 mmol), and ethanol (10 mL) were added to a microwave tube. The resultant mixture was subjected to microwave irradiation at 100 °C for 1 h. After this time, the mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The resulting residue was purified by FCC (eluent: petroleum ether: ethyl acetate = 10:1 to 0:1 ) to give (R _; S)-3-(2-(3-chlorophenyl)thiazol-

4-yl)-3-hydroxy-1-methylpyrrolidin-2-one (350 mg, 48%) as a white solid. MS (ESI): Mass calcd. for C14H13CIN2O2S, 308.0; m/z found, 309.2 [M+H] ⁺ .

Step D: (R _; S)-3-Hydroxy-1-methyl-3-(2-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)thiazol-4-yl)pyrrolidin-2-one. (R,S)-3-(2-(3- Chlorophenyl)thiazol-4-yl)-3-hydroxy-1-methylpyrrolidin-2-on e (350 mg, 1.13 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (576 mg, 2.27 mmol), and KOAc (334 mg, 3.40 mmol) were added to a round-bottomed flask and the resultant mixture dissolved in 1 ,4-dioxane (30 mL). The mixture was sparged with Ar for 5 minutes and then treated with chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1 ,1- biphenyl)[2-(2-amino-1 , 1 -biphenyl)]palladium(ll) (89.2 mg, 0.113 mmol). The mixture was sparged with Ar for another 5 minutes and then heated at 110 °C for 16 h under Ar atmosphere. After this time, the mixture was cooled to room temperature, filtered through a pad of diatomaceous earth and the pad washed with ethyl acetate (20 mL x 2). The filtrate was concentrated to dryness under reduced pressure to afford (R,S)-3- hydroxy-1 -methyl-3-(2-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)thiazol-4- yl)pyrrolidin-2-one (850 mg) as a black solid, which was used in the next step without further purification. MS (ESI): Mass calcd. for C20H25BN2O4S, 400.2; m/z found, 401.1 [M+1 ] ⁺ .

Step E: (R,S)-3-(2-(3-(4-Amino-2-c/-pyrido[3,2-c/]pyrimidin-6-yl)phe nyl)thiazol-4- yl)-3-hydroxy-1-methylpyrrolidin-2-one. (R,S)-3-Hydroxy-1 -methyl-3-(2-(3-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)thiazol-4-yl)pyrrolidin-2-one (0.32 mmol), 6- chloropyrido[3,2-c(]pynmidin-2-c/-4-amine (Intermediate 17, 70 mg, 0.4 mmol), and K3PO4 (245 mg, 1.15 mmol) were added to a microwave tube, and the resultant mixture dissolved in 1 ,4-dioxane/H2O (4:1 , 2.5 mL). This mixture was sparged with Ar for 5 minutes and then treated with Pd(dtbpf)Cl2 (25 mg, 0.039 mmol). The reaction mixture was sparged with Ar for another 5 minutes and then subjected to microwave irradiation at 100 °C for 1 h. The reaction was then cooled to room temperature, poured into H2O (20 mL), and extracted with ethyl acetate (30 mL x 4). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The resulting residue was purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 0:1 , then ethyl acetate: methanol =10:1 ) to afford (R,S)-3-(2-(3-(4-amino-2-d-pyrido[3,2-c/]pyrimidin-6-yl)phen yl)thiazol-4- yl)-3-hydroxy-1 -methylpyrrolidin-2-one (100 mg, 56%) as a white solid. MS (ESI): Mass calcd. for C21 H17DN6O2S, 419.1 ; m/z found, 420.1 [M+1 ] ⁺ .

Step F: (R)-3-(2-(3-(4-Amino-2-d-pyrido[3,2-d]pyrimidin-6-yl)phenyl) thiazol-4-yl)- 3-hydroxy-1 -methylpyrrolidin-2-one. The (R) and (S) enantiomers of (R,S)-3-(2-(3-(4- amino-2-c/-pyrido[3,2-c/]pyrimidin-6-yl)phenyl)thiazol-4-yl) -3-hydroxy-1 -methylpyrrolidin- 2-one (100 mg) were separated by SFC using an SFC column, such as a DAICEL CHIRALPAK® OJ-H 250 mm x 30 mm x 5 pm column (isocratic elution EtOH : supercritical CO2, 30% : 70%). The second eluting product, (R)-3-(2-(3-(4-amino-2-c/- pyrido[3,2-c/]pynmidin-6-yl)phenyl)thiazol-4-yl)-3-hydroxy-1 -methylpyrrolidin-2-one, was collected and concentrated under reduced pressure. This product was suspended in water (10 mL), the mixture was frozen by insertion into a -78 °C bath, and then lyophilized to dryness to afford (R)-3-(2-(3-(4-amino-2-c/-pyrido[3,2-c/]pyrimidin-6- yl)phenyl)thiazol-4-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (18 mg, 18%) as a white solid. MS (ESI): Mass calcd. for C21 H17DN6O2S, 419.1 ; m/z found, 420.1 [M+1 ] ⁺ . ¹ H NMR (400 MHz, DMS0-d ₆ ) 8 8.71 - 8.67 (m, 1 H), 8.57 - 8.53 (m, 1 H), 8.51 (d, J = 8.8 Hz, 1 H), 8.19 (d, J = 9.0 Hz, 1 H), 8.15 (br s, 1 H), 8.09 - 8.02 (m, 2H), 7.71 - 7.63 (m, 2H), 6.28 (br s, 1 H), 3.63 - 3.55 (m, 1 H), 3.52 - 3.44 (m, 1 H), 2.85 (s, 3H), 2.73 - 2.64 (m, 1 H), 2.27 - 2.18 (m, 1 H).

Example 34: (R)-3-(3-(3-(4-Aminopyrido[3,2-c/]pyrimidin-6-yl-2-c/)phenyl )-1H-1 ,2,4- triazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one.

Step A: 3,5-Dibromo-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-1 ,2,4-triazole. 2- (Trimethylsilyl)ethoxymethyl chloride (2.7 mL, 15 mmol) was added dropwise to a mixture of 3,5-dibromo-1 H-1 ,2,4-triazole (3.5 g, 15 mmol), EtsN (3.0 mL, 22 mmol), molecular sieves (3.5 g), and methylene chloride (45 mL). The resultant mixture was stirred at room temperature for 30 minutes. After this time, the mixture was concentrated to dryness under reduced pressure. The resulting residue was purified by FCC (eluent: petroleum ether: EtOAc = 0:1 to 5:1 ) to afford 3,5-dibromo-1 -((2- (trimethylsilyl)ethoxy)methyl)-1 H-1 ,2,4-triazole (3.7 g, 59%) as a colorless solid.

Step B: (R,S)-3-(3-Bromo-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-1 ,2,4-triazol-5- yl)-3-hydroxy-1 -methylpyrrolidin-2-one. n-Butyllithium (3.2 mL, 2.5 M in hexanes, 8.0 mmol) was added to a solution of 3,5-dibromo-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H- 1 ,2,4-triazole (2.38 g, 6.66 mmol) and dry THF (25 mL) that had been cooled to -72 °C. The resultant mixture was stirred at -72 °C for 30 minutes before it was treated with 1 - methylpyrrolidine-2, 3-dione (905 mg, 8.00 mmol) by syringe. The resultant mixture was stirred at -72 °C for 2 h. H2O (30 mL) was added and the aqueous layer was extracted with EtOAc/MeOH (10:1 , 30 mL x 5). The organic extracts were concentrated to dryness under reduced pressure. The resulting residue was purified by preparative HPLC using an HPLC column, such as an Xtimate C18, 150 mm x 40 mm x 10 pm column (eluent: 30% to 60%, water (0.04% NH ₄ OH + 10 mM NH ₄ HCO3)-CH ₃ CN) to afford (R,S)-3-(3- bromo-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-1 ,2,4-triazol-5-yl)-3-hydroxy-1 - methylpyrrolidin-2-one. (1.65 g, 63%) as a yellow solid. MS (ESI): Mass calcd. for Ci ₃ H23BrN ₄ O ₃ Si, 390.1 ; m/z found, 391.0 [M+1] ⁺ .

Step C: 6-(3-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)pyrido[3,2- d]pyrimidin-2-c/-4-amine. A mixture of 6-(3-chlorophenyl)pyrido[3,2-c/]pynmidin-2-c/-4- amine (200 mg, 0.776 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (394 mg, 1.55 mmol), KOAc (229 mg, 2.33 mmol), and 1 ,4-dioxane (8 mL) was purged with Ar for 5 minutes. Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1 ,T- biphenyl)[2-(2'-amino-1 ,1'-biphenyl)]palladium(ll) (61 mg, 0.078 mmol) was added. The resultant mixture was purged with Ar for another 5 minutes and then subjected to microwave irradiation at 100 °C for 1 h. After this time, the mixture was cooled to room temperature, and concentrated to dryness under reduced pressure to afford the product, which was purified by FCC (eluent: petroleum ether: EtOAc = 1 :0 to 0:1 ) to give 6-(3- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)pyrido[3,2-c/]pynmidin-2-c/-4- amine (170 mg, 53%) as a yellow solid. MS (ESI): Mass calcd. for CigH2oBDN ₄ 02, 349.2; m/z found, 350.1 [M+H] ⁺ .

Step D: (R _; S)-3-(3-(3-(4-Aminopyrido[3,2-c/]pyrimidin-6-yl-2-c/)p henyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1 H-1 ,2,4-triazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one. A mixture of 6-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)pyrido[3,2- d]pyrimidin-2-c/-4-amine (150 mg, 0.430 mmol), (R,S)-3-(3-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1 H-1 ,2,4-triazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (252 mg, 0.644 mmol), K ₃ PO ₄ (274 mg, 1 .29 mmol), 1 ,4-dioxane (4 mL), and H2O (1 mL) was purged with Ar for 5 minutes. 1 ,1'-Bis(di-fe/t butylphosphino)ferrocene palladium dichloride (28 mg, 0.043 mmol) was added to the mixture. The resultant mixture was purged with Ar for another 5 minutes and the mixture was subjected to microwave irradiation at 80 °C for 1 h. After this time, the mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The resulting residue was purified by FCC (eluent: petroleum ether: EtOAc = 1 :0 to 1 :0) to afford (R, S)-3-(3-(3-(4-aminopyrido[3,2-c/]pyrimidin-6-yl-2-c/)phenyl) -1 -((2- (trimethylsilyl)ethoxy)methyl)-1 H-1 ,2,4-triazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (146 mg, 51 %) as a brown solid. MS (ESI): Mass calcd. for C26H3i DNsO3Si, 533.2; m/z found, 534.2 [M+H] ⁺ .

Step E: (R _; S)-3-(3-(3-(4-Aminopyrido[3,2-c/]pyrimidin-6-yl-2-c/)p henyl)-1 H-1 ,2,4- triazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one. Tetrabutylammonium fluoride hydrate (0.65 mL, 1 .0 M in THF, 0.65 mmol) was added to a flask containing (R,S)-3-(3-(3-(4- aminopyrido[3,2-c(]pyrimidin-6-yl-2-c/)phenyl)-1-((2-(trimet hylsilyl)ethoxy)methyl)-1 H- 1 ,2,4-triazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (116 mg, 0.217 mmol). The resultant mixture was heated at 90 °C for 16 h. The mixture was concentrated to dryness under reduced pressure. The resulting residue was initially purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 0:1 ), and then further purified by preparative HPLC using an HPLC column, such as a Boston Prime C18, 150 x 30 mm x 5 pm column (eluent: 15% to 45%, water (0.05% NH ₄ OH + 10 mM NH ₄ HCO3)-CH ₃ CN) to afford (R _; S)-3-(3-(3-(4-aminopyrido[3,2-c/]pyrimidin-6-yl-2-c/)p henyl)-1 H-1 ,2,4-triazol- 5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (68.1 mg, 72%) as a white solid. MS (ESI): Mass calcd. for C20H17DN8O2, 403.2; m/z found, 404.2 [M+H] ⁺ .

Step F: (R)-3-(3-(3-(4-Amino-2-c/-pyrido[3,2-c/]pyrimidin-6-yl)pheny l)-1 H-1 ,2,4- triazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one. The (R) and (S) enantiomers of (R,S)- 3-(3-(3-(4-aminopyrido[3,2-c/]pynmidin-6-yl-2-c/)phenyl)-1 H-1 ,2,4-triazol-5-yl)-3-hydroxy- 1 -methylpyrrolidin-2-one (68.1 mg) were separated by SFC using an SFC column, such as a DAICEL CHIRALPAK® AD, 250 x 30 mm x 10 pm column (isocratic elution IPA : supercritical CO2, 55% : 45%). The first eluting product, (R)-3-(3-(3-(4-amino-2-c/- pyrido[3,2-c/]pynmidin-6-yl)phenyl)-1 H-1 ,2,4-triazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2- one, was collected and concentrated under reduced pressure. This product was suspended in water (10 mL), the mixture was frozen by insertion into a -78 °C bath, and then lyophilized to dryness to afford (R)-3-(3-(3-(4-amino-2-d-pyrido[3,2-d]pyrimidin-6- yl)phenyl)-1 /-/-1 ,2,4-triazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (19 mg, 26%) as a white solid. MS (ESI): Mass calcd. for C20H17DN8O2, 403.2; m/z found, 404.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 14.75 - 13.50 (m, 1 H), 8.77 (s, 1 H), 8.54 - 8.42 (m, 2H), 8.18 (d, J = 8.8 Hz, 1 H), 8.12 - 7.99 (m, 3H), 7.68 - 7.60 (m, 1 H), 6.52 (br s, 1 H), 3.60 - 3.52 (m, 1 H), 3.52 - 3.45 (m, 1 H), 2.87 - 2.71 (m, 4H), 2.31 - 2.15 (m, 1 H).

Example 35: (R)-3-(1 -(3-(4-Aminopyrido[3,2-c/]pyrimidin-6-yl-2-c/)phenyl)-1/-/-1 ,2,3- triazol-4-yl)-3-hydroxy-1 -methylpyrrolidin-2-one.

Step A: 1 -Azido-3-bromobenzene. Azidotrimethylsilane (435 mg, 3.78 mmol) was added dropwise to a solution of 3-bromoaniline (500 mg, 2.91 mmol) and CH3CN (10 mL) that had been cooled to 0 °C. Then te/Y-butyl nitrite (360 mg, 3.49 mmol) was added. The mixture was stirred for 2 h with gradual warming to room temperature to yield 1 -azido-3-bromobenzene. The reaction mixture was used in the next step without further purification.

Step B: (R)-3-(1 -(3-Bromophenyl)-1/-/-1 ,2,3-triazol-4-yl)-3-hydroxy-1- methylpyrrolidin-2-one. (R)-3-Ethynyl-3-hydroxy-1 -methylpyrrolidin-2-one (Intermediate 1 , 184 mg, 1.32 mmol) was added to a solution of 1 -azido-3-bromobenzene (574 mg, 2.90 mmol, in 10 mL CH3CN), sodium 2-(1 ,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5- dihydrofuran-3-olate (52 mg, 0.26 mmol), copper(ll) sulfate (42 mg, 0.26 mmol), DMF (10 mL), and H2O (2 mL). The resultant mixture was heated at 100 °C for 16 h. The mixture was then cooled to room temperature, quenched with H2O (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The product was purified by FCC (eluent: petroleum ether: ethyl acetate = 10:1 to 0:1 ) to afford (R)-3-(1-(3-bromophenyl)-1 /-/-1 ,2,3-triazol-4-yl)-3- hydroxy-1-methylpyrrolidin-2-one (360 mg, 81 %) as a yellow oil. MS (ESI): Mass calcd. for Ci3Hi3BrN4O2, 336.0; m/z found, 337.0 [M+1] ⁺ .

Step C: (R)-3-Hydroxy-1 -methyl-3-(1 -(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)phenyl)-1 H-1 ,2,3-triazol-4-yl)pyrrolidin-2-one. (R)-3-(1 -(3-Bromophenyl)-1 H-1 ,2,3- triazol-4-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (350 mg, 1.0 mmol), 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (395 mg, 1.56 mmol), KOAc (306 mg, 3.12 mmol), and 1 ,4-dioxane (10 mL) were added to a microwave tube. The mixture was sparged with N2 for 5 minutes and then treated with Pd(dppf)Cl2 (76 mg, 0.10 mmol). The resultant mixture was subjected to microwave irradiation at 90 °C for 1 h. The mixture was then cooled to room temperature and concentrated to dryness under reduced pressure. The product was purified by FCC (eluent: petroleum ether: ethyl acetate = 10:1 to 0:1 ) to give (R)-3-hydroxy-1 -methyl-3-(1 -(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)-1 /-/-1 ,2,3-triazol-4-yl)pyrrolidin-2-one (280 mg, 61 %) as a brown oil. MS (ESI): Mass calcd. for C19H25BN4O4, 384.2; m/z found, 385.2 [M+H] ⁺ .

Step D: (R)-3-(1 -(3-(4-Aminopyrido[3,2-d]pyrimidin-6-yl-2-d)phenyl)-1 H-1 ,2,3- triazol-4-yl)-3-hydroxy-1 -methylpyrrolidin-2-one. 6-Chloropyrido[3,2-c/]pyrimidin-2-c/-4- amine (Intermediate 17, 90.0 mg, 0.50 mmol), (R)-3-hydroxy-1 -methyl-3-(1 -(3-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-1 H-1 ,2,3-triazol-4-yl)pyrrolidin-2-one (Intermediate s, 194 mg, 0.51 mmol), K3PO4 (316 mg, 1.49 mmol), 1 ,4-dioxane (5 mL), and H2O (1 mL) were added to a microwave tube. The mixture was sparged with Ar for 5 minutes and then treated with Pd(dtbpf)Cl2 (32.0 mg, 0.05 mmol). The mixture was sparged with Ar for another 5 minutes and then the resultant mixture was subjected to microwave irradiation at 90 °C for 1 h. The mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The product was initially purified by FCC (eluent: petroleum ether: ethyl acetate = 10:1 to 0:1 ). The product was then further purified by preparative HPLC using an HPLC column, such as a Phenomenex Gemini- NX C18, 75 x 30 mm x 3 pm column (eluent: 20% to 50%, CH3CN and H2O (with 0.05% NH4OH + 10 mM NH4HCO3)). The product was suspended in water (10 mL), the mixture was frozen by insertion into a -78 °C bath, and then lyophilized to dryness to afford (R)- 3-(1 -(3-(4-aminopyrido[3,2-c/]pyrimidin-6-yl-2-c/)phenyl)-1 H-1 ,2,3-triazol-4-yl)-3-hydroxy- 1 -methylpyrrolidin-2-one (74.1 mg, 36.0%) as a white solid. MS (ESI): Mass calcd. for C20H17DN8O2, 403.2; m/z found, 404.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.99 (s, 1 H), 8.84 (s, 1 H), 8.62 (d, J = 9.0 Hz, 1 H), 8.53 (d, J = 7.9 Hz, 1 H), 8.36 (br s, 1 H), 8.18 (d, J = 8.8 Hz, 1 H), 8.11 - 8.03 (m, 2H), 7.79 - 7.70 (m, 1 H), 6.31 (s, 1 H), 3.54 - 3.43 (m, 2H), 2.83 (s, 3H), 2.78 - 2.70 (m, 1 H), 2.35 - 2.23 (m, 1 H). Example 36: (S)-3-(1 -(3-(4-Aminopyrido[3,2-d]pyrimidin-6-yl-2-c/)phenyl)-1 H-1 ,2,3- triazol-4-yl)-3-hydroxy-1 -methylpyrrolidin-2-one.

Step A: (S)-3-(1 -(3-Bromophenyl)-1 H-1 ,2,3-triazol-4-yl)-3-hydroxy-1 - methylpyrrolidin-2-one. (S)-3-Ethynyl-3-hydroxy-1 -methylpyrrolidin-2-one (Intermediate 2, 202 mg, 1.45 mmol) was added to a solution of 1 -azido-3-bromobenzene (633 mg, 3.20 mmol in 10 mL CH3CN), sodium 2-(1 ,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5- dihydrofuran-3-olate (57 mg, 0.29 mmol), copper(ll) sulfate (46 mg, 0.29 mmol), DMF (15 mL), and H2O (3 mL). The mixture was heated at 100 °C for 16 hours. The mixture was then cooled to room temperature, quenched with H2O (80 mL), and extracted with ethyl acetate (60 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by FCC (eluent: petroleum ether: ethyl acetate = 10:1 to 0:1 ) to give (S)-3- (1-(3-bromophenyl)-1H-1 ,2,3-triazol-4-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (360 mg, 74%) as a yellow oil. MS (ESI): Mass calcd. or GnHisBrlSUCte 336.0 m/z found 337.0 [M+H] ⁺ .

Step B: (S)-3-Hydroxy-1 -methyl-3-(1 -(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)phenyl)-1 H-1 ,2,3-triazol-4-yl)pyrrolidin-2-one. (S)-3-(1 -(3-Bromophenyl)-1 H-1 ,2,3- triazol-4-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (360 mg, 1.1 mmol) was added to a mixture of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane (691 mg, 2.72 mmol), KOAc (315 mg, 3.21 mmol), and 1 ,4-dioxane (15 mL). The mixture was sparged with Ar for 5 minutes and then treated with Pd(dppf)Cl2 (78 mg, 0.11 mmol). The mixture was sparged with Ar for another 5 minutes and then subjected to microwave irradiation at 85 °C for 1 hour. The mixture was then cooled to room temperature and concentrated to dryness. The product was purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 0:1 ) to afford (S)-3-hydroxy-1 -methyl-3-(1 -(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)phenyl)-1 H-1 ,2,3-triazol-4-yl)pyrrolidin-2-one (350 mg, 53%) as a brown oil. MS (ESI): Mass calcd. for C19H25BN4O4, 384.2; m/z found, 385.2 [M+H] ⁺ .

Step C: (S)-3-(1 -(3-(4-Aminopyrido[3,2-c/]pyrimidin-6-yl-2-c/)phenyl)-1 H-1 ,2,3- triazol-4-yl)-3-hydroxy-1 -methylpyrrolidin-2-one. (S)-3-Hydroxy-1 -methyl-3-(1 -(3- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-1 H-1 , 2, 3-triazol-4-y l)pyrrolid in-2- one (165 mg, 0.429 mmol), 6-chloropyrido[3,2-c/]pynmidin-2-c/-4-amine (Intermediate 17, 95 mg, 0.47 mmol), K3PO4 (273 mg, 1.29 mmol), 1 ,4-dioxane (12 mL), and H2O (3 mL) were added to a microwave tube. The mixture was sparged with Ar for 5 minutes and then treated with Pd(dtbpf)Cl2 (28 mg, 0.043 mmol). The mixture was sparged with Ar for another 5 minutes and then subjected to microwave irradiation at 90 °C for 1 h before cooling to room temperature. The reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was initially purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 0:1 , then ethyl acetate: methanol = 1 :0 to 10:1 ). This product was further purified by preparative HPLC using an HPLC column, such as a Phenomenex Gemini NX-C18 75 mm x 30 mm x 3 pm column (eluent: 15% to 45%, CH3CN and H2O (with 10 mM NH4HCO3)). The product was then suspended in water (10 mL), the mixture was frozen by insertion into a -78 °C bath, and then lyophilized to dryness to afford (S)-3-(1 -(3-(4-aminopyndo[3,2-c/]pyrimidin-6-yl-2-c/)phenyl)-1 H-1 ,2,3- triazol-4-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (31.5 mg, 18%) as a white solid. MS (ESI): Mass calcd. for C20H17DN8O2, 403.2; m/z found, 404.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-c/e) 8 8.99 (s, 1 H), 8.85 (m, 1 H), 8.62 (d, J = 9.0 Hz, 1 H), 8.54 (d, J = 7.8 Hz, 1 H), 8.36 (s, 1 H), 8.19 (d, J = 8.8 Hz, 1 H), 8.12 - 8.03 (m, 2H), 7.80 - 7.71 (m, 1 H), 6.31 (s, 1 H), 3.56 - 3.45 (m, 2H), 2.84 (s, 3H), 2.80 - 2.71 (m, 1 H), 2.35 - 2.24 (m, 1 H).

Example 37: (S)-3-(5-(3-(4-Aminopyrido[3,2-d]pyrimidin-6-yl-2-c/)phenyl) -1 H-pyrazol-3- yl)-3-hydroxy-1-methylpyrrolidin-2-one.

Step A: (R _; S)-3-(3-(3-(4-aminopyrido[3,2-c/]pyrimidin-6-yl-2-c/)p henyl)-1 -((2- (trimethylsilyl)ethoxy)methyl)-1 H-pyrazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one. 6-(3- (4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)pyrido[3,2-c/]pyrimidin-2-c/-4 -amine (Example 34, step C, 116 mg, 0.33 mmol), (R,S)-3-(3-bromo-1 -((2- (trimethylsilyl)ethoxy)methyl)-1 H-pyrazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (Example 31 , step B, 194 mg, 0.49 mmol), and CS2CO3 (325 mg, 0.99 mmol) were added to a microwave tube and the mixture dissolved in 1 ,4-dioxane (1 .6 mL) and H2O (0.4 mL). The resultant mixture was purged with Ar for 5 minutes and then treated with chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1 ,1-biphenyl)[2-(2-amino-1 ,1- biphenyl)]palladium( 11) (26 mg, 0.033 mmol). This mixture was purged with Ar for another 5 minutes and then subjected to microwave irradiation at 100 °C for 1 hour. The mixture was then concentrated to dryness under reduced pressure to give the product which was purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 0:1 ) to afford (R _; S)-3-(3-(3-(4-aminopyrido[3,2-c(]pyrimidin-6-yl-2-c/)p henyl)-1 -((2- (trimethylsilyl)ethoxy)methyl)-1 /-/-pyrazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (127 mg, 55%) as a yellow solid. MS (ESI): Mass calcd. for C27H32DN?O3Si, 532.3; m/z found, 533.5 [M+H] ⁺ .

Step B: (R _; S)-3-(5-(3-(4-Aminopyrido[3,2-c/]pyrimidin-6-yl-2-c/)p henyl)-1 /-/- pyrazol-3-yl)-3-hydroxy-1 -methylpyrrolidin-2-one. (R,S)-3-(3-(3-(4-aminopyrido[3,2- d]pyrimidin-6-yl-2-c/)phenyl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1/-/-pyrazol-5-yl)-3- hydroxy-1 -methylpyrrolidin-2-one (127 mg, 0.24 mmol) was added to a solution of TBAF (0.72 mL, 1.0 M in THF, 0.72 mmol). The resultant mixture was heated at 90 °C for 16 hours. The mixture was then concentrated to dryness under reduced pressure. The resulting residue was purified by FCC (eluent: ethyl acetate: methanol = 1 :0 to 10:1 ) to afford (R,S)-3-(5-(3-(4-aminopyrido[3,2-c(]pyrimidin-6-yl-2-c0pheny l)-1 /-/-pyrazol-3-yl)-3- hydroxy-1 -methylpyrrolidin-2-one (71 mg, 65%) as a yellow solid. MS (ESI): Mass calcd. for C21 H18DN7O2, 402.2; m/z found, 403.4 [M+H] ⁺ .

Step C: (S)-3-(5-(3-(4-Aminopyrido[3,2-d]pyrimidin-6-yl-2-c/)phenyl) -1 /-/-pyrazol-3- yl)-3-hydroxy-1 -methylpyrrolidin-2-one. The (R) and (S) enantiomers of (R,S)-3-(3-(3- (4-amino-2-c/-pyrido[3,2-c/]pyrimidin-6-yl)phenyl)-1 /-/-pyrazol-5-yl)-3-hydroxy-1- methylpyrrolidin-2-one (71 mg, 0.15 mmol) were separated by SFC using an SFC column, such as a DAICEL CHIRALCEL® OJ-H 250 mm x 30 mm x 5 pm column (isocratic elution, EtOH : supercritical CO2 = 50% : 50%). The first eluting product was (S)-3-(5-(3-(4-aminopyrido[3,2-c(]pyrimidin-6-yl-2-c/)phenyl )-1 /-/-pyrazol-3-yl)-3-hydroxy- 1 -methylpyrrolidin-2-one and the second eluting product was (R)-3-(5-(3-(4- aminopyrido[3,2-c(]pyrimidin-6-yl-2-c0phenyl)-1 /-/-pyrazol-3-yl)-3-hydroxy-1 - methylpyrrolidin-2-one (Example 38). (S)-3-(5-(3-(4-Aminopyrido[3,2-c(]pyrimidin-6-yl-2- c/)phenyl)-1 /-/-pyrazol-3-yl)-3-hydroxy-1 -methylpyrrolidin-2-one was collected and concentrated under reduced pressure. This residue was then suspended in water (10 mL), the mixture was frozen by insertion into a -78 °C bath, and then lyophilized to dryness to afford (S)-3-(5-(3-(4-aminopyndo[3,2-c/]pyrimidin-6-yl-2-c/)phenyl) -1 /-/- pyrazol-3-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (21 mg, 33%) as a colorless solid. MS (ESI): Mass calcd. for C21 H18DN7O2, 402.4; m/z found, 403.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-c/e) 8 13.39 - 12.70 (m, 1 H), 8.77 - 8.64 (m, 1 H), 8.53 (d, J = 8.8 Hz, 1 H), 8.36 (d, J = 7.9 Hz, 1 H), 8.21 - 8.01 (m, 3H), 7.96 - 7.79 (m, 1 H), 7.65 - 7.54 (m, 1 H), 6.91 (s, 1 H), 6.38 - 5.73 (m, 1 H), 3.42 - 3.42 (m, 2H), 2.80 (s, 3H), 2.71 - 2.59 (m, 1 H), 2.31 - 2.09 (m, 1 H).

Example 38: (R)-3-(5-(3-(4-Aminopyrido[3,2-d]pyrimidin-6-yl-2-c/)phenyl) -1/-/-pyrazol-3- yl)-3-hydroxy-1 -methylpyrrolidin-2-one. (R)-3-(5-(3-(4-Am inopyrido[3,2-c/]pyrimidin-6-yl-2-c/)phenyl)-1 /-/-pyrazol-3-yl)-3- hydroxy-1-methylpyrrolidin-2-one, the second eluting product from Example 37, was further purified with preparative HPLC using an HPLC column, such as a Phenomenex Gemini NX-C18 75 x 30 mm x 3 pm column (eluent: 15% to 45%, CH3CN and H2O (with 0.05% NH4OH and 10 mM NH4HCO3)). The product was suspended in water (10 mL), the mixture was frozen by insertion into a -72 °C bath, and then lyophilized to dryness to afford (R)-3-(5-(3-(4-aminopyrido[3,2-c/]pyrimidin-6-yl-2-c0phenyl) -1 /-/-pyrazol-3-yl)-3- hydroxy-1 -methylpyrrolidin-2-one (12 mg, 17%) as a colorless solid. MS (ESI): Mass calcd. for C21 H18DN7O2, 402.43; m/z found 403.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 13.35 - 12.72 (m, 1 H), 8.81 - 8.60 (m, 1 H), 8.53 (d, J = 8.8 Hz, 1 H), 8.36 (d, J = 7.9 Hz, 1 H), 8.23 - 7.79 (m, 4H), 7.66 - 7.53 (m, 1 H), 6.91 (s, 1 H), 6.41 - 5.78 (m, 1 H), 3.48 - 3.43 (m, 2H), 2.80 (s, 3H), 2.75 - 2.61 (m, 1 H), 2.32 - 2.07 (m, 1 H).

Example 39: (R)-3-(2-(3-(4-Aminopyrido[3,2-d]pyrimidin-6-yl-2-c/)phenyl) oxazol-5-yl)-3- hydroxy-1-methylpyrrolidin-2-one.

Step A: 2-(3-Chlorophenyl)oxazole. 1 -Bromo-3-chlorobenzene (4.0 g, 21 mmol), oxazole (1.7 g, 25 mmol) and LiOtBu (3.3 g, 41 mmol) were added to 1 ,4-dioxane (40 mL). The mixture was sparged with N2 for 2 minutes and then treated with Pd(PPhs)4 (2.4 g, 2.1 mmol). The mixture was sparged with N2 for another 2 minutes and then heated at 100 °C for 12 hours under a N2 atmosphere. After this time, the mixture was cooled to room temperature and filtered. The filtrate was diluted with water (80 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the product, which was purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 7:3) to afford 2-(3-chlorophenyl)oxazole (3.5 g, 80%) as a colorless oil. MS (ESI): Mass calcd. for CgHeCINO, 179.0; m/z found, 180.2 [M+H] ⁺ .

Step B: 5-Bromo-2-(3-chlorophenyl)oxazole. /V-Bromosuccinimide (1.75 g, 9.83 mmol) was added to a mixture of 2-(3-chlorophenyl)oxazole (1.75 g, 9.74 mmol) and DMF (10 mL). The resultant mixture was subjected to microwave irradiation at 80 °C for 20 minutes. After this time, the mixture was diluted with water (80 mL) and extracted with ethyl acetate (80 mL x 2). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the product, which was purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 20:1 ) to afford 5-bromo-2-(3-chlorophenyl)oxazole (3.0 g) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 7.94 - 7.88 (m, 2H), 7.65 - 7.55 (m, 2H), 7.53 (s, 1 H).

Step C: 4-Bromo-2-(3-chlorophenyl)oxazole. Lithium diisopropylamide (12 mL, 24 mmol, 2.0 M in THF) was added to a mixture of 5-bromo-2-(3-chlorophenyl)oxazole (3.0 g, 11.6 mmol) and THF (20 mL) that had been cooled to -72 °C . The resultant mixture was stirred at -72 °C for 30 minutes. After this time, the mixture was warmed to room temperature, diluted with saturated aqueous NH4CI solution (60 mL), and extracted with ethyl acetate (60 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the product, which was purified by preparative HPLC using an HPLC column, such as a YMC-Triart Prep C18 150 x 40 mm x 7 pm column (eluent: 62% to 72%, H2O (0.04% NH4OH +10 mM NH4HCO3)-CH3CN). This product was then suspended in water (10 mL), the mixture was frozen by insertion into a -78 °C bath, and then lyophilized to dryness to afford 4-bromo-2-(3-chlorophenyl)oxazole (700 mg, 23%) as a yellow solid. MS (ESI): Mass calcd. for CgHsBrCINO, 256.9 m/z; found 257.9 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-c/e) 8 8.54 (s, 1 H), 7.96 - 7.91 (m, 2H), 7.67 - 7.56 (m, 2H).

Step D: (R,S)-3-(2-(3-Chlorophenyl)oxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2- one. n-Butyllithium (1.3 mL, 2.5 M in hexanes, 3.3 mmol) was added dropwise to a solution of 4-bromo-2-(3-chlorophenyl)oxazole (700 mg, 2.71 mmol) and THF (10 mL) that had been cooled to -72 °C. The resultant mixture was stirred at -72 °C for 20 minutes before it was treated with a solution of 1 -methylpyrrolidine-2, 3-dione (371 mg, 3.28 mmol) in THF (5 mL). This mixture was stirred at -72 °C for 2 h. After this time, the mixture was diluted with saturated aqueous NH4CI solution (30 mL) and extracted with ethyl acetate (30 mLx 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the product, which was purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 0:1 ) to afford (R,S)~ 3-(2-(3-chlorophenyl)oxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (200 mg, 22%) as a colorless oil. MS (ESI): Mass calcd. for C14H13CIN2O3, 292.1 ; m/z found, 293.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 7.97 - 7.88 (m, 2H), 7.66 - 7.53 (m, 2H), 7.28 (s, 1 H), 6.53 (s, 1 H), 3.50 - 3.39 (m, 2H), 2.82 (s, 3H), 2.65 - 2.55 (m, 1 H), 2.29 - 2.18 (m, 1 H).

Step E: (R,S)-3-Hydroxy-1-methyl-3-(2-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)oxazol-5-yl)pyrrolidin-2-one. A mixture of (R,S)-3-(2-(3- chlorophenyl)oxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (200 mg, 0.68 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane (696 mg, 2.74 mmol), KOAc (404 mg, 4.12 mmol), and 1 ,4-dioxane (10 mL) was sparged with N2 for 2 minutes and then treated with chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1 ,1 '-biphenyl)[2-(2'- amino-1 ,T-biphenyl)]palladium(ll) (160 mg, 0.20 mmol). The resultant mixture was sparged with N2 for another 2 minutes and then subjected to microwave irradiation at 90 °C for 1 h. After this time, the mixture was cooled to room temperature and filtered. The filtrate was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the product, which was purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 0:1 ) to afford (R,S)-3- hydroxy-1 -methyl-3-(2-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)oxazol-5- yl)pyrrolidin-2-one (270 mg, 76%) as a colorless oil. MS (ESI): Mass calcd. for C20H25BN2O5, 384.2; m/z found, 385.4 [M+H] ⁺ .

Step F: (R _; S)-3-(2-(3-(4-Aminopyrido[3,2-c/]pynmidin-6-yl-2-c/)ph enyl)oxazol-5-yl)- 3-hydroxy-1 -methylpyrrolidin-2-one. A mixture of (R,S)-3-hydroxy-1 -methyl-3-(2-(3- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)oxazol-5-yl)pyrrolidin-2-one (220 mg, 0.57 mmol), 6-chloropyrido[3,2-c/]pyrimidin-2-c/-4-amine (Intermediate 17, 136 mg, 0.75 mmol), K3PO4 (233 mg, 1.10 mmol), and 1 ,4-dioxane:H2O (4:1 , 10 mL) was sparged with N2 for 2 minutes and then treated with Pd(dtbpf)Cl2 (75.0 mg, 0.12 mmol). The resultant mixture was sparged with N2 for another 2 minutes and then subjected to microwave irradiation at 100 °C for 1 h. After this time, the mixture was cooled to room temperature and filtered. The filtrate was diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC using an HPLC column, such as a Phenomenex Gemini-NX 80 x 40 mm x 3 pm column (eluent: 16% to 41 %, H2O (0.04% NH4OH + 10 mM NH4HCO3)-CH3CN) to afford the product. This product was then suspended in water (10 mL), the mixture was frozen by insertion into a -78 °C bath, and then lyophilized to dryness to afford (R,S)-3-(2-(3-(4-aminopyrido[3,2-c/]pyrimidin-6-yl-2- c/)phenyl)oxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (53 mg, 21 %) as a yellow solid. MS (ESI): Mass calcd. for CgHsBrCINO, 403.4; m/z found 404.4 [M+H] ⁺ .

Step G: (R)-3-(2-(3-(4-Aminopyrido[3,2-c/]pyrimidin-6-yl-2-c0phenyl) oxazol-5-yl)- 3-hydroxy-1 -methylpyrrolidin-2-one. The (R) and (S) enantiomers of (R,S)-3-(2-(3-(4- aminopyrido[3,2-c(]pyrimidin-6-yl-2-c0phenyl)oxazol-5-yl)-3- hydroxy-1-methylpyrrolidin-2- one (53 mg, 0.13 mmol) were separated by SFC using an SFC column, such as a DAICEL CHIRALPAK® AD 250 mm x 30 mm x 10 pm column (isocratic elution: EtOH (containing 0.1 % of 25% aqueous NH3 solution): supercritical CO2, 55%: 45%). The first eluting product was (R)-3-(2-(3-(4-aminopyrido[3,2-d]pyrimidin-6-yl-2-c/)phenyl) oxazol-5- yl)-3-hydroxy-1 -methylpyrrolidin-2-one and the second eluting product was (S)-3-(2-(3- (4-aminopyrido[3,2-c(]pyrimidin-6-yl-2-c/)phenyl)oxazol-5-yl )-3-hydroxy-1 - methylpyrrolidin-2-one (Example 40). The fractions containing (R)-3-(2-(3-(4- aminopyrido[3,2-c(]pyrimidin-6-yl-2-c0phenyl)oxazol-5-yl)-3- hydroxy-1-methylpyrrolidin-2- one were collected and concentrated under reduced pressure. This product was suspended in water (10 mL), the mixture was frozen by insertion into a -78 °C bath, and then lyophilized to dryness to afford (R)-3-(2-(3-(4-aminopyrido[3,2-d]pyrimidin-6-yl-2- c/)phenyl)oxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (22.5 mg, 42%) as a white solid. MS (ESI): Mass calcd. for C21 H17DN6O3, 403.2; m/z found, 404.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 8 8.77 (s, 1 H), 8.62 (d, J = 7.9 Hz, 1 H), 8.50 (d, J = 8.8 Hz, 1 H), 8.19 (d, J = 8.8 Hz, 1 H), 8.14 - 8.01 (m, 3H), 7.77 - 7.67 (m, 1 H), 7.29 (s, 1 H), 6.73 - 6.31 (m, 1 H), 3.51 - 3.41 (m, 2H), 2.84 (s, 3H), 2.71 - 2.61 (m, 1 H), 2.33 - 2.22 (m, 1 H). Example 40: (S)-3-(2-(3-(4-Aminopyrido[3,2-d]pyrimidin-6-yl-2-c/)phenyl) oxazol-5-yl)-3- hydroxy-1-methylpyrrolidin-2-one.

(S)-3-(2-(3-(4-Aminopyrido[3,2-c/]pynmidin-6-yl-2-c/)phen yl)oxazol-5-yl)-3- hydroxy-1-methylpyrrolidin-2-one was the second eluting product from Example 39. The fractions containing this product were collected and concentrated under reduced pressure. The product was suspended in water (10 mL), the mixture was frozen by insertion into a -78 °C bath, and then lyophilized to dryness to afford (S)-3-(2-(3-(4- aminopyrido[3,2-c(]pyrimidin-6-yl-2-c0phenyl)oxazol-5-yl)-3- hydroxy-1-methylpyrrolidin-2- one (20.6 mg, 38%) as a white solid. MS (ESI): Mass calcd. for C21 H17DN6O3, 403.2; m/z found, 404.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.77 (s, 1 H), 8.62 (d, J = 8.0 Hz, 1 H), 8.50 (d, J = 8.9 Hz, 1 H), 8.19 (d, J = 8.8 Hz, 1 H), 8.15 - 8.00 (m, 3H), 7.76 - 7.68 (m, 1 H), 7.29 (s, 1 H), 6.68 - 6.42 (m, 1 H), 3.51 - 3.41 (m, 2H), 2.84 (s, 3H), 2.71 - 2.62 (m, 1 H), 2.32 - 2.22 (m, 1 H).

Example 41 : (R)-3-(2-(3-(4-Aminopyrido[3,2-d]pyrimidin-6-yl-2-c/)phenyl) oxazol-4-yl)-3- hydroxy-1 -methylpyrrolidin-2-one.

Step A: (R, S)-3-(2-(3-Chlorophenyl)oxazol-4-yl)-3-hydroxy-1 -methylpyrrolidin-2- one. n-Butyllithium (1.9 mL, 0.48 mmol, 2.5 M in hexanes) was added dropwise to a solution of 4-bromo-2-(3-chlorophenyl)oxazole (1.0 g, 3.9 mmol) in methylene chloride (10 mL ) that had been cooled to -72 °C. The resultant mixture was stirred at -72 °C for 20 minutes, treated with a solution of 1 -methylpyrrolidine-2, 3-dione (530 mg, 4.7 mmol) in methylene chloride (5 mL), and stirred at -72 °C for 2 hours. After this time, the mixture was quenched with saturated aqueous NhUCI solution (30 mL), warmed to room temperature, and extracted with ethyl acetate (50 mL x 2). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 1 :2) to afford (R,S)-3-(2-(3- chlorophenyl)oxazol-4-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (470 mg, 38%) as a yellow solid. MS (ESI): Mass calcd. for C14H13CIN2O3, 292.1 ; m/z found 293.2 [M+H] ⁺ .

Step B: (R,S)-3-Hydroxy-1-methyl-3-(2-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)oxazol-4-yl)pyrrolidin-2-one. (R,S)-3-(2-(3- Chlorophenyl)oxazol-4-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (470 mg, 0.161 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (815 mg, 3.21 mmol), KOAc (0.94 g, 9.6 mmol), and 1 ,4-dioxane (10 mL) were added to microwave tube. The resultant mixture was sparged with N2 for 5 minutes, treated with chloro(2- dicyclohexylphosphino-2',4',6'-triisopropyl-1 , 1 '-biphenyl)[2-(2'-amino-1 , 1 '- biphenyl)]palladium(l I) (376 mg, 0.478 mmol), sparged with N2 for another 5 minutes, and then subjected to microwave irradiation at 90 °C for 1 h. After this time, the mixture was cooled to room temperature and filtered. The filtrate was concentrated to afford (R,S)-3-hydroxy-1 -methyl-3-(2-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)oxazol-4-yl)pyrrolidin-2-one (750 mg) as a black solid. MS (ESI): Mass calcd. for C20H25BN2O5, 384.2; m/z found 385.4 [M+H] ⁺ .

Step C: (R,S)-3-(2-(3-(4-Aminopyrido[3,2-c/]pyrimidin-6-yl-2-c0pheny l)oxazol-4- yl)-3-hydroxy-1-methylpyrrolidin-2-one. (R,S)-3-Hydroxy-1 -methyl-3-(2-(3-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)oxazol-4-yl)pyrrolidin-2-one (750 mg, 1.96 mmol), 6-chloropyrido[3,2-c/]pyrimidin-2-c/-4-amine (Intermediate 17, 100 mg, 0.60 mmol) and K3PO4 (225 mmol, 1 .06 mmol) were added to a microwave tube and the resultant mixture dissolved in 1 ,4-dioxane/H2O (4:1 ) (10 mL). This mixture was sparged with N2 for 5 minutes and then treated with Pd(dtbpf)Cl2 (36 mg, 0.055 mmol). The mixture was sparged with N2 for another 5 minutes and then subjected to microwave irradiation at 100 °C for 1 h. After this time, the mixture was cooled to room temperature and filtered. The filtrate was diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the product, which was purified by preparative HPLC using an HPLC column, such as a Xtimate C18 150 x 40 mm x 5 pm column (eluent: 19% to 39%, H2O (0.04% NH4OH + 10 mM NH4HCO3) : CH3CN). The product was suspended in water (10 mL), the mixture was frozen by insertion into a -78 °C bath, and then lyophilized to dryness to afford (R,S)-3-(2-(3-(4-aminopyrido[3,2-c(]pyrimidin-6-yl-2-c0pheny l)oxazol-4-yl)-3-hydroxy-1 - methylpyrrolidin-2-one (50 mg, 18%) as a yellow solid. MS (ESI): Mass calcd. for C21 H17DN6O3, 403.2; m/z found 404.2 [M+H] ⁺ .

Step D: (R)-3-(2-(3-(4-Aminopyrido[3,2-c(]pyrimidin-6-yl-2-c0phenyl) oxazol-4-yl)- 3-hydroxy-1 -methylpyrrolidin-2-one. The (R) and (S) enantiomers of (R,S)-3-(2-(3-(4- aminopyrido[3,2-c(]pyrimidin-6-yl-2-c0phenyl)oxazol-4-yl)-3- hydroxy-1-methylpyrrolidin-2- one (50 mg, 0.124 mmol) were separated by SFC using an SFC column, such as a DAICEL CHIRALCEL® OD-H, 250 mm x 30 mm x 5 pm column using an isocratic elution of EtOH : supercritical CO2 (35% : 65%). The second eluting enantiomer was (R)-3-(2-(3-(4-aminopyrido[3,2-c/]pyrimidin-6-yl-2-c0phenyl) oxazol-4-yl)-3-hydroxy-1- methylpyrrolidin-2-one. The fractions containing this compound were collected and concentrated under reduced pressure. The product was suspended in water (10 mL), the mixture was frozen by insertion into a -78 °C bath, and then lyophilized to dryness to afford (R)-3-(2-(3-(4-aminopyrido[3,2-c/]pynmidin-6-yl-2-c/)phenyl) oxazol-4-yl)-3-hydroxy- 1 -methylpyrrolidin-2-one (14.5 mg, 29%) as a colorless solid. MS (ESI): Mass calcd. for C21 H17DN6O3, 403.15; m/z found, 404.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.76 (s, 1 H), 8.60 (d, J = 7.7 Hz, 1 H), 8.53 - 8.48 (m, 1 H), 8.21 - 8.15 (m, 2H), 8.12 - 8.01 (m, 3H), 7.74 - 7.68 (m, 1 H), 6.39 - 6.06 (m, 1 H), 3.49 - 3.45 (m, 2H), 2.84 (s, 3H), 2.66 - 2.57 (m, 1 H), 2.25 - 2.15 (m, 1 H).

Example 42: (S)-6-(3-(4-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 H-1 , 2, 3-triazol-1 - yl)phenyl)picolinamide.

(S)-3-Hydroxy-1 -methyl-3-(1 -(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)-1 /-/-1 ,2,3-triazol-4-yl)pyrrolidin-2-one (Example 36, step B, 165 mg, 0.429 mmol), 6-chloropicolinamide (82 mg, 0.47 mmol), K3PO4 (273 mg, 1.29 mmol), 1 ,4- dioxane (8 mL), and H2O (2 mL) were added to a microwave tube. The mixture was sparged with Ar for 5 minutes and then treated with Pd(dtbpf)Cl2 (28 mg, 0.043 mmol). The mixture was sparged with Ar for another 5 minutes and then subjected to microwave irradiation at 90 °C for 1 h. After this time, the mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The resulting residue was initially purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 0:1 ). The product was further purified by preparative HPLC using an HPLC column, such as a Phenomenex Gemini NX-C18, 75 mm x 30 mm x 3 pm column (eluent: 20% to 50%,CH3CN and H2O (with 10 mM NH4HCO3)) to afford the product. The product was suspended in water (10 mL), the mixture was frozen by insertion into a -78 °C bath, and then lyophilized to dryness to afford (S)-6-(3-(4-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)-1/-/-1 ,2,3-triazol-1-yl)phenyl)picolinamide (20 mg, 12%) as a white solid. MS (ESI): Mass calcd. for CwHisNeOs, 378.1 ; m/z found, 379.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-cfe) 8 8.96 (s, 1 H), 8.75 - 8.70 (m, 1 H), 8.53 (s, 1 H), 8.43 (d, J = 7.9 Hz, 1 H), 8.37 (d, J = 7.7 Hz, 1 H), 8.16 - 8.09 (m, 1 H), 8.08 - 8.02 (m, 2H), 7.77 (s, 1 H), 7.76 - 7.71 (m, 1 H), 6.30 (s, 1 H), 3.54 - 3.44 (m, 2H), 2.83 (s, 3H), 2.79 - 2.71 (m, 1 H), 2.32 - 2.22 (m, 1 H).

Example 43. (R)-3-(5-(3-(4-Aminopyrido[3,2-c/]pyrimidin-6-yl-2-c/)phenyl )-1-methyl-1 /-/- pyrazol-3-yl)-3-hydroxy-1 -methylpyrrolidin-2-one.

Step A: 3,5-Dibromo-1-methyl-1/-/-pyrazole. Sodium hydride (2.51 g, 60 wt. % in mineral oil, 62.8 mmol) was added to a solution of 3,5-dibromo-1/-/-pyrazole (7.00 g, 31 .0 mmol) and THF (80 mL) that had been cooled to 0 °C. The mixture was then stirred at 0 °C for 1 hour, treated with methyl iodidie (15.6 g, 110 mmol) dropwise, and then stirred for 2 h with gradual warming to room temperature. After this time, the mixture was quenched with with saturated aqueous NH4CI solution (100 mL), and extracted with ethyl acetate (200 mL x 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The resulting residue was purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 1 :1 ) to afford 3,5-dibromo-1-methyl-1/-/-pyrazole (7.0 g, 84%) as a yellow oil. MS (ESI): Mass calcd. for C4H4Br2N2, 237.9; m/z found, 238.8 [M+H] ⁺ .

Step B: 3-Bromo-5-(3-chlorophenyl)-1-methyl-1/-/-pyrazole. 3,5-Dibromo-1- methyl-1/-/-pyrazole (7.00 g, 29.0 mmol) was added to a mixture of (3- chlorophenyl)boronic acid (3.88 g, 24.8 mmol), K2CO3 (12.1 g, 87.5 mmol), 1 ,4-dioxane (100 mL), and H2O (20 mL). The mixture was sparged with Ar for 5 minutes and then treated with Pd(dppf)Cl2 (2.14 g, 2.93 mmol). The mixture was sparged with Ar for another 5 minutes and then heated at 105 °C for 16 h. After this time, the mixture was cooled to room temperature, poured into H2O (30 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give the product, which was initially purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 3:1 ). The product was further purified by preparative HPLC using an HPLC column, such as an Xtimate C18, 150 x 40 mm x 5 pm column (eluent: 45% to 75%, CH3CN and H2O (with 0.05% NH4OH)) to afford product. The product was suspended in water (10 mL), the mixture was frozen by insertion into a -72 °C bath, and then lyophilized to dryness to afford 3-bromo-5-(3-chlorophenyl)-1 -methyl-1 /-/-pyrazole (2.5 g, 30%) as a white solid. MS (ESI): Mass calcd. for Ci oHsBrCIN2, 270.0; m/z found, 271 .0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 7.65 - 7.63 (m, 1 H), 7.56 - 7.51 (m, 3H), 6.64 (s, 1 H), 3.83 (s, 3H).

Step C: 3-(5-(3-Chlorophenyl)-1 -methyl-1 /-/-pyrazol-3-yl)-3-hydroxy-1 - methylpyrrolidin-2-one. n-BuLi (1.62 mL, 4.05 mmol, 2.5 M in hexanes) was added dropwise to a solution of 3-bromo-5-(3-chlorophenyl)-1 -methyl-1 H-pyrazole (1.0 g, 3.7 mmol) and methlyene chloride (15 mL) that had been cooled to -70 °C under a N2 atmosphere. The resultant mixture was stirred at -70 °C for 0.5 hour before it was treated with a solution of 1 -methylpyrrolidine-2, 3-dione (500 mg, 4.4 mmol) in methlyene chloride (5 mL). The resultant mixture was stirred at -70 °C for another 1 h. After this time, the mixture was quenched with saturated aqueous NH4CI solution (50 mL), warmed to room temperature, and extracted with ethyl acetate (80 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The resulting residue was purified by FCC (eluent: petroleum ether: ethyl acetate = 0:1 to 0:1 ) to afford 3-(5-(3-chlorophenyl)- 1 -methyl-1 H-pyrazol-3-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (500 mg, 44%) as a yellow solid. MS (ESI): Mass calcd. for C15H16CIN3O2, 305.1 ; m/z found, 306.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 7.59 - 7.57 (m, 1 H), 7.54 - 7.47 (m, 3H), 7.54 - 7.47 (m, 1 H), 6.49 (s, 1 H), 3.80 (s, 3H), 3.39 - 3.35 (m, 2H), 2.76 (s, 3H), 2.69 - 2.62 (m, 1 H), 2.16 - 2.08 (m, 1 H).

Step D: 3-Hydroxy-1 -methyl-3-(1 -methyl-5-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)-1 /-/-pyrazol-3-yl)pyrrolidin-2-one. Chloro(2- dicyclohexylphosphino-2',4',6'-triisopropyl-1 , 1 '-biphenyl)[2-(2'-amino-1 , 1 '- biphenyl)]palladium(l I) (129 mg, 0.16 mmol) was added to a mixture of 3-(5-(3- chlorophenyl)-1 -methyl-1 /-/-pyrazol-3-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (500 mg, 1.6 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (831 mg, 3.27 mmol), KOAc (481 mg, 4.90 mmol), and 1 ,4-dioxane (30 mL) under a N2 atmosphere. The resultant mixture was heated at 110 °C for 6 h. After this time, the mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The resulting residue was purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 0:1 ) to afford 3-hydroxy-1 -methyl-3-(1 -methyl-5-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)-1 /-/-pyrazol-3-yl)pyrrolidin-2-one (600 mg, 41 %) as a brown oil. MS (ESI): Mass calcd. for C21 H28BN3O4, 397.2; m/z found, 398.2 [M+H] ⁺ .

Step E: (R, S)-3-(5-(3-(4-Aminopyrido[3,2-d]pyrimidin-6-yl-2-c/)phenyl)- 1 -methyl- 1 /-/-pyrazol-3-yl)-3-hydroxy-1 -methylpyrrolidin-2-one. 6-Chloropyrido[3,2-d]pyrimidin-2- cM-amine (Intermediate 17, 70 mg, 0.4 mmol), 3-hydroxy-1-methyl-3-(1 -methyl-5-(3- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-1 /-/-pyrazol-3-yl)pyrrolidin-2-one (200 mg, 0.50 mmol), and K3PO4 (240 mg, 1.13 mmol) were added to a microwave tube and dissolved in 1 ,4-dioxane (10 mL) and H2O (2.5 mL). The resultant mixture was sparged with Ar for 5 minutes and then treated with Pd(dtbpf)Cl2 (25 mg, 0.04 mmol). The mixture was sparged with Ar for another 5 minutes and then subjected to microwave irradiation at 80 °C for 1 h. After this time, the mixture was cooled to room temperature. The reaction mixture was combined with another batch and concentrated to dryness under reduced pressure to afford the product, which was purified by preparative HPLC using an HPLC column, such as a Boston Prime C18, 150 x 30 mm x 5 pm column (eluent: 20% to 50%,CH3CN and H2O with (0.04% NH4OH +10 mM NH4HCO3)) to afford (R _; S)-3-(5-(3-(4-aminopyrido[3,2-c/]pynmidin-6-yl-2-c/)ph enyl)-1 - methyl-1 /-/-pyrazol-3-yl)-3-hydroxy-1 -methylpyrrolidin-2-one. This racemic product was suspended in water (10 mL), the mixture was frozen by insertion into a -78 °C bath, and then concentrated to dryness to afford (R,S)-3-(5-(3-(4-aminopyrido[3,2-c(]pyrimidin-6-yl- 2-c/)phenyl)-1 -methyl-1 /-/-pyrazol-3-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (110 mg, 66%) as a white solid.

Step F. (R)-3-(5-(3-(4-Aminopyrido[3,2-c/]pyrimidin-6-yl-2-c/)phenyl )-1 -methyl-1 H- pyrazol-3-yl)-3-hydroxy-1 -methylpyrrolidin-2-one. The enantiomers of (R,S)-3-(5-(3-(4- aminopyrido[3,2-c(]pyrimidin-6-yl-2-c/)phenyl)-1 -methyl-1 /-/-pyrazol-3-yl)-3-hydroxy-1 - methylpyrrolidin-2-one were separated by SFC using an SFC column, such as a DAICEL CHIRALPAK® AD 250 mm x 30 mm, 10 pm column (isocratic elution: i-PrOH (containing 0.1 % of 25% aqueous NH3 solution): supercritical CO2, from 55%: 45%) to provide the first eluting enantiomer ((R)-3-(5-(3-(4-aminopyrido[3,2-c/]pynmidin-6-yl-2- c/)phenyl)-1 -methyl-1 /-/-pyrazol-3-yl)-3-hydroxy-1 -methylpyrrolidin-2-one) and the second eluting enantiomer ((S)-3-(5-(3-(4-aminopyrido[3,2-c/]pyrimidin-6-yl-2-c/)pheny l)- 1 -methyl-1 H-pyrazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2 -one) (Example 44). The fractions containing (R)-3-(5-(3-(4-aminopyrido[3,2-c/]pynmidin-6-yl-2-c/)phenyl) -1- methyl-1 H-pyrazol-3-yl)-3-hydroxy-1 -methylpyrrolidin-2-one were collected and concentrated under reduced pressure. Then, it was suspended in water (10 mL) and the mixture was frozen by insertion into a -78 °C bath and then lyophilized to dryness to afford (R)-3-(5-(3-(4-aminopyrido[3,2-c/]pyrimidin-6-yl-2-c0phenyl) -1 -methyl-1 /-/-pyrazol- 3-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (23.8 mg, 21.6%) as a white solid. MS (ESI): Mass calcd. for C22H20DN7O2, 416.2; m/z found, 417.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCI ₃ ) 8 8.21 - 8.16 (m, 1 H), 8.12 - 8.02 (m, 3H), 7.60 - 7.54 (m, 1 H), 7.51 - 7.42 (m, 1 H), 7.13 (br s, 1 H), 6.78 (br s, 1 H), 6.51 (s, 1 H), 5.01 (br s, 1 H), 3.87 (s, 3H), 3.61 - 3.53 (m, 1 H), 3.52 - 3.44 (m, 1 H), 2.97 (s, 3H), 2.91 - 2.84 (m, 1 H), 2.50 - 2.40 (m, 1 H).

Example 44: (S)-3-(5-(3-(4-Aminopyrido[3,2-d]pyrimidin-6-yl-2-c/)phenyl) -1 -methyl-1 H- pyrazol-3-yl)-3-hydroxy-1 -methylpyrrolidin-2-one.

(S)-3-(5-(3-(4-Aminopyrido[3,2-c/]pynmidin-6-yl-2-c/)phen yl)-1 -methyl-1 /-/-pyrazol- 3-yl)-3-hydroxy-1 -methylpyrrolidin-2-one was the second eluting product from Example 43. The fractions containing this compound were collected and concentrated under reduced pressure. The product was suspended in water (10 mL), the mixture was frozen by insertion into a -78 °C bath, and then lyophilized to dryness to afford (S)-3-(5- (3-(4-aminopyrido[3,2-d]pyrimidin-6-yl-2-c/)phenyl)-1 -methyl-1 /-/-pyrazol-3-yl)-3-hydroxy- 1 -methylpyrrolidin-2-one (50.1 mg) as a white solid. MS (ESI): Mass calcd. for C22H20DN7O2, 416.2; m/z found, 417.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCI3) 8 8.24 - 8.18 (m, 1 H), 8.16 - 8.05 (m, 3H), 7.64 - 7.56 (m, 1 H), 7.52 - 7.47 (m, 1 H), 7.10 (br .s, 1 H), 6.50 (s, 1 H), 6.36 (br s, 1 H), 4.42 (br s, 1 H), 3.88 (s, 3H), 3.61 - 3.53 (m, 1 H), 3.51 - 3.44 (m, 1 H), 2.97 (s, 3H), 2.91 - 2.83 (m, 1 H), 2.50 - 2.40 (m, 1 H).

Example 45: (R)-3-Amino-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-4-methylpicolinamide.

Step A: Methyl (R)-3-amino-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)-4-methylpicolinate. The mixture of methyl 3-amino-6-chloro-4- methylpicolinate (26.0 mg, 0.13 mmol), (R)-3-hydroxy-1-methyl-3-(3-(3-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 50.0 mg, 0.13 mmol), tri-fe/Y-butylphosphine (10.0 mg, 0.05 mmol), tris(dibenzylideneacetone)dipalladium(0) (24.0 mg, 0.026 mmol), and potassium fluoride (7.6 mg, 0.13 mmol) in 1 ,4-dioxane/H2O (1 .0 mL/ 1 .0 mL) was degassed for 10 min with nitrogen. Then the mixture was heated at 90 °C for 1 .5 h. The mixture was partitioned with H2O (1 mL) and extracted with EtOAc (3 x 2 mL). The organic extracts were combined and concentrated. The residue was purified by silica gel chromatography (5- 10% MeOH/ DCM) to provide methyl (R)-3-amino-6-(3-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-4-methylpicolinate (15 mg). MS (ESI): Mass calcd. for C22H22N4O5, 422.1 ; m/z found, 423.1 [M+H] ⁺ .

Step B: (R)-3-Amino-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-4-methylpicolinamide. To methyl (R)-3-amino-6-(3-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-4-methylpicolinate (15 mg, 0.035 mmol) in a vial was added NH3 in MeOH (2 M, 5 mL). The mixture was heated at 60 °C for 24 h. The mixture was concentrated and purified by silica gel chromatography (5-10% MeOH/ DCM) to provide (R)-3-amino-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol- 3-yl)phenyl)-4-methylpicolinamide (4.0 mg, 27%) as a solid. MS (ESI): Mass calcd. for C21 H21 N5O4, 407.1 ; m/z found, 408.1 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 5 8.51 - 8.45 (m, 1 H), 8.15 - 8.02 (m, 1 H), 7.87 - 7.74 (m, 2H), 7.61 - 7.47 (m, 1 H), 7.00 (s, 1 H),

3.62 - 3.54 (m, 2H), 2.97 (s, 3H), 2.81 - 2.70 (m, 1 H), 2.48 - 2.36 (m, 1 H), 2.31 (s, 3H).

Example 46: (R)-3-Amino-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-4-methoxypicolinamide.

Step A: 3-Amino-4-chloro-6-methoxypicolinamide. To 3-amino-4,6- dichloropicolinonitrile (188 mg, 1.00 mmol) in DMA (0.5 mL), NaOMe (0.46 mmol, 2.00 mmol, 25% wt in MeOH) was added. The mixture was heated at 50 °C for 16 h. Saturated aqueous NH4CI solution (1 mL) was added and solids were formed. These solids were collected by filtration, washed with DCM (2 x 2 mL) and dried to afford 3- amino-4-chloro-6-methoxypicolinamide as a solid (110 mg, 55%). MS (ESI): Mass calcd. for C21 H21 N5O5, 201 .1 ; m/z found, 202.1 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 5 6.91 (s, 1 H), 3.96 (s, 3H).

Step B: (R)-3-Amino-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-4-methoxypicolinamide. The mixture of 3-amino-4-chloro-6- methoxypicolinamide (52.0 mg, 0.26 mmol), (R)-3-hydroxy-1 -methyl-3-(3-(3-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 100 mg, 0.26 mmol), tri-tert-butylphosphine (52.0 mg, 0.26 mmol), tris(dibenzylideneacetone)dipalladium(0) (119 mg, 0.13 mmol), and potassium fluoride (181 mg, 3.0 mmol) in 1 ,4-dioxane/H2O (2.0 mL/ 1 .0 mL) was degassed for 10 min with nitrogen. Then the mixture was heated at 90 °C for 1 .5 h. The mixture was cooled to room temperature, H2O (1 mL) was added and the resulting solution was extracted with EtOAc (3 x 2 mL). The organic extracts were combined and concentrated. The residue was purified by silica gel chromatography (5-10% MeOH/ DCM) to yield (R)-3-amino-6- (3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-4- methoxypicolinamide (13 mg, 12%) as a solid. MS (ESI): Mass calcd. for C21 H21 N5O5, 423.1 ; m/z found, 424.1 [M+H] ⁺ . ¹ H NMR (500 MHz, CD ₃ OD) 5 8.48 (t, J = 1 .8 Hz, 1 H), 8.18 - 8.05 (m, 1 H), 7.83 - 7.74 (m, 1 H), 7.56 (t, J = 7.8 Hz, 1 H), 7.47 (s, 1 H), 7.01 (s, 1 H), 4.06 (s, 3H), 3.60 - 3.55 (m, 2H), 2.96 (s, 3H), 2.78 - 2.71 (m, 1 H), 2.44 - 2.37 (m, 1 H).

Example 47: (R)-4-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)- 6-methoxypicolinamide.

Step A: 4-Chloro-6-methoxypicolinamide. To methyl 4-chloro-6- methoxypicolinate (200 mg, 0.99 mmol) in a vial, was added NH3 (5 mL, 2 M in MeOH). The mixture was heated at 60 °C for 24 h. The mixture was then concentrated to provide 4-chloro-6-methoxypicolinamide (185 mg, 100%). MS (ESI): Mass calcd. for C7H7CIN2O2, 186.0; m/z found, 187.0 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 5 7.68 (d, J = 1.6 Hz, 1 H), 7.05 (d, J = 1.8 Hz, 1 H), 4.01 (s, 3H).

Step B: (R)-4-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-6-methoxypicolinamide. 4-Chloro-6-methoxypicolinamide (74.0 mg, 0.40 mmol), (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 168 mg, 0.44 mmol), bis(triphenylphosphine)palladium(ii) chloride (45 mg, 0.07 mmol) and K2CO3 ( 1.2 mL, 2.5 mmol, 2 M in H2O) in 1 ,4-dioxane/EtOH (1 .4 mL / 1 .0 mL) was degassed for 10 min with nitrogen. Then the mixture was heated at 170 °C for 10 min and then allowed to cool to room temperature. The mixture was partitioned with EtOAc/H2O (2 mL/2 mL) and extracted with EtOAc (3 x 2 mL). The organic extracts were combined and concentrated. The residue was purified by silica gel chromatography (10% MeOH in DCM) to yield (R)-4-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)- 6-methoxypicolinamide (30 mg, 18%) as a solid. MS (ESI): Mass calcd. for C21 H20N4O5, 408.1 ; m/z found, 409.1 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 8.20 (d, J = 2.0 Hz, 1 H), 8.05 (d, J = 1 .5 Hz, 1 H), 8.00 - 7.90 (m, 1 H), 7.90 - 7.79 (m, 1 H), 7.64 (t, J = 7.8 Hz, 1 H), 7.30 (t, J = 1 .4 Hz, 1 H), 6.99 (s, 1 H), 4.05 (s, 3H), 3.61 - 3.54 (m, 2H), 2.96 (s, 3H), 2.79 - 2.70 (m, 1 H), 2.46 - 2.34 (m, 1 H).

