Targeted protein degradation

Abstract

This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt thereof) that degrade and / or otherwise modulate (e.g., inhibit) NIMA Related Kinase 7 (NEK7). Said chemical entities are useful, e.g., for treating a subject (e.g., a human subject) having one or more disorders or diseases associated with NLRP3 inflammasome activation. Said disorders or diseases include but are not limited to, autoinflammatory and autoimmune disorders (e.g., gout, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis), neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease), cardiovascular and metabolic disorders (eg. pericarditis, atherosclerosis, Type 2 diabetes, obesity, and metabolic syndrome), fibrotic disorders (e.g. interstitial lung disease, chronic kidney disease), hematology (eg. anemia of inflammation) and eye disorders (eg. macular degeneration). In embodiments, and while not wishing to be bound by theory, it is believed that the chemical entities described herein directly target (e.g., directly bind to) NEK7, thereby altering (e.g., attenuating) the inflammatory response modulated by the NLRP3 inflammasome. This disclosure also features compositions containing the same as well as methods of using and making the same.

Description

[0001] TARGETED PROTEIN DEGRADATION TECHNICAL FIELD

[0002] This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt thereof) that degrade and / or otherwise inhibit NIMA Related Kinase 7 (NEK7). Said chemical entities are useful, e.g., for treating a subject (e.g., a human subject) having a disorder or disease associated with NLRP3 inflammasome activation. This disclosure also features compositions containing the same as well as methods of using and making the same.

[0003] BACKGROUND

[0004] The ubiquitin proteasome system can be manipulated with different small molecules to trigger targeted degradation of specific proteins of interest. Promoting the targeted degradation of pathogenic proteins using small molecule degraders is emerging as a new modality in the treatment of diseases. One such modality relies on redirecting the activity of E3 ligases such as cereblon (a phenomenon known as E3 reprogramming) using low molecular weight compounds, which have been termed molecular glues to promote the poly-ubiquitination and ultimately proteasomal degradation of new protein substrates involved in the development of diseases. The molecular glues bind to both the E3 ligase and the target protein, thereby mediating an alteration of the ligase surface and enabling an interaction with the target protein. Particularly relevant compounds for the E3 ligase cereblon are the IMiD (immunomodulatory imide drugs) class including Thalidomide, Lenalidomide and Pomalidomide. These IMiDs have been approved by the FDA for use in haematological cancers. However, compounds for efficiently targeting other diseases are still required.

[0005] Inflammasomes are multi-protein complexes whose activation plays a central role in innate immunity and inflammation. NLRP3 inflammasome activation occurs in response to infectious or cell damage-related stress, and acts to initiate or amplify inflammation. The NLRP3 inflammasome is composed of NLRP3, ASC, and caspase-I, which, when activated forms an intracellular complex that cleaves gasdermin D and the cytokines IL-ip and IL- 18 to release their active forms1,2. Cleaved gasdermin D then forms pores in the cell membrane, which allows the release of active IL-ip and IL- 18 and, in most cases, the rupture of the cell membrane in a highly inflammatory process known as pyroptosis3. NLRP3 activation is known to contribute to many settings of inappropriate or unwanted inflammation that is associated with autoinflammatory and autoimmune disease4,5. NEK7 is a serine / threonine kinase and a member of the family of NIMA-related kinases (NEKs) that are associated with mitotic entry, cell cycle progression, cell division, and mitotic progression. NEK7 is expressed in a variety of tissues and acts as an NLRP3-binding protein to facilitate its oligomerization and activation6.

[0006] References:

[0007] 1. Fu J & Wu H. Structural mechanisms of NLRP3 inflammasome assembly and activation.

[0008] Ann Rev Immunol. 2023; 41:301-316

[0009] 2. McKee CM & Coll RC. NLRP3 inflammasome priming: A riddle wrapped in a mystery inside an enigma. J Leuk Biol. 2020; 108:937-952

[0010] 3. Devant P & Kagan JC. Molecular mechanisms of gasdermin D pore-forming activity. Nat Immunol. 2023; 24:1064-1075

[0011] 4. Mangan MSJ, Olhava EJ, Roush WR, Seidl HM, Glick GD, Latz E. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat Rev Drug Discov. 2018; 17:588-606 5. Mullard A. NLRP3 inhibitors stoke anti-inflammatory ambitions. Nat Rev Drug Discov.

[0012] 2019; 18:405-407

[0013] 6. Sharif H, Wang L, Wang WL, Magupalli VG, Andreeva L, Qiao Q, Hauenstein AV, Wu Z, Núñez G, Mao Y, Wu H. Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome. Nature 2019; 570(7761):338-343

[0014] SUMMARY

[0015] This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt thereof) that degrade and / or otherwise modulate (e.g., inhibit) NIMA Related Kinase 7 (NEK7). Said chemical entities are useful, e.g., for treating a subject (e.g., a human subject) having one or more disorders or diseases associated with NLRP3 inflammasome activation. Said disorders or diseases include but are not limited to, autoinflammatory and autoimmune disorders (e.g., gout, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis), neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson’s disease), cardiovascular and metabolic disorders (e.g., pericarditis, atherosclerosis, Type 2 diabetes, obesity, metabolic syndrome, metabolic dysfunction-associated steatohepatitis (MASH), fibrotic disorders (e.g. interstitial lung disease, chronic kidney disease), hematology (eg. anemia of inflammation) and eye disorders (eg. macular degeneration). In embodiments, and while not wishing to be bound by theory, it is believed that the chemical entities described herein directly target (e.g., directly bind to) NEK7, thereby altering (e.g., attenuating) the inflammatory response modulated by the NLRP3 inflammasome. This disclosure also features compositions containing the same as well as methods of using and making the same.

[0016] In one aspect, this disclosure features compounds of Formula (I):

[0017]

[0018] or a pharmaceutically acceptable salt thereof; wherein R1, R2a, R2b, R3, and R4can be as defined anywhere herein.

[0019] In another aspect, this disclosure features pharmaceutical compositions that include one or more of the compounds described herein, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

[0020] In a further aspect, this disclosure features methods of modulating (e.g., inhibiting) NIMA Related Kinase 7 (NEK7) in a subject, which include administering to the subject an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0021] In still another aspect, this disclosure features methods of altering (e.g., attenuating) the inflammatory response modulated by the NLRP3 inflammasome in a subject, which include administering to the subject an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In one aspect, this disclosure features methods of degrading NIMA Related Kinase 7 (NEK7) in a subject, which include administering to the subject an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0022] In another aspect, this disclosure features methods of degrading NIMA Related Kinase 7 (NEK7), which include one or both of the following: (i) contacting a compound described herein or a pharmaceutically acceptable salt thereof with an E3 ligase; and (ii) interacting the contacted E3 ligase with NEK7, thereby degrading NEK7.

[0023] In a further aspect, this disclosure features methods of treating a disorder associated with NLRP3 inflammasome activation in a subject in need thereof, which includes administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0024] Compounds and pharmaceutical compositions described herein can be used in the treatment of disorders in subjects in need thereof. Said disorders include, but are not limited to, those disorders caused by or associated with increased (e.g., excessive) NLRP3 inflammasome activation.

[0025] Accordingly, in one embodiment, described herein is a method of treating a disorder caused by or associated with NLRP3 inflammasome activation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments, the disorder is a disorder of the immune system, hematopeoitic system, joints, renal system, gastro-intestinal tract, skin, eye, respiratory system, central nervous system, cardiovascular system, hepatic system, and / or endocrine system.

[0027] In some embodiments, the disorder is selected from the group consisting of: (i) inflammatory reactions in the joints; (ii) hyperactive inflammation with underlying genetic mutations; (iii) autoimmune diseases; (iv) respiratory diseases; (v) kidney diseases; (vi) central nervous system diseases; (vii) ocular diseases; (viii) cardiovascular diseases; (ix) viral infections and subsequent immune hyperactivation; (x) diseases of the hematopoietic system; (xi) liver disease; (xii) inflammatory reactions in the skin; (xiii) metabolic diseases; (xiv) cancers; (xv) infectious diseases; and (xvi) allergic disease.

[0028] In certain embodiments, the disorder is inflammatory reactions in the joints.

[0029] In certain of these embodiments, the disorder is gout, for instance acute or chronic gout. In certain of these embodiments, the disorder is tophaceous gout.

[0030] In certain of these embodiments, the disorder is pseudo-gout or calcium pyrophosphate deposition disease.

[0031] In certain of these embodiments, the disorder is osteoarthritis.

[0032] In certain of these embodiments, the disorder is psoriatic arthritis.

[0033] In certain of these embodiments, the disorder is systemic juvenile idiopathic arthritis. In certain of these embodiments, the disorder is adult-onset Still’s disease.

[0034] In certain of these embodiments, the disorder is relapsing polychondritis.

[0035] In certain of these embodiments, the disorder is tendonitis.

[0036] In certain of these embodiments, the disorder is frozen shoulder.

[0037] In certain of these embodiments, the disorder is pyogenic arthritis.

[0038] In some embodiments, the disorder is selected from the group consisting of: (ii) hyperactive inflammation with underlying genetic mutations; (iii) autoimmune diseases; (iv) respiratory diseases; (v) kidney diseases; (vi) central nervous system diseases; (vii) ocular diseases; (viii) cardiovascular diseases; and (ix) metabolic diseases.

[0039] In certain embodiments, the hyperactive inflammation with underlying genetic mutations is selected from the group consisting of cryopyrin-associated periodic syndrome (CAPS): Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS) and neonatal -onset multisystem inflammatory disease (NOMID); familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MVK), hyperimmunoglobuliemia D and periodic fever syndrome (HIDS), deficiency of interleukin 1 receptor (DIRA) antagonist), VEXAS syndrome, Majeed syndrome, pyoderma gangrenosum, acne and hidradenitis suppurative syndrome, haploinsufficency of A20, pediatric granulomatous arthritis (PGA), PLCG2 -associated antibody deficiency and immune dysregulation (PLAID), sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD), Sweet’s syndrome, chronic non-bacterial osteomyelitis (CNO), chronic recurrent multifocal osteomyelitis (CRMO) and synovitis, acne, pustulosis, hyperostosis, osteitis syndrome (SAPHO) and any disease where an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3 or NEK7.

[0040] In certain embodiments, the autoimmune disease is selected from the group consisting of multiple sclerosis (MS), rheumatoid arthritis, Behget’ s disease, Sjogren’s syndrome, systemic sclerosis, mixed connective tissue disease, myositis, vasculitis, lupus, including systemic and cutaneous forms, lupus nephritis, type-1 diabetes, psoriasis, Schnitzler’s syndrome, Grave’s disease, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, microscopic polyangiitis, inflammatory bowel disease, colitis, and Crohn’s disease.

[0041] In certain embodiments, the respiratory disease is selected from the group consisting of chronic obstructive pulmonary disorder (COPD), acute respiratory distress syndrome (ARDS), steroid-resistant asthma, asbestosis, silicosis, sarcoidosis, cystic fibrosis and interstitial lung disease (ILD), including, but not limited to idiopathic pulmonary fibrosis (IPF), fibrotic hypersensitivity pneumonitis, rheumatoid arthritis-associated ILD, autoimmune myositis-associated ILD, systemic sclerosis-associated ILD, idiopathic interstitial pneumonia and progressive fibrosing ILD.

[0042] In certain embodiments, the kidney disease is selected from the group consisting of chronic kidney disease (CKD), including CKD associated with high uric acid, AP0L1 mutations, complement-mediated kidney diseases such as C3 glomerulopathy, IgA nephropathy, atypical hemalytic uremic syndrome and membranous nepropathy, idiopathic nephrotic syndrome, oxalate nephropathy and diabetic nephropathy.

[0043] In certain embodiments, the central nervous system disease is selected from the group consisting of Parkinson’s disease, Alzheimer’s disease, motor neuron disease, Huntington’s disease, cerebral malaria, post-traumatic brain injury, sub-arachnoid hemorrhage and brain injury from pneumococcal meningitis, cerebral amyloid angiopathy, migraine, depression, and psychological stress.

[0044] In certain embodiments, the ocular disease is selected from the group consisting of those of the ocular epithelium, age-related macular degeneration (AMD), corneal infection, uveitis and dry eye.

[0045] In certain embodiments, the cardiovascular disease is selected from the group consisting of myocarditis, inflammatory cardiomyopathy, atherosclerosis, stroke, myocardial infarction, hypertension, abdominal aortic aneurism, pericarditis including Dressier’s syndrome, thromboembolism, ischemia reperfusion injury, transthyretin amyloidosis, and vasculitis. In certain embodiments, the cardiovascular disease is selected from heart failure or heart failure with preserved ejection fraction. In certain embodiments, the metabolic disease is selected from the group consisting of obesity, metabolic syndrome, and Type 2 diabetes and related morbidities including diabetic foot ulcers, atherosclerosis, diabetic cardiomyopathy, and diabetic retinopathy. In certain embodiments, the metabolic disease is MASH.

[0046] In some embodiments, the disorder is a cancer, tumor or other malignancy.

[0047] In some embodiments, the disorder is pericarditis or gout.

[0048] In one aspect, this disclosure features methods of degrading NIMA Related Kinase 7 (NEK7) in a subject suffering from any one or more of the disorders described herein, comprising administering to the subject an effective amount of a compound of described herein or a pharmaceutically acceptable salt thereof.

[0049] Embodiments can include one or more of the following features. The compounds described herein can include any one or more of the structural features delineated throughout this specification and / or the claims. The compounds described herein can mediate the interaction of a NEK7 protein with an E3 ligase, e.g., thereby increasing degradation of the NEK7 protein. NEK7 can be an activator of an NLRP3 inflammasome. The compounds described herein can interact with the E3 ligase prior to the interaction of NEK7 with the E3 ligase. The E3 ligase can include cereblon. The methods described herein can further include identifying a subject in need thereof.

[0050] Additional details of one or more embodiments of the invention are set forth in the description below. Other features and advantages of the compounds, compositions, and methods featured herein will be apparent from the description and the claims.

[0051] DETAILED DESCRIPTION

[0052] This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt thereof) that degrade and / or otherwise modulate (e.g., inhibit) NIMA Related Kinase 7 (NEK7). Said chemical entities are useful, e.g., for treating a subject (e.g., a human subject) having one or more disorders or diseases associated with NLRP3 inflammasome activation. Said disorders or diseases include but are not limited to, autoinflammatory and autoimmune disorders (e.g., gout, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis), neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson’s disease), cardiovascular and metabolic disorders (eg. pericarditis, atherosclerosis, Type 2 diabetes, obesity, metabolic syndrome, and MASH), fibrotic disorders (e.g. interstitial lung disease, chronic kidney disease), hematology disorders (eg. anemia of inflammation) and eye disorders (eg. macular degeneration). In embodiments, and while not wishing to be bound by theory, it is believed that the chemical entities described herein directly target (e.g., directly bind to) NEK7, thereby altering (e.g., attenuating) the inflammatory response modulated by the NLRP3 inflammasome. This disclosure also features compositions containing the same as well as methods of using and making the same.

[0053] Compounds

[0054] In one aspect, this disclosure features compounds having the following formula:

[0055]

[0056] or a pharmaceutically acceptable salt thereof; wherein:

[0057] R1, R2a, and R2bare defined according to (A) and (B) below:

[0058] (A)

[0059] R1is:

[0060] • heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o- 2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc;

[0061] • heterocyclyl including 4-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc;

[0062] • C3-7 cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc;

[0063] • heterocycloalkenyl including 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc; or

[0064] • Ce-io aryl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc; and

[0065] each of R2aand R2bis independently selected from the group consisting of:

[0066] • H;

[0067] • C1-2 alkyl optionally substituted with from 1-5 Ra;

[0068] • C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb;

[0069] • C1-4 alkoxy;

[0070] • C1-4 haloalkoxy; or

[0071] • cyano; or

[0072] R2aand R2btaken together with the carbon atom to which each is attached forms:

[0073] • C3-7 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb;

[0074] • heterocyclyl including 4-7 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb;

[0075] (B) R1taken together with (i) the carbon atom to which it is attached and (ii) and one of R2aand R2bforms:

[0076] • C8-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc; or

[0077] • heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc; and

[0078] the other of R2aand R2bis H or C1-2 alkyl optionally substituted with from 1-5 Ra;

[0079] R3is H; C1-2 alkyl, which is optionally substituted with 1-5 fluoro; fluoro; or chloro; R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro;

[0080] each occurrence of Rais independently selected from the group consisting of: -OH; -halo; -NReRf; C1-4 alkoxy; Ci-4haloalkoxy,; -C(=O)O(Ci-4alkyl); -C(=O)(Ci-4alkyl); -C(=O)OH; -CONR’R”; -S(O)I-2NR’R”; -S(O)1-2(C1-4alkyl); and cyano;

[0081] each occurrence of Rbis independently selected from the group consisting of: halo; cyano; Ci-10 alkyl which is optionally substituted with from 1-6 independently selected Ra; C2-6 alkenyl; C2-6 alkynyl; Ci-4alkoxy; -O(Ci-3 alkylene)-(C3-6 cycloalkyl); Ci-4haloalkoxy; -S(0)o-2(Ci-4alkyl); -NReRf; -OH; -S(O)I-2NR’R”; -NO2; -C(=0)(Ci-io alkyl); -C(=O)O(Ci-4alkyl); -C(=O)OH; and -C(=O)NR’R”;

[0082] each occurrence of Rcis independently selected from the group consisting of:

[0083] • C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb;

[0084] • heterocyclyl or heterocycloalkenyl including 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb; • heteroaryl including 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rb; and

[0085] • Ce-io aryl optionally substituted with from 1-4 Rb;

[0086] each occurrence of Rdis independently selected from the group consisting of: Ci-6 alkyl optionally substituted with from 1-3 independently selected Ra; -C(O)(Ci-4 alkyl); -C(O)O(Ci-4 alkyl); -CONR’R”; -S(O)I-2NR’R”; -S(O)1-2(C1-4alkyl); -OH; and Ci-4alkoxy; and

[0087] each occurrence of Reand Rfis independently selected from the group consisting of: H; Ci-6 alkyl; -C(O)(Ci-4alkyl); -C(O)O(Ci-4alkyl); -CONR’R”; -S(O)I-2NR’R”; -S(O)1-2(C1-4alkyl); -OH; and Ci-4 alkoxy; and

[0088] each occurrence of R’ and R” is independently selected from the group consisting of: H; and Ci -4 alkyl.

[0089] Embodiments can include one or more of the following features.

[0090] In some embodiments, R1, R2a, and R2bare defined according to (A).

[0091] In some embodiments, R1is heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

[0092] In certain embodiments, R1is heteroaryl including 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

[0093] In certain embodiments, R1is heteroaryl including 6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc. In certain embodiments, R1is heteroaryl including 6 ring atoms, wherein 1-2 ring atoms are N, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

[0094] In some of the foregoing embodiments, R1is unsubstituted.

[0095] In some of the foregoing embodiments, R1is substituted with at least one substituent (e.g., Rbor Rcor a combination thereof).

[0096] In certain of the foregoing embodiments, R1is substituted with one substituent (e.g., Rbor Rc)

[0097] In certain of the foregoing embodiments, R1is substituted with two substituents, each independently selected from the group consisting of Rband Rc.

[0098] In certain of the foregoing embodiments, R1is substituted with three substituents, each independently selected from the group consisting of Rband Rc.

[0099] In some of the foregoing embodiments, R1is substituted with one Rbor one Rc.

[0100] In some of the foregoing embodiments, R1is substituted with one Rb.

[0101] In certain of the foregoing embodiments, Rbis Ci-io alkyl, which is optionally substituted with 1-6 independently selected Ra.

[0102] In certain of the foregoing embodiments, Rbis Ci-6 alkyl, which is optionally substituted with 1-6 independently selected Ra.

[0103] In certain of the foregoing embodiments, Rbis C1-3 alkyl, which is optionally substituted with 1-6 independently selected Ra.

[0104] In certain embodiments, Rbis C1-3 alkyl, which is substituted with 1-6 (e.g., 1-4, 1-3, 1-2, or 1) independently selected Ra.

[0105] By way of example, Ra, or each occurrence of Ra, can be an independently selected halo; e.g., Ra, or each occurrence of Ra, can be fluoro. A representative Rbgroup is -CF3. Another representative Rbgroup is -CHF2.