Example 48: (R)-3-Hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 /-/-pyrazolo[3,4-b]pyridin-6- yl)phenyl)isoxazol-5-yl)-1 -methylpyrrolidin-2-one.

(R)-3-Hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 45 mg, 0.12 mmol) in freshly distilled DMF (1 mL) was evacuated and argon was bubbled through the solution. 6- Chloro-4-methoxy-1 -methyl-1 /-/-pyrazolo[3,4-b]pyridine (27 mg, 0.13 mmol), butyldi(1 - adamantanyl)phosphine (4.6 mg, 0.012 mmol), and methanesulfonato-2'-methylamino- 1 ,1'-biphenyl-2-yl-palladacycles generation 4 (RuPhos Pd G4, (CAS # 1599466-85-9), 5.1 mg, 0.0060 mmol) were added and the mixture was heated at 80 °C for 12 h. The mixture was then cooled to room temperature and a precipitate formed. The precipitate was filtered off and discarded and the filtrate concentrated. The product was purified by HPLC using an HPLC column such as, a SUNFIRE® C18 100 x 20 mm 5 pm to provide Example 48, (R)-3-hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 /-/-pyrazolo[3,4-b]pyridin-6- yl)phenyl)isoxazol-5-yl)-1-methylpyrrolidin-2-one, as a solid (15 mg, 29%). MS (ESI): Mass calcd. for C22H21 N5O4, 419.6; m/z found, 420.5 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3CN) 5 8.07 (s, 1 H), 7.80 (d, J = 7.9 Hz, 1 H), 7.58 (s, 1 H), 7.43 (d, J = 7.7 Hz, 1 H), 7.12 (t, J = 7.8 Hz, 1 H), 6.81 (s, 1 H), 6.60 (s, 1 H), 6.19 (s, 1 H), 3.62 (s, 3H), 3.54 (s, 3H), 2.99 - 2.84 (m, 2H), 2.29 (s, 3H), 2.08-2.02 (m, 1 H), 1 .78-1 .75 (m, 1 H).

Example 49: (R)-3-(3-(3-(1 /-/-Pyrrolo[2,3-b]pyridin-4-yl)phenyl)isoxazol-5-yl)-3-hydro xy- 1 -methylpyrrolidin-2-one.

(R)-3-(3-(3-(1 /-/-Pyrrolo[2,3-b]pyridin-4-yl)phenyl)isoxazol-5-yl)-3-hydro xy-1 - methylpyrrolidin-2-one (22.7 mg) was prepared in a manner analogous to Example 48 using 4-bromo-1 /-/-pyrrolo[2,3-b]pyridine instead on 6-chloro-4-methoxy-1 -methyl-1 /-/- pyrazolo[3,4-b]pyridine. MS (ESI): Mass calcd. for C21 H18N4O3, 374,1 ; m/z found, 375.2 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3CN) 8 9.95 (s, 1 H), 8.36 (d, J = 4.9 Hz, 1 H), 8.19 (s, 1 H), 7.96 (d, J = 7.8 Hz, 1 H), 7.91 (d, J = 7.7 Hz, 1 H), 7.68 (t, J = 7.7 Hz, 1 H), 7.49 (d, J = 3.6 Hz, 1 H), 7.29 (d, J = 4.9 Hz, 1 H), 6.90 (s, 1 H), 6.70 (d, J = 3.6 Hz, 1 H), 4.75 (s, 1 H), 3.51 (t, J = 6.6 Hz, 2H), 2.91 (s, 3H), 2.69 (d, J = 5.7 Hz, 1 H), 2.38 (d, J = 7.5 Hz, 1 H).

Example 50: (R)-3-Amino-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-4-(trifluoromethyl)picolinamide

Step A: 3-Amino-6-chloro-4-(trifluoromethyl)picolinonitrile. (1 ,10- Phenanthroline)(trifluoromethyl)copper(l) (1.62 g, 5.18 mmol) was added to a mixture of 3-amino-4-bromo-6-chloropicolinonitrile (1.0 g, 4.3 mmol) in DMF (20 mL). This mixture was sparged with N2 for 5 minutes and then heated at 100 °C for 16 h. After this time, the mixture was cooled to room temperature, poured into H2O (20 mL), and extracted with ethyl acetate (40 mL x 3). The combined organic solvent extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (eluent: ethyl acetate: petroleum ether = 0:1 to 1 :3) to afford 3-amino-6-chloro-4-(trifluoromethyl)picolinonitrile (150 mg, 15% yield) as a yellow solid. MS (ESI): Mass calcd. for C7H3CIF3N3, 221 .0; m/z found, 222.1 [M+H] ⁺ .

Step B: 3-Amino-6-chloro-4-(trifluoromethyl)picolinamide. Hydrogen peroxide (0.27 mL, 30 wt. % in H2O, 2.73 mmol) was added to a mixture of 3-amino-6-chloro-4- (trifluoromethyl)picolinonitrile (150 mg, 0.68 mmol), K2CO3 (37.5 mg, 0.27 mmol), and DMF (3 mL). This mixture was heated at 30 °C for 48 h. After this time, the mixture was cooled to room temperature, diluted with saturated aqueous Na2S2SOs solution (5 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic solvent extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 3-amino-6-chloro-4-(trifluoromethyl)picolinamide (160 mg, 91 % yield) as a yellow solid. MS (ESI): Mass calcd. for C7H5CIF3N3O, 239.0; m/z found, 240.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.00 (br s, 1 H), 7.75 - 7.64 (m, 2H), 7.49 (br s, 2H).

Step C: (R)-3-Amino-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-4-(trifluoromethyl)picolinamide. 3-Amino-6-chloro-4- (trifluoromethyl)picolinamide (150 mg, 0.63 mmol) was added to a mixture of (R)-3- hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol- 5-yl)pyrrolidin-2-one (Intermediate 4, 263 mg, 0.680 mmol), K3PO4 (398 mg, 1.88 mmol), and 1 ,4-dioxane/H2O (v/v = 4/1 , 8 mL). The resultant mixture was sparged with N2 for 5 minutes and then treated with Pd(dtbpf)Cl2 (38 mg, 0.060 mmol). This mixture was then sparged with N2 for another 5 minutes and subjected to microwave irradiation at 80 °C for 1 h. After this time, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to afford the product, which was purified by preparative HPLC using an HPLC column, such as a Phenomenex Gemini-NX 150 x 30 mm x 5 pm column (eluent: 34% to 62% CH3CN in H2O (with 0.05% NH3*H2O)). The product was then suspended in water (5 mL), the mixture was frozen at - 78 °C, and then lyophilized to afford (R)-3-amino-6-(3-(5-(3- hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)- 4- (trifluoromethyl)picolinamide (98 mg, 34% yield) as a colorless solid. MS (ESI): Mass calcd. for C21 H18F3N5O4, 461.1 ; m/z found, 462.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.49 (s, 1 H), 8.51 - 8.47 (m, 1 H), 8.47 - 8.42 (m, 1 H), 8.39 - 8.32 (m, 1 H), 8.25 (s, 1 H), 7.93 - 7.87 (m, 1 H), 7.80 (br s, 1 H), 7.62 - 7.55 (m, 2H), 7.28 (s, 1 H), 6.74 (s, 1 H), 3.55 - 3.41 (m, 2H), 2.85 (s, 3H), 2.63 - 2.54 (m, 1 H), 2.37 - 2.23 (m, 1 H).

Example 51 : (R)-3-Hydroxy-3-(3-(3-(imidazo[1 ,5-a]pyridin-6-yl)phenyl)isoxazol-5-yl)-1- methylpyrrolidin-2-one.

(R)-3-Hydroxy-3-(3-(3-(imidazo[1 ,5-a]pyridin-6-yl)phenyl)isoxazol-5-yl)-1- methylpyrrolidin-2-one was synthesized in a manner analogous to the synthesis of Example 48, (R)-3-hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 /-/-pyrazolo[3,4-b]pyridin-6- yl)phenyl)isoxazol-5-yl)-1 -methylpyrrolidin-2-one, using 6-bromoimidazo[1 ,5-a]pyridine in place of 6-chloro-4-methoxy-1 -methyl-1 /-/-pyrazolo[3,4-b]pyridine, to give the title compound as a solid (10.8 mg). Purification: RP-HPLC using column: SunFire C18 100 x 19 mm, 5 pm). MS (ESI): Mass calcd. for C21 H18N4O3 374,14, m/z found, 375.2 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO-d ₆ ) 8 8.82 (d, J = 1.4 Hz, 1 H), 8.38 (s, 1 H), 8.15 (d, J = 1 .8 Hz, 1 H), 7.90 - 7.84 (m, 1 H), 7.86 - 7.78 (m, 1 H), 7.65 (d, J = 9.5 Hz, 1 H), 7.60 (t, J = 7.8 Hz, 1 H), 7.38 (s, 1 H), 7.26 - 7.20 (m, 1 H), 7.14 (s, 1 H), 6.70 (s, 1 H), 3.52 - 3.45 (m, 1 H), 3.45 - 3.35 (m, 1 H), 2.82 (s, 3H), 2.57 - 2.53 (m, 1 H), 2.30 - 2.23 (m, 1 H).

Example 52: (R)-3-Hydroxy-1 -methyl-3-(3-(3-(pyrrolo[2, 1 -f][1 , 2 , 4]triazin-4- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one.

(R)-3-Hydroxy-1 -methyl-3-(3-(3-(pyrrolo[2, 1 -f][1 ,2,4]triazin-4-yl)phenyl)isoxazol-5- yl)pyrrolidin-2-one was synthesized in a manner analogous to Example 48, (R)-3- hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 /-/-pyrazolo[3,4-b]pyridin-6-yl)phenyl)isoxazol-5- yl)-1 -methylpyrrolidin-2-one, using 4-chloropyrrolo[2,1 -/][1 ,2,4]triazine in place of 6- chloro-4-methoxy-1 -methyl-1 /-/-pyrazolo[3,4-b]pyridine, to give the title compound as a solid (15.1 mg). Purification: RP-HPLC SunFire 100 x 19 mm, 5 pm. MS (ESI): Mass calcd. for C20H17N5O3 290.2, m/z found, 291 .3 [M+H] ⁺ . ¹ H NMR (500 MHz, Acetonitrile- cfe) 8 8.56 (d, J = 11 .5 Hz, 2H), 8.24 (d, J = 7.8 Hz, 1 H), 8.10 (d, J = 7.7 Hz, 1 H), 8.00 (d, J = 2.7 Hz, 1 H), 7.74 (t, J = 7.8 Hz, 1 H), 7.19 (d, J = 4.7 Hz, 1 H), 7.12 - 7.08 (m, 1 H), 6.91 (s, 1 H), 4.55 (s, 1 H), 3.55 - 3.48 (m, 2H), 2.91 (s, 3H), 2.69 (d, J = 5.7 Hz, 1 H), 2.37 (d, J = 7.6 Hz, 1 H).

Example 53: (R)-3-(3-(3-(2-Aminopyridin-4-yl)phenyl)isoxazol-5-yl)-3-hyd roxy-1 - methylpyrrolidin-2-one.

(R)-3-(3-(3-(2-Aminopyridin-4-yl)phenyl)isoxazol-5-yl)-3- hydroxy-1 - methylpyrrolidin-2-one was synthesized in a manner analogous to Example 48, (R)-3- hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 /-/-pyrazolo[3,4-b]pyridin-6-yl)phenyl)isoxazol-5- yl)-1 -methylpyrrolidin-2-one, using 4-bromopyridin-2 -amine in place of 6-chloro-4- methoxy-1-methyl-1 /-/-pyrazolo[3,4-b]pyridine, to give the title compound as a solid (14.4 mg). Purification: RP HPLC; column SunFire C18 100 x 19 mm, 5 pm. MS (ESI): Mass calcd. for C19H18N4O3 350.14, m/z found, 351.2 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO-c/e) 8 8.07 (d, J = 2.0 Hz, 1 H), 7.97 (d, J = 5.3 Hz, 1 H), 7.90 (d, J = 7.8 Hz, 1 H), 7.74 (d, J = 8.2 Hz, 1 H), 7.60 (t, J = 7.7 Hz, 2H), 7.10 (s, 1 H), 6.88 - 6.82 (m, 1 H), 6.75 (d, J = 1 .6 Hz, 1 H), 6.68 (s, 1 H), 5.98 (s, 2H), 3.52 - 3.34 (m, 2H), 2.81 (s, 3H), 2.30 - 2.20 (m, 1 H).

Example 54: (R)-N-(4-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)pyridin-2-yl)acetamide.

(R)-N-(4-(3-(5-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)i soxazol-3- yl)phenyl)pyridin-2-yl)acetamide was synthesized in a manner analogous to Example 48, (R)-3-hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 H-pyrazolo[3,4-b]pyridin-6- yl)phenyl)isoxazol-5-yl)-1 -methylpyrrolidin-2-one, using N-(4-chloropyridin-2- yl)acetamide in place of 6-chloro-4-methoxy-1 -methyl-1 /-/-pyrazolo[3,4-b]pyridine, to give the title compound as a solid (13.7 mg). Purification: RP HPLC; column SunFire C18 100 x 19 mm, 5 pm. MS (ESI): Mass calcd. for C21 H20N4O4 392.2, m/z found, 393.2 [M+H] ⁺ . ¹ H NMR (500 MHz, Aceton itrile-cfe) 8 8.84 (s, 1 H), 8.48 (s, 1 H), 8.36 (d, J = 5.2 Hz, 1 H), 8.13 (d, J = 2.0 Hz, 1 H), 7.95 (d, J = 7.8 Hz, 1 H), 7.91 - 7.75 (m, 1 H), 7.64 (t, J = 7.8 Hz, 1 H), 7.58 - 7.46 (m, 1 H), 7.48 - 7.40 (m, 1 H), 4.66 (s, 1 H), 3.50 (d, J = 5.4 Hz, 2H), 2.90 (d, J = 5.6 Hz, 3H), 2.67 (d, J = 5.6 Hz, 1 H), 2.37 (d, J = 7.9 Hz, 1 H), 2.18 (s, 3H).

Example 55: (R)-3-(3-(3-(1 -Ethyl-1 /-/-pyrazolo[3,4-b]pyridin-5-yl)phenyl)isoxazol-5-yl)-3- hydroxy-1 -methylpyrrolidin-2-one.

(R)-3-(3-(3-(1 -Ethyl-1 /-/-pyrazolo[3,4-b]pyridin-5-yl)phenyl)isoxazol-5-yl)-3- hydroxy-1-methylpyrrolidin-2-one was synthesized in a manner analogous to Example 48, (R)-3-hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 H-pyrazolo[3,4-b]pyridin-6- yl)phenyl)isoxazol-5-yl)-1 -methylpyrrolidin-2-one, using 5-bromo-1 -ethyl-1 /-/- pyrazolo[3,4-b]pyridine in place of 6-chloro-4-methoxy-1 -methyl-1 /-/-pyrazolo[3, 4- b]pyridine, to give the title compound as a solid (22 mg). Purification: RP HPLC; column SunFire C18 100 x 19 mm, 5 pm. MS (ESI): Mass calcd. for C22H215O3 403.2, m/z found, 404.0 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO-d ₆ ) 8 8.94 (d, J = 2.2 Hz, 1 H), 8.59 (d, J = 2.2 Hz, 1 H), 8.21 (d, J = 3.9 Hz, 2H), 7.94 - 7.79 (m, 2H), 7.62 (t, J = 7.7 Hz, 1 H), 7.17 (s, 1 H), 6.69 (s, 1 H), 4.52 (q, J = 7.2 Hz, 2H), 3.43 (dddd, J = 32.0, 9.8, 7.7, 5.1 Hz, 2H), 3.26 (s, 1 H), 2.82 (s, 3H), 2.26 (ddd, J = 13.6, 8.1 , 5.7 Hz, 1 H), 1.44 (t, J = 7.3 Hz, 3H).

Example 56: (R)-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)- 6,7-dihydrofuro[3,2-c]pyridin-4(5H)-one.

(R)-2-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isox azol-3-yl)phenyl)-6,7- dihydrofuro[3,2-c]pyridin-4(5H)-one was synthesized in a manner analogous to Example 48, (R)-3-hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 H-pyrazolo[3,4-b]pyridin-6- yl)phenyl)isoxazol-5-yl)-1 -methylpyrrolidin-2-one, using 2-bromo-4H,5H,6H,7/-/-furo[3,2- c]pyridin-4-one in place of 6-chloro-4-m ethoxy-1 -methyl-1 /-/-pyrazolo[3,4-b]pyridine, to give the title compound as a solid (8.0 mg). Purification: RP HPLC; column: SunFire C18 100 x 18 mm, 5 pm). MS (ESI): Mass calcd. for C21 H19N3O5 393.1 , m/z found, 394.2 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO-d ₆ ) 8 8.20 (d, J = 1 .7 Hz, 1 H), 7.83 (d, J = 1 .7 Hz, 1 H), 7.82 - 7.74 (m, 1 H), 7.54 (t, J = 7.8 Hz, 1 H), 7.40 (s, 1 H), 7.33 (s, 1 H), 7.13 (s, 1 H), 6.69 (s, 1 H), 3.47 (dt, J = 7.4, 3.6 Hz, 2H), 3.46 - 3.42 (m, 1 H), 3.40 (dd, J = 7.6, 5.7 Hz, 1 H), 2.98 (t, J = 7.1 Hz, 2H), 2.81 (s, 3H), 2.54 - 2.52 (m, 1 H), 2.25 (ddd, J = 13.6, 8.1 , 5.8 Hz, 1 H).

Example 57: (R)-3-Hydroxy-1-methyl-3-(3-(3-(1 -methylimidazo[1 ,5-a]pyridin-6- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. (R)-3-Hydroxy-1 -methyl-3-(3-(3-(1 -methylimidazo[1 , 5-a]pyrid in-6- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one was synthesized in a manner analogous to Example 48, (R)-3-hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 H-pyrazolo[3,4-b]pyridin-6- yl)phenyl)isoxazol-5-yl)-1 -methylpyrrolidin-2-one, using 6-bromo-1 -methylimidazo[1 ,5- a]pyridine in place of 6-chloro-4-methoxy-1 -methyl-1 /-/-pyrazolo[3,4-b]pyridine, to give the title compound as a solid (15.6 mg). Purification: RP HPLC; column: SunFire C18 100 x 19 mm, 5 pm. MS (ESI): Mass calcd. for C22H20N4O3 388.15, m/z found, 389.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 9.12 (s, 1 H), 8.55 (s, 1 H), 8.34 (s, 1 H), 8.06 (d, J = 7.8 Hz, 1 H), 7.97 (d, J = 8.0 Hz, 1 H), 7.72 (t, J = 7.7 Hz, 1 H), 7.09 (s, 1 H), 6.76 (s, 1 H), 4.20 (s, 3H), 3.44 (s, 2H), 2.84 (s, 3H), 2.27 (s, 2H).

Example 58: (R)-3-hydroxy-1 -methyl-3-(3-(3-(pyrazolo[1 ,5-a]pyridin-5- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one.

(R)-3-Hydroxy-1 -methyl-3-(3-(3-(pyrazolo[1 ,5-a]pyridin-5-yl)phenyl)isoxazol-5- yl)pyrrolidin-2-one was synthesized in a manner analogous to Example 48, (R)-3- hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 H-pyrazolo[3,4-b]pyridin-6-yl)phenyl)isoxazol-5- yl)-1 -methylpyrrolidin-2-one, using 5-bromopyrazolo[1 ,5-a]pyridine in place of 6-chloro- 4-methoxy-1 -methyl-1 /-/-pyrazolo[3,4-b]pyridine, to give the title compound as a solid (20.4 mg). Purification: RP HPLC; column: SunFire C18 100 x 18 mm, 5 pm. MS (ESI): Mass calcd. for C21H18N4O3 374.1 , m/z found, 375.4 [M+H] ⁺ , ¹ H NMR (600 MHz, DMSO- cfe) 8 8.75 (d, J = 7.3 Hz, 1 H), 8.24 (d, J = 1 .8 Hz, 1 H), 8.14 (d, J = 2.0 Hz, 1 H), 8.02 (d, J = 2.3 Hz, 1 H), 7.95 - 7.81 (m, 2H), 7.62 (t, J = 7.8 Hz, 1 H), 7.33 (dd, J = 7.3, 2.1 Hz, 1 H), 7.19 (s, 1 H), 6.70 (s, 1 H), 6.66 (d, J = 2.3 Hz, 1 H), 3.46 (ddd, J = 9.9, 8.0, 4.7 Hz, 1 H), 3.43 - 3.33 (m, 1 H), 2.82 (s, 3H), 2.60 - 2.55 (m, 1 H), 2.26 (ddd, J = 13.5, 8.0, 5.7 Hz, 1 H). Example 59: (R)-4-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- y l)pheny l)isoindol in-1 -one.

(R)-4-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isox azol-3-yl)phenyl)isoindolin-1 - one was synthesized in a manner analogous to Example 48, (R)-3-hydroxy-3-(3-(3-(4- methoxy-1 -methyl-1 H-pyrazolo[3,4-b]pyridin-6-yl)phenyl)isoxazol-5-yl)-1 - methylpyrrolidin-2-one, using 4-bromo-2,3-dihydro-1 /-/-isoindol-1 -one in place of 6- chloro-4-methoxy-1 -methyl-1 /-/-pyrazolo[3,4-b]pyridine, to give the title compound as a solid (12.1 mg). Purification: RP HPLC; column SunFire 100 x 19 mm, 5 pm. MS (ESI): Mass calcd. for C22H19N3O4 389.14, m/z found, 390.4 [M+H] ⁺ . ¹ H NMR (500 MHz, Aceton itrile-c/3) 8 8.01 (s, 1 H), 7.93 (d, J = 7.6 Hz, 1 H), 7.80 (d, J = 7.5 Hz, 1 H), 7.73 (d, J = 7.5 Hz, 1 H), 7.71 - 7.52 (m, 3H), 6.88 (s, 2H), 4.51 (d, J = 8.9 Hz, 3H), 3.50 (dd, J = 7.6, 5.6 Hz, 2H), 2.90 (s, 3H), 2.67 (dt, J = 13.5, 5.7 Hz, 1 H), 2.36 (dt, J = 14.2, 7.5 Hz, 1 H).

Example 60: (R)-4-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- y l)pheny l)isoi ndol in-1 -one.

(R)-3-hydroxy-1 -methyl-3-(3-(3-(3-methylimidazo[1 ,5-a]pyridin-7- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one was synthesized in a manner analogous to Example 48, (R)-3-hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 H-pyrazolo[3,4-b]pyridin-6- yl)phenyl)isoxazol-5-yl)-1 -methylpyrrolidin-2-one, using 7-bromo-3-methylimidazo[1 ,5- a]pyridine in place of 6-chloro-4-methoxy-1 -methyl-1 /-/-pyrazolo[3,4-b]pyridine, to give the title compound as a solid (20.2 mg). Purification: RP HPLC; column: SUNFIRE C18 100 x 20 mm, 5 pm. MS (ESI): Mass calcd. for C22H20N4O3 388.15, m/z found, 389.0 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO-d ₆ ) 8 8.18 (d, J = 1 .8 Hz, 1 H), 8.15 (d, J = 7.5 Hz, 1 H), 7.98 (s, 1 H), 7.92 - 7.77 (m, 2H), 7.57 (t, J = 7.8 Hz, 1 H), 7.33 (s, 1 H), 7.18 (s, 1 H), 7.13 (dd, J = 7.4, 1.8 Hz, 1 H), 6.70 (s, 1 H), 3.52 - 3.44 (m, 1 H), 3.44 - 3.37 (m, 1 H), 3.14 (s, 1 H), 2.82 (s, 3H), 2.60 (s, 3H), 2.26 (ddd, J = 13.6, 8.1 , 5.8 Hz, 1 H).

Example 61 : (R)-3-Hydroxy-3-(3-(3-(imidazo[1 ,2-a]pyrazin-3-yl)phenyl)isoxazol-5-yl)-1 - methylpyrrolidin-2-one.

(R)-3-Hydroxy-3-(3-(3-(imidazo[1 ,2-a]pyrazin-3-yl)phenyl)isoxazol-5-yl)-1 - methylpyrrolidin-2-one was synthesized in a manner analogous to Example 48, (R)-3- hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 H-pyrazolo[3,4-b]pyridin-6-yl)phenyl)isoxazol-5- yl)-1 -methylpyrrolidin-2-one, using 3-chloroimidazo[1 ,2-a]pyrazine in place of 6-chloro- 4-methoxy-1 -methyl-1 /-/-pyrazolo[3,4-b]pyridine, to give the title compound as a solid (17.5 mg). Purification: RP HPLC; column SunFire 100 x 19 mm, 5 pm. MS (ESI): Mass calcd. for C20H17N5O3 375.13, m/z found, 376.0 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO-d ₆ ) 8 9.15 (s, 1 H), 8.66 (d, J = 4.8 Hz, 1 H), 8.19 (s, 1 H), 8.16 (s, 1 H), 7.96 (dd, J = 14.1 , 6.2 Hz, 2H), 7.86 (d, J = 7.7 Hz, 1 H), 7.71 (t, J = 7.8 Hz, 1 H), 7.15 (s, 1 H), 6.72 (s, 1 H), 3.47 (dt, J = 8.3, 4.2 Hz, 1 H), 3.42 (td, J = 14.2, 12.7, 7.2 Hz, 1 H), 2.82 (s, 3H), 2.26 (ddd, J = 13.6, 8.0, 5.6 Hz, 1 H), 2.06 (s, 1 H).

Example 62: (R)-3-Hydroxy-1-methyl-3-(3-(3-(1 -methyl-1/-/-benzo[d]imidazol-6- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one.

(R)-3-Hydroxy-1 -methyl-3-(3-(3-(1 -methyl-1 /-/-benzo[d]imidazol-6- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one was synthesized in a manner analogous to Example 48, (R)-3-hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 H-pyrazolo[3,4-b]pyridin-6- yl)phenyl)isoxazol-5-yl)-1 -methylpyrrolidin-2-one, using 6-bromo-1 -methyl-1 H-1 ,3- benzodiazole in place of 6-chloro-4-methoxy-1 -methyl-1 /-/-pyrazolo[3,4-b]pyridine, to give the title compound as a solid (12.1 mg). Purification: RP HPLC; column SunFire 100 x 19 mm, 5 pm. MS (ESI): Mass calcd. for C22H20N4O3 388.2, m/z found, 389.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO-d ₆ ) 8 8.22 (s, 1 H), 8.21 - 8.11 (m, 1 H), 7.96 (d, J = 1 .7 Hz, 1 H), 7.85 (dd, J = 11 .8, 7.8 Hz, 2H), 7.72 (d, J = 8.4 Hz, 1 H), 7.60 (ddd, J = 7.8, 4.4, 2.7 Hz, 2H), 7.14 (s, 1 H), 6.73 (s, 1 H), 3.90 (s, 3H), 3.47 (dt, J = 9.9, 4.1 Hz, 1 H), 3.45 - 3.37 (m, 1 H), 3.15 (d, J = 4.5 Hz, 1 H), 2.83 (s, 3H), 2.27 (ddd, J = 13.6, 8.1 , 5.7 Hz, 1 H).

Example 63: (R)-3-Hydroxy-1 -methyl-3-(3-(3-(2-methylbenzo[d]oxazol-5- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one.

(R)-3-Hydroxy-1 -methyl-3-(3-(3-(2-methylbenzo[d]oxazol-5-yl)phenyl)isoxazol -5- yl)pyrrolidin-2-one was synthesized in a manner analogous to Example 48, (R)-3- hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 H-pyrazolo[3,4-b]pyridin-6-yl)phenyl)isoxazol-5- yl)-1 -methylpyrrolidin-2-one, using 5-chloro-2-methyl-1 ,3-benzoxazole in place of 6- chloro-4-methoxy-1 -methyl-1 /-/-pyrazolo[3,4-b]pyridine, to give the title compound as a solid (19.0 mg). Purification: RP HPLC; column SunFire C18 100 x 19 mm, 5 pm. MS (ESI): Mass calcd. for C22H19N3O4389.1 , m/z found, 390.2 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO-c/e) 88.15 (d, J= 1.8 Hz, 1H), 8.03 (d, J= 1.6 Hz, 1H), 7.85 (d, J = 7.7 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.77-7.68 (m, 2H), 7.58 (t, J = 7.8 Hz, 1H), 7.17 (s, 1H), 6.68 (s, 1H), 3.45 (ddd, J = 9.9, 8.1, 4.7 Hz, 1H), 3.41 (dd, J= 7.6, 5.9 Hz, 1H), 2.81 (s, 3H), 2.62 (s, 3H), 2.54 (d, J =5.1 Hz, 1H), 2.25 (ddd, J = 13.7, 8.1,5.9 Hz, 1H).

Example 64: (R)-3-Hydroxy-1-methyl-3-(3-(3-(pyrrolo[1 ,2-b]pyridazin-5- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one.

(R)-3-Hydroxy-1-methyl-3-(3-(3-(pyrrolo[1,2-b]pyridazin-5 -yl)phenyl)isoxazol-5- yl)pyrrolidin-2-one was synthesized in a manner analogous to Example 48, (R)-3- hydroxy-3-(3-(3-(4-methoxy-1-methyl-1 H-pyrazolo[3,4-b]pyridin-6-yl)phenyl)isoxazol-5- yl)-1-methylpyrrolidin-2-one, using 5-bromopyrrolo[1,2-b]pyridazine in place of 6-chloro- 4-methoxy-1-methyl-1/-/-pyrazolo[3,4-b]pyridine, to give the title compound as a solid (12.3 mg). Purification: RP HPLC; column: SUNFIRE C18100 x 20 mm, 5 pm. MS (ESI): Mass calcd. for C26H26N6O 438.2, m/z found, 439.2 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO-c/e) 814.12 (s, 1H), 8.54-8.45 (m, 1H), 8.38 (s, 1H), 8.22 (s, 1H), 8.06 (s, 1H), 7.66 (dd, J = 11.6, 7.5 Hz, 3H), 7.59 (dd, J = 9.0, 3.1 Hz, 1 H), 7.45 (q, J = 8.0 Hz, 3H), 7.40 - 7.30 (m, 3H), 3.35 (t, J = 5.1 Hz, 4H), 2.51 (s, 4H), 2.23 (s, 3H).

Example 65: (R)-3-Hydroxy-1-methyl-3-(3-(3-(2-methylimidazo[1,2-b]pyrida zin-6- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. (R)-3-Hydroxy-1 -methyl-3-(3-(3-(2-methylimidazo[1 ,2-b]pyridazin-6- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one was synthesized in a manner analogous to Example 48, (R)-3-hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 H-pyrazolo[3,4-b]pyridin-6- yl)phenyl)isoxazol-5-yl)-1 -methylpyrrolidin-2-one, using 6-bromo-2-methylimidazo[1 ,2- b]pyridazine hydrobromide in place of 6-chloro-4-methoxy-1 -methyl-1/-/-pyrazolo[3,4- b]pyridine, to give the title compound as a solid (31.7 mg). Purification: RP HPLC; column SunFire C18 100 x 19 mm, 5 pm. MS (ESI): Mass calcd. for C21 H19N5O3 389.2, m/z found, 390.4 [M+H] ⁺ . ¹ H NMR (500 MHz, Aceton itrile-c/3) 8 8.46 (d, J = 2.0 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 7.98 (dd, J = 18.5, 8.6 Hz, 2H), 7.92 (s, 1 H), 7.77 - 7.58 (m, 2H), 6.93 (s, 1 H), 4.49 (s, 1 H), 3.51 (dd, J = 7.6, 5.6 Hz, 2H), 2.91 (s, 3H), 2.69 (dt, J = 13.7, 5.5 Hz, 1 H), 2.48 (s, 3H), 2.37 (dd, J = 13.7, 7.2 Hz, 1 H).

Example 66: (R)-3-(3-(3-(Furo[3,2-b]pyridin-5-yl)phenyl)isoxazol-5-yl)-3 -hydroxy-1 - methylpyrrolidin-2-one,

(R)-3-(3-(3-(Furo[3,2-b]pyridin-5-yl)phenyl)isoxazol-5-yl )-3-hydroxy-1 - methylpyrrolidin-2-one was synthesized in a manner analogous to Example 48, (R)-3- hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 H-pyrazolo[3,4-b]pyridin-6-yl)phenyl)isoxazol-5- yl)-1 -methylpyrrolidin-2-one, using 5-bromofuro[3,2-b]pyridine in place of 6-chloro-4- methoxy-1-methyl-1 /-/-pyrazolo[3,4-b]pyridine, to give the title compound as a solid (12.3 mg). Purification: RP HPLC; column: SunFire C18 100 x 19 mm, 5 pm. MS (ESI): Mass calcd. for C21H17N3O4 375.1 , m/z found, 376.2 [M+H] ⁺ . ¹ H NMR (500 MHz, Aceton itrile-c/3) 8 8.55 (d, J = 2.0 Hz, 1 H), 8.21 (d, J = 7.9 Hz, 1 H), 8.09 (d, J = 2.4 Hz, 1 H), 7.99 (d, J = 8.7 Hz, 1 H), 7.96 - 7.78 (m, 2H), 7.64 (t, J = 7.8 Hz, 1 H), 7.09 (d, J = 2.4 Hz, 1 H), 6.92 (s, 1 H), 4.54 (s, 1 H), 3.51 (dd, J = 7.6, 5.6 Hz, 2H), 2.91 (s, 3H), 2.69 (dt, J = 13.5, 5.6 Hz, 1 H), 2.38 (dt, J = 13.4, 7.5 Hz, 1 H). Example 67: (R)-3-Hydroxy-3-(3-(3-(imidazo[1 ,5-a]pyridin-7-yl)phenyl)isoxazol-5-yl)-1- methylpyrrolidin-2-one.

(R)-3-hydroxy-3-(3-(3-(imidazo[1 ,5-a]pyridin-7-yl)phenyl)isoxazol-5-yl)-1 - methylpyrrolidin-2-one was synthesized in a manner analogous to Example 48, (R)-3- hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 H-pyrazolo[3,4-b]pyridin-6-yl)phenyl)isoxazol-5- yl)-1 -methylpyrrolidin-2-one, using 7-bromoimidazo[1 ,5-a]pyridine in place of 6-chloro-4- methoxy-1-methyl-1 /-/-pyrazolo[3,4-b]pyridine, to give the title compound as a solid (23.6 mg). Purification: RP HPLC; column SunFire C18 100 x 19 mm, 5 pm. MS (ESI): Mass calcd. for C21H18N4O3 374.1 , m/z found, 375.4 [M+H] ⁺ . ¹ H NMR (500 MHz, Aceton itrile-c/3) 8 8.33 - 8.20 (m, 1 H), 8.15 (d, J = 1.9 Hz, 1 H), 7.88 (d, J = 6.5 Hz, 1 H), 7.82 (d, J = 7.8 Hz, 1 H), 7.61 (t, J = 7.8 Hz, 1 H), 7.45 (s, 1 H), 7.04 (dd, J = 7.5, 1 .9 Hz, 1 H), 6.92 (s, 1 H), 4.53 (s, 1 H), 3.50 (dd, J = 7.6, 5.6 Hz, 2H), 2.92 (s, 3H), 2.82 - 2.60 (m, 2H), 2.37 (dt, J = 13.4, 7.5 Hz, 2H).

Example 68: (R)-3-Hydroxy-1-methyl-3-(3-(3-(pyrazolo[1 ,5-a]pyrimidin-5- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one

(R)-3-Hydroxy-1 -methyl-3-(3-(3-(pyrazolo[1 ,5-a]pyrimidin-5-yl)phenyl)isoxazol-5- yl)pyrrolidin-2-one was synthesized in a manner analogous to Example 48, (R)-3- hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 H-pyrazolo[3,4-b]pyridin-6-yl)phenyl)isoxazol-5- yl)-1 -methylpyrrolidin-2-one, using 5-bromopyrazolo[1 ,5-a]pyrimidine in place of 6- chloro-4-methoxy-1 -methyl-1 /-/-pyrazolo[3,4-b]pyridine, to give the title compound as a solid (18.5 mg). Purification: RP HPLC; column: SUNFIRE C18 100 x 20 mm, 5 pm. MS (ESI): Mass calcd. for C20H17N5O3 375.1 , m/z found, 376.4 [M+H] ⁺ . ¹ H NMR (500 MHz, Aceton itrile-c/3) 8 8.88 (d, J = 7.4 Hz, 1 H), 8.60 (d, J = 2.0 Hz, 1 H), 8.28 (d, J = 7.9 Hz, 1 H), 8.17 (d, J = 2.4 Hz, 1 H), 8.00 (d, J = 7.7 Hz, 1 H), 7.68 (t, J = 7.8 Hz, 1 H), 7.55 (d, J = 7.4 Hz, 1 H), 6.94 (s, 1 H), 6.72 (d, J = 2.3 Hz, 1 H), 4.64 (s, 1 H), 3.51 (dd, J = 7.6, 5.6 Hz, 2H), 2.91 (s, 3H), 2.69 (dt, J = 13.6, 5.7 Hz, 1 H), 2.39 (dt, J = 14.1 , 7.5 Hz, 1 H).

Example 69: (R)-3-(3-(3-(Benzo[d]oxazol-6-yl)phenyl)isoxazol-5-yl)-3-hyd roxy-1 - methylpyrrolidin-2-one.

(R)-3-(3-(3-(Benzo[d]oxazol-6-yl)phenyl)isoxazol-5-yl)-3- hydroxy-1 - methylpyrrolidin-2-one was synthesized in a manner analogous to Example 48, (R)-3- hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 H-pyrazolo[3,4-b]pyridin-6-yl)phenyl)isoxazol-5- yl)-1 -methylpyrrolidin-2-one, using 6-bromo-1 ,3-benzoxazole in place of 6-chloro-4- methoxy-1-methyl-1 /-/-pyrazolo[3,4-b]pyridine, to give the title compound as a solid (18.8 mg). Purification: RP HPLC; column SunFire 100 x 19 mm, 5 pm. MS (ESI): Mass calcd. for C21 H17N3O4 375.1 , m/z found, 376.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO-d ₆ ) 8 8.79 (s, 1 H), 8.21 (d, J = 8.2 Hz, 2H), 7.89 (d, J = 7.9 Hz, 2H), 7.81 (d, J = 8.3 Hz, 1 H), 7.61 (t, J = 7.7 Hz, 1 H), 7.19 (s, 1 H), 6.70 (s, 1 H), 3.46 (td, J = 9.3, 5.0 Hz, 1 H), 3.42 (q, J = 4.9, 3.0 Hz, 1 H), 2.83 (s, 3H), 2.56 (d, J = 6.9 Hz, 1 H), 2.52 (s, 1 H), 2.26 (dt, J = 13.8, 6.9 Hz, 1 H).

Example 70: (R)-3-Hydroxy-3-(3-(3-(imidazo[1 ,2-a]pyrazin-6-yl)phenyl)isoxazol-5-yl)-1 - methylpyrrolidin-2-one.

(R)-3-Hydroxy-3-(3-(3-(imidazo[1 ,2-a]pyrazin-6-yl)phenyl)isoxazol-5-yl)-1 - methylpyrrolidin-2-one was synthesized in a manner analogous to Example 48, (R)-3- hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 H-pyrazolo[3,4-b]pyridin-6-yl)phenyl)isoxazol-5- yl)-1 -methylpyrrolidin-2-one, using 6-chloroimidazo[1 ,2-a]pyrazine in place of 6-chloro- 4-methoxy-1 -methyl-1 /-/-pyrazolo[3,4-b]pyridine, to give the title compound as a solid (15.1 mg). MS (ESI): Mass calcd. for C20H17N5O3 375.1 , m/z found, 376.0 [M+H] ⁺ . ¹ H NMR (600 MHz, Aceton itrile-c/3) 8 9.09 (d, J = 1 .5 Hz, 1 H), 8.93 (d, J = 1 .6 Hz, 1 H), 8.47 (t, J = 1.8 Hz, 1 H), 8.15 (d, J = 7.7 Hz, 1 H), 7.96 (s, 1 H), 7.90 (d, J = 7.7 Hz, 1 H), 7.80 (s, 1 H), 7.64 (t, J = 7.8 Hz, 1 H), 6.91 (s, 1 H), 4.47 (s, 1 H), 3.50 (dd, J = 7.5, 5.7 Hz, 2H), 2.90 (s, 3H), 2.69 (dt, J = 13.5, 5.6 Hz, 1 H), 2.37 (dt, J = 14.1 , 7.6 Hz, 1 H).

Example 71 : (R)-3-Hydroxy-3-(3-(3-(imidazo[1 ,2-a]pyridin-6-yl)phenyl)isoxazol-5-yl)-1- methylpyrrolidin-2-one

(R)-3-Hydroxy-3-(3-(3-(imidazo[1 ,2-a]pyridin-6-yl)phenyl)isoxazol-5-yl)-1- methylpyrrolidin-2-one was synthesized in a manner analogous to Example 48, (R)-3- hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 /-/-pyrazolo[3,4-b]pyridin-6-yl)phenyl)isoxazol-5- yl)-1 -methylpyrrolidin-2-one, using 6-bromoimidazo[1 ,2-a]pyridine in place of 6-chloro-4- methoxy-1-methyl-1 /-/-pyrazolo[3,4-b]pyridine, to give the title compound as a solid (12.0 mg). Purification: RP HPLC; column SunFire C18 100 x 19 mm, 5 pm. MS (ESI): Mass calcd. for C21H18N4O3 374.1 , m/z found, 375.2 [M+H] ⁺ . ¹ H NMR (500 MHz, Aceton itrile-c/3) 8 8.70 (s, 1 H), 8.12 (d, J = 1 .9 Hz, 1 H), 7.90 (d, J = 7.7 Hz, 1 H), 7.83 (s, 1 H), 7.79 (d, J = 7.6 Hz, 1 H), 7.70 - 7.53 (m, 3H), 6.92 (s, 1 H), 4.62 (s, 1 H), 3.50 (dd, J = 7.6, 5.6 Hz, 2H), 2.69 (dt, J = 13.5, 5.7 Hz, 1 H), 2.52 (s, 3H), 2.38 (dt, J = 13.4, 7.5 Hz, 1 H).

Example 72: (R)-3-Hydroxy-1 -methyl-3-(3-(3-(thieno[2,3-c/]pyrimidin-4- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one.

(R)-3-Hydroxy-1 -methyl-3-(3-(3-(thieno[2,3-d]pyrimidin-4-yl)phenyl)isoxazol -5- yl)pyrrolidin-2-one was synthesized in a manner analogous to Example 48, (R)-3- hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 H-pyrazolo[3,4-b]pyridin-6-yl)phenyl)isoxazol-5- yl)-1 -methylpyrrolidin-2-one, using 4-chlorothieno[2,3-d]pyrimidine in place of 6-chloro- 4-methoxy-1 -methyl-1 /-/-pyrazolo[3,4-b]pyridine, to give the title compound as a solid (18.0 mg). Purification: RP HPLC; column SunFire C18 100 x 19 mm, 5 pm. MS (ESI): Mass calcd. for C20H16N4O3S 392.1 , m/z found, 393.2 [M+H] ⁺ . ¹ H NMR (500 MHz, Aceton itrile-cfa) 8 9.15 (s, 1 H), 8.45 (s, 1 H), 8.10 (dd, J = 19.9, 7.7 Hz, 2H), 7.83 (d, J = 6.1 Hz, 1 H), 7.78 - 7.51 (m, 2H), 6.91 (s, 1 H), 4.50 (s, 1 H), 3.64 - 3.43 (m, 2H), 3.04 (s, 3H), 2.69 (dt, J = 12.0, 5.8 Hz, 1 H), 2.37 (dt, J = 14.2, 7.6 Hz, 1 H).

Example 73: (R)-3-(3-(3-(5-Ethyl-7/-/-pyrrolo[2,3-d]pyrimidin-4-yl)pheny l)isoxazol-5-yl)-3- hydroxy-1-methylpyrrolidin-2-one (R)-3-(3-(3-(5-Ethyl-7/-/-pyrrolo[2,3-d]pyrim idin-4-yl)phenyl)isoxazol-5-yl)-3- hydroxy-1-methylpyrrolidin-2-one was synthesized in a manner analogous to Example 48, (R)-3-hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 H-pyrazolo[3,4-b]pyridin-6- yl)phenyl)isoxazol-5-yl)-1 -methylpyrrolidin-2-one, using 4-chloro-5-ethyl-7/-/-pyrrolo[2,3- d]pyrimidine in place of 6-chloro-4-methoxy-1 -methyl-1 /-/-pyrazolo[3,4-b]pyridine, to give the title compound as a solid (4.0 mg). Purification: RP HPLC; column SunFireC18 100 x 19 mm, 5 pm. MS (ESI): Mass calcd. for C22H21 N5O3 403.2, m/z found, 404.2 [M+H] ⁺ . ¹ H NMR (500 MHz, Acetonitrile-ck) 8 9.15 (s, 1 H), 8.45 (s, 1 H), 8.10 (dd, J = 19.9, 7.7 Hz, 2H), 7.83 (d, J = 6.1 Hz, 1 H), 7.78 - 7.51 (m, 2H), 6.91 (s, 1 H), 4.50 (s, 1 H), 3.64 - 3.43 (m, 2H), 3.04 (s, 3H), 2.69 (dt, J = 12.0, 5.8 Hz, 1 H), 2.37 (dt, J = 14.2, 7.6 Hz, 1 H).

Example 74: (R)-3-(3-(3-(3-Amino-[1 ,2,4]triazolo[4,3-a]pyridin-6-yl)phenyl)isoxazol-5-yl)- 3-hydroxy-1 -methylpyrrolidin-2-one

(R)-3-(3-(3-(3-Amino-[1 ,2,4]triazolo[4,3-a]pyridin-6-yl)phenyl)isoxazol-5-yl)-3- hydroxy-1-methylpyrrolidin-2-one was synthesized in a manner analogous to Example 48, (R)-3-hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 /-/-pyrazolo[3,4-b]pyridin-6- yl)phenyl)isoxazol-5-yl)-1 -methylpyrrolidin-2-one, using 6-bromo-[1 , 2,4]triazolo[4, 3- a]pyridin-3-amine in place of 6-chloro-4-methoxy-1 -methyl-1 /-/-pyrazolo[3,4-b]pyridine, to give the title compound as a solid (31 .3 mg). Purification: RP HPLC; column: SunFire C18 100 x 18 mm, 5 pm). MS (ESI): Mass calcd. for C20H18N6O3 390.1 m/z found, 391 .4 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO-d ₆ ) 8 8.50 (d, J = 1 .5 Hz, 1 H), 8.14 (t, J = 1 .8 Hz, 1 H), 7.89 (s, 1 H), 7.85 - 7.74 (m, 1 H), 7.62 (t, J = 7.8 Hz, 1 H), 7.53 (d, J = 1 .3 Hz, 2H), 7.12 (s, 1 H), 6.46 (s, 2H), 3.53 - 3.35 (m, 2H), 2.82 (s, 3H), 2.59 - 2.52 (m, 2H), 2.25 (ddd, J = 13.6, 8.1 , 5.7 Hz, 1 H). Example 75: (R)-3-(3-(3-(2/-/-pyrazolo[3,4-c]pyridin-5-yl)phenyl)isoxazo l-5-yl)-3-hydroxy- 1 -methylpyrrolidin-2-one.

(R)-3-(3-(3-(2/-/-pyrazolo[3,4-c]pyridin-5-yl)phenyl)isox azol-5-yl)-3-hydroxy-1 - methylpyrrolidin-2-one was synthesized in a manner analogous to Example 48, (R)-3- hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 /-/-pyrazolo[3,4-b]pyridin-6-yl)phenyl)isoxazol-5- yl)-1 -methylpyrrolidin-2-one, using 5-bromo-1 /-/-pyrazolo[3,4-c]pyridine hydrochloride in place of 6-chloro-4-methoxy-1 -methyl-1 /-/-pyrazolo[3,4-b]pyridine, to give the title compound as a solid (2.0 mg). MS (ESI): Mass calcd. for C20H17N5O3 375.1 , m/z found, 376.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO-d ₆ ) 8 9.15 (s, 1 H), 8.59 (s, 1 H), 8.45 (s, 1 H), 8.27 (s, 1 H), 8.24 (d, J = 7.9 Hz, 1 H), 7.86 (d, J = 7.6 Hz, 1 H), 7.60 (t, J = 7.8 Hz, 1 H), 7.11 (s, 1 H), 6.64 (d, J = 64.6 Hz, 1 H), 3.56 - 3.37 (m, 2H), 2.83 (s, 3H), 2.64 - 2.52 (m, 1 H), 2.27 (ddd, J = 13.6, 8.0, 5.8 Hz, 1 H), 1.09 (s, 1 H).

Example 76: (R)-3-Hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 H-indazol-6- yl)phenyl)isoxazol-5-yl)-1 -methylpyrrolidin-2-one.

Step A: 6-Bromo-4-methoxy-1 -methyl-1 /-/-indazole. To a solution of 6-bromo-4- methoxy-1 /-/-indazole (100 mg, 0.44 mmol) dissolved in DMF/ THF (1 :1 mixture of 5 mL) was added NaH (53.0 mg, 1.32 mmol, 60% dispersion in mineral oil). After 5 minutes methyl iodide (83 pL, 1 .32 mmol) was added and the reaction mixture was heated at 46 °C for 18 hours. The reaction mixture was quenched with NH4CI (aq), and the aqueous layer was extracted with EtOAc (3X). The combined organic extracts were washed with brine, dried with MgSCM, filtered, concentrated and purified with HPLC (Column TRIART 20 x 100 mm, 5 pm; H2O I AcCN + NH3; gradient 40-60%) to provide the title compound (28 mg, 27%). MS (ESI): Mass calcd. for C9H ₉ BrN ₂ O 240.0, m/z found, 241.0 [M+H] ⁺ .

Step B: (R)-3-Hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 /-/-indazol-6- yl)phenyl)isoxazol-5-yl)-1 -methylpyrrolidin-2-one. (R)-3-Hydroxy-3-(3-(3-(4-methoxy-1 - methyl-1 /-/-indazol-6-yl)phenyl)isoxazol-5-yl)-1 -methylpyrrolidin-2-one was synthesized in a manner analogous to Example 48, (R)-3-hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 H- pyrazolo[3,4-b]pyridin-6-yl)phenyl)isoxazol-5-yl)-1 -methylpyrrolidin-2-one, using 6- bromo-4-methoxy-1 -methyl-1 /-/-indazole in place of 6-chloro-4-methoxy-1 -methyl-1 /-/- pyrazolo[3,4-b]pyridine, to give the title compound as a solid (2.4 mg). MS (ESI): Mass calcd. for C23H22N4O4418.5, m/z found, 419.4 [M+H] ⁺ . ¹ H NMR (600 MHz, Acetonitrile- d ₃ ) 8 8.18 (t, J = 1.8 Hz, 1 H), 7.97 (d, J = 0.9 Hz, 1 H), 7.90 - 7.84 (m, 2H), 7.60 (t, J = 7.7 Hz, 1 H), 7.40 (d, J = 1 .0 Hz, 1 H), 6.94 (s, 1 H), 6.86 (d, J = 1 .0 Hz, 1 H), 4.61 (s, 1 H), 4.06 (d, J = 10.3 Hz, 6H), 3.52 - 3.46 (m, 2H), 2.90 (s, 3H), 2.71 - 2.64 (m, 1 H), 2.41 - 2.32 (m, 1 H).

Example 77: (R)-3-(3-(3-(1/-/-lndol-4-yl)phenyl)isoxazol-5-yl)-3-hydroxy -1 - methylpyrrolidin-2-one.

(R)-3-(3-(3-(1 /-/-indol-4-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2- one was synthesized in a manner analogous to Example 48, (R)-3-hydroxy-3-(3-(3-(4- methoxy-1 -methyl-1 H-pyrazolo[3,4-b]pyridin-6-yl)phenyl)isoxazol-5-yl)-1 - methylpyrrolidin-2-one, using 4-bromoindole in place of 6-chloro-4-methoxy-1 -methyl- 1 /-/-pyrazolo[3,4-b]pyridine, to give the title compound as a solid (3.0 mg). MS (ESI): Mass calcd. for C22H19N3O3 373.4, m/z found, 374.2 [M+H] ⁺ . ¹ H NMR (400 MHz,

DMSO-c/e) 8 11.32 (s, 1 H), 8.13 (s, 1 H), 7.86 (s, 1 H), 7.79 (s, 1 H), 7.64 (s, 1 H), 7.44 (s, 2H), 7.20 (d, J = 12.7 Hz, 2H), 7.08 (s, 1 H), 6.72 (s, 1 H), 6.56 (s, 1 H), 3.45 (s, 2H), 2.84 (s, 3H), 2.36 - 2.25 (m, 2H).

Example 78: (R)-3-Hydroxy-1 -methyl-3-(3-(3-(1 -methyl-1 /-/-pyrazolo[3,4-b]pyridin-6- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one.

(R)-3-Hydroxy-1 -methyl-3-(3-(3-(1 -methyl-1 /-/-pyrazolo[3,4-b]pyridin-6- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one was synthesized in a manner analogous to Example 48, (R)-3-hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 H-pyrazolo[3,4-b]pyridin-6- yl)phenyl)isoxazol-5-yl)-1 -methylpyrrolidin-2-one, using 6-chloro-1 -methyl-1 H- pyrazolo[3,4-B]pyridine in place of 6-chloro-4-methoxy-1 -methyl-1 /-/-pyrazolo[3, 4- b]pyridine, to give the title compound as a solid (3.2 mg). MS (ESI): Mass calcd. for C21 H19N5O3 389.4, m/z found, 390.4 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO-d ₆ ) 8 8.64 (t, J = 1.8 Hz, 1 H), 8.37 - 8.31 (m, 2H), 8.16 (d, J = 1.5 Hz, 1 H), 8.00 - 7.91 (m, 2H), 7.71 - 7.63 (m, 1 H), 7.16 (d, J = 1.6 Hz, 1 H), 6.72 (s, 1 H), 4.13 (d, J = 1.5 Hz, 3H), 3.51 - 3.38 (m, 2H), 2.84 (s, 1 H), 2.83 (s, 2H), 2.62 - 2.50 (m, 1 H), 2.32 - 2.23 (m, 1 H).

Example 79: (R)-3-Hydroxy-1-methyl-3-(3-(3-(2-methylimidazo[1 ,2-a]pyridin-6- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one.

(R)-3-Hydroxy-1 -methyl-3-(3-(3-(2-methylimidazo[1 ,2-a]pyridin-6- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one was synthesized in a manner analogous to Example 48, (R)-3-hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 H-pyrazolo[3,4-b]pyridin-6- yl)phenyl)isoxazol-5-yl)-1 -methylpyrrolidin-2-one, using 6-bromo-2-methylimidazo[1 ,2- a]pyridine in place of 6-chloro-4-methoxy-1 -methyl-1 /-/-pyrazolo[3,4-b]pyridine, to give the title compound as a solid (5.3 mg). MS (ESI): Mass calcd. for C22H20N4O3 388.4, m/z found, 389.2 [M+H] ⁺ . ¹ H NMR (500 MHz, Aceton itrile-cfe) 8 8.61 (s, 1 H), 8.10 (d, J = 2.1 Hz, 1 H), 7.88 (d, J = 7.7 Hz, 1 H), 7.77 (d, J = 7.8 Hz, 1 H), 7.65 - 7.50 (m, 4H), 6.91 (s, 1 H), 3.54 - 3.47 (m, 2H), 2.91 (s, 3H), 2.73 - 2.64 (m, 1 H), 2.44 - 2.33 (m, 4H), 1 .95 - 1.90 (m, 1 H).

Example 80: (R)-7-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)- 1 -methyl-3,4-dihydroquinoxalin-2(1 /-/)-one

(R)-7-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-1 - methyl-3,4-dihydroquinoxalin-2(1 /-/)-one was synthesized in a manner analogous to Example 48, (R)-3-hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 H-pyrazolo[3,4-b]pyridin-6- yl)phenyl)isoxazol-5-yl)-1 -methylpyrrolidin-2-one, using 7-bromo-1 -methyl-1 ,2,3,4- tetrahydroquinoxalin-2-one in place of 6-chloro-4-methoxy-1 -methyl-1 /-/-pyrazolo[3, 4- b]pyridine, to give the title compound as a solid (6.1 mg). MS (ESI): Mass calcd. for C23H22N4O4 418.5, m/z found, 419.2 [M+H] ⁺ . ¹ H NMR (600 MHz, Aceton itrile-c/3) 8 8.03 (d, J = 2.0 Hz, 1 H), 7.81 - 7.74 (m, 1 H), 7.74 - 7.69 (m, 1 H), 7.53 (t, J = 7.7 Hz, 1 H), 7.28 (d, J = 1.9 Hz, 1 H), 7.27 - 7.23 (m, 1 H), 6.90 (s, 1 H), 6.83 (d, J = 8.1 Hz, 1 H), 4.84 (s, 1 H), 3.87 (d, J = 1 .8 Hz, 2H), 3.71 (s, 1 H), 3.53 - 3.41 (m, 2H), 3.38 (d, J = 3.6 Hz, 3H), 2.89 (d, J = 3.3 Hz, 3H), 2.74 - 2.59 (m, 1 H), 2.41 - 2.31 (m, 1 H).

Example 81 : (R)-3-Hydroxy-3-(3-(3-(6-methoxy-1 ,3-dihydroisobenzofuran-5- yl)phenyl)isoxazol-5-yl)-1-methylpyrrolidin-2-one. (R)-3-Hydroxy-3-(3-(3-(6-methoxy-1 ,3-dihydroisobenzofuran-5- yl)phenyl)isoxazol-5-yl)-1-methylpyrrolidin-2-one was synthesized in a manner analogous to Example 48, (R)-3-hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 H-pyrazolo[3,4- b]pyridin-6-yl)phenyl)isoxazol-5-yl)-1 -methylpyrrolidin-2-one, using 5-bromo-6-methoxy- 1 ,3-dihydro-2-benzofuran in place of 6-chloro-4-methoxy-1 -methyl-1 /-/-pyrazolo[3,4- b]pyridine, to give the title compound as a solid (10.2 mg). MS (ESI): Mass calcd. for C23H22N2O5 406.4, m/z found, 407.2 [M+H] ⁺ . ¹ H NMR (500 MHz, Acetonitrile-cfc) 8 7.96 (d, J = 1 .9 Hz, 1 H), 7.82 (d, J = 7.9 Hz, 1 H), 7.63 (d, J = 7.8 Hz, 1 H), 7.54 (t, J = 7.7 Hz, 1 H), 7.28 (s, 1 H), 7.06 (s, 1 H), 6.84 (s, 1 H), 5.13 - 4.98 (m, 4H), 4.51 (s, 1 H), 3.81 (s, 3H), 3.53 - 3.41 (m, 2H), 2.90 (s, 3H), 2.72 - 2.60 (m, 1 H), 2.41 - 2.30 (m, 1 H).

Example 82: (R)-5-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)isoquinolin-1 (2/-/)-one.

(R)-5-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)isoquinolin-1 (2/-/)-one was synthesized in a manner analogous to Example 48, (R)-3-hydroxy-3-(3-(3-(4-methoxy-1-methyl-1 H-pyrazolo[3,4-b]pyridin-6- yl)phenyl)isoxazol-5-yl)-1-methylpyrrolidin-2-one, using 5-bromo-1 ,2-dihydroisoquinolin- 1 -one in place of 6-chloro-4-methoxy-1 -methyl-1 /-/-pyrazolo[3,4-b]pyridine, to give the title compound as a solid (4.0 mg). MS (ESI): Mass calcd. for C23H19N3O4401 .4, m/z found, 402.2 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO-d ₆ ) 8 11 .35 (s, 1 H), 8.25 (d, J = 8.0 Hz, 1 H), 7.94 (d, J = 7.8 Hz, 1 H), 7.89 (d, J = 1 .8 Hz, 1 H), 7.70 - 7.66 (m, 1 H), 7.63 (t, J = 7.7 Hz, 1 H), 7.58 - 7.51 (m, 2H), 7.14 (d, J = 7.4 Hz, 1 H), 7.07 (s, 1 H), 6.32 (d, J = 7.4 Hz, 1 H), 3.46 - 3.41 (m, 1 H), 3.41 - 3.35 (m, 1 H), 3.14 (s, 1 H), 2.80 (s, 4H), 2.62 - 2.57 (m, 1 H).

Example 83: (R)-3-(3-(3-(1 /-/-pyrazolo[4,3-c]pyridin-6-yl)phenyl)isoxazol-5-yl)-3-hydr oxy- 1 -methylpyrrolidin-2-one.

(R)-3-(3-(3-(1 /-/-pyrazolo[4,3-c]pyridin-6-yl)phenyl)isoxazol-5-yl)-3-hydr oxy-1 - methylpyrrolidin-2-one was synthesized in a manner analogous to Example 48, (R)-3- hydroxy-3-(3-(3-(4-methoxy-1 -methyl-1 H-pyrazolo[3,4-b]pyridin-6-yl)phenyl)isoxazol-5- yl)-1 -methylpyrrolidin-2-one, using 6-chloro-1 /-/-pyrazolo[4,3-c]pyridine in place of 6- chloro-4-methoxy-1 -methyl-1 /-/-pyrazolo[3,4-b]pyridine, to give the title compound as a solid (1 .7 mg). MS (ESI): Mass calcd. for C20H17N5O3 375.4 m/z found, 376.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO-d ₆ ) 8 13.54 (s, 1 H), 9.21 (s, 1 H), 8.63 (s, 1 H), 8.33 (s, 1 H), 8.28 (d, J = 7.8 Hz, 1 H), 8.14 (s, 1 H), 7.91 (d, J = 7.7 Hz, 1 H), 7.62 (t, J = 7.8 Hz, 1 H), 7.12 (s, 1 H), 6.65 (d, J = 55.7 Hz, 1 H), 3.49 - 3.39 (m, 2H), 2.83 (s, 3H), 2.65 - 2.53 (m, 1 H), 2.32 - 2.23 (m, 1 H).

Example 84: (R)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)- 3-methyl-1/-/-pyrazolo[3,4-b]pyridine-4-carboxamide.

(R)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-3- methyl-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxamide (27 mg) was prepared in a manner analogous to Example 47 using ethyl 6-chloro-3-methyl-1 /-/-pyrazolo[3,4-b]pyridine-4- carboxylate instead of methyl 4-chloro-6-methoxypicolinate in Step A. MS (ESI): Mass calcd. for C22H20N6O4, 432.2; m/z found, 433.2 [M+H] ⁺ . ¹ H NMR (600 MHz, CD3OD) 58.70 - 8.59 (m, 1 H), 8.30 (d, J = 7.5 Hz, 1 H), 7.98 (d, J = 6.2 Hz, 1 H), 7.89 (s, 1 H), 7.69 (t, J = 7.8 Hz, 1 H), 7.03 (s, 1 H), 3.66 - 3.56 (m, 2H), 3.00 (s, 3H), 2.83 - 2.71 (m, 1 H), 2.64 (s, 3H), 2.49 - 2.40 (m, 1 H). Example 85: (R)-4-Cyclopropyl-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)pyrimidine-2-carboxamide.

(R)-4-Cyclopropyl-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)pyrimidine-2 -carboxamide (57 mg) was prepared in a manner analogous to Example 47 using methyl 4-chloro-6-cyclopropylpyrimidine-2-carboxylate instead of methyl 4-chloro-6-methoxypicolinate in Step A. MS (ESI): Mass calcd. for C22H21 N5O4, 419.2; m/z found, 420.2 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 58.79 (t, J = 1 .8 Hz, 1 H), 8.49 - 8.35 (m, 1 H), 8.12 - 8.02 (m, 2H), 7.67 (t, J = 7.8 Hz, 1 H), 7.11 (s, 1 H), 3.63 - 3.52 (m, 2H), 2.97 (s, 3H), 2.82 - 2.69 (m, 1 H), 2.47 - 2.36 (m, 1 H), 2.36 - 2.26 (m, 1 H), 1.41 - 1.29 (m, 2H), 1.25 - 1.14 (m, 2H).

Example 86: (R)-3-(3-(3-(2-Aminoquinazolin-8-yl)phenyl)isoxazol-5-yl)-3- hydroxy-1 - methylpyrrolidin-2-one.

(R)-3-(3-(3-(2-Aminoquinazolin-8-yl)phenyl)isoxazol-5-yl) -3-hydroxy-1 - methylpyrrolidin-2-one (88 mg) was prepared in a manner analogous to Example 47 Step B using 8-bromoquinazolin-2-amine instead of 4-chloro-6-methoxypicolinamide. MS (ESI): Mass calcd. for C22H19N5O3, 401 .1 ; m/z found, 402.1 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 5 8.01 - 7.94 (m, 1 H), 7.89 (t, J = 1 .8 Hz, 1 H), 7.71 - 7.63 (m, 1 H), 7.58 - 7.51 (m, 1 H), 7.49 (dd, J = 7.5, 1 .6 Hz, 1 H), 7.42 (dd, J = 7.6, 1 .6 Hz, 1 H), 7.36 (t, J = 7.6 Hz, 1 H), 7.01 - 6.91 (m, 1 H), 5.84 (s, 1 H), 3.66 - 3.52 (m, 2H), 2.95 (s, 3H), 2.79 - 2.68 (m, 1 H), 2.44 - 2.35 (m, 1 H).

Example 87: (R)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)- 3-methoxypicolinamide.

(R)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-3- methoxypicolinamide (125 mg) was prepared in a manner analogous to Example 47 using methyl 6-chloro-3-methoxypyridine-2-carboxylate instead of methyl 4-chloro-6- methoxypicolinate in Step A. MS (ESI): Mass calcd. for C21 H20N4O5, 408.1 ; m/z found, 409.1 [M+H] ⁺ . ¹ H NMR (500 MHz, CD ₃ OD) 58.51 (t, J = 1.7 Hz, 1 H), 8.19 - 8.10 (m, 1 H), 8.06 (d, J = 8.8 Hz, 1 H), 7.90 - 7.81 (m, 1 H), 7.69 (d, J = 8.9 Hz, 1 H), 7.61 - 7.51 (m, 1 H), 7.01 (s, 1 H), 3.97 (s, 3H), 3.64 - 3.50 (m, 2H), 2.96 (s, 3H), 2.79 - 2.68 (m, 1 H), 2.46 - 2.34 (m, 1 H).

Example 88: (R)-3-Amino-4-cyclopropyl-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)picolinamide.

Step A: 3-Amino-6-chloro-4-cyclopropylpicolinamide. A vial was charged with toluene (10 mL) and H2O (1 mL). The solution was sparged under nitrogen for 15 minutes before the addition of CATACXIUM PD G4 (CAS# 2230788-67-5, 237 mg, 0.319 mmol), which formed a light brown mixture. To this mixture, CS2CO3 (2.08 g, 6.38 mmol) was added, which formed a dark brown solution. The brown solution was then stirred while being continuously sparged with nitrogen. Potassium cyclopropyltrifluoroborate (472 mg, 2.19 mmol) was added followed by 3-amino-4,6- dichloropicolinonitrile (401 mg, 2.13 mmol). The vial was then sealed and stirred for 24 hours in the microwave at 90 °C. After this time, the solution was filtered over diatomaceous earth and washed with acetone. The resulting filtered solution was evaporated to dryness and purified by FCC (EtOAc/CH2Cl2) providing two products: 3- amino-6-chloro-4-cyclopropylpicolinonitrile (180 mg, 43.7%), MS (ESI): Mass calcd. for CgHsCIOs, 193.0; m/z found, 194.1 [M+H] ⁺ , and 3-amino-6-chloro-4- cyclopropylpicolinamide (78 mg, 43%), MS (ESI): Mass calcd. for C9H10CIN3O, 211.1 ; m/z found, 212.1 [M+H] ⁺ .