[0106] In certain of the foregoing embodiments, Rbis cyano. As another example, Ra, or each occurrence of Ra, can be an independently selected C1-4 alkoxy; e.g., Ra, or each occurrence of Ra, is -OCH3. A representative Rbgroup is CH2OCH3.

[0107] As a further example, Racan be-OH. A representative Rbgroup is CH2OH.

[0108] In other embodiments, Rbis unsubstituted C1-3 alkyl. For example, Rbcan be -CH3.

[0109] In certain of the foregoing embodiments, Rbis C1-4 alkoxy. For example, Rbcan be -OCH3. In certain of the foregoing embodiments, Rbis C1-4 haloalkoxy. For example, Rbcan be -OCHF2.

[0110] In certain of the foregoing embodiments, Rbis halo. For example, Rbcan be fluoro. As another example, Rbcan be chloro.

[0111] In some of the foregoing embodiments, R1is substituted with 1 Rc.

[0112] In certain of the foregoing embodiments, Rcis C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb.

[0113] In certain of the foregoing embodiments, Rcis C3-10 cycloalkyl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb

[0114] In certain of the foregoing embodiments, Rcis C3-6 cycloalkyl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb

[0115] In certain of the foregoing embodiments, Rcis cyclopropyl, which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb; e.g., unsubstituted cyclopropyl.

[0116] In certain of the foregoing embodiments, wherein R1has the formula:

[0117]

[0118] in which each of Xi, X2, X3 and X4 is, independently, CH or N; and R11is H, Rb, or Rc. In certain embodiments of formula (II- A), not more than two of Xi, X2, X3 and X4 are N.

[0119] In certain embodiments of formula (II-A), Xi and X4 are N. In certain of these embodiments, X2 and X3 is CH. For example, R1can have the formula:

[0120]

[0121] In certain embodiments of formula (II-A), Xi and X2 are N. In certain of these embodiments, X3 is CH. In certain of these embodiments, X4 is CH. For example, R1can have the formula:

[0122]

[0123] In certain embodiments of formula (II-A), Xi and X3 are N. In certain of these embodiments, X2 is CH. In certain of these embodiments, X4 is CH. For example, R1can have the formula:

[0124]

[0125] In certain embodiments of formula (II-A), R1has the formula:

[0126]

[0127] In certain embodiments of formula (II-A), R1has the formula:

[0128]

[0129] In certain embodiments of formula (II-A), R11is H.

[0130] In certain embodiments of formula (II-A), (II-A-1), (II-A-2), (II-A-3), (II-A-4), or (II-A-5) R11is Rb

[0131] In certain embodiments of formula (II-A), (II-A-1), (II-A-2), (II-A-3), (II-A-4), or (II-A-5) R11is Ci-3 alkyl, which is substituted with from 1-6 (e.g., 1-4, 1-3, 1-2, or 1) groups independently selected from Ra.

[0132] By way of example, Ra, or each occurrence of Ra, can be an independently selected from halo; e.g., Ra, or each occurrence of Ra, can be fluoro. A representative R11group is -CF3. Another representative R11group is -CHF2.

[0133] In certain embodiments of formula (II-A), (II-A-1), (II-A-2), (II-A-3), (II-A-4), or (II-A-5) R11is cyano.

[0134] As another example, Ra, or each occurrence of Ra, can be an independently selected from C1-4 alkoxy; e.g., Ra, or each occurrence of Ra, is -OCH3. A representative R11group is CH2OCH3.

[0135] As a further example, Racan be -OH. A representative R11group is CH2OH.

[0136] In certain embodiments of formula (II-A), (II-A-1), (II-A-2), (II-A-3), (II-A-4), or (II-A-5) R11is unsubstituted C1-3 alkyl. For example, R11can be CH3.

[0137] In certain embodiments of formula (II-A), (II-A-1), (II-A-2), (II-A-3), (II-A-4), or (II-A-5) R11is Ci -4 alkoxy. For example, R11can be -OCH3.

[0138] In certain embodiments of formula (II-A), (II-A-1), (II-A-2), (II-A-3), (II-A-4), or (II-A-5) R11is C1-4 haloalkoxy. For example, R11can be -OCHF2.

[0139] In certain embodiments of formula (II-A), (II-A-1), (II-A-2), (II-A-3), (II-A-4), or (II-A-5) R11is halo. For example, R11can be chloro.

[0140] In certain embodiments of formula (II-A), (II-A-1), (II-A-2), (II-A-3), (II-A-4), or (II-A-5) R11is Rc In certain embodiments of formula (II-A), (II-A-1), (II-A-2), (II-A-3), (II-A-4), or (II-A-5) R11is cyclopropyl, which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; e.g., unsubstituted cyclopropyl.

[0141] In certain embodiments, R1is heteroaryl including 8-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

[0142] In certain embodiments, R1is heteroaryl including 8-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

[0143] In certain embodiments, R1is heteroaryl including 10 ring atoms, wherein 1-4 ring atoms are N, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

[0144] For example, R1can be:

[0145]

[0146] In certain embodiments, R1is heteroaryl including 9 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

[0147] In certain embodiments, R1has the formula:

[0148]

[0149] X5is N, O, or CH; and

[0150] X6is N or CH.

[0151] X7is N or CH.

[0152] X8is N or CH.

[0153] In certain embodiments of formula (II-B), X6and X7are CH.

[0154] In certain embodiments of formula (II-B), X6and X8are CH.

[0155] In certain embodiments of formula (II-B), X7and X8are CH.

[0156] In certain embodiments of formula (II-B), X6, X7and X8are CH.

[0157] In certain embodiments of formula (II-B), X4is O, X5is N, and X6is CH.

[0158] In certain embodiments of formula (II-B), one of X6, X7or X8is CH, and the other of X6and X7is N. In embodiments, X6and X7are CH; and X8is N. In embodiments, X6and X8are CH; and X7is N. In embodiments, X7and X8are CH; and X6is N.

[0159] In certain of these embodiments, X4 is O or S.

[0160] For example, X4can be O or S; X5can be N; and X6can be N.

[0161] As another example, X4can be O, X5can be N; and X6can be CH.

[0162] For example, R1can be:

[0163]

[0164] In certain embodiments, R1is heteroaryl including 5 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of Rband Rc.

[0165] In certain embodiments, R1has the formula:

[0166]

[0167] wherein:

[0168] X9is NH, NCH3, O, or S;

[0169] Xio is N, C, CH, CCF3, CCHF2, C(cyclopropyl), or CCH3;

[0170] X11is N, C, CH, or CCH3;

[0171] X12is N, C, CH, or CCH3; and

[0172] X13is N, C, CH, CCF3, CCHF2, C(cyclopropyl), or CCH3.

[0173] In certain embodiments, R1has the formula:

[0174]

[0175] wherein:

[0176] X9is N, O, CH, or S;

[0177] X10is N, O, CH, or CCH3;

[0178] X11is CH, or CCH3; and

[0179] X12is O, N, CH, COCH3, or CCH3.

[0180] In certain embodiments of formula (II-C) or (II-C-1), X9is N. In certain embodiments of formula (II-C) or (II-C-1), X10is N. In certain embodiments of formula (II-C) or (II-C-1), X11is CH. In certain embodiments of formula (II-C) or (II-C-1), X12is O. In certain embodiments of formula (II-C) or (II-C-1), X11is CCH3.

[0181] For example, R1can have the formula:

[0182]

[0183] In certain embodiments of formula (II-C) or (II-C-1), X9is O or S. In certain embodiments of formula (II-C) or (II-C-1), X10is N.

[0184] In certain embodiments of formula (II-C) or (II-C-1), X9is O; and X10is N.

[0185] In certain embodiments of formula (II-C) or (II-C-1), X9is S; and X10is N.

[0186] In certain embodiments of formula (II-C) or (II-C-1), X9is CH or CCH3.

[0187] In certain embodiments of formula (II-C) or (II-C-1), X12is CH or CCH3.

[0188] In certain embodiments of formula (II-C) or (II-C-1), X11is CH or CCH3; and X12is CH or CCH3.

[0189] In certain embodiments of formula (II-C) or (II-C-1), X9is O; X10is N; X11is CH or CCH3; and X12is CH or CCH3.

[0190] In certain embodiments of formula (II-C) or (II-C-1), X9is S; X10is N; X11is CH or CCH3; and X12is CH or CCH3.

[0191] In certain embodiments of formula (II-C) or (II-C-1)

[0192] X9is NH, NCH3, or O;

[0193] X10is CH or CCH3;

[0194] X11is N; and

[0195] X12is CH or CCH3.

[0196] In certain embodiments of formula (II-C) or (II-C-1), X11is N; and X9is O.

[0197] In certain embodiments of formula (II-C) or (II-C-1)

[0198] X9is NCH3;

[0199] X10is CH or CCH3;

[0200] X11is N; and

[0201] X12is N.

[0202] In certain embodiments of formula (II-C) or (II-C-1)

[0203] X9is N;

[0204] X10is O;

[0205] X11is CH or CCH3; and

[0206] X12is CH or COCH3. In certain embodiments of formula (II-C) or (II-C-1):

[0207] X9is O;

[0208] X10is CH or CCH3;

[0209] X11is CH or CCH3; and

[0210] X12is N.

[0211] In certain embodiments of formula (II-C) or (II-C-1)

[0212] X9is CH;

[0213] X10is N;

[0214] X11is CCH3; and

[0215] X12is O.

[0216] In some embodiments, R1is Ce-io aryl optionally substituted with 1-4 substituents independently selected from the group consisting of Rb, and Rc.

[0217] In certain embodiments, R1is phenyl optionally substituted with 1-4 substituents independently selected from the group consisting of Rb, and Rc.

[0218] In certain embodiments, R1has the formula:

[0219]

[0220] wherein each R11is independently selected from the group consisting of H, Rb, and Rc; each R12is independently selected from the group consisting of Rband Rc; and q is 0, 1, or 2.

[0221] In certain embodiments of formula (II-D), R11is H, fluoro, CN, CH3, CHF2, -SO2NH2, SO2CH3, -C(O)NH2, or cyclopropyl.

[0222] In certain embodiments of formula (II-D), R11is H.

[0223] In certain embodiments of formula (II-D), R11is CH3.

[0224] In certain embodiments of formula (II-D), R11is CN

[0225] In certain embodiments of formula (II-D), q is 1.

[0226] In certain embodiments of formula (II-D), R12is F. In some embodiments, each of R2aand R2bis independently selected from the group consisting of H and C1-2 alkyl optionally substituted with from 1-5 Ra.

[0227] In certain embodiments, each of R2aand R2bis an independently selected C1-2 alkyl optionally substituted with from 1-5 Ra.

[0228] In certain embodiments, each of R2aand R2bis an independently selected unsubstituted Ci-2 alkyl.

[0229] For example, each of R2aand R2bcan be CH3.

[0230] In some embodiments, R2aand R2btaken together with the carbon atom to which each is attached forms:

[0231] • C3-7 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb;

[0232] • heterocyclyl including 4-7 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb.

[0233] In certain embodiments, R2aand R2btaken together with the carbon atom to which each is attached forms C3-7 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb.

[0234] In certain embodiments, R2aand R2btaken together with the carbon atom to which each is attached forms:

[0235]

[0236] In some embodiments, R2aand R2btaken together with the carbon atom to which each is attached forms heterocyclyl including 4-7 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb.

[0237] In certain embodiments, R2aand R2btaken together with the carbon atom to which each is attached forms:

[0238]

[0239] In some embodiments, R1, R2a, and R2bare defined according to (B).

[0240] In certain embodiments, wherein R1taken together with (i) the carbon atom to which it is attached and (ii) and one of R2aand R2bforms:

[0241]

[0242] wherein as indicated in the formula above, the other of R2aand R2bis CH3.

[0243] In some embodiments, R3is Cl.

[0244] In some embodiments, R3is F.

[0245] In some embodiments, R3is H.

[0246] In some embodiments, R4is Cl.

[0247] In some embodiments, R4is Br.

[0248] In some embodiments, R4is F.

[0249] In some embodiments, R3is Cl, and R4is Cl.

[0250] In some embodiments, R3is H, and R4is Cl.

[0251] In some embodiments, R3is H, and R4is Br.

[0252] In some embodiments, R3is CH3, and R4is Cl.

[0253] In some embodiments, R3is Cl, and R4is F.

[0254] In some embodiments, the compound has the formula:

[0255]

[0256] (I-A).

[0257] In some embodiments of formula (I-A), R1is heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting ofN, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

[0258] In certain embodiments of formula (I-A), R1is heteroaryl including 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

[0259] In certain embodiments of formula (I-A), R1is heteroaryl including 6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting ofN, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

[0260] In certain embodiments of formula (I-A), R1is heteroaryl including 6 ring atoms, wherein 1-2 ring atoms are N, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

[0261] In certain embodiments of formula (I-A), R1is unsubstituted.

[0262] In certain embodiments of formula (I-A), R1is substituted with at least one substituent (e.g., Rbor Rcor a combination thereof).

[0263] In certain embodiments formula (I-A), R1is substituted with one substituent (e.g., Rbor Rc)

[0264] In certain embodiments of formula (I-A), R1is substituted with two substituents, each independently selected from the group consisting of Rband Rc. In certain embodiments of formula (I-A), R1is substituted with three substituents, each independently selected from the group consisting of Rband Rc.

[0265] In certain embodiments formula (I-A), R1is substituted with one Rbor one Rc.

[0266] In certain embodiments of formula (I-A), R1is substituted with one Rb.

[0267] In certain of these embodiments of formula (I-A), Rbis Ci-io alkyl, which is optionally substituted with 1-6 independently selected Ra.

[0268] In certain embodiments of formula (I-A), Rbis Ci-6 alkyl, which is optionally substituted with 1-6 independently selected Ra.

[0269] In certain of these embodiments of formula (I-A), Rbis C1-3 alkyl, which is optionally substituted with 1-6 independently selected Ra.

[0270] In certain of these embodiments of formula (I-A), Rbis C1-3 alkyl, which is substituted with 1-6 (e.g., 1-4, 1-3, 1-2, or 1) independently selected Ra.

[0271] By way of example, Ra, or each occurrence of Ra, can be an independently selected halo; e.g., Ra, or each occurrence of Ra, can be fluoro. A representative Rbgroup is -CF3. Another representative Rbgroup is -CHF2.

[0272] In certain of these embodiments of formula (I-A), Rbis cyano.

[0273] As another example, Ra, or each occurrence of Ra, can be an independently selected C1-4 alkoxy; e.g., Ra, or each occurrence of Ra, is -OCH3. A representative Rbgroup is CH2OCH3.

[0274] As a further example, Racan be-OH. A representative Rbgroup is CH2OH.

[0275] In certain of these embodiments of formula (I-A), Rbis unsubstituted C1-3 alkyl. For example, Rbcan be -CH3.

[0276] In certain of these embodiments of formula (I-A), Rbis C1-4 alkoxy. For example, Rbcan be -OCH3.

[0277] In certain of these embodiments of formula (I-A), Rbis C1-4 haloalkoxy. For example, Rbcan be -OCHF2.

[0278] In certain of these embodiments of formula (I-A), Rbis halo. For example, Rbcan be fluoro. As another example, Rbcan be chloro.

[0279] In certain embodiments of formula (I-A), R1is substituted with 1 Rc. In certain of these embodiments of formula (I-A), Rcis C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb.

[0280] In certain of these embodiments of formula (I-A), Rcis C3-10 cycloalkyl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb

[0281] In certain of these embodiments of formula (I-A), Rcis C3-6 cycloalkyl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb

[0282] In certain of these embodiments of formula (I-A), Rcis cyclopropyl, which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb; e.g., unsubstituted cyclopropyl.

[0283] In certain embodiments of formula (I-A), R3is Cl.

[0284] In certain embodiments of formula (I-A), R3is H.

[0285] In certain embodiments of formula (I-A), R3is CH3.

[0286] In certain embodiments of formula (I-A), R4is Cl.

[0287] In certain embodiments of formula (I-A), R4is Br.

[0288] In certain embodiments of formula (I-A), R4is F (e.g., when R3is Cl).

[0289] In certain embodiments of formula (I-A), R3is Cl, and R4is Cl.

[0290] In certain embodiments of formula (I-A), R3is H, and R4is Cl.

[0291] In certain embodiments of formula (I-A), R3is H, and R4is Br.

[0292] In certain embodiments of formula (I-A), R3is CH3, and R4is Cl.

[0293] In certain embodiments of formula (I-A), R3is Cl, and R4is F.

[0294] In some embodiments, the compound has the formula:

[0295] (I B),

[0296]

[0297] in which each of Xi, X2, X3 and X4 is, independently, CH or N; and R11is H, Rb, or Rc.

[0298] In some embodiments of formula (I-B), not more than two of Xi, X2, X3 and X4 are N. In certain embodiments of formula (I-B), Xi and X4 are N. In certain of these embodiments, X2 and X3 is CH. For example, R1can have the formula:

[0299]

[0300] (II-A-1)

[0301] In certain embodiments of formula (I-B), Xi and X2 are N. In certain of these embodiments, X3 is CH. In certain of these embodiments, X4 is CH. For example, R1can have the formula:

[0302]

[0303] (II-A-2)

[0304] In certain embodiments of formula (I-B), Xi and X3 are N. In certain of these embodiments, X2 is CH. In certain of these embodiments, X4 is CH. For example, R1can have the formula:

[0305]

[0306] In certain embodiments of formula (I-B), R1has the formula:

[0307]

[0308] In certain embodiments of formula (I-B), R1has the formula:

[0309]

[0310] In certain embodiments of formula (I-B), (II-A), (II-A-1), (II-A-2), (II-A-3), (II-A-4), or (II-A-5) R11is H.

[0311] In certain embodiments of formula (I-B), (II-A), (II-A-1), (II-A-2), (II-A-3), (II-A-4), or (II-A-5) R11is Rb

[0312] In certain embodiments of formula (I-B), (II-A), (II-A-1), (II-A-2), (II-A-3), (II-A-4), or (II-A-5) R11is Ci-3 alkyl, which is substituted with from 1-6 (e.g., 1-4, 1-3, 1-2, or 1) groups independently selected from Ra.

[0313] By way of example, Ra, or each occurrence of Ra, can be an independently selected from halo; e.g., Ra, or each occurrence of Ra, can be fluoro. A representative R11group is -CF3. Another representative R11group is -CHF2.

[0314] In certain embodiments of formula (I-B), (II-A), (II-A-1), (II-A-2), (II-A-3), (II-A-4), or (II-A-5) Rbis cyano.

[0315] As another example, Ra, or each occurrence of Ra, can be an independently selected from C1-4 alkoxy; e.g., Ra, or each occurrence of Ra, is -OCH3. A representative R11group is CH2OCH3.

[0316] As a further example, Racan be-OH. A representative R11group is CH2OH.

[0317] In certain of these embodiments of formula (I-B), (II-A), (II-A-1), (II-A-2), (II-A-3), (II-A-4), or (II-A-5) R11is unsubstituted C1-3 alkyl. For example, R11can be CH3.

[0318] In certain embodiments of formula (I-B), (II-A), (II-A-1), (II-A-2), (II-A-3), (II-A-4), or (II-A-5) R11is C1-4 alkoxy. For example, R11can be -OCH3. In certain embodiments of formula (I-B), (II-A), (II-A-1), (II-A-2), (II-A-3), (II-A-4), or (II-A-5) R11is Ci-4 haloalkoxy. For example, R11can be -OCHF2.

[0319] In certain embodiments of formula (I-B), (II-A), (II-A-1), (II-A-2), (II-A-3), (II-A-4), or (II-A-5) R11is halo. For example, R11can be fluoro. As another example, R11can be chloro.

[0320] In certain embodiments of formula (I-B), (II-A), (II-A-1), (II-A-2), (II-A-3), (II-A-4), or (II-A-5) R11is Rc.

[0321] In certain embodiments of formula (I-B), (II-A), (II-A-1), (II-A-2), (II-A-3), (II-A-4), or (II-A-5) R11is cyclopropyl, which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rc; e.g., unsubstituted cyclopropyl.

[0322] In certain embodiments of formula (I-B), R3is Cl.

[0323] In certain embodiments of formula (I-B), R3is H.

[0324] In certain embodiments of formula (I-B), R3is CH3.

[0325] In certain embodiments of formula (I-B), R4is Cl.

[0326] In certain embodiments of formula (I-B), R4is Br.