Step B: (R)-3-Amino-4-cyclopropyl-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)picolinamide. (R)-3-Amino-4-cyclopropyl-6-(3-(5-(3-hydroxy-1 - methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinamid e (68 mg, 43%) was prepared in a manner analogous to Example 47 Step B using 3-amino-6-chloro-4- cyclopropylpicolinamide instead of 4-chloro-6-methoxypicolinamide. MS (ESI): Mass calcd. for C23H23N5O4, 433.2; m/z found, 434.2 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 58.42 (t, J = 1 .8 Hz, 1 H), 8.12 - 8.00 (m, 1 H), 7.80 - 7.72 (m, 1 H), 7.59 (d, J = 0.8 Hz, 1 H), 7.53 (t, J = 7.8 Hz, 1 H), 6.99 (s, 1 H), 3.65 - 3.49 (m, 2H), 2.97 (s, 3H), 2.81 - 2.66 (m, 1 H), 2.47 - 2.34 (m, 1 H), 1.86 - 1.70 (m, 1 H), 1.15 - 1.02 (m, 2H), 0.82 - 0.70 (m, 2H).

Example 89: (R)-3-Amino-5-fluoro-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)picolinamide.

Step A: 3-Amino-6-bromo-5-fluoropicolinamide. To a colorless solution of 3- amino-6-bromo-5-fluoropicolinic acid (247 mg, 105 mmol) in THF (10 mL) at 0 °C was added CICCteEt (160 mg, 1 .47 mmol) and EtsN (0.219 mL, 1 .58 mmol) The mixture was stirred at this temperature for 30 minutes. An aqueous solution of NH4CI (1 .5 mL, 1 .0 M) was added, then H2O (5 mL) was added. The resulting mixture was extracted with EtOAc (30 mL x 2). The combined organic layers were dried over anhydrous MgSCk, filtered and concentrated to provide the title compound (210 mg, 85%). MS (ESI): Mass calcd. for CeHsBrFNsO, 233.0; m/z found, 234.0 [M+H] ⁺ .

Step B: (R)-3-Amino-5-fluoro-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)picolinamide. (R)-3-Amino-5-fluoro-6-(3-(5-(3-hydroxy-1 -methyl- 2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinamide (50 mg, 23%) was prepared in a manner analogous to Example 47 Step B using 3-amino-6-bromo-5-fluoropicolinamide instead of 4-chloro-6-methoxypicolinamide. MS (ESI): Mass calcd. for C20H18FN5O4, 411 .1 ; m/z found, 412.1 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 58.32 (q, J = 1 .6 Hz, 1 H), 8.04 - 7.92 (m, 1 H), 7.83 - 7.73 (m, 1 H), 7.53 (t, J = 7.8 Hz, 1 H), 7.01 - 6.88 (m, 2H), 3.63 - 3.48 (m, 2H), 2.96 (s, 3H), 2.80 - 2.67 (m, 1 H), 2.47 - 2.33 (m, 1 H).

Example 90: (R)-1 -Ethyl-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-1 H-imidazo[4,5-c]pyridine-4-carboxamide.

Step A: 6-Chloro-1 -ethyl-1 /-/-imidazo[4,5-c]pyridine-4-carbonitrile. A mixture of 6- chloro-1 H-imidazo[4,5-c]pyridine-4-carbonitrile (178 mg, 0.997 mmol), ethyl iodide (164 mg, 1 .05 mmol), and K2CO3 (275 mg, 1 .99 mmol) in DMF (1 mL) was stirred for 8 h at RT. Water (20 mL) was added. The solid was filtered and dried to provide the title compound (120 mg, 58%). MS (ESI): Mass calcd. for C9H7CIN4, 206.0; m/z found, 207.1 [M+H] ⁺ .

Step B: (R)-1 -Ethyl-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-1 /-/-imidazo[4,5-c]pyridine-4-carbonitrile. (R)-1 -Ethyl-6-(3-(5-(3-hydroxy-1 - methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-1 /-/-imidazo[4,5-c]pyridine-4- carbonitrile (50 mg, 24%) was prepared in a manner analogous to Example 47 Step B using 6-chloro-1 -ethyl-1 H-imidazo[4,5-c]pyridine-4-carbonitrile instead of 4-chloro-6- methoxypicolinamide. MS (ESI): Mass calcd. for C23H20N6O3, 428.1 ; m/z found, 429.1 [M+H] ⁺ .

Step C: (R)-1 -Ethyl-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-1 H-imidazo[4,5-c]pyridine-4-carboxamide. To a mixture of (R)-1 -ethyl-6-(3-(5- (3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)pheny l)-1 /-/-imidazo[4,5- c]pyridine-4-carbonitrile (30 mg, 0.07 mmol) in MeOH (2 mL), NaOMe (0.04 mL, 30% in MeOH) was added. The mixture was heated at 130 °C for 16 h. Then it was cooled to RT and concentrated. The residue was purified with HPLC (H2O/CH3CN) to provide the title compound (15 mg, 48%). MS (ESI): Mass calcd. for C23H22N6O4, 446.2; m/z found, 447.1 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 59.44 (s, 1 H), 8.68 (d, J = 13.0 Hz, 2H), 8.46 - 8.32 (m, 1 H), 7.93 (d, J = 7.6 Hz, 1 H), 7.66 (t, J = 7.8 Hz, 1 H), 7.08 (s, 1 H), 4.63 (q, J = 7.3 Hz, 2H), 3.70 - 3.52 (m, 2H), 2.98 (d, J = 0.9 Hz, 3H), 2.85 - 2.69 (m, 1 H), 2.54 - 2.37 (m, 1 H), 1 .68 (t, J = 7.3 Hz, 3H).

Example 91 : (R)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)- 4-(trifluoromethyl)picolinamide.

(R)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-4- (trifluoromethyl)picolinamide (90 mg) was prepared in a manner analogous to Example 89 using 6-chloro-4-(trifluoromethyl)picolinic acid instead of 3-amino-6-bromo-5- fluoropicolinic acid in Step A. MS (ESI): Mass calcd. for C21 H17F3N4O4, 446.1 ; m/z found, 447.1 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 58.68 (t, J = 1 .8 Hz, 1 H), 8.40 (dd, J = 1 .6, 0.8 Hz, 1 H), 8.37 - 8.24 (m, 2H), 8.00 - 7.91 (m, 1 H), 7.65 (t, J = 7.8 Hz, 1 H), 7.07 (s, 1 H), 3.67 - 3.51 (m, 2H), 2.98 (s, 3H), 2.83 - 2.70 (m, 1 H), 2.49 - 2.33 (m, 1 H). Example 92: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)imidazo[1 ,2-a]pyridine-8-carboxamide.

(R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)imidazo[1 ,2-a]pyridine-8-carboxamide (130 mg) was prepared in a manner analogous to Example 47 using methyl 2-bromoimidazo[1 ,2-a]pyridine-8-carboxylate instead of methyl 4-chloro-6-methoxypicolinate in Step A. MS (ESI): Mass calcd. for C22H19N5O4, 417.1 ; m/z found, 418.1 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 5 8.59 (dd, J = 6.7, 1.3 Hz, 1 H), 8.44 (t, J = 1.6 Hz, 1 H), 8.37 (s, 1 H), 8.15 - 8.06 (m, 2H), 7.82 - 7.73 (m, 1 H), 7.61 - 7.50 (m, 1 H), 7.03 (t, J = 7.0 Hz, 1 H), 6.96 (s, 1 H), 3.65 - 3.49 (m, 2H), 2.98 (s, 3H), 2.81 - 2.70 (m, 1 H), 2.51 - 2.33 (m, 1 H).

Example 93: (R)-1 -(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)- 5,6,7,8-tetrahydroimidazo[1 ,5-a]pyridine-3-carboxamide.

(R)-1 -(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)- 5,6,7,8-tetrahydroimidazo[1 ,5-a]pyridine-3-carboxamide (70 mg) was prepared in a manner analogous to Example 89 using 1 -bromo-5,6,7,8-tetrahydroimidazo[1 ,5- a]pyridine-3-carboxylic acid instead of 3-amino-6-bromo-5-fluoropicolinic acid in Step A. MS (ESI): Mass calcd. for C22H23N5O4, 421.2; m/z found, 422.2 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 5 8.11 (d, J = 1 .8 Hz, 1 H), 7.90 - 7.79 (m, 1 H), 7.79 - 7.70 (m, 1 H), 7.58 (t, J = 7.8 Hz, 1 H), 6.93 (s, 1 H), 4.50 (t, J = 6.2 Hz, 2H), 3.65 - 3.49 (m, 2H), 3.04 (t, J = 6.4 Hz, 2H), 2.96 (s, 3H), 2.80 - 2.66 (m, 1 H), 2.45 - 2.35 (m, 1 H), 2.10 - 1 .98 (m, 2H), 1.98 - 1.85 (m, 2H).

Example 94: (R)-4-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)- 1 /-/-pyrrolo[2,3-b]pyridine-6-carboxamide.

(R)-4-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-1 /-/- pyrrolo[2,3-b]pyridine-6-carboxamide (42 mg) was prepared in a manner analogous to Example 47 using methyl 4-chloro-1 /-/-pyrrolo[2,3-b]pyridine-6-carboxylate instead of methyl 4-chloro-6-methoxypicolinate in Step A. MS (ESI): Mass calcd. for C22H19N5O4, 417.1 ; m/z found, 418.2 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 88.43 - 8.19 (m, 1 H), 8.18 - 7.83 (m, 3H), 7.80 - 7.50 (m, 2H), 7.07 - 6.92 (m, 1 H), 6.87 - 6.58 (m, 1 H), 3.64 - 3.50 (m, 2H), 2.96 (s, 3H), 2.81 - 2.70 (m, 1 H), 2.47 - 2.31 (m, 1 H).

Example 95: (R)-1 -(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)- 4,5,6,7-tetrahydro-1 /-/-indazole-3-carboxylic acid.

Step A: Methyl (R)-1 -(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-4,5,6,7-tetrahydro-1 /-/-indazole-3-carboxylate. A mixture of methyl 4, 5,6,7- tetrahydro-1 /-/-indazole-3-carboxylate (225 mg, 1.25 mmol), (R)-3-hydroxy-1-methyl-3- (3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 670 mg, 1.74 mmol), Cu(OAc)2 (68 mg, 0.38 mmol), and pyridine (0.312 mL, 3.88 mmol) in DMF (2.5 mL) was heated at 92 °C for 3 h, and cooled to RT. H2O (50 mL) was added and the mixture was extracted with EtOAc (3x 30 mL). The organic extracts were combined and concentrated. The residue was purified with FCC (5% MeOH/CH2Cl2) and provided the title compound (50 mg, 9%). MS (ESI): Mass calcd. for C23H24N4O5, 436.2; m/z found, 437.2 [M+H] ⁺ .

Step B: (R)-1 -(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-4,5,6,7-tetrahydro-1 /-/-indazole-3-carboxylic acid. A mixture of methyl (R)-1 - (3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-4,5,6,7-t etrahydro- 1 /-/-indazole-3-carboxylate (50mg, 0.12 mmol) in NH3 (10 mL, 2 M in MeOH) was heated at 80 °C for 16 h. Aqueous NH4OH (5 N, 5 mL) was added and the mixture was heated at 150 °C for 3 h. Then, the reaction mixture was cooled to RT and concentrated. The residue was purified with reverse HPLC (CH3CN/H2O) to provide the title compound (21 mg, 43%). MS (ESI): Mass calcd. for C22H22N4O5, 422.2; m/z found, 423.2 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 57.98 - 7.82 (m, 2H), 7.57 (t, J = 7.8 Hz, 1 H), 7.52 - 7.42 (m, 1 H), 6.91 (s, 1 H), 3.60 - 3.50 (m, 2H), 2.95 (s, 3H), 2.84 (t, J = 6.1 Hz, 2H), 2.76 - 2.65 (m, 3H), 2.46 - 2.27 (m, 1 H), 1.92 - 1 .77 (m, 4H).

Example 96: (R)-8-Amino-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)pyrido[3,2-d]pyrimidin-4(3/-/)-one.

Step A: (R)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-imidazo[4,5-c]pyridine-4-carbonitrile. (R)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-1 -((2- (trimethylsilyl)ethoxy)methyl)-1 /-/-imidazo[4,5-c]pyridine-4-carbonitrile (130 mg) was prepared in a manner analogous to Example 47 (Step A and Step B) using 2- (trimethylsilyl)ethoxymethyl chloride instead of ethyl iodide. MS (ESI): Mass calcd. for C27H ₃ oN ₆ 04Si, 530.6; m/z found, 531.2 [M+H] ⁺ . ¹ H NMR (500 MHz, CD ₃ OD) 58.73 - 8.64 (m, 1 H), 8.62 - 8.49 (m, 2H), 8.32 - 8.09 (m, 1 H), 7.99 - 7.90 (m, 1 H), 7.70 - 7.60 (m, 1 H), 7.12 - 7.00 (m, 1 H), 5.95 - 5.70 (m, 2H), 3.77 - 3.54 (m, 4H), 3.09 - 2.95 (m, 3H), 2.91 - 2.76 (m, 1 H), 2.57 - 2.37 (m, 1 H), 1.04 - 0.89 (m, 2H), 0.04 - -0.14 (m, 9H).

Step B: (R)-8-Amino-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)pyrido[3,2-d]pyrimidin-4(3H)-one. To a solution of (R)-6-(3-(5-(3-hydroxy-1 - methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 /-/- imidazo[4,5-c]pyridine-4-carbonitrile (60 mg, 0.1 mmol) in MeOH (2 mL), NaOMe (0.062 mL, 0.34 mmol, 30% in MeOH) and TBAF (0.11 mL, 0,11 mmol, 1 M in THF) were added. The mixture was heated at 130 °C for 16 h, then cooled to RT and concentrated. The residue was partitioned between with EtOAc/ H2O (15/7 mL). The organic layer was separated and concentrated. The HPLC purification (CH3CN/H2O) provided two products: the title compound (18 mg, 38%) and (R)-6-(3-(5-(3-hydroxy-1 - methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-1 /-/-imidazo[4,5-c]pyridine-4- carboxamide (Example 97) (7 mg, 18%). MS (ESI): Mass calcd. for C21H18N6O4, 418.1 ; m/z found, 419.1 [M+H] ⁺ . ¹ H NMR (600 MHz, CD3OD) 88.55 (s, 1 H), 8.18 - 8.06 (m, 1 H), 8.00 (s, 1 H), 7.90 (d, J = 7.7 Hz, 1 H), 7.56 (t, J = 7.8 Hz, 1 H), 7.40 (s, 1 H), 7.07 (s, 1 H), 3.64 - 3.52 (m, 2H), 2.97 (s, 3H), 2.78 - 2.68 (m, 1 H), 2.47 - 2.34 (m, 1 H).

Example 97: (R)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)- 1 H-imidazo[4,5-c]pyridine-4-carboxamide

(R)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-1 /-/- imidazo[4,5-c]pyridine-4-carboxamide (7 mg) was prepared as described in Example 96. MS (ESI): Mass calcd. for C21H18N6O4, 418.1 ; m/z found, 419.1 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 8 8.73 - 8.59 (m, 1 H), 8.53 - 8.21 (m, 3H), 7.95 - 7.81 (m, 1 H), 7.65 - 7.50 (m, 1 H), 7.09 - 6.98 (m, 1 H), 4.56 (s, 1 H), 3.68 - 3.51 (m, 2H), 2.98 (s, 3H), 2.82 - 2.68 (m, 1 H), 2.50 - 2.31 (m, 1 H). Example 98: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)- 6-(trifluoromethyl)pyrimidine-4-carboxamide.

Step A: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-6-(trifluoromethyl)pyrimidine-4-carboxylic acid. (R)-2-(3-(5-(3-Hydroxy-1 - methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-6-(trifluo romethyl)pyrimidine-4- carboxylic acid (136 mg, 55%) was prepared in a manner analogous to Example 47 Step B using ethyl 2-chloro-6-(trifluoromethyl)pyrimidine-4-carboxylate instead of 4- chloro-6-methoxypicolinamide. MS (ESI): Mass calcd. for C20H15F3N4O5, 448.1 ; m/z found, 449.1 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 59.14 (s, 1 H), 8.73 (d, J = 7.8 Hz, 1 H), 8.17 (s, 1 H), 8.08 (d, J = 7.7 Hz, 1 H), 7.66 (t, J = 7.4 Hz, 1 H), 7.12 (s, 1 H), 3.58 (dd, J = 7.4, 5.8 Hz, 2H), 2.97 (s, 3H), 2.80 - 2.70 (m, 1 H), 2.49 - 2.37 (m, 1 H).

Step B: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-6-(trifluoromethyl)pyrimidine-4-carboxamide. (R)-2-(3-(5-(3-Hydroxy-1 - methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-6-(trifluo romethyl)pyrimidine-4- carboxamide (40 mg, 67%) was prepared in a manner analogous to Example 89 Step A using (R)-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-6- (trifluoromethyl)pyrimidine-4-carboxylic acid instead of 3-amino-6-bromo-5- fluoropicolinic acid. MS (ESI): Mass calcd. for C20H16F3N5O4, 447.1 ; m/z found, 448.1 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 59.00 (t, J = 1 .9 Hz, 1 H), 8.71 - 8.58 (m, 1 H), 8.27 (s, 1 H), 8.07 - 7.95 (m, 1 H), 7.65 (t, J = 7.8 Hz, 1 H), 7.04 (s, 1 H), 3.70 - 3.50 (m, 2H), 2.98 (s, 3H), 2.83 - 2.71 (m, 1 H), 2.51 - 2.35 (m, 1 H).

Example 99: (R)-1 -(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)- 5-(1 -methyl-1 /-/-pyrazol-3-y l)-1 /-/-indazole-3-carboxamide.

Step A: Ethyl (R)-5-bromo-1-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)-1 H-indazole-3-carboxylate. Ethyl (R)-5-bromo-1 -(3-(5-(3- hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-1 /-/-indazole-3-carboxylate (100 mg, 19%) was prepared in a manner analogous to Example 95 Step A using ethyl 5-bromo-1 /-/-indazole-3-carboxylate instead of methyl 4,5,6,7-tetrahydro-1 /-/-indazole-3- carboxylate. MS (ESI): Mass calcd. for C24H2i BrN40s, 524.1 ; m/z found, 525.0 [M+H] ⁺ .

Step B: Ethyl (R)-1 -(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-(1 -methyl-1 /-/-pyrazol-3-y l)-1 /-/-indazole-3-carboxylate. Ethyl (R)-1 -(3-(5-(3- hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5-(1 -methyl-1 /-/-pyrazol-3- yl)-1/-/-indazole-3-carboxylate (50 mg, 50%) was prepared in a manner analogous to Example 47 Step B using ethyl (R)-5-bromo-1 -(3-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-1 /-/-indazole-3-carboxylate and 1 -methyl-3- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrazole instead of 4-chloro-6- methoxypicolinamide and (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. MS (ESI): Mass calcd. for C28H26N6O5, 526.1 ; m/z found, 527.1 [M+H] ⁺ .

Step C: (R)-1 -(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-(1 -methyl-1 /-/-pyrazol-3-y l)-1 H-indazole-3-carboxamide. (R)-1 -(3-(5-(3- Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5-(1 -methyl-1 /-/-pyrazol-3- yl)-1/-/-indazole-3-carboxamide (18 mg, 36%) was prepared in a manner analogous to Example 47 Step A using ethyl (R)-1 -(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)-5-(1 -methyl-1 /-/-pyrazol-3-y l)-1 /-/-indazole-3-carboxylate instead of methyl 4-chloro-6-methoxypicolinate. MS (ESI): Mass calcd. for C26H23N7O4, 497.2; m/z found, 498.3 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 58.72 (dd, J = 1 .6, 0.8 Hz, 1 H), 8.32 (t, J = 1 .9 Hz, 1 H), 8.04 (dd, J = 8.9, 1 .7 Hz, 1 H), 8.02 - 7.93 (m, 2H), 7.91 (dd, J = 8.9, 0.8 Hz, 1 H), 7.76 (t, J = 7.9 Hz, 1 H), 7.64 (d, J = 2.3 Hz, 1 H), 7.02 (s, 1 H), 6.72 (d, J = 2.3 Hz, 1 H), 3.96 (s, 3H), 3.62 - 3.55 (m, 2H), 2.97 (s, 3H), 2.81 - 2.72 (m, 1 H), 2.48 - 2.37 (m, 1 H).

Example 100: (R)-4-(3,3-Difluoroazetidin-1 -yl)-6-(3-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinamide.

Step A: Methyl 6-chloro-4-(3,3-difluoroazetidin-1 -yl)picolinate. To 3,3- difluoroazetidine hydrochloride (259 mg, 2.00 mmol) and methyl 4,6-dichloropicolinate (412 mg, 2 mmol) in DMA (1 .5 mL), EtsN (1 .39 mL, 10 mmol) was added. The mixture was heated at 80 °C for 16 h. Solids were formed, filtered, collected and dried to provide the title compound (410 mg, 78%). MS (ESI): Mass calcd. for C10H9 CIF2N2O2, 262.1 ; m/z found, 263.1 [M+H] ⁺ .

Step B: (R)-4-(3,3-Difluoroazetidin-1 -yl)-6-(3-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinamide. (R)-4-(3,3-Difluoroazetidin-1-yl)-6- (3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinami de (65 mg) was prepared in a manner analogous to Example 47 using methyl 6-chloro-4-(3,3- difluoroazetidin-1 -yl)picolinate instead of methyl 4-chloro-6-methoxypicolinate. MS (ESI): Mass calcd. for C23H21 F2N5O4, 469.2; m/z found, 470.1 [M+H] ⁺ . ¹ H NMR (600 MHz, CD3OD) 5 8.33 (d, J = 1 .9 Hz, 1 H), 8.13 - 8.02 (m, 1 H), 7.98 (d, J = 7.7 Hz, 1 H), 7.70 (t, J = 7.8 Hz, 1 H), 7.34 (d, J = 2.3 Hz, 1 H), 7.12 (d, J = 2.4 Hz, 1 H), 7.01 (s, 1 H), 4.74 (t, J = 11 .6 Hz, 4H), 3.66 - 3.50 (m, 2H), 2.79 - 2.69 (m, 1 H), 2.47 - 2.35 (m, 1 H).

Example 101 : (R)-5-Fluoro-1 -(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- y I ) ph eny I )- 1 /-/-indazole-3-carboxam ide.

(R)-5-Fluoro-1 -(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-1 H-indazole-3-carboxamide (50 mg) was prepared in a manner analogous to Example 95 using ethyl 5-fluoro-1 /-/-indazole-3-carboxylate instead of methyl 4, 5,6,7- tetrahydro-1 /-/-indazole-3-carboxylate. MS (ESI): Mass calcd. for C22H18FN5O4, 435.1 ; m/z found, 436.3 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 58.24 (t, J = 1 .9 Hz, 1 H), 7.98 - 7.82 (m, 4H), 7.71 (t, J = 7.9 Hz, 1 H), 7.39 - 7.29 (m, 1 H), 7.00 (s, 1 H), 3.62 - 3.52 (m, 2H), 2.96 (s, 3H), 2.82 - 2.69 (m, 1 H), 2.47 - 2.35 (m, 1 H).

Example 102: (R)-1 -(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-4,5,6,7-tetrahydro-1 /-/-indazole-3-carboxamide.

(R)-1 -(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)- 4,5,6,7-tetrahydro-1 /-/-indazole-3-carboxamide (62 mg) was prepared in a manner analogous to Example 89 Step A using (R)-1-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin- 3-yl)isoxazol-3-yl)phenyl)-4,5,6,7-tetrahydro-1 /-/-indazole-3-carboxylic acid (Example 95) instead of 3-amino-6-bromo-5-fluoropicolinic acid. MS (ESI): Mass calcd. for C22H23N5O4, 421 .2; m/z found, 422.3 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 5 8.07 (t, J = 1 .8 Hz, 1 H), 7.94 - 7.87 (m, 1 H), 7.75 - 7.59 (m, 2H), 6.97 (s, 1 H), 3.63 - 3.51 (m, 2H), 2.96 (s, 3H), 2.87 - 2.67 (m, 5H), 2.45 - 2.38 (m, 1 H), 1 .88 - 1 .78 (m, 4H). Example 103: (R)-1 -(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-methoxy-1 /-/-indazole-3-carboxamide.

(R)-1 -(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5- methoxy-1 H-indazole-3-carboxamide (110 mg) was prepared in a manner analogous to Example 89 Step A using (R)-1 -(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol- 3-yl)phenyl)-5-methoxy-1 H-indazole-3-carboxylic acid (prepared in a manner analogous to Example 95 using ethyl 5-methoxy-1 /-/-indazole-3-carboxylate instead of methyl 4,5,6,7-tetrahydro-1 /-/-indazole-3-carboxylate) instead of 3-amino-6-bromo-5- fluoropicolinic acid. MS (ESI): Mass calcd. for C23H21 N5O5, 447.1 ; m/z found, 448.3 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 5 8.19 (t, J = 1.9 Hz, 1 H), 7.90 - 7.82 (m, 2H), 7.73 - 7.61 (m, 3H), 7.12 (dd, J = 9.2, 2.5 Hz, 1 H), 6.98 (s, 1 H), 3.87 (s, 3H), 3.63 - 3.54 (m, 2H), 2.96 (s, 3H), 2.79 - 2.67 (m, 1 H), 2.47 - 2.32 (m, 1 H).

Example 104: (R)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-3-(methylamino)picolinamide.

Step A: 6-chloro-3-(methylamino)picolinamide. Methylamine (3 mL, 2 N in THF) and 6-chloro-3-fluoropyridine-2 -carboxylic acid (175 mg, 1 mmol) in THF (1.5 mL) were mixed at RT. The mixture was heated at 110 °C for 3 h. After it cooled to RT, aqueous HCI solution (1 N) was added to adjust the pH to pH 3. Solids were formed, filtered off and dried to provide the title compound (90 mg, 48%). MS (ESI): Mass calcd. for C7H8CIN30, 185.0; m/z found, 186.3 [M+H] ⁺ . Step B: (R)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-3-(methylamino)picolinamide. (R)-6-(3-(5-(3-Hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-3-(methylamino)pico linamide (7 mg) was prepared in a manner analogous to Example 89 (step B) using 6-chloro-3- (methylamino)picolinamide instead of (R)-3-Amino-5-fluoro-6-(3-(5-(3-hydroxy-1 -methyl- 2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinamide. MS (ESI): Mass calcd. for C21 H21 N5O4, 407.2; m/z found, 408.3 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 5 8.53 - 8.42 (m, 1 H), 8.16 - 8.06 (m, 1 H), 7.97 (d, J = 8.9 Hz, 1 H), 7.81 - 7.74 (m, 1 H), 7.61 - 7.50 (m, 1 H), 7.29 (d, J = 8.9 Hz, 1 H), 6.99 (s, 1 H), 3.67 - 3.52 (m, 2H), 3.02 - 2.90 (m, 6H), 2.82 - 2.71 (m, 1 H), 2.48 - 2.36 (m, 1 H).

Example 105: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-(oxetan-3-ylamino)pyrimidine-4-carboxamide.

Step A: Ethyl 2-chloro-5-(oxetan-3-ylamino)pyrimidine-4-carboxylate. 3- Oxetanamine (129 mg, 1.77 mmol), ethyl 2-chloro-5-fluoropyrimidine-4-carboxylate (361 mg, 1 77 mmol) and EtsN (1 .23 mL, 8.83 mmol) in THF (10 mL) were mixed at RT. The mixture was heated at 150 °C for 16 h. The reaction mixture was then cooled to RT and concentrated to provide the title compound (395 mg, 90.0%). MS (ESI): Mass calcd. for C10H12 CIN3O3, 257.1 ; m/z found, 258.3 [M+H] ⁺ .

Step B: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-(oxetan-3-ylamino)pyrimidine-4-carboxamide. (R)-2-(3-(5-(3-Hydroxy-1- methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5-(oxetan- 3-ylamino)pyrimidine-4- carboxamide (50 mg) was prepared in a manner analogous to Example 47 using ethyl 2-chloro-5-(oxetan-3-ylamino)pyrimidine-4-carboxylate instead of methyl 4-chloro-6- methoxypicolinate. MS (ESI): Mass calcd. for C22H22N6O5, 450.2; m/z found, 451.1 [M+H] ⁺ . ¹ H NMR (500 MHz, CD ₃ OD) 58.82 (t, J = 1 .8 Hz, 1 H), 8.51 - 8.41 (m, 1 H), 8.34 (s, 1 H), 7.93 - 7.79 (m, 1 H), 7.58 (t, J = 7.8 Hz, 1 H), 7.00 (s, 1 H), 5.07 (t, J = 6.7 Hz, 2H), 4.99 - 4.90 (m, 1 H), 4.63 (t, J = 6.7 Hz,, 2H), 3.66 - 3.54 (m, 2H), 2.97 (s, 3H), 2.80 - 2.69 (m, 1 H), 2.48 - 2.35 (m, 1 H).

Example 106: (R)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-3-((oxetan-3-ylmethyl)amino)picolinamide.

(R)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-3- ((oxetan-3-ylmethyl)amino)picolinamide (28 mg) was prepared in a manner analogous to Example 104 using oxetan-3-ylmethanamine instead of methylamine. MS (ESI): Mass calcd. for C24H25N5O5, 463.2; m/z found, 464.1 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 88.53 - 8.36 (m, 2H), 8.15 - 8.04 (m, 1 H), 7.99 - 7.86 (m, 1 H), 7.81 - 7.73 (m, 1 H), 7.61 - 7.47 (m, 1 H), 7.35 (d, J = 8.9 Hz, 1 H), 6.99 (d, J = 2.1 Hz, 1 H), 4.90 - 4.84 (m, 2H), 4.56 - 4.41 (m, 2H), 3.64 - 3.51 (m, 4H), 3.39 - 3.33 (m, 1 H), 2.96 (s, 3H), 2.79 - 2.64 (m, 1 H), 2.46 - 2.32 (m, 1 H).

Example 107: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-((oxetan-3-ylmethyl)amino)pyrimidine-4-carboxam ide. (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5- ((oxetan-3-ylmethyl)amino)pyrimidine-4-carboxamide (10 mg) was prepared in a manner analogous to Example 105 using oxetan-3-ylmethanamine instead of 3- oxetanamine. MS (ESI): Mass calcd. for C23H24N6O5, 464.2; m/z found, 465.2 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 58.81 (t, J = 1 .7 Hz, 1 H), 8.64 (s, 1 H), 8.53 - 8.44 (m, 1 H), 7.90 - 7.81 (m, 1 H), 7.58 (t, J = 7.8 Hz, 1 H), 7.00 (s, 1 H), 4.92 - 4.88 (m, 2H), 4.58 - 4.49 (m, 3H), 3.78 - 3.66 (m, 2H), 3.63 - 3.54 (m, 2H), 3.43 - 3.36 (m, 1 H), 2.97 (s, 3H), 2.83 - 2.70 (m, 1 H), 2.46 - 2.34 (m, 1 H).

Example 108: (R)-3-Amino-4-cyclopropyl-6-(3-(3-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-5-yl)phenyl)picolinamide.

(R)-3-Amino-4-cyclopropyl-6-(3-(3-(3-hydroxy-1-methyl-2-o xopyrrolidin-3- yl)isoxazol-5-yl)phenyl)picolinamide (60 mg) was prepared in a manner analogous to Example 88 using (R)-3-hydroxy-1 -methyl-3-(5-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one (Intermediate 5) instead of (R)-3- hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol- 5-yl)pyrrolidin-2-one. MS (ESI): Mass calcd. for C23H23N5O4, 433.2; m/z found, 434.1 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 88.39 (d, J = 2.1 Hz, 1 H), 8.09 (d, J = 8.1 Hz, 1 H), 7.78 (d, J = 7.4 Hz, 1 H), 7.64 (d, J = 1 .1 Hz, 1 H), 7.57 (t, J = 7.5 Hz, 1 H), 7.05 (s, 1 H), 4.55 (s, 1 H), 3.60 - 3.48 (m, 2H), 2.97 - 2.82 (m, 4H), 2.44 - 2.14 (m, 1 H), 1.86 - 1.76 (m, 1 H), 1.13 - 1.04 (m, 2H), 0.81 - 0.71 (m, 2H).

Example 109: (R)-1 -(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)imidazo[1 ,5-a]pyrazine-3-carboxamide.

Step A: Ethyl (R)-1 -(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)imidazo[1 ,5-a]pyrazine-3-carboxylate. Ethyl (R)-1 -(3-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)imidazo[1 ,5-a]pyrazine-3-carboxylate (262 mg, 80%) was prepared in a manner analogous to Example 47 Step B using ethyl 1- bromoimidazo[1 ,5-a]pyrazine-3-carboxylate instead of 4-chloro-6-methoxypicolinamide. MS (ESI): Mass calcd. for C23H21 N5O5, 447.2; m/z found, 448.2 [M+H] ⁺ .

Step B: (R)-1 -(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)imidazo[1 ,5-a]pyrazine-3-carboxamide. (R)-1 -(3-(5-(3-Hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)imidazo[1 ,5-a]pyrazine-3-carboxamide (87 mg, 36%) was prepared in a manner analogous to Example 47 Step A using ethyl (R)-1-(3- (5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)imidazo[1 ,5-a]pyrazine- 3-carboxylate instead of methyl 4-chloro-6-methoxypicolinate. MS (ESI): Mass calcd. for C21 HI ₈ N ₆ O4, 418.1 ; m/z found, 419.2 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 5 9.55 - 9.41 (m, 1 H), 9.26 (dd, J = 5.1 , 1.6 Hz, 1 H), 8.47 (t, J = 1.8 Hz, 1 H), 8.18 - 8.06 (m, 1 H), 7.96 - 7.85 (m, 1 H), 7.82 (d, J = 5.0 Hz, 1 H), 7.65 (t, J = 7.8 Hz, 1 H), 7.00 (s, 1 H), 3.67 - 3.53 (m, 2H), 2.97 (s, 3H), 2.83 - 2.71 (m, 1 H), 2.47 - 2.34 (m, 1 H).

Example 110: (R)-3-Amino-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)pyrazine-2-carboxamide. (R)-3-Amino-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)pyrazine-2-carboxamide (16 mg) was prepared in a manner analogous to Example 109 using methyl 3-amino-6-bromopyrazine-2-carboxylate instead of ethyl 1- bromoimidazo[1 ,5-a]pyrazine-3-carboxylate. MS (ESI): Mass calcd. for CigHisNeCU, 394.1 ; m/z found, 395.2 [M+H] ⁺ . ¹ H NMR (500 MHz, CD ₃ OD) 58.79 (s, 1 H), 8.50 (s, 1 H), 8.13 (d, J = 7.9 Hz, 1 H), 7.84 (d, J = 7.7 Hz, 1 H), 7.59 (t, J = 7.8 Hz, 1 H), 7.02 (s, 1 H), 4.56 (s, 2H), 3.69 - 3.47 (m, 2H), 2.97 (s, 3H), 2.87 - 2.70 (m, 1 H), 2.41 (s, 1 H).

Example 111 : (R)-5-(Cyclopropylamino)-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)pyrimidine-4-carboxamide.

(R)-5-(Cyclopropylamino)-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)pyrimidine-4-carboxamide (26 mg) was prepared in a manner analogous to Example 105 using cyclopropanamine instead of 3-oxetanamine. MS (ESI): Mass calcd. for C22H22N6O4, 434.2; m/z found, 435.2 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 58.92 (d, J = 0.6 Hz, 1 H), 8.82 (t, J = 1 .8 Hz, 1 H), 8.54 - 8.44 (m, 1 H), 7.91 - 7.81 (m, 1 H), 7.58 (t, J = 7.8 Hz, 1 H), 7.01 (s, 1 H), 3.64 - 3.50 (m, 2H), 2.97 (s, 3H), 2.80 - 2.69 (m, 1 H), 2.69 - 2.60 (m, 1 H), 2.48 - 2.35 (m, 1 H), 1 .02 - 0.85 (m, 2H), 0.68 - 0.54 (m, 2H).

Example 112: (R)-5-Cyclopropyl-1 -(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)-1 /-/-indazole-3-carboxamide.

Step A: Ethyl (R)-5-cyclopropyl-1 -(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)-1 H-indazole-3-carboxylate. Ethyl (R)-5-cyclopropyl-1 -(3-(5-(3- hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-1 /-/-indazole-3-carboxylate (63 mg, 70%) was prepared in a manner analogous to Example 88 Step A using ethyl (R)-5-bromo-1 -(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-1 H- indazole-3-carboxylate (Example 99 Step A) instead of 3-amino-4,6- dichloropicolinonitrile. MS (ESI): Mass calcd. for C27H26N4O5, 486.2; m/z found, 487.2 [M+H] ⁺ .

Step B: (R)-5-Cyclopropyl-1 -(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)-1 /-/-indazole-3-carboxamide. (R)-5-Cyclopropyl-1 -(3-(5-(3- hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-1 /-/-indazole-3-carboxamide (19 mg, 33%) was prepared in a manner analogous to Example 47 Step A using ethyl (R)-5-cyclopropyl-1 -(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-y l)phenyl)- 1 /-/-indazole-3-carboxylate instead of methyl 4-chloro-6-methoxypicolinate. MS (ESI): Mass calcd. for C25H23N5O4, 457.2; m/z found, 458.2 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 58.34 - 8.18 (m, 1 H), 8.11 - 7.84 (m, 3H), 7.84 - 7.64 (m, 2H), 7.39 - 7.23 (m, 1 H), 7.09 - 6.94 (m, 1 H), 3.73 - 3.49 (m, 2H), 2.96 (s, 3H), 2.84 - 2.63 (m, 1 H), 2.53 - 2.34 (m, 1 H), 2.18 - 1.97 (m, 1 H), 1.11 - 0.95 (m, 2H), 0.90 - 0.72 (m, 2H).

Example 113: (R)-3-(3-(5-(4-Amino-8-methoxypyrido[3,2-c(]pynmidin-6-yl)-2 ,4- difluorophenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one.

Step A: (R)-3-(3-(2,4-Difluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one. (R)-3-(3-(2,4-Difluoro-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1 - methylpyrrolidin-2-one (1215 mg) was prepared in a manner analogous to Intermediate 3 and Intermediate 4 using 5-bromo-2,4-difluorobenzaldehyde instead of 3- bromobenzaldehyde. MS (ESI): Mass calcd. for C20H23BF2N2O5, 420.2; m/z found, 421.2 [M+H] ⁺ .

Step B: (R)-3-(3-(5-(4-Amino-8-methoxypyrido[3,2-c/]pyrimidin-6-yl)- 2,4- difluorophenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one. (R)-3-(3-(5-(4-Amino- 8-methoxypyrido[3,2-d]pyrimidin-6-yl)-2,4-difluorophenyl)iso xazol-5-yl)-3-hydroxy-1 - methylpyrrolidin-2-one (12 mg, 10%) was prepared in a manner analogous to Example 47 Step A using 6-chloro-8-methoxypyrido[3,2-d]pyrimidin-4-amine (Example 119 Step B) and (R)-3-(3-(2,4-difluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one instead of 4-chloro-6- methoxypicolinamide and (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one, respectively. MS (ESI): Mass calcd. for C22H18F2N6O4, 468.1 ; m/z found, 469.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD3OD) 58.75 (t, J = 8.5 Hz, 1 H), 8.39 (s, 1 H), 7.77 - 7.66 (m, 1 H), 7.37 (t, J = 10.9 Hz, 1 H), 6.96 (d, J = 3.2 Hz, 1 H), 4.14 (s, 4H), 3.64 - 3.52 (m, 3H), 2.97 (s, 4H), 2.80 - 2.68 (m, 1 H), 2.49 - 2.35 (m, 1 H).

Example 114: (R)-4-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-1 -methyl-1 /-/-imidazole-2-carboxamide.

(R)-4-(3-(5-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isox azol-3-yl)phenyl)-1- methyl-1H-imidazole-2-carboxamide (15 mg) was prepared in a manner analogous to Example 47: (R)-4-(3-(5-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazo l-3-yl)phenyl)- 6-methoxypicolinamide. using methyl 4-bromo-1-methyl-1/-/-imidazole-2-carboxylate instead of methyl 4-chloro-6-methoxypicolinate. MS (ESI): Mass calcd. for C19H19N5O4, 381.1 ; m/z found, 382.3 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 58.26 (t, J = 1 .7 Hz, 1 H), 7.94 - 7.84 (m, 1 H), 7.78 - 7.70 (m, 1 H), 7.67 (s, 1 H), 7.48 (t, J = 7.7 Hz, 1 H), 6.93 (s, 1 H), 4.05 (s, 3H), 3.62 - 3.51 (m, 2H), 2.96 (s, 3H), 2.79 - 2.69 (m, 1 H), 2.44 - 2.36 (m, 1 H).

Example 115: (3R,5S)-3-(3-(5-(4-Amino-8-methoxypyrido[3,2-c/]pyrimidin-6- yl)-2,4- difluorophenyl)isoxazol-5-yl)-3-hydroxy-1-methyl-5-(trifluor omethyl)pyrrolidin-2-one.

Step A: (3R,5S)-3-(3-(2,4-Difluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)-3-hydroxy-1 -methyl-5-(trifluoromethyl)pyrrolidin-2-one (750 mg) was prepared in a manner analogous to Intermediate 3 and 4 using 5-bromo-2,4- difluorobenzaldehyde and (3R,5S)-3-ethynyl-3-hydroxy-1 -methyl-5- (trifluoromethyl)pyrrolidin-2-one (Intermediate 45) instead of 3-bromobenzaldehyde and (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one. MS (ESI): Mass calcd. for C21 H22BF5N2O5, 488.1 ; m/z found, 489.0 [M+H] ⁺ .

Step B: (3R,5S)-3-(3-(5-(4-Amino-8-methoxypyrido[3,2-c/]pyrimidin-6- yl)-2,4- difluorophenyl)isoxazol-5-yl)-3-hydroxy-1-methyl-5-(trifluor omethyl)pyrrolidin-2-one. (3R,5S)-3-(3-(5-(4-Amino-8-methoxypyrido[3,2-c/]pyrimidin-6- yl)-2,4- difluorophenyl)isoxazol-5-yl)-3-hydroxy-1 -methyl-5-(trifluoromethyl)pyrrolidin-2-one (57 mg, 14%) was prepared in a manner analogous to Example 47Example 47: (R)-4-(3-(5- (3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-6-methoxy picolinamide., Step B using 6-chloro-8-methoxypyrido[3,2-c(]pyrimidin-4-amine (Example 119 Step B) and (3R,5S)-3-(3-(2,4-difluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)-3-hydroxy-1 -methyl-5-(trifluoromethyl)pyrrolidin-2-one instead of 4-chloro-6-methoxypicolinamide and (R)-3-hydroxy-1 -methyl-3-(3-(3-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one , respectively. MS (ESI): Mass calcd. for C23H17F5N6O4, 536.1 ; m/z found, 537.2 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 5 8.80 (t, J = 8.4 Hz, 1 H), 8.64 (s, 1 H), 7.96 (s, 1 H), 7.42 (t, J = 10.9 Hz, 1 H), 7.02 (d, J = 3.1 Hz, 1 H), 4.54 - 4.45 (m, 1 H), 4.26 (s, 3H), 3.14 - 3.02 (m, 4H), 2.46 (dd, J = 14.7, 4.7 Hz, 1 H).

Example 116: (3R,5S)-3-(3-(3-(4-amino-8-methoxypyrido[3,2-c/]pyrimidin-6- yl)-4- fluorophenyl)isoxazol-5-yl)-3-hydroxy-1 -methyl-5-(trifluoromethyl)pyrrolidin-2-one.

Step A: (3R,5S)-3-(3-(4-Fluoro-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)-3-hydroxy-1 -methyl-5-(trifluoromethyl)pyrrolidin-2-one. (3R,5S)- 3-(3-(4-Fluoro-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)-3- hydroxy-1-methyl-5-(trifluoromethyl)pyrrolidin-2-one (750 mg) was prepared in a manner analogous to Intermediate 3 and 4 using 3-bromo-4-fluorobenzaldehyde and (3R,5S)-3- ethynyl-3-hydroxy-1 -methyl-5-(trifluoromethyl)pyrrolidin-2-one (Intermediate 45) instead of 3-bromobenzaldehyde and (R)-3-ethynyl-3-hydroxy-1 -methylpyrrolidin-2-one. MS (ESI): Mass calcd. for C21 H23BF4N2O5, 470.8; m/z found, 471.3 [M+H] ⁺ .

Step B: (3R,5S)-3-(3-(3-(4-Amino-8-methoxypyrido[3,2-c/]pyrimidin-6- yl)-4- fluorophenyl)isoxazol-5-yl)-3-hydroxy-1 -methyl-5-(trifluoromethyl)pyrrolidin-2-one. (3R,5S)-3-(3-(3-(4-Amino-8-methoxypyrido[3,2-c/]pyrimidin-6- yl)-4-fluorophenyl)isoxazol- 5-yl)-3-hydroxy-1 -methyl-5-(trifluoromethyl)pyrrolidin-2-one (65 mg, 18%) was prepared in a manner analogous to Example 47, Step B using 6-chloro-8-methoxypyrido[3,2- d]pyrimidin-4-amine (Example 119 Step B) and (3R,5S)-3-(3-(4-fluoro-3-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1 -methyl-5- (trifluoromethyl)pyrrolidin-2-one instead of 4-chloro-6-methoxypicolinamide and (R)-3- hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol- 5-yl)pyrrolidin-2-one. MS (ESI): Mass calcd. for C23H18F4N6O4, 518.1 ; m/z found, 519.2 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 88.74 (dd, J = 7.4, 2.3 Hz, 1 H), 8.65 (s, 1 H), 8.12 - 8.04 (m, 1 H), 8.01 (s, 1 H), 7.47 (dd, J = 11.3, 8.6 Hz, 1 H), 7.11 (s, 1 H), 4.54 - 4.43 (m, 1 H), 4.27 (s, 3H), 3.14 - 3.02 (m, 4H), 2.44 (dd, J = 14.6, 5.0 Hz, 1 H).

Example 117: (R)-4-Cyclopropyl-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)picolinamide.

(R)-4-Cyclopropyl-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)picolinamide (90 mg) was prepared in a manner analogous to Example 88 using 4-bromo-6-chloropicolinonitrile instead of 3-amino-4,6-dichloropicolinonitrile in Step A. MS (ESI): Mass calcd. For C23H22N4O4, 418.2; m/z found, 419.1 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 8 8.60 (t, J = 1 .8 Hz, 1 H), 8.28 - 8.16 (m, 1 H), 7.95 - 7.86 (m, 1 H), 7.84 (d, J = 1 .6 Hz, 1 H), 7.73 (d, J = 1 .5 Hz, 1 H), 7.61 (t, J = 7.8 Hz, 1 H), 7.04 (s, 1 H), 3.65 - 3.51 (m, 2H), 2.97 (s, 3H), 2.82 - 2.69 (m, 1 H), 2.46 - 2.35 (m, 1 H), 2.17 - 2.06 (m, 1 H), 1.30 - 1.17 (m, 2H), 1.05 - 0.92 (m, 2H).

Example 118: (R)-3-(3-(3-(4-Amino-8-methoxypyrido[3,2-c(]pyrimidin-6- yl)phenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one.

(R)-3-(3-(3-(4-Amino-8-methoxypyrido[3,2-d]pyrimidin-6-yl )phenyl)isoxazol-5-yl)- 3-hydroxy-1 -methylpyrrolidin-2-one (180 mg, 53%) was prepared in a manner analogous to Example 47, Step B using 6-chloro-8-methoxypyrido[3,2-d]pyrimidin-4- amine (Example 119 Step B) instead of 4-chloro-6-methoxypicolinamide. MS (ESI): Mass calcd. for C22H20N6O4, 432.2; m/z found, 433.3 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 58.81 (s, 1 H), 8.41 (d, J = 14.0 Hz, 2H), 8.02 - 7.96 (m, 1 H), 7.86 (d, J = 1 .2 Hz, 1 H), 7.69 (t, J = 7.8 Hz, 1 H), 7.12 (s, 1 H), 4.23 (s, 3H), 3.70 - 3.51 (m, 2H), 3.00 (s, 3H), 2.86 - 2.73 (m, 1 H), 2.54 - 2.27 (m, 1 H).

Example 119: (R)-3-(3-(3-(4-Amino-8-methoxypyrido[3,2-c(]pyrimidin-6-yl)- 4- fluorophenyl)isoxazol-5-yl)-4,4-difluoro-3-hydroxy-1 -methylpyrrolidin-2-one.

Step A: (R)-(5-(5-(4,4-Difluoro-3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol- 3-yl)-2-fluorophenyl)boronic acid. (R)-(5-(5-(4,4-Difluoro-3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)-2-fluorophenyl)boronic acid (78 mg) was prepared in a manner analogous to Intermediate 3 and 4 using 3-bromo-4-fluorobenzaldehyde and (R)-3-ethynyl-4,4-difluoro-3-hydroxy-1-methylpyrrolidin-2-on e (Intermediate 44) instead of 3-bromobenzaldehyde and (R)-3-ethynyl-3-hydroxy-1 -methylpyrrolidin-2-one. MS (ESI): Mass calcd. for C14H12BF3N2O5, 356.0; m/z found, 356.9 [M+H] ⁺ .

Step B: 6-Chloro-8-methoxypyrido[3,2-c/]pyrimidin-4-amine. To 6,8- dichloropyrido[3,2-d]pyrimidin-4-amine (620 mg, 2.88 mmol) in DMA (2 mL), NaH (60% dispersion in mineral oil) (150 mg, 3.75 mmol) was added, followed by MeOH (0.234 mL, 5.76 mmol). The mixture was heated at 60 °C for 3 h. Water (30 mL) was added and the solids were formed. After filtration, the solid was collected and dried to provide the title compound (490 mg, 81 %). MS (ESI): Mass calcd. for C8H7CIN4O, 210.0; m/z found, 211.1 [M+H] ⁺ .

Step C: (R)-3-(3-(3-(4-Amino-8-methoxypyrido[3,2-d]pyrimidin-6-yl)-4 - fluorophenyl)isoxazol-5-yl)-4,4-difluoro-3-hydroxy-1 -methylpyrrolidin-2-one. (R)-3-(3-(3- (4-Amino-8-methoxypyrido[3,2-c/]pyrimidin-6-yl)-4-fluorophen yl)isoxazol-5-yl)-4,4- difluoro-3-hydroxy-1-methylpyrrolidin-2-one (16 mg, 8.8%) was prepared in a manner analogous to Example 47 Step B using 6-chloro-8-methoxypyrido[3,2-d]pyrimidin-4- amine and (R)-(5-(5-(4,4-difluoro-3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)- 2-fluorophenyl)boronic acid instead of 4-chloro-6-methoxypicolinamide and (R)-3- hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol- 5-yl)pyrrolidin-2-one. MS (ESI): Mass calcd. for C22H17F3N6O4, 486.1 ; m/z found, 487.2 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 58.60 (dd, J = 7.4, 2.4 Hz, 1 H), 8.53 (s, 1 H), 7.97 - 7.91 (m, 1 H), 7.87 (s, 1 H), 7.33 (dd, J = 11.3, 8.6 Hz, 1 H), 7.10 (s, 1 H), 4.15 (s, 3H), 4.01 - 3.82 (m, 2H), 2.96 (s, 3H).

Example 120: (R)-3-(3-(3-(4-Amino-8-methoxypyrido[3,2-c(]pyrimidin-6-yl)- 4- fluorophenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one.

Step A: (R)-3-(3-(4-Fluoro-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one. (R)-3-(3-(4-Fluoro-3- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1 - methylpyrrolidin-2-one (470 mg) was prepared in a manner analogous to Intermediate 3 and 4 using 3-bromo-4-fluorobenzaldehyde instead of 3-bromobenzaldehyde. MS (ESI): Mass calcd. for C20H24BFN2O5, 402.2; m/z found, 403.2 [M+H] ⁺ . Step B: (R)-3-(3-(3-(4-Amino-8-methoxypyrido[3,2-c/]pyrimidin-6-yl)- 4- fluorophenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one. (R)-3-(3-(3-(4-Amino-8- methoxypyrido[3,2-d]pyrimidin-6-yl)-4-fluorophenyl)isoxazol- 5-yl)-3-hydroxy-1 - methylpyrrolidin-2-one (26 mg, 18%) was prepared in a manner analogous to Example 47 Step A using 6-chloro-8-methoxypyrido[3,2-d]pyrimidin-4-amine (Example 119 Step B) and (R)-3-(3-(4-fluoro-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol- 5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one instead of 4-chloro-6-methoxypicolinamide and (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. MS (ESI): Mass calcd. for C22H19FN6O4, 450.1 ; m/z found, 451 .3 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 58.69 (dd, J = 7.4, 2.4 Hz, 1 H), 8.42 (s, 1 H), 8.08 - 7.95 (m, 1 H), 7.77 (s, 1 H), 7.45 (dd, J = 11 .2, 8.5 Hz, 1 H), 7.06 (s, 1 H), 4.17 (s, 3H), 3.65 - 3.56 (m, 2H), 2.99 (s, 3H), 2.82 - 2.71 (m, 1 H), 2.50 - 2.34 (m, 1 H).

Example 121 : (R)-2-(2-Fluoro-5-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-(oxetan-3-ylamino)pyrimidine-4-carboxamide.

Step A: (R)-3-(3-(4-Fluoro-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (470 mg) was prepared in a manner analogous to Intermediate 3 and 4 using 3-bromo-4-fluorobenzaldehyde instead of 3-bromobenzaldehyde. MS (ESI): Mass calcd. for C20H24BFN2O5, 402.2; m/z found, 403.2 [M+H] ⁺ .

Step B: (R)-2-(2-Fluoro-5-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-(oxetan-3-ylamino)pyrimidine-4-carboxamide. (R)-2-(2-Fluoro-5-(5-(3- hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5-(oxetan -3- ylamino)pyrimidine-4-carboxamide (7 mg, 3%) was prepared in a manner analogous to Example 105 using (R)-3-(3-(4-fluoro-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (Example 120, Step A) instead of (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. MS (ESI): Mass calcd. for C22H21 FN6O5, 468.2; m/z found, 469.1 [M+H] ⁺ . ¹ H NMR (500 MHz, Chloroform-d) 88.44 (d, J = 6.2 Hz, 1 H), 8.25 (dd, J = 7.4, 2.4 Hz, 1 H), 8.10 (s, 1 H), 8.03 (d, J = 4.4 Hz, 1 H), 7.67 - 7.62 (m, 1 H), 7.07 (dd, J = 10.9, 8.6 Hz, 1 H), 6.62 (s, 1 H), 5.78 (d, J = 4.0 Hz, 1 H), 4.96 (t, J = 6.7 Hz, 2H), 4.80 - 4.69 (m, 1 H), 4.61 (t, J = 6.1 Hz, 2H), 3.62 - 3.50 (m, 1 H), 3.47 - 3.37 (m, 1 H), 2.92 (s, 3H), 2.72 - 2.59 (m, 1 H), 2.46 - 2.31 (m, 1 H).

Example 122: (R)-1 -Cyclopropyl-4-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)-5-methyl-1 H-imidazole-2-carboxamide.

Step A: Ethyl 4-bromo-1 -cyclopropyl-5-methyl-1/-/-imidazole-2-carboxylate. Ethyl 4-bromo-1 -cyclopropyl-5-methyl-1 /-/-imidazole-2-carboxylate (35 mg, 13%) was prepared in a manner analogous to Example 95 Step A using ethyl 4-bromo-5-methyl- 1 /-/-imidazole-2-carboxylate and cyclopropylboronic acid instead of methyl 4, 5,6,7- tetrahydro-1 /-/-indazole-3-carboxylate and (R)-3-hydroxy-1 -methyl-3-(3-(3-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one . MS (ESI): Mass calcd. for CwHi3BrN2O2, 272.0; m/z found, 273.1 [M+H] ⁺ .

Step B: (R)-1 -Cyclopropyl-4-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)-5-methyl-1 /-/-imidazole-2-carboxamide. (R)-1 -Cyclopropyl-4-(3- (5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5-methyl- 1 /-/- imidazole-2-carboxamide (7 mg) was prepared in a manner analogous to Example 109 using ethyl 4-bromo-1 -cyclopropyl-5-methyl-1 /-/-imidazole-2-carboxylate instead of ethyl 1 -bromoimidazo[1 ,5-a]pyrazine-3-carboxylate. MS (ESI): Mass calcd. for C22H23N5O4, 421.2; m/z found, 422.2 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 88.18 - 8.04 (m, 1 H), 7.97 - 7.87 (m, 1 H), 7.79 - 7.71 (m, 1 H), 7.66 (t, J = 7.8 Hz, 1 H), 6.96 (s, 1 H), 3.68 - 3.48 (m, 3H), 2.98 (s, 3H), 2.83 - 2.70 (m, 1 H), 2.61 (s, 3H), 2.48 - 2.38 (m, 1 H), 1 .39 - 1.30 (m, 2H), 1.14 - 1.06 (m, 2H).

Example 123: (R)-3-(3-(3-(8-amino-4-methylpyrimido[5,4-d]pyrimidin-2-yl)- 4,5- difluorophenyl)isoxazol-5-yl)-4,4-difluoro-3-hydroxy-1 -methylpyrrolidin-2-one.

Step A: (R)-(5-(5-(4,4-Difluoro-3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol- 3-yl)-2,3-difluorophenyl)boronic acid. (R)-(5-(5-(4,4-Difluoro-3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)-2,3-difluorophenyl)boronic acid (610 mg) was prepared in a manner analogous to Intermediate 3 and 4 using 3-bromo-4,5-difluorobenzaldehyde and (R)-3-ethynyl-4,4-difluoro-3-hydroxy-1 -methylpyrrolidin-2-one (Intermediate 44) instead of 3-bromobenzaldehyde and (R)-3-ethynyl-3-hydroxy-1 -methylpyrrolidin-2-one. MS (ESI): Mass calcd. for C14H11 BF4N2O5, 374.1 ; m/z found, 375.1 [M+H] ⁺ .

Step B: (R)-3-(3-(3-(8-Amino-4-methylpyrimido[5,4-c/]pyrimidin-2-yl) -4,5- difluorophenyl)isoxazol-5-yl)-4,4-difluoro-3-hydroxy-1 -methylpyrrolidin-2-one. (R)-3-(3- (3-(8-Amino-4-methylpyrimido[5,4-d]pyrimidin-2-yl)-4,5-diflu orophenyl)isoxazol-5-yl)-4,4- difluoro-3-hydroxy-1-methylpyrrolidin-2-one (16 mg, 8.8%) was prepared in a manner analogous to Example 47 Step A using 6-chloro-8-methylpyrimido[5,4-d]pyrimidin-4- amine and (R)-(5-(5-(4,4-difluoro-3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)- 2,3-difluorophenyl)boronic acid instead of 4-chloro-6-methoxypicolinamide and (R)-3- hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol- 5-yl)pyrrolidin-2-one. MS (ESI): Mass calcd. for C21 H15F4N7O3, 489.1 ; m/z found, 490.3 [M+H] ⁺ . ¹ H NMR (500 MHz, CD ₃ OD) 58.61 - 8.51 (m, 2H), 8.04 - 7.94 (m, 1 H), 7.22 (s, 1 H), 4.13 - 3.90 (m, 2H), 3.07 (s, 3H), 2.99 (s, 3H). Example 124: (R)-3-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5, 6, 7, 8-tetrahydroisoquinoline-1 -carboxamide.

Step A: 3-Chloro-5,6,7,8-tetrahydroisoquinoline 2-oxide. The mixture of 3-chloro- 5,6,7,8-tetrahydroisoquinoline (503 mg, 3.00 mmol) with 3-chloroperoxybenzoic acid (1.03 g, 6.00 mmol) in dichloromethane (20 mL) was stirred at room temperature for 4 h. The mixture was then washed saturated aqueous NaHCOs solution (20 mL). The organic layer was separated and concentrated. The residue was purified by FCC (DCM/MeOH) providing the title compound (360 mg, 65.3%). MS (ESI): Mass calcd. for C9H10CINO, 183.0; m/z found, 184.2 [M+H] ⁺ .

Step B: 3-Chloro-5, 6, 7, 8-tetrahydroisoquinoline-1 -carbonitrile. Trimethylsilyl cyanide (389 mg, 3.92 mmol) was added to a stirred solution of 3-chloro-5, 6,7,8- tetrahydroisoquinoline 2-oxide (360 mg, 1.96 mmol) and EtsN (0.817 mL, 5.88 mmol) in CH3CN (25 mL) at room temperature. The mixture was then heated at 110° C for 12 h, cooled down to room temperature, and the solvent was evaporated. DCM (25 mL) and saturated aqueous NaHCOs solution (15 mL) were added. The organic layers were separated and concentrated. The residue was washed with ether and filtered, then evaporated to give the product (201 mg, 52.2%). MS (ESI): Mass calcd. for C10H19CIN2, 192.1 ; m/z found, 193.1 [M+H] ⁺ .

Step C: (R)-3-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5,6,7,8-tetrahydroisoquinoline-1 -carboxamide. (R)-3-(3-(5-(3-Hydroxy-1 - methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5,6,7,8-te trahydroisoquinoline-1- carboxamide (150 mg) was prepared in a manner analogous to Example 90 (Step B and Step C) using 3-chloro-5, 6, 7, 8-tetrahydroisoquinoline-1 -carbonitrile instead of 6- chloro-1 -ethyl-1 H-imidazo[4,5-c]pyridine-4-carbonitrile. MS (ESI): Mass calcd. for C24H24N4O4, 432.2; m/z found, 433.2 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 5 8.39 (t, J = 1 .8 Hz, 1 H), 8.08 - 7.98 (m, 1 H), 7.89 - 7.83 (m, 1 H), 7.77 (s, 1 H), 7.61 - 7.42 (m, 2H), 6.92 (s, 1 H), 3.59 - 3.43 (m, 2H), 3.08 - 2.99 (m, 2H), 2.88 (s, 5H), 2.73 - 2.62 (m, 1 H), 2.37 - 2.27 (m, 1 H), 1.87 - 1.69 (m, 4H).

Example 125: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5,6,7,8-tetrahydroquinazoline-4-carboxamide.

Step A: (R)-3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)benzonitrile. To a solution of 3-cyano-N-hydroxybenzimidoyl chloride (541 mg, 3.00 mmol) in DCM (20 mL) was added (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 1 , 417 mg, 3.00 mmol) followed by TEA (1 .25 mL, 9.00 mmol). The reaction mixture was stirred at 25 °C for 3.5 h and concentrated. The residue was diluted with H2O (100 mL). Then the solids were formed, filtered and dried providing the title compound (610 mg, 72%). MS (ESI): Mass calcd. for C15H13N3O3, 283.3; m/z found, 284.3 [M+H] ⁺ .

Step B: (R)-3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)benzimidamide. LiHMDS (1 .75 mL, 1.75 mmol, 1 N-solution in n-hexanes) was added to (R)-3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)benzonitrile (141 mg, 0.500 mmol) in THF (10 mL). The reaction was stirred for 2 h at rt. The mixture was concentrated to dryness to provide the title compound which was used as it is for the next step. MS (ESI): Mass calcd. for C15H16N4O3, 300.1 ; m/z found, 301 .2 [M+H] ⁺ .

Step C: Ethyl (R)-2-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazo l-3- yl)phenyl)-5,6,7,8-tetrahydroquinazoline-4-carboxylate. The mixture of (R)-3-(5-(3- hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)benzimid amide (150 mg, 0.50 mmol), ethyl 2-oxo-2-(2-oxocyclohexyl)acetate (99 mg, 0.50 mmol) and EtsN (0.209 mL, 1 .50 mmol) in CH3CN (10 mL) was heated at 130 °C for 16 h. The solids were filtered out and the filtrate was concentrated. The residue was re-dissolved into DMSO (2 mL) and purified with HPLC (CH3CN/H2O) to provide the title compound (19 mg, 8.2%). MS (ESI): Mass calcd. for C25H26N4O5, 462.2; m/z found, 463.3 [M+H] ⁺ .

Step D: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5,6,7,8-tetrahydroquinazoline-4-carboxamide. (R)-2-(3-(5-(3-Hydroxy-1 - methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5,6,7,8-te trahydroquinazoline-4- carboxamide (4.0 mg, 22%) was prepared in a manner analogous to Example 47 Step A using ethyl (R)-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)- 5,6,7,8-tetrahydroquinazoline-4-carboxylate instead of methyl 4-chloro-6- methoxypicolinate. MS (ESI): Mass calcd. for C23H23N5O4, 433.2; m/z found, 434.2 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d) 58.82 (t, J = 1 .7 Hz, 1 H), 8.58 - 8.40 (m, 1 H), 7.97 - 7.85 (m, 1 H), 7.58 (t, J = 7.8 Hz, 1 H), 6.84 (s, 1 H), 3.73 - 3.58 (m, 1 H), 3.58 - 3.48 (m, 1 H), 3.33 (t, J = 6.3 Hz, 2H), 3.12 - 2.99 (m, 5H), 2.87 - 2.74 (m, 1 H), 2.57 - 2.43 (m, 1 H), 1.98 - 1.85 (m, 4H).

Example 126: 5-Amino-2-(3-(5-((R)-3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-N-((S)-tetrahydrofuran-3-yl)pyrimidine-4-carboxam ide.

5-Amino-2-(3-(5-((R)-3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-N-((S)-tetrahydrofuran-3-yl)pyrimidine-4-carboxam ide (19 mg) was prepared as one of the two products in a manner analogous to Example 105 using (S)- tetrahydrofuran-3-amine instead of 3-oxetanamine. The other product is described as Example 127. MS (ESI): Mass calcd. for C23H24N6O5, 464.2; m/z found, 465.3 [M+H] ⁺ . ¹ H NMR (600 MHz, CD3OD) 58.79 (s, 1 H), 8.53 (s, 1 H), 8.44 (d, J = 7.9 Hz, 1 H), 7.93 - 7.81 (m, 1 H), 7.58 (t, J = 7.8 Hz, 1 H), 6.99 (s, 1 H), 4.66-4.61 (m, 2H), 4.12 - 4.04 (m, 1 H), 4.04 - 3.94 (m, 1 H), 3.92 - 3.85 (m, 1 H), 3.85 - 3.77 (m, 1 H), 3.62 - 3.52 (m, 2H), 2.97 (s, 3H), 2.81 - 2.65 (m, 1 H), 2.49 - 2.35 (m, 2H), 2.19 - 2.08 (m, 1 H). Example 127: 2-(3-(5-((R)-3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-(((S)-tetrahydrofuran-3-yl)amino)pyrimidine-4-c arboxamide.

2-(3-(5-((R)-3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5- (((S)-tetrahydrofuran-3-yl)amino)pyrimidine-4-carboxamide (62 mg) was prepared as one of the two products in a manner analogous to Example 105 using (S)- tetrahydrofuran-3-amine instead of 3-oxetanamine. The other product is described as Example 126. MS (ESI): Mass calcd. for C23H24N6O5, 464.2; m/z found, 465.2 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 58.82 (t, J = 1 .8 Hz, 1 H), 8.62 (s, 1 H), 8.50 - 8.42 (m, 1 H), 7.91 - 7.83 (m, 1 H), 7.58 (t, J = 7.8 Hz, 1 H), 7.01 (s, 1 H), 4.45 - 4.36 (m, 1 H), 4.13 - 3.95 (m, 2H), 3.95 - 3.88 (m, 1 H), 3.76 (dd, J = 9.2, 3.0 Hz, 1 H), 3.62 - 3.54 (m, 2H), 2.97 (s, 3H), 2.82 - 2.72 (m, 1 H), 2.48 - 2.36 (m, 2H), 2.03 - 1 .90 (m, 1 H).

Example 128: 5-Amino-2-(3-(5-((R)-3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-N-((R)-tetrahydrofuran-3-yl)pyrimidine-4-carboxam ide.

5-Amino-2-(3-(5-((R)-3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-N-((R)-tetrahydrofuran-3-yl)pyrimidine-4-carboxam ide (15 mg) was prepared as one of the two products in a manner analogous to Example 105 using (R)- tetrahydrofuran-3-amine instead of 3-oxetanamine. The other product is described as Example 129. MS (ESI): Mass calcd. for C23H24N6O5, 464.2; m/z found, 465.3 [M+H] ⁺ . ¹ H NMR (600 MHz, CD3OD) d 8.79 (s, 1 H), 8.53 (s, 1 H), 8.44 (d, J = 7.9 Hz, 1 H), 7.93 - 7.81 (m, 1 H), 7.58 (t, J = 7.8 Hz, 1 H), 6.99 (s, 1 H), 4.66-4.61 (m, 2H), 4.12 - 4.04 (m, 1 H), 4.04 - 3.94 (m, 1 H), 3.92 - 3.85 (m, 1 H), 3.85 - 3.77 (m, 1 H), 3.62 - 3.52 (m, 2H), 2.97 (s, 3H), 2.81 - 2.65 (m, 1 H), 2.49 - 2.35 (m, 2H), 2.19 - 2.08 (m, 1 H).

Example 129: 2-(3-(5-((R)-3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-(((R)-tetrahydrofuran-3-yl)amino)pyrimidine-4-c arboxamide.

2-(3-(5-((R)-3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5- (((R)-tetrahydrofuran-3-yl)amino)pyrimidine-4-carboxamide (105 mg) was prepared in a manner analogous to Example 105 using (R)-tetrahydrofuran-3-amine instead of 3- oxetanamine. The other product is described as Example 128. MS (ESI): Mass calcd. for C23H24N6O5, 464.2; m/z found, 465.2 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 5 8.82 (t, J = 1 .8 Hz, 1 H), 8.62 (s, 1 H), 8.52 - 8.44 (m, 1 H), 7.91 - 7.84 (m, 1 H), 7.58 (t, J = 7.8 Hz, 1 H), 7.01 (s, 1 H), 4.44 - 4.36 (m, 1 H), 4.09 - 3.97 (m, 2H), 3.95 - 3.87 (m, 1 H), 3.76 (dd, J = 9.2, 3.0 Hz, 1 H), 3.63 - 3.53 (m, 2H), 2.97 (s, 3H), 2.81 - 2.74 (m, 1 H), 2.48 - 2.36 (m, 2H), 2.03 - 1.85 (m, 1 H).

Example 130: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-((1 -methyl-1 H-pyrazol-3-yl)amino)pyrimidine-4-carboxamide.

Step A: Ethyl 2-chloro-5-((1 -methyl-1 /-/-pyrazol-3-yl)amino)pyrimidine-4- carboxylate. Ethyl 2-chloro-5-((1 -methyl-1 /-/-pyrazol-3-yl)amino)pyrimidine-4-carboxylate (1 .2 g, 98%) was prepared in a manner analogous to Example 105 Step A using 1 - methyl-1 H-pyrazol-3-ylamine instead of 3-oxetanamine. MS (ESI): Mass calcd. for C11 H12 CIN5O2, 281.1 ; m/z found, 282.2 [M+H] ⁺ .

Step B: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-(oxetan-3-ylamino)pyrimidine-4-carboxamide. (R)-2-(3-(5-(3-Hydroxy-1- methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5-(oxetan- 3-ylamino)pyrimidine-4- carboxamide (25 mg) was prepared in a manner analogous to Example 109 using ethyl 2-chloro-5-((1 -methyl-1 /-/-pyrazol-3-yl)amino)pyrimidine-4-carboxylate instead of ethyl 1- bromoimidazo[1 ,5-a]pyrazine-3-carboxylate. MS (ESI): Mass calcd. for C23H22N8O4, 474.2; m/z found, 475.4 [M+H] ⁺ . ¹ H NMR (600 MHz, CD3OD) 59.67 (s, 1 H), 8.87 (s, 1 H), 8.52 (d, J = 7.9 Hz, 1 H), 7.90 (d, J = 7.6 Hz, 1 H), 7.60 (t, J = 7.7 Hz, 1 H), 7.52 (d, J = 2.3 Hz, 1 H), 7.02 (s, 1 H), 6.05 (d, J = 2.3 Hz, 1 H), 3.87 (s, 3H), 3.65 - 3.51 (m, 2H), 2.97 (s, 3H), 2.83 - 2.65 (m, 1 H), 2.46 - 2.36 (m, 1 H).

Example 131 : 6-(3-(5-((R)-3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-4-(((S)-tetrahydrofuran-3-yl)amino)picolinamide.

Step A: (S)-6-Chloro-4-((tetrahydrofuran-3-yl)amino)picolinonitrile. (S)-6-Chloro- 4-((tetrahydrofuran-3-yl)amino)picolinonitrile (450 mg, 100%) was prepared in a manner analogous to Example 105 Step A using (S)-tetrahydrofuran-3-amine and 4-bromo-6- chloropicolinonitrile instead of 3-oxetanamine and ethyl 2-chloro-5-fluoropyrimidine-4- carboxylate. MS (ESI): Mass calcd. for C10H10CIN3O2, 223.1 ; m/z found, 224.2 [M+H] ⁺ .

Step B: 6-(3-(5-((R)-3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-4-(((S)-tetrahydrofuran-3-yl)amino)picolinamide. 6-(3-(5-((R)-3-Hydroxy-1 - methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-4-(((S)-te trahydrofuran-3- yl)amino)picolinamide (26 mg) was prepared in a manner analogous to Example 90 (Step B and Step C) using (S)-6-chloro-4-((tetrahydrofuran-3-yl)amino)picolinonitrile instead of 6-chloro-1 -ethyl-1 /-/-imidazo[4,5-c]pyridine-4-carbonitrile. MS (ESI): Mass calcd. for C24H25N5O5, 463.2; m/z found, 464.3 [M+H] ⁺ . ¹ H NMR (600 MHz,

CD3OD) 88.17 - 8.08 (m, 1 H), 7.90 (d, J = 9.9 Hz, 1 H), 7.79 (d, J = 12.5 Hz, 1 H), 7.68 - 7.55 (m, 2H), 7.02 - 6.91 (m, 2H), 4.68 - 4.60 (m, 1 H), 4.11 - 4.04 (m, 1 H), 4.04 - 3.92 (m, 1 H), 3.92 - 3.85 (m, 1 H), 3.74 - 3.67 (m, 1 H), 3.62 - 3.54 (m, 2H), 2.96 (s, 3H), 2.78 - 2.69 (m, 1 H), 2.47 - 2.32 (m, 2H), 1 .99 - 1 .90 (m, 1 H).

Example 132: (R)-5-Amino-6-cyclopropyl-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)pyrimidine-4-carboxamide.

Step A: Methyl 5-amino-2-chloro-6-cyclopropylpyrimidine-4-carboxylate. Methyl 5-amino-2-chloro-6-cyclopropylpyrimidine-4-carboxylate (87 mg, 38%) was prepared in a manner analogous to Example 88 using methyl 5-amino-2,6-dichloropyrimidine-4- carboxylate instead of 3-amino-4,6-dichloropicolinonitrile. MS (ESI): Mass calcd. for C9H10N3O2, 227.0; m/z found, 228.1 [M+H] ⁺ .

Step B: (R)-5-Amino-6-cyclopropyl-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)pyrimidine-4-carboxamide. (R)-5-Amino-6-cyclopropyl-2-(3-(5-(3- hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)p yrimidine-4-carboxamide (30 mg) was prepared in a manner analogous to Example 109 using methyl 5-amino-2- chloro-6-cyclopropylpyrimidine-4-carboxylate instead of ethyl 1 -bromoimidazo[1 ,5- a]pyrazine-3-carboxylate. MS (ESI): Mass calcd. for C22H22N6O4, 434.2; m/z found, 435.2 [M+H] ⁺ . ¹ H NMR (600 MHz, CD3OD) 88.78 (t, J = 1 .8 Hz, 1 H), 8.43 (d, J = 7.9 Hz, 1 H), 7.91 - 7.78 (m, 1 H), 7.54 (t, J = 7.8 Hz, 1 H), 6.98 (s, 1 H), 3.66 - 3.52 (m, 2H), 2.97 (s, 3H), 2.83 - 2.71 (m, 1 H), 2.48 - 2.38 (m, 1 H), 2.35 - 2.26 (m, 1 H), 1.34 - 1 .22 (m, 2H), 1.22 - 1.08 (m, 2H). Example 133: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-6-((1 -methyl-1 H-pyrazol-3-yl)amino)-5-(trifluoromethyl)pyrimidine-4- carboxamide.

(R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-6-((1 - methyl-1 H-pyrazol-3-yl)amino)-5-(trifluoromethyl)pyrimidine-4-carbox amide (40 mg) was prepared in a manner analogous to Example 122 using methyl 2,6-dichloro-5- (trifluoromethyl)-4-pyrimidinecarboxylate instead of ethyl 2-chloro-5-fluoropyrimidine-4- carboxylate. MS (ESI): Mass calcd. for C24H21 F3N8O4, 542.2; m/z found, 543.1 [M+H] ⁺ . ¹ H NMR (600 MHz, CD3OD) 58.85 (s, 1 H), 8.49 (d, J = 8.0 Hz, 1 H), 8.02 (d, J = 7.6 Hz, 1 H), 7.70 (d, J = 2.5 Hz, 1 H), 7.62 (t, J = 7.8 Hz, 1 H), 6.91 (d, J = 7.6 Hz, 1 H), 6.72 (d, J = 2.4 Hz, 1 H), 3.91 (s, 3H), 3.64 - 3.53 (m, 2H), 2.97 (s, 3H), 2.78-2.71 ( m, 1 H), 2.45- 2.38 (s, 1 H).

Example 134: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide.

Step A: Methyl 2-chloro-5-tosyl-5/-/-pyrrolo[3,2-d]pyrimidine-4-carboxylate .

To a mixture of methyl 2-chloro-5/-/-pyrrolo[3,2-d]pynmidine-4-carboxylate (211 mg, 0.997 mmol), p-toluenesulfonyl chloride (215 mg, 1.12 mmol), and DMAP (12 mg, 0.010 mmol) in DCM (10 mL) was added EtsN (0.21 mL, 1.5 mmol). The mixture was heated at 50 °C for 16 h. Then it was cooled down and diluted with saturated aqueous NaHCOs solution (5 mL). The organic layer was separated and concentrated providing the desired product which was used as it is for the next step (301 mg, 82.1 %). MS (ESI): Mass calcd. For C15H12CIN3O4S, 365.0; m/z found, 366.1 [M+H] ⁺ .

Step B: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-tosyl-5/-/-pyrrolo[3,2-d]pyrimidine-4-carboxyla te. (R)-2-(3-(5-(3-Hydroxy-1- methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5-tosyl-5/ -/-pyrrolo[3,2-c(]pynmidine-4- carboxylate (210 mg, 44%) was prepared in a manner analogous to Example 47 Step B using methyl 2-chloro-5-tosyl-5/-/-pyrrolo[3,2-d]pyrimidine-4-carboxylate instead of 4- chloro-6-methoxypicolinamide. MS (ESI): Mass calcd. for C29H25N5O7S, 418.1 ; m/z found, 419.3 [M+H] ⁺ .

Step C: (R)-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide. A mixture of methyl (R)-2-(3-(5- (3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5-tosyl-5 /-/-pyrrolo[3,2- c/]pyrimidine-4-carboxylate (210 mg, 0.36 mmol) in NH3 (1.79 mL, 7 M in MeOH) was heated at 120 °C for 16 h. The reaction mixture was concentrated and the residue was purified with reverse phase HPLC to provide the desired product (22 mg, 15%). MS (ESI): Mass calcd. for C21 HwNeCM, 418.1 ; m/z found, 419.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD3OD) 59.03 (t, J = 1 .7 Hz, 1 H), 8.75 - 8.62 (m, 1 H), 8.04 - 7.92 (m, 2H), 7.67 (t, J = 7.8 Hz, 1 H), 7.08 (s, 1 H), 6.81 (d, J = 3.2 Hz, 1 H), 3.69 - 3.56 (m, 2H), 3.00 (s, 3H), 2.89 - 2.73 (m, 1 H), 2.54 - 2.36 (m, 1 H).

Example 135: (R)-5-Amino-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)pyrim idine-4-carboxam ide.

(R)-5-Amino-2-(3-(5-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3 -yl)isoxazol-3- yl)phenyl)pyrimidine-4-carboxamide (30 mg) was prepared in a manner analogous to Example 109 using ethyl 5-amino-2-chloropyrimidine-4-carboxylate instead of ethyl 1- bromoimidazo[1 ,5-a]pyrazine-3-carboxylate. MS (ESI): Mass calcd. for C19H18N6O4, 394.1 ; m/z found, 395.3 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 88.86 - 8.68 (m, 1 H), 8.53 (s, 1 H), 8.50 - 8.37 (m, 1 H), 7.91 - 7.82 (m, 1 H), 7.65 - 7.52 (m, 1 H), 7.02 (s, 1 H), 3.66 - 3.54 (m, 2H), 2.99 (s, 3H), 2.84 - 2.70 (m, 1 H), 2.53 - 2.34 (m, 1 H).

Example 136: (R)-3-(3-(3-(5-Amino-4,6-dimethoxypyrimidin-2-yl)phenyl)isox azol-5-yl)-3- hydroxy-1 -methylpyrrolidin-2-one.

(R)-3-(3-(3-(5-Amino-4,6-dimethoxypyrimidin-2-yl)phenyl)i soxazol-5-yl)-3- hydroxy-1-methylpyrrolidin-2-one (42 mg) was prepared in a manner analogous to Example 47 using 2-chloro-4,6-dimethoxy-5-pyrimidinamine instead of methyl 4-chloro- 6-methoxypicolinate in Step A. MS (ESI): Mass calcd. for C20H21 N5O5, 411 .2; m/z found, 412.1 [M+H] ⁺ . ¹ H NMR (600 MHz, CD ₃ OD) 88.81 (t, J = 1.8 Hz, 1 H), 8.54 - 8.40 (m, 1 H), 7.96 - 7.83 (m, 1 H), 7.57 (t, J = 7.7 Hz, 1 H), 6.94 (s, 1 H), 4.17 (s, 6H), 3.65 - 3.56 (m, 2H), 2.99 (s, 3H), 2.84 - 2.69 (m, 1 H), 2.48 - 2.35 (m, 1 H).

Example 137: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-((1 -methyl-1 H-pyrazol-4-yl)amino)pyrimidine-4-carboxamide.

(R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5-((1 - methyl-1 H-pyrazol-4-yl)amino)pyrimidine-4-carboxamide (98 mg) was prepared in a manner analogous to Example 130 using 1-methyl-1 /-/-pyrazol-4-amine instead of 1- methyl-1 /-/-pyrazol-3-ylamine. MS (ESI): Mass calcd. for C23H22N8O4, 474.2; m/z found, 475.2 [M+H] ⁺ . ¹ H NMR (600 MHz, CD3OD) 58.85 (t, J = 1 .6 Hz, 1 H), 8.66 (s, 1 H), 8.53 - 8.47 (m, 1 H), 7.94 - 7.88 (m, 1 H), 7.79 (d, J = 0.8 Hz, 1 H), 7.61 (t, J = 7.8 Hz, 1 H), 7.57 (d, J = 0.9 Hz, 1 H), 7.03 (s, 1 H), 3.95 (s, 3H), 3.66 - 3.55 (m, 2H), 2.99 (s, 3H), 2.83 - 2.73 (m, 1 H), 2.50 - 2.38 (m, 1 H).

Example 138: (R)-5-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-2-methoxypyrimidine-4-carboxamide.

Step A: Ethyl (R)-2-chloro-5-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)pyrimidine-4-carboxylate. The mixture of ethyl 5-bromo-2- chloropyrimidine-4-carboxylate (265 mg, 0.998 mmol), (R)-3-hydroxy-1 -methyl-3-(3-(3- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 383 mg, 0.998 mmol), potassium phosphate (648 mmol, 2.99 mmol) and 1 , 1 '-bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (46 mg, 0.056 mmol) in THF (5 mL)/H2O (1 mL) was heated at 100 °C for 2 h. Then it was cooled, and the organic layer was separated and concentrated providing the title compound (300 mg, 67.8%). MS (ESI): Mass calcd. for C21 H19N4O5, 442.1 ; m/z found, 443.1 [M+H] ⁺ .

Step B: (R)-5-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-2-methoxypyrimidine-4-carboxamide. Ethyl (R)-2-chloro-5-(3-(5-(3-hydroxy-1- methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)pyrimidine- 4-carboxylate (200 mg, 0.45 mmol) in NH3 (7 M in MeOH) (2.25 mL, 15.8 mmol) was heated at 70 °C for 16 h. Then it was cooled to RT during which time a precipitate formed. After filtration, the solids were collected, re-dissolved in DMSO and purified with HPLC reverse phased (CH3CN/H2O) providing the title compound (163 mg, 88.1 %). MS (ESI): Mass calcd. for C20H19N5O5, 409.1 ; m/z found, 410.1 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 5 8.73 (s, 1 H), 8.01 - 7.83 (m, 2H), 7.63 - 7.52 (m, 2H), 6.92 (s, 1 H), 4.13 (s, 3H), 3.67 - 3.49 (m, 2H), 2.98 (s, 3H), 2.83 - 2.69 (m, 1 H), 2.51 - 2.38 (m, 1 H).

Example 139: (R)-5-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-1 H-pyrrolo[2,3-c]pyridine-7-carboxamide.

Step A: 5-Chloro-7-(1 -ethoxyvinyl)-1 /-/-pyrrolo[2,3-c]pyridine. The mixture of 7- bromo-5-chloro-1 H-pyrrolo[2,3-c]pyridine (2.31 g, 9.99 mmol), tributyl(1 -ethoxyvinyl)tin (4.87 g, 13.5 mmol) and bis(triphenylphosphine)palladium(ii) chloride (715 mg, 0.998 mmol) in DMF (5 mL) was heated at 70 °C for 3 h. It was cooled down and an aqueous solution of KF (2 mL, 10 M) was added. The mixture was shaken well. Then H2O (100 mL) was added. Semi-solids were formed. The aqueous layer was decanted. The semisolids were re-dissolved into THF (100 mL). The in-soluble material was filtered off. The organic layer was concentrated to provide the title compound (2.1 g, 94%). MS (ESI): Mass calcd. for C11H11CIN2O, 223.1 ; m/z found, 224.1 [M+H] ⁺ .

Step B: Ethyl 5-chloro-1 /-/-pyrrolo[2,3-c]pyridine-7-carboxylate. A solution of NalCM (2.47 g, 11.6 mmol) in H2O (100 mL) was added to a solution of 5-chloro-7-(1 - ethoxyvinyl)-1 /-/-pyrrolo[2,3-c]pyridine (647 mg, 2.89 mmol) in dioxane (100 mL). To this mixture was added a solution of KMnCM (182 mg, 1.16 mmol) in H2O (10 mL), and the resulting mixture was stirred for 16 h at 50 °C. The solids were filtered out. The resulting solution was extracted with DCM (4 x 100 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum to afford the title compound (449 mg, 69.2%). MS (ESI): Mass calcd. for C10H19CIN2O2, 224.0; m/z found, 225.1 [M+H] ⁺ .

Step C: (R)-5-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-1 H-pyrrolo[2,3-c]pyridine-7-carboxamide. (R)-5-(3-(5-(3-Hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-1 /-/-pyrrolo[2,3-c]pyridine-7-carboxamide (41 mg) was prepared in a manner analogous to Example 134 using ethyl 5-chloro-1 /-/- pyrrolo[2,3-c]pyridine-7-carboxylate instead of methyl 2-chloro-5/-/-pyrrolo[3,2- d]pyrimidine-4-carboxylate. MS (ESI): Mass calcd. for C22H19N5O4, 417.1 ; m/z found, 418.1 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 88.74 - 8.60 (m, 1 H), 8.37 (s, 1 H), 8.31 - 8.24 (m, 1 H), 7.90 - 7.82 (m, 1 H), 7.69 - 7.60 (m, 2H), 7.05 (s, 1 H), 6.73 (d, J = 3.1 Hz, 1 H), 3.66 - 3.55 (m, 2H), 3.00 (s, 3H), 2.84 - 2.74 (m, 1 H), 2.49 - 2.40 (m, 1 H).

Example 140: (R)-2-(5-(5-(4,4-Difluoro-3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol- 3-yl)-2-fluorophenyl)-5/-/-pyrrolo[3,2-d]pyrimidine-4-carbox amide.

Step A: (R)-(5-(5-(4,4-Difluoro-3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol- 3-yl)-2-fluorophenyl)boronic acid. (R)-(5-(5-(4,4-Difluoro-3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)-2-fluorophenyl)boronic acid (500 mg) was prepared in a manner analogous to Intermediate 3 and 4 using 3-bromo-4-fluorobenzaldehyde and (R)-3-ethynyl-4,4-difluoro-3-hydroxy-1-methylpyrrolidin-2-on e (Intermediate 44) instead of 3-bromobenzaldehyde and (R)-3-ethynyl-3-hydroxy-1 -methylpyrrolidin-2-one. MS (ESI): Mass calcd. for C14H12BF3N2O5, 356.0; m/z found, 356.9 [M+H] ⁺ .

Step B: (R)-2-(5-(5-(4,4-Difluoro-3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)-2-fluorophenyl)-5H-pyrrolo[3,2-c(]pyrimidi ne-4-carboxamide. (R)-2-(5-(5- (4,4-Difluoro-3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)-2-fluorophenyl)- 5/-/- pyrrolo[3,2-d]pyrimidine-4-carboxamide (13 mg) was prepared in a manner analogous to Example 134 using (R)-(5-(5-(4,4-difluoro-3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)-2-fluorophenyl)boronic acid (Example 119, Step A) instead of (R)-3- hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol- 5-yl)pyrrolidin-2-one. MS (ESI): Mass calcd. for C21 H15F3N6O4, 472.1 ; m/z found, 473.1 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 88.62 (dd, J = 7.2, 2.3 Hz, 1 H), 8.08 - 7.93 (m, 2H), 7.48 - 7.39 (m, 1 H), 7.17 (s, 1 H), 6.83 (d, J = 3.2 Hz, 1 H), 4.17 - 3.90 (m, 2H), 3.07 (s, 3H).

Example 141 : (R)-5-((1 /-/-Pyrazol-4-yl)amino)-2-(3-(5-(3-hydroxy-1-methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)pyrimidine-4-carboxa mide.

(R)-5-((1 /-/-Pyrazol-4-yl)amino)-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)pyrimidine-4-carboxamide (20 mg) was prepared in a manner analogous to Example 130 using 1 /-/-pyrazol-4-amine instead of 1 -methyl-1 /-/-pyrazol-3- ylamine. MS (ESI): Mass calcd. for C22H20N8O4, 460.2; m/z found, 461.1 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 5 8.91 - 8.77 (m, 1 H), 8.64 (s, 1 H), 8.54 - 8.45 (m, 1 H), 7.94 - 7.87 (m, 1 H), 7.76 (s, 1 H), 7.64 - 7.57 (m, 1 H), 7.03 (s, 1 H), 3.67 - 3.55 (m, 2H), 2.99 (s, 3H), 2.83 - 2.73 (m, 1 H), 2.51 - 2.34 (m, 1 H).

Example 142: (R)-5-((3,5-Dimethyl-1 /-/-pyrazol-4-yl)amino)-2-(3-(5-(3-hydroxy-1 -methyl- 2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)pyrimidine-4-carbo xamide.

((R)-5-((3,5-Dimethyl-1 /-/-pyrazol-4-yl)amino)-2-(3-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)pyrimidine-4-carboxa mide (1.5 mg) was prepared in a manner analogous to Example 130 using 3,5-dimethyl-1 /-/-pyrazol-4-amine instead of 1 -methyl-1 /-/-pyrazol-3-ylamine. MS (ESI): Mass calcd. for C24H24N8O4, 488.2; m/z found, 489.6 [M+H] ⁺ . ¹ H NMR (600 MHz, CD3OD) 88.86 (t, J = 1 .7 Hz, 1 H), 8.56 - 8.44 (m, 1 H), 8.20 (s, 1 H), 7.93 - 7.86 (m, 1 H), 7.61 (t, J = 7.8 Hz, 1 H), 7.03 (s, 1 H), 3.68 - 3.51 (m, 2H), 2.99 (s, 3H), 2.83 - 2.70 (m, 1 H), 2.50 - 2.40 (m, 1 H), 2.18 (s, 6H).

Example 143: (R)-5-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-1 /-/-pyrazolo[3,4-c]pyridine-7-carboxamide.

Step A: Ethyl 5-chloro-1 /-/-pyrazolo[3,4-c]pyridine-7-carboxylate. Ethyl 5-chloro- 1 /-/-pyrazolo[3,4-c]pyridine-7-carboxylate (510 mg) was prepared in a manner analogous to Example 139 (Step A and B) using 5,7-dichloro-1 /-/-pyrazolo[3,4-c]pyridine instead of 7-bromo-5-chloro-1 /-/-pyrrolo[2,3-c]pyridine MS (ESI): Mass calcd. for C9H8CIN3O2, 225.1 ; m/z found, 226.1 [M+H] ⁺ .

Step B: (R)-3-Hydroxy-1 -methyl-3-(3-(3-(trimethylstannyl)phenyl)isoxazol-5- yl)pyrrolidin-2-one. The mixture of (R)-3-(3-(3-bromophenyl)isoxazol-5-yl)-3-hydroxy-1 - methylpyrrolidin-2-one (2.02 g, 6.00 mmol), hexamethylditin (1.96 g, 6.00 mmol) and tetrakis(triphenylphosphine)palladium(0) (693 mg, 0.6 mmol) in 1 ,4-dioxane (12 mL) was heated at 110 °C for 16 h. It was cooled to rt, filtered and purified with HPLC reverse phase (CH3CN/H2O) to provide the title compound (1.1 g, 44%). MS (ESI): Mass calcd. for Ci7H ₂ 2N2O ₃ Sn, 422.0; m/z found, 423.0 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 87.79 - 7.69 (m, 1 H), 7.59 - 7.45 (m, 1 H), 7.46 - 7.34 (m, 1 H), 7.29 - 7.18 (m, 1 H), 6.68 (s, 1 H), 3.45 - 3.30 (m, 2H), 2.77 (s, 3H), 2.60 - 2.48 (m, 1 H), 2.28 - 2.12 (m, 1 H), 0.13 (s, 9H).

Step C: Ethyl (R)-5-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-1 /-/-pyrazolo[3,4-c]pyridine-7-carboxylate. A mixture of (R)-3-hydroxy-1- methyl-3-(3-(3-(trimethylstannyl)phenyl)isoxazol-5-yl)pyrrol idin-2-one (210 mg, 0.50 mmol), ethyl 5-chloro-1 /-/-pyrazolo[3,4-c]pyridine-7-carboxylate (113 mg, 0.499 mmol) and bis(triphenylphosphine)palladium(ll) chloride (36 mg, 0.050 mmol) in DMF (0.5 mmol) was heated at 150 °C for 1 h. After the reaction mixture cooled to RT it was filtered and purified with HPLC reverse phase (CH3CN/H2O) to provide the title compound (89 mg, 39%). MS (ESI): Mass calcd. for C23H21N5O5, 447.2; m/z found, 448.1 [M+H] ⁺ .

Step D: (R)-5-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-1 /-/-pyrazolo[3,4-c]pyridine-7-carboxamide. A mixture of ethyl (R)-5-(3-(5-(3- hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-1 /-/-pyrazolo[3,4-c]pyridine- 7-carboxylate (89 mg, 0.20 mmol) in NH3 (7 M in MeOH) (1.0 mL, 7 mmol) was heated at 100 °C for 16 h and then cooled to RT. The mixture was concentrated and purified with reverse phase HPLC (CH3CN/H2O) which provided the title compound (7 mg, 8%). MS (ESI): Mass calcd. for C21 HwNeCM, 418.1 ; m/z found, 419.4 [M+H] ⁺ . ¹ H NMR (600 MHz, CD3OD) 5 8.72 (t, J = 1 .8 Hz, 1 H), 8.58 (s, 1 H), 8.38 - 8.27 (m, 2H), 7.95 - 7.87 (m, 1 H), 7.65 (t, J = 7.8 Hz, 1 H), 7.07 (s, 1 H), 3.68 - 3.55 (m, 2H), 3.00 (s, 3H), 2.83 - 2.74 (m, 1 H), 2.50 - 2.39 (m, 1 H).

Example 144: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-((4-methoxy-1 -methyl-1 H-pyrazol-3-yl)amino)pyrimidine-4-carboxamide.

(R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5-((4- methoxy-1-methyl-1 H-pyrazol-3-yl)amino)pyrimidine-4-carboxamide (11 mg) was prepared in a manner analogous to Example 130 using 4-methoxy-1-methyl-1 /-/-pyrazol- 3-amine instead of 1 -methyl-1 /-/-pyrazol-3-ylamine. MS (ESI): Mass calcd. for C24H24N8O5, 504.2; m/z found, 505.4 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 5 9.57 (s, 1 H), 8.89 (t, J = 1 .8 Hz, 1 H), 8.60 - 8.49 (m, 1 H), 7.97 - 7.86 (m, 1 H), 7.63 (t, J = 7.8 Hz, 1 H), 7.40 (s, 1 H), 7.05 (s, 1 H), 3.84 - 3.82 (m, 6H), 3.66 - 3.56 (m, 2H), 3.00 (s, 3H), 2.84 - 2.74 (m, 1 H), 2.50 - 2.40 (m, 1 H).

Example 145: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-((1 -(2,2,2-trifluoroethyl)-1 H-pyrazol-4-yl)amino)pyrimidine-4-carboxamide

(R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5-((1 - (2,2,2-trifluoroethyl)-1 /-/-pyrazol-4-yl)amino)pyrimidine-4-carboxamide (5 mg) was prepared in a manner analogous to Example 130 using 1 -(2,2,2-trifluoroethyl)-1 H- pyrazol-4-amine instead of 1 -methyl-1 /-/-pyrazol-3-ylamine. MS (ESI): Mass calcd. for C24H21 F3N8O4, 542.2; m/z found, 543.6 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 5 8.90 - 8.80 (m, 1 H), 8.67 (s, 1 H), 8.54 - 8.47 (m, 1 H), 7.98 (d, J = 0.8 Hz, 1 H), 7.94 - 7.87 (m, 1 H), 7.74 - 7.67 (m, 1 H), 7.64 - 7.59 (m, 1 H), 7.03 (s, 1 H), 4.99 (q, J = 8.7 Hz, 2H), 3.65 - 3.55 (m, 2H), 2.99 (s, 3H), 2.82 - 2.72 (m, 1 H), 2.47 - 2.40 (m, 1 H).

Example 146: (R)-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)pyrimidine-4-carboxamide.

A solution of (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 122 mg, 0.32 mmol), 2-chloropyrimidine-4-carboxamide (60 mg, 0.38 mmol), potassium phosphate (202 mg, 0.95 mmol) and bis(tri-tert-butylphosphine)palladium(0) (16 mg, 0.032 mmol) in DMF (2 mL) and water (2 mL) was heated to 90 °C under and N2 atmosphere for 12 h. The reaction mixture was cooled to rt, filtered and purified by preparative HPLC (Xtimate C18 10 pm, 21 .2 x 250 mm, mobile phase (10 mM NH4HCO3 in water + 0.025% NH3*H2O I ACN, Gradient 33% to 48% ACN over 7 min, 15 min run). Detection, UV at 25 °C = 214/254 nM) to afford (R)-2-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)pyrimidine-4-carboxamide (25 mg, 21 % yield) as a brown solid. MS (ESI): Mass calcd. for C19H17N5O4, 379.37; m/z found, 380.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-c/e) 8 9.18 (d, J = 4.8 Hz, 1 H), 9.01 (s, 1 H), 8.77 (d, J = 8.0 Hz, 1 H), 8.76 (s, 1 H), 8.07 (t, J = 8.0 Hz, 1 H), 8.06 (s, 1 H), 7.96 (d, J = 4.8 Hz, 1 H), 7.70 (t, J = 8.0 Hz, 1 H), 7.21 (s, 1 H), 6.75 (s, 1 H), 3.40-3.52 (m, 2H), 2.85 (s, 3H), 2.55-2.63 (m, 1 H), 2.25-2.33 (m, 1 H).

Example 147: (R)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)pyrazine-2-carboxamide.

The title compound was prepared in a manner analogous to Example 146 using 6-chloropyrazine-2 -carboxamide in place of 2-chloropyrimidine-4-carboxamide to afford (R)-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)pyrazine-2 - carboxamide (12 mg, 12% yield) as a colorless solid. MS (ESI): Mass calcd. for C19H17N5O4, 379.37; m/z found, 380 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 9.63 (s, 1 H), 9.17 (s, 1 H), 8.77 (s, 1 H), 8.63 (s , 1 H), 8.55 (d, J = 8.0 Hz, 1 H), 8.07 (d, J = 8.0 Hz, 1 H), 7.98 (s, 1 H), 7.71 (t, J = 8.0 Hz, 1 H), 7.33 (s, 1 H), 6.79(s, 1 H), 3.40-3.52 (m, 2H), 2.86 (s, 3H), 2.52-2.62 (m, 1 H), 2.23-2.33 (m, 1 H).

Example 148: (R)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)picolinamide.

The title compound was prepared in a manner analogous to Example 146 using 6-chloropicolinamide in place of 2-chloropyrimidine-4-carboxamide to afford (R)-6-(3-(5- (3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinami de (19 mg, 15% yield) as a colorless solid. MS (ESI): Mass calcd. for C20H18N4O4, 378.12; m/z found, 379 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.55 (s, 1 H), 8.43-8.48 (m, 3H), 8.33 (d, J = 8.0 Hz, 1 H), 8.10 (t, J = 8.0 Hz, 1 H), 7.99-8.04 (m, 2H), 7.76 (s, 1 H), 7.66 (t, J = 8.0 Hz, 1 H), 7.28 (s, 1 H), 6.75 (s, 1 H), 3.43-3.50 (m, 2H), 2.85 (s, 2H), 2.55-2.59 (m, 1 H), 2.27-2.32 (m, 1 H).

Example 149: (S)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)picolinamide.

The title compound was prepared in a manner analogous to Example 146 using (S)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 27) in place of (R)-3-hydroxy-1 - methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5- yl)pyrrolidin-2-one and 6-chloropicolinamide in place of 2-chloropyrimidine-4- carboxamide to afford (S)-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)picolinamide (37 mg, 16% yield) as a colorless solid. MS (ESI): Mass calcd. for C20H18N4O4, 378.12; m/z found, 379.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.55 (s, 1 H), 8.43-8.48 (m, 2H), 8.33 (dd, J = 0.8, 8.0 Hz, 1 H), 8.10 (t, J = 8.0 Hz, 1 H), 7.99- 8.04 (m, 2H), 7.76 (s, 1 H), 7.66 (t, J = 8.0 Hz, 1 H), 7.28 (s, 1 H), 6.75 (s, 1 H), 3.41-3.52 (m, 2H), 2.85 (s, 3H), 2.54-2.61 (m, 1 H), 2.25-2.32 (m, 1 H).

Example 150: (R)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)-4- methylphenyl)picolinamide.

The title compound was prepared in a manner analogous to Example 146 using (R)-3-hydroxy-1 -methyl-3-(3-(2-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 29) in place of (R)-3-hydroxy-1 - methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5- yl)pyrrolidin-2-one and 6-chloropicolinamide in place of 2-chloropyrimidine-4- carboxamide to afford (R)-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)-4-methylphenyl)picolinamide (25 mg, 15% yield) as a colorless solid. MS (ESI): Mass calcd. for C21 H20N4O4, 392.41 ; m/z found, 393.0. [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 5 8.41 (s, 1 H), 8.33-8.40 (m, 2H), 8.27 (d, J = 8.0 Hz, 1 H), 8.06 (t, J = 8.0 Hz, 1 H), 7.98 (d, J = 8.0 Hz, 1 H), 7.75 (s, 1 H), 7.51 (d, J = 8.8 Hz, 1 H), 7.03 (s, 1 H), 6.75 (s, 1 H), 3.38-3.45 (m, 2H), 2.85 (s, 3H), 2.52-2.66 (m, 1 H), 2.22-2.35 (m, 1 H).

Example 151 : (R)-6-(5-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)-2- methylphenyl)picolinamide. The title compound was prepared in a manner analogous to Example 146 using (R)-3-hydroxy-1 -methyl-3-(3-(4-methyl-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 30) in place of (R)-3-hydroxy-1 - methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5- yl)pyrrolidin-2-one and 6-chloropicolinamide in place of 2-chloropyrimidine-4- carboxamide to afford (R)-6-(5-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)-2-methylphenyl)picolinamide (31 mg, 19% yield) as a colorless solid. MS (ESI): Mass calcd. for C21 H20N4O4, 392.41 ; m/z found, 393.0. [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.00-8.20 (m, 3H), 7.95 (s, 1 H), 7.80-7.94 (m, 2H), 7.70 (s,1 H), 7.49 (d, J = 6.0 Hz, 1 H), 7.10 (s, 1 H), 6.71 (s, 1 H), 3.40-3.60 (m, 2H), 2.83 (s, 3H), 2.50-2.60 (m, 1 H), 2.42 (s, 3H), 2.20-2.40 (m, 1 H).

Example 152: (R)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)-5- methylphenyl)picolinamide.

The title compound was prepared in a manner analogous to Example 146 using (R)-3-hydroxy-1 -methyl-3-(3-(3-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 28) in place of (R)-3-hydroxy-1 - methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5- yl)pyrrolidin-2-one and 6-chloropicolinamide in place of 2-chloropyrimidine-4- carboxamide to afford (R)-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)-5-methylphenyl)picolinamide (73 mg, 25% yield) as a colorless solid. MS (ESI): Mass calcd. for C21 H20N4O4, 392.41 ; m/z found, 393.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.44 (s, 2H), 8.30-8.32 (m, 2H), 8.08 (t, J = 7.6 Hz, 1 H), 8.02 (d, J = 7.6 Hz, 1 H), 7.82 (s, 1 H), 7.78 (s, 1 H), 7.25 (s, 1 H), 6.74 (s, 1 H), 3.40-3.51 (m, 2H), 2.85 (s, 3H), 2.54- 2.60 (m, 1 H), 2.50 (s, 3H), 2.25-2.32 (m, 1 H). Example 153: (R)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)-5- methoxyphenyl)picolinamide.

The title compound was prepared in a manner analogous to Example 146 using (R)-3-hydroxy-3-(3-(3-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)-1 -methylpyrrolidin-2-one (Intermediate 31 ) in place of (R)-3- hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol- 5-yl)pyrrolidin-2-one and 6-chloropicolinamide in place of 2-chloropyrimidine-4- carboxamide to afford (R)-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)-5-methoxyphenyl)picolinamide (26 mg, 17% yield) as a colorless solid. MS (ESI): Mass calcd. for C21H20N4O5, 408.41 ; m/z found, 409.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-cfe) 8 8.44 (s, 1 H), 8.32 (d, J = 7.2 Hz, 1 H), 8.23(s, 1 H), 8.10 (t, J = 7.6 Hz, 1 H), 8.03 (d, J = 7.2 Hz, 1 H), 7.99 (s, 1 H), 7.75 (s, 1 H), 7.52 (s, 1 H), 7.29 (s, 1 H), 6.74 (s, 1 H), 3.95 (s, 3H), 3.41-3.51 (m, 2H), 2.85 (s, 3H), 2.54-2.61 (m, 1 H), 2.26-2.32 (m, 1 H).

Example 154: (R)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-3-methylpicolinamide.

The title compound was prepared in a manner analogous prepared in a manner analogous to Example 146 using 6-chloro-3-methylpicolinamide in place of 2- chloropyrimidine-4-carboxamide to afford (R)-6-(3-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-3-methylpicolinamid e (25 mg, 14% yield) as a colorless solid. MS (ESI): Mass calcd. for C21 H20N4O4, 392.41 ; m/z found, 393.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.63 (s, 1 H), 8.47 (d, J = 7.6 Hz, 1 H), 8.41 (s, 1 H), 8.19 (s, 1 H), 7.99 (d, J = 7.6 Hz, 1 H), 7.88 (s, 1 H), 7.73 (s, 1 H), 7.65 (t, J = 8.0 Hz, 1 H), 7.28 (s, 1 H), 3.42-3.50 (m, 2H), 2.85 (s, 3H), 2.54-2.60 (m, 1 H), 2.52 (s, 3H), 2.27-2.33 (m, 1 H).

Example 155: (R)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-4-methylpicolinamide.

The title compound was prepared in a manner analogous to Example 146 using 6-chloro-4-methylpicolinamide in place of 2-chloropyrimidine-4-carboxamide to afford (R)-6-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazo l-3-yl)phenyl)-4- methylpicolinamide (25 mg, 14% yield) as a colorless solid. MS (ESI): Mass calcd. for C21 H20N4O4, 392.41 ; m/z found, 393.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.63 (s, 1 H), 8.47 (d, J = 7.6 Hz, 1 H), 8.41 (s, 1 H), 8.19 (s, 1 H), 7.99 (d, J = 7.6 Hz, 1 H), 7.88 (s, 1 H), 7.73 (s, 1 H), 7.65 (t, J = 8.0 Hz, 1 H), 7.28 (s, 1 H), 3.42-3.50 (m, 2H), 2.85 (s, 3H), 2.54-2.60 (m, 1 H), 2.52 (s, 3H), 2.27-2.33 (m, 1 H).

Example 156: (R)-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-methylpicolinamide. The title compound was prepared in a manner analogous to Example 146 using 6-bromo-5-methylpicolinamide in place of 2-chloropyrimidine-4-carboxamide to afford (R)-6-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazo l-3-yl)phenyl)-5- methylpicolinamide (21 mg, 14% yield) as a colorless solid. MS (ESI): Mass calcd. for C21 H20N4O4, 392.41 ; m/z found, 393 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.10 (s, 1 H), 8.04 (s, 1 H), 7.92-8.00 (m, 3H), 7.98 (d, J = 7.6 Hz, 1 H), 7.60-7.68 (m, 2H), 7.13 (s, 1 H), 6.73 (s, 1 H), 3.40-3.52 (m, 2H), 2.84 (s, 3H), 2.50-2.62 (m, 1 H), 2.43 (s, 3H), 2.23-2.30 (m, 1 H).

Example 157: (R)-3'-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)-[1 ,T- biphenyl]-3-carboxam ide.

The title compound was prepared in a manner analogous to Example 146 using 3-bormobenzamide in place of 2-chloropyrimidine-4-carboxamide to afford (R)-3'-(5-(3- hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)-[1 , 1 '-biphenyl]-3-carboxamide (9 mg, 4% yield) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.16-8.25 (m, 3H), 7.80-8.00 (m, 4H), 7.60-7.70 (m, 2H), 7.50 (s,1 H), 7.18 (s, 1 H), 6.75 (s, 1 H), 3.40-3.52 (m, 2H), 2.85 (s, 3H), 2.50-2.62 (m, 1 H), 2.20-2.40 (m, 1 H).

Example 158: (R)-7-Fluoro-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)quinazoline-4-carboxamide. The title compound was prepared in a manner analogous to Example 146 using 2-chloro-7-fluoroquinazoline-4-carboxamide (Intermediate 38) in place of 2- chloropyrimidine-4-carboxamide to afford (R)-7-fluoro-2-(3-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)quinazoline-4-carbox amide (5 mg, 4% yield) as a colorless solid. MS (ESI): Mass calcd. for C23H18FN5O4, 447.42; m/z found, 448 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 9.08 (s, 1 H), 9.00 (t, J = 2.8 Hz, 1 H), 8.70-8.90 (m, 2H), 8.23 (br. s, 1 H), 8.11 (d, J = 7.6 Hz, 1 H), 7.90-8.05 (m, 1 H), 7.70-7.80 (m, 2H), 7.18 (s, 1 H), 6.78 (s, 1 H), 3.40-3.50 (m, 2H), 2.86 (s, 3H), 2.50-2.65 (m, 1 H), 2.20- 2.40 (m, 1 H).

Example 159: (R)-3-(3-(5-(4-Amino-2-methylpyrido[3,2-c(]pyrimidin-6-yl)fu ran-2- yl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one.

The title compound was prepared in a manner analogous to Example 146 using 6-chloro-2-methylpyrido[3,2-c(]pynmidin-4-amine (Intermediate 16) in place of 2- chloropyrimidine-4-carboxamide and (R)-3-hydroxy-1 -methyl-3-(3-(5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)furan-2-yl)isoxazol-5-yl)pyrrolidin-2 -one (Intermediate 32) in place of (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one to afford (R)-3-(3-(5-(4-amino-2- methylpyrido[3,2-d]pyrimidin-6-yl)furan-2-yl)isoxazol-5-yl)- 3-hydroxy-1 -methylpyrrolidin- 2-one (55 mg, 22% yield) as a colorless solid. MS (ESI): Mass calcd. for C20H18N6O4, 406.40; m/z found, 407.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.22 (d, J = 8.8 Hz, 1 H), 8.06 (d, J = 8.8Hz, 1 H), 7.97 (br. s, 1 H), 7.91 (br. s, 1 H), 7.67 (d, J = 3.6 Hz, 1 H), 7.39 (d, J = 3.6 Hz, 1 H), 7.05 (s, 1 H), 6.79 (s, 1 H), 3.39-3.52 (m, 2H), 2.85 (s, 3H), 2.53-2.60 (m, 1 H), 2.46 (s, 3H), 2.25-2.32 (m, 1 H). Example 160: (R)-7-Fluoro-2-(3-(3-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-5- yl)phenyl)quinazoline-4-carboxamide.

Step A: Ethyl (R)-7-fluoro-2-(3-(3-(3-hydroxy-1-methyl-2-oxopyrrolidin-3- yl)isoxazol-5-yl)phenyl)quinazoline-4-carboxylate. The title compound was prepared in a manner analogous to Example 146 using ethyl 2-chloro-7-fluoroquinazoline-4- carboxylate in place of 2-chloropyrimidine-4-carboxamide and (R)-3-hydroxy-1 -methyl- 3-(5-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2- one (Intermediate 5) in place of (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one to afford ethyl (R)-7-fluoro- 2-(3-(3-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)quinazolin e-4- carboxamide (80 mg, 36% yield) as a yellow solid. MS (ESI): Mass calcd. for C25H21 FN4O5, 476.15; m/z found, 477 [M+H] ⁺ .

Step B: (R)-7-Fluoro-2-(3-(3-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-5- yl)phenyl)quinazoline-4-carboxamide. A solution of ethyl (R)-7-fluoro-2-(3-(3-(3-hydroxy- 1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)quinazolin e-4-carboxylate (68 mg, 0.14 mmol) in NH3 in MeOH (2 mL, 7 M, 14 mmol) was heated to 50 °C for 4 h. The reaction mixture was concentrated and purified by prep TLC (EtOAc) followed by reverse phase HPLC using a BOSTON pHlex ODS 21.1 x 250 mm 10 pm column and mobile phase A: water +0.1 % formic acid and B: ACN with a gradient 40-50% B over 8 min at 30 mL/min to afford (R)-7-fluoro-2-(3-(3-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-5-yl)phenyl)quinazoline-4-carboxamide (2.2 mg, 3% yield) as a colorless solid. MS (ESI): Mass calcd. for C23H18FN5O4, 447.42; m/z found, 448.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 9.00-9.10 (m, 2H), 8.75-8.85 (m, 2H), 8.22 (s, 1 H), 8.10 (d, J = 7.6 Hz, 1 H), 7.99 (dd, J = 2.4 and 6.0 Hz, 1 H), 7.60-7.80 (m, 2H), 7.27 (s, 1 H), 6.57 (s, 1 H), 3.30-3.50 (m, 2H), 2.82 (s, 3H), 2.63-2.75 (m, 1 H), 2.20-2.32 (m, 1 H). Example 161 : (R _; S)-2-(3-(3-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-5- yl)phenyl)pyrim idine-4-carboxam ide.

The title compound was prepared in a manner analogous to Example 160 using methyl 2-chloropyrimidine-4-carboxylate in place of ethyl 2-chloro-7-fluoroquinazoline-4- carboxylate and (R _; S)-3-hydroxy-1-methyl-3-(5-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one in place of (R)-3-hydroxy-1 - methyl-3-(5-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3- yl)pyrrolidin-2-one in Step A to afford (R,S)-2-(3-(3-(3-hydroxy-1 -methyl-2-oxopyrrolidin- 3-yl)isoxazol-5-yl)phenyl)pyrimidine-4-carboxamide (5 mg, 26%) as a yellow solid. MS (ESI): Mass calcd. for C19H17N5O4, 379.37; m/z found, 380 [M+H] ^{+ 1} HNMR (400 MHz, DMSO-cfe) 8 9.18 (d, J = 4.8 Hz, 1 H), 9.03 (s, 1 H), 8.82 (s, 1 H), 8.75 (d, J = 8.0 Hz, 1 H), 8.08 (s, 1 H), 8.06 (s, 1 H), 7.98 (d, J = 4.8 Hz, 1 H), 7.73 (t, J = 8.0 Hz, 1 H), 7.31 (s, 1 H), 6.54 (s, 1 H), 3.39-3.48 (m, 2H), 2.82 (s, 3H), 2.65-2.72 (m, 1 H), 2.22-2.29 (m, 1 H).

Example 162: (R)-4-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)pyrim idine-2-carboxam ide.

Step A: (R)-3-(3-(3-(2-Chloropyrimidin-4-yl)phenyl)isoxazol-5-yl)-3- hydroxy-1 - methylpyrrolidin-2-one. A mixture of (R)-3-hydroxy-1 -methyl-3-(3-(3-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 380 mg, 0.30 mmol), 2,4-dichloropyrimidine (66 mg, 0.45 mmol), potassium phosphate (189 mg, 0.89 mmol) and tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.015 mmol) in DMF (4 mL) and water (1 mL) was heated to 90 °C under and N2 atmosphere for 16 h. The reaction mixture was cooled to rt, filtered and purified by preparative HPLC (BOSTON PHlex C18 10 pm, 21 .2 x 250 mm, mobile phase (47% 0.1 % formic acid in water and ACN over 8 min, 14 min run, detection, UV at 25°C = 214/254 nM) to afford (R)-3-(3-(3-(2-chloropyrimidin-4-yl)phenyl)isoxazol-5-yl)-3- hydroxy-1-methylpyrrolidin-2-one (60 mg, 54% yield) as a colorless solid. MS (ESI): Mass calcd. for C18H15CIN4O3, 370.08; m/z found, 371 [M+H] ⁺ .

Step B: Methyl (R)-4-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)pyrimidine-2 -carboxylate. A mixture of (R)-3-(3-(3-(2-chloropyrimidin-4- yl)phenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (15 mg, 0.041 mmol), [1 ,1 ' -bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane (1.7 mg, 0.002 mmol) was heated to 60 °C under an atmosphere of CO(g) for 16 h. The mixture was filtered and concentrated to dryness to afford methyl (R)-4-(3-(5-(3- hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)pyrirnidin e-2 -carboxylate (15 mg, 94% yield) as a yellow solid. MS (ESI): Mass calcd. for C20H18N4O5, 394.12; m/z found, 395 [M+H] ⁺ .

Step C: (R)-4-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)pyrimidine-2-carboxamide. The title compound was prepared in a manner analogous to Example 166 Step B using methyl (R)-4-(3-(5-(3-hydroxy-1-methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)pyrimidine-2-carboxy late in place of (R)-ethyl 1 - (3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-1 /-/-indazole-3- carboxylate to afford (R)-4-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)pyrimidine-2 -carboxamide (2.5 mg, 17% yield) as a colorless solid. MS (ESI): Mass calcd. for C19H17N5O4, 379.13; m/z found, 380 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-c/e) 8 9.05 (d, J = 5.2 Hz, 1 H), 8.76 (s, 1 H), 8.53 (d, J = 9.2 Hz, 1 H), 8.46 (s, 1 H), 8.39 (d, J = 5.2 Hz, 1 H), 8.11 (d, J = 8.0 Hz, 1 H), 7.91 (s, 1 H), 7.74 (t, J = 8.0 Hz, 1 H), 7.26 (s, 1 H), 6.78 (s, 1 H), 3.40-3.52 (m, 2H), 2.86 (s, 3H), 2.52-2.62 (m, 1 H), 2.24- 2.35 (m, 1 H).

Example 163: (R)-3-(3-(3-(5/-/-Pyrrolo[2,3-b]pyrazin-7-yl)phenyl)isoxazol -5-yl)-3- hydroxy-1 -methylpyrrolidin-2-one.

Step A: (R)-3-Hydroxy-1 -methyl-3-(3-(3-(5-tosyl-5/-/-pyrrolo[2,3-b]pyrazin-7- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. The title compound was prepared in a manner analogous to Example 146 using 7-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5-tosyl- 5/-/-pyrrolo[2,3-b]pyrazine in place of 2-chloropyrimidine-4-carboxamide and (R)-3-(3-(3- bromophenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one in place of (R)-3- hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol- 5-yl)pyrrolidin-2-one to afford (R)-3-hydroxy-1 -methyl-3-(3-(3-(5-tosyl-5/-/-pyrrolo[2,3- b]pyrazin-7-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (160 mg, 51 % yield) as a colorless solid. MS (ESI): Mass calcd. for C27H23N5O5S, 529.14; m/z found, 530.2 [M+H] ⁺ .

Step B: ((R)-3-(3-(3-(5/-/-Pyrrolo[2,3-b]pyrazin-7-yl)phenyl)isoxazo l-5-yl)-3- hydroxy-1-methylpyrrolidin-2-one. A solution of (R)-3-hydroxy-1-methyl-3-(3-(3-(5-tosyl- 5/-/-pyrrolo[2,3-b]pyrazin-7-yl)phenyl)isoxazol-5-yl)pyrroli din-2-one (180 mg, 0.34 mmol), and aq. NaOH (2 mL, 1 M, 2 mmol) in THF (8 mL) and MeOH (2 mL) was stirred at 15 °C for 5 h and then diluted with EtOAc (30 mL) and washed with brine (2 x 15 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase HPLC on a Xtimate C18 10 pm, 21.2 x 250 mm column using 10 mM NH4HCO3 water + 0.025% NH3 and ACN; 5% B for 3 min then 30-35%B over 10 min to afford ((R)-3-(3-(3-(5/-/-pyrrolo[2,3-b]pyrazin-7-yl)phenyl)isoxazo l-5-yl)-3- hydroxy-1-methylpyrrolidin-2-one (37 mg, 29% yield) as a pale yellow solid. MS (ESI): Mass calcd. for C20H17N5O3, 375.39; m/z found, 376.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 82.30 (s, 1 H), 8.70 (s, 1 H), 8.61 (s, 1 H), 8.55 (d, J = 2.8 Hz, 1 H), 8.42 (d, J = 8.0 Hz, 1 H), 8.34 (d, J = 2.8 Hz, 1 H), 7.73 (d, J = 8.0 Hz, 1 H), 7.57 (t, J = 8.0 Hz, 1 H), 7.07 (s, 1 H), 6.75 (s, 1 H), 3.41-3.52 (m, 2H), 2.85 (s, 3H), 2.55-2.62 (m, 1 H), 2.25- 2.32 (m, 1 H).

Example 164: (R)-6-(5-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)furan- 2-yl)picolinamide.

Step A: (R)-Methyl 6-(5-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)furan-2-yl)picolinate. A mixture of (R)-3-(3-(5-(6-chloropyridin-2-yl)furan-2-yl)isoxazol- 5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (160 mg, 0.45 mmol, Intermediate 33), 1 ,1'- bis(diphenylphosphino) ferrocene-palladium(ll)dichloride dichloromethane complex (18 mg, 0.022 mmol) and triethylamine (90 mg, 0.89 mmol) in MeOH (30 mL) was heated at 60 °C under CO gas for 48 h. The reaction mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by prep-TLC (silica, UV-254, EtOAc) to afford (R)-methyl 6-(5-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)furan- 2-yl)picolinate (110 mg, 64%) as a yellow oil. MS (ESI): Mass calcd. for C19H17N3O6, 383.355; m/z found, 384.1 [M+H] ⁺ .

Step B: (R)-6-(5-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)furan-

2-yl)picolinamide. A mixture of (R)-methyl 6-(5-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-

3-yl)isoxazol-3-yl)furan-2-yl)picolinate (110 mg, 0.29 mmol) and 7 N NH3 in ethanol (8 mL) was heated at 75 °C for 16 h in a sealed tube. The reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC using Xtimate C18 10 μm, 21.2 x 250 mm column using a 20% to 45% gradient of ACN/ 10 mM NH4HCO3 and 0.025% NH ₃ «H ₂ O in H2O; 15 min gradient to afford (R)-6- (5-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)furan-2-yl)picoli namide (44 mg, 41 %) as a white solid. MS (ESI): Mass calcd. for C18H16N4O5, 368.343; m/z found, 369.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.36 (s, 1 H), 8.10 (t, J = 7.6 Hz, 1 H), 8.02 (d, J = 7.8 Hz, 1 H), 7.97 (d, J = 7.8 Hz, 1 H), 7.78 (s, 1 H), 7.72 (d, J = 3.6 Hz, 1 H), 7.38 (d, J = 3.6 Hz, 1 H), 7.02 (s, 1 H), 6.78 (s, 1 H), 3.39-3.52 (m, 2H), 2.85 (s, 3H), 2.53-2.60 (m, 1 H), 2.25-2.32 (m, 1 H).

Example 165: (R,S)-6-(5-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)furan-2-yl)picolinamide.

Step A: 3-(5-(3-(8-Chloropyrido[3,4-c/]pyrimidin-2-yl)phenyl)isoxazo l-3-yl)-3- hydroxy-1-methylpyrrolidin-2-one. To a suspension of 8-chloro-2-(methylthio)pyrido[3,4- c/]pyrimidine (60 mg, 0.28 mmol), (3-(3-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-5-yl)phenyl)boronic acid (103 mg, 0.34 mmol, Intermediate 36), and copperthiophenecarboxylate (108 mg, 0.57 mmol) in THF (8 mL) was added bis(dibenzylideneacetone)palladium(0) (26 mg, 0.028mmol), followed by tri(2- furyl)phosphine (7 mg, 0.028 mmol) under argon. The reaction mixture was heated in a microwave at 80 °C for 4 h. The reaction mixture was diluted with EtOAc (20 mL) and filtered. The filtrate was concentrated and purified by prep-TLC (DCM:MeOH, 20:1 ) to afford 3-(5-(3-(8-chloropyrido[3,4-c/]pyrimidin-2-yl)phenyl)isoxazo l-3-yl)-3-hydroxy-1- methylpyrrolidin-2-one (70 mg, 59% yield) as a yellow solid. MS (ESI): Mass calcd. for C21 H16CIN5O3, 421.09; m/z found, 422.1 [M+H] ⁺ .

Step B: (R, S)-6-(5-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)furan-2-yl)picolinamide. A solution of 3-(5-(3-(8-chloropyrido[3,4-c/]pyrimidin-2- yl)phenyl)isoxazol-3-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (60 mg, 0.14 mmol) in dioxane (2 mL) was treated with NH3 in water (6 mL, 12 M, 72 mmol) and then heated at 70 °C for 16 h. The reaction mixture was cooled to rt, concentrated to dryness and purified by reverse phase HPLC BOSTON pHlex ODS 21.1 x 250 mm 10 pm using mobile phase A: water +0.1 % Formic acid and B: ACN with a gradient 40-50%B over 8 min at 30 mL/min to afford (R,S)-6-(5-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)furan-2-yl)picolinamide (5.6 mg, 10% yield). MS (ESI): Mass calcd. for C21 H18N6O3, 402.41 ; m/z found, 403.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 9.57 (s, 1 H), 9.09 (s, 1 H), 8.81 (d, J = 8.0 Hz, 1 H), 8.04 (d, J = 8.0 Hz, 1 H), 8.03 (d, J = 5.6 Hz, 1 H), 7.73 (t, J = 8.0 Hz, 1 H), 7.56 (s, 2H), 7.33 (s, 1 H), 7.05 (d, J = 5.6 Hz, 1 H), 6.54 (s, 1 H), 3.40-3.49 (m, 2H), 2.81 (s, 3H), 2.65-2.72 (m, 1 H), 2.22-2.29 (m, 1 H). Example 166: (R)-1 -(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- y I ) ph eny I )- 1 H-indazole-3-carboxam ide.

Step A: (R)-Ethyl 1 -(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-1 H-indazole-3-carboxylate. A mixture of ethyl 1 /-/-indazole-3-carboxylate (103 mg, 0.55 mmol), (R)-3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3 - yl)phenylboronic acid (110 mg, 0.36 mmol), Cu(OAc)2 (66.139 mg, 0.364 mmol) and molecular sieves (500 mg) in chloroform (8 mL) and pyridine (144 mg, 1.82 mmol) was heated at 40 °C for 72 h under O2. The mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/EtOAc=3/1 ) to afford (R)-ethyl 1 -(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-1 H- indazole-3-carboxylate (55 mg, 34%) as a white solid. MS (ESI): Mass calcd. for C24H22N4O5, 446.45; m/z found, 447.1 [M+H] ⁺ .

Step B: (R)-1 -(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-1 /-/-indazole-3-carboxamide. To a sealed tube containing (R)-ethyl 1 -(3-(5-(3- hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-1 /-/-indazole-3-carboxylate (55 mg, 0.12 mmol) was added ammonia (7 N in methanol) (8 mL). The mixture was heated at 75 °C for 16 h and concentrated to dryness. The residue was purified by reverse phase HPLC on a Xtimate C18 10 pm, 21.2 x 250 mm column using a 20% to 45% gradient of ACN/ 10 mM NH4HCO3 and 0.025% NHs’FhO in H2O; 15 min gradient to afford (R)-1 -(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-1 H- indazole-3-carboxamide (15.2 mg, 30%) as a white solid. MS (ESI): Mass calcd. for C22H19N5O4, 417.42; m/z found, 418.1 [M+H] ⁺ . ¹ H NMR(400 MHz, DMSO-d ₆ ) 8 8.31 - 8.33 (m, 2H), 7.99 - 8.05 (m, 3H), 7.93 (d, J = 8.0 Hz, 1 H), 7.78 (t, J = 8.0 Hz, 1 H), 7.56 - 7.60 (m, 2H), 7.41 (t, J = 8.0 Hz, 1 H), 7.18 (s, 1 H), 6.76 (s, 1 H), 3.43-3.49 (m, 2H), 2.84 (s, 3H), 2.54 - 2.61 (m, 1 H), 2.25 - 2.32 (m, 1 H). Example 167: (R,S)-1 -(3-(3-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-5- y I ) ph eny I )- 1 H-indazole-3-carboxam ide.

The title compound was prepared in a manner analogous to Example 166 using (R, S)-(3-(3-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)boronic acid (Intermediate 36) in place of (R)-3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol- 3-yl)phenylboronic acid in Step A to afford (R,S)-1 -(3-(3-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-5-yl)phenyl)-1 /-/-indazole-3-carboxamide. MS (ESI): Mass calcd. for C22H19N5O4, 417.42; m/z found, 418.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 5 8.31 -8.35 (m, 2H), 7.95-8.08 (m, 4H), 7.80 (t, J = 7.6 Hz, 1 H), 7.57-7.61 (m, 2H), 7.42 (t, J = 7.6 Hz, 1 H), 7.28 (s, 1 H), 6.53 (s, 1 H), 3.37-3.49 (m, 2H), 2.81 (s, 3H), 2.64-2.70 (m, 1 H), 2.22-2.29 (m, 1 H).

Example 168: (R)-4'-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)-[2,2'- bipyridine]-6-carboxamide.

A solution of 6-(tributylstannyl)picolinamide (100 mg, 0.24 mmol, Intermediate 40), (R)-3-(3-(2-bromopyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (Intermediate 7, 82 mg, 0.24 mmol) and tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.012 mmol) in DMF (2 mL) was heated to 125 °C for 16 h under N2. The mixture was filtered, concentrated, and the residue was purified by reverse phase HPLC on a Xtimate C18 10 pm, 21.2 x 250 mm column using 10 mM NH4HCO3 water + 0.025% NH3 and ACN; 5% B for 3 min then 30-35% B over 10min to afford (R)-4'-(5-(3-hydroxy- 1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)-[2,2'-bipyridine ]-6-carboxamide (16 mg, 18% yield) as a colorless solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 9.08 (s, 1 H), 8.50 (d, J = 4.8 Hz, 1 H), 8.71 (s, 1 H), 8.20 (d, J = 6.0 Hz, 1 H), 8.10-8.20 (m, 2H), 7.98 (d, J = 8.8 Hz, 1 H), 7.83 (s, 1 H), 7.49 (s, 1 H), 6.84 (s, 1 H), 3.40-3.50 (m, 2H), 2.86 (s, 3H), 2.60-2.65 (m, 1 H), 2.20-2.40 (m, 1 H).

Example 169: (R)-5-Amino-4'-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)i soxazol-3-yl)- [2,2'-bipyridine]-6-carboxamide.

The title compound was prepared analogous to Example 168 using 3-amino-6- (tributylstannyl)picolinamide (Intermediate 41 ) in place of 6-(tributylstannyl)picolinamide to afford (R)-5-amino-4'-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)-[2,2'- bipyridine]-6-carboxamide (6 mg, 7% yield) as a colorless solid. MS (ESI): Mass calcd. for C19H18N6O4, 394.39; m/z found, 395 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.80 (s, 1 H), 8.71 (d, J = 4.8 Hz, 1 H), 8.46 (s, 1 H), 8.31 (d, J = 8.4 Hz, 1 H), 7.78 (dd, J = 1 .6, 4.8 Hz, 1 H), 7.50 (s, 1 H), 7.47 (s, 1 H), 7.16-7.35 (m, 3H), 6.80 (s, 1 H), 3.40-3.53 (m, 2H), 2.85 (s, 3H), 2.50-2.60 (m, 1 H), 2.25-2.35 (m, 1 H).

Example 170: (R)-3-(3-(2-(4-Amino-2-methylpyrido[3,2-c(]pynmidin-6-yl)pyn din-4- yl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one.

The title compound was prepared analogous to Example 168 using 6-chloro-2- methylpyrido[3,2-c/]pyrimidin-4-amine (Intermediate 16) in place of 6- (tributy Istanny l)picolinam ide and (R)-3-hydroxy-1 -methyl-3-(3-(2-(tributylstannyl)pyridin- 4-yl)isoxazol-5-yl)pyrrolidin-2-one in place of (R)-3-(3-(2-bromopyridin-4-yl)isoxazol-5- yl)-3-hydroxy-1 -methylpyrrolidin-2-one to afford (R)-3-(3-(2-(4-amino-2- methylpyrido[3,2-d]pyrimidin-6-yl)pyridin-4-yl)isoxazol-5-yl )-3-hydroxy-1 - methylpyrrolidin-2-one (5 mg, 2% yield) as a colorless solid. MS (ESI): Mass calcd. for C21 H19N7O3, 417.43; m/z found, 418 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 9.17 (s, 1 H), 8.85 (d, J = 5.2 Hz, 1 H), 8.79 (d, J = 9.2 Hz, 1 H), 8.43 (s, 1 H), 8.11 (d, J = 9.2 Hz, 1 H), 8.05 (s, 1 H), 7.96 (d, J = 5.2 Hz, 1 H), 7.48 (s, 1 H), 6.84 (s, 1 H), 3.44-3.53 (m, 2H), 2.86 (s, 3H), 2.56-2.61 (m, 1 H), 2.48 (s, 3H), 2.30-2.35 (m, 1 H).

Example 171 : (5R,8S)-2-(3-(5-((R)-3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-6,7,8,9-tetrahydro-5/-/-5,8-epoxycyclohepta[c/]py rimidine-4-carboxamide.