[0327] In certain embodiments of formula (I-B), R4is F (e.g., when R3is Cl).

[0328] In certain embodiments of formula (I-B), R3is Cl, and R4is Cl.

[0329] In certain embodiments of formula (I-B), R3is H, and R4is Cl.

[0330] In certain embodiments of formula (I-B), R3is H, and R4is Br.

[0331] In certain embodiments of formula (I-B), R3is CH3, and R4is Cl.

[0332] In certain embodiments of formula (I-B), R3is Cl, and R4is F.

[0333] Pharmaceutical Compositions

[0334] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound described herein, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises an effective amount of the compound. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound. The pharmaceutical compositions provided herein can be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration.

[0335] Compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. In some embodiments, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound is usually a minor component with the remainder being various vehicles or excipients and processing aids helpful for forming the desired dosing form.

[0336] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0337] Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable excipients known in the art. As before, the active compound in such compositions is typically a minor component with the remainder being the injectable excipient and the like.

[0338] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s). When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or Formulation. All such known transdermal formulations and ingredients are included within the scope of the disclosure provided herein.

[0339] The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0340] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0341] Methods of Use

[0342] Compounds and pharmaceutical compositions described herein can be used in the treatment of disorders in subjects in need thereof. Said disorders include, but are not limited to, those disorders caused by or associated with NLRP3 inflammasome activation.

[0343] Accordingly, in one embodiment, described herein is a method of treating a disorder caused by or associated with NLRP3 inflammasome activation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0344] In some embodiments, the disorder is gout.

[0345] In some embodiments, the disorder is pericarditis.

[0346] In some embodiments, the disorder is a disorder of the immune system, hematopeoitic system, joints, renal system, gastro-intestinal tract, skin, eye, respiratory system, central nervous system, cardiovascular system, hepatic system, and / or endocrine system.

[0347] In some embodiments, the disorder is an autoinflammatory or autoimmune disorder. In certain of these embodiments, the disorder is gout (e.g., acute and chronic gout, tophaceous gout, or pseudo-gout).

[0348] In certain of these embodiments, the disorder is inflammatory bowel disease.

[0349] In certain of these embodiments, the disorder is rheumatoid arthritis. In certain of these embodiments, the disorder is multiple sclerosis.

[0350] In some embodiments, the disorder is a neurodegenerative disorder (e.g., Alzheimer's disease).

[0351] In some embodiments, the disorder is a cardiovascular or metabolic disorder (e.g., pericarditis, atherosclerosis, Type 2 diabetes, obesity or metabolic syndrome). Other examples of metabolic diseases include MASH or lysosomal storage disease.

[0352] In some embodiments, the disorder is a fibrotic disorder (e.g., interstitial lung disease or chronic kidney disease).

[0353] In some embodiments, the disorder is a disorder associated with hematology (e.g., anemia of inflammation).

[0354] In some embodiments, the disorder is an eye disorder (e.g., macular degeneration).

[0355] In some embodiments, the disorder is a disorder of the immune system, hematopeoitic system, joints, renal system, gastro-intestinal tract, skin, eye, respiratory system, central nervous system, cardiovascular system, hepatic system, and / or endocrine system.

[0356] In some embodiments, the disorder is a cancer, tumour or other malignancy.

[0357] In some embodiments, the disorder is selected from the group consisting of

[0358] (i) inflammatory reactions in the joints including acute and chronic gout, tophaceous gout, pseudo-gout (calcium pyrophosphate deposition disease), osteoarthritis, psoriatic arthritis, systemic juvenile idiopathic arthritis, adult-onset Still’s disease, relapsing polychondritis, tendonitis, frozen shoulder and pyogenic arthritis;

[0359] (ii) hyperactive inflammation with underlying genetic mutations, including auto-inflammatory diseases such as cryopyrin-associated periodic syndrome (CAPS): Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FC AS) and neonatal -onset multisystem inflammatory disease (NOMID); familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MVK), hyperimmunoglobuliemia D and periodic fever syndrome (HIDS), deficiency of interleukin 1 receptor (DIRA) antagonist), VEXAS syndrome, Majeed syndrome, pyoderma gangrenosum, acne and hidradenitis suppurative syndrome, haploinsufficency of A20, pediatric granulomatous arthritis (PGA), PLCG2 -associated antibody deficiency and immune dysregulation (PLAID), sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD), Sweet’s syndrome, chronic non-bacterial osteomyelitis (CNO), chronic recurrent multifocal osteomyelitis (CRMO) and synovitis, acne, pustulosis, hyperostosis, osteitis syndrome (SAPHO) and any disease where an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3 or NEK7

[0360] (iii) autoimmune diseases including multiple sclerosis (MS), rheumatoid arthritis, Behgef s disease, Sjogren’s syndrome, systemic sclerosis, mixed connective tissue disease, myositis, vasculitis, lupus, including systemic and cutaneous forms, lupus nephritis, type-1 diabetes, psoriasis and Schnitzler’s syndrome, Grave’s disease, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, microscopic polyangiitis, inflammatory bowel disease, colitis, Crohn’s disease;

[0361] (iv) respiratory diseases including chronic obstructive pulmonary disorder (COPD), acute respiratory distress syndrome (ARDS), steroid-resistant asthma, asbestosis, silicosis, sarcoidosis, cystic fibrosis and interstitial lung disease (ILD), including, but not limited to idiopathic pulmonary fibrosis (IPF), fibrotic hypersensitivity pneumonitis, rheumatoid arthritis-associated ILD, autoimmune myositis-associated ILD, systemic sclerosis-associated ILD, idiopathic interstitial pneumonia and progressive fibrosing ILD;

[0362] (v) kidney disease including chronic kidney disease (CKD), including CKD associated with high uric acid, AP0L1 mutations, complement-mediated kidney diseases such as C3 glomerulopathy, IgA nephropathy, atypical hemalytic uremic syndrome and membranous nepropathy, idiopathic nephrotic syndrome, oxalate nephropathy and diabetic nephropathy;

[0363] (vi) central nervous system diseases including Parkinson’s disease, Alzheimer’s disease, motor neuron disease, Huntington’s disease, cerebral malaria, post-traumatic brain injury, subarachnoid hemorrhage and brain injury from pneumococcal meningitis, cerebral amyloid angiopathy, migraine, depression, psychological stress;

[0364] (vii) ocular diseases including those of the ocular epithelium, age-related macular degeneration (AMD), corneal infection, uveitis and dry eye;

[0365] (viii) cardiovascular diseases including myocarditis, inflammatory cardiomyopathy, atherosclerosis, stroke, myocardial infarction, hypertension, abdominal aortic aneurism, pericarditis including Dressier’s syndrome, thromboembolism, ischemia reperfusion injury, transthyretin amyloidosis, vasculitis; or cardiovascular diseases including heart failure or heart failure with preserved ejection fraction;

[0366] (ix) viral infections and subsequent immune hyperactivation including alphavirus including Chikungunya and Ross River virus, and flavivirus including Dengue and Zika viruses, COVID-19 / SARS-CoV-2, influenza, HIV;

[0367] (x) diseases of the hematopoietic system including anemia of inflammation (anemia of chronic disease), paroxysmal nocturnal hemaglobinuria (PNH), sickle cell disease;

[0368] (xi) liver disease including non-alcoholic steatohepatitis or MASH, alcoholic liver disease, drug-induced liver injury and Wilson disease;

[0369] (xii) inflammatory reactions in the skin including contact hypersensitivity and sunburn, psoriasis, hidradenitis suppurativa (HS) and other cyst-causing skin diseases, dermatomyositis, pemphigus, pyoderma gangrenosum;

[0370] (xiii) metabolic diseases including obesity, metabolic syndrome, and Type 2 diabetes and related morbidities including diabetic foot ulcers, atherosclerosis, obesity, diabetic cardiomyopathy and diabetic retinopathy;

[0371] (xiv) cancers including lung cancer and lung cancer metastasis, pancreatic cancers, gastric cancers, myelodysplastic syndrome, leukemia and melanoma; polymyositis; graft-versus-host disease and transplant rejection;

[0372] (xv) infectious diseases including bacterial infections, including Clostridium species, viral infections, helminth infections; wound healing; sepsis; gangrene; and

[0373] (xvi) allergic diseases and Type 2 inflammation-associated diseases including asthma, atopic dermatitis, eosinophilic esophagitis, chronic obstructive pulmonary disease, chronic sinusitis, nasal polyps.

[0374] In some embodiments, the disorder is selected from the group consisting of pericarditis, gout, atherosclerosis, obesity, MASH, Alzheimer’s disease, Parkinson’s disease, and Wilson’s disease.

[0375] In some embodiments, the metabolic disorder is a lysosomal storage disease, which includes sphingolipidoses, oligosaccharidoses, mucopolysaccharidoses (MPS), neuronal ceroid lipofuscinoses (NCL) (Batten disease), sialic acid disorders, mucolipidoses, and glycogenoses.

[0376] The sphingolipidosis may be GM2 gangliosidosis (such as Type A - Tay Sachs disease; Type O - Sandhoff disease; or Type AB - GM2 activator deficiency); Niemann-Pick disease (such as Type A, B, or C); Gaucher disease (such as Type 1, 2, or 3); Fabry disease (such as classic, or late-onset); metachromatic leukodystrophy; globoid leukodystrophy (Krabbe disease); GM1 gangliosidosis (such as Type 1, 2, or 3); or multiple sulfatase deficiency.

[0377] The oligosaccharidosis may be alfa mannosidosis; Schindler disease; asphartylglucosaminuria; or fucosidosis.

[0378] The mucopolysaccharidosis may be Hurler syndrome (Type I); Scheie syndrome (Type I); Hunter syndrome (Type II); Sanfilippo syndrome (Type III) Morquio syndrome (Type IV); Maroteaux-Lamy syndrome (Type VI); Sly syndrome (Type VII); or Natowicz syndrome (Type IX).

[0379] Batten disease may be of the CLN1, CLN2, CLN3, CLN4, CLN5, CLN6, CLN7, CLN8, CLN9, CLN10, CLN11, CLN12, CLN13 or CLN14 designation.

[0380] The sialic acid disorder may be galactosialidosis; free sialic acid storage disorder (FSASD); Salla disease; or sialuria.

[0381] The mucolipidosis may be Type I, II, III or IV.

[0382] The glycogenosis may be Pompe disease; or Danon disease.

[0383] The lysosomal storage disease may be lysosomal acid lipase deficiency (such as infantile and childhood / adult types); or cystinosis.

[0384] NLRP3, Caspase-1 and / or IL-1β are implicated in lysosomal storage disease, as demonstrated in:

[0385] (1) Platt N, Shepherd D, Smith DA, Smith C, Wallom K-L, Luqmani R, Churchill GC, Galione A, Platt FM, Dysregulation of the NLRP3 inflammasome and promotion of disease by IL-1β in a murine model of Sandhoff disease. Cells, 2025 Jan 1; 14(1):35;

[0386] (2) Aflaki E, Moaven N, Borger DK, Lopez G, Westbroek W, Chae JJ etal., Lysosomal storage and impaired autophagy lead to inflammasome activation in Gaucher macrophages. Aging Cell, 2015 Oct21; 15(I):77-88. doi:10.1111 / acel.12409

[0387] (3) Panicker LM, Miller D, Awad O, Bose V, Lun Y, Park TS, Zambidis ET, Sgambato J A, Feldman RA, Gaucher iPSC-derived macrophages produce elevated levels of inflammatory mediators and serve as a new platform for therapeutic development. Stem Cells, 2014 Sep; 32(9):2338-2349.

[0388] (4) Ormazabal ME, Pavan E, Vaena E, Ferino D, Biasizzo J, Mucci JM, Serra F, Cifu A, Scarpa M, Rozenfeld PA, Dardis AE, Exploring the pathophysiologic cascade leading to osteoclastogenic activation in Gaucher disease monocytes generated via CRISPR / Cas9 technology. Int J Mol Sci, 2023 Jul 7; 24(13): 11204.

[0389] (5) Polgreen LE, Chen AH, Pak Y, Luzzi A, Morales Garval A, Acevedo J, Bitan G, lacovino M, O’Neill C, Eisengart JB, etal., Anakinra in Sanfilippo syndrome: a phase 1 / 2 trial. Nature Medicine, 2024; 30:2473-2479.

[0390] (6) Parker H, Ellison SM, Holley RJ, O’Leary C, Liao A, Asadi J, Glover E, Ghosh A, Jones S, Wilkinson FL, Brough D, Pinteaux E, Boutin H, Bigger BW, Haematopoietic stem cell gene therapy with IL-IRa rescues cognitive loss in mucopolysaccharidosis IIIA. EMBO Mol Med, 2020 Mar 6; 12(3):e11185.

[0391] (7) Burkovetskaya M, Bosch ME, Karpuk N, Fallet R, Kielian T, Caspase 1 activity influences juvenile Batten disease (CLN3) pathogenesis. J Neurochem, 2019 Mar; 148(5):652-668.

[0392] (8) Prencipe G, Caiello I, Cherqui S, Whisenant T, Petrini S, Emma F, De Benedetti F, Inflammasome activation by cystine crystals: implications for the pathogenesis of cystinosis. J Am Soc Nephrol, 2014 Jun; 25(6): 1163-1169.

[0393] In another embodiment, described herein is a method of degrading NIMA Related Kinase 7 (NEK7) in a subject suffering from any one or more of the disorders described herein, comprising administering to the subject an effective amount of a compound of described herein or a pharmaceutically acceptable salt thereof.

[0394] In an aspect, the disclosure provides a compound or pharmaceutically acceptable salt as described herein for use in any of the above-recited methods of treatment. In a further aspect, the disclosure provides the use of a compound or pharmaceutically acceptable salt as described herein for the manufacture of a medicament for any of the above-recited methods of treatment. In an aspect, the disclosure provides a degrader conjugate as described herein for use in any of the aboverecited methods of treatment.

[0395] NEK7 Degradation

[0396] The compounds described herein can act as degraders of NIMA-Related Kinase 7 (NEK7). NEK7 is an activator of the NLRP3 inflammasome, a central regulator of cellular inflammatory responses to pathogens, damage and stress. The NLRP3 inflammasome is a multiprotein complex that serves as a central node to integrate cellular signals generated by pathogens, damage and stress, and triggers the generation of pro-inflammatory cytokines. The assembly of NLRP3 / NEK7 with ASC and pro-caspase 1 in a multi -protein complex induces cleavage of pro-caspase 1, which then activates multiple inflammatory responses including secretion or release of the cytokines interleukin-1β and interleukin-18 and induction of pyroptosis. Additionally, multiple activating NLRP3 mutations have been shown to be associated with Cryopyrin-associated periodic syndromes.

[0397] NEK7, a serine / threonine-protein kinase, activates the NLRP3 inflammasome in a kinase independent manner. Increased (e.g., excessive) NLRP3 inflammasome activation has been implicated in the pathogenesis of several of the disorders described herein (e.g., disorders of the immune system, hematopeoitic system, joints, renal system, gastro-intestinal tract, skin, eye, respiratory system, central nervous system, cardiovascular system, hepatic system, and / or endocrine system). In certain embodiments, the increased (e.g., excessive) NLRP3 inflammasome activation is chronically increased (e.g., excessive) NLRP3 inflammasome activation. In certain embodiments, the NLRP3 / NEK7 inflammasome activation is occurring in the brain or central nervous system (CNS), thereby requiring CNS penetration and exposure of any therapeutic agent targeting this inflammasome. NEK7 binding to NLRP3 has been shown to be involved in promoting the assembly of the NLRP3 inflammasome. While not wishing to be bound by theory, by being able to degrade NEK7, the compounds described herein may be used to treat disorders caused by or associated with increased (e.g., excessive) NLRP3 inflammasome activation.

[0398] In an embodiment, described herein is a method of degrading NIMA Related Kinase 7 (NEK7) in a subject, comprising administering to the subject an effective amount of a compound described herein (e.g., Compound 1), or pharmaceutically acceptable salt thereof. In some embodiments, the compound mediates the interaction of aNEK7 protein with an E3 ligase, thereby increasing degradation of the NEK7 protein. In some embodiments, NEK7 is an activator of an NLRP3 inflammasome. In an embodiment, the compound interacts with the E3 ligase prior to the interaction of NEK7 with the E3 ligase. In some embodiments, the E3 ligase comprises cereblon.

[0399] In another embodiment, described herein is a method of degrading NIMA Related Kinase 7 (NEK7), comprising: (i) contacting a compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt thereof with an E3 ligase; and (ii) interacting the contacted E3 ligase with NEK7, thereby degrading NEK7.

[0400] In other embodiments, the compounds described herein (e.g., Compound 1) are capable of selectively binding to a specific amino acid sequence of NEK7, thereby causing degradation of NEK7. In other embodiments, such degradation of NEK7 is mediated by the compound interacting with both the specific amino acid sequence of NEK7 and an E3 ligase. In other embodiments, the E3 ligase comprises cereblon.

[0401] Degrader Conjugates

[0402] In an aspect is a conjugate comprising a compound of Formula (I) as defined anywhere herein. For instance, in an aspect is an antibody -degrader conjugate or pharmaceutically acceptable salt thereof comprising a compound of Formula (I). The conjugate includes a compound of Formula (I) or pharmaceutically acceptable salt thereof which is conjugated to an antibody via a linker structure moiety.

[0403] In some embodiments, the conjugate has a structure according to Formula (A) below:

[0404] Bm - (- M- I)a

[0405] Formula (A)

[0406] in which I is a compound of Formula (I) or any subformula defined herein, or a pharmaceutically acceptable salt thereof, M is a linker moiety, Bm is a binding moiety that is capable of specifically binding to an antigen, and a is from 1 to 10. The binding moiety may be an antibody, antibody fragment or an antibody -binding fragment.

[0407] In some embodiments, I is one of Compounds 1-131.

[0408] Thus, in some embodiments of Formula (A), the disclosure provides an antibody-drug conjugate or pharmaceutically acceptable salt thereof according to formula (Al):

[0409]

[0410] Formula (Al)

[0411] in which R1, R2a, R2b, R3and R4can be as defined anywhere herein, M is a linker moiety, Bm is a binding moiety that is capable of specifically binding to a protein, as defined above, and a is from 1 to 10. In some embodiments, R1, R2a, R2b, R3and R4are defined to provide a compound selected from any one of Compounds 1-131.

[0412] In some embodiments, the disclosure provides an antibody-drug conjugate or pharmaceutically acceptable salt thereof according to Formula (A4):

[0413]

[0414] in which R1, R2a, R2b, R3and R4can be as defined anywhere here, M is a linker moiety, Bm is a binding moiety that is capable of specifically binding to a protein, as defined above and a is from 1 to 10. In some embodiments, R1, R2a, R2b, R3and R4are defined to provide a compound selected from any one of Compounds 1-131. In some embodiments, M is a linker as defined in WO 2021 / 198966, which is incorporated by reference in its entirety. The linker may be a cleavable linker or non-cleavable linker. In certain aspects, the linker can contain a heterobifunctional group. In the present disclosure, the term "heterobifunctional group" refers to a chemical moiety that connects the linker of which it is a part to the binding moiety. Heterobifunctional groups are characterized as having different reactive groups at either end of the chemical moiety. Attachment to Bm can be accomplished through chemical or enzymatic conjugation, or a combination of both. Chemical conjugation involves the controlled reaction of accessible amino acid residues on the surface of the binding moiety with a reaction handle on the heterobifunctional group. Examples of chemical conjugation include, but are not limited to, lysine amide coupling, cysteine mediated coupling, and coupling via a nonnatural amino acid incorporated by genetic engineering, wherein non-natural amino acid residues with a desired reaction handle are installed onto Bm. In enzymatic conjugation, an enzyme mediates the coupling of the linker with an accessible amino residue on the binding moiety. Examples of enzymatic conjugation include, but are not limited to, transpeptidation using sortase, transpeptidation using microbial transglutaminase, and N-glycan engineering. Chemical conjugation and enzymatic conjugation may also be used sequentially. For example, enzymatic conjugation can also be used for installing unique reaction handles on Bm to be utilized in subsequent chemical conjugation.