Step A: (5R,8S)-2-(3-((E)-(Hydroxyimino)methyl)phenyl)-6,7,8,9-tetra hydro-5/-/- 5,8-epoxycyclohepta[d]pyrimidine-4-carboxamide. To a solution of (5R,8S)-2-(3- formylphenyl)-6,7,8,9-tetrahydro-5/-/-5,8-epoxycyclohepta[c/ ]pyrimidine-4-carboxamide (200 mg, 0.647 mmol, Intermediate 37) in EtOH (8 mL) was added NH2OH (50% in H2O) (25.6 mg, 0.776 mmol). The mixture was stirred at 30 °C for 4 h. The mixture was concentrated to afford the title compound (202 mg, 96% yield). MS (ESI): Mass calcd. for C17H16N4O3, 324.3; m/z found, 324.8 [M+H] ⁺ .

Step B: (5R,8S)-2-(3-(5-((R)-3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-6,7,8,9-tetrahydro-5/-/-5,8-epoxycyclohepta[c/]py rimidine-4-carboxamide. N- Chlorosuccinimide (82.3 mg, 0.617 mmol) was added portion wise to a solution of (5R,8S)-2-(3-((E)-(hydroxyimino)methyl)phenyl)-6,7,8,9-tetra hydro-5/-/-5,8- epoxycyclohepta[c/]pyrimidine-4-carboxamide (100 mg, 0.308 mmol) in dry dichloromethane (4 mL) and the reaction mixture was heated at 30 °C for 16 h. Then (R)-3-ethynyl-3-hydroxy-1 -methylpyrrolidin-2-one (Intermediate 1 , 42.9 mg, 0.308 mmol) and TEA (93.422 mg, 0.925 mmol) was added. The mixture was heated at 40 °C for 3 h. The mixture was concentrated and purified by reverse phase HPLC on a Xtimate 10 pm 150A, 21 .2 x 250 mm column using a 5 to 40% gradient of MeCN/ 10 mM NH4HCO3 and 0.025% NHs’FW in H2O; 18 min gradient to afford the title compound as a white solid (11.5 mg, 8.1 %). MS (ESI): Mass calcd. for C24H23N5O5, 461.47; m/z found, 461.8 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.90 (s, 1 H), 8.66 (d, J = 8.0 Hz, 1 H), 8.62 (s, 1 H), 8.04 (d, J = 8.0 Hz, 1 H), 7.96 (s, 1 H), 7.68 (t, J = 8.0 Hz, 1 H), 7.16 (s, 1 H), 6.76 (s, 1 H), 5.90 (d, J = 6.0 Hz, 1 H), 4.80 (t, J = 6.0 Hz, 1 H), 3.33-3.52 (m, 2H), 2.80-2.90 (m, 1 H), 2.85 (s, 3H), 2.55-2.70 (m, 1 H), 2.07-2.32 (m, 4H), 1.78 (br. s, 1 H), 1.24 (br. s, 1 H).

Example 172: (5R,8S)-2-(3-(5-((S)-3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-6,7,8,9-tetrahydro-5/-/-5,8-epoxycyclohepta[c/]py rimidine-4-carboxamide.

The title compound was prepared in a manner analogous to Example 171 Step B using (S)-3-ethynyl-3-hydroxy-1 -methylpyrrolidin-2-one in place of (R)-3-ethynyl-3- hydroxy-1-methylpyrrolidin-2-one to afford (5R,8S)-2-(3-(5-((S)-3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-6,7,8,9-tetrahydro- 5/-/-5,8- epoxycyclohepta[c/]pyrimidine-4-carboxamide (20 mg, 6% yield) as a colorless solid. MS (ESI): Mass calcd. for C24H23N5O5, 461.47; m/z found, 462.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-c/e) 88.90 (s, 1 H), 8.67 (d, J = 8.0 Hz, 1 H), 8.63 (s, 1 H), 8.05 (d, J = 6.4 Hz, 1 H), 7.97 (s, 1 H), 7.67 (t, J = 8.0 Hz, 1 H), 7.16 (d, J = 2.0 Hz, 1 H), 6.75 (d, J = 2.0 Hz, 1 H), 5.89 (d, J = 2.4 Hz, 1 H), 4.81 (t, J = 6.4 Hz, 1 H), 3.38-3.51 (m, 3H), 2.82-2.86 (m, 4H), 2.55-2.62 (m, 1 H), 2.26-2.32 (m, 1 H), 2.16-2.25 (m, 2H), 2.05-2.10 (m, 1 H), 1.76-1.78 (m, 1 H).

Example 173: (5R,8S)-2-(3-(5-((R)-3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 /-/-pyrazol- 3-yl)phenyl)-6,7,8,9-tetrahydro-5/-/-5,8-epoxycyclohepta[c/] pyrimidine-4-carboxamide.

To a solution of p-toluenesulfonyl hydrazide (18 mg, 0.097 mmol) in ACN (3 mL) was added (5R,8S)-2-(3-formylphenyl)-6,7,8,9-tetrahydro-5/-/-5,8-epoxy cyclohepta[c/] pyrimidine-4-carboxamide (30 mg, 0.097 mmol, Example 174 Step A) and the reaction mixture was stirred at rt for 3 h. An aqueous solution of NaOH (5 N, 0.02 mL) was then added. The mixture was stirred for 20 min and (R)-3-ethynyl-3-hydroxy-1 - methylpyrrolidin-2-one (Intermediate 1 , 40.5 mg, 0.291 mmol) was added and heating was continued at 50 °C for 16 h. The crude reaction mixture was concentrated and purified by reverse phase HPLC on an Xtimate 10 pm 150A, 21.2 x 250 mm column using 30% t of ACN/ 10 mM NH4HCO3 and 0.025% NHs’FW in H2O; 10 min gradient to afford (5R,8S)-2-(3-(5-((R)-3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 /-/- pyrazol-3-yl)phenyl)-6,7,8,9-tetrahydro-5/-/-5,8-epoxycycloh epta[c/]pyrimidine-4- carboxamide (2 mg, 4.4%) as a yellow solid. MS (ESI): Mass calcd. For C24H24N6O4, 460.485; m/z found, 460.7 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCI3) 8 8.69 (s, 1 H), 8.18 (s, 2H), 7.52 (s, 1 H), 7.34-7.48 (m, 2H), 6.61 (s, 1 H), 6.29 (s, 1 H), 6.15 (s, 1 H), 4.84 (s, 1 H), 3.38-3.52 (m, 3H), 2.89 (s, 3H), 2.62-2.78 (m, 2H), 2.55 (s, 1 H), 2.20-2.42 (m, 2H), 2.12-2.20 (m, 1 H), 1.60-1.85 (m, 2H)

Example 174: (5R,8S)-2-(3-(5-((R)-3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 /-/-pyrazol- 3-yl)phenyl)-6,7,8,9-tetrahydro-5/-/-5,8-epoxycyclohepta[c/] pyrimidine-4-carboxamide. Step A: (5R,8S)-2-(3-Formylphenyl)-6,7,8,9-tetrahydro-5/-/-5,8- epoxycyclohepta[d] pyrimidine-4-carboxamide. To a solution of (5R,8S)-2-(3- vinylphenyl)-6,7,8,9-tetrahydro-5/-/-5,8-epoxycyclohepta[c/] pyrimidine-4-carboxamide (260 mg, 0.85 mmol, Intermediate 37 Step A) in f-BuOH (6 mL), THF (4 mL) and H2O (3 mL) was added N-methylmorpholine N-oxide (119 mg, 1 .02 mmol) followed by OsCM (11 mg, 0.042 mmol). The reaction mixture was stirred at rt for 7 h and then NaHCOs (852 mg, 10.151 mmol), NalCM (579 mg, 2.71 mmol) and H2O (2 mL) were subsequently added. The mixture was stirred for 45 min and then poured into sat. aq. Na2SOs. The aqueous phase was extracted with ether, dried (MgSCM), filtered and concentrated. The residue was purified by prep-TLC (DCM/MeOH=40/1 , silica, UV=254 nm) to afford (5R,8S)-2-(3-formylphenyl)-6,7,8,9-tetrahydro-5/-/-5,8-epoxy cyclohepta[c(] pyrimidine-4- carboxamide (200 mg, 76.4%) as a white solid. MS (ESI): Mass calcd. for C17H15N3O3, 309.3; m/z found, 310.2 [M+H] ⁺ .

Step B: (5R,8S)-2-(3-(5-((R)-3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)-1 /-/-pyrazol- 3-yl)phenyl)-6,7,8,9-tetrahydro-5/-/-5,8-epoxycyclohepta[d]p yrimidine-4-carboxamide. To a solution of p-toluenesulfonyl hydrazide (24 mg, 0.13 mmol) in ACN (3 mL), was added (5R,8S)-2-(3-formylphenyl)-6,7,8,9-tetrahydro-5/-/-5,8-epoxy cyclohepta[c(]pyrimidine-4- carboxamide (40 mg, 0.13 mmol, Intermediate 37) and the mixture was stirred at rt for 3 h. A solution of aqueous NaOH (5 N, 0.12 mmol) was added. The mixture was stirred for 20 min and (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 1 , 90 mg, 0.65 mmol) was added, and the stirring was continued at 50 °C for 16 h. The mixture was concentrated and purified by reverse phase HPLC on a Xtimate 10 pm 150 A, 21.2 x 250 mm column using a 30 to 60% gradient of ACN/ 10 mM NH4HCO3 and 0.025% NH3*H2O in H2O; 10 min gradient to afford (5R,8S)-2-(3-(5-((S)-3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)-1 /-/-pyrazol-3-yl)phenyl)-6,7,8,9-tetrahydro-5/-/-5,8- epoxycyclohepta[c/]pyrimidine-4-carboxamide (7.2 mg, 11.7%) as an off-white solid. MS (ESI): Mass calcd. For C24H24N6O4, 460.485; m/z found, 460.9 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCI3) 8 8.67 (s, 1 H), 8.15 (s, 2H), 7.49 (s, 1 H), 7.29-7.40 (m, 1 H), 6.61 (s, 1 H), 6.32 (s, 1 H), 6.11 (s, 1 H), 4.85 (s, 1 H), 3.30-3.52 (m, 3H), 2.89 (s, 3H), 2.62-2.80 (m, 2H), 2.50- 2.60 (m, 1 H), 2.30-2.50 (m, 2H), 2.20-2.30 (m, 1 H), 1 .60-1 .80 (m, 2H). Example 175: (R)-3-(5-(3-(7-Aminothiazolo[5,4-c(]pyrimidin-2-yl)-4- methylphenyl)isoxazol-3-yl)-3-hydroxy-1-methylpyrrolidin-2-o ne.

Step A: /V-(4,6-Dichloropyrimidin-5-yl)-5-iodo-2-methylbenzamide. A solution of 4,6-dichloropyrimidin-5-amine (1.2 g, 7.49 mmol) in NMP was treated with 5-iodo-2- methylbenzoyl chloride (2.1 g, 7.49 mmol) at 0 °C. The reaction mixture was then heated to 70 °C for 16 h, poured into water (50 mL), and the precipitated material was isolated by filtration to afford /V-(4,6-dichloropyrimidin-5-yl)-5-iodo-2-methylbenzamide (2.6 g, 85% yield) as a colorless solid. MS (ESI): Mass calcd. For C12H8CI2IN3O, 406.91 ; m/z found, 408 [M+H] ⁺ .

Step B: 2-(5-lodo-2-methylphenyl)thiazolo[5,4-c(]pyrimidine-7 -thiol . A solution of N-(4,6-dichloropyrimidin-5-yl)-5-iodo-2-methylbenzamide (2.20 g, 5.39 mmol) and Lawesson’s Reagent (2.18 g, 5.39 mmol) in toluene (60 mL) was heated to reflux for 16 h. The product was isolated by filtration and the solid was washed with toluene (20 mL) to afford 2-(5-iodo-2-methylphenyl)thiazolo[5,4-c(]pyrimidine-7 -thiol (1.5 g, 72% yield) as a yellow solid. MS (ESI): Mass calcd. For C12H8IN3S2, 384.92; m/z found, 386 [M+H] ⁺ .

Step C: 2-(5-lodo-2-methylphenyl)-7-(methylthio)thiazolo[5,4-c/]pyri midine. A solution of 2-(5-iodo-2-methylphenyl)thiazolo[5,4-d]pyrimidine-7-thiol (1.4 g, 3.63 mmol) and DIEA (1.25 mL, 0.75 g/mL, 7.27 mmol) was treated with methyl iodide (0.68 mL, 2.28 g/mL, 10.90 mmol). The reaction mixture was stirred for 16 h at rt, poured into water (300 mL) and the precipitate was collected by filtration and washed with water (30 mL), followed by MeOH (10 mL) to afford 2-(5-lodo-2-methylphenyl)-7- (methylthio)thiazolo[5,4-c(]pyrimidine (1.0 g, 69% yield) as a yellow solid. MS (ESI): Mass calcd. For C13H10IN3S2, 399.27; m/z found, 400 [M+H] ⁺ .

Step D: Methyl 4-methyl-3-(7-(methylthio)thiazolo[5,4-d]pyrimidin-2-yl)benz oate. A mixture of 2-(5-iodo-2-methylphenyl)-7-(methylthio)thiazolo[5,4-c(]pyri midine (620 mg, 1.55 mmol), Rd(dppf)Cl2«CH ₂ Cl2 (63 mg, 0.078 mmol), and TEA (0.43 mL, 0.73 g/mL, 3.11 mmol) in MeOH (40 mL) was heated to 60 °C for 48 h under CO(g). The mixture was concentrated to dryness and purified by FCC (DCM:MeOH, 20:1 ) to afford methyl 4-methyl-3-(7-(methylthio)thiazolo[5,4-c/]pyrimidin-2-yl)ben zoate (350 mg, 68% yield) as a colorless solid. MS (ESI): Mass calcd. For C15H13N3O2S2, 331.04; m/z found, 332 [M+H] ⁺ .

Step E: 4-Methyl-3-(7-(methylthio)thiazolo[5,4-c/]pynmidin-2-yl)benz oic acid. A solution of methyl 4-methyl-3-(7-(methylthio)thiazolo[5,4-c/]pyrimidin-2-yl)ben zoate (150 mg, 0.45 mmol) and sodium hydroxide (36 mg, 0.91 mmol) in MeOH (5 mL) and water (2.5 mL) was stirred at rt for 1 h. The reaction mixture was partially concentrated, diluted with water (2 mL), and treated with 1 M HCI(aq) until a precipitate was formed. The solid was filtered and washed with water to afford 4-methyl-3-(7-(methylthio)thiazolo[5,4- d]pyrimidin-2-yl)benzoic acid (140 mg, 71 % yield) as a colorless solid. MS (ESI): Mass calcd. For C14H11N3O2S2, 317.03; m/z found, 318.0 [M+H] ⁺ .

Step F: 4-Methyl-3-(7-(methylthio)thiazolo[5,4-c(]pyrimidin-2-yl)ben zoyl chloride. A solution of 4-methyl-3-(7-(methylthio)thiazolo[5,4-c(]pyrimidin-2-yl)ben zoic acid (140 mg, 0.44 mmol) in thionyl chloride (3 mL, 1 .64 g/mL, 41 .36 mmol) was heated to 80 °C for 2 h. The reaction mixture was concentrated to dryness to afford 4-methyl-3-(7- (methylthio)thiazolo[5,4-c(]pyrimidin-2-yl)benzoyl chloride as a yellow oil. MS (ESI): Mass calcd. For C14H10CIN3OS2, 334.00; m/z found, 332.0 [M-CI +OH] ⁺ .

Step G: (R)-3-Hydroxy-1 -methyl-3-(3-(4-methyl-3-(7-(methylthio)thiazolo[5,4- d]pyrimidin-2-yl)phenyl)-3-oxoprop-1-yn-1-yl)pyrrolidin-2-on e. To a solution of (R)-3- ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 1 , 46 mg, 0.33 mmol) at -20 °C, was added bis(triphenylphosphine)palladium(ll) dichloride (9.2 mg, 0.13 mmol) followed by copper(l)iodide (3.1 mg, 0.016 mmol) and TEA. After 5 min, a solution of 4- methyl-3-(7-(methylthio)thiazolo[5,4-d]pyrimidin-2-yl)benzoy l chloride (110 mg, 0.33 mmol) in THF (5 mL) was added dropwise and the mixture was allowed to warm to 0 °C and stirred for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, concentrated and the residue was purified by FCC (DCM:MeOH, 100:1 ) to afford (R)-3-hydroxy-1-methyl-3-(3-(4-methyl-3-(7- (methylthio)thiazolo[5,4-c(]pyrimidin-2-yl)phenyl)-3-oxoprop -1-yn-1-yl)pyrrolidin-2-one (500 mg, 81 % yield) as a yellow solid. MS (ESI): Mass calcd. For C21 H18N4O3S2, 438.08; m/z found, 439.0 [M+H] ⁺ .

Step H. (R)-3-Hydroxy-1 -methyl-3-(5-(4-methyl-3-(7-(methylthio)thiazolo[5,4- d]pyrimidin-2-yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one. A solution of (R)-3-hydroxy-1 - methyl-3-(3-(4-methyl-3-(7-(methylthio)thiazolo[5,4-c(]pyrim idin-2-yl)phenyl)-3-oxoprop- 1-yn-1-yl)pyrrolidin-2-one (50 mg, 0.11 mmol) and sodium azide (37 mg, 0.57 mmol) in DCM (2 mL) was cooled to 0 °C and treated with AcOH (0.033 mL, 0.57 mmol) followed by TEA (0.003 mL, 0.02 mmol). The reaction mixture was allowed to warm to rt, stirred for 16 h and then treated with sat. aq. NaHCO3 (5 mL) for 10 min. The organic layer was separated and the aqueous layer was further extracted with DCM (2 x 10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated using a stream of N2 and purified by FCC (DCM:MeOH, 50:1 ) to afford (R)-3-hydroxy-1-methyl-3-(5-(4- methyl-3-(7-(methylthio)thiazolo[5,4-c/]pyrimidin-2-yl)pheny l)isoxazol-3-yl)pyrrolidin-2- one (30 mg, 73% yield) as a yellow oil. MS (ESI): Mass calcd. For C21 H19N5O3S2, 453.09; m/z found, 454.0 [M+H] ⁺ .

Step I. (R)-3-(5-(3-(7-aminothiazolo[5,4-d]pyrimidin-2-yl)-4- methylphenyl)isoxazol-3-yl)-3-hydroxy-1 -methylpyrrolidin-2-one. A solution of (R)-3- hydroxy-1-methyl-3-(5-(4-methyl-3-(7-(methylthio)thiazolo[5, 4-c/]pyrimidin-2- yl)phenyl)isoxazol-3-yl)pyrrolidin-2-one (30 mg, 0.066 mmol) in NH3 in MeOH (5 mL, 7 M, 35 mmol) was heated to 75 °C for 48 h in a sealed tube. The reaction mixture was cooled to rt, concentrated and purified by reverse phase HPLC Xtimate C18 2 x 250 mm 10 pm using mobile phase A: 10 mM NH4CO3 in water +0.1 % 0.025% NH4OH and B: ACN with a gradient 5% B for 3 min then 5-40% B over 7 min at 30 mL/min to afford (R)-3-(5-(3-(7-aminothiazolo[5,4-d]pyrimidin-2-yl)-4-methylp henyl)isoxazol-3-yl)-3- hydroxy-1 -methylpyrrolidin-2-one (3.3 mg, 11 % yield) as a colorless solid. MS (ESI): Mass calcd. for C23H18FN5O4, 447.42; m/z found, 448.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-c/e) 88.36 (s, 1 H), 8.26 (d, J = 2 Hz, 1 H), 7.96 (dd, J = 1.6, 8.0 Hz, 1 H), 7.83 (s, 2H), 7.61 (d, J = 8 Hz, 1 H), 7.19 (s, 1 H), 6.51 (s, 1 H), 3.38-3.45 (m, 2H), 2.81 (s, 3H), 2.69 (s, 3H), 2.63-2.67 (m, 1 H), 2.23-2.27 (m, 1 H). Example 176: (R _; S)-3-(5-(3-((7-Aminothiazolo[5,4-c/]pyrimidin-2- yl)amino)phenyl)isoxazol-3-yl)-3-hydroxy-1 -methylpyrrolidin-2-one.

Step A: (R, S)-3-Hydroxy-3-(5-(3-isothiocyanatophenyl)isoxazol-3-yl)-1 - methylpyrrolidin-2-one. To a solution of (R,S)-3-(5-(3-aminophenyl)isoxazol-3-yl)-3- hydroxy-1-methylpyrrolidin-2-one (60 mg, 0.22 mmol, Intermediate 35) in THF (10 mL) at 0 °C, was added ice (100 mg), followed by thiophosgene (0.034 mL, 0.44 mmol). The reaction mixture was stirred at 0 °C for 2 h, transferred to a separatory funnel and washed with water (2 x 15 mL) followed by sat. aq. NaHCOs (15 mL). The organic layer was dried (Na2SO4), filtered and concentrated at 20 °C to afford (R,S)-3-hydroxy-3-(5- (3-isothiocyanatophenyl)isoxazol-3-yl)-1 -methylpyrrolidin-2-one (65 mg, 94% yield) as a yellow oil. MS (ESI): Mass calcd. for C15H13N3O3S, 315.07; m/z found, 316.1 [M+H] ⁺ .

Step B: (R _; S)-3-(5-(3-((7-Chlorothiazolo[5,4-d]pynmidin-2- yl)amino)phenyl)isoxazol-3-yl)-3-hydroxy-1 -methylpyrrolidin-2-one. To a solution of (R,S)-3-hydroxy-3-(5-(3-isothiocyanatophenyl)isoxazol-3-yl)- 1 -methylpyrrolidin-2-one (65 mg, 0.21 mmol) in ACN (6 mL) was added 4,6-dichloropyrimidin-5-amine (100 mg, 0.62 mmol), followed by CS2CO3 (269 mg, 0.82 mmol). The reaction mixture was heated to 50 °C for 2 h, cooled to rt and the solid was removed by filtration. The filter cake was washed with ACN (5 mL) and the filtrate was concentrated and purified by prep-TLC (DCM:MeOH, 20:1 ) to afford (R _; S)-3-(5-(3-((7-chlorothiazolo[5,4-c/]pyrimidin-2- yl)amino)phenyl)isoxazol-3-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (30 mg, 33% yield) as a yellow oil. MS (ESI): Mass calcd. for C19H15CIN6O3S, 442.06; m/z found, 442.9 [M+H] ⁺ .

Step C. (R _; S)-3-(5-(3-((7-Aminothiazolo[5,4-d]pyrimidin-2- yl)amino)phenyl)isoxazol-3-yl)-3-hydroxy-1 -methylpyrrolidin-2-one. A solution of (R,S)~ 3-(5-(3-((7-chlorothiazolo[5,4-d]pyrimidin-2-yl)amino)phenyl )isoxazol-3-yl)-3-hydroxy-1- methylpyrrolidin-2-one (30 mg, 0.067 mmol) in NH3 in EtOH (5 mL, 7 M, 35 mmol) was heated to 75 °C for 16 h in a sealed tube. The reaction mixture was cooled to rt, concentrated and purified by reverse phase HPLC Xtimate C18 2 x 250 mm 10 pm using mobile phase A: 10 mM NH4CO3 in water +0.1 % (0.025% NH4OH) and B: ACN with a gradient 5% B for 3 min then 5-40% B over 7 min at 30 mL/min to afford (R,S)-3- (5-(3-((7-aminothiazolo[5,4-c/]pyrimidin-2-yl)amino)phenyl)i soxazol-3-yl)-3-hydroxy-1 - methylpyrrolidin-2-one (5.1 mg, 18% yield) as a colorless solid. MS (ESI): Mass calcd. for C19H17N7O3S, 423.46; m/z found, 424.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 10.78 (s, 1 H), 8.40 (d, J = 6.8 Hz, 1 H), 8.14 (s, 1 H), 7.87 (s, 1 H), 7.48-7.52 (m, 2H), 7.18 (br. s, 2H), 7.06 (s, 1 H), 6.51 (s, 1 H), 3.36-3.48 (m, 2H), 2.81 (s, 3H), 2.64-2.70 (m, 1 H), 2.20-2.28 (m, 1 H).

Example 177: (R)-3-Amino-4-cyclopropyl-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl-4,4,5,5-c/4)isoxazol-3-yl)phenyl)picolinamide,

(R)-3-Amino-4-cyclopropyl-6-(3-(5-(3-hydroxy-1-methyl-2-o xopyrrolidin-3-yl- 4,4,5,5-c/4)isoxazol-3-yl)phenyl)picolinamide (27 mg) was prepared in a manner analogous to Example 23, using (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one -4,4,5,5-c/4 (Intermediate 47) and 3-amino-6-chloro-4-cyclopropylpicolinamide (Example 88 Step A) instead of (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one and 1 -bromoimidazo[1 ,5-a]pyridine-3- carboxamide. MS (ESI): Mass calcd. for C23H23N5O4437.49 m/z found 438.30 [M+H] ⁺ . ¹ H NMR (400 MHz, CD3OD) 8 8.44 (t, J = 1.8 Hz, 1 H), 8.08 (dt, J = 8.1 , 1.3 Hz, 1 H), 7.77 (dt, J = 7.7, 1 .3 Hz, 1 H), 7.63 (d, J = 0.9 Hz, 1 H), 7.54 (t, J = 7.8 Hz, 1 H), 7.00 (s, 1 H), 2.96 (s, 3H), 1.88 - 1.71 (m, 1 H), 1.18 - 1.00 (m, 2H), 0.81 - 0.67 (m, 2H). Example 178: 3-Amino-4-cyclopropyl-6-(3-(5-((3R,5S)-3-hydroxy-1 -methyl-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)isoxazol-3-yl)phenyl)picoli namide

3-Amino-4-cyclopropyl-6-(3-(5-((3R,5S)-3-hydroxy-1 -methyl-2-oxo-5- (trifluoromethyl)pyrrolidin-3-yl)isoxazol-3-yl)phenyl)picoli namide (105 mg) was prepared in a manner analogous to Example 23, using (3R,5S)-3-hydroxy-1-methyl-3-(3-(3- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)-5- (trifluoromethyl)pyrrolidin-2-one (Intermediate 48) and 3-amino-6-chloro-4- cyclopropylpicolinamide (Example 88 Step A) instead of (R)-3-hydroxy-1 -methyl-3-(3-(3- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one and 1- bromoimidazo[1 ,5-a]pyridine-3-carboxamide. MS (ESI): Mass calcd for C24H22F3N5O4 501 .46 m/z found 502.20 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d) 5 8.15 (t, J = 1 .8 Hz, 1 H), 8.07 (br s, 1 H), 7.93 - 7.81 (m, 1 H), 7.58-7.62 (m, 1 H), 7.48 - 7.36 (m, 2H), 6.78 (s, 1 H), 6.43 (br s, 2H), 5.73 (d, J = 4.5 Hz, 1 H), 4.73 (br s, 1 H), 4.38 - 4.17 (m, 1 H), 3.10 (s, 3H), 3.02 (dd, J = 14.1 , 7.8 Hz, 1 H), 2.51 (dd, J = 14.2, 6.8 Hz, 1 H), 1.76 - 1.58 (m, 1 H), 1.16 - 0.97 (m, 2H), 0.81 - 0.59 (m, 2H).

Example 179: (R)-3-Amino-4-cyclopropyl-6-(3-(5-(3-hydroxy-1-(methyl-c/3)- 2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinamide (R)-3-Amino-4-cyclopropyl-6-(3-(5-(3-hydroxy-1 -(methyl-c/3)-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)picolinamide (131 mg) was prepared in a manner analogous to Example 23, using (R)-3-hydroxy-1 -(methyl-d3)-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 50) and 3-amino- 6-chloro-4-cyclopropylpicolinamide (Example 88 Step A) instead of (R)-3-hydroxy-1 - methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5- yl)pyrrolidin-2-one and 1 -bromoimidazo[1 ,5-a]pyridine-3-carboxamide. MS (ESI): Mass calcd. for C23H23N5O4436.49 m/z found 437.30 [M+H] ⁺ . ¹ H NMR (400 MHz, CD3OD) 5 8.44 (br s, 1 H), 8.13 - 8.01 (m, 1 H), 7.74-7.78 (m, 1 H), 7.62 (br s, 1 H), 7.54 (t, J = 7.8 Hz, 1 H), 7.00 (s, 1 H), 3.64 - 3.49 (m, 2H), 2.72-2.78 (m, 1 H), 2.37 -2.44 (m, 1 H), 1 .89 - 1.69 (m, 1 H), 1.11 - 1.04 (m, 2H), 0.86 - 0.69 (m, 2H).

Example 180: (R)-1 -(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl-4,4,5,5-c/4)isoxazol-

3-yl)phenyl)-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyridine-3-carboxamide

(R)-1 -(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl-4,4,5,5-c/4)isoxazol-3- yl)phenyl)-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyridine-3-carboxamide (21 mg) was prepared in a manner analogous to Example 89 using (R)-3-hydroxy-1 -methyl-3-(3-(3- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one - 4,4,5,5-C/4 (Intermediate 47) and 1 -bromo-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyridine-3- carboxylic acid instead of (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one and 3-amino-6-bromo-5- fluoropicolinic acid. MS (ESI): Mass calcd. for C23H23N5O4436.49 m/z found 437.30 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d) 5 8.04 (t, J = 1 .7 Hz, 1 H), 7.68-7.71 (m, 1 H), 7.64 - 7.56 (m, 1 H), 7.47 - 7.30 (m, 2H), 6.75 (s, 1 H), 5.78 (s, 1 H), 4.96 (s, 1 H), 4.44- 4.51 (m, 2H), 3.07 - 2.85 (m, 6H), 2.04 - 1 .90 (m, 2H), 1 .90 - 1 .76 (m, 2H). Example 181 : (R)-1 -(3-(5-(3-Hydroxy-1 -(methyl-c/3)-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyridine-3-carboxamide

(R)-1 -(3-(5-(3-Hydroxy-1 -(methyl-c/3)-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)- 5,6,7,8-tetrahydroimidazo[1 ,5-a]pyridine-3-carboxamide (21 mg) was prepared in a manner analogous to Example 89, using (R)-3-hydroxy-1 -(methyl-c/3)-3-(3-(3-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 50) and 1-bromo-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyridine-3-carboxylic acid instead of (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one and 3-amino-6-bromo-5-fluoropicolinic acid. MS (ESI): Mass calcd. for C22H23N5O4424.47 m/z found 425.30 [M+H] ⁺ . ¹ H NMR (500 MHz, Chloroform-d) 5 8.08 (br s, 1 H), 7.73 (dt, J = 7.8, 1 .4 Hz, 1 H), 7.63 (dt, J = 7.9, 1 .3 Hz, 1 H), 7.43 (t, J = 7.8 Hz, 1 H), 7.35 - 7.28 (m, 1 H), 6.75 (s, 1 H), 5.56 (br s, 1 H), 4.58 - 4.46 (m, 2H), 4.39 (br s, 1 H), 3.60-3.65 (m, 1 H), 3.44-3.51 (m, 1 H), 3.07 - 2.91 (m, 4H), 2.78-2.82 (m, 1 H), 2.42-2.50 (m, 1 H), 2.05 - 1 .94 (m, 2H), 1 .84-1 .90 (m, 2H).

Example 182: (R)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-4-(1 -methyl-1 /-/-pyrazol-5-yl)picolinamide

(R)-3-Hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 162 mg, 0.42 mmol), 6-chloro- 4-(1 -methyl-1 /-/-pyrazol-5-yl)picolinamide (Intermediate 52, 100 mg, 0.42 mmol), Pd(dtbpf)Cl2 (41 mg, 0.063 mmol), K3PO4 (366 mg, 1.69 mmol), 1 ,4-dioxane (2.1 mL), and H2O (0.5 mL) were added to a 5 mL vial, which was subsequently evacuated and refilled with Ar (x3), and stirred for 3 h at 85 °C. The resulting residue was purified by preparative HPLC (XBridge OBD C18 5 pm, 50 x 100 mm column using a 0 to 95% gradient of ACN/ 20 mM NH4OH in H2O over 16 min. Detection, UV at 25 °C = 220-254 nM) to yield a yellow solid (24 mg, 12%). MS (ESI): Mass calcd. for C24H22N6O4458.2 m/z, found 459.2 [M+H] ⁺ . ¹ H NMR (600 MHz, CD3OD) 5 8.67 (t, J = 1 .8 Hz, 1 H), 8.31 (ddd, J = 7.9, 1.8, 1.1 Hz, 1 H), 8.20 (dd, J = 23.1 , 1.5 Hz, 2H), 7.93 (dt, J = 7.7, 1.3 Hz, 1 H), 7.64 (t, J = 7.8 Hz, 1 H), 7.60 (d, J = 2.0 Hz, 1 H), 7.06 (s, 1 H), 6.71 (d, J = 2.0 Hz, 1 H), 4.04 (s, 3H), 3.66 - 3.54 (m, 2H), 2.99 (s, 3H), 2.76 (ddd, J = 13.6, 7.2, 4.7 Hz, 1 H), 2.43 (ddd, J = 13.6, 8.1 , 6.4 Hz, 1 H).

Example 183: (R)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-4-(isothiazol-5-yl)picolinamide

The title compound (60 mg, 59%) was prepared with analogous conditions to those described in Example 182 using 6-chloro-4-(isothiazol-5-yl)picolinamide in place of 6- chloro-4-(1 -methyl-1 /-/-pyrazol-5-yl)picolinamide. MS (ESI): Mass calcd. for C23H19N5O4S 461 .1 m/z, found 462.3 [M+H] ⁺ . ¹ H NMR (600 MHz, CD3OD) 5 8.75 (t, J = 1 .8 Hz, 1 H), 8.65 (d, J = 1 .8 Hz, 1 H), 8.45 (d, J = 1 .5 Hz, 1 H), 8.40 (ddd, J = 7.9, 1 .9, 1 .0 Hz, 1 H), 8.36 (d, J = 1 .6 Hz, 1 H), 8.04 (d, J = 1 .8 Hz, 1 H), 8.00 (dt, J = 7.8, 1 .2 Hz, 1 H), 7.70 (t, J = 7.8 Hz, 1 H), 7.11 (s, 1 H), 3.67 - 3.57 (m, 2H), 3.00 (s, 3H), 2.84 - 2.73 (m, 1 H), 2.44 (ddd, J = 13.6, 8.0, 6.5 Hz, 1 H).

Example 184: (R)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-4-(thiazol-5-yl)picolinamide

The title compound (60 mg, 59%) was prepared with analogous conditions to those described in Example 182 using 6-chloro-4-(isothiazol-5-yl)picolinamide in place of 6- chloro-4-(1 -methyl-1 /-/-pyrazol-5-yl)picolinamide. MS (ESI): Mass calcd. for C23H19N5O4S 461 .1 m/z, found 462.3 [M+H] ⁺ . ¹ H NMR (600 MHz, CD3OD) 5 8.75 (t, J = 1 .8 Hz, 1 H), 8.65 (d, J = 1 .8 Hz, 1 H), 8.45 (d, J = 1 .5 Hz, 1 H), 8.40 (ddd, J = 7.9, 1 .9, 1 .0 Hz, 1 H), 8.36 (d, J = 1 .6 Hz, 1 H), 8.04 (d, J = 1 .8 Hz, 1 H), 8.00 (dt, J = 7.8, 1 .2 Hz, 1 H), 7.70 (t, J = 7.8 Hz, 1 H), 7.11 (s, 1 H), 3.67 - 3.57 (m, 2H), 3.00 (s, 3H), 2.84 - 2.73 (m, 1 H), 2.44 (ddd, J = 13.6, 8.0, 6.5 Hz, 1 H).

Example 185: (R)-4-(1 -Cyclopropyl-1 /-/-pyrazol-5-yl)-6-(3-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinamide

To a mixture of (R)-4-chloro-6-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)picolinamide (Intermediate 57, 50 mg, 0.12 mmol) and 1 -cyclopropyl-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrazole (51 mg, 0.12 mmol) in 1 ,4- dioxane (1.2 mL) and water (0.24 mL) were added K3PO4 (79 mg, 0.36 mmol) and Pd(dppf)Cl2 (13 mg, 0.021 mmol) and the resulting mixture was degassed and purged with N2 3 times, and then the mixture was heated at 100 °C for 2 h under a N2 atmosphere. The reaction mixture was filtered through a syringe filter. The resulting solution was purified by preparative HPLC (Waters XBridge BEH C18, 5 pm, 30x150 mm using a 10 to 45% gradient of ACN/ 20 mM NH4OH in H2O over 20 min. Detection, UV at 25 °C = 220-254 nM) to yield an orange residue (31 mg, 53%). MS (ESI): Mass calcd. for C26H24N6O4484.2 m/z, found 485.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD3OD) 5 8.76 (t, J = 1.7 Hz, 1 H), 8.44 (dd, J = 9.5, 1.5 Hz, 2H), 8.38 (ddd, J = 7.9, 1.9, 1.1 Hz, 1 H), 7.99 (ddd, J = 7.8, 1 .8, 1 .1 Hz, 1 H), 7.70 (t, J = 7.8 Hz, 1 H), 7.59 (d, J = 2.0 Hz, 1 H), 7.09 (s, 1 H), 6.79 (d, J = 2.0 Hz, 1 H), 3.97 - 3.89 (m, 1 H), 3.66 - 3.53 (m, 2H), 2.99 (s, 3H), 2.78 (ddd, J = 13.6, 6.8, 5.1 Hz, 1 H), 2.43 (ddd, J = 13.5, 7.9, 6.7 Hz, 1 H), 1.18 - 1.04 (m, 4H).

Example 186: (R)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-4-(2-methyloxazol-5-yl)picolinamide

The title compound as its TFA salt was prepared with analogous conditions to those described in Example 185 using 2-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)oxazole in place of 1 -cyclopropyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/- pyrazole. The resulting solution was purified by preparative HPLC (Waters XSelect CSH C18, 5 pm, 30x150 mm using a 10 to 45% gradient of ACN/ 0.16% TFA in H2O/0.16% TFA over 15 min. Detection, UV at 25 °C = 220-254 nM) to yield an orange residue as a TFA salt (25 mg, 35%). MS (ESI): Mass calcd. for C24H21 N5O5 459.2 m/z, found 460.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD3OD) 5 8.71 (t, J = 1 .6 Hz, 1 H), 8.39 - 8.32 (m, 3H), 7.99 - 7.94 (m, 1 H), 7.88 (s, 1 H), 7.68 (t, J = 7.8 Hz, 1 H), 7.09 (s, 1 H), 3.64 - 3.57 (m, 2H), 3.00 (s, 3H), 2.79 (ddd, J = 13.6, 6.8, 5.2 Hz, 1 H), 2.63 (s, 3H), 2.44 (ddd, J = 13.5, 7.8, 6.7 Hz, 1 H).

Example 187: (R)-4-(1 -Ethyl-3-methyl-1 /-/-pyrazol-4-yl)-6-(3-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinamide

The title compound as its TFA salt was prepared with analogous conditions to those described in Example 185 using 1-ethyl-3-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 /-/-pyrazole in place of 1-cyclopropyl-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 /-/-pyrazole. The resulting solution was purified by preparative HPLC (Waters XSelect CSH C18, 5 pm, 30x150 mm using a 10 to 45% gradient of ACN/ 0.16% TFA in H ₂ O/0.16% TFA over 15 min. Detection, UV at 25 °C = 220-254 nM) to yield an orange residue as a TFA salt (49 mg, 67%). MS (ESI): Mass calcd. for C26H26N6O4 486.2 m/z, found 487.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD3OD) 5 8.68 (t, J = 1.7 Hz, 1 H), 8.31 (ddd, J = 7.9, 1.9, 1.1 Hz, 1 H), 8.24 (s, 1 H), 8.19 (dd, J = 11.1 , 1.6 Hz, 2H), 7.95 (ddd, J = 7.8, 1 .8, 1 .1 Hz, 1 H), 7.67 (t, J = 7.8 Hz, 1 H), 7.07 (s, 1 H), 4.22 (q, J = 7.3 Hz, 2H), 3.64 - 3.58 (m, 2H), 3.00 (s, 3H), 2.78 (ddd, J = 13.5, 6.8, 5.1 Hz, 1 H), 2.55 (s, 3H), 2.44 (ddd, J = 13.5, 7.8, 6.7 Hz, 1 H), 1 .53 (t, J = 7.3 Hz, 3H).

Example 188: (R)-4-(1 -Ethyl-3-(trifluoromethyl)-1 /-/-pyrazol-5-yl)-6-(3-(5-(3-hydroxy-1 - methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinamid e

The title compound was prepared with analogous conditions to those described in Example 185 using (1 -ethyl-3-(trifluoromethyl)-1 /-/-pyrazol-5-yl)boronic acid in place of 1 -cyclopropyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole. The resulting solution was purified by preparative HPLC (Waters XBridge BEH C18, 5 pm, 30x150 mm using a 30 to 65% gradient of ACN/ 20 mM NH4OH in H2O over 15 min. Detection, UV at 25 °C = 220-254 nM) to yield an orange residue (46 mg, 70%). MS (ESI): Mass calcd. for C26H23F3N6O4540.2 m/z, found 541.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD3OD) 8 8.73 (t, J = 1.7 Hz, 1 H), 8.36 (ddd, J = 8.0, 1.9, 1.1 Hz, 1 H), 8.29 (d, J = 1.5 Hz, 1 H), 8.20 (d, J = 1 .5 Hz, 1 H), 7.97 (dt, J = 7.8, 1 .3 Hz, 1 H), 7.67 (t, J = 7.8 Hz, 1 H), 7.08 (s, 1 H), 7.02 (s, 1 H), 4.39 (q, J = 7.2 Hz, 2H), 3.63 - 3.56 (m, 2H), 2.99 (s, 3H), 2.77 (ddd, J = 13.5, 6.9, 5.0 Hz, 1 H), 2.43 (ddd, J = 13.5, 7.9, 6.5 Hz, 1 H), 1 .50 (t, J = 7.2 Hz, 3H).

Example 189: (R)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-4-(1 -(2-methoxyethyl)-1 /-/-pyrazol-4-yl)picolinamide

The title compound as its TFA salt was prepared with analogous conditions to those described in Example 185 using 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 /-/-pyrazole in place of 1-cyclopropyl-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 /-/-pyrazole. The resulting solution was purified by preparative HPLC (Waters XSelect CSH C18, 5 pm, 30x150 mm using a 10 to 45% gradient of ACN/ 0.16% TFA in H ₂ O/0.16% TFA over 15 min. Detection, UV at 25 °C = 220-254 nM) to yield an orange residue as a TFA salt (50 mg, 67%). MS (ESI): Mass calcd. for C26H26N6O5 502.2 m/z, found 503.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD3OD) 8 8.68 (t, J = 1.7 Hz, 1 H), 8.31 (ddd, J = 7.9, 1.9, 1.1 Hz, 1 H), 8.24 (s, 1 H), 8.19 (dd, J = 11.1 , 1.6 Hz, 2H), 7.95 (ddd, J = 7.8, 1 .8, 1 .1 Hz, 1 H), 7.67 (t, J = 7.8 Hz, 1 H), 7.07 (s, 1 H), 4.22 (q, J = 7.3 Hz, 2H), 3.64 - 3.58 (m, 2H), 3.00 (s, 3H), 2.78 (ddd, J = 13.5, 6.8, 5.1 Hz, 1 H), 2.55 (s, 3H), 2.44 (ddd, J = 13.5, 7.8, 6.7 Hz, 1 H), 1 .53 (t, J = 7.3 Hz, 3H).

Example 190: (R)-4-(3-Cyclopropyl-1 /-/-pyrazol-4-yl)-6-(3-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinamide

The title compound was prepared with analogous conditions to those described in Example 185 using 3-cyclopropyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/- pyrazole in place of 1 -cyclopropyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/- pyrazole. The resulting solution was purified by preparative HPLC (Waters XBridge BEH C18, 5 pm, 30x150 mm using a 10 to 45% gradient of ACN/ 20 mM NH4OH in H2O over 15 min. Detection, UV at 25 °C = 220-254 nM) to yield an orange residue (9 mg, 15%). MS (ESI): Mass calcd. for C26H24N6O4 484.2 m/z, found 485.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CD3OD) 5 8.71 (t, J = 1 .7 Hz, 1 H), 8.45 (d, J = 1 .6 Hz, 1 H), 8.40 (d, J = 1 .6 Hz, 1 H), 8.33 (ddd, J = 7.9, 1.9, 1.1 Hz, 1 H), 7.95 (ddd, J = 7.7, 1.8, 1.1 Hz, 1 H), 7.67 (t, J = 7.8 Hz, 1 H), 7.07 (s, 1 H), 3.67 - 3.56 (m, 2H), 3.00 (s, 3H), 2.78 (ddd, J = 13.5, 6.7, 5.2 Hz, 1 H), 2.44 (ddd, J = 13.5, 7.8, 6.7 Hz, 1 H).

Example 191 : (R)-6-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-4-(2-methoxythiazol-5-yl)picolinamide

The title compound was prepared with analogous conditions described in Example 185 using 2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)thiazole in place of 1- cyclopropyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrazole. The resulting solution was purified by preparative HPLC (Waters XBridge BEH C18, 5 pm, 30x150 mm using a 10 to 45% gradient of ACN/ 20 mM NH4OH in H2O over 15 min. Detection, UV at 25 °C = 220-254 nM) to yield a yellow residue (6 mg, 10%). MS (ESI): Mass calcd. for C24H21 N5O5S 491.1 m/z, found 492.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD3OD) 5 8.76 - 8.68 (m, 1 H), 8.32 - 8.25 (m, 1 H), 8.20 - 8.14 (m, 1 H), 8.04 - 7.95 (m, 2H), 7.74 - 7.65 (m, 1 H), 7.13 - 7.05 (m, 1 H), 4.19 (s, 2H), 3.66 - 3.56 (m, 3H), 3.00 (s, 3H), 2.81

- 2.73 (m, 2H), 2.48 - 2.37 (m, 2H).

Example 192: (R)-1 -(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-4-methyl-1 /-/-pyrazole-3-carboxamide

Step A: Ethyl (R)-1 -(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-4-methyl-1 H-pyrazole-3-carboxylate. (R)-3-Hydroxy-1 -methyl-3-(3-(3-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 174 mg, 0.45 mmol), ethyl 4-methyl-1 /-/-pyrazole-3-carboxylate (50 mg, 0.32 mmol), CU(0AC)2 (17 mg, 0.099 mmol), pyridine (0.08 mL, 1.01 mmol), and DMF (0.65 mL) were added to a 5 mL vial, which was subsequently evacuated and refilled with Ar (x3), and stirred for 12 h at 120 °C. The resulting mixture was diluted with water and extracted with ethyl acetate. The resulting organic solution was then dried over MgSCM, filtered, and evaporated to dryness to afford a green residue (133 mg) which was used without further purification. MS (ESI): Mass calcd. for C21 H22N4O5 410.2 m/z, found 411.2 [M+H] ⁺ .

Step B: (R)-1 -(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-4-methyl-1 /-/-pyrazole-3-carboxamide. A vial charged with ethyl (R)-1-(3-(5- (3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-4-methyl- 1 /-/-pyrazole-3- carboxylate (100 mg, 0.25 mmol) in 0.72 mL of methanolic ammonia (7 M) was heated at 110 °C for 24 hours. The resulting solution was filtered through a syringe filter and evaporated to dryness. The resulting residue was purified by preparative HPLC (Waters XBridge BEH C18, 5 pm, 30x150 mm using a 10 to 50% gradient of ACN/ 20 mM NH4OH in H2O over 15 min. Detection, UV at 25 °C = 220-254 nM) to yield an orange residue (5 mg, 5%). MS (ESI): Mass calcd. for C19H19N5O4 381.1 m/z, found 382.2 [M+H] ⁺ . ¹ H NMR (500 MHz, CD3OD) 5 8.33 (t, J = 1 .9 Hz, 1 H), 8.19 (q, J = 0.9 Hz, 1 H), 7.94 (ddd, J = 8.2, 2.3, 1 .0 Hz, 1 H), 7.82 (ddd, J = 7.8, 1 .6, 1 .0 Hz, 1 H), 7.61 (t, J = 7.9 Hz, 1 H), 7.00 (s, 1 H), 3.61 - 3.54 (m, 2H), 2.96 (s, 3H), 2.74 (ddd, J = 13.5, 7.0, 4.8 Hz, 1 H), 2.40 (ddd, J = 13.6, 8.1 , 6.6 Hz, 1 H), 2.37 (d, J = 0.9 Hz, 3H).

Example 193: (R)-1 -(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-1 /-/-pyrazole-3-carboxamide

Step A: Methyl (R)-1 -(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-1 H-pyrazole-3-carboxylate. (R)-3-Hydroxy-1 -methyl-3-(3-(3-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 212 mg, 0.55 mmol), methyl 1/-/-pyrazole-3-carboxylate (50 mg, 0.40 mmol), CU(0AC)2 (22 mg, 0.12 mmol), pyridine (0.1 mL, 1.23 mmol), and DMF (0.79 mL) were added to a vial, which was subsequently evacuated and refilled with Ar (x3), and heated for 12 h at 120 °C. The resulting mixture was diluted with water and extracted with ethyl acetate. The resulting organic solution was then dried over MgSCM, filtered, and evaporated to dryness to afford a green residue (151 mg) which was used without further purification. MS (ESI): Mass calcd. for C19H18N4O5 382.1 m/z, found 383.1 [M+H] ⁺ .

Step B: (R)-1 -(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-1 /-/-pyrazole-3-carboxamide. Methyl (R)-1 -(3-(5-(3-hydroxy-1-methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-1 /-/-pyrazole-3-carboxylate is dissolved in 0.75 mL of methanolic ammonia (7 M) and was heated at 110 °C for 24 hours. The resulting solution was filtered through a syringe filter and evaporated to dryness. The resulting residue was purified by preparative HPLC (Waters XBridge BEH C18, 5 pm, 30x150 mm using a 10 to 50% gradient of ACN/ 20 mM NH4OH in H2O over 15 min. Detection, UV at 25 °C = 220-254 nM) to yield an orange residue (5 mg, 5%). MS (ESI): Mass calcd. for C18H17N5O4 367.1 m/z, found 368.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD3OD) 5

8.44 (d, J = 2.6 Hz, 1 H), 8.40 (t, J = 1 .9 Hz, 1 H), 8.01 (ddd, J = 8.2, 2.3, 1 .0 Hz, 1 H), 7.88 (ddd, J = 7.8, 1 .6, 1 .0 Hz, 1 H), 7.66 (t, J = 8.0 Hz, 1 H), 7.03 (s, 1 H), 7.00 (d, J =

2.6 Hz, 1 H), 3.63 - 3.57 (m, 2H), 2.99 (s, 3H), 2.76 (ddd, J = 13.5, 6.9, 5.0 Hz, 1 H), 2.43 (ddd, J = 13.4, 7.9, 6.6 Hz, 1 H).

Example 194: (R)-1 -(6-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)pyridin-

2-y l)-1 /-/-pyrazole-4-carboxamide

A mixture of (R)-3-(3-(6-bromopyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1 - methylpyrrolidin-2-one (50 mg, 0.148 mmol, Intermediate 43), 1 /-/-pyrazole-4- carboxamide (24.6 mg, 0.222 mmol), CS2CO3 (144 mg, 0.444 mmol), and DMF (1 mL, 12.915 mmol) was heated to 100 °C for 24 h. The reaction mixture was diluted with water and extracted with ethyl acetate and then 9:1 v/v DCM:IPA. The organic extracts were combined, dried with MgSCM, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC using an HPLC column, such as a Waters XBridge BEH C18, 5 μm, 30x150 mm column using an 8% to 35% gradient of CH3CN/H2O (pH 10 ammonium hydroxide) to afford (R)-1 -(6-(5-(3-hydroxy- 1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)pyridin-2-yl)-1 /-/-pyrazole-4- carboxamide (11.2 mg, 20.6%) as a white powder. MS (ESI): Mass calcd. for C17H16N6O4, 368.1 ; m/z found, 369.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 9.28 (d, J = 0.8 Hz, 1 H), 8.23 - 8.15 (m, 2H), 8.06 (dd, J = 8.2, 1.0 Hz, 1 H), 8.01 (dd, J = 7.6, 0.9 Hz, 1 H), 7.91 (s, 1 H), 7.28 (s, 1 H), 7.19 (s, 1 H), 6.79 (s, 1 H), 3.56 - 3.40 (m, 2H), 2.86 (s, 3H), 2.67 - 2.54 (m, 1 H), 2.37 - 2.22 (m, 1 H). Example 195: (R)-3-Amino-1 -(6-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)pyridin-2-yl)-1 /-/-pyrazole-4-carboxamide

A mixture of (R)-3-(3-(6-bromopyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1 - methylpyrrolidin-2-one (50.0 mg, 0.148 mmol, Intermediate 43), 3-amino-1 /-/-pyrazole-4- carboxamide (24.6 mg, 0.195 mmol), CS2CO3 (144 mg, 0.444 mmol) and DMF (1 mL, 12.9 mmol) was heated at 100 °C for 24 h. The reaction mixture was diluted with water and extracted with ethyl acetate and then 9:1 v/v DCM:IPA. The organic extracts were combined, dried with MgSCM, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC using an HPLC column, such as a Waters XBridge BEH C18, 5 μm, 30x150 mm column using an 8% to 35% gradient of CH3CN/H2O (pH 10 ammonium hydroxide) to afford (R)-3-amino-1 -(6-(5-(3-hydroxy-1 - methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)pyridin-2-yl)-1 /-/-pyrazole-4- carboxamide (7.3 mg, 13%) as a white powder. MS (ESI): Mass calcd. for C17H17N7O4, 383.1 ; m/z found, 384.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 9.16 (s, 1 H), 8.08 (t, J = 7.9 Hz, 1 H), 7.85 (dd, J = 7.7, 0.9 Hz, 1 H), 7.83 - 7.68 (m, 2H), 7.09 (s, 2H), 6.79 (s, 1 H), 5.91 (s, 2H), 3.59 - 3.38 (m, 2H), 2.86 (s, 3H), 2.63 - 2.54 (m, 1 H), 2.36 - 2.22 (m, 1 H).

Example 196: (R)-5-(6-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)pyridin- 2-y I )isoquinol in-1 (2/-/)-one

A mixture of (R)-3-(3-(6-bromopyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2- one (50 mg, 0.148 mmol, Intermediate 43), 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)isoquinolin-1 (2H)-one (60 mg, 0.22 mmol), 1 ,4-dioxane (0.5 mL), K2CO3 (0.37 mL, 1 M in water, 0.37 mmol) and [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (10.9 mg, 0.0148 mmol) was heated at 100 °C for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was dried with MgSCM, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC using an HPLC column such as a Waters XSelect CSH C18, 5 pm, 30x150 mm column using a 10% to 45% gradient of MeCN/FW (0.16% TFA) to afford (R)-5-(6-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)pyridin-2- yl)isoquinolin-1 (2H)-one (50.8 mg, 85.4%) as a yellow powder. MS (ESI): Mass calcd. for C22H18N4O4, 402.1 ; m/z found, 403.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 11 .45 - 11.28 (m, 1 H), 8.42 - 8.31 (m, 1 H), 8.13 (t, J = 7.7 Hz, 1 H), 8.10 - 8.05 (m, 1 H), 7.89 (dd, J = 7.4, 1.4 Hz, 1 H), 7.77 (dd, J = 7.6, 1.1 Hz, 1 H), 7.62 (t, J = 7.7 Hz, 1 H), 7.23 - 7.14 (m, 1 H), 6.96 (s, 1 H), 6.68 (d, J = 7.4 Hz, 1 H), 3.51 - 3.38 (m, 2H), 2.83 (s, 3H), 2.64 - 2.54 (m, 1 H), 2.31 - 2.21 (m, 1 H).

Example 197: (R)-8-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)quinazolin-4(3/-/)-one. A mixture of Intermediate 4: (R)-3-Hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one . (Intermediate 4, 57 mg, 0.148 mmol), 8-bromoquinazolin-4(3/-/)-one (33 mg, 0.15 mmol), [1 ,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (10.9 mg, 0.0148 mmol), 1 ,4- dioxane (0.57 mL), and K2CO3 (0.371 mL, 1 M in water, 0.371 mmol) was heated to 100 °C for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was dried with MgSCM, filtered and concentrated. The resulting residue was purified by reverse phase HPLC using an HPLC column, such as a Waters XBridge BEH C18, 5 pm, 30x150 mm column using a 10% to 40% gradient of CH3CN/H2O (pH 10 ammonium hydroxide) to afford (R)-8-(3-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)quinazolin-4(3/-/)-o ne (16.8 mg, 28.1 %) as a yellow powder. MS (ESI): Mass calcd. for C22H18N4O4, 402.1 ; m/z found, 403.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.20 (dd, J = 7.9, 1 .6 Hz, 1 H), 8.12 (s, 1 H), 8.09 - 8.03 (m, 1 H), 7.96 - 7.84 (m, 2H), 7.77 - 7.67 (m, 1 H), 7.67 - 7.54 (m, 2H), 7.05 (s, 1 H), 3.52 - 3.39 (m, 2H), 2.84 (s, 3H), 2.61 - 2.52 (m, 1 H), 2.34 - 2.21 (m, 1 H).

Example 198: (R)-6'-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)-[2,2'- bipyridine]-4-carboxamide

A mixture of (R)-3-(3-(6-bromopyridin-2-yl)isoxazol-5-yl)-3-hydroxy-1 - methylpyrrolidin-2-one (100 mg, 0.296 mmol, Intermediate 43), 2-chloroisonicotinamide (46 mg, 0.30 mmol), tetrakis(triphenylphosphine)palladium(0) (34 mg, 0.030 mmol), hexamethylditin (97 mg, 0.30 mmol) and DMF (1 mL) was heated to 160 °C in a microwave reactor for 1 h. The reaction mixture was diluted with NaOH solution (1 M in water) and extracted with ethyl acetate. The organic extract was dried with MgSCM, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC using an HPLC column, such as a Waters XBridge BEH C18, 5 pm, 30x150 mm column using an 8% to 35% gradient of CH3CN/H2O (pH 10 ammonium hydroxide) to afford (R)-6'-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)-[2,2'-bipyridine]-4-carboxamide (12.7 mg, 11.3%) as a white powder. MS (ESI): Mass calcd. for C19H17N5O4, 379.1 ; m/z found, 380.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.91 - 8.82 (m, 2H), 8.53 (dd, J = 7.6, 1 .3 Hz, 1 H), 8.47 (s, 1 H), 8.19 - 8.02 (m, 2H), 7.93 - 7.85 (m, 1 H), 7.83 (s, 1 H), 7.24 (s, 1 H), 6.83 (s, 1 H), 3.56 - 3.43 (m, 2H), 2.86 (s, 3H), 2.66 - 2.57 (m, 1 H), 2.36 - 2.25 (m, 1 H).

Example 199 and Example 200: (R)-3-(3-((R)-1-(4-Amino-8-methylpyrido[3,2- d]pyrimidin-6-yl)piperidin-3-yl)isoxazol-5-yl)-3-hydroxy-1-m ethylpyrrolidin-2-one and (R)- 3-(3-((S)-1-(4-Amino-8-methylpyrido[3,2-d]pyrimidin-6-yl)pip eridin-3-yl)isoxazol-5-yl)-3- hydroxy-1-methylpyrrolidin-2-one.

Step A: (3R)-3-Hydroxy-1 -methyl-3-(3-(piperidin-3-yl)isoxazol-5-yl)pyrrolidin-2- one (2000 mg, Intermediate 63), 6-chloro-8-methylpyrido[3,2-d]pyrimidin-4-amine (Example 26 Step C, 293 mg, 1 .51 mmol), TEA (525 pL, 3.77 mmol), and DMA (10 mL) were added to a 20 mL microwave tube. The resultant mixture was heated at 140 °C via microwave irradiation for 3 h. After this time, the reaction vessel was removed from the microwave heating device and allowed to gradually cool to room temperature. The mixture was concentrated to dryness in vacuo. The residue was subjected to silica gel chromatography (0-10% MeOH/DCM), and then purified by HPLC (Phenomenex Gemini-NX C18 column, 3 pm, 75 x 30 mm, 14-44% (v/v) CH3CN/H2O with 0.05% NH3H2O +10 mM NH4HCO3) to afford, after lyophilization, (R)-3-(3-((R,S)-1-(4-amino-8- methylpyrido[3,2-d]pyrimidin-6-yl)piperidin-3-yl)isoxazol-5- yl)-3-hydroxy-1- methylpyrrolidin-2-one as a white solid (70 mg, 9%). MS (ESI): Mass calcd. for C21 H25N7O3 423.20, found 424.2 [M+H] ⁺ . Step B: The (R) and (S) diastereomers of the racemic mixture of (R)-3-(3-((R,S)- 1-(4-arnino-8-methylpyrido[3,2-d]pyrimidin-6-yl)piperidin-3- yl)isoxazol-5-yl)-3-hydroxy-1- methylpyrrolidin-2-one (70 mg, 0.165 mmol) were separated by SFC (AD column, 10 pm, 250 x 30 mm; 45% IPA with 0.1% NHs’FhO/supercritical CO2) to give two products. The first eluting product was designated as diastereomer 1 of (R)-3-(3-(1-(4-amino-8- methylpyrido[3,2-d]pyrimidin-6-yl)piperidin-3-yl)isoxazol-5- yl)-3-hydroxy-1- methylpyrrolidin-2-one (Example 199), and was obtained as a white solid (16.4 mg, 23% yield, RT of SFC = 8.349 min). MS (ESI): Mass calcd. for C21H25N7O3423.20 m/z, found 424.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 88.18 (s, 1H), 7.43 (s, 1H), 7.37- 7.18 (m, 2H), 6.63 (s, 1 H), 6.58 (s, 1 H), 4.66 - 4.56 (m, 1 H), 4.52 - 4.43 (m, 1 H), 3.37 - 3.33 (m, 2H), 3.20 - 3.14 (m, 1 H), 3.10 - 3.01 (m, 1 H), 2.97 - 2.88 (m, 1 H), 2.81 (s, 3H), 2.49 - 2.42 (m, 4H), 2.26- 2.17 (m, 1H), 2.10-2.00 (m, 1H), 1.83- 1.69 (m, 2H), 1.65-1.55 (m, 1 H). The second eluting product was designated as diastereomer 2 of (R)-3-(3-(1- (4-amino-8-methylpyrido[3,2-d]pyrimidin-6-yl)piperidin-3-yl) isoxazol-5-yl)-3-hydroxy-1- methylpyrrolidin-2-one (Example 200), and was obtained as a white solid (11.5 mg, 15.5% yield, RT of SFC = 9.872 min). MS (ESI): Mass calcd. for C21H25N7O3423.20 m/z, found 424.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 88.18 (s, 1 H), 7.42 (s, 1 H), 7.38 - 7.17 (m,2H), 6.63 (s, 1H), 6.57 (s, 1H), 4.65-4.55 (m, 1H), 4.52-4.41 (m, 1H), 3.37- 3.33 (m, 2H), 3.20- 3.15 (m, 1H), 3.10-3.01 (m, 1H), 2.98- 2.89 (m, 1H), 2.80 (s, 3H), 2.49-2.43 (m, 4H), 2.26 -2.16 (m, 1H), 2.11 -2.01 (m, 1H), 1.83-1.72 (m, 2H), 1.66- 1.54 (m, 1H)..

Example 201 : (3R)-3-(3-(1-(4-Aminopyrido[3,2-d]pyrimidin-6-yl)piperidin-3 -yl)isoxazol-5- yl)-3-hydroxy-1-methylpyrrolidin-2-one

(3R)-3-Hydroxy-1-methyl-3-(3-(piperidin-3-yl)isoxazol-5-y l)pyrrolidin-2-one

(Intermediate 63, 1.90 g, 20 wt.%, 1.43 mmol), 6-chloropyrido[3,2-d]pyrimidin-4-amine

(259 mg, 1.43 mmol, Intermediate 59), TEA (500 pL, 3.59 mmol), and DMA (10 mL) were added into a 20 mL microwave tube. The resultant mixture was stirred while heating at 140 °C via microwave irradiation for 3 h. After this time, the reaction vessel was removed from the microwave heating device and allowed to gradually cool to room temperature. The mixture was concentrated to dryness in vacuo. The residue was subjected to silica gel chromatography (0-10% MeOH/DCM), and then purified by HPLC (Xtimate C18 column, 5 pm, 150 x 40 mm, 17-44% (v/v) CH3CN/H2O with 0.05% NH3H2O) to afford, after lyophilization, (3R)-3-(3-(1 -(4-aminopyrido[3,2-c/]pynmidin-6- yl)piperidin-3-yl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidi n-2-one as a white solid (150 mg, 26%). MS (ESI): Mass calcd. for C20H23N7O3 409.19 m/z found 410.1 [M+1 ] ⁺ .

Example 202 and Example 203: (R)-3-(3-((R)-1 -(4-aminopyrido[3,2-d]pyrimidin-6- yl)piperidin-3-yl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one and (R)-3-(3-((S)-1 - (4-Aminopyrido[3,2-d]pyrimidin-6-yl)piperidin-3-yl)isoxazol- 5-yl)-3-hydroxy-1- methylpyrrolidin-2-one.

Step A: te/t-Butyl (te/Y-butoxycarbonyl)(6-((R,S)-3-(5-((R)-3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)piperidin-1 -yl)pyrido[3,2-d]pyrimidin-4-yl)carbamate. BOC2O (139 mg, 0.637 mmol) was added to a solution consisting of (3R)-3-(3-(1-(4- aminopyrido[3,2-c(]pyrimidin-6-yl)piperidin-3-yl)isoxazol-5- yl)-3-hydroxy-1 - methylpyrrolidin-2-one (Example 201 , 130 mg, 0.318 mmol), DMAP (116 mg, 0.950 mmol), and DCM (20 mL). The resultant mixture was stirred at room temperature for 16 h. After this time, the reaction was quenched with water (25 mL) and extracted with DCM (3 x 25 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give tert-butyl (tert-butoxycarbonyl)(6- ((R,S)-3-(5-((R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)iso xazol-3-yl)piperidin-1 - yl)pyrido[3,2-d]pyrimidin-4-yl)carbamate (180 mg) as a white solid. MS (ESI): Mass calcd. for C30H39N7O7 609.29 m/z found 610.2 [M+1 ] ⁺ . tert-Butyl (te/Y-butoxycarbonyl)(6-((R)-3-(5-((R)-3-hydroxy-1-methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)piperidin-1-yl)pyrido[3,2-d ]pyrimidin-4-yl)carbamate and te/Y-butyl (te/Y-butoxycarbonyl)(6-((S)-3-(5-((R)-3-hydroxy-1-methyl-2- oxopyrrolidin-3- yl)isoxazol-3-yl)piperidin-1-yl)pyrido[3,2-d]pyrimidin-4-yl) carbamate. The (R) and (S) diastereomers of the racemic mixture of te/t-butyl (te/Y-butoxycarbonyl)(6-((R,S)-3-(5- ((R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)p iperidin-1-yl)pyrido[3,2- d]pyrimidin-4-yl)carbamate (180 mg, 0.295 mmol) were separated by SFC (IG column, 10 pm, 250 mm x 30 mm; 50% (v/v) EtOH (containing 0.1 % of 25% aq. NH3)/CO2) to give two products. The first eluting product was designated as diastereomer 1 of tertbutyl (tert-butoxycarbonyl)(6-(3-(5-((R)-3-hydroxy-1-methyl-2-oxop yrrolidin-3-yl)isoxazol-

3-yl)piperidin-1-yl)pyrido[3,2-d]pyrimidin-4-yl)carbamate and was obtained as a white solid (45 mg, 25%). MS (ESI): Mass calcd. for C30H39N7O7 609.29 m/z found 610.2 [M+1] ⁺ . The second eluting product was designated as diastereomer 2 of tert-butyl (tert- butoxycarbonyl)(6-(3-(5-((R)-3-hydroxy-1-methyl-2-oxopyrroli din-3-yl)isoxazol-3- yl)piperidin-1-yl)pyrido[3,2-d]pyrimidin-4-yl)carbamate.