[0415] In some embodiments, M is a linker as defined in WO 2023 / 037268, which is incorporated by reference in its entirety. M may have the structure:

[0416]

[0417] wherein:

[0418] indicates the point of attachment of M to I (preferably attached as shown in formula (A4) above); R7is selected from the group consisting of hydrogen, -(CH2CH2O)v-CH3, C2-Cealkenyl, Ci-Cealkyl; C2-Cealkynyl, benzyl, Cs-Cecycloalkyl, and C3-C6cycloalkyl(Ci-C3alkyl), wherein v is from 1 to 24;

[0419] and L is selected from the group consisting of:

[0420]

[0421] wherein:

[0422] q is from 2 to 10;

[0423] Z1, Z2, Z3, Z4, and Z5are each independently absent or a naturally occurring amino acid residue in the L- or D-configuration, provided that at least two of Z1, Z2, Z3, Z4, and Z5are amino acid residues;

[0424] is the point of attachment of L to NR7-CH2-I; and

[0425] is the point of attachment to the binding moiety Bm.

[0426] In some embodiments, Z1, Z2, Z3, Z4, and Z5are independently absent or selected from the group consisting of L-valine, D-valine, L-citrulline, D-citrulline, L-alanine, D-alanine, L- glutamine, D-glutamine, L-glutamic acid, D-glutamic acid, L-aspartic acid, D-aspartic acid, L- asparagine, D-asparagine, L-phenylalanine, D-phenylalanine, L-lysine, D-lysine, and glycine; provided that at least two of Z1, Z2, Z3, Z4, and Z5are amino acid residues.

[0427] The term “binding moiety” as used herein refers to any molecule that recognizes and binds to a cell surface marker or receptor. The binding moiety may be an antibody, antibody fragment, or an antigen-binding fragment. An antibody is a protein generated by the immune system that is capable of recognizing and binding to a specific antigen. A target antigen generally has numerous binding sites, also called epitopes, recognized by CDRs on multiple antibodies. Each antibody that specifically binds to a different epitope has a different structure. Thus, one antigen may have more than one corresponding antibody. The term "antibody" herein is used in the broadest sense and specifically covers monoclonal antibodies, single domain antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired biological activity. Antibodies may be murine, human, humanized, chimeric, or derived from other species. A monoclonal antibody (mAb) to an antigen-of-interest can be prepared by using any technique known in the art which provides for the production of antibody molecules by continuous cell lines in culture. These include, but are not limited to, the hybridoma technique, the human B cell hybridoma technique, and the EBV-hybridoma technique. Such antibodies may be of any immunoglobulin class including IgG, IgM, IgE, IgA, and IgD and any subclass thereof. The hybridoma producing the mAbs of use in this disclosure may be cultivated in vitro or in vivo.

[0428] The skilled person would understand how to provide an appropriate binding moiety for use in a conjugate depending on the intended therapeutic use. This is described, for example, in Nature Reviews Drug Discovery volume 22, pages 641-661 (2023), which is incorporated by reference in its entirety. In particular, an antibody, antibody fragment or an antibody-binding fragment used as a binding moiety must be capable of targeting a particular cell surface marker or receptor associated with the disorder to be treated. For example, the antibody trastuzumab can be employed if the desired target is HER2.

[0429] In some embodiments, the binding moiety is capable of binding to an antigen selected from CDllb, CD68, CD14, CDla, CD141, CDlc, CD15, CD66b, CD49d, CSF1R, CD64, CX3CR1, CD206, CD33, CD20, CD19, BAFFR, CD38, α4β7 integrin, IL6R, TSLPR, CD40, IFNAR1, or combinations thereof. In preferred embodiments, the binding moiety is capable of binding to an antigen selected from CDllb, CD68, CD14 and CD15. In some embodiments, the binding moiety comprises an antibody selected from Vedolizumab, Etrolizumab, Gemtuzumab, Rituximab, Ublituximab, Ofatumumab, Ocrelizumab, Inebilizumab, Tafasitamab, Loncastuximab, Isatuximab, Daratumumab, Tocilizumab, Iscalimab, Bleselumab, Anifrolumab.

[0430] In some embodiments, the binding moiety is capable of binding to CD 19 and is preferably Tafasitamab, Loncastuximab or Inebilizumab. In some embodiments, the binding moiety is capable of binding to CD20 and is preferably Rituximab, Ublituximab, Ofatumumab, Ocrelizumab or Inebilizumab. In some embodiments, the binding moiety is capable of binding to CD33 and is preferably Gemtuzumab. In some embodiments, the binding moiety is capable of binding to CD38 and is preferably Isatuximab or Daratumumab.

[0431] Exemplary combinations of antibodies, target antigens, and associated therapeutic indications are listed in the table below. In some embodiments, the binding moiety of the antibody-drug conjugate comprises an antibody listed in the table below and targets an antigen listed in the table below. In some aspects, the disclosure provides a method of treating a disorder listed in the table below comprising administering to a subject in need thereof an antibody-drug conjugate comprising an antibody listed in table 1 below.

[0432] Table 1

[0433]

[0434]

[0435] Definitions

[0436] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0437] Pharmaceutically acceptable salts include those derived from suitable inorganic and organic acids and bases. In particular, “pharmaceutically acceptable salts” encompasses any multicomponent form comprising a compound as defined herein and a suitable (in)organic acid or base, including salts in which the proton is completely transferred from the acid to the base, and cocrystals in which the proton remains in the acid molecule, and together the base and the acid form a unique crystal structure.

[0438] A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a paediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0439] Disease, disorder, and condition are used interchangeably herein.

[0440] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (“therapeutic treatment”), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition (“prophylactic treatment”).

[0441] In general, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the present disclosure may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject.

[0442] As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent. The present disclosure, in an alternative embodiment, also embraces isotopically labelled compounds which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36C1, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium.

[0443] The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0444] The term "alkyl" refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, Ci-io indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Alkyl groups can either be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, / .w-propyl, tert-butyl, / / -hexyl. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and / or other substituents as defined herein.

[0445] The term "haloalkyl" refers to an alkyl, in which one or more hydrogen atoms is / are replaced with an independently selected halo.

[0446] The term "alkoxy" refers to an -O-alkyl radical (e.g., -OCH3).

[0447] The term "alkylene" refers to a divalent alkyl (e.g., -CH2-).

[0448] The term "alkenyl" refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkenyl groups can either be unsubstituted or substituted with one or more substituents.

[0449] The term "alkynyl" refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkynyl groups can either be unsubstituted or substituted with one or more substituents.

[0450] The term "aryl" refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, dihydro-IH-indenyl and the like.

[0451] The term "cycloalkyl" as used herein refers to cyclic saturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl may include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl includes: bicyclo[1.1.0]butanyl, bicyclo[2.1.0]pentanyl, bicyclo[l.l.l]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[4.2.0]octanyl, bicyclo[3.2.1]octanyl, bicyclo[2.2.2]octanyl, and the like. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, spiro[3.5]nonanyl, spiro[3.5]nonanyl, spiro[4.4]nonanyl, spiro[2.6]nonanyl, spiro[4.5]decanyl, spiro[3.6]decanyl, spiro[5.5]undecanyl, and the like. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms.

[0452] The term "cycloalkenyl" as used herein means partially unsaturated cyclic hydrocarbon groups having 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkenyl group may be optionally substituted. Examples of cycloalkenyl groups include, without limitation, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. As partially unsaturated cyclic hydrocarbon groups, cycloalkenyl groups may have any degree of unsaturation provided that one or more double bonds is present in the ring, none of the rings in the ring system are aromatic, and the cycloalkenyl group is not fully saturated overall. Cycloalkenyl may include multiple fused and / or bridged and / or spirocyclic rings.

[0453] The term “heteroaryl”, as used herein, means a mono-, bi-, tri- or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms; and having 6, 10, or 14 pi electrons shared in a cyclic array; wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups can either be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotri azolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-Z>]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-Z>]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-Z>]pyridinyl, tetrazolyl, chromanyl, 2,3-dihydrobenzo[Z>][l,4]dioxinyl, benzo[ ][l,3]dioxolyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[Z>][l,4]oxathiinyl, isoindolinyl, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.

[0454] The term "heterocyclyl" refers to a mono-, bi-, tri-, or polycyclic saturated ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Heterocyclyl may include multiple fused and bridged rings. Non-limiting examples of fused / bridged heterocyclyl includes: 2-azabicyclo[1.1.0]butanyl, 2-azabicyclo[2.1.0]pentanyl, 2-azabicyclo[1.1.1]pentanyl, 3-azabicyclo[3.1.0]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 3-azabicyclo[3,2.0]heptanyl, octahydrocyclopenta[c]pyrrolyl, 3-azabicyclo[4.1.0]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 7-azabicyclo[4.2.0]octanyl, 2-azabicyclo[2.2.2]octanyl, 3-azabicyclo[3.2.1]octanyl, 2-oxabicyclo[1.1.0]butanyl, 2-oxabicyclo[2.1.0]pentanyl, 2-oxabicyclo[1.1.1]pentanyl, 3-oxabicyclo[3.1.0]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.2.0]heptanyl, 3-oxabicyclo[4.1.0]heptanyl, 7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.1.1 ]heptanyl, 7-oxabicyclo[4.2.0]octanyl, 2-oxabicyclo[2.2.2]octanyl, 3-oxabicyclo[3.2.1]octanyl, and the like. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentanyl, 4-azaspiro[2.5]octanyl, l-azaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, 7-azaspiro[3.5]nonanyl, 2-azaspiro[4.4]nonanyl, 6-azaspiro[2.6]nonanyl, l,7-diazaspiro[4.5]decanyl, 7-azaspiro[4.5]decanyl 2,5-diazaspiro[3.6]decanyl, 3-azaspiro[5.5]undecanyl, 2-oxaspiro[2.2]pentanyl, 4-oxaspiro[2.5]octanyl, l-oxaspiro[3.5]nonanyl, 2-oxaspiro[3.5]nonanyl, 7-oxaspiro[3.5]nonanyl, 2-oxaspiro[4.4]nonanyl, 6-oxaspiro[2.6]nonane, l,7-dioxaspiro[4.5]decanyl, 2,5-dioxaspiro[3.6]decanyl, l-oxaspiro[5.5]undecanyl, 3-oxaspiro[5.5]undecanyl, 3-oxa-9-azaspiro[5.5]undecanyl and the like. The term “saturated” as used in this context means only single bonds present between constituent ring atoms and other available valences occupied by hydrogen and / or other substituents as defined herein.

[0455] The term "heterocycloalkenyl" as used herein means partially unsaturated cyclic ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Examples of heterocycloalkenyl groups include, without limitation, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl. As partially unsaturated cyclic groups, heterocycloalkenyl groups may have any degree of unsaturation provided that one or more double bonds is present in the ring, none of the rings in the ring system are aromatic, and the heterocycloalkenyl group is not fully saturated overall. Heterocycloalkenyl may include multiple fused and / or bridged and / or spirocyclic rings.

[0456] As used herein, when a ring is described as being “aromatic”, it means said ring has a continuous, delocalized 7t-electron system. Typically, the number of out of plane 7t-electrons corresponds to the Hiickel rule (4n+2). Examples of such rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, and the like.

[0457] As used herein, when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

[0458] For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms (e.g., [x.x. O] ring systems, in which 0 represents a zero atom

[0459]

[0460]

[0461] stems having

[0462]

[0463] In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include13C and14C.

[0464] In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing the moiety:

[0465]

[0466] encompasses the tautomeric form containing the moiety:

[0467]

[0468] . Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.

[0469] As used herein, the phrase “optionally substituted” when used in conjunction with a structural moiety (e.g., alkyl) is intended to encompass both the unsubstituted structural moiety (i.e., none of the substitutable hydrogen atoms are replaced with one or more non-hydrogen substituents) and substituted structural moieties substituted with the indicated range of nonhydrogen substituents. For example, “ C1-C4 alkyl optionally substituted with 1-4 Ra” is intended to encompass both unsubstituted C1-C4 alkyl and C1-C4 alkyl substituted with 1-4 Ra.

[0470] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims.

[0471] Non-Limiting Exemplary Compounds

[0472] In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table 2 or a pharmaceutically acceptable salt thereof.

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480] EXAMPLES

[0481] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization.

[0482] Abbreviations: DCM: dichloromethane; DIEA: N, N-diisopropylethylamine; DMF: dimethylformamide; DMSO: dimethyl sulfoxide; EtOH: ethanol; ESI: electrospray ionization; h: hours; HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HPLC: high-performance liquid chromatography; MeCN: acetonitrile; MS: mass spectrometry; NCS: N-chlorosuccinimide; NMR: nuclear magnetic resonance; TEA: triethylamine; and THF: tetrahydrofuran.

[0483] General Schemes

[0484] General Scheme 1

[0485]

[0486] A general synthetic strategy that may be used to prepare compounds of formula (I) is depicted in General Scheme 1. A benzylamine A-1 may be coupled with compound A-2 using any suitable amide coupling conditions to afford compounds of formula (I). For example, Mukaiyama’s reagent may be used in a polar aprotic solvent such as DMF, in the presence of a base such as DIPEA. The specific groups R1, R2a, R2b, R3, and R4are selected on the basis of the desired groups in the compound of formula (I).

[0487] General Scheme 2

[0488]

[0489] General Scheme 2 provides an exemplary synthetic strategy for the preparation of (hetero)cyclic compounds of formula A-1, which may be used as starting materials in General Scheme 1. Starting from fluorobenzene B-1, compounds of formula B-5 may be prepared in two ways: either by an SNAr reaction with dihydrouracil B-2, or in a two-step fashion via reaction with 3-aminopropanamide B-3 to afford B-4, followed by cyclization in the presence of a reagent such as carbonyl diimidazole to reach B-5. Next, reduction of the nitrile in B-5 and concomitant protection of the amine affords B-6, where PG1is any suitable protecting group that is labile to treatment with acid. The reduction can be carried out using a heterogeneous hydrogenation catalyst, for example Raney nickel, under hydrogen atmosphere. Intermediate A-l may be obtained from B-6 upon treatment with an acid, such as HCl 2M in ethyl acetate, at room temperature. The specific groups R3and R4are selected on the basis of the desired groups in the compound of formula (I).

[0490] General Scheme 3

[0491]

[0492] General Scheme 3 provides an exemplary synthetic strategy for the preparation of (hetero)cyclic compounds of formula C-3, which may be used as starting materials A-2 in General Scheme 1. Starting from a compound of formula C-l, where W1is a nitrile, ester or carboxylic acid, compounds of formula C-2 can be obtained via an alkylation reaction with a methylating reagent in the presence of a base. For example, methyl iodide may be used in the presence of sodium hydride, in a solvent such as DMF. Carboxylic acids of formula C-3 may be obtained via hydrolysis of compound C-2 in acidic medium. 6 molar HC1 may be used as the solvent, and the hydrolysis can be carried out at elevated temperature (for example, 100 degrees Celsius). Z may be N, C-H, or C-R5. R5is selected on the basis of the desired groups in the compound of formula (I).

[0493] General Scheme 4

[0494]

[0495] General Scheme 4 provides an exemplary synthetic strategy for the preparation of (hetero)cyclic compounds of formula D-4, which may be used as starting materials A-2 in General Scheme 1. Starting from a compound of formula D-l, where Hal1is any suitable halogen (e.g. Cl, Br or I), compounds of formula D-3 can be obtained via a metal-catalysed coupling reaction with a compound of formula D-2, where Q1is a group such that D-2 is an a-dimethyl ester, isobutyronitrile, or a silyl ketyl acetal. A palladium catalyst can be used, for example Pd(PtBu3)2in a polar aprotic solvent such as DMF, at elevated temperatures (100 degrees Celsius). Carboxylic acids of formula D-4 may be obtained via hydrolysis of compound D-3 in basic medium. Abase such as LiOH·H2O may be used in a solvent mixture such as THF:H2O 1:1, and the hydrolysis can be carried out at elevated temperature (for example, 100 degrees Celsius). Z may be N, C-H, or C-R5. R5is selected on the basis of the desired groups in the compound of formula (I).

[0496] General Scheme 5

[0497]

[0498] General Scheme 5 provides an exemplary synthetic strategy for the preparation of heterocyclic compounds of formula E-4, which may be used as starting materials A-2 in General Scheme 1. Compounds of formula E-2 may be obtained from E-l via a cyanation reaction. LG1is any suitable leaving group for nucleophilic substitution reactions (e.g. Cl, Br, I, OMs, OTf) and Y may be C-H, C-R6, N, O, or S. Cyanating reagent systems such as TMSCN and TBAF in a polar aprotic solvent (for example, MeCN or THF) may be used. Next, compounds of formula E-3 may be obtained from E-2 via an alkylation reaction with a methylating reagent in the presence of a base. For example, methyl iodide may be used in the presence of sodium hydride, in a solvent such as DMF. Carboxylic acids of formula E-4 may be obtained via hydrolysis of compound E-3 in acidic medium. 6 molar HC1 may be used as the solvent, and the hydrolysis can be carried out at elevated temperature (for example, 60 degrees Celsius). R6is selected on the basis of the desired groups in the compound of formula (I). Example 1. Synthesis of Representative Compounds

[0499] Synthesis of Compound 1

[0500]

[0501] Step 1. To a solution of ethyl 2-(pyridin-4-yl)acetate (1.00 g, 6.05 mmol, 1.00 eq.) in dimethylformamide (10 mL) was added lithium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 7.57 mL, 1.25 eq.). The reaction was stirred at 20 °C for 30 min. Then methyl iodide (1.29 g, 9.08 mmol, 1.50 eq.) was added at 0 °C and stirred at 20 °C for 1 h. Further lithium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 7.57 mL, 1.25 eq.) and dimethylformamide (8 mL) was added and stirred at 20 °C for 30 min. And then methyl iodide (1.29 g, 9.08 mmol, 1.50 eq.) was added at 0 °C and stirred at 20 °C for 12 h. The mixture was poured to saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (80 mL). The organic phase was washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluting with ethyl acetate / petroleum ether) to give ethyl 2-methyl-2-(pyridin-4-yl)propanoate (850 mg, 4.18 mmol, 69% yield) as a yellow oil. Step 2. To a solution of methyl 2-((pyrazin-2-ylmethyl)sulfonyl)-l,2,3,4-tetrahydroisoquinoline-3-carboxylate (500 mg, 2.59 mmol, 1.00 eq.) in ethyl alcohol (8 mL) was added sodium hydroxide (2 M, 8 mL, 6.18 eq.). The reaction mixture was stirred at 20 °C for 12 h. Ethanol was removed by evaporation and the aqueous residue was neutralized with cold hydrochloric acid (pH = 7). The mixture was concentrated to dryness, the colourless residue triturated three times with dichloromethane / methanol (10:1). The combined filtrates were evaporated to dryness to give 2-methyl-2-(pyridin-4-yl)propanoic acid (400 mg, 2.18 mmol, 84% yield) as a white solid.

[0502] Step 3. To a solution of 3-aminopropanamide hydrochloride (0.900 g, 7.22 mmol, 1.53 eq.) and 3,5-dichloro-4-fluorobenzonitrile (0.900 g, 4.74 mmol, 1.00 eq.) in dimethylsulfoxide (10 mL) was added diisopropylethylamine (3.06 g, 23.7 mmol, 4.12 mL, 5.00 eq.) in one portion. The mixture was bubbled with nitrogen for 1 min. The mixture was stirred at 100 °C for 12 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (30 mL) and water (30 mL), and the layers were separated. The aqueous phase was extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with water (2 x 50 mL) followed by brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 3 -((2,6-dichloro-4-cyanophenyl)amino)propanamide (1.20 g, 4.60 mmol, 97% yield) as a white solid. Step 4. To a solution of 3-((2,6-dichloro-4-cyanophenyl)amino)propanamide (1.00 g, 3.87 mmol, 1.00 eq.) in toluene (20 mL) was added di(l / / -imidazol-l-yl)methanone (2.00 g, 12.3 mmol, 3.18 eq.) in one portion. The mixture was stirred at 80 °C for 3 h. Then additional di(17 / -imidazol-l-yl)methanone (2.00 g, 12.3 mmol, 3.18 eq.) was added. The mixture was stirred at 80 °C for 12 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (50 mL) and water (50 mL), and the layers were separated. The aqueous phase was extracted with ethyl acetate (50 mL). The combined organic layers were washed with IM hydrochloric acid (60 mL) followed by brine (60 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was triturated with petroleum ether / ethyl acetate (4 mL / 20 mL) at 25 °C for 2 h. The solid was collected by filtration and dried under reduced pressure to give 3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin- l(27 / )-yl)benzonitrile (0.900 g, 2.60 mmol, 67% yield) as an off-white solid.