Step C: (R)-3-(3-((R)-1 -(4-aminopyrido[3,2-d]pyrimidin-6-yl)piperidin-3- yl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one and (R)-3-(3-((S)-1 -(4- aminopyrido[3,2-d]pyrimidin-6-yl)piperidin-3-yl)isoxazol-5-y l)-3-hydroxy-1- methylpyrrolidin-2-one. TMSCI (84 pL, 0.66 mmol) was added dropwise to a 0 °C mixture consisting of diastereomer 1 of tert-butyl (tert-butoxycarbonyl)(6-(3-(5-((R)-3- hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)piperidi n-1-yl)pyrido[3,2-d]pyrimidin-

4-yl)carbamate (40 mg, 0.066 mmol), Nal (98.3 mg, 0.656 mmol), and CH3CN (5 mL). The resultant mixture was stirred at room temperature for 16 h, quenched with NH4OH (0.5 mL, 28 wt.% in H2O), and concentrated to dryness in vacuo. The residue was subjected to HPLC (Boston Prime C18 column, 5 pm, 150 x 30 mm; 20-50% (v/v) CH3CN/H2O with 0.05% NH3H2O + 10 mM NH4HCO3) to give, after lyophilization, diastereomer 1 of (R)-3-(3-(1-(4-aminopyrido[3,2-d]pyrimidin-6-yl)piperidin-3- yl)isoxazol-

5-yl)-3-hydroxy-1-methylpyrrolidin-2-one (Example 202) as a white solid (10.2 mg, 38%). MS (ESI): Mass calcd. for C20H23N7O3 409.19 m/z found 410.2 [M+1 ] ⁺ . ¹ H NMR (400 MHz, DMSO-c/e) 8 8.16 (s, 1 H), 7.77 (d, J = 9.3 Hz, 1 H), 7.53 (d, J = 9.3 Hz, 1 H), 7.49 - 7.22 (m, 2H), 6.78 - 6.40 (m, 2H), 4.68 - 4.58 (m, 1 H), 4.49 - 4.41 (m, 1 H), 3.47 - 3.41 (m, 2H), 3.24 - 3.19 (m, 1 H), 3.14 - 3.06 (m, 1 H), 2.99 - 2.91 (m, 1 H), 2.81 (s, 3H), 2.46 - 2.41 (m, 1 H), 2.25 - 2.16 (m, 1 H), 2.08 - 2.01 (m, 1 H), 1.83 - 1.74 (m, 2H), 1.67 - 1.56 (m, 1 H).

Diastereomer 2 of (R)-3-(3-(1 -(4-aminopyrido[3,2-d]pyrimidin-6-yl)piperidin-3- yl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (Example 203; 10.5 mg, 34%) was made analogously to Example 202, using diastereomer 2 of tert-butyl (tert- butoxycarbonyl)(6-(3-(5-((R)-3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)piperidin-1 -yl)pyrido[3,2-d]pyrimidin-4-yl)carbamate in place of diastereomer 1 of tertbutyl (tert-butoxycarbonyl)(6-(3-(5-((R)-3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol- 3-yl)piperidin-1-yl)pyrido[3,2-d]pyrimidin-4-yl)carbamate. MS (ESI): Mass calcd. for C20H23N7O3 409.19 m/z found 410.1 [M+1 ] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.16 (s, 1 H), 7.77 (d, J = 9.4 Hz, 1 H), 7.53 (d, J = 9.4 Hz, 1 H), 7.47 - 7.19 (m, 2H), 6.65 - 6.54 (m, 2H), 4.67 - 4.57 (m, 1 H), 4.51 - 4.41 (m, 1 H), 3.47 - 3.39 (m, 2H), 3.25 - 3.19 (m, 1 H), 3.16 - 3.07 (m, 1 H), 2.99 - 2.91 (m, 1 H), 2.80 (s, 3H), 2.47 - 2.42 (m, 1 H), 2.25 - 2.16 (m, 1 H), 2.08 - 2.01 (m, 1 H), 1 .83 - 1 .71 (m, 2H), 1 .66 - 1 .55 (m, 1 H).

Example 204: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)thiazole-4-carboxamide

A mixture of (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 140 mg, 0.36 mmol), 2-bromothiazole-4-carboxamide (80 mg, 0.39 mmol), K3PO4 (149 mg, 1.09 mmol), 1 ,4-dioxane (5 mL), and water (0.5 mL) was evacuated and refilled with N2 3 times, treated with Pd(dtbpf)Cl2 (24 mg, 0.036 mmol), and heated at 100 °C for 2 h under N2. The reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The mixture was filtered through a pad of diatomaceous earth and the pad was washed with EtOAc (15 mL). The filtrate was concentrated in vacuo. The residue was subjected to HPLC (Boston Green ODS column, 5 pm, 150 x 30 mm; 30-60% (v/v) CH3CN/H2O with 0.225% FA) to give, after lyophilization, (R)-2-(3-(5-(3-hydroxy-1- methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)thiazole-4- carboxamide as a white solid (33.3 mg, 24%). MS (ESI): Mass calcd. for C18H16N4O4S 384.09 m/z, found 385.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.52 (s, 1 H), 8.35 (s, 1 H), 8.16 (d, J = 8.0 Hz, 1 H), 8.10 - 8.01 (m, 2H), 7.77 - 7.66 (m, 2H), 7.17 (s, 1 H), 6.79 (s, 1 H), 3.53 - 3.47 (m, 2H), 2.85 (s, 3H), 2.63 - 2.55 (m, 1 H), 2.34 - 2.25 (m, 1 H). ¹ H NMR (400 MHz, CD3OD) 8 8.55 (s, 1 H), 8.29 (s, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 8.00 (d, J = 8.0 Hz, 1 H), 7.70 - 7.61 (m, 1 H), 7.04 (s, 1 H), 3.64 - 3.56 (m, 2H), 2.99 (s, 3H), 2.81 - 2.72 (m, 1 H), 2.48 - 2.38 (m, 1 H).

Example 205: (R)-4-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)thiazole-2 -carboxamide

Step A: 4-Bromothiazole-2-carbonyl chloride. To a mixture consisting of 4- bromothiazole-2-carboxylic acid (500 mg, 2.4 mmol) and SOCI2 (5 mL) was added anhydrous DMF (50 mg, 0.68 mmol) in one portion. The resultant mixture was heated at 80 °C for 2 h to afford a clear light yellow solution. The reaction vessel was removed from the oil bath and allowed to gradually cool to RT. The reaction mixture was concentrated in vacuo to afford 4-bromothiazole-2-carbonyl chloride as a light yellow gum (600 mg), which was used for the next step directly.

Step B: 4-Bromothiazole-2-carboxamide. To a solution consisting of 4- bromothiazole-2-carbonyl chloride (600 mg, 2.65 mmol), and anhydrous CH2CI2 (20 mL) was added NH3 (0.95 mL, 6.6 mmol, 7 M in MeOH) in portions at 0 °C over 5 min, and stirred for 1 h with gradual warming to room temperature. After this time, the solution was concentrated to dryness in vacuo. The residue was subjected to silica gel chromatography (0-100% EtOAc/petroleum ether) to afford 4-bromothiazole-2- carboxamide (180 mg, 33%) as a yellow solid. MS (ESI): Mass calcd. for C4H3BrN2OS 205.91 m/z, found 206.9 [M+H] ⁺ .

Step C: (R)-4-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)thiazole-2 -carboxamide. A mixture consisting of (R)-3-hydroxy-1-methyl-3-(3- (3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 140 mg, 0.36 mmol), 4-bromothiazole-2-carboxamide (82 mg, 0.40 mmol), K3PO4 (149 mg, 1.09 mmol), 1 ,4-dioxane (5 mL), and water (0.5 mL) was evacuated and refilled with N2 for 3 times, treated with Pd(dtbpf)Cl2 (24 mg, 0.036 mmol), and heated at 100 °C for 20 h under N2. The reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The reaction mixture was filtered through a pad of diatomaceous earth and the pad washed with EtOAc (15 mL). The filtrate was concentrated to dryness in vacuo. The residue was subjected to HPLC (Boston Green ODS column, 5 pm, 150 x 30 mm; 25-55% CH3CN/H2O with 0.225% FA) to give, after lyophilization (R)-4-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)thiazole-2-carboxamide as a white solid (65.9 mg, 47%). MS (ESI): Mass calcd. for C18H16N4O4S 384.09 m/z, found 385.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 5 8.57 (s, 1 H), 8.54 (s, 1 H), 8.38 (s, 1 H), 8.20 (d, J = 8.0 Hz, 1 H), 7.97 (s, 1 H), 7.90 (d, J = 8.0 Hz, 1 H), 7.66 - 7.59 (m, 1 H), 7.13 (s, 1 H), 6.79 (s, 1 H), 3.58 - 3.50 (m, 2H), 2.85 (s, 3H), 2.64 - 2.54 (m, 1 H), 2.34 - 2.24 (m, 1 H). ¹ H NMR (400 MHz, CD3OD) 5 8.54 (s, 1 H), 8.26 (s, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 7.88 (d, J = 8.0 Hz, 1 H), 7.64 - 7.56 (m, 1 H), 7.03 (s, 1 H), 3.64 - 3.56 (m, 2H), 2.99 (s, 3H), 2.82 - 2.71 (m, 1 H), 2.48 - 2.38 (m, 1 H).

Example 206: (R)-5-Amino-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)thiazole-4-carboxamide

Step A: 5-Amino-2-iodothiazole-4-carboxamide. To a solution consisting of 5- aminothiazole-4-carboxamide (1.00 g, 6.99 mmol), and DMF (15 mL) was added NIS (2.36 g, 10.5 mmol) in one portion at room temperature. After addition, the solution was stirred for 2 h at room temperature. The solution was diluted with EtOAc (150 mL) and washed with water (20 mL x 3) and brine (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was subjected to silica gel chromatography (0-50% EtOAc/petroleum ether) to afford 5-amino-2-iodothiazole-4- carboxamide as a pale yellow solid (700 mg, 37%). MS (ESI): Mass calcd. for C4H4IN3OS 268.91 m/z, found 270.0 [M+H] ⁺ .

Step B: (R)-5-Amino-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)thiazole-4-carboxamide. A mixture of (R)-3-hydroxy-1-methyl-3-(3-(3-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 400 mg, 1.04 mmol), 5-amino-2-iodothiazole-4-carboxamide (560 mg, 2.08 mmol), Pd(dtbpf)Cl2 (68 mg, 0.104 mmol), and 1 ,4-dioxane (15 mL) was sparged with N2 for 5 min, treated with KF (2.6 mL, 2.6 mmol, 1 M in H2O), and heated at 70 °C for 20 h under N2 atmosphere. The reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The mixture was filtered through a pad of diatomaceous earth, and the pad washed with EtOAc (25 mL). The filtrate was concentrated in vacuo. The residue was subjected to HPLC with a Boston Green ODS column, 5 pm, 150 x 30 mm; 20-50% CH3CN/H2O with 0.225% FA) to give, after lyophilization, (R)-5-amino-2-(3-(5- (3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)pheny l)thiazole-4-carboxamide as an off-white solid (91.8 mg, 22%). MS (ESI): Mass calcd. for C18H17N5O4S 399.10 m/z, found 400.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.27 (s, 1 H), 7.87 (d, J = 8.0 Hz, 2H), 7.63 - 7.54 (m, 1 H), 7.44 (s, 3H), 7.14 (br s, 1 H), 7.12 (s, 1 H), 6.75 (br s, 1 H), 3.53 - 3.43 (m, 2H), 2.85 (s, 3H), 2.62 - 2.54 (m, 1 H), 2.35 - 2.23 (m, 1 H). ¹ H NMR (400 MHz, CD3OD) 8 8.29 (s, 1 H), 7.91 - 7.80 (m, 2H), 7.59 - 7.51 (m, 1 H), 6.99 (s, 1 H), 3.63 - 3.56 (m, 2H), 2.99 (s, 3H), 2.80 - 2.72 (m, 1 H), 2.47 - 2.37 (m, 1 H).

Example 207: (R)-5-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)furan-2-carboxamide

A mixture consisting of (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 140 mg, 0.36 mmol), 5-bromo-2-furamide (75 mg, 0.40 mmol), K3PO4 (149 mg, 1 .09 mmol), 1 ,4- dioxane (5 mL), and water (0.5 mL) was sparged with N2 for 5 min, treated with Pd(dtbpf)Cl2 (24 mg, 0.036 mmol), and heated at 100 °C for 20 h. The reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The reaction mixture was then filtered through a pad of diatomaceous earth, and the pad washed with EtOAc (15 mL). The filtrate was concentrated to dryness in vacuo. The residue was subjected to HPLC (Boston Green ODS column 5 pm, 150 x 30 mm; 25-55% (v/v) CH3CN2O with 0.225% FA) to give, after lyophilization, (R)-5-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin- 3-yl)isoxazol-3-yl)phenyl)furan-2-carboxamide as a white solid (61.6 mg, 46%). MS (ESI): Mass calcd. for C19H17N3O5 367.12 m/z, found 368.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-cfe) 8 8.36 (s, 1 H), 8.09 (s, 1 H), 8.04 (d, J = 7.6 Hz, 1 H), 7.88 (d, J = 7.6 Hz, 1 H), 7.67 - 7.58 (m, 1 H), 7.54 (s, 1 H), 7.26 (d, J = 3.6 Hz, 1 H), 7.21 (d, J = 3.6 Hz, 1 H), 7.15 (s, 1 H), 6.79 (s, 1 H), 3.54 - 3.48 (m, 1 H), 2.85 (s, 3H), 2.63 - 2.54 (m, 1 H), 2.37 - 2.24 (m, 1 H). ¹ H NMR (400 MHz, CD3OD) 8 8.36 (s, 1 H), 7.98 (d, J = 8.0 Hz, 1 H), 7.86 (d, J = 8.0 Hz, 1 H), 7.63 - 7.54 (m, 1 H), 7.26 (d, J = 3.6 Hz, 1 H), 7.06 (d, J = 3.6 Hz, 1 H), 7.04 (s, 1 H), 3.65 - 3.55 (m, 2H), 2.99 (s, 3H), 2.83 - 2.71 (m, 1 H), 2.48 - 2.37 (m, 1 H). Example 208: (R)-5-Cyclopropyl-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)thiazole-4-carboxamide

Step A: Ethyl 5-cyclopropylthiazole-4-carboxylate. Ethyl 5-bromothiazole-4- carboxylate (2.00 g, 8.47 mmol), cyclopropylboronic acid (1.60 g, 18.6 mmol), K3PO4 (5.40 g, 25.4 mmol), and Pd(dppf)Cl2 (620 mg, 0.847 mmol) were added to a mixture of toluene (60 mL) and H2O (3 mL). The resultant mixture was sparged with N2 for 5 times and heated at 110 °C for 5 h. The reaction vessel was removed from the oil bath and allowed to gradually cool to RT. The mixture was filtered, and the filtrate concentrated to dryness in vacuo. The residue was subjected to silica gel chromatography (0-100% EtOAc/petroleum ether) to afford ethyl 5-cyclopropylthiazole-4-carboxylate as a yellow oil (1.44 g, 82.5%). MS (ESI): Mass calcd. for C9H11 NO2S 197.05 m/z, found 197.9 [M+1 ] ⁺ .

Step B: Ethyl 2-bromo-5-cyclopropylthiazole-4-carboxylate. NBS (1.95 g, 11.0 mmol) was added to a solution consisting of ethyl 5-cyclopropylthiazole-4-carboxylate (1.44 g, 7.30 mmol) in ACN (20 mL). The resulting mixture was heated at 70 °C for 18 h. The reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The mixture was then quenched with sat. aqueous NaHSOs (40 mL) and extracted with EtOAc (40 mL x 2). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to afford the product, which was subjected to silica gel chromatography (0-50% EtOAc/petroleum ether) to give ethyl 2-bromo-5- cyclopropylthiazole-4-carboxylate as a yellow oil (1.00 g, 40.6%). MS (ESI): Mass calcd. for C9HioBrN0 ₂ S 274.96 m/z, found 275.6 [M+1 ] ⁺ .

Step C: 2-Bromo-5-cyclopropylthiazole-4-carboxylic acid. Lithium hydroxide monohydrate (760 mg, 18.1 mmol) was added to a solution of ethyl 2-bromo-5- cyclopropylthiazole-4-carboxylate (1.0 g, 3.62 mmol) in THF (23 mL), water (4.6 mL), and methanol (2.3 mL). The resulting mixture was stirred for 2 h at rt. After this time, the reaction mixture was acidified to pH = 2 with 1 .0 M aqueous HCI and extracted with EtOAc (30 mL x 2). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give 2-bromo-5- cyclopropylthiazole-4-carboxylic acid (560 mg, 60.9%) as a pale-yellow solid. The product was used without further purification. MS (ESI): Mass calcd. for CyHeBrNCteS 246.93 m/z, found 247.6 [M+1 ] ⁺ .

Step D: 2-Bromo-5-cyclopropylthiazole-4-carboxamide. To a mixture consisting of 2-bromo-5-cyclopropylthiazole-4-carboxylic acid (560 mg, 2.26 mmol) and EtsN (0.94 mL, 6.77 mmol) in DMF (10 mL) was added HATU (1 .29 g, 3.39 mmol) and NH ₄ CI (1 .21 g, 22.6 mmol). The resulting mixture was stirred at room temperature for 12 h. After this time, the mixture was diluted with EtOAc (30 mL) and washed with H2O (10 x 3 mL). The combined organic extracts were dried over anhydrous Na2SO ₄ , filtered, and concentrated to dryness in vacuo. The residue was subjected to silica gel chromatography (0-100% EtOAc/petroleum ether) to afford 2-bromo-5- cyclopropylthiazole-4-carboxamide (410 mg, 71.4%) as a white solid. MS (ESI): Mass calcd. for CyHyBrN ₂ OS 245.95 m/z, found 247.9 [M+1 ] ⁺ .

Step E: (R)-5-Cyclopropyl-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)thiazole-4-carboxamide. A mixture consisting of 2-bromo-5- cyclopropylthiazole-4-carboxamide (178 mg, 0.721 mmol), (R)-3-hydroxy-1 -methyl-3-(3- (3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 230 mg, 0.599 mmol), K3PO ₄ (318 mg, 1.50 mmol), 1 ,4-dioxane (4 mL), and H2O (1 mL) was sparged with N2 for 5 min, treated with Pd(dppf)Cl2 (43.8 mg, 0.06 mmol), and heated at 100 °C for 3 h. After this time, the reaction vessel was removed from the oil bath and allowed to gradually cool to RT. The mixture was concentrated to dryness in vacuo. The residue was subjected to HPLC (Phenomenex Gemini-NX C18 column, 3 pm, 75 x 30 mm; 29-59% (v/v) CH3CN/H2O with 0.05% NH3H2O +10 mM NH ₄ HCO3) to give, after lyophilization, the title compound as a white solid (145.8 mg, 56%). MS (ESI): Mass calcd. for C2iH ₂ oN ₄ 0 ₄ S 424.12 m/z, found 425.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-c/e) 8 8.41 - 8.37 (m, 1 H), 8.03 (d, J = 7.6 Hz, 1 H), 7.98 - 7.92 (m, 2H), 7.63 - 7.56 (m, 2H), 7.14 (s, 1 H), 6.73 (s, 1 H), 3.50 - 3.35 (m, 3H), 2.81 (s, 3H), 2.58 - 2.50 (m, 1 H), 2.31 - 2.20 (m, 1 H), 1 .29 - 1 .21 (m, 2H), 0.76 - 0.69 (m, 2H). Example 209: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-(methylamino)thiazole-4-carboxamide

Step A: Ethyl 5-(methylamino)thiazole-4-carboxylate. 1 ,8- Diazabicyclo[5.4.0]undec-7-ene (10 mL, 68 mmol) was added to a mixture consisting of ethyl 5-bromothiazole-4-carboxylate (4.0 g, 17 mmol), methanamine hydrochloride (1.3 g, 19 mmol), and MeCN (30 mL). The resulting mixture was heated at 80 °C for 1 h via microwave irradiation. The reaction vessel was removed from the microwave heating device and allowed to gradually cool to rt. The mixture was concentrated to dryness in vacuo, and the residue subjected to HPLC (Xtimate C18 column, 5 pm, 150 x 40 mm; 11 -41 % MeCN/water with 0.05% NHs’FW) to give, after lyophilization, ethyl 5- (methylamino)thiazole-4-carboxylate as a yellow solid (560 mg, 15%). MS (ESI): Mass calcd. for C7H10N2O2S 186.05 m/z, found 187.1 [M+H] ⁺ .

Step B: 5-(Methylamino)thiazole-4-carboxylic acid. Sodium hydroxide (8.7 mL, 17 mmol, 2 M in H2O) was added to a mixture consisting of ethyl 5-(methylamino)thiazole- 4-carboxylate (540 mg, 2.90 mmol) and EtOH (5 mL). The resulting mixture was stirred for 16 h at room temperature. After this time, the mixture was acidified to pH = 2 with 1 N aqueous HCI (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford 5-(methylamino)thiazole-4-carboxylic acid as a colorless oil (318 mg, 58%). MS (ESI): Mass calcd. for C5H6N2O2S 158.01 m/z, found 158.6 [M+H] ⁺ .

Step C: 5-(Methylamino)thiazole-4-carboxamide. HATU (0.92 g, 2.41 mmol) was added to a mixture consisting of 5-(methylamino)thiazole-4-carboxylic acid (318 mg, 2.01 mmol), TEA (0.84 mL, 6.0 mmol, 0.725 g/mL), and DMF (6 mL). The resultant mixture was stirred for 30 min at room temperature, treated with NH4CI (1 .08 g, 20.1 mmol), and stirred for 16 h at room temperature. After this time, the mixture was poured into water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was subjected to silica gel chromatography (0-100% EtOAc/petroleum ether) to give 5-(methylamino)thiazole-4- carboxamide as a yellow solid (220 mg, 38%). MS (ESI): Mass calcd. for C5H7N3OS 157.03 m/z, found 157.7 [M+H] ⁺ .

Step D: 2-Bromo-5-(Methylamino)thiazole-4-carboxamide. 1-Bromopyrrolidine- 2, 5-dione (125 mg, 0.700 mmol) was added to a solution consisting of 5- (methylamino)thiazole-4-carboxamide (100 mg, 0.636 mmol) in MeCN (2 mL). The resultant mixture was stirred at 25 °C for 1 h. After this time, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was subjected to silica gel chromatography (0-100% EtOAc/petroleum ether) to afford 2-bromo-5- (methylamino)thiazole-4-carboxamide as a gray solid (80 mg, 53%). MS (ESI): Mass calcd. for CsHeBrNsOS 234.94 m/z, found 235.9 [M+1 ]+.

Step E: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-(methylamino)thiazole-4-carboxamide. 1 ,1'-Bis(di-te/t- butylphosphino)ferrocene palladium dichloride (22 mg, 0.034 mmol) was added to a mixture consisting of 2-bromo-5-(methylamino)thiazole-4-carboxamide (80 mg, 0.34 mmol), (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 104 mg, 0.271 mmol), K3PO4 (216 mg, 1.02 mmol) and 1 ,4-dioxane/H2O (2 mL, v/v = 4:1 ) under a N2 atmosphere. The resultant mixture was sparged with N2 for 5 min, and then heated for 1 hour at 80 °C via microwave irradiation. The reaction vessel was removed from the microwave heating device and allowed to gradually cool to rt. The mixture was poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was subjected to HPLC (Welch Xtimate C18 column, 5 |im, 150 x 30 mm; 30-60% MeCN/water with 0.05% NHs’FW + 10 mM NH4HCO3), and then subjected to SFC (DAICEL CHIRALCEL® OJ column, 10 pm, 250 mm x 30 mm; 40% EtOH (containing 0.1 % of NH3*H2O)/supercritical CO2), to give, after lyophilization, (R)-2-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazo l-3-yl)phenyl)-5- (methylamino)thiazole-4-carboxamide as a colorless solid (10.4 mg, 7%). MS (ESI): Mass calcd. for C19H19N5O4S 413.12 m/z, found 414.2 [M+1 ] ⁺ . ¹ H NMR (400 MHz, DMSO-c/e) 8 8.31 - 8.26 (m, 1 H), 7.93 - 7.89 (m, 1 H), 7.89 - 7.85 (m, 2H), 7.61 - 7.54 (m, 1 H), 7.43 (s, 1 H), 7.20 - 7.11 (m, 2H), 6.75 (s, 1 H), 3.51 - 3.41 (m, 2H), 2.99 (d, J = 4.9 Hz, 3H), 2.84 (s, 3H), 2.61 - 2.55 (m, 1 H), 2.31 - 2.24 (m, 1 H).

Example 210: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-(oxetan-3-ylamino)thiazole-4-carboxamide

Step A: 5-Bromothiazole-4-carboxamide. Ethyl 5-bromothiazole-4-carboxylate (2.0 g, 8.5 mmol) and ammonia hydrate (20 mL) were added to a 100 mL round- bottomed flask, and the resulting mixture stirred for 3 h at 40 °C. After this time, the reaction mixture was filtered through a pad of diatomaceous earth, and the filtrate concentrated to dryness in vacuo to give 5-bromothiazole-4-carboxamide as a yellow solid (1 .4 g). MS (ESI): Mass calcd. for C4H ₃ BrN ₂ OS 205.91 m/z, found 206.7 [M+H] ⁺ .

Step B: 5-(Oxetan-3-ylamino)thiazole-4-carboxamide. 5-Bromothiazole-4- carboxamide (2.0 g, 9.7 mmol), oxetan-3-amine (2.0 mL, 29 mmol), CS2CO3 (6.3 g, 19 mmol), and 1 ,4-dioxane (60 mL) were added to a 250 mL three port flask. The resulting mixture was sparged with N2 for 5 min, charged with RuPhos-Pd-G3 (80 mg, 0.968 mmol), and heated for 16 h at 80 °C. After this time, the reaction vessel was removed from the oil bath and allowed to gradually cool to room temperature. The reaction was then diluted with water (40 mL), extracted with ethyl acetate (70 mL x 3), and the combined extracts were treated with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give a yellow solid. The yellow solid was then subjected to HPLC purification (Boston Uni C18 column, 5 pm, 150 x 40 mm; 10-40% ACN/water with 0.225% FA) to give, after lyophilization, 5-(oxetan-3- ylamino)thiazole-4-carboxamide as a yellow solid (350 mg, 5%). MS (ESI): Mass calcd. for C7H9N3O2S 199.04 m/z, found 199.9 [M+1 ]+.

Step C: 2-Bromo-5-(oxetan-3-ylamino)thiazole-4-carboxamide. 5-(Oxetan-3- ylamino)thiazole-4-carboxamide (240 mg, 1.21 mmol) and ACN (10 mL) were added to a 50 mL round-bottomed flask, and charged with NBS (120 mg, 0.674 mmol) at 0 °C. The resulting mixture was stirred for 15 min at 0 °C, and then diluted with water (8 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give a white solid. The white solid was then subjected to HPLC (Boston Uni C18 column, 5 pm, 150 x 40 mm; 8-38% ACN/water with 0.225% FA) to give, after lyophilization, 2-bromo-5-(oxetan-3-ylamino)thiazole-4-carboxamide as a white solid (70 mg, 21 %). MS (ESI): Mass calcd. for CyHsBrNsCteS 276.95 m/z, found 277.8 [M+1] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.41 - 8.33 (m, 1 H), 7.37 - 7.21 (m, 2H), 4.81 - 4.73 (m, 2H), 4.58 - 4.52 (m, 2H), 4.50 - 4.40 (m, 1 H).

Step D: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-(oxetan-3-ylamino)thiazole-4-carboxamide. 2-Bromo-5-(oxetan-3- ylamino)thiazole-4-carboxamide (60 mg, 0.058 mmol), (R)-3-hydroxy-1 -methyl-3-(3-(3- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 34 mg, 0.088 mmol), K3PO4 (36 mg, 0.17 mmol), and 1 ,4-dioxane/H2O (1.8 mL, v/v = 4:1 ) were added to a 5 mL tube, which was subsequently evacuated and refilled with N2 (x 3), and then charged with Pd(dtbpf)Cl2 (6 mg, 0.009 mmol). The resulting mixture was heated for 1 h at 80 °C. The reaction vessel was removed from the oil bath and allowed to gradually cool to rt. After this time, the mixture was diluted with water (3 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic extracts were washed with brine (4 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give a white solid. The white solid was then subjected to HPLC (Welch Xtimate C18 column, 5 pm, 150 x 30 mm; 27-57% MeCN/H20 with 0.05% NH3H2O + 10 mM NH4HCO3)) to give, after lyophilization, the title compound as a colorless solid (3.6 mg, 13%). MS (ESI): Mass calcd. for C21 H21 N5O5S 455.13 m/z, found 456.2 [M+1 ] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.40 - 8.34 (m, 1 H), 8.31 - 8.22 (m, 1 H), 7.94 - 7.86 (m, 2H), 7.62 - 7.53 (m, 2H), 7.36 - 7.29 (m, 1 H), 7.12 (s, 1 H), 6.78 - 6.68 (m, 1 H), 4.91 - 4.78 (m, 2H), 4.66 - 4.50 (m, 3H), 3.54 - 3.41 (m, 2H), 2.84 (s, 3H), 2.62 - 2.56 (m, 1 H), 2.33 - 2.22 (m, 1 H).

Example 211 : (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-((1 -methyl-1 H-pyrazol-4-yl)amino)thiazole-4-carboxamide

Step A: Ethyl 5-((1 -methyl-1 /-/-pyrazol-4-yl)amino)thiazole-4-carboxylate. 1 ,8- diazabicyclo[5.4.0]undec-7-ene (5.1 mL, 34 mmol) was added to a mixture consisting of ethyl 5-bromothiazole-4-carboxylate (2.0 g, 8.5 mmol), 1 -methyl-1 /-/-pyrazol-4-amine (905 mg, 9.31 mmol), and MeCN (30 mL). The resulting mixture was heated at 80 °C via microwave irradiation. The reaction vessel was removed from microwave heating device and allowed to gradually cool to rt. The mixture was concentrated to dryness in vacuo, and the residue subjected to silica gel chromatography (0-30% EtOAc/petroleum ether) to afford ethyl 5-((1-methyl-1/-/-pyrazol-4-yl)amino)thiazole-4-carboxylate as a colorless solid (1.05 g, 47%).

Step B: Ethyl 2-bromo-5-((1-methyl-1 /-/-pyrazol-4-yl)amino)thiazole-4- carboxylate. 1 -Bromopyrrolidine-2, 5-dione (705 mg, 3.96 mmol) was added to a solution consisting of ethyl 5-((1 -methyl-1/-/-pyrazol-4-yl)amino)thiazole-4-carboxylate (1.0 g, 4.0 mmol) in MeCN (10 mL). The resulting mixture was heated at 70 °C for 16 h. The reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The mixture was poured into water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo, and the residue subjected to silica gel chromatography (0-50% EtOAc/petroleum ether) to afford ethyl 2-bromo-5-((1 -methyl- 1 /-/-pyrazol-4-yl)amino)thiazole-4-carboxylate as a yellow solid (872 mg, 63%). MS (ESI): Mass calcd. for CioHnBrN ₄ 0 ₂ S 329.98 m/z, found 330.7 [M+H] ⁺ .

Step C: (R)-Ethyl 2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-((1 -methyl-1 /-/-pyrazol-4-yl)amino)thiazole-4-carboxylate. 1 , 1 '-Bis(di-fe/Y- butylphosphino)ferrocene palladium dichloride (79 mg, 0.12 mmol) was added to a mixture consisting of ethyl 2-bromo-5-((1-methyl-1 /-/-pyrazol-4-yl)amino)thiazole-4- carboxylate (400 mg, 1.21 mmol), (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 464 mg, 1.21 mmol), K3PO4 (769 mg, 3.62 mmol) and 1 ,4-dioxane/H2O (8 mL, v/v = 4:1 ) under a N2 atmosphere. The resulting mixture was heated for 1 hour at 80 °C via microwave irradiation. The reaction vessel was removed from the microwave heating device and allowed to gradually cool to rt. The mixture was poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to dryness in vacuo, and the residue subjected to silica gel chromatography (0-100% EtOAc/petroleum ether) to afford (R)-ethyl 2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5- ((1 -methyl-1 H-pyrazol-4-yl)amino)thiazole-4-carboxylate as a yellow solid (136 mg, 18%). MS (ESI): Mass calcd. for C2 ₄ H2 ₄ N ₆ O ₅ S 508.15 m/z, found 509.1 [M+H] ⁺ .

Step D: (R)-N-(2,4-Dimethoxybenzyl)-2-(3-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5-((1 -methyl-1 /-/-pyrazol-4-yl)amino)thiazole-4- carboxamide. Trimethylaluminum (0.2 mL, 2 mmol) was added to a mixture consisting of (R)-ethyl 2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5-((1 - methyl-1 /-/-pyrazol-4-yl)amino)thiazole-4-carboxylate (100 mg, 0.197 mmol), (2,4- dimethoxyphenyl)methanamine (89 pL, 0.59 mmol) and toluene (1 mL). The resulting mixture was heated for 2 hours at 70 °C. After this time, the reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The mixture was quenched with MeOH (2 mL) and concentrated to dryness in vacuo. The residue was subjected to silica gel chromatography (0-100% EtOAc/petroleum ether) to afford (R)-N- (2,4-dimethoxybenzyl)-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-((1 -methyl-1 H-pyrazol-4-yl)amino)thiazole-4-carboxamide as a yellow solid (93 mg, 45%). MS (ESI): Mass calcd. for C31 H31 N7O6S 629.21 m/z, found 630.1 [M+1 ] ⁺ .

Step E: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-((1 -methyl-1 H-pyrazol-4-yl)amino)thiazole-4-carboxamide. 2,2,2- Trifluoroacetic acid (189 piL, 32.54 mmol) was added to a mixture consisting of (R)-N- (2,4-dimethoxybenzyl)-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-((1 -methyl-1 H-pyrazol-4-yl)amino)thiazole-4-carboxamide (80 mg, 0.13 mmol) in DCM (1 mL) and the resulting mixture stirred for 16 h at room temperature. After this time, the mixture was concentrated to dryness in vacuo. The residue was subjected to HPLC (Phenomenex Gemini-NX C18 column, 3 |im, 75 x 30 mm; 25-55% MeCN/water with 0.05% NHs’FW + 10 mM NH4HCO3) to give, after lyophilization, the title compound as a yellow solid (10.1 mg, 16%). MS (ESI): Mass calcd. for C22H21 N7O4S 479.14 m/z, found 480.2 [M+1 ] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 9.61 (s, 1 H), 8.29 (s, 1 H), 7.97 - 7.93 (m, 2H), 7.89 (d, J = 7.9 Hz, 1 H), 7.65 (s, 1 H), 7.62 - 7.56 (m, 2H), 7.41 (s, 1 H), 7.13 (s, 1 H), 6.74 (s, 1 H), 3.85 (s, 3H), 3.51 - 3.45 (m, 2H), 2.84 (s, 3H), 2.61 - 2.57 (m, 1 H), 2.32 - 2.23 (m, 1 H).

Example 212: (R)-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)thiazole-5-carboxamide.

1 ,1'-Bis(di-fe/Y-butylphosphino)ferrocene palladium dichloride (31 mg, 0.048 mmol) was added to a mixture consisting of 2-bromothiazole-5-carboxamide (100 mg, 0.483 mmol), (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 186 mg, 0.483 mmol), K3PO4 (308 mg, 1.45 mmol), and 1 ,4-dioxane/H2O = 4:1 (2 mL) under a N2 atmosphere. The resulting mixture was stirred for 1 hour at 80 °C via microwave irradiation. The reaction vessel was removed from the microwave heating device and allowed to gradually cool to rt. The mixture was concentrated to dryness in vacuo, and the residue subjected to HPLC (Welch Xtimate C18 column, 5 pm, 150 x 30 mm; 17-47% MeCN/water with 0.05% NH3*H2O + 10 mM NH4HCO3) to give, after lyophilization, the title compound (98 mg, 53%) as a colorless solid. MS (ESI): Mass calcd. for C18H16N4O4S 384.09 m/z, found 385.0 [M+1 ] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.49 (s, 1 H), 8.46 - 8.42 (m, 1 H), 8.26 (s, 1 H), 8.11 (d, J = 7.7 Hz, 1 H), 8.04 (d, J = 7.9 Hz, 1 H), 7.77 - 7.63 (m, 2H), 7.18 (s, 1 H), 6.76 (s, 1 H), 3.50 - 3.42 (m, 2H), 2.85 (s, 3H), 2.63 - 2.54 (m, 1 H), 2.33 - 2.23 (m, 1 H).

Example 213: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-((2-methoxypyridin-3-yl)amino)thiazole-4-carbox amide

Step A: Ethyl 5-((2-methoxypyridin-3-yl)amino)thiazole-4-carboxylate. A mixture consisting of ethyl 5-chlorothiazole-4-carboxylate (1.00 g, 5.22 mmol), 2- methoxypyridin-3-amine (1.26 g, 0.180 mmol), CsF (1.59g, 10.4 mmol), and DMF (10 mL) was heated at 150 °C for 4 h via microwave irradiation. The reaction vessel was removed from the microwave heating device and allowed to gradually cool to rt. The mixture was filtered, and the filter cake washed with EtOAc (25 mL). The filtrate was concentrated in vacuo to give a brown gum. The brown gum was subjected to silica gel chromatography (0-50% EtOAc/petroleum ether) to afford ethyl 5-((2-methoxypyridin-3- yl)amino)thiazole-4-carboxylate as an off-yellow solid (1.10 g, 74.3%). MS (ESI): Mass calcd. for C12H13N3O3S 279.07 m/z, found 279.7 [M+H] ⁺ .

Step B: Ethyl 2-bromo-5-((2-methoxypyridin-3-yl)amino)thiazole-4-carboxyla te. Ethyl 5-((2-methoxypyridin-3-yl)amino)thiazole-4-carboxylate (1.00 g, 3.58 mmol) and DMF (10.0 mL) were added to a 40 mL vial and the resulting mixture cooled to 0 °C (ice/water), treated with NBS (796 mg, 4.48 mmol), and stirred at 0 °C for 2 h. After this time, the mixture was concentrated to dryness in vacuo, and the residue was subjected to silica gel chromatography (0-30% EtOAc/petroleum ether) to afford ethyl 2-bromo-5- ((2-methoxypyridin-3-yl)amino)thiazole-4-carboxylate as an off-white solid (650 mg, 46%). MS (ESI): Mass calcd. for Ci2Hi2BrN ₃ O ₃ S 355.98 m/z, found 356.1 [M+H] ⁺ .

Step C: (R)-Ethyl 2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-((2-methoxypyridin-3-yl)amino)thiazole-4-carbox ylate. (R)-3-Hydroxy-1 - methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5- yl)pyrrolidin-2-one (Intermediate 4, 107 mg, 0.279 mmol), Pd(dtbpf)Cl2 (18.2 mg, 0.028 mmol), K3PO4 (0.558 mL, 0.558 mmol, 1 N in H2O), and 1 ,4-dioxane (1 .50 mL) were added to a 8 mL vial, which was subsequently evacuated and refilled with Ar (x3). The resulting mixture was treated with a solution of ethyl 2-bromo-5-((2-methoxypyridin-3- yl)amino)thiazole-4-carboxylate (100 mg, 0.279 mmol) in 1 ,4-dioxane (1.50 mL) dropwise over 1 .5 h at 85 °C, and then the resulting mixture was heated at 85 °C for 1 h. After this time, the reaction vessel was removed from the heating device and allowed to gradually cool to rt. The mixture was filtered, and the filtrate concentrated in vacuo to give a yellow oil. The oil was subjected to silica gel chromatography (0-15% MeOH/CH2Cl2) to afford (R)-ethyl 2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)-5-((2-methoxypyridin-3-yl)amino)thi azole-4-carboxylate (240 mg, 80%) as a yellow oil. LCMS (ESI): Mass calcd. for C26H25N5O6S 535.15 m/z, found 535.9 [M+H] ⁺ .

Step D: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-((2-methoxypyridin-3-yl)amino)thiazole-4-carbox amide. (R)-Ethyl 2-(3-(5-(3- hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)- 5-((2-methoxypyridin-3- yl)amino)thiazole-4-carboxylate (145 mg, 0.271 mmol) and 7 M NH ₃ in MeOH (15 mL) was added to a 40 mL vial. The resulting mixture was heated at 75 °C for 16 h. The reaction vessel was removed from heat and allowed to gradually cool to rt. The mixture was filtered, and the filtrate concentrated in vacuo to give a yellow oil. The yellow oil was then subjected to silica gel chromatography (0-15% MeOH/CH2Cl2), and then subjected to HPLC (Welch Xtimate C18 column, 5 pm, 150 x 30 mm; 37-67% MeCN/water with 0.05% NH ₃ H2O + 10 mM NH4HCO ₃ ) to give, after lyophilization, (R)-2- (3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5-((2- methoxypyridin-3-yl)amino)thiazole-4-carboxamide as a yellow solid (31.5 mg, 16%). MS (ESI): Mass calcd. for C24H22N6O5S 506.14 m/z, found 507.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-cfe) 8 11 .03 (s, 1 H), 8.40 (s, 1 H), 8.08 (d, J = 7.6 Hz, 1 H), 7.98 - 7.88 (m, 2H), 7.86 - 7.81 (m, 1 H), 7.77 (d, J = 7.6 Hz, 1 H), 7.67 - 7.59 (m, 2H), 7.16 (s, 1 H), 7.13 - 7.07 (m, 1 H), 6.75 (s, 1 H), 4.01 (s, 3H), 3.53 - 3.40 (m, 2H), 2.85 (s, 3H), 2.62 - 2.54 (m, 1 H), 2.35 - 2.25 (m, 1 H). ¹ H NMR (400 MHz, MeOH-d ₄ ) 8 8.38 (s, 1 H), 8.00 (d, J = 7.2 Hz, 1 H), 7.87 (d, J = 7.2 Hz, 1 H), 7.78 (d, J = 4.4 Hz, 1 H), 7.71 (d, J = 7.6 Hz, 1 H), 7.63 - 7.51 (m, 1 H), 7.15 - 6.94 (m, 2H), 4.08 (s, 3H), 3.69 - 3.53 (m, 2H), 3.00 (s, 3H), 2.84 - 2.67 (m, 1 H), 2.53 - 2.35 (m, 1 H).

Example 214: (R)-2-Bromo-5-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)thiazole-4-carboxamide

Step A: 2,5-Dibromothiazole-4-carboxamide. Methyl 2,5-dibromothiazole-4- carboxylate (2.0 g, 6.6 mmol) and NH3 (40 mL, 7 M in MeOH) were added to a 250 mL three port flask, and the resulting mixture stirred for 1.5 h at 50 °C. After this time, the reaction vessel was removed from the oil bath and allowed to gradually cool to room temperature. The reaction mixture was filtered, and the filtrate concentrated to dryness in vacuo to give 2,5-dibromothiazole-4-carboxamide as a white solid (800 mg). MS (ESI): Mass calcd. for C4H ₂ Br2N ₂ OS 283.83 m/z found 284.6 [M+H] ⁺ .

Step B: (R)-5-Bromo-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)thiazole-4-carboxamide. 2,5-Dibromothiazole-4-carboxamide (714 mg, 2.50 mmol), (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 500 mg, 1.30 mmol), K2CO3 (1.0 g, 7.74 mmol), and 1 ,4-dioxane/H2O (4:1 ) (20 mL) were added to a 100 mL three port flask, which was subsequently evacuated and refilled with N2 (x 3), and charged with Pd(dppf)Cl2 (186 mg, 0.254 mmol). The resulting mixture was stirred for 3 h at 50 °C. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (25 mL x 3). The combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give a white solid, which was subjected to HPLC (Xtimate C18 column, 5 pm, 150 x 40 mm; 25-55% MeCN/H ₂ O with 0.05% NH3H2O) to give (R)-5-bromo-2-(3-(5-(3- hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)thiazole-4 -carboxamide as a white solid (10 mg, 7%). MS (ESI): Mass calcd. for CwHisBrlSkCMS 462.00 m/z found 462.7 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.47 (s, 1 H), 8.17 - 8.09 (m, 2H), 8.08 - 8.02 (m, 1 H), 7.77 (br s, 1 H), 7.72 - 7.63 (m, 1 H), 7.19 (s, 1 H), 6.76 (s, 1 H), 3.51 - 3.41 (m, 2H), 2.85 (s, 3H), 2.62 - 2.54 (m, 1 H), 2.33 - 2.22 (m, 1 H).

Step C: (R)-2-Bromo-5-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)thiazole-4-carboxamide. (R)-5-Bromo-2-(3-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)thiazole-4-carboxami de (20 mg, 0.043 mmol) was subjected to SFC (DAICEL CHIRALCEL® OD-H column, 5 pm, 250 x 30 mm; 45- 55% (v/v) EtOH (containing 0.1 % NH3*H2O)/CO2)) to give two products. First eluting: title compound as a colorless solid (4 mg, 20%). LC-MS (ESI): RT = 1.38 min, MS (ESI): Mass calcd. for CisHisBrN^S 462.00 m/z found 463.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-c/e) 8 8.05 - 8.02 (m, 1 H), 7.96 - 7.91 (m, 1 H), 7.90 - 7.87 (m, 1 H), 7.69 - 7.63 (m, 2H), 7.61 - 7.54 (m, 1 H), 7.04 (s, 1 H), 6.75 (s, 1 H), 3.49 - 3.43 (m, 2H), 2.84 (s, 3H), 2.59 - 2.55 (m, 1 H), 2.34 - 2.21 (m, 1 H).

Example 215: (R)-5-Bromo-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)thiazole-4-carboxamide (R)-5-Bromo-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)thiazole-4-carboxamide was isolated during the purification of (R)-2-bromo-5- (3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)thiazole-4 - carboxamide (Example 214), eluting out as the second compound, yielding the title compound as a colorless solid (10 mg, 49%). MS (ESI): Mass calcd. for CisHisBrlSUCMS 462.00 m/z found 463.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.49 - 8.45 (m, 1 H), 8.17 - 8.10 (m, 2H), 8.08 - 8.03 (m, 1 H), 7.77 (s, 1 H), 7.71 - 7.66 (m, 1 H), 7.19 (s, 1 H), 6.77 (s, 1 H), 3.50 - 3.42 (m, 2H), 2.85 (s, 3H), 2.60 - 2.54 (m, 1 H), 2.35 - 2.24 (m, 1 H).

Example 216: (R)-5-((1 -Acetylazetidin-3-yl)amino)-2-(3-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)thiazole-4-carboxami de

Step A: 5-Chlorothiazole-4-carboxamide. A mixture consisting of ethyl 5- chlorothiazole-4-carboxylate (1650 mg, 8.6 mmol), and NH4OH (10 mL, 7 M in MeOH) was stirred for 4 h at 35 °C. After this time, the mixture was filtered. The filter cake was washed with H2O (50 mL) and dried in vacuo to give 5-chlorothiazole-4-carboxamide as a light yellow solid (1 .0 g, 71 %). ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 9.04 (s, 1 H), 7.81 (br s, 1 H), 7.67 (br s, 1 H).

Step B: 5-((1 -Acetylazetidin-3-yl)amino)thiazole-4-carboxamide. 5- Chlorothiazole-4-carboxamide (500 mg, 3.1 mmol), 1 -(3-aminoazetidin-1 -yl)ethanone (695 mg, 4.6 mmol), CS2CO3 (2.5 g, 7.7 mmol), and MeCN (10 mL) were added to a 20 mL vial. The resulting mixture was heated at 80 °C for 20 h. After this time, the reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The mixture was combined with other 3 batches, filtered, and the filtrate concentrated to dryness in vacuo to give a brown gum, which was subjected to silica gel chromatography (0-10% MeOH/CH2Cl2) to afford 5-((1-acetylazetidin-3-yl)amino)thiazole-4-carboxamide (500 mg, 17%) as a light brown solid. MS (ESI): Mass calcd. for C9H12N4O2S 240.07 m/z, found 240.6 [M+H] ⁺ .

Step C: 5-((1-Acetylazetidin-3-yl)amino)-2-iodothiazole-4-carboxamid e. A mixture consisting of 5-((1-acetylazetidin-3-yl)amino)thiazole-4-carboxamide (250 mg, 1.04 mmol) and ACN (10 mL) was treated with NIS (272 mg, 1.04 mmol) in one portion. The resulting mixture was stirred at room temperature for 30 min. After this time, the mixture was concentrated in vacuo to give an orange solid, which was subjected to silica gel chromatography (0-10% MeOH/CH2Cl2) to afford 5-((1-acetylazetidin-3-yl)amino)-2- iodothiazole-4-carboxamide (150 mg, 39%) as a light brown solid.

Step D: (R)-5-((1-Acetylazetidin-3-yl)amino)-2-(3-(5-(3-hydroxy-1-me thyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)thiazole-4-carboxami de. (R)-3-Hydroxy-1-methyl- 3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2- one (Intermediate 4, 126 mg, 0.330 mmol), Pd(dtbpf)Cl2 (36 mg, 0.055 mmol), K3PO4 (1.1 mL, 1.1 mmol, 1 M in H2O), 5-((1-acetylazetidin-3-yl)amino)-2-iodothiazole-4- carboxamide (200 mg, 0.068 mmol, in 5 mL of 1 ,4-dioxane), and 1 ,4-dioxane (5 mL) were added to a 20 mL vial, which was subsequently evacuated and refilled with N2 for 3 times. The resulting mixture was stirred for 2 h at 80 °C. After this time, the reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The mixture was filtered through a pad of diatomaceous earth, and the pad washed with EtOAc (25 mL). The filtrate was concentrated in vacuo to give a brown gum, which was subjected to HPLC (Boston Green ODS column, 5 pm, 150 x 30 mm; 20-50% (v/v) CH3CN/H2O with 0.225% FA) to give, after lyophilization, (R)-5-((1-acetylazetidin-3-yl)amino)-2-(3-(5- (3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)pheny l)thiazole-4-carboxamide as an off-white solid (18.7 mg, 7%). MS (ESI): Mass calcd. for C23H24N6O5S 496.15 m/z, found 497.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 88.35 - 8.23 (m, 2H), 7.93 (d, J = 8.0 Hz, 1 H), 7.89 (d, J = 8.0 Hz, 1 H), 7.65 - 7.54 (m, 2H), 7.32 (br s, 1 H), 7.12 (s, 1 H), 6.77 (s, 1 H), 4.46 (d, J = 7.6 Hz, 1 H), 4.28 - 4.19 (m, 2H), 4.19 - 4.12 (m, 1 H), 3.88 - 3.79 (m, 1 H), 3.54 - 3.52 (m, 2H), 2.84 (s, 3H), 2.59 (br d, J = 2.4 Hz, 1 H), 2.32 - 2.23 (m, 1 H), 1.78 (s, 3H). ¹ H NMR (400 MHz, CD3OD) 88.38 - 8.29 (m, 1 H), 7.96 - 7.90 (m, 1 H), 7.89 - 7.84 (m, 1 H), 7.60 - 7.53 (m, 1 H), 7.00 (s, 1 H), 4.67 - 4.60 (m, 1 H), 4.45 - 4.32 (m, 2H), 4.24 (dd, J = 4.4, 8.8 Hz, 1 H), 3.98 (dd, J = 4.4, 9.6 Hz, 1 H), 3.65 - 3.55 (m, 2H), 2.99 (s, 3H), 2.80 - 2.71 (m, 1 H), 2.47 - 2.38 (m, 1 H), 1 .93 (s, 3H).

Example 217: (R)-2-(3-(5-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazo l-3- yl)phenyl)-5-methylthiazole-4-carboxamide

Step A: Ethyl 2-bromo-5-methylthiazole-4-carboxylate. NBS (3.12 g, 17.5 mmol) was added to a solution consisting of ethyl 5-methylthiazole-4-carboxylate (2.00 g, 11.7 mmol) in ACN (20 mL). The reaction was heated at 70 °C for 18 h. After this time, the reaction vessel was removed from the oil bath and allowed to gradually cool to room temperature. The reaction was quenched with sat. aqueous NaHSOs (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was subjected to silica gel chromatography (0-100% EtOAc/petroleum ether), and then subjected to HPLC (Xtimate C18 column, 5 pm, 150 x 40 mm; 31-61 % CH3CN/H2O with 0.05% NH3H2O) to give, after lyophilization, ethyl 2-bromo-5- methylthiazole-4-carboxylate as a white solid (600 mg, 20.5%). MS (ESI): Mass calcd. for C7H ₈ BrNO ₂ S 250.11 m/z, found 251 .8 [M+1 ] ⁺ . ¹ H NMR (400 MHz, CDCI3) 84.45 - 4.34 (m, 2H), 2.71 (d, J = 3.1 Hz, 3H), 1.45 - 1.34 (m, 3H).

Step B: (R)-Ethyl 2-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-methylthiazole-4-carboxylate. Ethyl 2-bromo-5-methylthiazole-4- carboxylate (220 mg, 0.880 mmol), (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 280 mg, 0.729 mmol), K3PO4 (390 mg, 1 .84 mmol), Pd(dppf)Cl2 (55 mg, 0.075 mmol), 1 ,4- dioxane (4 mL), and H2O (1 mL) were added to a 8 mL vial. The resultant mixture was evacuated and refilled with N2 for 3 times, and then heated at 100 °C for 12 h. The reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The resultant mixture was diluted with H2O (15 mL) and extracted with dichloromethane (15 mL x 3). The combined organic extracts were washed with H2O (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was subjected to silica gel chromatography (0-100% EtOAc/petroleum ether) to give (R)- ethyl 2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5- methylthiazole-4-carboxylate as a yellow solid (280 mg, 70.4%). MS (ESI): Mass calcd. for C21 H21 N3O5S 427.12 m/z, found 428.0 [M+1 ] ⁺ .

Step C: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-methylthiazole-4-carboxamide. (R)-Ethyl 2-(3-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5-methylthiazole-4- carboxylate (260 mg, 0.608 mmol) was added into a solution of 7 M NH3 in MeOH (26 mL, 182 mmol). The resultant mixture was stirred for 72 h at 50 °C. After this time, the mixture was concentrated in vacuo. The residue was subjected to HPLC (Phenomenex Gemini-NX C18 column, 3 pm, 75 x 30 mm; 24-54% (v/v) CH3CN/H2O with 0.04% NH3H2O + 10 mM NH4HCO3) to give, after lyophilization, (R)-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-methylthiazole-4-carboxamide as a white solid (106.8 mg, 43.9%). MS (ESI): Mass calcd. for C19H18N4O4S 398.10 m/z found 399.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-c/e) 8 8.44 - 8.48 (m, 1 H) 8.05 - 8.10 (m, 1 H) 7.96 - 8.02 (m, 2 H) 7.63 - 7.69 (m, 1 H) 7.58 (br s, 1 H) 7.17 (s, 1 H) 6.75 (s, 1 H) 3.39 - 3.54 (m, 1 H) 3.39 - 3.54 (m, 1 H) 2.85 (s, 3 H) 2.80 (s, 3 H) 2.55 - 2.62 (m, 1 H) 2.23 - 2.35 (m, 1 H).

Example 218: (R)-5-Ethyl-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)thiazole-4-carboxamide Step A: (R)-Methyl 5-ethyl-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)thiazole-4-carboxylate. 1 , 1 '-Bis(di-te/Y-butylphosphino)ferrocene palladium dichloride (26 mg, 0.040 mmol) was added to a mixture consisting of methyl

2-bromo-5-ethylthiazole-4-carboxylate (100 mg, 0.400 mmol), (R)-3-hydroxy-1 -methyl-3- (3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 154 mg, 0.400 mmol), K3PO4 (255 mg, 1.20 mmol), and 1 ,4- dioxane/FW = 4:1 (2 mL) under N2 atmosphere. The resulting mixture was stirred for 1 hour at 80 °C via microwave irradiation. The reaction vessel was removed from the microwave heating device and allowed to gradually cool to rt. The mixture was concentrated to dryness in vacuo, and the residue subjected to silica gel chromatography (0-100% EtOAc/petroleum ether) to afford (R)-methyl 5-ethyl-2-(3-(5- (3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)thiazole-4 -carboxylate (150 mg, 85%) as a yellow oil. MS (ESI): Mass calcd. for C21 H21 N3O5S 427.12 m/z, found 428.1 [M+H] ⁺ .

Step B: (R)-5-Ethyl-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)thiazole-4-carboxamide. NH3 in MeOH (4.0 mL, 28 mmol) was added to a solution of (R)-methyl 5-ethyl-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-

3-yl)phenyl)thiazole-4-carboxylate (150 mg, 0.351 mmol) in MeOH (2 mL). The resulting mixture was stirred for 40 h at 50 °C. After this time, the mixture was concentrated to dryness in vacuo, and the residue subjected to HPLC (Phenomenex Gemini-NX C18 column, 3 pm, 75 x 30 mm; 30-60% MeCN/water with 0.04% NH3*H2O + 10 mM NH4HCO3) to give, after lyophilization, the title compound as a colorless solid (62 mg, 43%). MS (ESI): Mass calcd. for C20H20N4O4S 412.46 m/z, found 413.2 [M+1 ] ⁺ . ¹ H NMR (400 MHz, DMSO-c/e) 8 8.49 - 8.44 (m, 1 H), 8.10 (d, J = 7.9 Hz, 1 H), 8.04 - 7.95 (m, 2H), 7.69 - 7.62 (m, 1 H), 7.58 (s, 1 H), 7.17 (s, 1 H), 6.75 (s, 1 H), 3.53 - 3.41 (m, 2H), 3.34 - 3.31 (m, 2H), 2.85 (s, 3H), 2.61 - 2.54 (m, 1 H), 2.32 - 2.24 (m, 1 H), 1.32 - 1 .27 (m, 3H).

Example 219: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-isopropylthiazole-4-carboxamide

Step A: (R)-Methyl 2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-isopropylthiazole-4-carboxylate. Methyl 2-bromo-5-isopropylthiazole-4- carboxylate (100 mg, 0.379 mmol), (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 189 mg, 0.472 mmol), K3PO4 (241 mg, 1.14 mmol), and 1 ,4-dioxane/H2O (4:1 ) (2 mL) were added to a 25 mL three port flask, which was subsequently evacuated and refilled with N2 (x 3), and charged with Pd(dtbpf)Cl2 (25 mg, 0.038 mmol). The resulting mixture was stirred for 1 h at 90 °C. The reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The reaction was then diluted with water (3 mL), extracted with ethyl acetate (5 mL x 3), and the combined extracts were washed with brine (4 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give a yellow solid. The yellow solid was subjected to silica gel chromatography (0-100% ethyl acetate/petroleum ether) to give (R)-methyl 2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin- 3-yl)isoxazol-3-yl)phenyl)-5-isopropylthiazole-4-carboxylate as a white solid (150 mg, 76%). MS (ESI): Mass calcd. for C22H23N3O5S 441.14 m/z, found 442.1 [M+1 ] ⁺ .

Step B: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-isopropylthiazole-4-carboxamide. (R)-Methyl2-(3-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5-isopropylthiazole -4-carboxylate (135 mg, 0.306 mmol) and NH3 (5.4 mL, 7 M in MeOH) were added to a 25 mL round-bottomed flask. And the resulting mixture stirred for 16 h at 50 °C. After this time, the mixture was concentrated to dryness in vacuo to give a yellow solid. The solid was then subjected to HPLC (Welch Xtimate C18 column, 5 pm, 150 x 30 mm 40-70% MeCN/FW with 0.05% NH3H2O + 10 mM NH4HCO3) to give (R)-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)-5-isopropylthiazole-4-carboxamide as a colorless solid (42 mg, 32%). MS (ESI): Mass calcd. for C21H22N4O4S 426.14 m/z found 427.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-cfe) 8 8.48 - 8.45 (m, 1 H), 8.14 - 8.10 (m, 1 H), 8.02 - 7.98 (m, 2H), 7.68 - 7.58 (m, 2H), 7.19 (s, 1 H), 6.76 (s, 1 H), 4.39 - 4.29 (m, 1 H), 3.53 - 3.41 (m, 2H), 2.85 (s, 3H), 2.63 - 2.54 (m, 1 H), 2.37 - 2.23 (m, 1 H), 1.35 - 1 .29 (m, 6H).

Example 220: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-isobutylthiazole-4-carboxamide

Step A: Methyl 2-bromo-5-isobutylthiazole-4-carboxylate. f-BuONO (1.69 mL, 14.1 mmol) was added to a solution consisting of methyl 2-amino-5-isobutylthiazole-4- carboxylate (1.00 g, 4.67 mmol) and CuBr ₂ (2.06 g, 9.24 mmol) in CH3CN (25 mL). The resulting mixture was heated at 50 °C for 2 h. After this time, the suspension was filtered and the filtrate concentrated to dryness in vacuo. The residue was subjected to silica gel chromatography (eluent: PE : EA: = 1 :0 to 3:1 ) to afford methyl 2-bromo-5- isobutylthiazole-4-carboxylate as a red oil (1.15 g, 86.0%). MS (ESI): Mass calcd. for C9Hi ₂ BrNO ₂ S 276.98 m/z, found 277.6 [M+1 ] ⁺ .

Step B: (R)-Methyl 2-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-isobutylthiazole-4-carboxylate. Methyl 2-bromo-5-isobutylthiazole-4- carboxylate (260 mg, 0.935 mmol), (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 300 mg, 0.781 mmol), K3PO4 (418 mg, 1 .97 mmol), Pd(dppf)CI ₂ (59 mg, 0.081 mmol), 1 ,4- dioxane (4 mL), and H2O (1 mL) were added to a 40 mL vial. The resultant mixture was purged with N2 for 5 min and then stirred for 12 h at 100 °C. The reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The mixture was diluted with H2O (15 mL) and extracted with dichloromethane (15 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was subjected to silica gel chromatography (0-100% EtOAc/petroleum ether) to afford (R)-methyl 2-(3-(5-(3- hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)- 5-isobutylthiazole-4- carboxylate as a yellow solid (220 mg, 52% yield). MS (ESI): Mass calcd. for C23H25N3O5S 455.15 m/z, found 456.1 [M+1 ] ⁺ .

Step C: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-isobutylthiazole-4-carboxamide. (R)-Methyl 2-(3-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5-isobutylthiazole- 4-carboxylate (220 mg, 0.483 mmol) was added into a solution of 7 M NH3 in MeOH (21 mL, 147 mmol). The resultant mixture was stirred for 70 h at 50 °C. After this time, the mixture was concentrated in vacuo. The residue was subjected to HPLC (Phenomenex Gemini-NX C18 column, 3 pm, 75 x 30 mm; 36-66% (v/v) CH3CN/H2O with 0.05% NH3H2O +10 mM NH4HCO3) to give, after lyophilization, (R)-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-isobutylthiazole-4-carboxamide as a white solid (93 mg, 42%). MS (ESI): Mass calcd. for C22H24N4O4S 440.15 m/z found 441.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-c/e) 8 8.51 - 8.44 (m, 1 H), 8.14 - 8.07 (m, 1 H), 8.04 - 7.96 (m, 2H), 7.69 - 7.61 (m, 1 H), 7.57 (br s, 1 H), 7.18 (s, 1 H), 6.75 (s, 1 H), 3.53 - 3.40 (m, 2H), 3.24 (d, J = 7.2 Hz, 2H), 2.85 (s, 3H), 2.62 - 2.53 (m, 1 H), 2.35 - 2.22 (m, 1 H), 2.01 - 1 .86 (m, 1 H), 0.95 (d, J = 6.8 Hz, 6H).

Example 221 : (R)-5-Cyclobutyl-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)thiazole-4-carboxamide

Step A: Methyl 2-amino-5-cyclobutylthiazole-4-carboxylate. A solution of NaOMe (2.79 g, 51 .6 mmol) in MeOH (40 mL) was added to a mixture consisting of methyl 2,2- dichloroacetate (5.33 mL, 47.7 mmol) and cyclobutanecarbaldehyde (3.90 g, 46.4 mmol) in THF (40 mL) dropwise at 0 °C. The resultant mixture was stirred at 0 °C for 1 hour. After this time, the reaction mixture was quenched with H2O (120 mL) and extracted with ethyl acetate (80 mL x 2). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to afford a colorless oil. Thiourea (3.51 g, 46.1 mmol) and the colorless oil were added to MeOH (40 mL) and the resulting mixture was refluxed for 16 h. After this time, the mixture was concentrated to dryness in vacuo, and the residue subjected to silica gel chromatography (0-100% EtOAc/petroleum ether) to afford methyl 2-amino-5- cyclobutylthiazole-4-carboxylate as a yellow solid (400 mg, 4%). MS (ESI): Mass calcd. for C9H12N2O2S 212.06 m/z, found 213.0 [M+1 ] ⁺ .

Step B: Methyl 2-bromo-5-cyclobutylthiazole-4-carboxylate. f-BuONO (0.85 mL, 7.12 mmol) was added to a solution consisting of methyl 2-amino-5-cyclobutylthiazole- 4-carboxylate (500 mg, 2.36 mmol), CuBr2 (1.04 g, 4.66 mmol), and CH3CN (10 mL). The resultant mixture was stirred for 2 h at 50 °C. After this time, the suspension was filtered and the filtrate concentrated to dryness in vacuo. The residue was subjected to silica gel chromatography (0-25% EtOAc/petroleum ether) to afford methyl 2-bromo-5- cyclobutylthiazole-4-carboxylate (440 mg, 67.6%) as a yellow oil. MS (ESI): Mass calcd. for C9HioBrN0 ₂ S 274.96 m/z, found 275.7 [M+1 ] ⁺ .

Step C: (R)-Methyl 5-cyclobutyl-2-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)thiazole-4-carboxylate. Methyl 2-bromo-5-cyclobutylthiazole-4- carboxylate (260 mg, 0.942 mmol), (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 300 mg, 0.781 mmol), K3PO4 (418 mg, 1 .97 mmol), Pd(dppf)CI ₂ (59 mg, 0.081 mmol), 1 ,4- dioxane (4 mL), and H2O (1 mL) were added to a 10 mL flask, and the resulting mixture purged with N2 for 5 min and then stirred for 12 h at 100 °C. The reaction vessel was removed from the oil bath and allowed to gradually cool to RT. The reaction mixture was diluted with H2O (15 mL) and extracted with dichloromethane (15 mL x 3). The combined organic extracts were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was subjected to silica gel chromatography (0-100% EtOAc/petroleum ether) to afford (R)-methyl 5- cyclobutyl-2-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl) isoxazol-3- yl)phenyl)thiazole-4-carboxylate as a yellow oil (260 mg, 59.1 % yield). MS (ESI): Mass calcd. for C23H23N3O5S 453.14 m/z, found 454.0 [M+1] ⁺ .

Step D: (R)-5-Cyclobutyl-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)thiazole-4-carboxamide. (R)-Methyl 5-cyclobutyl-2-(3-(5-(3- hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)t hiazole-4-carboxylate (260 mg, 0.573 mmol) was added to a solution of 7 M NH3 in MeOH (25 mL, 175 mmol), and the resulting mixture was stirred for 70 h at 50 °C. After this time, the mixture was concentrated in vacuo. The residue was subjected to HPLC (Phenomenex Gemini-NX C18 column, 3 pm, 75 x 30 mm (35-65% CH3CN/H2O with 0.05% NH3H2O + 10 mM NH4HCO3)) to give, after lyophilization, (R)-5-cyclobutyl-2-(3-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)thiazole-4-carboxami de as a white solid (103.3 mg, 40.8%). MS (ESI): Mass calcd. for C22H22N4O4S 438.14 m/z, found 439.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.50 - 8.45 (m, 1 H), 8.15 - 8.09 (m, 1 H), 8.04 - 7.98 (m, 1 H), 7.94 (br s, 1 H), 7.70 - 7.61 (m, 1 H), 7.57 (br s, 1 H), 7.19 (s, 1 H), 6.75 (s, 1 H), 4.74 - 4.61 (m, 1 H), 3.54 - 3.39 (m, 2H), 2.85 (s, 3H), 2.63 - 2.52 (m, 3H), 2.35 - 2.24 (m, 1 H), 2.14 - 1.95 (m, 3H), 1.94 - 1.83 (m, 1 H).