[0503] Step 5. To a suspension of Raney-Ni (0.5 g, 5.84 mmol, 2.25 eq.) in tetrahydrofuran (20 mL) were added 3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-l(2J7)-yl)benzonitrile (0.900 g, 2.60 mmol, 1.00 eq.), di-tert-butyl dicarbonate (1.13 g, 5.20 mmol, 1.19 mL, 2.00 eq.) and triethylamine (436 mg, 4.31 mmol, 0.6 mL, 1.66 eq.) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen 3 times. Then the mixture was stirred at 60 °C for 12 h under hydrogen atmosphere (15 psi). After cooling to room temperature, the mixture was filtered through a pad of celite and washed with acetonitrile (20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase column (0.1% formic acid in water / acetonitrile) and concentrated under reduced pressure to give tert-butyl (3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-l(277)-yl)benzyl)carbamate (0.800 g, 1.92 mmol, 74% yield) as a white solid.

[0504] Step 6. A mixture of tert-butyl (3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-l(277)-yl)benzyl)carbamate (0.300 g, 772 / / mol, 1.00 eq.) and hydrogen chloride / ethyl acetate (4 M, 10 mL) was stirred at 25 °C for 2 h. A large amount of precipitate formed. The precipitate was collected by filtration and washed with petroleum ether to give l-(4-(aminomethyl)-2,6-dichlorophenyl)dihydropyrimidine-2, 4(1 / 7, 37 / )-dione hydrochloride (160 mg, 493 / mol, 64% yield) as a white solid.

[0505] ’H NMR (400 MHz, DMSO-tL) 8 = 10.65 (s, 1H), 8.51 (s, 3H), 7.78 (s, 2H), 4.08 (d, J= 5.2 Hz, 2H), 3.63 (t, J= 6.8 Hz, 2H), 2.77 (t, J= 6.8 Hz, 2H).

[0506] Step 7. To a solution of 2-methyl-2-(4-pyridyl)propanoic acid (30.0 mg, 163 / / mol, 1.00 eq.) and l-(4-(aminomethyl)-2,6-di chi orophenyl)dihydropyrimidine-2, 4(177, 377)-di one hydrochloride (64.0 mg, 196 / / mol, 1.2 eq.) in dimethylformamide (2 mL) were added A-ethyl-A-propan-2-ylpropan-2-amine (74.0 mg, 574 / / mol, 3.51 eq.) and 2-chloro-l-methyl-pyridin-l-ium iodide (60.0 mg, 235 / / mol, 1.44 eq.) in one portion. The mixture was stirred at 70 °C for 12 h. The mixture was filtered, and the filtrate was collected. The filtrate was purified by / c -HPLC (column: Phenomenex Luna C18 150*25mm*10 / / m; mobile phase: [water(formic acid)-acetonitrile]; B%: l%-30%, 10 min) and lyophilized to give A-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-l(277)-yl)benzyl)-2-methyl-2-(pyridin-4-yl)propanamide formate (37.05 mg, 76.2 / / mol, 47% yield) as a yellow solid.

[0507] ’H NMR (400 MHz, DMSO-tL) 6 = 10.59 (s, 1H), 8.56 - 8.48 (m, 2H), 8.23 (s, 1H), 8.18 (t, J = 6.0 Hz, 1H), 7.33 - 7.28 (m, 2H), 7.28 (s, 2H), 4.25 (d, J = 6.0 Hz, 2H), 3.60 (t, J= 6.8 Hz, 2H), 2.75 (t, J= 6.8 Hz, 2H), 1.50 (s, 6H). MS (ESI) m / z 435.0 / 437.1 [M+H]+ Synthesis of Compound 2

[0508]

[0509] Step 1. To a solution of l-(4-(aminomethyl)-2,6-dichlorophenyl)dihydropyrimidine-2,4(lH,3H)-dione hydrochloride (100 mg, 308 / mol, 1.00 eq.) and 2-(4-fluorophenyl)-2-methylpropanoic acid (56.1 mg, 308 / mol, 1.00 eq.) in dimethylformamide (3 mL) were added 2-chloro-l-methylpyridinium iodide (94.4 mg, 369 / / mol, 1.20 eq.) and N, N-diisopropylethylamine (119 mg, 924 / / mol, 160 / / L, 3.00 eq.). The mixture was stirred at 70 °C for 12 h. The mixture was diluted with ethyl acetate (20 mL) and water (10 mL). The layers were separated. The organic layer was washed with water (2 x 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Phenomenex Luna C18 150 * 25 mm * 10 / / m; mobile phase: [water (formic acid) acetonitrile]; B%: 32% - 62%, 10 min). The desired fraction was collected and lyophilized to give N-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)benzyl)-2-(4-fluorophenyl)-2-methylpropanamide (39.96 mg, 87.4 / / mol, 28% yield) as a white solid.

[0510] ’H NMR (400 MHz, DMSO-tL) d = 10.59 (s, 1H), 8.06 (t, J = 6.0 Hz, 1H), 7.36 - 7.32 (m, 2H), 7.21 (s, 2H), 7.18 - 7.12 (m, 2H), 4.23 (d, J= 6.0 Hz, 2H), 3.59 (t, J= 6.8 Hz, 2H), 2.74 (t, J= 6.8 Hz, 2H), 1.49 (s, 6H). MS (ESI) m / z 452.2 [M+H]+ Synthesis of Compound 4

[0511]

[0512] Step 1. To a solution of methyl 2-(4-bromophenyl)-2-methylpropanoate (5.00 g, 19.4 mmol, 1.00 eq.) in dimethylformamide (30 mL) was added tetrakis[triphenylphosphine]palladium(0) (600 mg, 519 pmol, 0.03 eq.) and dicyanozinc (1.65 g, 14.0 mmol, 0.75 eq.). The mixture was stirred at 80 °C under nitrogen atmosphere for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with hydrochloric acid (0.5 M, 100 mL) and brine (100 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-10% ethyl acetate / petroleum ether) to afford methyl 2-(4-cyanophenyl)-2-methylpropanoate (400 mg, 1.97 mmol, 10% yield) as a colourless oil.

[0513] Step 2. To a solution of methyl 2-(4-cyanophenyl)-2-methylpropanoate (400 mg, 1.97 mmol, 1.00 eq.) in tetrahydrofuran (6 mL) was added lithium hydroxide monohydrate (170 mg, 4.05 mmol, 2.06 eq.) in water (2 mL). The mixture was stirred at 50 °C for 3 h. The mixture was diluted with water (30 mL) and ethyl acetate (30 mL). The aqueous phase was separated and washed with ethyl acetate (20 mL). The aqueous phase was adjusted to pH = 3-4 with hydrochloric acid (1 M) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with brine (60 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 2-(4-cyanophenyl)-2-methylpropanoic acid (280 mg, 1.18 mmol, 60% yield) as a white solid. The crude product was used in the next step without purification.

[0514] Step 3. To a solution of 2-(4-cyanophenyl)-2-methylpropanoic acid (100 mg, 528 pmol, 1.52 eq.) in dimethylformamide (2 mL) was added N,N-diisopropylethylamine (190 pL, 1.09 mmol, 3.14 eq.), 17 / -benzo[ ][l,2,3]triazol-l-ol (57.0 mg, 422 pmol, 1.22 eq.) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80.0 mg, 417 pmol, 1.20 eq.) at 0 °C. The mixture was stirred at 20 °C for 30 min. The 3-(4-(aminomethyl)-2,6-dichlorophenyl)piperidine-2, 6-dione (100 mg, 347 pmol, 1.00 eq.) was added to the mixture. The mixture was stirred at 20 °C for 15.5 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by / c -HPLC (column: YMC-Actus Triart C18 150 x 30 mm x

[0515]

[0516] mobile phase:

[0517] [water (formic acid) - acetonitrile]; gradient: 35%-65% B over 10 min) and lyophilized to afford 2-(4-cyanophenyl)-7V-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-l(2J7)-yl)benzyl)-2-methylpropanamide (41.61 mg, 86.2 pmol, 24% yield) as a white solid.

[0518] ’H NMR (400 MHz, DMSO-tL) d = 10.59 (s, 1H), 8.15 (t, J= 6.0 Hz, 1H), 7.85-7.75 (m, 2H), 7.55-7.45 (m, 2H), 7.25-7.15 (m, 2H), 4.24 (d, J= 6.0 Hz, 2H), 3.60 (t, J= 6.8 Hz, 2H), 2.75 (t, J = 6.4 Hz, 2H), 1.52 (s, 6H). MS (ESI) m / z 458.9 [M+H]+

[0519] Synthesis of Compound 5

[0520]

[0521] Step 1. To a solution of lithium diisopropylamide (6.20 mL, 2 M, 1.47 eq.) was added methyl isobutyrate (1.29 g, 12.7 mmol, 1.50 eq.) in tetrahydrofuran (5 mL) at -60 °C under nitrogen atmosphere. The reaction mixture was stirred at -60 °C for 30 min, then 2,5-dibromopyridine (2.00 g, 8.44 mmol, 1.00 eq.) in tetrahydrofuran (15 mL) was added to the mixture at -60 °C, and the reaction mixture was stirred at 20 °C for 2 h. The reaction was quenched with saturated ammonium chloride solution (20 mL) at 0 °C. The reaction mixture was diluted with ethyl acetate (30 mL) and water (15 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0—15 % ethyl acetate / petroleum ether) to afford methyl 2-(5-bromopyridin-2-yl)-2-methylpropanoate (1.60 g, 6.07 mmol, 72% yield) as a light-yellow oil. Step 2. To a solution of methyl 2-(5-bromopyridin-2-yl)-2-methylpropanoate (400 mg, 1.55 mmol, 1.00 eq.) in methanol (5 mL) was added sodium hydroxide (186 mg, 4.65 mmol, 3.00 eq.) in water (5 mL) at 0 °C. The reaction mixture was stirred at 50 °C for 2 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (10 mL) and water (5 mL). The layers were separated, and the aqueous phase was acidified to pH=5 with IM hydrochloric acid. The aqueous phase was extracted with ethyl acetate (10 mL). The organic layer was washed with brine (10 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 2-(5-bromopyridin-2-yl)-2-methylpropanoic acid (300 mg, 1.18 mmol, 76% yield) as a white solid.

[0522] Step 3. To a solution of 2-(5-bromopyridin-2-yl)-2-methylpropanoic acid (80.0 mg, 328 pmol, 1.00 eq.) and A, A-diisopropylethylamine (160 mg, 1.24 mmol, 3.78 eq.) in dimethylformamide (2 mL) was added 2-chloro-l-methyl-pyridin-l-ium iodide (96.0 mg, 376 pmol, 1.15 eq.) at 0 °C. The mixture was stirred at 20 °C for 15 min, then l-(4-(aminomethyl)-2,6-dichlorophenyl)dihydropyrimidine-2, 4(1 / 7, 37 / )-dione (100 mg, 308 pmol, 0.94 eq.) was added to the mixture, and the reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with ethyl acetate (15 mL) and water (15 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0~60 % ethyl acetate / petroleum ether) to afford 2-(5-bromopyridin-2-yl)-7V-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-l(277)-yl)benzyl)-2-methylpropanamide (140 mg, 264 pmol, 81% yield) as a white solid. Step 4. To a solution of 2-(5-bromopyridin-2-yl)-7V-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-l(2J7)-yl)benzyl)-2-methylpropanamide (140 mg, 272 pmol, 1.00 eq.) and zinc cyanide (50.0 mg, 426 pmol, 1.56 eq.) in dimethylformamide (2 mL) was added 1,1-bis(diphenylphosphino)ferrocene (14.0 mg, 25.3 pmol, 0.10 eq.) and tris(dibenzylideneacetone)dipalladium(0) (28.0 mg, 30.6 pmol, 0.11 eq.) under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 12 h. The resulting mixture was filtered, then diluted with ethyl acetate (5 mL) and water (5 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 × 5 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by / c -HPLC (column: YMC-Actus Triart C18 150 x 30mm x 7 / / m; mobile phase: [water(formic acid) - acetonitrile]; gradient: 30%-60% B over 10 min) and lyophilized to afford 2-(5-cyanopyridin-2-yl)-7V-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-l(2J7)-yl)benzyl)-2-methylpropanamide (41.65 mg, 89.6 pmol, 33% yield) as a white solid.

[0523] ’H NMR(400 MHz, DMSO-6) d = 10.61 (s, 1H), 8.99 (d, J= 2.0 Hz, 1H), 8.31 (dd, J= 2.4, 8.4 Hz, 1H), 8.14 (t, J= 6.0 Hz, 1H), 7.63 (d, J= 8.4 Hz, 1H), 7.34 (s, 2H), 4.26 (d, J= 6.0 Hz, 2H), 3.61 (t, J= 6.8 Hz, 2H), 2.75 (t, J= 6.8 Hz, 2H), 1.55 (s, 6H). MS (ESI) m / z 460.3 [M+H]+

[0524] Synthesis of Compound 13

[0525]

[0526] Step 1. To a solution of 5-bromobenzo[ ]oxazole (1.00 g, 5.05 mmol, 1.00 eq.), zinc(II) fluoride (1.04 g, 10.1 mmol, 2.00 eq.) and palladium tri-tert-butylphosphane (258 mg, 505 pmol, 0.10 eq.) in dimethylformamide (20 mL) was added ((l-methoxy-2-methylprop-l-en-l-yl)oxy)trimethylsilane (1.76 g, 10.1 mmol, 2.00 eq.). The mixture was degassed and purged with nitrogen three times, and then the mixture was stirred at 100 °C for 16 h under nitrogen atmosphere. After reaction completion, the mixture was cooled to 25 °C, filtered, and diluted with water (20 mL), then extracted with ethyl acetate (4 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-10% ethyl acetate / petroleum ether) to give methyl 2-(benzo[<7]oxazol-5-yl)-2-methylpropanoate (842 mg, 3.49 mmol, 69% yield) as a yellow oil. Step 2. To a solution of methyl 2-(benzo[d]oxazol-5-yl)-2-methylpropanoate (200 mg, 912 pmol, 1.00 eq.) in tetrahydrofuran (10 mL) was added dropwise lithium hydroxide monohydrate (76.6 mg, 1.82 mmol, 2.00 eq.) in water (10 mL). The resulting mixture was stirred at 20 °C for 12 h. The reaction mixture was washed with ethyl acetate (10 mL), then the pH was adjusted to 7 with hydrochloric acid (12 M). The mixture was extracted with ethyl acetate (3 x 10 mL) and di chloromethane (3 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 2-(benzo[d]oxazol-5-yl)-2-m ethylpropanoic acid (106 mg, 408 pmol, 45% yield) as a yellow oil.

[0527] Step 3. To a solution of 2-(benzo[<7]oxazol-5-yl)-2-methylpropanoic acid (66.0 mg, 254 pmol, 1.50 eq.) in dimethylformamide (2 mL) was added 1 -(3 -dimethylaminopropyl)-3 -ethylcarbodiimide hydrochloride (39.0 mg, 203 pmol, 1.20 eq.), 1 -hydroxybenzotriazole (27.5 mg, 203 pmol, 1.20 eq.) and A, A-diisopropylethylamine (87.6 mg, 677 pmol, 4.00 eq.) at 0 °C. After addition, the mixture was stirred at 20 °C for 0.5 h, and then l-(4-(aminomethyl)-2,6-dichlorophenyl)dihydropyrimidine-2, 4(1 / 7, 37 / )-dione hydrochloride (55.0 mg, 169 pmol, 1.00 eq.) in dimethylformamide (1 mL) was added dropwise. The resulting mixture was stirred at 20 °C for 11.5 h. After reaction completion, the reaction mixture was cooled to 25 °C, then diluted with water (5 mL) and extracted with ethyl acetate (5 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by / c -HPLC (column: Waters Xbridge 150 x 25 mm x 5 pm; mobile phase: [water -acetonitrile]; gradient: 22%-52% B over 9 min) to give 2-(benzo[d]oxazol-5-yl)-A-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-l(277)-yl)benzyl)-2-methylpropanamide (38.2 mg, 78.8 pmol, 47% yield) as a white solid.

[0528] ’H NMR (400 MHz, DMSO-tL) d = 10.57 (s, 1H), 8.73 (s, 1H), 8.04 (t, J= 6.0 Hz, 1H), 7.78 -7.75 (m, 1H), 7.71 (d, = 8.8 Hz, 1H), 7.36 (dd, J= 2.0, 8.8 Hz, 1H), 7.15 (s, 2H), 4.22 (d, J= 6.0 Hz, 2H), 3.58 (t, J= 6.8 Hz, 2H), 2.73 (t, J= 6.8 Hz, 2H), 1.57 (s, 6H). MS (ESI)TWZZ 475.2 [M+l]+ Synthesis of Compound 14

[0529]

[0530] Step 1. To a mixture of ethyl 2-(5-bromopyrimidin-2-yl)acetate (1.00 g, 4.08 mmol, 1.00 eq.) in dimethylformamide (20 mL) was added sodium hydride (489 mg, 12.2 mmol, 60% purity, 3.00 eq.) in portions at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then iodomethane (1.74 g, 12.2 mmol, 3.00 eq.) was added and the mixture was stirred at 20 °C for 1 h. The reaction was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give ethyl 2-(5-bromopyrimidin-2-yl)-2-methylpropanoate (1.18 g, 3.93 mmol, 96% yield) as a yellow oil.

[0531] Step 2. To a mixture of ethyl 2-(5-bromopyrimidin-2-yl)-2-methylpropanoate (500 mg, 1.83 mmol, 1.00 eq.), potassium carbonate (759 mg, 5.49 mmol, 3.00 eq.), palladium(II) acetate (41.1 mg, 183 pmol, 0.10 eq.) and 2-dicyclohexylphosphino-2',6'-di-i-propoxy-l,l'-biphenyl (85.4 mg, 183 pmol, 0.10 eq.) in toluene (4 mL) and water (1 mL) was added cyclopropylboronic acid (314 mg, 3.66 mmol, 2.00 eq.) in portions at 25 °C. The mixture was stirred at 120 °C under nitrogen atmosphere for 12 h. The mixture was cooled to 25 °C then poured into water (20 mL). The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-20% ethyl acetate / petroleum ether) to give ethyl 2-(5-cyclopropylpyrimidin-2-yl)-2-methylpropanoate (370 mg, 1.58 mmol, 86% yield) as a colourless oil.

[0532] Step 3. To a mixture of ethyl 2-(5-cyclopropylpyrimidin-2-yl)-2-methylpropanoate (370 mg, 1.58 mmol, 1.00 eq.) in methanol (2 mL) and water (2 mL) was added sodium hydroxide (315 mg, 7.90 mmol, 5.00 eq.) in portions at 20 °C. The mixture was stirred at 20 °C for 12 h. The mixture was poured into water (20 mL) and adjusted to pH = 2 with 36% aqueous hydrochloric acid, then extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with brine (20 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-(5-cyclopropylpyrimidin-2-yl)-2-methylpropanoic acid (280 mg, 1.34 mmol, 85% yield) as a white solid.

[0533] Step 4. To a mixture of 2-(5-cyclopropylpyrimidin-2-yl)-2-methylpropanoic acid (95.3 mg, 462 pmol, 1.50 eq.) and 2-chloro-1-methyl-pyridin-1-ium iodide (118 mg, 462 μmol, 1.50 eq.) in dimethylformamide (2 mL) was added diisopropylethylamine (159 mg, 1.23 mmol, 4.00 eq.) dropwise at 25 °C. The mixture was stirred at 25 °C for 0.5 h then 1-(4-(aminomethyl)-2,6-dichlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (100 mg, 308 pmol, 1.00 eq.) was added and the mixture was stirred at 25 °C for 1.5 h. The mixture was poured into water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: YMC-Actus Triart C18 150 mm × 30 mm ×

[0534]

[0535] mobile phase: [water (formic acid)-acetonitrile]; gradient: 33%-63% B over 10 min) then lyophilized to give 2-(5-cyclopropylpyrimidin-2-yl)-N-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzyl)-2-methylpropanamide (77.6 mg, 161 μmol, 52% yield) as a white solid.