Example 222: (R)-5-(Difluoromethyl)-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)thiazole-4-carboxamide

Step A: Methyl 2-bromo-5-(dibromomethyl)thiazole-4-carboxylate. To a mixture consisting of methyl 2-bromo-5-methylthiazole-4-carboxylate (500 mg, 2.12 mmol), N- bromosuccinimide (1.36 g, 6.35 mmol), and carbon tetrachloride (20 mL) in a 40 mL vial was added benzoyl peroxide (103 mg, 0.42 mmol) in one portion. The resulting mixture was stirred for 3 h at 80 °C. After this time, the reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The orange mixture was combined with 3 other batches of reaction mixture and concentrated in vacuo to give an orange solid, which was subjected to silica gel chromatography (0-10% EtOAc/petroleum ether) to afford methyl 2-bromo-5-(dibromomethyl)thiazole-4-carboxylate (3.0 g, 90%) as a pale yellow oil. MS (ESI): Mass calcd. for Ceb^BrsNChS 390.75 m/z, found 391.8 [M+H] ⁺ .

Step B Methyl 2-bromo-5-formylthiazole-4-carboxylate. Methyl 2-bromo-5- (dibromomethyl)thiazole-4-carboxylate (500 mg, 1.27 mmol), silver nitrate (524 mg, 5.08 mmol), ethanol (10 mL), and water (1 mL) were added to a 40 mL vial. The resulting mixture was stirred for 3 h at 80 °C. After this time, the reaction vessel was removed from the heating device and allowed to gradually cool to rt. The mixture was combined with the other 3 batches, filtered through a pad of diatomaceous earth and the pad washed with EtOAc (50 mL). The filtrate was diluted with EtOAc (100 mL) and washed with water (20 mL x 3) and brine (20 mL x 3), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a white solid, which was subjected to silica gel chromatography (0-10% EtOAc/petroleum ether) to give methyl 2- bromo-5-formylthiazole-4-carboxylate (1.0 g, 79%) as a white solid. ¹ H NMR (400 MHz, CDCh) 8 10.61 (s, 1 H), 4.07 (s, 3H).

Step C: Methyl 2-bromo-5-(difluoromethyl)thiazole-4-carboxylate. Methyl 2- bromo-5-formylthiazole-4-carboxylate (750 mg, 3.00 mmol) and CH2CI2 (30 mL) were added to a 100 mL three-necked round-bottomed flask. The resulting mixture was cooled with an ice/water bath, treated with DAST (1 .94 mL, 12.0 mmol, in 2.5 mL of anhydrous CH2CI2) dropwise over a course of 10 min, and stirred for 2 h at 0 °C. After this time, the reaction was quenched with saturated aqueous NaHCOs (25 mL) at 0 °C and extracted with CH2CI2 (25 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and the filtrate concentrated in vacuo to give a pale yellow gum, which was subjected to silica gel chromatography (0-10% EtOAc/petroleum ether) to give methyl 2-bromo-5-(difluoromethyl)thiazole-4-carboxylate as a colorless oil (600 mg, 74%).

Step D: 2-Bromo-5-(difluoromethyl)thiazole-4-carboxamide. Methyl 2-bromo-5- (difluoromethyl)thiazole-4-carboxylate (500 mg, 1.84 mmol), and MeOH (5 mL) were added to a 40 mL vial. NH3 (2.6 mL, 18 mmol, 7 M in MeOH) was added in one portion. The vial was capped and stirred for 4 h at room temperature. The mixture was concentrated in vacuo to give a white solid, which was subjected to silica gel chromatography (0-50% EtOAc/petroleum ether) to afford 2-bromo-5- (difluoromethyl)thiazole-4-carboxamide as a white solid (380 mg, 80%).

Step E: (R)-5-(Difluoromethyl)-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)thiazole-4-carboxamide. (R)-3-Hydroxy-1 -methyl-3-(3-(3- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 314 mg, 0.817 mmol), 2-bromo-5-(difluoromethyl)thiazole-4- carboxamide (300 mg, 1.17 mmol), NaHCOs (196 mg, 2.33 mmol), Pd(dtbpf)Cl2 (76 mg, 0.12 mmol), H2O (1 mL), and 1 ,4-dioxane (10 mL) were added to a 40 mL vial. The vial was subsequently evacuated and refilled with N2 3 times. The vial was capped and heated at 80 °C for 2 h. After this time, the reaction vessel was removed from the heating device and allowed to gradually cool to rt. The mixture was filtered through a pad of diatomaceous earth, and the pad washed with MeOH (10 mL). The filtrate was concentrated to dryness in vacuo to give a brown gum. The gum was subjected to HPLC (Boston Green ODS column, 5 pm, 150 x 30 mm; 25-55% CH3CN/H2O with 0.225% FA), and then subjected to SFC (DAICEL CHIRALCEL® AS column, 10 pm, 250 x 30 mm; 70% EtOH (containing 0.1 % NHsFhOj/supercritical CO2) to give, after lyophilization, (R)-5-(difluoromethyl)-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)thiazole-4-carboxamide as a white solid (65.3 mg, 13%). MS (ESI): Mass calcd. for C19H16F2N4O4S 434.09 m/z, found 435.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-cfe) 8 8.59 (s, 1 H), 8.37 (s, 1 H), 8.23 (d, J = 8.0 Hz, 1 H), 8.13 - 7.77 (m, 3H), 7.75 - 7.66 (m, 1 H), 7.22 (s, 1 H), 6.78 (s, 1 H), 3.54 - 3.41 (m, 2H), 2.85 (s, 3H), 2.62 - 2.54 (m, 1 H), 2.34 - 2.24 (m, 1 H). ¹ H NMR (400 MHz, CD3OD) 8 8.54 (s, 1 H), 8.14 (d, J = 8.0 Hz, 1 H), 8.05 - 7.71 (m, 2H), 7.68 - 7.61 (m, 1 H), 7.04 (s, 1 H), 3.66 - 3.55 (m, 2H), 2.99 (s, 3H), 2.83 - 2.70 (m, 1 H), 2.48 - 2.38 (m, 1 H).

Example 223: (R)-5-((Cyclopentylamino)methyl)-2-(3-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)thiazole-4-carboxami de

Step A: Methyl 2-bromo-5-(bromomethyl)thiazole-4-carboxylate. Methyl 2-bromo- 5-methylthiazole-4-carboxylate (100 mg, 0.424 mmol), /V-bromosuccinimide (75.4 mg, 0.424 mmol), benzoyl peroxide (20.5 mg, 0.085 mmol), and carbon tetrachloride (4 mL) were added to an 8 mL vial. The resulting mixture was stirred for 3 h at 80 °C. The reaction vessel was removed from the heating device and allowed to gradually cool to rt. The reaction mixture was concentrated in vacuo to give an orange solid, which was then subjected to silica gel chromatography (0-10% EtOAc/petroleum ether) to afford methyl 2-bromo-5-(bromomethyl)thiazole-4-carboxylate as a pale yellow oil (70 mg, 52%). ¹ H NMR (400 MHz, CDCh) 8 5.12 - 5.00 (m, 2H), 4.03 - 3.96 (m, 3H).

Step B: Methyl 2-bromo-5-((cyclopentylamino)methyl)thiazole-4-carboxylate. Methyl 2-bromo-5-(bromomethyl)thiazole-4-carboxylate (200 mg, 0.635 mmol), cyclopentanamine (54.1 mg, 0.635 mmol), DIPEA (0.221 mL, 1.27 mmol), and CH2CI2 (3 mL) were added to a 8 mL vial, and the resulting mixture stirred for 16 h at rt. After this time, the mixture was concentrated in vacuo to give a orange solid, which was then subjected to silica gel chromatography (0-20% EtOAc/petroleum ether) to afford methyl

2-bromo-5-((cyclopentylamino)methyl)thiazole-4-carboxylat e as a yellow oil (100 mg, 49%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 84.10 (s, 2H), 3.81 (s, 3H), 3.13 - 3.06 (m, 1 H), 2.93 (s, 1 H), 1 .77 - 1 .67 (m, 2H), 1 .66 - 1 .58 (m, 2H), 1.51 - 1 .43 (m, 2H), 1.36 - 1 .25 (m, 2H).

Step C: (R)-Methyl 5-((cyclopentylamino)methyl)-2-(3-(5-(3-hydroxy-1-methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)thiazole-4-carboxyla te. (R)-3-Hydroxy-1-methyl-

3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2- one (Intermediate 4, 102 mg, 0.265 mmol), methyl 2-bromo-5- ((cyclopentylamino)methyl)thiazole-4-carboxylate (84.7 mg, 0.265 mmol), Pd(dtbpf)Cl2 (17.3 mg, 0.027 mmol), K3PO4 (113 mg, 0.531 mmol), 1 ,4-dioxane (3.00 mL), and H2O (0.3 mL) were added to an 8 mL vial, which was subsequently evacuated and refilled with Ar (x3), and then stirred for 3 h at 85 °C. The reaction vessel was removed from the heating device and allowed to gradually cool to room temperature. The reaction mixture was then concentrated in vacuo to give a brown oil, which was subjected to silica gel chromatography (0-20% MeOH/CH2Cl2) to afford (R)-methyl 5- ((cyclopentylamino)methyl)-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)thiazole-4-carboxylate as a dark yellow oil (200 mg, 98%). MS (ESI): Mass calcd. for C25H28N4O5S 496.18 m/z, found 497.3 [M+H] ⁺ .

Step D: (R)-5-((Cyclopentylamino)methyl)-2-(3-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)thiazole-4-carboxami de. (R)-Methyl 5- ((cyclopentylamino)methyl)-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)thiazole-4-carboxylate (190 mg, 0.383 mmol) and NH3 (15 mL, 0.105 mol, 7 M in MeOH) were added to a 40 mL vial and the resulting mixture heated to 50 °C and stirred for 16 h. The reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The mixture was concentrated to dryness in vacuo, and the residue subjected to HPLC (Welch Xtimate C18 column, 5 μm, 150 x 30 mm; 30-60% MeCN/water with 0.05% NH3H2O + 10 mM NH4HCO3) to give, after lyophilization, (R)-5- ((cyclopentylamino)methyl)-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)thiazole-4-carboxamide as yellow solid (52.3 mg, 25%). MS (ESI): Mass calcd. for C24H27N5O4S 481.18 m/z, found 482.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 5 8.46 (s, 1 H), 8.11 (d, J = 7.6 Hz, 1 H), 8.02 - 7.94 (m, 2H), 7.68 - 7.61 (m, 1 H), 7.58 (s, 1 H), 7.17 (s, 1 H), 6.75 (s, 1 H), 4.24 (s, 2H), 3.52 - 3.46 (m, 2H), 3.18 - 3.05 (m, 1 H), 2.85 (s, 3H), 2.63 - 2.53 (m, 2H), 2.35 - 2.21 (m, 1 H), 1 .80 - 1 .69 (m, 2H), 1 .68 - 1 .59 (m, 2H), 1.53 - 1.42 (m, 2H), 1.41 - 1.29 (m, 2H). ¹ H NMR (400 MHz, MeOH-d ₄ ) 8 8.50 (s, 1 H), 8.10 (d, J = 7.6 Hz, 1 H), 7.97 (d, J = 7.6 Hz, 1 H), 7.66 - 7.60 (m, 1 H), 7.03 (s, 1 H), 4.32 (s, 2H), 3.65 - 3.55 (m, 2H), 3.23 - 3.14 (m, 1 H), 2.99 (s, 3H), 2.82 - 2.72 (m, 1 H), 2.48 - 2.38 (m, 1 H), 1.98 - 1 .86 (m, 2H), 1.82 - 1 .70 (m, 2H), 1 .66 - 1 .54 (m, 2H), 1.51 - 1.40 (m, 2H).

Example 224: (R)-3-Hydroxy-3-(3-(3-(4-methoxy-1 /-/-pyrazolo[3,4-b]pyridin-6- yl)phenyl)isoxazol-5-yl)-1 -methylpyrrolidin-2-one

Step A: Ethyl 5-amino-1-(4-methoxybenzyl)-1 /-/-pyrazole-4-carboxylate. (4- Methoxybenzyl) hydrazine (4.9 g, 33 mmol) was added to a solution consisting of (E)- ethyl 2-cyano-3-ethoxyacrylate (5.0 g, 30 mmol) and anhydrous EtOH (70 mL). The resulting mixture was heated at 90 °C for 16 h. The reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The reaction mixture was filtered through a pad of diatomaceous earth. The filtrate was diluted with CH2CI2 (30 mL), washed with H2O (30 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was subjected to silica-gel chromatography (0-30% EtOAc/petroleum ether) to afford ethyl 5-amino-1-(4- methoxybenzyl)-1/-/-pyrazole-4-carboxylate (1.8 g, 22%) as a white solid. MS (ESI): Mass calcd. for C14H17N3O3 275.12, m/z found 276.2 [M+H] ⁺ .

Step B: Ethyl 1-(4-methoxybenzyl)-4,6-dioxo-4,5,6,7-tetrahydro-1/-/-pyrazo lo[3,4- b]pyridine-5-carboxylate. Diethyl malonate (0.873 g, 5.45 mmol) was dissolved in anhydrous EtOH (8 mL), then cooled to 0 °C (ice water bath). Then, a 20% solution of NaOEt (1.85 g, 5.45 mmol) in EtOH was added dropwise (within 10 min) at 0 °C. The cooling bath was removed and the reaction was stirred at room temperature for 15 min, treated with ethyl 5-amino-1-(4-methoxybenzyl)-1/-/-pyrazole-4-carboxylate (300 mg, 1 .09 mmol) in portions (within 2 min), and heated at 90 °C under reflux condensation for 3 days. The reaction was cooled to room temperature and concentrated to dryness in vacuo. The residue was combined with 7 other batches of this reaction, suspended in CH2Cl2 (200 mL) and extracted with H2O (100 mL *3). The combined aqueous phases were concentrated to dryness in vacuo to afford ethyl 1-(4-methoxybenzyl)-4,6-dioxo- 4,5,6,7-tetrahydro-1/-/-pyrazolo[3,4-b]pyridine-5-carboxylat e (10 g) as a yellow solid. MS (ESI): Mass calcd. for C17H17N3O5 343.1 m/z, found 344.1 [M+H] ⁺ .

Step C: 1-(4-Methoxybenzyl)-1/-/-pyrazolo[3,4-b]pyridine-4,6-diol. Sodium hydroxide (7.5 g, 188 mmol) was slowly added to H2O (42 mL) within 10 minutes. After the previous mixture had cooled to room temperature, the sodium hydroxide mixture and ethyl 1 -(4-methoxybenzyl)-4,6-dioxo-4,5,6,7-tetrahydro-1 /-/-pyrazolo[3,4-b]pyridine- 5-carboxylate (5 g, 15 mmol) were added to a 250 mL three-neck round-bottomed flask equipped with a condenser, and a thermometer. The resulting mixture was heated at 100 °C for 16 h. The reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The reaction mixture was then neutralized to pH 6-7 with 2 M aqueous HCI and filtered. The filter cake was dried in vacuo to afford 1 -(4- methoxybenzyl)-1 /-/-pyrazolo[3,4-b]pyridine-4,6-diol (1 g, 25%) as a pink solid. MS (ESI): Mass calcd. for C14H13N3O3 271 .09, m/z found 272.1 [M+H] ⁺ .

Step D: 4,6-Dichloro-1 -(4-methoxybenzyl)-1 /-/-pyrazolo[3,4-b]pyridine. A mixture consisting of 1 -(4-methoxybenzyl)-1 /-/-pyrazolo[3,4-b]pyridine-4,6-diol (1.00 g, 3.69 mmol) and phenylphosphonic dichloride (5.0 mL) was heated at 150 °C for 3 h. The reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The reacion mixture was then poured into ice water (200 mL), neutralized with 28% NH4OH to pH 7-8, and extracted with DCM (40 mL x 3). The combined extracts were washed with brine (20 mL), dried with anhydrous Na2SO4, filtered, and concentrated in vacuo to afford a residue, which was subjected to silica gel chromatography (0-20% EtOAc/petroleum ether) to afford 4,6-dichloro-1-(4-methoxybenzyl)-1 /-/-pyrazolo[3,4- b]pyridine (348 mg, 30%) as a white solid. MS (ESI): Mass calcd. for C14H11 CI2N3O 307.02 m/z, found 308.0 [M+H] ⁺ .

Step E: 6-Chloro-4-methoxy-1 -(4-methoxybenzyl)-1 /-/-pyrazolo[3,4-b]pyridine. To a solution consisting of 4,6-dichloro-1 -(4-methoxybenzyl)-1 /-/-pyrazolo[3,4-b]pyridine (348 mg, 1.13 mmol) in anhydrous THF (5.0 mL) was added NaOMe (0.90 mL, 0.90 mmol, 1 .0 M in THF) dropwise within 2 min. The resultant mixture was stirred for 2 h at 60 °C. The reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The reaction mixture was then purified by silica gel chromatography (0-10% EtOAc/petroleum ether) to afford 6-chloro-4-methoxy-1 -(4-methoxybenzyl)-1 /-/- pyrazolo[3,4-b]pyridine as a white solid (215 mg, 62%). ¹ H NMR (400 MHz, CDCI3) 8 7.99 (s, 1 H), 7.32 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 6.53 (s, 1 H), 5.55 (s, 2H), 4.02 (s, 3H), 3.77 (s, 3H).

Step F: (R)-3-Hydroxy-3-(3-(3-(4-methoxy-1 -(4-methoxybenzyl)-1 /-/-pyrazolo[3,4- b]pyridin-6-yl)phenyl)isoxazol-5-yl)-1 -methylpyrrolidin-2-one. (R)-3-Hydroxy-1 -methyl-3- (3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 190 mg, 0.026 mmol), 6-chloro-4-methoxy-1-(4-methoxybenzyl)-1 /-/- pyrazolo[3,4-b]pyridine (150 mg, 0.49 mmol), K3PO4 (336 mg, 1.48 mmol), 1 ,4-dioxane (8 mL), and water (0.8 mL) were added to a 20 mL microwave tube, which was subsequently evacuated and refilled with argon (x 3). The mixture was treated with Pd(dtbpf)Cl2 (32 mg, 0.049 mmol), and heated at 100 °C for 2 h under N2. The reaction vessel was removed from oil bath and allowed to gradually cool to rt. The mixture was then filtered through a pad of diatomaceous earth, and the pad washed with EtOAc (15 mL). The filtrate was concentrated to dryness in vacuo. The residue was subjected to silica gel chromatography (0-100% EtOAc/petroleum ether) to afford (R)-3-hydroxy-3-(3- (3-(4-methoxy-1 -(4-methoxybenzyl)-1 /-/-pyrazolo[3,4-b]pyridin-6-yl)phenyl)isoxazol-5-yl)- 1 -methylpyrrolidin-2-one as a pale yellow gum (200 mg, 77%). MS (ESI): Mass calcd. for C29H27N5O5 525.20, m/z found 526.2 [M+H] ⁺ .

Step G: (R)-3-Hydroxy-3-(3-(3-(4-methoxy-1 /-/-pyrazolo[3,4-b]pyridin-6- yl)phenyl)isoxazol-5-yl)-1 -methylpyrrolidin-2-one. A solution consisting of (R)-3-hydroxy- 3-(3-(3-(4-methoxy-1 -(4-methoxybenzyl)-1 /-/-pyrazolo[3,4-b]pyridin-6-yl)phenyl)isoxazol- 5-yl)-1 -methylpyrrolidin-2-one (200 mg, 0.38 mmol) and TFA (10 mL) was stirred at room temperature for 20 h. After this time, the mixture was concentrated in vacuo. The residue was subjected to HPLC with a Boston Green ODS 150 x 30 mm x 5 pm column (eluent: 25-55% (v/v) CH3CN and H2O with 0.225% FA) to give, after lyophillization, (R)- 3-hydroxy-3-(3-(3-(4-methoxy-1 /-/-pyrazolo[3,4-b]pyridin-6-yl)phenyl)isoxazol-5-yl)-1 - methylpyrrolidin-2-one (73.7 mg, 48.0%) as a white solid. MS (ESI): Mass calcd. for C21 H19N5O4 405.4, m/z found 406.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 13.66 (s, 1 H), 8.64 (s, 1 H), 8.31 (d, J = 8.0 Hz, 1 H), 8.15 (s, 1 H), 7.98 (d, J = 7.6 Hz, 1 H), 7.72 - 7.63 (m, 1 H), 7.34 (s, 1 H), 7.12 (s, 1 H), 6.77 (s, 1 H), 4.17 (s, 3H), 3.53 - 3.45 (m, 2H), 2.86 (s, 3H), 2.63 - 2.55 (m, 1 H), 2.35 - 2.25 (m, 1 H). ¹ H NMR (400 MHz, CD3OD) 8 8.60 - 8.54 (m, 1 H), 8.22 (d, J = 8.4 Hz, 1 H), 8.11 (s, 1 H), 7.94 (d, J = 8.0 Hz, 1 H), 7.68 - 7.60 (m, 1 H), 7.21 (s, 1 H), 7.02 (s, 1 H), 4.19 (s, 3H), 3.63 - 3.57 (m, 2H), 2.99 (s, 3H), 2.81 - 2.72 (m, 1 H), 2.48 - 2.38 (m, 1 H). Example 225: (R)-3-Hydroxy-1 -methyl-3-(3-(3-(4-(trifluoromethyl)-1 /-/-pyrazolo[3,4- b]pyridin-6-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one

Step A: 4-lodo-1 /-/-pyrazolo[3,4-b]pyridine 7-oxide. A solution consisting of 4- iodo-1 /-/-pyrazolo[3,4-b]pyridine (750 mg, 3.1 mmol) and CH2CI2 (15 mL) was added m- CPBA (1 .24 g, 6.1 mmol, 85% purity) in portions over 2 min. The mixture was stirred for 18 h at room temperature. After this time, the mixture was diluted with 25 mL of MTBE and filtered. The filter cake was washed with MTBE (15 mL) and concentrated to dryness in vacuo to afford 4-iodo-1 /-/-pyrazolo[3,4-b]pyridine 7-oxide as a pale yellow solid (600 mg, 75%). MS (ESI): Mass calcd. for C6H4IN3O 261 .02, m/z found 262.0 [M+H] ⁺ .

Step B: 6-Chloro-4-iodo-1 /-/-pyrazolo[3,4-b]pyridine. To a mixture consisting of 4- iodo-1 /-/-pyrazolo[3,4-b]pyridine 7-oxide (600 mg, 2.3 mmol) and MeCN (5 mL) was added POCI3 (1 .5 mL) in portions over 2 min. The resultant mixture was stirred for 2 h at room temperature. After this time, the mixture was neutralized with 1 N aqueous NaOH and filtered. The filter cake was washed with water and concentrated to dryness in vacuo to afford the title compound, 6-chloro-4-iodo-1 /-/-pyrazolo[3,4-b]pyridine, as a pale yellow solid (600 mg, 93%). MS (ESI): Mass calcd. for C6H3CIIN3 278.90, m/z found 279.9 [M+H] ⁺ .

Step C: 6-Chloro-4-iodo-1 -(tetrahydro-2/-/-pyran-2-yl)-1 /-/-pyrazolo[3,4-b]pyridine. A mixture consisting of 6-chloro-4-iodo-1 /-/-pyrazolo[3,4-b]pyridine (300 mg, 1.07 mmol), pyridinium p-toluenesulfonate (45 mg, 0.11 mmol), 3,4-dihydro-2/-/-pyran (0.29 mL, 3.2 mmol), and CH2CI2 (5.0 mL) was refluxed for 18 h under a N2 atmosphere. The reaction vessel was removed from the oil bath and allowed to gradually cool to RT. The reaction mixture was concentrated to dryness in vacuo. The residue was purified by silica gel chromatography (0-20% EtOAc/petroleum ether) to afford 6-chloro-4-iodo-1 -(tetrahydro- 2/-/-pyran-2-yl)-1 /-/-pyrazolo[3,4-b]pyridine as a pale yellow solid (180 mg, 46%). MS (ESI): Mass calcd. for C11 H11 CIIN3O 362.96, m/z found 364.0 [M+H] ⁺ . Step D: 6-Chloro-1 -(tetrahydro-2/-/-pyran-2-yl)-4-(trifluoromethyl)-1 H- pyrazolo[3,4-b]pyridine. 6-Chloro-4-iodo-1 -(tetrahydro-2/-/-pyran-2-yl)-1 /-/-pyrazolo[3,4- b]pyridine (120 mg, 0.33 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (159 mg, 0.83 mmol), Cui (157 mg, 0.83 mmol), and DMF (2.5 mL) were added to an 8 mL vial. The resulting mixture was purged with N2 for 5 minutes, and then heated at 100 °C for 20 h. The reaction vessel was removed from oil bath and allowed to gradually cool to room temperature. The reaction mixture was then filtered through a pad of diatomaceous earth, and the pad washed with EtOAc (15 mL). The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (0-20% EtOAc/petroleum ether) to afford 6-chloro-1-(tetrahydro-2/-/-pyran-2-yl)-4- (trifluoromethyl)-1/-/-pyrazolo[3,4-b]pyridine as a pale yellow solid (50 mg, 50%). MS (ESI): Mass calcd. for C12H11CIF3N3O 305.05, m/z found 222.1 [M-THP] ⁺ .

Step E: (R)-3-Hydroxy-1 -methyl-3-(3-(3-(1 -(tetrahydro-2/-/-pyran-2-yl)-4- (trifluoromethyl)-1/-/-pyrazolo[3,4-b]pyridin-6-yl)phenyl)is oxazol-5-yl)pyrrolidin-2-one. A mixture consisting of (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 63 mg, 0.16 mmol), 6-chloro-1 -(tetrahydro-2H-pyran-2-yl)-4-(trifluoromethyl)-1 /-/-pyrazolo[3,4- b]pyridine (50 mg, 0.16 mmol), K3PO4(67 mg, 0.49 mmol), 1 ,4-dioxane (5 mL), and water (0.5 mL) was sparged with N2 for 5 minutes, treated with Pd(dtbpf)Cl2 (16 mg, 0.025 mmol), and heated at 100 °C for 2 h under a N2 atmosphere. The reaction vessel was removed from the oil bath and allowed to gradually cool to room temperature. The reaction mixture was filtered through a pad of diatomaceous earth and the pad washed with EtOAc (15 mL). The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc/petroleum ether) to afford (R)-3-hydroxy-1- methyl-3-(3-(3-(1-(tetrahydro-2/-/-pyran-2-yl)-4-(trifluorom ethyl)-1/-/-pyrazolo[3,4- b]pyridin-6-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (65 mg, 77%) as a pale yellow solid. MS (ESI): Mass calcd. for C26H24F3N5O4527.17, m/z found 528.2 [M+H] ⁺ .

Step F: (R)-3-Hydroxy-1 -methyl-3-(3-(3-(4-(trifluoromethyl)-1 /-/-pyrazolo[3,4- b]pyridin-6-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. To a solution consisting of (R)-3- hydroxy-1 -methyl-3-(3-(3-(1 -(tetrahydro-2H-pyran-2-yl)-4-(trifluoromethyl)-1 H- pyrazolo[3,4-b]pyridin-6-yl)phenyl)isoxazol-5-yl)pyrrolidin- 2-one (60 mg, 0.114 mmol) and MeOH (2.5 mL) was added HCI (2.5 mL, 2.0 mmol, 4 M in 1 ,4-dioxane) in one portion. The resultant mixture was stirred for 2 h at room temperature. After this time, the mixture was concentrated in vacuo. The residue was subjected to HPLC (Boston Green ODS column, 5 pm, 150 x 30 mm; 40-70% (v/v) CH3CN/H2O with 0.225% FA) to give, after lyophillization, (R)-3-hydroxy-1 -methyl-3-(3-(3-(4-(trifluoromethyl)-1 /-/- pyrazolo[3,4-b]pyridin-6-yl)phenyl)isoxazol-5-yl)pyrrolidin- 2-one as a white solid (16.6 mg, 33%). MS (ESI): Mass calcd. for C21 H16F3N5O3 443.4 m/z, found 444.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 14.38 (br s, 1 H), 8.72 (s, 1 H), 8.41 (d, J = 8.0 Hz, 1 H), 8.35 (d, J = 1 .2 Hz, 1 H), 8.32 (s, 1 H), 8.05 (d, J = 8.0 Hz, 1 H), 7.76 - 7.68 (m, 1 H), 7.20 (s, 1 H), 6.79 (s, 1 H), 3.54 - 3.46 (m, 2H), 2.86 (s, 3H), 2.64 - 2.55 (m, 1 H), 2.35 - 2.24 (m, 1 H). ¹ H NMR (400 MHz, CDCI3) 8 12.17 (br s, 1 H), 8.40 (s, 1 H), 8.23 (d, J = 1.2 Hz, 1 H), 8.04 (d, J = 8.0 Hz, 1 H), 7.82 - 7.75 (m, 2H), 7.56 - 7.47 (m, 1 H), 6.85 (s, 1 H), 5.30 (br s, 1 H), 3.71 - 3.62 (m, 1 H), 3.59 - 3.49 (m, 1 H), 3.03 (s, 3H), 2.85 - 2.76 (m, 1 H), 2.57 - 2.46 (m, 1 H).

Example 226: (R)-3-(3-(3-(1 /-/-Pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)isoxazol-5-yl)-3- hydroxy-1-methylpyrrolidin-2-one

Step A: 6-Chloro-1 -(tetrahydro-2/-/-pyran-2-yl)-1/-/-pyrazolo[3,4-c/]pyrimidin e. A mixture consisting of 6-chloro-1 /-/-pyrazolo[3,4-c/]pyrimidine (1.0 g, 6.5 mmol), pyridinium p-toluenesulfonate (271 mg, 0.65 mmol), 3,4-dihydro-2/-/-pyran (1.2 mL, 12.9 mmol), and CH2CI2 (15.0 mL) was refluxed for 18 h under a N2 atmosphere. The reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The mixture was then concentrated to dryness in vacuo and the residue subjected to silica gel chromatography (0-40% EtOAc/petroleum ether) to give 6-chloro-1 -(tetrahydro-2/-/- pyran-2-yl)-1 /-/-pyrazolo[3,4-c/]pynmidine as a white solid (1.2 g, 78%). ¹ H NMR (400 MHz, CDCI3) 8 9.06 (s, 1 H), 8.22 (s, 1 H), 6.11 - 6.03 (m, 1 H), 4.19 - 4.10 (m, 1 H), 3.89 - 3.79 (m, 1 H), 2.66 - 2.53 (m, 1 H), 2.22 - 2.12 (m, 1 H), 2.01 - 1.93 (m, 1 H), 1.85 - 1.73 (m, 2H), 1.72 - 1.67 (m, 1 H).

Step B: (R)-3-Hydroxy-1 -methyl-3-(3-(3-(1 -(tetrahydro-2/-/-pyran-2-yl)-1 H- pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)isoxazol-5-yl)pyrrolidi n-2-one. A mixture consisting of (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 90 mg, 0.23 mmol), 6-chloro-1 - (tetrahydro-2/-/-pyran-2-yl)-1 /-/-pyrazolo[3,4-c/]pyrimidine (61.5 mg, 0.26 mmol), K3PO4 (159 mg, 0.70 mmol), 1 ,4-dioxane (5.0 mL), and water (0.5 mL) was sparged with N2 for 5 minutes, treated with Pd(dtbpf)Cl2 (31 mg, 0.047 mmol), and then heated at 100 °C for 18 h under N2 atmosphere. The reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The mixture was then filtered through a pad of diatomaceous earth, and the pad washed with EtOAc (10 mL). The filtrate was concentrated to dryness in vacuo and the residue subjected to silica gel chromatography (0-100% EtOAc/petroleum ether) to give (R)-3-hydroxy-1 -methyl-3-(3- (3-(1 -(tetrahydro-2/-/-pyran-2-yl)-1 /-/-pyrazolo[3,4-c(]pynmidin-6-yl)phenyl)isoxazol-5- yl)pyrrolidin-2-one as a yellow solid (70 mg, 65%). MS (ESI): Mass calcd. for C24H24N6O4 460.18, m/z found 461 .2 [M+H] ⁺ .

Step C: (R)-3-(3-(3-(1 /-/-Pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)isoxazol-5-yl)-3- hydroxy-1 -methylpyrrolidin-2-one. A solution consisting of (R)-3-hydroxy-1 -methyl-3-(3- (3-(1 -(tetrahydro-2/-/-pyran-2-yl)-1 /-/-pyrazolo[3,4-c(]pynmidin-6-yl)phenyl)isoxazol-5- yl)pyrrolidin-2-one (70 mg, 0.15 mmol), and MeOH (2.5 mL) was added HCI/1 ,4-dioxane (2.5 mL, 10 mmol, 4.0 M in 1 ,4-dioxane) in one portion. The resultant mixture was stirred for 2 h at room temperature and then concentrated to dryness in vacuo. The residue was subjected to HPLC (Boston Green ODS column, 5 pm, 150 x 30 mm, 25- 55% (v/v) CH3CN/H2O with 0.225% FA) to afford, after lyophilization, (R)-3-(3-(3-(1 H- pyrazolo[3,4-c/]pyrimidin-6-yl)phenyl)isoxazol-5-yl)-3-hydro xy-1-methylpyrrolidin-2-one as a white solid (20.1 mg, 35%). MS (ESI): Mass calcd. for C19H16N6O3 376.12, m/z found 377.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCI3) 5 11 .64 (br s, 1 H), 9.27 (s, 1 H), 8.79 (s, 1 H), 8.54 (d, J = 8.0 Hz, 1 H), 8.20 (s, 1 H), 7.93 (d, J = 7.6 Hz, 1 H), 7.59 - 7.50 (m, 1 H), 6.88 (s, 1 H), 4.84 (br s, 1 H), 3.70 - 3.61 (m, 1 H), 3.58 - 3.49 (m, 1 H), 3.04 (s, 3H), 2.88 - 2.76 (m, 1 H), 2.58 - 2.46 (m, 1 H). ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 14.16 (br s, 1 H), 9.48 (s, 1 H), 9.04 - 8.95 (m, 1 H), 8.61 (d, J = 8.0 Hz, 1 H), 8.40 (s, 1 H), 8.05 (d, J = 7.6 Hz, 1 H), 7.78 - 7.67 (m, 1 H), 7.07 (s, 1 H), 6.75 (s, 1 H), 3.54 - 3.42 (m, 2H), 2.86 (s, 3H), 2.65 - 2.56 (m, 1 H), 2.34 - 2.24 (m, 1 H).

Example 227: (R)-3-Hydroxy-1 -methyl-3-(3-(3-(1 -methyl-1 /-/-pyrazolo[3,4-d]pyrimidin-6- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one

Step A: 6-Chloro-1 -methyl-1/-/-pyrazolo[3,4-c/]pyrimidine. A mixture consisting of 6-chloro-1 /-/-pyrazolo[3,4-d]pyrimidine (500 mg, 3.2 mmol) and anhydrous DMF (8 mL) was subsequently evacuated and refilled with N2 (x 3), then treated with NaH (207 mg, 60 wt.%, 5.18 mmol) in five portions over 5 min at 0 °C. The mixture was stirred for 30 min at 0 °C, treated with Mel (0.25 mL in 2 mL of DMF) slowly over 2 min, then stirred for 1 h at 0 °C followed by stirring 1 h with gradual warming to room temperature. After this time, the reaction mixture was quenched with H2O (20 mL) at 0 °C and then extracted with EtOAc (25 mL x 3). The combined organic extracts were washed with water (20 mL x 2) and brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was subjected to silica gel chromatography (0-100% EtOAc/petroleum ether) to afford 6-chloro-1 -methyl-1 /-/- pyrazolo[3,4-d]pyrimidine as a pale yellow solid (450 mg, 83%). ¹ H NMR (400 MHz, CDCI ₃ ) 8 9.05 (S, 1 H), 8.16 (S, 1 H), 4.13 (S, 3H).

Step B: (R)-3-Hydroxy-1-methyl-3-(3-(3-(1 -methyl-1 /-/-pyrazolo[3,4-d]pyrimidin-6- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. A mixture consisting of (R)-3-hydroxy-1-methyl- 3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2- one (Intermediate 4, 70 mg, 0.18 mmol), 6-chloro-1-methyl-1 /-/-pyrazolo[3,4- c/]pyrimidine (34 mg, 0.20 mmol), K3PO4 (124 mg, 0.55 mmol), 1 ,4-dioxane (5.0 mL), and water (0.5 mL) was subsequently evacuated and refilled with N2 (x 3), treated with Pd(dtbpf)Cl2 (24 mg, 0.036 mmol), and heated at 100 °C for 18 h under a N2 atmosphere. The reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The mixture was then filtered through a pad of diatomaceous earth, and the pad washed with EtOAc (10 mL). The filtrate was concentrated in vacuo. The residue was subjected to HPLC (Boston Green ODS column, 5 pm, 150 x 30 mm; 30- 60% (v/v) CH3CN/H2O with 0.225% FA) to afford, after lyophilization, (R)-3-hydroxy-1- methyl-3-(3-(3-(1-methyl-1/-/-pyrazolo[3,4-c/]pyrimidin-6-yl )phenyl)isoxazol-5- yl)pyrrolidin-2-one (25.6 mg, 36%) as a white solid. MS (ESI): Mass calcd. for C20H18N6O3 390.14, m/z found 391.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 9.46 (s, 1 H), 9.01 (s, 1 H), 8.67 (d, J = 8.0 Hz, 1 H), 8.41 (s, 1 H), 8.05 (d, J = 8.0 Hz, 1 H), 7.81 - 7.66 (m, 1 H), 7.10 (s, 1 H), 6.82 (s, 1 H), 4.15 (s, 3H), 3.47 - 3.42 (m, 2H), 2.86 (s, 3H), 2.65 - 2.56 (m, 1 H), 2.30 (s, 1 H). ¹ H NMR (400 MHz, CDCI3) 8 9.21 (s, 1 H), 8.92 (s, 1 H), 8.62 (d, J = 8.0 Hz, 1 H), 8.12 (s, 1 H), 7.92 (d, J = 7.6 Hz, 1 H), 7.61 - 7.51 (m, 1 H), 6.86 (s, 1 H), 4.30 (s, 1 H), 4.19 (s, 3H), 3.72 - 3.62 (m, 1 H), 3.55 - 3.44 (m, 1 H), 3.01 (s, 3H), 2.85 - 2.76 (m, 1 H), 2.55 - 2.43 (m, 1 H).

Example 228: (R)-3-(3-(3-(1 /-/-Pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)-3- hydroxy-1-methylpyrrolidin-2-one

Step A: 5-Chloro-1 -(tetrahydro-2/-/-pyran-2-yl)-1 /-/-pyrazolo[4,3-b]pyridine. A mixture consisting of 5-chloro-1 /-/-pyrazolo[4,3-b]pyridine (0.5 g, 3.3 mmol), pyridinium p-toluenesulfonate (136 mg, 0.33 mmol), 3,4-dihydro-2/-/-pyran (0.59 mL, 6.5 mmol), and CH2CI2 (10.0 mL) was refluxed for 18 h under N2 atmosphere. After this time, the reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The mixture was then concentrated to dryness in vacuo and the residue subjected to silica gel chromatography (0-40% EtOAc/petroleum ether) to afford 5-chloro-1 -(tetrahydro-2/-/- pyran-2-yl)-1 /-/-pyrazolo[4,3-b]pyridine as a white solid (650 mg, 84%). MS (ESI): Mass calcd. for C11 H12CIN3O 237.06, m/z found 238.1 [M+H] ⁺ .

Step B: (R)-3-Hydroxy-1 -methyl-3-(3-(3-(1 -(tetrahydro-2/-/-pyran-2-yl)-1 H- pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)pyrrolidin- 2-one. A mixture consisting of (R)-3-hydroxy-1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 190 mg, 0.026 mmol), 5-chloro- 1-(tetrahydro-2/-/-pyran-2-yl)-1/-/-pyrazolo[4,3-b]pyridine (129 mg, 0.54 mmol), K3PO4 (336 mg, 1 .48 mmol), 1 ,4-dioxane(5 mL), and water (0.5 mL) was subsequently evacuated and refilled with N2 3 times. Pd(dtbpf)Cl2 (32 mg, 0.050 mmol) was added and then the reaction mixture was heated at 100 °C for 2 h under a N2 atmosphere. After this time, the reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The reaction mixture was filtered through a pad of diatomaceous earth, and the pad washed with CH2CI2 (10 mL). The filtrate was concentrated to dryness in vacuo and the residue subjected to silica gel chromatography (0-100% EtOAc/petroleum ether) to afford (R)-3-hydroxy-1-methyl-3-(3-(3-(1-(tetrahydro-2/-/- pyran-2-yl)-1 /-/-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)pyrroli din-2-one as a yellow solid (140 mg, 62%). MS (ESI): Mass calcd. for C25H25N5O4459.19, m/z found 460.2 [M+H] ⁺ .

Step C: (R)-3-(3-(3-(1 /-/-Pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazol-5-yl)-3- hydroxy-1-methylpyrrolidin-2-one. A solution consisting of (R)-3-hydroxy-1-methyl-3-(3- (3-(1-(tetrahydro-2/-/-pyran-2-yl)-1/-/-pyrazolo[4,3-b]pyrid in-5-yl)phenyl)isoxazol-5- yl)pyrrolidin-2-one (140 mg, 0.31 mmol), and MeOH (5.0 mL) was added HCI/1 ,4- dioxane (5.0 mL, 4.0 M in 1 ,4-dioxane, 20 mmol) in one portion. The resultant mixture was stirred for 1 h at room temperature. After this time, the mixture was concentrated to dryness in vacuo and the residue subjected to HPLC (Boston Green ODS column, 5 pm, 150 x 30 mm; 25-55% (v/v) CH3CN/H2O with 0.225% FA) to afford, after lyophilization, (R)-3-(3-(3-(1/-/-pyrazolo[4,3-b]pyridin-5-yl)phenyl)isoxazo l-5-yl)-3- hydroxy-1-methylpyrrolidin-2-one as a white solid (49.4 mg, 43%). MS (ESI): Mass calcd. for C20H17N5O3 375.13 m/z, found 376.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 13.43 (br s, 1 H), 8.62 (s, 1 H), 8.41 (s, 1 H), 8.28 (d, J = 8.0 Hz, 1 H), 8.19 - 8.08 (m, 2H), 7.95 (d, J = 8.0 Hz, 1 H), 7.70 - 7.62 (m, 1 H), 7.16 (s, 1 H), 6.77 (s, 1 H), 3.54 - 3.47 (m, 2H), 2.86 (s, 3H), 2.64 - 2.56 (m, 1 H), 2.35 - 2.23 (m, 1 H). ¹ H NMR (400 MHz, CD3CN) 8 11.44 (br s, 1 H), 8.60 - 8.51 (m, 1 H), 8.29 - 8.23 (m, 1 H), 8.23 - 8.16 (m, 1 H), 8.08 - 8.03 (m, 1 H), 7.98 - 7.93 (m, 1 H), 7.92 - 7.86 (m, 1 H), 7.66 - 7.58 (m, 1 H), 6.90 (s, 1 H), 4.65 (br s, 1 H), 3.54 - 3.44 (m, 2H), 2.89 (s, 3H), 2.73 - 2.63 (m, 1 H), 2.41 - 2.30 (m, 1 H).

Example 229: (R)-3-Hydroxy-1 -methyl-3-(3-(3-(1 -methyl-1 /-/-pyrazolo[4,3-b]pyridin-5- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one

Step A: 5-Chloro-1 -methyl-1 /-/-pyrazolo[4,3-b]pyridine. A mixture consisting of 5- chloro-1 /-/-pyrazolo[4,3-b]pyridine (1.0 g, 6.5 mmol) and anhydrous THF (22 mL) was subsequently evacuated and refilled with N2 for 3 times, treated with NaH (418 mg, 10.4 mmol, 60 wt.%) portion wise at 0 °C, and then stirred for 30 min at 0 °C. The mixture was further treated with Mel (0.5 mL, 8 mmol, in 3 mL of THF) and stirred for 1 h at 0 °C, and then stirred for 1 h with gradual warming to room temperature. After this time, the reaction was quenched with H2O (20 mL) at 0 °C and extracted with EtOAc (25 mL x 3). The combined organic extracts were washed with water (20 mL x 2) and brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was subjected to silica gel chromatography (0-30% EtOAc/petroleum ether) to afford 5-chloro-1 -methyl-1 /-/-pyrazolo[4,3-b]pyridine as a pale yellow solid (400 mg, 37%). ¹ H NMR (400 MHz, CDCI3) 8 8.13 (s, 1 H), 7.73 (d, J = 8.8 Hz, 1 H), 7.30 (d, J = 8.8 Hz, 1 H), 4.11 (s, 3H).

Step B: (R)-3-Hydroxy-1 -methyl-3-(3-(3-(1 -methyl-1 /-/-pyrazolo[4,3-b]pyridin-5- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one. A mixture consisting of (R)-3-hydroxy-1-methyl- 3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2- one (Intermediate 4, 180 mg, 0.47 mmol), 5-chloro-1 -methyl-1 /-/-pyrazolo[4,3-b]pyridine (86.4 mg, 0.52 mmol), K3PO4 (319 mg, 1 .41 mmol), 1 ,4-dioxane (5.0 mL), and water (0.5 mL) was subsequently evacuated and refilled with N2 for 3 times, treated with Pd(dtbpf)Cl2 (31 mg, 0.047 mmol), and heated at 100 °C for 18 h under a N2 atmosphere. After this time, the reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The mixture was filtered through a pad of diatomaceous earth and the pad washed with CH2CI2 (10 mL). The filtrate was concentrated in vacuo and the residue subjected to HPLC (Boston Green ODS column, 5 pm, 150 x 30 mm; 28-58% (v/v) CH3CN/H2O with 0.225% FA) to afford, after lyophilization, the title compound (57.3 mg, 31 %) as a white solid. MS (ESI): Mass calcd. for C21 H19N5O3 389.14, m/z found 390.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCI3) 8 8.41 (s, 1 H), 8.28 (s, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 7.87 - 7.78 (m, 3H), 7.60 - 7.53 (m, 1 H), 6.81 (s, 1 H), 4.13 (s, 3H), 4.04 (s, 1 H), 3.71 - 3.61 (m, 1 H), 3.53 - 3.45 (m, 1 H), 3.01 (s, 3H), 2.85 - 2.75 (m, 1 H), 2.54 - 2.43 (m, 1 H). ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.62 (s, 1 H), 8.37 (s, 1 H), 8.29 (d, J = 8.4 Hz, 2H), 8.18 (d, J = 9.2 Hz, 1 H), 7.95 (d, J = 8.0 Hz, 1 H), 7.71 - 7.61 (m, 1 H), 7.16 (s, 1 H), 6.76 (s, 1 H), 4.13 (s, 3H), 3.56 - 3.45 (m, 2H), 2.86 (s, 3H), 2.64 - 2.55 (m, 1 H), 2.35 - 2.23 (m, 1 H).

Example 230: (R)-3-Hydroxy-3-(3-(3-(4-methoxy-1 ,3-dimethyl-1 /-/-pyrazolo[3,4-b]pyridin-

6-yl)phenyl)isoxazol-5-yl)-1 -methylpyrrolidin-2-one

Step A: 1 ,3-Dimethyl-1 /-/-pyrazolo[3,4-b]pyridine-4,6(5H,7H)-dione. A mixture consisting of diethyl malonate (4.00 mL, 26.3 mmol) and 1 ,3-dimethyl-1 /-/-pyrazol-5- amine (2.00 g, 18.0 mmol) was heated at 180 °C for 5 h. After this time, the reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The mixture was poured into water (20 mL) and filtered. The filter cake was washed with water (10 mL), and concentrated in vacuo to afford 1 ,3-dimethyl-1/-/-pyrazolo[3,4-b]pyridine- 4,6(5H,7H)-dione as a yellow solid (4.96 g). ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 11.50 - 10.99 (m, 2H), 5.35 (s, 1 H), 3.67 (s, 3H), 2.29 (s, 3H).

Step B: 4,6-Dichloro-1 ,3-dimethyl-1 /-/-pyrazolo[3,4-b]pyridine. 1 ,3-Dimethyl-1 /-/- pyrazolo[3,4-b]pyridine-4,6(5/-/,7/-/)-dione (2.48 g, 13.8 mmol) was added into phenylphosphonic dichloride (15.0 mL, 106 mmol, 1.38 g/mL) and the resultant mixture was heated at 150 °C for 3 h. After this time, the reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The mixture was poured into ice water, brought to pH 8-9 with NH4OH (25 wt.% in H2O), and extracted with EtOAc (60 mL x 3). The combined organic extracts were washed with brine (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was subjected to silica gel chromatography (0-50% EtOAc/petroleum ether) to afford 4,6-dichloro-1 ,3- dimethyl-1 /-/-pyrazolo[3,4-b]pyridine as a white solid (2.0 g, 65%). MS (ESI): Mass calcd. for C8H7CI2N3 215.00 m/z, found 215.9 [M+H] ⁺ .

Step C: 6-Chloro-4-methoxy-1 ,3-dimethyl-1 /-/-pyrazolo[3,4-b]pyridine. Sodium methoxide (800 mg, 14.8 mmol) was added into a solution consisting of 4,6-dichloro- 1 ,3-dimethyl-1 /-/-pyrazolo[3,4-b]pyridine (1.00 g, 4.63 mmol) in CH3OH (15 mL). The resultant mixture was stirred for 16 h at room temperature. After this time, the mixture was concentrated to dryness in vacuo. The residue was subjected to silica gel chromatography (0-50% EtOAc/petroleum ether) to afford 6-chloro-4-methoxy-1 ,3- dimethyl-1 /-/-pyrazolo[3,4-b]pyridine as a white solid (0.8 g, 82%). ¹ H NMR (400 MHz, DMSO-c/e) 86.75 (s, 1 H), 6.78 - 6.72 (m, 1 H), 4.01 (s, 3H), 3.86 (s, 3H), 2.47 (s, 3H).

Step D: (R)-3-Hydroxy-3-(3-(3-(4-methoxy-1 ,3-dimethyl-1 /-/-pyrazolo[3,4- b]pyridin-6-y l)pheny l)isoxazol-5-y l)-1 -methylpyrrolidin-2-one. 6-Chloro-4-methoxy-1 ,3- dimethyl-1 /-/-pyrazolo[3,4-b]pyridine (90 mg, 0.43 mmol) was added into a mixture consisting of (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 135 mg, 0.351 mmol) and K3PO4 (225 mg, 1.06 mmol) in 1 ,4-dioxane (8 mL) and H2O (2 mL). The resultant mixture was subsequently evacuated and refilled with N2 3 times, treated with Pd(dtbpf)Cl2 (45 mg, 0.069 mmol), and heated at 100 °C for 16 h. After this time, the reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The mixture was diluted with H2O (15 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic extracts were washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was subjected to HPLC (Boston Prime C18 column, 5 pm, 150 mm x 30 mm; 35-65% (v/v) CH3CN/H2O with 0.05% NH3*H2O+10 mM NH4HCO3) to afford, after lyophilization, (R)-3-hydroxy-3-(3-(3- (4-methoxy-1 ,3-dimethyl-1 /-/-pyrazolo[3,4-b]pyridin-6-yl)phenyl)isoxazol-5-yl)-1 - methylpyrrolidin-2-one as a white solid (60.3 mg, 39%). MS (ESI): Mass calcd. for C23H23N5O4433.17 m/z found 434.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.65 - 8.59 (m, 1 H), 8.39 - 8.32 (m, 1 H), 8.01 - 7.95 (m, 1 H), 7.73 - 7.63 (m, 1 H), 7.29 (s, 1 H), 7.16 (s, 1 H), 6.76 (s, 1 H), 4.14 (s, 3H), 4.00 (s, 3H), 3.54 - 3.40 (m, 2H), 2.86 (s, 3H), 2.63 - 2.57 (m, 1 H), 2.55 (s, 3H), 2.32 - 2.25 (m, 1 H).

Example 231 : (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-(pyrrolidin-1 -ylmethyl)thiazole-4-carboxamide

Step A: (R)-Methyl 5-formyl-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)thiazole-4-carboxylate. (R)-3-Hydroxy-1 -methyl-3-(3-(3-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 250 mg, 0.651 mmol), methyl 2-bromo-5-formylthiazole-4-carboxylate (325 mg, 1.30 mmol, Example 222 Step B), Pd(dtbpf)Cl2 (85 mg, 0.13 mmol), K3PO4 (552 mg, 2.60 mmol), H2O (0.5 mL), and 1 ,4-dioxane (5 mL) were added to a 40 mL vial. The vial was subsequently evacuated and refilled with N2 3 times. The vial was capped and heated at 80 °C for 2 h. The reaction vessel was removed from the heating device and allowed to gradually cool to rt. The mixture was filtered through a pad of diatomaceous earth. The filtrate was concentrated to dryness in vacuo to give a brown gum. The gum was subjected to silica gel chromatography (0-5% MeOH/CH2Cl2) to give (R)-methyl 5- formyl-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)thiazole-4 - carboxylate as a light brown solid (200 mg, 36%). MS (ESI): Mass calcd. for C20H17N3O6S 427.08 m/z, found 428.1 [M+H] ⁺ .

Step B: (R)-Methyl 2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- y l)pheny l)-5-(pyrrol id in-1 -ylmethyl)thiazole-4-carboxylate. (R)-Methyl 5-formyl-2-(3-(5-(3- hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)thiazole-4 -carboxylate (150 mg, 0.351 mmol), pyrrolidine (89 pL, 0.70 mmol), titanium(IV) isopropoxide (110 mg, 0.386 mmol), NaBHsCN (55 mg, 0.88 mmol), and MeOH (8 mL) were added to a 40 mL vial, and the resulting mixture was stirred for 18 h at 60 °C. The reaction vessel was removed from the heating device and allowed to gradually cool to rt. The mixture was filtered through a pad of diatomaceous earth, and the filtrate concentrated to dryness in vacuo to give a brown gum. The gum was subjected to silica gel chromatography (0-5% MeOH/CH2Cl2) to give (R)-methyl 2-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)-5-(pyrrolidin-1-ylmethyl)thiazole-4 -carboxylate as a light brown solid (120 mg, 71 %). MS (ESI): Mass calcd. for C24H26N4O5S 482.16 m/z, found 483.2 [M+H] ⁺ .

Step C: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- y l)pheny l)-5-(pyrrol id in-1 -ylmethyl)thiazole-4-carboxamide. (R)-Methyl 2-(3-(5-(3- hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)- 5-(pyrrolidin-1- ylmethyl)thiazole-4-carboxylate (100 mg, 0.207 mmol), NH3 (8 mL, 56 mmol, 7 M in MeOH), and MeOH (2.5 mL) were added to a 40 mL vial, and the resulting mixture stirred for 18 h at 75 °C. The reaction vessel was removed from the heating device and allowed to gradually cool to rt. The mixture was concentrated in vacuo to give a brown gum, which was subjected to HPLC (Boston Green ODS column, 5 pm, 150 x 30 mm; 9-39% CH3CN/H2O with 0.225% FA), and then subjected to SFC (DAICEL CHIRALCEL® AS column, 10 pm, 250 x 30 mm; 65% EtOH (containing 0.1 % NH3*H2O)/supercritical CO2) to give, after lyophilization, (R)-2-(3-(5-(3-hydroxy-1 - methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5-(pyrroli din-1-ylmethyl)thiazole-4- carboxamide as a white solid (43.6 mg, 66%). MS (ESI): Mass calcd. for C23H25N5O4S 467.16 m/z, found 468.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 88.48 (s, 1 H), 8.13 (d, J = 7.2 Hz, 1 H), 8.01 (d, J = 7.6 Hz, 2H), 7.70 - 7.58 (m, 2H), 7.19 (s, 1 H), 6.74 (s, 1 H), 4.29 (br s, 2H), 3.54 - 3.44 (m, 2H), 2.85 (s, 3H), 2.75 - 2.61 (m, 4H), 2.59 - 2.54 (m, 1 H), 2.35 - 2.24 (m, 1 H), 1.81 - 1.71 (m, 4H). ¹ H NMR (400 MHz, CD3OD) 8 8.52 - 8.47 (m, 1 H), 8.09 (d, J = 8.0 Hz, 1 H), 7.97 (d, J = 8.0 Hz, 1 H), 7.67 - 7.57 (m, 1 H), 7.02 (s, 1 H), 4.44 (s, 2H), 3.63 - 3.54 (m, 2H), 2.97 (s, 3H), 2.87 - 2.80 (m, 4H), 2.79 - 2.70 (m, 1 H), 2.45 - 2.35 (m, 1 H), 1 .93 - 1.83 (m, 4H). Example 232: (R)-3-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-7-(3,3,3-trifluoropropyl)-5,6,7,8-tetrahydroimida zo[1 ,5-a]pyrazine-1 - carboxamide

Step A: Ethyl 3-bromo-7-(3,3,3-trifluoropropyl)-5,6,7,8-tetrahydroimidazo[ 1 ,5- a]pyrazine-1 -carboxylate. Ethyl 3-bromo-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyrazine-1 - carboxylate (290 mg, 0.934 mmol, Intermediate 64), 1 ,1 ,1 -trifluoro-3-iodopropane (547 μL, 4.67 mmol), and DMF (3 mL) were added to a 20 mL microwave tube, and charged with DIEA (813 μL, 4.67 mmol). The resulting mixture was stirred for 2 h at 120 °C via microwave irradiation. The vessel was removed from the heating device and allowed to gradually cool to rt. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give a yellow oil. The oil was then subjected to silica gel chromatography (0-50% EtOAc/petroleum ether) to give ethyl 3- bromo-7-(3,3,3-trifluoropropyl)-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyrazine-1 -carboxylate as a yellow oil (300 mg, 86%). LCMS (ESI): Mass calcd. for C^HisBrFsNsCh 369.0 m/z, found 369.9 [M+H] ⁺ .

Step B: (R)-Ethyl 3-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-7-(3,3,3-trifluoropropyl)-5,6,7,8-tetrahydroimida zo[1 ,5-a]pyrazine-1 - carboxylate. Ethyl 3-bromo-7-(3,3,3-trifluoropropyl)-5,6,7,8-tetrahydroimidazo[ 1 ,5- a]pyrazine-1 -carboxylate (200 mg, 0.540 mmol), (R)-3-hydroxy-1 -methyl-3-(3-(3- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 200 mg, 0.521 mmol), K3PO4 (344 mg, 1.62 mmol) and 1 ,4- dioxane/H2O = 4:1 (2 mL) were added to an oven-dried and N2-purged 8 mL microwave tube. The mixture was sparged with N2 for 5 min, treated with Pd(dtbpf)Cl2 (35 mg, 0.054 mmol), and heated to 80 °C for 1 hour via microwave irradiation. After this time, the reaction vessel was removed from the heating device and allowed to gradually cool to rt. The reaction mixture was then diluted with H2O (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give a brown oil. The oil was then subjected to silica gel chromatography (0-100% EtOAc/petroleum ether) to give (R)-ethyl 3-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-7-(3,3,3-trifluoropropyl)-5,6,7,8-tetrahydroimida zo[1 ,5-a]pyrazine-1- carboxylate as an orange solid (170 mg, 57%). LCMS (ESI): Mass calcd. for C26H28F3N5O5 547.20 m/z, found 548.3 [M+H] ⁺ .

Step C: (R)-3-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-7-(3,3,3-trifluoropropyl)-5,6,7,8-tetrahydroimida zo[1 ,5-a]pyrazine-1 -carboxylic acid. (R)-ethyl 3-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-7- (3,3,3-trifluoropropyl)-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyrazine-1 -carboxylate (130 mg, 0.237 mmol), LiOH*H2O (60 mg, 1.4 mmol), H2O (1 mL) and anhydrous THF (2 mL) were added to an 8 mL vial. The resulting mixture was stirred for 16 h at 40 °C. After this time the reaction mixture was acidified with 1 .0 M aqueous HCI to pH=2 and extracted with DCM (20 mL x 2). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give a yellow solid. The solid was then subjected to silica gel chromatography (0-100% EtOAc/petroleum ether followed by 0-10% MeOH/EtOAc) to give (R)-3-(3-(5-(3-hydroxy- 1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-7-(3,3,3 -trifluoropropyl)-5,6,7,8- tetrahydroimidazo[1 ,5-a]pyrazine-1 -carboxylic acid as a yellow oil (70 mg, 50%). LCMS (ESI): Mass calcd. for C24H24F3N5O5 519.17 m/z, found 520.2 [M+1 ] ⁺ .

Step D: (R)-3-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-7-(3,3,3-trifluoropropyl)-5,6,7,8-tetrahydroimida zo[1 ,5-a]pyrazine-1- carboxamide. (R)-3-(3-(5-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazo l-3- yl)phenyl)-7-(3,3,3-trifluoropropyl)-5,6,7,8-tetrahydroimida zo[1 ,5-a]pyrazine-1 -carboxylic acid (70 mg, 0.14 mmol) and DMF (1 mL) were added to an 8 mL vial, and charged with TEA (56 pL, 0.40 mmol), HATU (61 mg, 0.16 mmol) and NH ₄ CI (72 mg, 1 .3 mmol). The mixture was stirred at room temperature for 16 h. After this time, the mixture was poured into water (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to afford a brown oil. The oil was then subjected to HPLC (Welch Xtimate C18 column, 5 pm, 150 x 30 mm; 25-55% (v/v) MeCN/water (0.05% NHs’FW + 10 mM NH4HCO3)) to give a colorless solid, which was further purified by SFC (DAICEL CHIRALCEL® OD-H column, 5 pm, 250 x 30 mm; 40% (v/v) EtOH (0.1 % NH ₃ H2O)/CO2)) to give the title compound as a colorless solid (15.1 mg, 50%). LCMS (ESI): Mass calcd. for C24H25F3N6O4 518.19 m/z, found 519.2 [M+1 ] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.22 (s, 1 H), 7.96 (d, J = 7.5 Hz, 1 H), 7.88 (d, J = 7.5 Hz, 1 H), 7.68 - 7.59 (m, 1 H), 7.33 (br s, 1 H), 7.17 - 7.04 (m, 2H), 6.72 (s, 1 H), 4.26 - 4.16 (m, 2H), 4.00 (s, 2H), 3.47 - 3.40 (m, 2H), 2.90 - 2.85 (m, 2H), 2.85 - 2.79 (m, 5H), 2.62 - 2.54 (m, 3H), 2.31 - 2.22 (m, 1 H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) 8 -63.42 (s, 3F).

Example 233: (R)-3-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-7-isopropyl-5, 6, 7, 8-tetrahydroimidazo[1 ,5-a]pyrazine-1 -carboxamide

Step A: Ethyl 3-bromo-7-isopropyl-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyrazine-1 - carboxylate. Ethyl 3-bromo-5, 6, 7, 8-tetrahydroimidazo[1 ,5-a]pyrazine-1 -carboxylate (220 mg, 0.80 mmol, Intermediate 64), and MeOH (6 mL) were added to a 40 mL flask, and then propan-2-one (0.9 mL, 12.3 mmol) and AcOH (138 uL, 2.41 mmol) were added. The mixture was stirred at room temperature for 0.5 h, treated with NaBHsCN (150 mg, 2.39 mmol), and heated at 45 °C for 3 h. After this time, the mixture was concentrated to dryness in vacuo to give a black solid. The black solid was subjected to silica gel chromatography (0-100% EtOAc/petroleum ether) to give ethyl 3-bromo-7-isopropyl- 5, 6, 7, 8-tetrahydroimidazo[1 ,5-a]pyrazine-1 -carboxylate as a yellow solid (100 mg, 35%). LCMS (ESI): Mass calcd. for Ci2Hi ₈ BrN ₃ O2 315.06 m/z, found 316.0 [M+1 ] ⁺ .

Step B: (R)-Ethyl 3-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-7-isopropyl-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyrazine-1 -carboxylate. (R)-3- Hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol- 5-yl)pyrrolidin-2-one (Intermediate 4, 120 mg, 0.312 mmol), 1 ,4-dioxane (1.6 mL), and H2O (0.4 mL) were added to a nitrogen-purged 8 mL vial, and then ethyl 3-bromo-7- isopropyl-5, 6, 7, 8-tetrahydroimidazo[1 ,5-a]pyrazine-1 -carboxylate (90 mg, 0.29 mmol), Pd(dtbpf)Cl2 (28 mg, 0.043 mmol), and K3PO4 (186 mg, 0.876 mmol) were added. The resulting mixture was heated at 100 °C for 6 h. The reaction vessel was removed from the heating device and allowed to gradually cool to RT. The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic extracts were dried with anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give a nearly black viscous oil. The oil was then subjected to silica gel chromatography (0-100% EtOAc/petroleum ether) to give (R)-ethyl 3-(3-(5-(3-hydroxy-1 - methyl-2 -oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-7-isopropyl-5, 6,7,8- tetrahydroimidazo[1 ,5-a]pyrazine-1 -carboxylate as a red solid (130 mg, 85%). LCMS (ESI): Mass calcd. for C26H31N5O5493.23 m/z, found 494.3 [M+1 ] ⁺ .

Step C: (R)-3-(3-(5-(3-Hydroxy-1 -methyl-2 -oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-7-isopropyl-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyrazine-1 -carboxylic acid. (R)- Ethyl 3-(3-(5-(3-hydroxy-1 -methyl-2 -oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-7-isopropyl- 5, 6, 7, 8-tetrahydroimidazo[1 ,5-a]pyrazine-1 -carboxylate (110 mg, 0.223 mmol), THF (4 mL), EtOH (0.4 mL), and H2O (1 mL) were added to a nitrogen-purged 50 mL round- bottomed flask, and then LiOH’FW (100 mg, 2.38 mmol) was added. The mixture was stirred at rt for 16 h. The reaction mixture was acidified to pH=2 with 1 .0 M aqueous HCI and extracted with DCM (20 mL x 2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness in vacuo to give (R)-3- (3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-7-isoprop yl-5, 6,7,8- tetrahydroimidazo[1 ,5-a]pyrazine-1 -carboxylic acid (90 mg, 85%) as a pale-yellow solid. The product was used to next step directly without further purification. LCMS (ESI): Mass calcd. for C24H27N5O5 465.20 m/z, found 466.1 [M+1 ] ⁺ .

Step D: (R)-3-(3-(5-(3-Hydroxy-1 -methyl-2 -oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-7-isopropyl-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyrazine-1 -carboxamide. (R)-3- (3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-7-isoprop yl-5, 6,7,8- tetrahydroimidazo[1 ,5-a]pyrazine-1 -carboxylic acid (80 mg, 0.17 mmol) and DMF (2 mL) were added to a nitrogen-purged 8 mL vial, and then TEA (90 pL, 0.65 mmol), HATU (95 mg, 0.25 mmol), and NH4CI (100 mg, 1.87 mmol) were added. The resulting mixture was stirred at room temperature for 6 h. After this time, the reaction mixture was filtered to give a yellow solution. The solution was then subjected to HPLC ((Boston Prime C18 column, 5 pm, 150 x 30 mm; 20-50% ACN/water(0.05% NH ₃ «H ₂ O + 10 mM NH4HCO3)) to yield (R)-3-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-7- isopropyl-5, 6, 7, 8-tetrahydroimidazo[1 ,5-a]pyrazine-1 -carboxamide as a white solid (10.8 mg, 13%). LCMS (ESI): Mass calcd. for C24H28N6O4464.22 m/z found 465.3 [M+1] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.31 - 8.24 (m, 1 H), 8.05 - 7.99 (m, 1 H), 7.96 - 7.90 (m, 1 H), 7.73 - 7.66 (m, 1 H), 7.37 (br s, 1 H), 7.18 (s, 1 H), 7.13 (br s, 1 H), 6.79 (s, 1 H), 4.32 - 4.19 (m, 2H), 4.05 (s, 2H), 3.57 - 3.51 (m, 2H), 3.06 - 2.95 (m, 1 H), 2.93 - 2.85 (m, 5H), 2.66 - 2.62 (m, 1 H), 2.38 - 2.27 (m, 1 H), 1 .14 (d, J = 6.4 Hz, 6H).