[0536] ’H NMR (400 MHz, DMSO-6) d = 10.61 (s, 1H), 8.56 (s, 2H), 8.06 ( t, J= 5.6 Hz, 1H), 7.46 (s, 2H), 4.28 ( d, J= 6.0 Hz, 2H), 3.61 ( t, J= 6.4 Hz, 2H), 2.75 ( t, J= 6.8 Hz, 2H), 2.00 - 1.89 (m, 1H), 1.53 (s, 6H), 1.10 - 0.98 (m, 2H), 0.88 - 0.76 (m, 2H). MS (ESI) m / z 476.2 [M+H]+ Synthesis of Compound 15

[0537]

[0538] Step 1. To a solution of methyl 2-methylpropanoate (3.23 g, 31.7 mmol, 1.50 eq.) in tetrahydrofuran (20 mL) was added lithium diisopropyl amide (2 M in tetrahydrofuran, 15.8 mL, 1.50 eq.) at -60 °C under nitrogen atmosphere. It was stirred at -60 °C for 30 min. Then a solution of 2,5-dibromopyridine (5.00 g, 21.1 mmol, 1.00 eq.) in tetrahydrofuran (40 mL) was added to the mixture at -60 °C under nitrogen atmosphere. It was stirred at 20 °C for 2 h. The reaction was quenched with saturated ammonium chloride (30 mL) at 0 °C. The reaction mixture was extracted with ethyl acetate (40 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (40 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5 / 1) to give methyl 2-(5-bromopyridin-2-yl)-2-methylpropanoate (4.60 g, 16.9 mmol, 80% yield) as a yellow oil.

[0539] Step 2. To a mixture of methyl 2-(5-bromopyridin-2-yl)-2-methylpropanoate (1.00 g, 3.87 mmol, 1.00 eq.), potassium carbonate (1.61 g, 11.6 mmol, 3.00 eq.), palladium(II) acetate (87.0 mg, 387 μmol, 0.10 eq.) and dicyclohexyl (2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphane (181 mg, 387 μmol, 0.10 eq.) in toluene (4.5 mL) and water (1.5 mL) was added cyclopropylboronic acid (333 mg, 3.87 mmol, 1.00 eq.) in portions at 25 °C. The mixture was stirred at 120 °C under nitrogen atmosphere for 12 h. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL). The organic layer was washed with water (3 x 15 mL) and brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5 / 1) to give methyl 2-(5-cyclopropylpyridin-2-yl)-2-methylpropanoate (740 mg, 3.27 mmol, 84% yield) as a yellow oil.

[0540] Step 3. To a solution of methyl 2-(5-cyclopropylpyridin-2-yl)-2-methylpropanoate (680 mg, 3.10 mmol, 1.00 eq.) in methanol (2 mL) and water (2 mL) was added sodium hydroxide (620 mg, 15.5 mmol, 5.00 eq.) at 0 °C. After addition, the mixture was stirred at 20 °C for 16 h. The pH was adjusted to 5 with IM hydrochloric acid. The mixture was extracted with ethyl acetate (5 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 2-(5-cyclopropylpyridin-2-yl)-2-methylpropanoic acid (540 mg, crude) as a yellow oil.

[0541] Step 4. To a solution of 2-(5-cyclopropylpyridin-2-yl)-2-methylpropanoic acid (228 mg, crude) in dimethylformamide (3 mL) were added N,N-diisopropylethylamine (1.39 mmol, 241 pL, 3.00 eq.) and 2-chloro-1-methyl-pyridin-1-ium iodide (142 mg, 555 μmol, 1.20 eq.). After addition, the mixture was stirred at 20 °C for 30 min, then 1-(4-(aminomethyl)-2,6-dichlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (150 mg, 462 / mol, 1.00 eq.) was added. The resulting mixture was stirred at 20 °C for 1 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with water (2 x 10 mL) and brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC [column: YMC-Actus Triart C18 150 × 30 mm × 7 μm; mobile phase: [water (formic acid) - acetonitrile]; gradient: 23% - 60% B over 10 min) and lyophilized to give 2-(5-cyclopropylpyridin-2-yl)-N-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzyl)-2-methylpropanamide (129.72 mg, 265 μmol, 57% yield) as a white solid.

[0542] ’H NMR (400 MHz, DMSO ) d = 10.62 (s, 1H), 8.39 (d, J= 2.4 Hz, 1H), 8.02 - 7.99 (t, J= 6.0 Hz, 1H), 7.41 - 7.39 (dd, J= 2.4, 8.4 Hz, 1H), 7.37 (s, 2H), 7.28 - 7.24 (d, J= 8.4 Hz, 1H), 4.26 -4.24 (d,.7= 6.0 Hz, 2H), 3.62 - 3.58 (t, = 6.8 Hz, 2H), 2.76 - 2.73 (t, J= 6.8 Hz, 2H), 1.97 - 1.91 (m, 1H), 1.49 (s, 6H), 1.01 - 0.96 (m, 2H), 0.73 - 0.69 (m, 2H). MS (ESI) m / z 475.3 [M+H]+ Synthesis of Compound 18

[0543]

[0544] Step 1. To a mixture of ethyl 2-(5-bromopyrimidin-2-yl) acetate (1.00 g, 4.08 mmol, 1.00 eq.) in dimethylformamide (20 mL) was added sodium hydride (489 mg, 12.2 mmol, 60% purity, 3.00 eq.) in portions at 0 °C. The mixture was stirred at 0 °C for 0.5 h, then iodomethane (1.74 g, 12.2 mmol, 3.00 eq.) was added. The mixture was stirred at 20 °C for 1 h. The mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-10% ethyl acetate / petroleum ether). The residue was purified by Prep-HPLC (column: Phenomenex luna C18 150 mm × 40 mm ×

[0545]

[0546] mobile phase: [water (formic acid)-acetonitrile]; gradient: 40%-70% B over 15 min) then concentrated under reduced pressure to give ethyl 2-(5-bromopyrimidin-2-yl)-2-methylpropanoate (820 mg, 2.94 mmol, 72% yield) as a yellow oil.

[0547] Step 2. To a solution of ethyl 2-(5-bromopyrimidin-2-yl)-2-methylpropanoate (620 mg, 2.27 mmol, 1.00 eq.) and methylboronic acid (679 mg, 11.4 mmol, 5.00 eq.) in dioxane (6 mL) were added tris(dibenzylideneacetone)-dipalladium(0) (103 mg, 113 μmol, 0.05 eq.), tri-tert-butylphosphonium tetrafluoroborate (65.8 mg, 227 μmol, 0.10 eq.) and caesium carbonate (2.22 g, 6.81 mmol, 3.00 eq.) in one portion at 20 °C under nitrogen atmosphere. The mixture was stirred at 100 °C for 12 h. The mixture was cooled to 20 °C and poured into water (10 mL). The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-22% ethyl acetate / petroleum ether) to give ethyl 2-methyl-2-(5-methylpyrimidin-2-yl)propanoate (400 mg, 1.73 mmol, 76% yield) as a yellow oil.

[0548] Step 3. To a solution of ethyl 2-methyl-2-(5-methylpyrimidin-2-yl)propanoate (400 mg, 1.92 mmol, 1.00 eq.) in methanol (4 mL) and water (4 mL) was added sodium hydroxide (384 mg, 9.60 mmol, 5.00 eq.) in one portion at 20 °C. The mixture was stirred at 20 °C for 12 h. The mixture was poured into water (10 mL). The mixture was adjusted to pH = 2-3 with 36% aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2-methyl-2-(5-methylpyrimidin-2-yl)propanoic acid (300 mg, 1.56 mmol, 81% yield) as a white solid.

[0549] Step 4. To a solution of 2-methyl-2-(5-methylpyrimidin-2-yl)propanoic acid (99.9 mg, 554 pmol, 1.20 eq.) and diisopropylethylamine (238 mg, 1.85 mmol, 4.00 eq.) in dimethylformamide (1 mL) were added 1 -(3 -dimethylaminopropyl)-3 -ethylcarbodiimide hydrochloride (106 mg, 554 pmol, 1.20 eq.) and 1 -hydroxybenzotriazole (74.9 mg, 554 pmol, 1.20 eq.) in one portion at 20 °C. The mixture was stirred at 20 °C for 0.5 h, then 1-(4-(aminomethyl)-2,6-dichlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (150 mg, 462 μmol, 1.00 eq.) was added. The mixture was stirred at 20 °C for 12 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: YMC-Actus Triart C18 150 mm × 30 mm × mobile phase: [water (formic acid)-acetonitrile]; gradient: 28%-58% B over 10 min) then lyophilized. The residue was purified by / Vc -HPLC (column: Waters Xbridge 150 mm

[0550]

[0551] mobile phase: [water (ammonium bicarbonate)-acetonitrile]; gradient: 20%-50% B over 9 min) then lyophilized to give N-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzyl)-2-methyl-2-(5-methylpyrimidin-2-yl)propanamide (87.8 mg, 193 μmol, 41% yield) as a white solid. ’H NMR (400 MHz, DMSO-6) d = 10.60 (s, 1H), 8.64 (s, 2H), 8.08 (t, J= 6.0 Hz, 1H), 7.48 (s, 2H), 4.28 (d, J= 6.0 Hz, 2H), 3.61 (t, J= 6.8 Hz, 2H), 2.75 (t, J= 6.8 Hz, 2H), 2.27 (s, 3H), 1.53 (s, 6H). MS (ESI) m / z 450.2 [M+H]+

[0552] Synthesis of Compound 20

[0553]

[0554] Step 1. To a mixture of ethyl 2-(5-bromopyrimidin-2-yl)acetate (1.00 g, 4.08 mmol, 1.00 eq.) in dimethylformamide (20 mL) was added sodium hydride (489 mg, 12.2 mmol, 60% purity, 3.00 eq.) in portions at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then iodomethane (1.74 g, 12.2 mmol, 3.00 eq.) was added, and the mixture was stirred at 20 °C for 1 h. The reaction was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give ethyl 2-(5-bromopyrimidin-2-yl)-2-methylpropanoate (1.18 g, 3.93 mmol, 96% yield) as a yellow oil.

[0555] Step 2. To a mixture of ethyl 2-(5-bromopyrimidin-2-yl)-2-methylpropanoate (200 mg, 732 pmol, 1.00 eq.) in methanol (1 mL) and water (1 mL) was added sodium hydroxide (146 mg, 3.66 mmol, 5.00 eq.) in one portion at 20 °C. The mixture was stirred at 20 °C for 12 h. The mixture was poured into water (10 mL) and adjusted to pH = 2 using 36% aqueous hydrochloric acid, then extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-(5-bromopyrimidin-2-yl)-2-methylpropanoic acid (170 mg, 596 pmol, 81% yield) as a white solid.

[0556] Step 3. To a mixture of 2-(5-bromopyrimidin-2-yl)-2-methylpropanoic acid (154 mg, 628 pmol, 1.20 eq.), 1H-benzo[d][1,2,3]triazol-1-ol (84.9 mg, 628 pmol, 1.20 eq.) and l-(3-dimethylaminopropyl)-3 -ethyl carbodiimide hydrochloride (120 mg, 628 pmol, 1.20 eq.) in dimethylformamide (2 mL) was added diisopropylethylamine (270 mg, 2.09 mmol, 4.00 eq.) dropwise at 25 °C. The mixture was stirred at 25 °C for 0.5 h then l-(4-(aminomethyl)-2,6-dichlorophenyl)dihydropyrimidine-2, 4(1 / 7, 37 / )-dione hydrochloride (170 mg, 523 pmol, 1.00 eq.) was added and the mixture was stirred at 25 °C for 12 h. The mixture was poured into water (20 mL), and the resulting precipitate was filtered and washed with water (2 x10 mL). The precipitate was collected and dried under vacuum to give 2-(5-bromopyrimidin-2-yl)-N-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzyl)-2-methylpropanamide (270 mg, 414 μmol, 79% yield) as a yellow solid.

[0557] Step 4. To a mixture of 2-(5-bromopyrimidin-2-yl)-N-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzyl)-2-methylpropanamide (170 mg, 329 μmol, 1.00 eq.), tris(dibenzylideneacetone)dipalladium(0) (30.2 mg, 33.0 μmol, 0.10 eq.) and 1,1'-bis(diphenylphosphino)ferrocene (18.2 mg, 33.0 μmol, 0.10 eq.) in dimethylformamide (2 mL) was added zinc cyanide (80.0 mg, 681 μmol, 2.06 eq.) in portions at 25 °C. The mixture was stirred at 100 °C under nitrogen atmosphere for 12 h. The mixture was cooled to 25 °C then filtered. The filtrate was quenched with water (50 mL) then extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: YMC-Actus Triart C18 150 mm × 30 mm × 7 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 28%-58% B over 10 min) then lyophilized to give 2-(5-cyanopyrimidin-2-yl)-N-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzyl)-2-methylpropanamide (82.1 mg, 176 μmol, 53% yield) as a white solid. ’H NMR (400 MHz, DMSO-6) = 10.61 (br s, 1H), 9.31 (s, 2H), 8.19 (t, J= 5.6 Hz, 1H), 7.43 (s, 2H), 4.28 ( d, J= 5.6 Hz, 2H), 3.62 ( t, J= 6.8 Hz, 2H), 2.76 (t, J= 6.8 Hz, 2H), 1.58 (s, 6H).

[0558] MS (ESI) m / z 461.1 [M+H]+

[0559] Synthesis of Compound 21

[0560]

[0561] Step 1. To a solution of methyl 2-methylpropanoate (1.30 g, 12.7 mmol, 1.50 eq.) in tetrahydrofuran (5 mL) was added lithium diisopropyl amide (2 M in tetrahydrofuran, 6.33 mL, 1.50 eq.) at -60 °C under nitrogen atmosphere. It was stirred at -60 °C for 30 min. Then a solution of 2,5-dibromopyridine (2.00 g, 8.44 mmol, 1.00 eq.) in tetrahydrofuran (20 mL) was added to the mixture at -60 °C under nitrogen atmosphere. It was stirred at 20 °C for 2 h. The reaction was quenched with saturated ammonium chloride (18 mL) at 0 °C. The reaction mixture was diluted with ethyl acetate (30 mL) and water (15 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (20 mL). The organic layer was washed with brine (30 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 20 g sepaflash® silica flash column, eluent of 0-20% ethyl acetate / petroleum ether gradient @ 60 mL / min) to give methyl 2-(5-bromopyridin-2-yl)-2-methylpropanoate (1.89 g, 6.59 mmol, 78% yield) as a colourless oil. Step 2. To a solution of methyl 2-(5-bromopyridin-2-yl)-2-methylpropanoate (1.00 g, 3.87 mmol, 1.00 eq.) in dimethylformamide (4 mL) were added triethylamine (11.6 mmol, 1.62 mL, 3.00 eq.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (142 mg, 194 μmol, 0.05 eq.). The mixture was degassed under vacuum and purged with carbon monoxide several times. The mixture was stirred under carbon monoxide (2.5 bar) at 80 °C for 12 h. The reaction mixture was cooled to room temperature, then diluted with ethyl acetate (50 mL) and water (40 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 30 mL). The combined extracts were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 12 g sepaflash® silica flash column, eluent of 0-30% ethyl acetate / petroleum ether gradient @ 50 mL / min) to give methyl 2-(5-formylpyridin-2-yl)-2-methylpropanoate (350 mg, 1.52 mmol, 39% yield) as a colourless oil.

[0562] Step 3. To a solution of methyl 2-(5-formylpyridin-2-yl)-2-methylpropanoate (350 mg, 1.69 mmol, 1.00 eq.) in di chloromethane (4 mL) was added (bis-(2-methoxyethyl)amino)sulfur trifluoride (3.38 mmol, 740 μL, 2.00 eq.) at 0 °C under nitrogen atmosphere. It was stirred at 0 °C for 2 h. The reaction mixture was quenched by addition of saturated sodium bicarbonate (15 mL) at 20°C and extracted with ethyl acetate (3 x 25 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g sepaflash® silica flash column, eluent of 0-20% ethyl acetate / petroleum ether gradient @ 30 mL / min) to give methyl 2-(5-(difluoromethyl)pyridin-2-yl)-2-methylpropanoate (250 mg, 981 μmol, 58% yield) as a colourless oil.

[0563] Step 4. To a solution of methyl 2-(5-(difluoromethyl)pyridin-2-yl)-2-methylpropanoate (250 mg, 1.09 mmol, 1.00 eq.) in methanol (4 mL) was added a solution of sodium hydroxide (218 mg, 5.45 mmol, 5.00 eq.) in water (4 mL). It was stirred at 20 °C for 2.5 h. The pH was adjusted to 6 with 2 M hydrochloric acid at 0 °C. Then it was diluted with water and lyophilized to give 2-(5-(difluoromethyl)pyridin-2-yl)-2-methylpropanoic acid (400 mg, crude) as a white solid.

[0564] Step 5. To a solution of 2-(5-(difluoromethyl)pyridin-2-yl)-2-methylpropanoic acid (155 mg, 346 μmol, 1.00 eq., 48% purity) in A / A-di methyl formamide (2 mL) were added N-ethyl-N-isopropylpropan-2-amine (1.72 mmol, 300 μL, 4.98 eq.) and 2-chloro-1-methyl-pyridin-1-ium iodide (110 mg, 431 μmol, 1.25 eq.) at 0 °C. The mixture was stirred at 20 °C for 0.5 h. Then 1- (4-(aminomethyl)-2,6-dichlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (100 mg, 308 μmol, 0.890 eq.) was added, and the resulting mixture was stirred at 20 °C for 1 h. The mixture was diluted with water (30 mL) and extracted with dichloromethane (3 × 15 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Welch Xtimate C18 150 × 25 mm × 5

[0565]

[0566] mobile phase: [water (0.225% formic acid) - acetonitrile]; gradient: 23%-53% B over 10 min) and lyophilized to give N-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzyl)-2-(5-(difluoromethyl)pyridin-2-yl)-2-methylpropanamide (89.7 mg, 183 pmol, 53% yield) as a white solid.

[0567] ’H NMR (400 MHz, DMSO-6) d = 10.58 (s, 1H), 8.77 (s, 1H), 8.10 (t, J= 6.0 Hz, 1H), 8.00 (dd, J= 1.2, 8.4 Hz, 1H), 7.57 (d, J= 8.4 Hz, 1H), 7.39 (s, 2H), 7.16 (t, J= 55.2 Hz, 1H), 4.27 (d, J = 6.0 Hz, 2H), 3.60 (t, J = 6.8 Hz, 2H), 2.75 (t, J = 6.8 Hz, 2H), 1.55 (s, 6H). MS (ESI) m / z 485.1 [M+H]+

[0568] Synthesis of Compound 26

[0569]

[0570] Step 1. To a solution of 2-chloropyrimidine-5-carbaldehyde (5.00 g, 35.1 mmol, 1.00 eq.) and 4-methylbenzenesulfonic acid (667 mg, 3.51 mmol, 0.10 eq.) in ethyl alcohol (60 mL) was added tri ethoxy methane (123 mmol, 20.4 mL, 3.50 eq.). The mixture was stirred at 80 °C for 3 h under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was added to saturated sodium bicarbonate solution (30 mL) at 0 °C, and then concentrated under reduced pressure to remove ethyl alcohol. The residue was extracted with ethyl acetate (5 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO ®; 40 g Sepa Flash ® Silica Flash Column, Eluent of 0~6% ethyl acetate / petroleum ether gradient @ 40 mL / min) to give 2-chloro-5-(diethoxymethyl) pyrimidine (7.29 g, 32.0 mmol, 91% yield) as a colourless oil.

[0571] Step 2. To a solution of 2-chloro-5-(diethoxymethyl) pyrimidine (7.28 g, 33.6 mmol, 1.00 eq.) in dimethyl sulfoxide (30 mL) was added caesium carbonate (27.4 g, 84.0 mmol, 2.50 eq.) in one portion at 20 °C. Then tert-butyl methyl malonate (33.6 mmol, 5.68 mL, 1.00 eq.) was added dropwise to the mixture. The mixture was stirred at 90 °C for 12 h. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with water (2 x 30 mL) and brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO ®; 120 g Sepa Flash ® Silica Flash Column, Eluent of 0-25% ethyl acetate / petroleum ether gradient @ 150 mL / min) to give 1 -(tert-butyl) 3-methyl 2-(5-(diethoxymethyl) pyrimidin-2-yl) malonate (8.35 g, 19.8 mmol, 59% yield) as a yellow oil.

[0572] Step 3. To a solution of 1 -(tert-butyl) 3-methyl 2-(5-(diethoxymethyl)pyrimidin-2-yl)malonate (4.00 g, 11.3 mmol, 1.00 eq.) in methanol (10 mL) and water (5 mL) was added sodium hydroxide (903 mg, 22.6 mmol, 2.00 eq.) at 20 °C. The mixture was stirred at 20 °C for 2 h. The pH of the mixture was adjusted to 6 with 2M hydrochloric acid. The mixture was extracted with ethyl acetate (4 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO ®; 40 g Sepa Flash ® Silica Flash Column, Eluent of 0-25% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give tert-butyl 2-(5-(diethoxymethyl) pyrimidin-2-yl) acetate (1.67 g, 4.51 mmol, 40% yield) as a yellow oil.

[0573] Step 4. To a solution of tert-butyl 2-(5-(diethoxymethyl)pyrimidin-2-yl)acetate (1.66 g, 5.60 mmol, 1.00 eq.) in tetrahydrofuran (15 mL) was added sodium hydride (672 mg, 16.8 mmol, 60% purity, 3.00 eq.) at 0 °C under nitrogen atmosphere. After addition, the mixture was stirred at 20 °C for 30 min. Then methyl iodide (22.4 mmol, 1.39 mL, 4.00 eq.) was added dropwise at 0 °C. The resulting mixture was stirred at 20 °C for 1 h. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL) at 0 °C and diluted with ethyl acetate (20 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO ®; 20 g Sepa Flash ® Silica Flash Column, Eluent of 0-25% ethyl acetate / petroleum ether gradient @ 80 mL / min) to give tert-butyl 2-(5-(diethoxymethyl)pyrimidin-2-yl)-2-methylpropanoate (1.08 g, 3.23 mmol, 58% yield) as a colourless oil.

[0574] Step 5. To a solution of tert-butyl 2-(5-(diethoxymethyl)pyrimidin-2-yl)-2-methylpropanoate (1.08 g, 3.33 mmol, 1.00 eq.) in tetrahydrofuran (5 mL) was added hydrochloric acid (1 M, 5 mL). The mixture was stirred at 40 °C for 16 h. The mixture was extracted with ethyl acetate (4 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO ®; 12 g Sepa Flash ® Silica Flash Column, Eluent of 0-25% ethyl acetate / petroleum ether gradient @ 50 mL / min) to give tert-butyl 2-(5-formylpyrimidin-2-yl)-2-methylpropanoate (760 mg, 2.37 mmol, 71% yield) as a yellow oil.

[0575] Step 6. To a solution of tert-butyl 2-(5-formylpyrimidin-2-yl)-2-methylpropanoate (850 mg, 3.40 mmol, 1.00 eq.) in di chloromethane (10 mL) was added 1,1,1-trifluoro-N,N-bis(2-methoxyethyl)-λ4-sulfanamine (6.79 mmol, 1.49 mL, 2.00 eq.) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched by saturated sodium bicarbonate (15 mL) at 20 °C and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO ®; 12 g Sepa Flash ® Silica Flash Column, Eluent of 0-25% ethyl acetate / petroleum ether gradient @ 50 mL / min) to give tert-butyl 2-(5-(difluorom ethyl) pyrimidin-2-yl)-2-methylpropanoate (660 mg, 2.38 mmol, 70% yield) as a colourless oil.

[0576] Step 7. To a solution of tert-butyl 2-(5-(difluoromethyl)pyrimidin-2-yl)-2-methylpropanoate (200 mg, 735 μmol, 1.00 eq.) in dichloromethane (2.5 mL) was added trifluoroacetic acid (0.5 mL) at 20 °C. The reaction was stirred at 20 °C for 14 h. The mixture was concentrated under reduced pressure, then diluted with di chloromethane (10 mL) and washed with saturated sodium bicarbonate (2 x 10 mL). The pH of the combined aqueous layers was adjusted to 5 with 2M hydrochloric acid, then it was extracted with dichloromethane (3 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 2- (5-(difluoromethyl)pyrimidin-2-yl)-2-methylpropanoic acid (98.0 mg, 431 μmol, 59% yield) as a colourless oil.

[0577] Step 8. To a solution of 2-(5-(difluoromethyl) pyrimidin-2-yl)-2-methylpropanoic acid (125 mg, 405 / / mol, 1.00 eq.) in dimethylformamide (3 mL) were added N,N-diisopropylethylamine (1.21 mmol, 212 μL, 3.00 eq.) and 2-chloro-l-methyl-pyridin-l-ium iodide (124 mg, 486 / / mol, 1.20 eq.). After addition, the mixture was stirred at 20 °C for 30 min, and then 1-(4-(aminomethyl)-2,6-dichlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (118 mg, 364 μmol, 0.90 eq.) was added. The resulting mixture was stirred at 20 °C for 1 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with water (2 x 10 mL) and brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC [column: YMC - Actus Triart C18 150 * 30 mm * 7 μm; mobile phase: [water (formic acid) - acetonitrile]; gradient: 30% - 60% B over 10 min). The desired fraction was collected and lyophilized to give N-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzyl)-2-(5-(difluoromethyl)pyrimidin-2-yl)-2-methylpropanamide (93.93 mg, 191 μmol, 47% yield) as a white solid.

[0578] ’H NMR (400 MHz, DMSO-t / ,) d = 10.60 (s, 1H), 9.04 (s, 2H), 8.20 - 8.17 (t, J= 6.0 Hz, 1H), 7.48 (s, 2H), 7.24 (t, J= 54.4 Hz, 1H), 4.30 - 4.29 (d, J= 6.0 Hz, 2H), 3.63 - 3.60 (t, J= 6.8 Hz, 2H), 2.77 - 2.74 (t, J= 6.8 Hz, 2H), 1.58 (s, 6H). MS (ESI) m / z 486.1 [M+H]+ Synthesis of Compound 27

[0579]

[0580] Step 1. To a solution of tert-butyl methyl malonate (2.30 g, 13.2 mmol, 1.21 eq.) in dimethylformamide (50 mL) was added sodium hydride (900 mg, 22.5 mmol, 60% purity, 2.05 eq.) in portions at 0 °C under nitrogen atmosphere. The mixture was stirred at 20 °C for 30 min. The 2-chloro-5-(trifluoromethyl)pyrimidine (2.00 g, 10.9 mmol, 1.00 eq.) was added to the mixture, and it was stirred at 50 °C for 15.5 h. The reaction was quenched with ice water (100 mL) at 0 °C and diluted with ethyl acetate (100 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-20% ethyl acetate / petroleum ether) to give l-(tert-butyl) 3-methyl 2-(5-(trifluoromethyl)pyrimidin-2-yl)malonate (2.00 g, 5.62 mmol, 51% yield) as a yellow oil.

[0581] Step 2. To a solution of 1 -(tert-butyl) 3-methyl 2-(5-(trifluoromethyl)pyrimidin-2-yl)malonate (1.00 g, 3.12 mmol, 1.00 eq.) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-30% ethyl acetate / petroleum ether) to give methyl 2-(5-(trifluoromethyl)pyrimidin-2-yl)acetate trifluoroacetate (280 mg, 804 μmol, 25% yield) as a yellow oil.

[0582] Step 3. To a solution of methyl 2-(5-(trifluoromethyl)pyrimidin-2-yl)acetate trifluoroacetate (280 mg, 838 μmol, 1.00 eq.) in dimethylformamide (5 mL) was added sodium hydride (200 mg, 5.00 mmol, 60% purity, 5.97 eq.) at 0 °C under the nitrogen atmosphere. The mixture was stirred at 20 °C for 30 min. The iodomethane (250 μL, 4.02 mmol, 4.79 eq.) was added, and the mixture was stirred at 20 °C for 30 min. The reaction mixture was added dropwise to water (20 mL) at 0 °C. Then the mixture was diluted with ethyl acetate (20 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-20% ethyl acetate / petroleum ether gradient) to give methyl 2-methyl-2-(5-(trifluoromethyl)pyrimidin-2-yl)propanoate (260 mg, crude) as a yellow oil.

[0583] Step 4. To a solution of methyl 2-methyl-2-(5-(trifluoromethyl)pyrimidin-2-yl)propanoate (260 mg, 1.05 mmol, 1.00 eq.) in methanol (3 mL) was added a solution of sodium hydroxide (200 mg, 5.00 mmol, 4.77 eq.) dissolved in water (0.5 mL). The mixture was stirred at 20 °C for 3 h. The mixture was diluted with water (10 mL) and ethyl acetate (10 mL). The aqueous phase was separated and washed with ethyl acetate (10 mL). The aqueous phase was adjusted to pH = 3-4 with hydrochloric acid (1 M) and extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were washed with brine (20 mL) and dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 2-methyl-2-(5-(trifluoromethyl)pyrimidin-2-yl)propanoic acid (160 mg, 410 μmol, 39% yield) as a white solid.

[0584] Step 5. To a solution of 2-methyl-2-(5-(trifluoromethyl)pyrimidin-2-yl)propanoic acid (160 mg, 683 pmol, 2.20 eq.) in dimethylformamide (4 mL) was added N,N-diisopropylethylamine (160 μL, 2.07 mmol, 2.98 eq.) and 2-chloro-1-methyl-pyridin-1-ium iodide (110 mg, 430 μmol, 1.40 eq.). The mixture was stirred at 20 °C for 0.5 h. Then 1-(4-(aminomethyl)-2,6-dichlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (100 mg, 308 μmol, 1.00 eq.) was added to the mixture and the mixture was stirred at 20 °C for 3.5 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: C18 150 × 30mm; mobile phase: [water (formic acid) - acetonitrile]; gradient: 38%-68% B over 7 min) and lyophilized to give N-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzyl)-2-methyl-2-(5-(trifluoromethyl)-pyrimidin-2-yl)propanamide (101.8 mg, 193 μmol, 63% yield) as a white solid.

[0585] ’H NMR (400 MHz, DMSO-d₆) δ = 10.61 (s, 1H), 9.26 (s, 2H), 8.17 (t, J= 6.0 Hz, 1H), 7.43 (s, 2H), 4.29 (d, J= 6.0 Hz, 2H), 3.61 (t, J= 6.8 Hz, 2H), 2.75 (t, J= 6.8 Hz, 2H), 1.60 (s, 6H). MS (ESI) m / z 504.1 [M+H]+

[0586] Synthesis of Compound 31

[0587]

[0588] Step 1. To a solution of 4-bromopyridine (5.00 g, 31.7 mmol, 1.00 eq.) in dichloromethane (50 mL) was added 3-chlorobenzoperoxoic acid (10.9 g, 53.8 mmol, 85% purity, 1.70 eq.) at 0 °C. The mixture was stirred at 25 °C for 12 h. The mixture was concentrated in vacuo. The crude product was purified by flash silica gel chromatography (ISCO®; 120 g Sepa Flash®Silica Flash Column, Eluent of 20-25% Methanol / Dichloromethane @ 50 mL / min) to give a crude product. The crude product was triturated with ethyl acetate (40 mL) at 25 °C for 30 min. The mixture was filtered, and the solid was collected and dried in vacuo to give 4-bromopyridine 1 -oxide (3.80 g, 20.8 mmol, 65% yield) as a white solid.

[0589] Step 2. To a solution of 4-bromopyridine 1-oxide (1.00 g, 5.75 mmol, 1.00 eq.) in tetrahydrofuran (10 mL) was added N,N-diisopropylethylamine (3.00 mL, 17.2 mmol, 3.00 eq.), ((l-methoxy-2-methylprop-l-en-l-yl)oxy)trimethylsilane (3.01 g, 17.3 mmol, 3.00 eq.) and bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (2.95 g, 6.33 mmol, 1.10 eq.). The mixture was stirred at 25 °C for 36 h under nitrogen atmosphere. (The reaction was carried out in 4 batches.) The reaction mixture was diluted with water (40 mL) then the mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (ISCO®; 40 g Sepa Flash® Silica Flash Column, Eluent of 5-10% Ethyl acetate / Petroleum ether gradient @ 45 mL / min) to give methyl 2-(4-bromopyridin-2-yl)-2-methylpropanoate (4.13 g, 15.2 mmol, 66% yield) as a yellow oil.

[0590] Step 3. To a solution of methyl 2-(4-bromopyridin-2-yl)-2-methylpropanoate (4.13 g, 16.0 mmol, 1.00 eq.) in dioxane (50 mL) were added caesium carbonate (11.0 g, 33.8 mmol, 2.11 eq.), tertbutyl carbamate (2.30 g, 19.6 mmol, 1.23 eq.) and (9,9-dimethyl-9Z7-xanthene-4,5-diyl)bis(di-tert-butylphosphine) (1.85 g, 3.20 mmol, 0.20 eq.). Then tris(dibenzylideneacetone)dipalladium (1.47 g, 1.60 mmol, 0.10 eq.) was added under nitrogen atmosphere. The mixture was stirred at 100 °C for 12 h under nitrogen atmosphere. The resulting mixture was filtered, and the filtrate was diluted with water (50 mL), then the mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (ISCO®; 40 g Sepa Flash®Silica Flash Column, Eluent of 20-30% Ethyl acetate / Petroleum ether gradient @ 45 mL / min) to give methyl 2-(4-((tert-butoxycarbonyl)amino)pyridin-2-yl)-2-methylpropanoate (3.49 g, 10.6 mmol, 66% yield) as a brown oil.

[0591] Step 4. A mixture of methyl 2-(4-((tert-butoxycarbonyl)amino)pyridin-2-yl)-2-methylpropanoate (500 mg, 1.70 mmol, 1.00 eq.) in hydrochloric acid (10 mL, 6 M) was stirred at 60 °C for 4 h. The mixture was concentrated under reduced pressure to give 2-(4-aminopyridin-2-yl)-2-methylpropanoic acid hydrochloride (345 mg, 1.54 mmol, 90% yield) as a yellow solid.

[0592] Step 5. To a solution of 2-(4-aminopyridin-2-yl)-2-methylpropanoic acid hydrochloride (220 mg, 1.02 mmol, 0.98 eq.) in 7V,7V-di methylformamide (4 mL) were added N,N-diisopropylethylamine (720 μL, 4.13 mmol, 4.03 eq.) and 2-chloro-1-methylpyridin-1-ium iodide (315 mg, 1.23 mmol, 1.20 eq.) at 0 °C. The mixture was stirred at 25 °C for 0.5 h. Then 1-(4-(aminomethyl)-2,6-dichlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (300 mg, 924 μmol, 0.90 eq.) was added, the resulting mixture was stirred at 25 °C for 1 h. The resulting mixture was filtered, and the filtrate concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Welch Xtimate C18 150 × 25mm × 5μm; mobile phase: [water (formic acid) - acetonitrile]; gradient: 1% - 28% B over 10 min) and lyophilized to give 2-(4-aminopyridin-2-yl)-N-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzyl)-2-methylpropanamide (215 mg, 473 μmol, 46% yield) as a white solid.

[0593] Step 6. A mixture of 2-(4-aminopyridin-2-yl)-N-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzyl)-2-methylpropanamide (95.0 mg, 211 μmol, 1.00 eq.) in tetrafluoroboric acid (2 mL, 40% in water) was stirred at 0 °C for 0.5 h. Then sodium nitrite (29.0 mg, 420 μmol, 1.99 eq.) was added, the resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into water (20 ml) at 0 °C. The mixture was adjusted to pH = 5 with saturated sodium bicarbonate, and it was extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Welch Xtimate C18 150 × 25mm × 5μm; mobile phase: [water (formic acid) - acetonitrile]; gradient: 20% - 50% B over 10 min) and lyophilized to give 7V-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-l(27 / )-yl)benzyl)-2-(4-fluoropyridin-2-yl)-2-methylpropanamide (48.6 mg, 104 pmol, 49% yield) as a white solid.

[0594] 'H NMR (400 MHz, DMSO-6) 8 = 10.58 (s, 1H), 8.60 (dd, J= 6.0, 9.6 Hz, 1H), 8.07 (t, J= 6.0 Hz, 1H), 7.40 (s, 2H), 7.31 (dd, J= 2.4, 10.8 Hz, 1H), 7.23 (ddd, J= 2.4, 6.0, 8.8 Hz, 1H), 4.27 (d, J = 6.0 Hz, 2H), 3.61 - 3.58 (m, 2H), 2.75 (t, J = 6.8 Hz, 2H), 1.52 (s, 6H). MS (ESI) m / z 453.2 [M+H]+ Synthesis of Compound 33

[0595]

[0596] Step 1. To a mixture of ethyl 2-(5-bromopyrimidin-2-yl)acetate (1.00 g, 4.08 mmol, 1.00 eq.) in dimethylformamide (20 mL) was added sodium hydride (489 mg, 12.2 mmol, 60% purity, 3.00 eq.) in portions at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then iodomethane (1.74 g, 12.2 mmol, 3.00 eq.) was added and the mixture was stirred at 20 °C for 1 h. The reaction was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give ethyl 2-(5-bromopyrimidin-2-yl)-2-methylpropanoate (1.18 g, 3.93 mmol, 96% yield) as a yellow oil.

[0597] Step 2. To a mixture of ethyl 2-(5-bromopyrimidin-2-yl)-2-methylpropanoate (2.00 g, 7.32 mmol, 1.00 eq.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.79 g, 10.9 mmol, 1.50 eq.), potassium acetate (2.16 g, 21.9 mmol, 3.00 eq.) in dioxane (32 mL) was added [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (535 mg, 732 μmol, 0.10 eq.) in one portion at 25 °C. The mixture was stirred at 100 °C under nitrogen atmosphere for 12 h. The mixture was cooled to 25 °C, then poured into water (50 mL). The mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-30% ethyl acetate / petroleum ether) to give ethyl 2-methyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)propanoate (2.20 g, 6.60 mmol, 90% yield) as a white solid. Step 3. To a solution of ethyl 2-methyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)propanoate (2.20 g, 6.87 mmol, 1.00 eq.) in dichloromethane (30 mL) was added hydrogen peroxide (4.91 g, 43.3 mmol, 30% purity, 6.30 eq.) dropwise at 0 °C over 0.5 h. The mixture was stirred at 25 °C for 12 h. A saturated sodium sulfite solution (100 mL) was added to this reaction solution and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-30% ethyl acetate / petroleum ether) to give ethyl 2-(5-hydroxypyrimidin-2-yl)-2-methylpropanoate (1.40 g, 6.53 mmol, 94% yield) as a white solid.

[0598] Step 4. To a solution of ethyl 2-(5-hydroxypyrimidin-2-yl)-2-methylpropanoate (300 mg, 1.43 mmol, 1.00 eq.) and caesium carbonate (1.39 g, 4.28 mmol, 3.00 eq.) in dimethylformamide (5 mL) was added methyl iodide (303 mg, 2.14 mmol, 1.50 eq.) dropwise at 20 °C. The mixture was stirred at 50 °C for 12 h. The mixture was cooled to 25 °C, then poured into water (20 mL). The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give ethyl 2-(5-methoxypyrimidin-2-yl)-2-methylpropanoate (200 mg, 874 μmol, 61% yield) as a yellow oil.

[0599] Step 5. To a mixture of ethyl 2-(5-methoxypyrimidin-2-yl)-2-methylpropanoate (200 mg, 891 μmol, 1.00 eq.) in methanol (1 mL) and water (1 mL) was added sodium hydroxide (178 mg, 4.46 mmol, 5.00 eq.) in portions at 20 °C. The mixture was stirred at 20 °C for 12 h. The mixture was poured into water (20 mL) and adjusted to pH = 2 with 36% aqueous hydrochloric acid, then extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-(5-methoxypyrimidin-2-yl)-2-methylpropanoic acid (160 mg, 807 μmol, 90% yield) as a colourless oil.