Example 234: (R)-7-Benzyl-3-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyrazine-1 -carboxamide

Step A: Ethyl 7-benzyl-3-bromo-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyrazine-1- carboxylate. Ethyl 3-bromo-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyrazine-1 -carboxylate (480 mg, 1.75 mmol, Intermediate 64), (bromomethyl)benzene (0.43 mL, 3.6 mmol), TEA (0.19 mL, 1.4 mmol), and THF (24 mL) were added to a 100 mL round-bottomed flask, and the resulting mixture stirred for 1 h at room temperature. The reaction mixture was then subjected to silica gel chromatography (0-50% EtOAc/petroleum ether) to give ethyl 7-benzyl-3-bromo-5, 6, 7, 8-tetrahydroimidazo[1 ,5-a]pyrazine-1 -carboxylate as a colorless oil (210 mg, 30%). LCMS (ESI): Mass calcd. for CwHisBrNsCte 363.06 m/z, found 363.8 [M+1 ] ⁺ .

Step B: (R)-Ethyl 7-benzyl-3-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyrazine-1 -carboxylate. Ethyl 7- benzyl-3-bromo-5, 6, 7, 8-tetrahydroimidazo[1 ,5-a]pyrazine-1 -carboxylate (190 mg, 0.522 mmol), (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 399 mg, 1.04 mmol), K3PO4 (333 mg, 1.57 mmol), and 1 ,4-dioxane/H2O (v/v=4:1 , 10 mL) were added to a 20 mL microwave tube, and charged with Pd(dtbpf)Cl2 (38 mg, 0.058 mmol). The resulting mixture was sparged with N2 for 5 min and stirred for 1 h at 90 °C via microwave irradiation. The reaction vessel was removed from the heating device and allowed to gradually cool to rt. The reaction mixture was diluted with water (15 mL), extracted with ethyl acetate (20 mL x 3), and the combined extracts were treated with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give a white solid. The white solid was then subjected to silica gel chromatography (0-100% EtOAc/petroleum ether) to give (R)-ethyl 7-benzyl-3-(3-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5,6,7,8-tetrahydroi midazo[1 ,5-a]pyrazine-1- carboxylate as a colorless oil (300 mg, 83%). LCMS (ESI): Mass calcd. for C30H31 N5O5 541.23 m/z, found 542.1 [M+1 ] ⁺ .

Step C: (R)-7-Benzyl-3-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5,6,7,8-tetrahydroimidazo[1 ,5-a]pyrazine-1 -carboxamide. (R)-Ethyl 7-benzyl- 3-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5, 6,7,8- tetrahydroimidazo[1 ,5-a]pyrazine-1 -carboxylate (260 mg, 0.480 mmol), and NH3 (20 mL, 7 M in MeOH) were added to a 50 mL round-bottomed flask, and the resulting mixture stirred for 48 h at 70 °C. After this time, the mixture was cooled to r.t. and concentrated to dryness in vacuo to give a colorless oil. The colorless oil was subjected to HPLC (Welch Xtimate C18 column, 5 pm, 150 x 30 mm; 25-55% ACN/water (0.05% NHs’FhO + 10 mM NH4HCO3)) to give a colorless solid. The colorless solid was then subjected to SFC (DAICEL CHIRALPAK® AD column, 10 pm, 250 x 30 mm; 45% IPA (containing 0.1 % of 25% aq. NH3)/CO2) to give the title compound as a colorless solid (20.4 mg, 41 %). LCMS (ESI): Mass calcd. for C28H28N6O4 512.22 m/z, found 513.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.22 (s, 1 H), 7.98 - 7.94 (m, 1 H), 7.91 - 7.86 (m, 1 H), 7.67 - 7.60 (m, 1 H), 7.43 - 7.35 (m, 4H), 7.34 - 7.28 (m, 2H), 7.13 (s, 1 H), 7.06 (br s, 1 H), 6.73 (s, 1 H), 4.29 - 4.21 (m, 2H), 3.96 - 3.91 (m, 2H), 3.79 - 3.75 (m, 2H), 3.53 - 3.41 (m, 2H), 2.89 - 2.76 (m, 5H), 2.61 - 2.54 (m, 1 H), 2.33 - 2.23 (m, 1 H). Example 235: (R)-5-((5-Cyano-2-methylpyridin-3-yl)amino)-2-(3-(5-(3-hydro xy-1 -methyl- 2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)thiazole-4-carboxa mide

Step A: Ethyl 5-((5-cyano-2-methylpyridin-3-yl)amino)thiazole-4-carboxylat e. 5- Chloro-6-methylnicotinonitrile (130 mg, 0.852 mmol), ethyl 5-aminothiazole-4- carboxylate (220 mg, 1.28 mmol), K2CO3 (353 mg, 2.56 mmol) and f-BuOH (3 mL) were added to a 5 mL microwave tube. The resultant mixture was sparged with N2 for 5 min and then treated with BrettPhos-Pd-G3 (77 mg, 0.085 mmol) and BrettPhos (46 mg, 0.085 mmol). The resulting mixture was sparged with N2 for another 5 min and then heated at 110 °C via microwave for 1 h. After this time, the reaction vessel was removed from the heating device and allowed to gradually cool to room temperature. The reaction mixture was concentrated to dryness in vacuo to give a brown solid, which was then subjected to silica gel chromatography (0-50% EtOAc/petroleum ether) to give ethyl 5-((5-cyano-2-methylpyridin-3-yl)amino)thiazole-4-carboxylat e as a yellow solid (246 mg, 92%). LCMS (ESI): Mass calcd. for C13H12N4O2S 288.07 m/z, found 289.1 [M+H] ⁺ .

Step B: Ethyl 2-bromo-5-((5-cyano-2-methylpyridin-3-yl)amino)thiazole-4- carboxylate. Ethyl 5-((5-cyano-2-methylpyridin-3-yl)amino)thiazole-4-carboxylat e (220 mg, 0.763 mmol), and MeCN (5 mL) were added to a 40 mL flask, which was charged with NBS (272 mg, 1 .53 mmol). The mixture was stirred for 16 h at room temperature. The mixture was concentrated to dryness in vacuo to give a yellow solid, which was then subjected to silica gel chromatography (0-30% EtOAc/petroleum ether) to give ethyl 2-bromo-5-((5-cyano-2-methylpyridin-3-yl)amino)thiazole-4-ca rboxylate as a yellow solid (177 mg, 58%). LCMS (ESI): Mass calcd. for CnHu BrN^S 365.98 m/z, found 367.0 [M+1 ] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 9.49 (s, 1 H), 8.74 - 8.67 (m, 1 H), 8.25 - 8.20 (m, 1 H), 4.29 (q, J = 7.0 Hz, 2H), 2.57 (s, 3H), 1 .27 (t, J = 7.1 Hz, 3H). Step C: (R)-Ethyl 5-((5-cyano-2-methylpyridin-3-yl)amino)-2-(3-(5-(3-hydroxy-1 - methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)thiazole-4- carboxylate. Ethyl 2-bromo- 5-((5-cyano-2-methylpyridin-3-yl)amino)thiazole-4-carboxylat e (100 mg, 0.272 mmol), (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 126 mg, 0.327 mmol), K3PO4 (173 mg, 0.817 mmol) and 1 ,4-dioxane/H2O (4:1 , 5 mL) were added to a 20 mL microwave tube. The resulting mixture was sparged with N2 for 5 min and then treated with Pd(dtbpf)Cl2 (18 mg, 0.027 mmol). The mixture was sparged with N2 for another 5 min and then heated at 80 °C via microwave irradiation for 1 h. After this time, the reaction vessel was removed from the heating device and allowed to gradually cool to room temperature. The reaction mixture was concentrated to dryness in vacuo to give a brown solid, which was then subjected to silica gel chromatography (0-100% EtOAc/petroleum ether) to give (R)-ethyl 5-((5-cyano-2-methylpyridin-3-yl)amino)-2-(3- (5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)thiazole-4 -carboxylate as a yellow solid (60 mg, 32%). LCMS (ESI): Mass calcd. for C27H24N6O5S 544.15 m/z, found 545.1 [M+1 ] ⁺ .

Step D: (R)-5-((5-Cyano-2-methylpyridin-3-yl)amino)-2-(3-(5-(3-hydro xy-1 - methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)thiazole-4- carboxamide. (R)-Ethyl 5-((5- cyano-2-methylpyridin-3-yl)amino)-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)thiazole-4-carboxylate (45 mg, 0.083 mmol) and NH3 (5.0 mL, 35 mmol, 7 M in MeOH) were added to a 40 mL flask. The resultant mixture was stirred for 16 h at 50 °C. After this time, the mixture was concentrated to dryness in vacuo to give a yellow solid, which was subjected to HPLC (Welch Xtimate C18 column, 5 pm, 150 x 30 mm; 33-63% (v/v) ACN/water (0.05% NH3H2O and 10 mM NH4HCO3)) to give, after lyophilization, the title compound as a colorless solid (5.3 mg, 12%). LCMS (ESI): Mass calcd. for C25H21 N7O4S 515.14 m/z, found 516.2 [M+1 ] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 5 11.14 (br s, 1 H), 8.60 (d, J = 1 .4 Hz, 1 H), 8.47 - 8.42 (m, 1 H), 8.15 (d, J = 1.4 Hz, 1 H), 8.13 - 8.10 (m, 1 H), 8.09 - 8.05 (m, 1 H), 8.00 - 7.94 (m, 1 H), 7.84 - 7.78 (m, 1 H), 7.68 - 7.61 (m, 1 H), 7.18 (s, 1 H), 6.78 (s, 1 H), 3.49 - 3.46 (m, 2H), 2.85 (s, 3H), 2.64 (s, 3H), 2.58 - 2.57 (m, 1 H), 2.31 - 2.25 (m, 1 H). Example 236: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-((1 -methyl-1 H-pyrazol-3-yl)amino)thiazole-4-carboxamide

Step A: Ethyl 5-((1 -methyl-1 /-/-pyrazol-3-yl)amino)thiazole-4-carboxylate. MeCN (10 mL), DBU (5.1 mL, 34 mmol), ethyl 5-bromothiazole-4-carboxylate (2.0 g, 8.5 mmol), and 1 -methyl-1/-/-pyrazol-3-amine (735 pL, 8.47 mmol) were added to a 20 mL microwave tube. The mixture was heated at 80 °C via microwave irradiation for 1 h. The reaction vessel was removed from the heating device and allowed to gradually cool to rt. The reaction mixture was concentrated to dryness in vacuo to give a brown oil. The oil was then subjected to silica gel chromatography (0-100% EtOAc/petroleum ether) to give ethyl 5-((1 -methyl-1 /-/-pyrazol-3-yl)amino)thiazole-4-carboxylate (390 mg, 18% yield) as a green solid. LCMS (ESI): Mass calcd. for C10H12N4O2S 252.07 m/z, found 253.1 [M+H] ⁺ .

Step B: Ethyl 5-((4-bromo-1 -methyl-1 /-/-pyrazol-3-yl)amino)thiazole-4- carboxylate. MeCN (15 mL), ethyl 5-((1 -methyl-1 /-/-pyrazol-3-yl)amino)thiazole-4- carboxylate (1 .2 g, 4.8 mmol) and NBS (847 mg, 4.76 mmol) was added to a 40 mL flask. The resultant mixture was stirred at room temperature for 2 h. After this time, the mixture was treated with sat. aqueous Na2S20s (20 mL), and then extracted with EtOAc (30 mL x 2). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give a brown oil. The oil was then subjected to silica gel chromatography (0-100% EtOAc/petroleum ether) to give ethyl 5-((4-bromo-1 - methyl-1 /-/-pyrazol-3-yl)amino)thiazole-4-carboxylate as a brown solid (1.6 g, 83%). LCMS (ESI): Mass calcd. for CioHu BrN ₄ 02S 329.98 m/z, found 332.7 [M+H] ⁺ .

Step C: Ethyl 5-((4-bromo-1 -methyl-1 /-/-pyrazol-3-yl)amino)-2-iodothiazole-4- carboxylate. Tetrahydrofuran (20 mL) and ethyl 5-((4-bromo-1-methyl-1 /-/-pyrazol-3- yl)amino)thiazole-4-carboxylate (1.6 g, 4.8 mmol) were added to a nitrogen-purged 100 mL three-necked flask, which was subsequently cooled to -72 °C (dry ice/ethanol) and charged with LDA (2.6 mL, 5.2 mmol, 2.0 M in THF). The resultant mixture was stirred at -72 °C (dry ice/ethanol) for 30 min, treated with I2 (1 .47 g, 5.80 mmol) in THF (5 mL) dropwise, and stirred at -72 °C (dry ice/ethanol) for about 20 min. After this time, the mixture was quenched with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give a brown oil, which was subjected to silica gel chromatography (0-100% EtOAc/petroleum ether) to give ethyl 5-((4-bromo-1 -methyl- 1 H-pyrazol-3-yl)amino)-2-iodothiazole-4-carboxylate (1.4 g, 47%) as a pale purple solid. LCMS (ESI): Mass calcd. for CioHioBrlN ₄ 0 ₂ S 455.88 m/z, found 456.9 [M+H] ⁺ .

Step D: (R)-Ethyl 5-((4-bromo-1 -methyl-1 /-/-pyrazol-3-yl)amino)-2-(3-(5-(3- hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)t hiazole-4-carboxylate. Ethyl 5-((4-bromo-1 -methyl-1 H-pyrazol-3-yl)amino)-2-iodothiazole-4-carboxylate (500 mg, 0.806 mmol), (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 200 mg, 0.521 mmol), K3PO4 (513 mg, 2.42 mmol), and 1 ,4-dioxane/H2O=4:1 (5 mL) were added to a N2-purged 20 mL microwave tube, and charged with Pd(dtbpf)Cl2 (53 mg, 0.081 mmol). The resultant mixture was sparged with N2 for 5 min, and then heated at 80 °C for 1 hour via microwave irradiation. The reaction mixture was then diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO ₄ , filtered, and concentrated to dryness in vacuo to give a brown oil. The oil was subjected to silica gel chromatography (0-100% EtOAc/petroleum ether) to give (R)-ethyl 5-((4-bromo-1 -methyl-1 /-/-pyrazol-3-yl)am ino)- 2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)thiazole-4 - carboxylate as a yellow oil (260 mg, 39%). LCMS (ESI): Mass calcd. for C2 ₄ H23BrN60sS 586.06 m/z, found 587.0 [M+1 ] ⁺ .

Step E: (R)-Ethyl 2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- y l)pheny l)-5-(( 1 -methyl-1 H-pyrazol-3-yl)amino)thiazole-4-carboxylate. (R)-Ethy I 5-((4- bromo-1 -methyl-1 /-/-pyrazol-3-yl)amino)-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)thiazole-4-carboxylate (260 mg, 0.443 mmol) and THF (10 mL) were added into a 50 mL flask and charged with dry Pd/C (260 mg, 0.244 mmol, 10 wt.%). The reaction vessel was evacuated and refilled with H2 for three times. The reaction mixture was stirred under H2 (15 psi) at rt for 16 hours. After this time, the mixture was filtered through a pad of diatomaceous earth, and the pad washed with MeOH (5 mL x 2). The filtrate was concentrated in vacuo to afford a colorless oil. The oil was subjected to SFC (DAICEL CHIRALCEL® OD, 10 pm, 250 x 30 mm; 55% (v/v) EtOH (0.1 % NH ₃ H ₂ O)/CO2)) to give (R)-ethyl 2-(3-(5-(3-hydroxy-1-methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5-((1 -methyl-1 /-/-pyrazol-3-yl)amino)thiazole-4- carboxylate as a colorless solid (110 mg, 47%). LCMS (ESI): Mass calcd. for C24H24N6O5S 508.15 m/z, found 509.2 [M+1 ] ⁺ .

Step F: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-((1 -methyl-1 H-pyrazol-3-yl)amino)thiazole-4-carboxamide. NH3 in MeOH (5 mL, 7 mmol) and (R)-ethyl 2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-((1 -methyl-1 /-/-pyrazol-3-yl)amino)thiazole-4-carboxylate (110 mg, 0.216 mmol) were added to a 40 mL vial. The resultant mixture was heated to 50 °C and stirred for 3 days. After this time, the mixture was concentrated to dryness in vacuo to afford a colorless oil. The oil was then subjected to SFC (DAICEL CHIRALCEL® OD-H column, 5 pm; 250 mm x 30 mm; 40% (v/v) EtOH (0.1 % NH3H2O)/CO2) to give, after lyophillization, the title compound as a yellow solid (11 .3 mg, 10%). LCMS (ESI): Mass calcd. for C22H21 N7O4S 479.14 m/z, found 480.2 [M+1 ] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 10.69 (s, 1 H), 8.41 - 8.36 (m, 1 H), 8.05 - 7.99 (m, 1 H), 7.93 - 7.87 (m, 1 H), 7.80 (s, 1 H), 7.66 (d, J = 2.3 Hz, 1 H), 7.64 - 7.58 (m, 1 H), 7.54 (s, 1 H), 7.14 (s, 1 H), 6.77 (s, 1 H), 6.12 (d, J = 2.3 Hz, 1 H), 3.83 (s, 3H), 3.50 - 3.45 (m, 2H), 2.85 (s, 3H), 2.61 - 2.58 (m, 1 H), 2.32 - 2.24 (m, 1 H).

Example 237: (R)-5-(Aminomethyl)-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)thiazole-4-carboxamide

Step A: Methyl 2-bromo-5-((1 ,3-dioxoisoindolin-2-yl)methyl)thiazole-4- carboxylate. Potassium 1 ,3-dioxoisoindolin-2-ide (70 mg, 0.378 mmol), and methyl 2- bromo-5-(bromomethyl)thiazole-4-carboxylate (100 mg, 0.317 mmol) in DMF (2 mL) were added to a 8 mL vial. The resulting mixture was stirred at 25 °C for 10 h. After this time, the mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give a yellow oil. The oil was subjected to silica gel chromatography (0-25% EtOAc/petroleum ether) to give methyl 2- bromo-5-((1 ,3-dioxoisoindolin-2-yl)methyl)thiazole-4-carboxylate as a white solid (80 mg, 61.1 % yield). LCMS (ESI): Mass calcd. for CuHgBrlShCMS 379.95 m/z, found 380.8 [M+1] ⁺ .

Step B: (R)-Methyl 5-((1 ,3-dioxoisoindolin-2-yl)methyl)-2-(3-(5-(3-hydroxy-1- methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)thiazole-4- carboxylate. (R)-3-Hydroxy- 1-methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5- yl)pyrrolidin-2-one (Intermediate 4, 55 mg, 0.14 mmol), 1 ,4-dioxane (1.6 mL) and H2O (0.4 mL) were added to a nitrogen-purged 8 mL flask, and charged with methyl 2- bromo-5-((1 ,3-dioxoisoindolin-2-yl)methyl)thiazole-4-carboxylate (66 mg, 0.17 mmol), Pd(dtbpf)Cl2 (10 mg, 0.015 mmol), and K3PO4 (93 mg, 0.44 mmol). The mixture was sparged with N2 for 5 min and then heated at 100 °C for 6 h. After this time, the reaction vessel was removed from the heating device and allowed to gradually cool to rt. The reaction mixture was then diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give a yellow oil. The oil was subjected to silica gel chromatography (0-100% EtOAc/petroleum ether) to give (R)-methyl 5-((1 ,3-dioxoisoindolin-2-yl)methyl)-2-(3-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)thiazole-4-carboxyla te as a white solid (25 mg, 29% yield). LCMS (ESI): Mass calcd. for C28H22N4O7S 558.12 m/z, found 559.1 [M+1 ] ⁺ .

Step C: (R)-5-(Aminomethyl)-2-(3-(5-(3-hydroxy-1-methyl-2-oxopyrroli din-3- yl)isoxazol-3-yl)phenyl)thiazole-4-carboxamide. (R)-Methyl 5-((1 ,3-dioxoisoindolin-2- yl)methyl)-2-(3-(5-(3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl) isoxazol-3- yl)phenyl)thiazole-4-carboxylate (120 mg, 0.215 mmol) and NH3 (12 mL, 84 mmol, 7 M in MeOH) were added to a 40 mL vial. The resultant mixture was heated at 50 °C for 16 h. After this time, the mixture was concentrated to dryness in vacuo to give a yellow oil. The oil was then subjected to HPLC ((Phenomenex C18 column, 3 pm, 75 x 30 mm); 17-47% ACN/water (0.05% NH ₃ «H ₂ O + 10 mM NH4HCO3)), and then subjected to HPLC ((Welch Xtimate C18 , 5 pm, 150 x 30 mm) 18-48% ACN/water (0.05% NH ₃ «H ₂ O + 10 mM NH4HCO3)) to give the title compound as a white solid (10.71 mg, 12%). LCMS (ESI): Mass calcd. for C19H19N5O4S 413.12 m/z found 414.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-c/e) 8 8.47 (s, 1 H), 8.10 (d, J = 8.0 Hz, 1 H), 7.99 (d, J = 8.0 Hz, 1 H), 7.93 (br s, 1 H), 7.68 - 7.61 (m, 1 H), 7.57 (br s, 1 H), 7.17 (s, 1 H), 6.74 (s, 1 H), 4.25 (s, 2H), 3.53 - 3.44 (m, 2H), 2.85 (s, 3H), 2.62 - 2.56 (m, 1 H), 2.35 - 2.23 (m, 1 H).

Example 238: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-(((1 -methyl-1 H-pyrazol-3-yl)amino)methyl)thiazole-4-carboxamide

Step A: (R)-Methyl 5-formyl-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)thiazole-4-carboxylate. (R)-3-Hydroxy-1 -methyl-3-(3-(3-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 250 mg, 0.651 mmol), methyl 2-bromo-5-formylthiazole-4-carboxylate (325 mg, 1.30 mmol, Example 222 Step B), Pd(dtbpf)Cl2 (85 mg, 0.13 mmol), K3PO4 (552 mg, 2.60 mmol), H2O (0.5 mL), and 1 ,4-dioxane (5 mL) were added to a 40 mL vial. The resultant mixture was sparged with N2 for 5 min, and then heated at 80 °C for 2 h. The reaction vessel was removed from the heating device and allowed to gradually cool to rt. The mixture was filtered through a pad of diatomaceous earth. The filtrate was concentrated to dryness in vacuo to give a brown gum. The gum was subjected to silica gel chromatography (0-5% MeOH/CH2Cl2) to give (R)-methyl 5-formyl-2-(3-(5-(3-hydroxy-1 - methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)thiazole-4- carboxylate as a light brown solid (200 mg, 36%). LCMS (ESI): Mass calcd. for C20H17N3O6S 427.08 m/z, found 428.1 [M+H] ⁺ .

Step B: (R)-Methyl 2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-(((1 -methyl-1 H-pyrazol-3-yl)amino)methyl)thiazole-4-carboxylate. (R)- Methyl 5-formyl-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)thiazole-4-carboxylate (200 mg, 0.468 mmol), 1 -methyl-1 /-/-pyrazol-3-amine (125 mg, 0.936 mmol), titanium(IV) propan-2-olate (199 mg, 0.702 mmol), and MeOH (8 mL) were added to a 40 mL vial. The vial was capped, placed on a stir plate, and stirred for 2 h at room temperature. NaBHsCN (73.5 mg, 1.17 mmol) was added in one portion, and the resulting mixture heated to 60 °C and stirred for 16 h. The reaction vessel was removed from the heating device and allowed to gradually cool to room temperature. The reaction mixture was used for the next step directly without workup and purification. LCMS (ESI): Mass calcd. for C24H24N6O5S 508.15 m/z, found 509.3 [M+H] ⁺ .

Step C: (R)-2-(3-(5-(3-Hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-5-(((1 -methyl-1 H-pyrazol-3-yl)amino)methyl)thiazole-4-carboxamide. To (R)- methyl 2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5-(((1 - methyl-1 H-pyrazol-3-yl)amino)methyl)thiazole-4-carboxylate (238 mg, 0.468 mmol) in MeOH (8 mL), NH3 (8 mL, 56 mmol, 7 M in MeOH) was added and the resulting mixture stirred for 18 h at 75 °C. The reaction vessel was removed from the heating device and allowed to gradually cool to rt. The mixture was concentrated in vacuo to give a brown gum, which was subjected to HPLC (Boston Prime C18 column, 5 pm, 150 x 30 mm; 25-55% CH3CN/H2O with 0.05% NH ₃ «H ₂ O + 10 mM NH4HCO3), and then subjected to SFC (DAICEL CHIRALCEL® AS column, 10 pm, 250 x 30 mm; 55% EtOH (containing 0.1 % NH3*H2O)/supercritical CO2) to give, after lyophilization, (R)-2-(3-(5-(3-hydroxy-1 - methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)-5-(((1 -methyl-1 /-/-pyrazol-3- yl)amino)methyl)thiazole-4-carboxamide as a white solid (49.9 mg, 66%). LCMS (ESI): Mass calcd. for C23H23N7O4S 493.15 m/z, found 494.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-cfe) 8 8.44 (s, 1 H), 8.07 (d, J = 8.0 Hz, 1 H), 8.03 (br s, 1 H), 7.98 (d, J = 8.0 Hz, 1 H), 7.66 (br s, 1 H), 7.65 - 7.59 (m, 1 H), 7.34 (d, J = 2.0 Hz, 1 H), 7.17 (s, 1 H), 6.76 (br s, 1 H), 6.10 - 6.02 (m, 1 H), 5.47 (d, J = 2.0 Hz, 1 H), 4.79 (d, J = 6.4 Hz, 2H), 3.60 (s, 3H), 3.52 - 3.43 (m, 2H), 2.84 (s, 3H), 2.61 - 2.54 (m, 1 H), 2.34 - 2.22 (m, 1 H). ¹ H NMR (400 MHz, CD3OD) 8 8.45 (s, 1 H), 8.04 (d, J = 8.0 Hz, 1 H), 7.94 (d, J = 8.0 Hz, 1 H), 7.64 - 7.55 (m, 1 H), 7.29 (d, J = 2.4 Hz, 1 H), 7.01 (s, 1 H), 5.61 (d, J = 2.4 Hz, 1 H), 4.91 - 4.90 (m, 2H), 3.69 (s, 3H), 3.63 - 3.56 (m, 2H), 2.99 (s, 3H), 2.80 - 2.70 (m, 1 H), 2.47 - 2.37 (m, 1 H).

Example 239: (R)-5-((1 ,4-Dimethyl-1 H-pyrazol-3-yl)amino)-2-(3-(5-(3-hydroxy-1 -methyl- 2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)thiazole-4-carboxa mide

Step A: Ethyl 5-((1 ,4-dimethyl-1 /-/-pyrazol-3-yl)amino)thiazole-4-carboxylate. Ethyl 5-bromo-1 ,3-thiazole-4-carboxylate (1.0 g, 4.2 mmol), 1 ,4-dimethylpyrazol-3- amine (471 mg, 4.24 mmol), CS2CO3 (3.45 g, 10.6 mmol), XPhos (735 mg, 1.27 mmol), 1 ,4-dioxane (10 mL), and Pd(dba)2 (244 mg, 0.424 mmol) were added to a 100 mL round-bottomed flask, which was evacuated and refilled with N2 for three times. The resultant mixture was heated at 100 °C for 8 h. After this time, the reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The reaction mixture was diluted with water (80 mL) and extracted with DCM (80 mL x 2). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was subjected to silica gel chromatography (1 -3% EtOAc/petroleum ether) to give ethyl 5-((1 ,4-dimethyl-1 /-/-pyrazol-3-yl)amino)thiazole-4-carboxylate as a yellow solid (721 mg, 64%). ¹ H NMR (400 MHz, CDCh) 8 9.88 (br s, 1 H), 8.06 (s, 1 H), 7.08 (s, 1 H), 4.46 (q, J = 7.2 Hz, 2H), 3.81 (s, 3H), 2.07 (s, 3H), 1 .47 (t, J = 7.2 Hz, 3H).

Step B: Ethyl 2-bromo-5-((1 ,4-dimethyl-1 /-/-pyrazol-3-yl)amino)thiazole-4- carboxylate. NBS (529 mg, 2.97 mmol) was added to a solution consisting of ethyl 5- ((1 ,4-dimethyl-1 H-pyrazol-3-yl)amino)thiazole-4-carboxylate (720 mg, 2.70 mmol) in MeCN (10 mL). The resultant mixture was stirred at rt for 1 h. After this time, the mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 2). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was subjected to silica gel chromatography (1 -3% EtOAc/petroleum ether) to afford ethyl 2-bromo-5-((1 ,4-dimethyl-1 /-/-pyrazol-3- yl)amino)thiazole-4-carboxylate as a yellow solid (421 mg, 45%). ¹ H NMR (400 MHz, chloroform-d) 8 9.97 (br s, 1 H), 7.08 (s, 1 H), 4.44 (q, J = 7.2 Hz, 2H), 3.80 (s, 3H), 2.06 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H).

Step C: (R)-Ethyl 5-((1 ,4-dimethyl-1 H-pyrazol-3-yl)amino)-2-(3-(5-(3-hydroxy-1- methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)thiazole-4- carboxylate. Ethyl 2-bromo- 5-((1 ,4-dimethyl-1 /-/-pyrazol-3-yl)amino)thiazole-4-carboxylate (150 mg, 0.434 mmol), (R)-3-hydroxy-1 -methyl-3-(3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)pyrrolidin-2-one (Intermediate 4, 184 mg, 0.478 mmol), 1 ,4- dioxane (6 mL), H2O (0.5 mL), Pd(PPh3)4 (50 mg, 0.044 mmol), and Na2COs (138 mg, 1 .3 mmol) were added to a 10 mL microwave tube. The mixture was sparged with N2 for 5 minutes and heated at 110 °C for 1 h via microwave irradiation. After this time, the reaction vessel was removed from the heating device and allowed to gradually cool to rt. The reaction mixture was diluted with water (30 mL) and extracted with DCM (30 mL x 2). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was subjected to silica gel chromatography (1-5% MeOH/DCM) to afford the desired product as a red solid (253 mg, 67%). LCMS (ESI): Mass calcd. for C25H26N6O5S 522.17 m/z, found 523.2 [M+H] ⁺ .

Step D: (R)-5-((1 ,4-Dimethyl-1 H-pyrazol-3-yl)amino)-2-(3-(5-(3-hydroxy-1 -methyl- 2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)thiazole-4-carboxa mide. (R)-Ethyl 5-((1 ,4- dimethyl-1 /-/-pyrazol-3-yl)amino)-2-(3-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)phenyl)thiazole-4-carboxylate (200 mg, 0.383 mmol) and NH3 (6 mL, 7 M in MeOH, 42 mmol) were added to a 10 mL microwave tube. The resultant mixture was heated at 125 °C via microwave irradiation for 5 h. After this time, the reaction vessel was removed from the heating device and allowed to gradually cool to rt. The reaction mixture was concentrated in vacuo. The residue was subjected to HPLC (Boston Green ODS column, 150 x 30 mm, 5 pm, 35-95% MeCNjTW (0.075%TFA)) to give the title compound as a yellow solid (11 .29 mg, 6%). LCMS (ESI): Mass calcd. for C23H23N7O4S 493.15 m/z, found 494.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 10.80 (s, 1 H), 8.38 (s, 1 H), 8.04 - 7.99 ( m, 1 H), 7.93 - 7.88 ( m, 1 H), 7.80 (s, 1 H), 7.64 - 7.58 (m, 1 H), 7.55 (s, 1 H), 7.49 (s, 1 H), 7.14 (s, 1 H), 6.76 (s, 1 H), 3.78 (s, 3H), 3.53 - 3.40 (m, 2H), 2.85 (s, 3H), 2.62 - 2.55 (m, 1 H), 2.35 - 2.26 (m, 1 H), 1 .99 (s, 3H). ¹ H NMR (400 MHz, MeOH-c/4) 8 8.37 (s, 1 H), 7.99 - 7.98 (m, 1 H), 7.85 - 7.83 ( m, 1 H), 7.57 - 7.54 ( m, 1 H), 7.28 (s, 1 H), 7.00 (s, 1 H), 3.81 (s, 3H), 3.64 - 3.54 (m, 2H), 2.98 (s, 3H), 2.82 - 2.71 (m, 1 H), 2.47 - 2.37 (m, 1 H), 2.04 (s, 3H).

Example 240: (R)-6-(2-Fluoro-5-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-4-(trifluoromethyl)picolinamide,

Step A: (E)-3-Bromo-4-fluorobenzaldehyde oxime. Na2COs (428 mg, 4.04 mmol) was added to a mixture consisting of 3-bromo-4-fluorobenzaldehyde (1 g, 4.9 mmol), hydroxylamine hydrochloride (550 mg, 7.92 mmol), EtOH (20 mL), and H2O (10 mL), and the mixture stirred at room temperature for 18 h. After this time, the mixture was concentrated in vacuo to remove EtOH and the aqueous extracted with EtOAc (25 mL x 3). The combined organic layer was washed with water (25 mL x 3) and brine (25 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford (E)-3- bromo-4-fluorobenzaldehyde oxime as a white solid (1 g, 93%). MS (ESI): Mass calcd. for CyHsBrFNO 216.95 m/z, found 218.0 [M+H] ⁺ . Step B: (Z)-3-Bromo-4-fluoro-N-hydroxybenzimidoyl chloride. To a solution consisting of (E)-3-bromo-4-fluorobenzaldehyde oxime (1 g, 4.6 mmol) and CH2CI2 (25 mL) was added NCS (643 mg, 4.82 mmol) in one portion. The resultant mixture was stirred at room temperature for 18 h. After this time, the solution was concentrated in vacuo, and the residue subjected to silica gel chromatography (0-30% EtOAc/petroleum ether) to afford (Z)-3-bromo-4-fluoro-/V-hydroxybenzimidoyl chloride as a pale yellow solid (620 mg, 54%). MS (ESI): Mass calcd. for CyFUBrCIFNO 250.91 m/z, found 251.9 [M+H] ⁺ .

Step C: (R)-3-(3-(3-Bromo-4-fluorophenyl)isoxazol-5-yl)-3-hydroxy-1 - methylpyrrolidin-2-one. (Z)-3-Bromo-4-fluoro-/V-hydroxybenzimidoyl chloride (567 mg, 2.25 mmol) was added to a mixture consisting of (R)-3-ethynyl-3-hydroxy-1 - methylpyrrolidin-2-one (Intermediate 1 , 250 mg, 1.8 mmol), NaHCOs (604 mg, 7.2 mmol), sodium ascorbate (107 mg, 0.54 mmol), Cu2SO4*5H2O (45 mg, 0.18 mmol), THF (10 mL) and H2O (10 mL). The resulting mixture was stirred at room temperature for 18 h. After this time, the mixture was diluted with water (10 mL) and extracted with EtOAc (25 mL x 3). The combined organic extracts were washed with water (10 mL x 2) and brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was subjected to silica gel chromatography (0-100% EtOAc/petroleum ether) to afford (R)-3-(3-(3-bromo-4-fluorophenyl)isoxazol-5-yl)-3-hydroxy-1- methylpyrrolidin-2-one as an off-white solid (550 mg, 86%). MS (ESI): Mass calcd. for Ci ₄ Hi2BrFN ₂ O3 354.00 m/z, found 355.0 [M+H] ⁺ .

Step D: (R)-(2-Fluoro-5-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)boronic acid. A mixture consisting of (R)-3-(3-(3-bromo-4- fluorophenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (200 mg, 0.56 mmol), (BPin)2 (286 mg, 1.13 mmol), KOAc (166 mg, 1 .69 mmol), and anhydrous 1 ,4-dioxane (5 mL) was sparged with N2 for 5 min, treated with X-Phos-Pd-G2 (44.3 mg, 0.056 mmol), and heated at 100 °C for 18 h under a N2 atmosphere. After this time, the reaction vessel was removed from the oil bath and allowed to gradually cool to room temperature. The reaction mixture was used to next step directly without work-up and purification. MS (ESI): Mass calcd. for C14H14BFN2O5 320.08 m/z, found 321.1 [M+H] ⁺ . Step E: (R)-6-(2-Fluoro-5-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-4-(trifluoromethyl)picolinamide. A mixture consisting of (R)-(2-fluoro-5-(5-(3- hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)b oronic acid (180 mg, 0.56 mmol, in 5 mL of 1 ,4-dioxane), 6-chloro-4-(trifluoromethyl)picolinamide (126 mg, 0.56 mmol), K3PO4 (230 mg, 1 .69 mmol) and water (0.5 mL) was sparged with N2 for 5 min, treated with Pd(dtbpf)Cl2 (37 mg, 0.056 mmol), and heated at 100 °C for 20 h. The reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The mixture was filtered through a pad of diatomaceous earth, and the pad washed with EtOAc (15 mL). The filtrate was concentrated in vacuo, and the residue subjected to HPLC (Boston Green ODS column, 5 pm, 150 x 30 mm; 38-68% (v/v) CH3CN/H2O with 0.225% FA), and then subjected to SFC (DAICEL CHIRALCEL® OD-H column, 5 pm, 250 x 30 mm; 35% EtOH (containing 0.1 % NH3*H2O)/supercritical CO2) to give, after lyophilization, (R)-6-(2-fluoro-5-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)-4-(trifluoromethyl)picolinamide as a white solid (46.6 mg, 20%). MS (ESI): Mass calcd. for C21H16F4N4O4 464.11 m/z, found 465.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-cfe) 8 8.64 - 8.57 (m, 1 H), 8.54 (s, 1 H), 8.36 (s, 1 H), 8.28 (s, 1 H), 8.14 - 8.08 (m, 1 H), 8.03 (s, 1 H), 7.61 - 7.54 (m, 1 H), 7.23 (s, 1 H), 6.77 (br s, 1 H), 3.52 - 3.43 (m, 2H), 2.85 (s, 3H), 2.60 - 2.53 (m, 1 H), 2.33 - 2.24 (m, 1 H). ¹ H NMR (400 MHz, CD3OD) 8 8.70 (dd, J = 2.4, 7.6 Hz, 1 H), 8.39 (s, 1 H), 8.35 (s, 1 H), 8.09 - 8.02 (m, 1 H), 7.52 - 7.43 (m, 1 H), 7.07 (s, 1 H), 3.64 - 3.56 (m, 2H), 2.99 (s, 3H), 2.81 - 2.72 (m, 1 H), 2.48 - 2.37 (m, 1 H).

Example 241 : (R)-5-Amino-4-cyclopropyl-4'-(5-(3-hydroxy-1-methyl-2-oxopyr rolidin-3- yl)isoxazol-3-yl)-[2,2'-bipyridine]-6-carboxamide,

Step A: 3-Amino-6-chloro-4-cyclopropylpicolinonitrile. Cyclopropylboronic acid (2.80 g, 32.6 mmol) was added into a solution of 3-amino-4-bromo-6- chloropicolinonitrile (5.00 g, 21 .5 mmol) and CS2CO3 (21 .0 g, 64.5 mmol) in 1 ,4-dioxane (100 mL) and H2O (25 mL). The resultant mixture was sparged with N2 for 5 min, treated with Pd(dppf)Cl2 (2.35 g, 3.21 mmol), and stirred while heating at 100 °C for 16 hours. The reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The reaction mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (120 mL x 3). The combined organic extracts were washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo and the residue subjected to silica gel chromatography (0-100% EtOAc/petroleum ether) to afford 3- amino-6-chloro-4-cyclopropylpicolinonitrile (1.95 g, 44%) as a yellow solid. MS (ESI): Mass calcd. for C9H8CIN3 193.04 m/z, found 194.0 [M+H] ⁺ .

Step B: 3-Amino-6-chloro-4-cyclopropylpicolinamide. H2O2 (4.10 mL, 40.9 mmol) was added to a mixture consisting of 3-amino-6-chloro-4-cyclopropylpicolinonitrile (1 .95 g, 10.1 mmol), K2CO3 (683 mg, 4.94 mmol) and DMF (20 mL). The resultant mixture was stirred at 30 °C for 24 h. After this time, the mixture was diluted with saturated aqueous Na2SOs (30 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic extracts were washed with 4% LiCI solution (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give 3-amino-6-chloro-4- cyclopropylpicolinamide as a yellow solid (1.88 g, 80%). MS (ESI): Mass calcd. for C9H10CIN3O 211 .05 m/z, found 211 .8 [M+H] ⁺ .

Step C: 3-Amino-4-cyclopropyl-6-(tributylstannyl)picolinamide. 1 , 1 ,1 , 2,2,2- Hexabutyldistannane (2.35 g, 4.05 mmol) was added into a mixture consisting of 3- amino-6-chloro-4-cyclopropylpicolinamide (500 mg, 2.36 mmol), LiCI (600 mg, 14.2 mmol) and 1 ,4-dioxane (30 mL). The resultant mixture was sparged with N2 for 5 min, treated with Pd2(dba)3 (110 mg, 0.120 mmol) and tricyclohexylphosphine (70 mg, 0.25 mmol), and stirred while heating at 120 °C for 16 h. The reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The mixture was quenched with sat. aqueous KF (30 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, concentrated to dryness in vacuo, and the residue subjected to HPLC (Xtimate C18 column, 5 pm, 150 x 40 mm, 95-99% (v/v) CH3CN/H2O with 0.05% NH3H2O) to give 3-amino-4-cyclopropyl-6-(tributylstannyl)picolinamide as a brown oil (315 mg, 27%). MS (ESI): Mass calcd. for C2iH ₃ 7N ₃ OSn 467.20 m/z, found 468.2 [M+H] ⁺ .

Step D: (R)-5-Amino-4-cyclopropyl-4'-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3- yl)isoxazol-3-yl)-[2,2'-bipyridine]-6-carboxamide. 3-Amino-4-cyclopropyl-6- (tributylstannyl)picolinamide (240 mg, 0.515 mmol) was added into a solution consisting of (R)-3-(3-(2-chloropyridin-4-yl)isoxazol-5-yl)-3-hydroxy-1-me thylpyrrolidin-2-one (Intermediate 65, 140 mg, 0.477 mmol), TEA (140 pL, 1 .00 mmol) and toluene (15 mL). The resultant mixture was sparged with N2 for 5 min, treated with Pd(PPh ₃ )4 (55 mg, 0.048 mmol) and stirred while heating at 120 °C for 16 h. The reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The reaction mixture was quenched with sat. aqueous KF (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was subjected to HPLC (Phenomenex Gemini-NX C18 column, 3 pm, 75 x 30 mm; 27-57% (v/v) CH ₃ CN/H2O with 0.05% NH ₃ H2O +10 mM NFUHCOs) to give (R)-5-amino-4-cyclopropyl-4'-(5-(3- hydroxy-1-methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)-[2,2'-b ipyridine]-6-carboxamide as a white solid (45.7 mg, 22%). MS (ESI): Mass calcd. for C22H22N6O4434.I7 m/z found 434.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 88.79 (s, 1 H), 8.71 (d, J = 5.1 Hz, 1 H), 8.51 (s, 1 H), 8.05 (s, 1 H), 7.80 - 7.75 (m, 1 H), 7.53 (s, 1 H), 7.45 (s, 1 H), 7.31 (br s, 2H), 6.79 (s, 1 H), 3.51 - 3.42 (m, 2H), 2.85 (s, 3H), 2.61 - 2.55 (m, 1 H), 2.31 - 2.25 (m, 1 H), 1.92 - 1 .83 (m, 1 H), 1.08 - 1 .03 (m, 2H), 0.70 - 0.66 (m, 2H).

Example 242: (R)-3-Amino-4-cyclopropyl-6-(2-fluoro-3-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinamide

Step A: (E)-3-Bromo-2 -fluorobenzaldehyde oxime. A mixture consisting of 3- bromo-2-fluorobenzaldehyde (5.00 g, 24.6 mmol), hydroxylamine hydrochloride (2.05 g, 29.6 mmol), NaOAc (2.43 g, 29.6 mmol) and EtOH (70 mL) was heated at 45 °C for 1 hour. After this time, the mixture was concentrated to dryness in vacuo, and the residue suspended in H2O (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to afford (E)-3-bromo-2-fluorobenzaldehyde oxime as a white solid (5.4 g, 99%). MS (ESI): Mass calcd. for CyHsBrFNO 216.95 m/z, found 217.9 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 11 .77 (s, 1 H), 8.23 (s, 1 H), 7.76 - 7.70 (m, 2H), 7.19 (t, J = 7.9 Hz, 1 H).

Step B: (Z)-3-Bromo-2-fluoro-N-hydroxybenzimidoyl chloride. NCS (1.35 g, 10.1 mmol) was added to a solution consisting of (E)-3-bromo-2-fluorobenzaldehyde oxime (2.00 g, 9.17 mmol) in DMF (20 mL). The resultant mixture was stirred at room temperature for 2 h, diluted with H2O (30 mL), and extracted with MTBE (30 mL x 3). The combined organic extracts were washed with 4% aqueous LiCI solution (100 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give (Z)-3-bromo-2-fluoro-/V-hydroxybenzimidoyl chloride as a white solid (2.3 g, 72%). MS (ESI): Mass calcd. for C7H ₄ BrCIFNO 250.91 m/z, found 251.9 [M+H] ⁺ .

Step C: (R)-3-(3-(3-Bromo-2-fluorophenyl)isoxazol-5-yl)-3-hydroxy-1 - methylpyrrolidin-2-one. (R)-3-Ethynyl-3-hydroxy-1 -methylpyrrolidin-2-one (Intermediate 1 , 441 mg, 3.17 mmol) was added to a mixture consisting of (Z)-3-bromo-2-fluoro-/V- hydroxybenzimidoyl chloride (800 mg, 3.17 mmol), TEA (1.32 mL, 9.5 mmol), and DCM (7 mL). The resultant mixture was stirred for 16 h at room temperature, treated with H2O (10 mL), and extracted with DCM (10 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was subjected to silica gel chromatography (0-25% EtOAc/petroleum ether) to give (R)-3-(3-(3-bromo-2-fluorophenyl)isoxazol-5-yl)-3- hydroxy-1-methylpyrrolidin-2-one as a white solid (677 mg, 58%). MS (ESI): Mass calcd. for Ci ₄ Hi2BrFN ₂ O3 354.00 m/z, found 355.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- cfe) 8 7.92 - 7.85 (m, 2H), 7.32 (t, J = 7.7 Hz, 1 H), 6.90 (d, J = 3.1 Hz, 1 H), 6.79 (s, 1 H), 3.51 - 3.38 (m, 2H), 2.83 (s, 3H), 2.61 - 2.53 (m, 1 H), 2.32 - 2.22 (m, 1 H).

Step D: (R)-3-(3-(2-Fluoro-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one. (R)-3-(3-(3-Bromo-2- fluorophenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (390 mg, 1.10 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (418 mg, 1.65 mmol) and KOAc (323 mg, 3.29 mmol) were added to a 10 mL flask and the resulting mixture dissolved in 1 ,4-dioxane (5 mL). The resultant mixture was sparged with N2 for 5 min, treated with Pd(dppf)Cl2 (80 mg, 0.11 mmol), and heated at 100 °C for 3 hour. The reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The reaction mixture was concentrated to dryness in vacuo, and the residue subjected to silica gel chromatography (0-100% EtOAc/petroleum ether) to give (R)-3-(3-(2-fluoro-3- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1 - methylpyrrolidin-2-one as a brown solid (190 mg, 35%). MS (ESI): Mass calcd. for C20H24BFN2O5 402.18 m/z, found 403.2 [M+H] ⁺ .

Step E: (R)-3-Amino-4-cyclopropyl-6-(2-fluoro-3-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinamide. (R)-3-(3-(2-Fluoro-3-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin- 2 -one (240 mg, 0.597 mmol), 3-amino-6-chloro-4-cyclopropylpicolinamide (126 mg, 0.597 mmol, Example 88 Step A), and K3PO4 (380 mg, 1 .79 mmol) were added to a 5 mL microwave tube and the resulting mixture dissolved in 1 ,4-dioxane (4 mL) and H2O (1 mL). The mixture was sparged with N2 for 5 min, treated with Pd(dtbpf)Cl2 (39 mg, 0.060 mmol), and heated at 90 °C via microwave irradiation for 1 h. The reaction vessel was removed from the microwave heating device and allowed to gradually cool to rt. The reaction mixture was concentrated to dryness in vacuo, and the residue subjected to HPLC (Boston Prime C18 column, 5 μm, 150 x 30 mm; 35-65% (v/v) ACN/H2O with 0.05% NH3*H2O and 10 mM NH4HCO3) to give the title compound as a colorless solid (80.1 mg, 30%). MS (ESI): Mass calcd. for C23H22FN5O4451 .17 m/z, found 452.1 [M+1 ] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.22 - 8.15 (m, 1 H), 8.14 - 8.07 (m, 1 H), 7.86 - 7.78 (m, 1 H), 7.52 - 7.44 (m, 2H), 7.43 - 7.36 (m, 1 H), 7.16 (br s, 2H), 6.93 (d, J = 3.1 Hz, 1 H), 6.77 (s, 1 H), 3.53 - 3.44 (m, 2H), 2.85 (s, 3H), 2.63 - 2.55 (m, 1 H), 2.35 - 2.24 (m, 1 H), 1.92 - 1.81 (m, 1 H), 1.08 - 0.99 (m, 2H), 0.73 - 0.65 (m, 2H).

Example 243: (R)-3-Amino-4-cyclopropyl-6-(3-fluoro-5-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinamide

Step A: (E)-3-Bromo-5-fluorobenzaldehyde oxime. To a mixture consisting of 3- bromo-5-fluorobenzaldehyde (2.0 g, 9.9 mmol), NFWH’HCI (1.1 g, 16 mmol), EtOH (40 mL) and H2O (20 mL) was added Na2COs (856 mg, 8.08 mmol) in one portion. The resulting mixture was stirred for 16 h at room temperature. After this time, the mixture was concentrated in vacuo to remove the volatiles, diluted with 10 mL of H2O, and extracted with EtOAc (30 mL x 2). The combined organic extracts were washed with water (30 mL x 3) and brine (30 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give (E)-3-bromo-5-fluorobenzaldehyde oxime as a white solid (2.14 g, 99.6%). MS (ESI): Mass calcd. for CyHsBrFNO 216.95 m/z, found 217.9 [M+H] ⁺ .

Step B: (Z)-3-Bromo-5-fluoro-N-hydroxybenzimidoyl chloride. To a solution of (E)-3-bromo-5-fluorobenzaldehyde oxime (400 mg, 1.84 mmol) in MeCN (4 mL) was added NCS (269 mg, 2.02 mmol) in one portion. The resulting mixture was stirred for 6.5 h at 0 °C. After this time, the reaction mixture containing (Z)-3-bromo-5-fluoro-N- hydroxybenzimidoyl chloride was used for next step directly without purification.

Step C: (R)-3-(3-(3-Bromo-5-fluorophenyl)isoxazol-5-yl)-3-hydroxy-1 - methylpyrrolidin-2-one. Sodium ascorbate (85 mg, 0.43 mmol) was added to a mixture consisting of (Z)-3-bromo-5-fluoro-/V-hydroxybenzimidoyl chloride (453 mg, 1.80 mmol), (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (Intermediate 1 , 200 mg, 1.44 mmol), NaHCOs (483 mg, 5.75 mmol), Cu2SO4*5H2O (36 mg, 0.14 mmol), MeCN (4 mL), and H2O (2.5 mL). The resulting mixture was stirred for 18 h at room temperature. After this time, the mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was purified by silica gel chromatography (0-60% EtOAc/petroleum ether) to afford (R)-3-(3-(3-bromo-5- fluorophenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one as a white solid (380 mg, 74%). ¹ H NMR (400 MHz, CDCh) 7.65 (s, 1 H), 7.41 - 7.36 (m, 1 H), 7.33 - 7.29 (m, 1 H), 6.64 (s, 1 H), 4.45 (s, 1 H), 3.71 - 3.59 (m, 1 H), 3.57 - 3.47 (m, 1 H), 3.01 (s, 3H), 2.76 - 2.72 (m, 1 H), 2.52 - 2.42 (m, 1 H).

Step D: (R)-3-(3-(3-Fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpyrrolidin-2-one. A mixture consisting of (R)-

3-(3-(3-bromo-5-fluorophenyl)isoxazol-5-yl)-3-hydroxy-1-m ethylpyrrolidin-2-one (300 mg, 0.85 mmol), (BPin)2 (429 mg, 1 .7 mmol), KOAc (207 mg, 2.11 mmol), and anhydrous 1 ,4-dioxane (10 mL) was sparged with N2 for 5 min, treated with Pd(dppf)Cl2*CH2Cl2 (69 mg, 0.084 mmol), and heated at 100 °C for 3 h under a N2 atmosphere. After this time the reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The reaction mixture containing (R)-3-(3-(3-fluoro-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1- methylpyrrolidin-2-one (340 mg) was used for next step directly without workup and purification. MS (ESI): Mass calcd. for C20H24BFN2O5 402.18 m/z, found 403.2 [M+H] ⁺ .

Step E: (R)-3-Amino-4-cyclopropyl-6-(3-fluoro-5-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinamide. A mixture consisting of (R)-3-(3-(3- fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1- methylpyrrolidin-2-one (340 mg, 0.85 mmol, in 10 mL of 1 ,4-dioxane), 3-amino-6-chloro-

4-cyclopropylpicolinamide (150 mg, 0.71 mmol, Example 88 Step A), K3PO4 (289 mg, 2.13 mmol) and water (1 mL) was sparged with N2 for 5 min, treated with Pd(dtbpf)Cl2 (46 mg, 0.071 mmol), and heated at 100 °C for 2 h under a N2 atmosphere. After this time, the reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The mixture was filtered through a pad of diatomaceous earth, and the pad washed with EtOH (15 mL). The filtrate was concentrated in vacuo. The residue was subjected to HPLC (Boston Green ODS column, 5 pm, 150 x 30 mm; 32-62% (v/v) CH3CN/H2O with 0.225% FA) to give, after lyophilization (R)-3-amino-4-cyclopropyl-6-(3-fluoro-5-(5- (3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinami de (49.5 mg, 15%) as a white solid. MS (ESI): Mass calcd. for C23H22FN5O4451.17 m/z, found 452.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 88.36 (d, J = 1.6 Hz, 1 H), 8.29 (s, 1 H), 8.23 (d, J = 10.4 Hz, 1 H), 7.68 (s, 1 H), 7.62 (d, J = 9.2 Hz, 1 H), 7.48 (s, 1 H), 7.31 (s, 1 H), 7.19 (br s, 2H), 6.77 (s, 1 H), 3.54 - 3.40 (m, 2H), 2.85 (s, 3H), 2.62 - 2.54 (m, 1 H), 2.33 - 2.24 (m, 1 H), 1.90 - 1.79 (m, 1 H), 1.05 - 0.98 (m, 2H), 0.87 - 0.80 (m, 2H).

Example 244: (R)-3-Amino-4-cyclopropyl-6-(4-fluoro-3-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinamide

Step A: 5-Bromo-2-fluorobenzaldehyde oxime. NH2OH*HCI (1.7 g, 25 mmol) was added to a mixture consisting of 5-bromo-2-fluorobenzaldehyde (5.0 g, 25 mmol), NaOAc (4.0 g, 49 mmol) and EtOH (60 mL). The resulting mixture was heated at 45 °C for 1 h. After this time, the mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to afford 5- bromo-2-fluorobenzaldehyde oxime (5.3 g, 98%) as a white solid. MS (ESI): Mass calcd. for CyHsBrFNO 216.95 m/z, found 217.7 [M+H] ⁺ .

Step B: 5-Bromo-2-fluoro-N-hydroxybenzimidoyl chloride. 1 -Chloropyrrolidine- 2, 5-dione (3.4 g, 25 mmol) was added to a mixture consisting of 5-bromo-2- fluorobenzaldehyde oxime (5.0 g, 23 mmol) and DMF (50 mL). The resulting mixture was stirred at room temperature for 4 h. After this time, the mixture was diluted with H2O (50 mL) and extracted with MTBE (50 mL x 3). The combined organic extracts were washed with 4% aqueous LiCI solution (100 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to give 5-bromo-2- fluoro-/V-hydroxybenzimidoyl chloride (6 g, 85%) as a white solid. MS (ESI): Mass calcd. for C ₇ H ₄ BrCIFNO 250.91 m/z, found 251 .9 [M+H] ⁺ .

Step C: (R)-3-(3-(5-Bromo-2-fluorophenyl)isoxazol-5-yl)-3-hydroxy-1 - methylpyrrolidin-2-one. Triethylamine (0.77 mL, 5.5 mmol) was added to a mixture consisting of 5-bromo-2-fluoro-/V-hydroxybenzimidoyl chloride (700 mg, 2.77 mmol) and (R)-3-ethynyl-3-hydroxy-1 -methylpyrrolidin-2-one (Intermediate 1 , 386 mg, 2.77 mmol) in DCM (10 mL). The resulting mixture was stirred for 16 h at room temperature. After this time, the mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo. The residue was subjected to silica gel chromatography (0-25% EtOAc/petroleum ether) to afford (R)-3-(3-(5-bromo-2- fluorophenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (700 mg, 71 %) as a white solid. MS (ESI): Mass calcd. for Ci4Hi2BrFN2O3 354.00 m/z, found 355.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CHLOROFORM-d) 5 8.00 - 7.93 (m, 1 H), 7.52 - 7.45 (m, 1 H), 7.07 - 6.95 (m, 1 H), 6.77 (d, J = 3.5 Hz, 1 H), 4.55 (br s, 1 H), 3.68 - 3.58 (m, 1 H), 3.52 - 3.43 (m, 1 H), 2.98 (s, 3H), 2.79 - 2.68 (m, 1 H), 2.50 - 2.40 (m, 1 H).

Step D: (R)-3-(3-(2-Fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one. [1 , T- Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (84 mg, 0.12 mmol) was added to a mixture consisting of (R)-3-(3-(5-bromo-2-fluorophenyl)isoxazol-5-yl)-3-hydroxy-1 - methylpyrrolidin-2-one (410 mg, 1.15 mmol), (BPin)2 (586 mg, 2.31 mmol), KOAc (340 mg, 3.46 mmol) and 1 ,4-dioxane (5 mL). The resulting mixture was sparged with N2 for 5 min, and then stirred for 3 hours at 90 °C. The reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The mixture was poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was subjected to silica gel chromatography (0- 100% EtOAc/ petroleum ether) to afford (R)-3-(3-(2-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1-methylpy rrolidin-2-one as a yellow solid (290 mg, 62%). MS (ESI): Mass calcd. for C20H24BFN2O5 402.22 m/z, found 403.2 [M+1 ] ⁺ .

Step E: (R)-3-Amino-4-cyclopropyl-6-(4-fluoro-3-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinamide. 1 ,1 '-Bis(di-te/t- butylphosphino)ferrocene palladium dichloride (47 mg, 0.072 mmol) was added to a mixture consisting of (R)-3-(3-(2-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (290 mg, 0.721 mmol), 3- amino-6-chloro-4-cyclopropylpicolinamide (153 mg, 0.721 mmol, Example 88 Step A) and K3PO4 (459 mg, 2.16 mmol) in 1 ,4-dioxane (4 mL) and H2O (1 mL) under a N2 atmosphere. The resulting mixture was sparged with N2 for 5 min, and then stirred for 1 hour at 90 °C via microwave irradiation. The reaction vessel was removed from the microwave heating device and allowed to gradually cool to rt. The mixture was concentrated to dryness under reduced pressure. The residue was subjected to silica gel chromatography (0-100% EtOAc/petroleum ether), and then purified by HPLC (Welch Xtimate C18 column, 5 pm, 150 x 30 mm; 30-60% MeCN/water (0.05% NH3*H2O+10 mM NH4HCO3)) to afford the title compound as a colorless solid (58 mg, 18%). MS (ESI): Mass calcd. for C23H22BFN5O4451 .17 m/z, found 452.1 [M+1 ] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.44 - 8.39 (m, 1 H), 8.37 - 8.31 (m, 1 H), 8.25 - 8.18 (m, 1 H), 7.58 (s, 1 H), 7.49 - 7.39 (m, 2H), 7.09 (br s, 2H), 6.99 - 6.96 (m, 1 H), 6.78 (s, 1 H), 3.54 - 3.45 (m, 2H), 2.85 (s, 3H), 2.62 - 2.55 (m, 1 H), 2.35 - 2.24 (m, 1 H), 1 .88 - 1 .80 (m, 1 H), 1 .05 - 0.98 (m, 2H), 0.83 - 0.77 (m, 2H).

Example 245: (R)-3-Amino-4-cyclopropyl-6-(2-fluoro-5-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinamide

Step A: (R)-3-(3-(4-Fluoro-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one. A mixture consisting of (R)- 3-(3-(3-bromo-4-fluorophenyl)isoxazol-5-yl)-3-hydroxy-1 -methylpyrrolidin-2-one (260 mg, 0.73 mmol, Example 240 Step C), (BPin)2 (557 mg, 2.2 mmol), KOAc (216 mg, 2.2 mmol) and anhydrous 1 ,4-dioxane (5 mL) was sparged with N2 for 5 min, treated with X- Phos-Pd-G2 (58 mg, 0.073 mmol), and stirred for 18 h at 100 °C under a N2 atmosphere. The reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The reaction mixture was used for the next step directly without work-up and purification. MS (ESI): Mass calcd. for C20H24BFN2O5 402.17 m/z, found 403.0 [M+H] ⁺ .

Step B: (R)-3-Amino-4-cyclopropyl-6-(2-fluoro-5-(5-(3-hydroxy-1 -methyl-2- oxopyrrolidin-3-yl)isoxazol-3-yl)phenyl)picolinamide. A mixture consisting of (R)-3-(3-(4- fluoro-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-5-yl)-3-hydroxy-1- methylpyrrolidin-2-one (Example 120 Step A, 234 mg, 0.58 mmol, in 5 mL of 1 ,4- dioxane), 3-amino-6-chloro-4-cyclopropylpicolinamide (103 mg, 0.49 mmol, Example 88 Step A), K3PO4 (198 mg, 1 .45 mmol), and water (0.5 mL) was sparged with N2 for 5 min, treated with Pd(dtbpf)Cl2 (31.6 mg, 0.048 mmol), and heated at 100 °C for 4 h under N2 atmosphere. The reaction vessel was removed from the oil bath and allowed to gradually cool to rt. The mixture was filtered through a pad of diatomaceous earth, and the pad washed with EtOAc (15 mL). The filtrate was concentrated in vacuo. The residue was subjected to HPLC (Boston Green ODS column, 5 pm, 150 x 30 mm; 32- 62% (v/v) CH3CN/H2O with 0.225% FA) to give, after lyophilization, (R)-3-amino-4- cyclopropyl-6-(2-fluoro-5-(5-(3-hydroxy-1 -methyl-2-oxopyrrolidin-3-yl)isoxazol-3- yl)phenyl)picolinamide (21 mg, 9.6%) as a white solid. MS (ESI): Mass calcd. for C23H22FN5O4451.17 m/z, found 452.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8 8.34 (dd, J = 2.0, 7.6 Hz, 1 H), 8.14 (d, J = 2.4 Hz, 1 H), 7.95 - 7.84 (m, 1 H), 7.49 (br d, J = 2.4 Hz, 1 H), 7.46 - 7.37 (m, 2H), 7.27 - 7.05 (m, 3H), 6.72 (s, 1 H), 3.51 - 3.43 (m, 2H), 2.84 (s, 3H), 2.59 - 2.54 (m, 1 H), 2.31 - 2.22 (m, 1 H), 1 .90 - 1 .81 (m, 1 H), 1 .06 - 0.98 (m, 2H), 0.70 - 0.63 (m, 2H). ¹ H NMR (400 MHz, CD3OD) 8.44 (dd, J = 2.4, 7.6 Hz, 1 H), 7.88 - 7.79 (m, 1 H), 7.57 (d, J = 2.0 Hz, 1 H), 7.32 (dd, J = 8.4, 11 .2 Hz, 1 H), 6.99 (s, 1 H), 3.64 - 3.55 (m, 2H), 2.98 (s, 3H), 2.79 - 2.71 (m, 1 H), 2.46 - 2.36 (m, 1 H), 1 .87 - 1.77 (m, 1 H), 1.14 - 1.07 (m, 2H), 0.74 - 0.67 (m, 2H).

Certain compounds described herein were tested in biological assays. The results of the assays are presented in Table 3 which is entitled Results of Biological Assays. The results are presented as an average of values obtained.

Biological Assay 1 : Inhibition of auto-phosphorylation of recombinant human NF- kappaB-inducing kinase (NIK/MAP3K14) activity (AlphaScreen®) NIK/MAP3K14 auto-phosphorylation activity was measured using the AlphaScreen® (ascreen) format (Perkin ElmeR). All compounds tested were dissolved in dimethyl sulfoxide (DMSO) and further dilutions were made in assay buffer. Final DMSO concentration was 0.7% (v/v) in assays. Assay buffer was 50 mM Tris pH 7.5 containing 1 mM EGTA (ethylene glycol tetraacetic acid), 1 mM DTT (dithiothreitol), 0.1 mM NasVCM, 5 mM MgCl2, 0.01% Tween® 20. Assays were carried out in 384 well Proxiplates (Perkin ElmeR). Incubations consisted of compound, 5 microM Adenosine- 5'-triphosphate (ATP), and 1 nM NIK/MAP3K14. Incubations were initiated by addition of GST-tagged NIK/MAP3K14 enzyme, carried out for 2 h at 25 °C and terminated by addition of stop buffer containing anti-phospho-IKK Seri 76/180 antibody. Protein A Acceptor and Glutathione-c/onor beads were added before reading using an EnVision® Multilabel Plate Reader (Perkin ElmeR). Signal obtained in the wells was normalized using high (full enzyme activity, 0.7% DMSO) and low controls (no enzyme activity, 0.7% DMSO, no ATP). ICso’s were determined by fitting a sigmoidal curve to % inhibition of control versus Logw compound concentration.

Biological Assay 2: Effect of compounds on p-IKKa levels in L363 (NIK translocated multiple myeloma) cells

All compounds tested were dissolved and serially diluted in DMSO, 1 :3 dilution for 11 points in an Echo compatible plate. 100% DMSO is added to columns 12 and 24 of the plate to serve as high and low signal controls. This compound plate was used to spot 20 nl of compound or DMSO into a Greiner 384 well TC plate (781080). Final DMSO concentration was 0.3% (v/v) in cell assays. Human L363 cells (ATCC) were cultured in RPMI 1640 medium supplemented with GlutaMax, non-essential amino acids, sodium pyruvate and 10% fetal bovine serum. Cells were routinely maintained at densities of 0.2x10 ⁶ cells per ml - 2x10 ⁶ cells per ml at 37°C in a humidified 5% CO2 atmosphere incubator. Cells were passaged twice a week splitting back to obtain the low density. The day before the assay, cells were washed twice in HBSS, resuspended in DMEM + 0.5% IgG and protease free BSA (Jackson Immuno Research Laboratories), +/- 250 ng/ml recombinant human B-cell activating factor (BAFF/BLyS/TNFSF13B) and incubated overnight at 37°C in a humidified 5% CO2 atmosphere (bulk stimulation with or without BAFF). The next day, cell concentration was adjusted to 1x10 ⁷ cells /ml in DMEM +/- 250 ng/ml BAFF +/- 10 uM MG132 and plated at 10 ul/ well into compound or DMSO spotted 384 well TC plates. Seeded cells were incubated at 37°C in a humidified 5% CO2 atmosphere for 6 h. After 6 h, plates were removed from the incubator and cell lysis was achieved by the addition of 2.5 pl 5x lysis buffer containing protease and phosphatase inhibitors, followed by shaking on a plate shaker at room temperature for 15 min. At the end of this incubation, lysed cells were sequentially treated and incubated with acceptor and donor bead mixes according to the manufacturer’s protocol for a 1 plate/ 2-incubation suspension cell assay (AlphaLISA SureFire Ultra p-IKKa (Ser 176/180) Assay Kit (Perkin ElmeR). Plates were read using an EnVision® Multilabel Plate Reader (Perkin ElmeR). Within an experiment, a concentration response curve for each compound was run in duplicate. Signal obtained in the test wells was normalized using high signal (BAFF stimulated cells, DMSO, MG132) and low signal (unstimulated cells, DMSO) controls. To determine the ICso, a sigmoidal curve was fitted to the plot of % inhibition versus Logw compound concentration.

Table 3 below provides ICso data for certain compounds described herein on NIK inhibition. In cases where the compound was tested more than once, the IC50 value was calculated as a simple average of the measured values. The average was then used to categorize the compound within one of the following ranges. A: IC50 < 100 nM;

B: 100 nM < IC50 < 500 nM;

C: IC50 > 501 nM

Table 3. Results of Biological Assays