[0600] Step 6. To a mixture of 2-(5-methoxypyrimidin-2-yl)-2-methylpropanoic acid (80.0 mg, 407 μmol, 1.00 eq.) and 2-chloro-1-methyl-pyridin-1-ium iodide (125 mg, 489 μmol, 1.20 eq.) in dimethylformamide (2 mL) was added diisopropylethylamine (210 mg, 1.63 mmol, 4.00 eq.) dropwise at 25 °C. The mixture was stirred at 25 °C for 0.5 h, then l-(4-(aminomethyl)-2,6- dichlorophenyl)dihydropyrimidine-2,4( / 7 / ,37 / )-dione hydrochloride (117 mg, 407 / / mol, 1.00 eq.) was added and the reaction was stirred at 25 °C for 12 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: YMC-Actus Triart C18 150 mm × 30 mm × 7 / m; mobile phase: [water (formic acid) -acetonitrile]; gradient: 28%-58% B over 10 min) then lyophilized to give 7V-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-l(2J7)-yl)benzyl)-2-(5-methoxypyrimidin-2-yl)-2-methylpropanamide (61.4 mg, 130 pmol, 32% yield) as a white solid.

[0601] ’H NMR (400 MHz, DMSO ) d = 10.60 (s, 1H), 8.53 (s, 2H), 8.03 (t, J= 6.0 Hz, 1H), 7.45 (s, 2H), 4.27 (d, J= 6.0 Hz, 2H), 3.90 (s, 3H), 3.61 (t, J= 6.8 Hz, 2H), 2.75 (t, J= 6.8 Hz, 2H), 1.53 (s, 6H). MS (ESI) m / z 466.1 [M+H]+

[0602] Synthesis of Compound 34

[0603]

[0604] Step 1. To a suspension of sodium hydride (2.13 g, 53.3 mmol, 60% purity, 2.01 eq.) in N,N-dimethylformamide (30 mL) was added tert-butyl ethyl malonate (10.0 mL, 53.0 mmol, 2.00 eq.) at 0 °C under nitrogen atmosphere. The mixture was stirred at 20 °C for 3 h under nitrogen atmosphere. Then 6-chloro-2-methoxy-3-nitropyridine (5.00 g, 26.5 mmol, 1.00 eq.) in N, N-dimethylformamide (20 mL) was added at 20 °C under nitrogen atmosphere. The mixture was stirred at 20 °C for 3 h under nitrogen atmosphere. The mixture was quenched with saturated aqueous ammonium chloride (100 mL) at 0 °C and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 6~6% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to afford 1 -(tert-butyl) 3-ethyl 2-(6-methoxy-5-nitropyridin-2-yl)malonate (7.40 g, 21.5 mmol, 81% yield) as a yellow oil.

[0605] Step 2. To a solution of 1 -(tert-butyl) 3-ethyl 2-(6-methoxy-5-nitropyridin-2-yl)malonate (7.40 g, 21.7 mmol, 1.00 eq.) in di chloromethane (50 mL) was added 2,2,2-trifluoroacetic acid (10 mL). The mixture was stirred at 20 °C for 12 h. The mixture was diluted with water (80 mL) and extracted with di chloromethane (2 x 60 mL). The combined organic layers were washed with brine (80 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 12~16% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to afford ethyl 2-(6-methoxy-5-nitropyridin-2-yl)acetate (5.25 g, 21.4 mmol, 98% yield) as a yellow oil.

[0606] Step 3. To a suspension of ethyl 2-(6-methoxy-5-nitropyridin-2-yl)acetate (3.20 g, 13.3 mmol, 1.00 eq.) and caesium carbonate (21.7 g, 66.6 mmol, 5.00 eq.) in acetonitrile (50 mL) was added iodomethane (7.68 mL, 123 mmol, 9.26 eq.). The mixture was stirred at 40 °C for 3 h under nitrogen atmosphere. The resulting precipitate was filtered and washed with ethyl acetate (80 mL). The filtrate was diluted with water (100 mL). The mixture was extracted with ethyl acetate (2 x 70 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford ethyl 2-(6-methoxy-5-nitropyridin-2-yl)-2-methylpropanoate (3.60 g, 13.0 mmol, 98% yield) as a yellow oil.

[0607] Step 4. A solution of ethyl 2-(6-methoxy-5-nitropyridin-2-yl)-2-methylpropanoate (4.90 g, 18.3 mmol, 1.00 eq.) in hydrogen bromide / acetic acid (50 mL) was stirred at 100 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (50 mL) and adjusted to pH = 6 with 1 M sodium hydroxide at 0 °C. The mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (250 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford ethyl 2-(6-hydroxy-5-nitropyri din-2 -yl)-2-methylpropanoate (4.90 g, 17.4 mmol, 95% yield) as a yellow oil. Step 5. To a solution of ethyl 2-(6-hydroxy-5-nitropyridin-2-yl)-2-methylpropanoate (4.90 g, 19.3 mmol, 1.00 eq.) in ethanol (50 mL) and water (50 mL) were added ammonium chloride (5.15 g, 96.2 mmol, 4.99 eq.) and ferrous powder (5.35 g, 95.8 mmol, 4.97 eq.). The mixture was stirred at 80 °C for 1 h. The mixture was filtered, and the filter cake was washed with methanol (50 mL), di chloromethane (40 mL), ethyl acetate (50 mL) and ethanol (50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 65-90% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford ethyl 2-(5-amino-6-hydroxypyri din-2 -yl)-2-methylpropanoate (2.70 g, 11.1 mmol, 58% yield) as a yellow solid.

[0608] Step 6. To a solution of ethyl 2-(5-amino-6-hydroxypyridin-2-yl)-2-methylpropanoate (1.00 g, 4.46 mmol, 1.00 eq.) in methanol (12 mL) was added sodium hydroxide (900 mg, 22.5 mmol, 5.05 eq.) in water (12 mL). The mixture was stirred at 60 °C for 1 h. The mixture was diluted with water (10 mL). The mixture was adjusted to pH = 7 with 1 M hydrochloric acid at 0 °C. The reaction mixture was concentrated under reduced pressure to remove methanol. The mixture was lyophilized to afford 2-(5-amino-6-hydroxypyridin-2-yl)-2-methylpropanoic acid (1.81 g, 4.15 mmol, 93% yield, 45% purity) as a brown solid.

[0609] Step 7. To a solution of 2-(5-amino-6-hydroxypyridin-2-yl)-2-methylpropanoic acid (540 mg, 1.24 mmol, 45% purity, 1.03 eq.) in N,N-dimethylformamide (10 mL) were added N, N-diisopropylethylamine (1.00 mL, 5.74 mmol, 4.79 eq.), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (280 mg, 1.46 mmol, 1.22 eq.) and 1H-benzo[d][1,2,3]triazol-1-ol (210 mg, 1.55 mmol, 1.30 eq.) at 0 °C. The mixture was stirred at 25 °C for 1 h. Then l-(4-(aminomethyl)-2,6-dichlorophenyl)dihydropyrimidine-2, 4(1 / 7, 3J7)-di one hydrochloride (350 mg, 1.08 mmol, 0.90 eq.) was added at 25 °C. The mixture was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure, and the residue was diluted with N, N-dimethylformamide (4 mL) and water (2 mL). The mixture was filtered, and the filtrate was purified by Prep-HPLC (column: Welch Xtimate C18 150 × 25 mm × 5 μm; mobile phase: [water (formic acid) - acetonitrile]; gradient: 5%-35% B over 10 min) and lyophilized to afford 2-(5-amino-6-hydroxypyridin-2-yl)-7V-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-l(2 / 7)-yl)benzyl)-2-methylpropanamide (290 mg, 616 pmol, 51% yield) as a brown solid.

[0610] Step 8. To a solution of 2-(5-amino-6-hydroxypyridin-2-yl)-7V-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-l(2 / 7)-yl)benzyl)-2-methylpropanamide (230 mg, 493 pmol, 1.00 eq.) in trimethoxymethane (23 mL) was added 4-methylbenzenesulfonic acid hydrate (11.0 mg, 57.8 pmol, 0.10 eq.). The mixture was stirred at 120 °C for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: [water (ammonium hydrogen carbonate) - acetonitrile]; gradient: 12%-42% B over 15 min) and lyophilized to afford 7V-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-l(2J7)-yl)benzyl)-2-methyl-2-(oxazolo[5,4-b]pyridin-5-yl)propanamide (95.8 mg, 199 pmol, 40% yield) as a yellow solid.

[0611] ’H NMR (400 MHz, DMSO-6) d = 10.59 (s, 1H), 8.89 (s, 1H), 8.26 (d, J= 8.0 Hz, 1H), 8.07 (t, J = 6.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.28 (s, 2H), 4.25 (d, J = 6.0 Hz, 2H), 3.59 (t, J= 6.8 Hz, 2H), 2.74 (t, J= 6.8 Hz, 2H), 1.60 (s, 6H). MS (ESI) m / z 476.2 [M+H]+

[0612] Synthesis of Compound 36

[0613]

[0614] Step 1. To a solution of 2-methylbenzo[d]oxazole (2.00 g, 15.0 mmol, 1.79 mL, 1.00 eq.) in tetrahydrofuran (30 mL) was added dropwise lithium diisopropylamide (2.0 M in tetrahydrofuran and w-heptane, 11.27 mL, 1.50 eq.) at -60 °C under nitrogen atmosphere. The mixture was stirred at -60 °C for 0.5 h under nitrogen atmosphere. Then methyl carbonochloridate (26.0 mmol, 2.01 mL, 1.73 eq.) was added at -60 °C under nitrogen atmosphere. The mixture was stirred at 20 °C for 2 h under nitrogen atmosphere. The mixture was quenched with saturated ammonium chloride (50 mL) at 0 °C under nitrogen atmosphere. The mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 12-12% ethyl acetate / petroleum ether gradient @ 30 mL / min) to give methyl 2-(benzo[d]oxazol-2-yl)acetate (650 mg, 3.23 mmol, 22% yield) as a yellow oil.

[0615] Step 2. To a solution of methyl 2-(benzo[d]oxazol-2-yl)acetate (450 mg, 2.35 mmol, 1.00 eq.) in tetrahydrofuran (10 mL) were added potassium 2-methylpropan-2-olate (1.32 g, 11.8 mmol, 5.01 eq.) and iodomethane (23.5 mmol, 1.47 mL, 10.0 eq.). The mixture was stirred at 25 °C for 40 h. The mixture was filtered, and the filter cake was washed with di chloromethane (15 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 5-8% ethyl acetate / petroleum ether gradient @ 36 mL / min) to give methyl 2-(benzo[t / ]oxazol-2-yl)-2-methylpropanoate (280 mg, 1.26 mmol, 54% yield) as a light-yellow oil.

[0616] Step 3. To a solution of methyl 2-(benzo[d]oxazol-2-yl)-2-methylpropanoate (280 mg, 1.28 mmol, 1.00 eq.) in methanol (2 mL) was added a solution of sodium hydroxide (511 mg, 12.8 mmol, 10.0 eq.) in water (2 mL). The mixture was stirred at 25 °C for 1 h. The mixture was diluted with water (20 mL) and adjusted to pH = 8 with 2 M hydrochloric acid. The mixture was concentrated under reduced pressure to remove methanol, then it was lyophilized to give 2-(benzo[d]oxazol-2-yl)-2-methylpropanoic acid (900 mg, 1.27 mmol, 99% yield, 29% purity, contains sodium chloride) as a light yellow solid.

[0617] Step 4. To a solution of 2-(benzo[d]oxazol-2-yl)-2-methylpropanoic acid (230 mg, 325 pmol, 29% purity, 1.00 eq.) in N,N-dimethylformamide (2 mL) were added N,N-diisopropylethylamine (1.72 mmol, 300 pL, 5.30 eq.) and 2-chloro-l-methyl-pyridin-l-ium iodide (100 mg, 391 pmol, 1.20 eq.) at 0 °C. The mixture was stirred at 25 °C for 0.5 h. Then l-(4-(aminomethyl)-2,6-dichlorophenyl)dihydropyrimidine-2, 4(17 / , 3 / / (-dione hydrochloride (100 mg, 308 pmol, 0.95 eq.) was added, and the resulting mixture was stirred at 25 °C for 1 h. The mixture was diluted with water (30 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by Prep-HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase:

[0618] [water - acetonitrile]; gradient: 28%-58% B over 9 min) and lyophilized to give 2-(benzo[d]oxazol- 2-yl)-7V-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-l(2rt)-yl)benzyl)-2-methyl-propanamide (58.4 mg, 122 pmol, 37% yield) as an off-white solid.

[0619] ’H NMR (400 MHz, DMSO-6) d = 10.60 (s, 1H), 8.52 (t, J = 6.0 Hz, 1H), 7.78 - 7.73 (m, 1H), 7.73 - 7.68 (m, 1H), 7.42 (s, 2H), 7.42 - 7.35 (m, 2H), 4.31 (d, J= 6.0 Hz, 2H), 3.60 (t, J= 6.8 Hz, 2H), 2.75 (t, J= 6.8 Hz, 2H), 1.68 (s, 6H). MS (ESI) m / z 475.1 [M+H]+

[0620] Synthesis of Compound 39

[0621]

[0622] Step 1. To a solution of 5-bromo-2-chloro-4-methylpyrimidine (5.00 g, 24.1 mmol, 1.00 eq.) in dimethylsulfoxide (150 mL) were added caesium carbonate (15.0 g, 46.0 mmol, 1.91 eq.) and tertbutyl methyl malonate (6.25 mL, 36.9 mmol, 1.53 eq.). The mixture was stirred at 80 °C for 3 h. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic extracts were washed with brine (400 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0~10% ethyl acetate / petroleum ether) to afford 1-(tert-butyl) 3-methyl 2-(5-bromo-4-methylpyrimidin-2-yl)malonate (4.00 g, 5.79 mmol, 24% yield) as a yellow oil. Step 2. A solution of 1 -(tert-butyl) 3-methyl 2-(5-bromo-4-methylpyrimidin-2-yl)malonate (3.50 g, 5.07 mmol, 1.00 eq.) in di chloromethane (30 mL) and trifluoroacetic acid (6 mL) was stirred at 25 °C for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with brine (80 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0~20% ethyl acetate / petroleum ether) to afford methyl 2-(5-bromo-4-methylpyrimidin-2-yl)acetate (1.20 g, 4.41 mmol, 87% yield) as a yellow oil.

[0623] Step 3. To a solution of methyl 2-(5-bromo-4-methylpyrimidin-2-yl)acetate (1.00 g, 4.08 mmol, 1.00 eq.) in tetrahydrofuran (10 mL) was added sodium hydride (650 mg, 16.2 mmol, 60% purity, 3.98 eq.) in portions at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 30 min. The iodomethane (1.00 mL, 16.0 mmol, 3.94 eq.) was added at 0°C, and the mixture was stirred at 0 °C for 1.5 h. The reaction mixture was poured into a saturated ammonium chloride solution (30 mL) at 0°C, then diluted with ethyl acetate (30 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-20% ethyl acetate / petroleum ether) to afford methyl 2-(5-bromo-4-methylpyrimidin-2-yl)-2-methylpropanoate (1.00 g, 3.62 mmol, 88% yield) as a yellow oil.

[0624] Step 4. To a solution of methyl 2-(5-bromo-4-methylpyrimidin-2-yl)-2-methylpropanoate (470 mg, 1.72 mmol, 1.00 eq.) and potassium trifluoro(methoxymethyl)borate (526 mg, 3.46 mmol, 2.01 eq.) in dioxane (8.46 mL) and water (2.82 mL) were added caesium carbonate (1.69 g, 5.19 mmol, 3.02 eq.), palladium(II) acetate (47.0 mg, 209 pmol, 0.12 eq.) and dicyclohexyl(2',6'-diisopropoxy-[l,l'-biphenyl]-2-yl)phosphane (188 mg, 403 pmol, 0.24 eq.) under nitrogen. The mixture was stirred at 100 °C for 12 h under nitrogen. The reaction mixture was filtered, and the filtrate was diluted with water (50 mL). The mixture was extracted with ethyl acetate (2 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 20~20% Ethyl acetate / Petroleum ether gradient @ 84 mL / min) to afford methyl 2-(5-(methoxymethyl)-4-methylpyrimidin-2-yl)-2-methylpropanoate (330 mg, 1.37 mmol, 80% yield) as a colourless oil.

[0625] Step 5. To a solution of methyl 2-(5-(methoxymethyl)-4-methylpyrimidin-2-yl)-2-methylpropanoate (150 mg, 630 pmol, 1.00 eq.) in methanol (5 mL) was added sodium hydroxide (128 mg, 3.20 mmol, 5.08 eq.) in water (1 mL). The mixture was stirred at 25 °C for 60 h. The mixture was diluted with water (40 mL) and adjusted to pH = 8 with 2 M hydrochloric acid at 0 °C. The mixture was concentrated under reduced pressure to remove methanol, then it was lyophilized to afford sodium 2-(5-(methoxymethyl)-4-methylpyrimidin-2-yl)-2-methylpropanoate (340 mg, 550 pmol, 87% yield, 40% purity) as a white solid.

[0626] Step 6. To a suspension of sodium 2-(5-(methoxymethyl)-4-methylpyrimidin-2-yl)-2-methylpropanoate (320 mg, 518 pmol, 40% purity, 1.00 eq.) in

[0627]

[0628] methylformamide (8 mL) were added 2-chloro-l-methylpyridin-l-ium iodide (160 mg, 626 pmol, 1.21 eq.) and 7V-ethyl-7V-isopropylpropan-2-amine (320 pL, 1.84 mmol, 3.55 eq.) at 0 °C. The mixture was stirred at 25 °C for 1 h. Then l-(4-(aminomethyl)-2,6-di chi orophenyl)dihydro-pyrimidine-2, 4(1 / 7, 3J7)-di one hydrochloride (110 mg, 339 pmol, 0.65 eq.) was added at 25 °C. The mixture was stirred at 25 °C for 0.5 h. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Welch Xtimate C18 150 × 25 mm × 5 μm; mobile phase: [water (formic acid) - acetonitrile]; gradient: 20%-50% B over 40 min) and lyophilized to afford 7V-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-l(2J7)-yl)benzyl)-2-(5-(methoxymethyl)-4-methylpyrimidin-2-yl)-2-methylpropanamide (67.0 mg, 134 pmol, 26% yield) as off-white solid.

[0629] ’H NMR (400 MHz, DMSO-6) d = 10.58 (s, 1H), 8.58 (s, 1H), 8.05 (t, J= 6.0 Hz, 1H), 7.45 (s, 2H), 4.47 (s, 2H), 4.28 (d, J = 6.0 Hz, 2H), 3.61 (t, J= 6.8 Hz, 2H), 3.33 (s, 3H), 2.75 (t, J= 6.8 Hz, 2H), 2.47 (s, 3H), 1.53 (s, 6H). MS (ESI) m / z 494.0 [M+H]+

[0630] Synthesis of Compound 40

[0631]

[0632] Step 1. To a solution of 3,6-dichloropyridazine (5.00 g, 33.6 mmol, 1.00 eq.) in dimethyl sulfoxide (30 mL) were added caesium carbonate (32.8 g, 101 mmol, 3.00 eq.) and tert-butyl methyl malonate (8.77 g, 50.3 mmol, 1.50 eq.). The mixture was stirred at 100 °C for 1 h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (2 x 100 mL) and brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0~25% ethyl acetate / petroleum ether) to give 1-(tert-butyl) 3-methyl 2-(6-chloropyridazin-3-yl)malonate (7.93 g, 26.0 mmol, 77% yield) as a yellow solid.

[0633] Step 2. To a solution of 1 -(tert-butyl) 3-methyl 2-(6-chloropyridazin-3-yl)malonate (7.70 g, 26.9 mmol, 1.00 eq.) in dichloromethane (30 mL) was added trifluoroacetic acid (6 mL) in one portion at 25 °C. The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure, then diluted with dichloromethane (20 mL). The mixture was washed with saturated sodium bicarbonate (2 x 20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 2-(6-chloropyridazin-3-yl)acetate (5.16 g, 26.0 mmol, 97% yield) as a yellow solid.

[0634] Step 3. To a solution of methyl 2-(6-chloropyridazin-3-yl) acetate (4.95 g, 26.5 mmol, 1.00 eq.) in acetonitrile (20 mL) were added caesium carbonate (25.9 g, 79.6 mmol, 3.00 eq.) and methyl iodide (16.5 mL, 265 mmol, 10.0 eq.) at 25 °C under nitrogen atmosphere. The mixture was stirred at 25 °C under nitrogen atmosphere for 12 h. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (40 mL). The organic layer was washed with water (2 x 30 mL) and brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0~16% ethyl acetate / petroleum ether) to give methyl 2-(6-chloropyridazin-3-yl)-2-methylpropanoate (3.63 g, 16.2 mmol, 61% yield) as a yellow solid.

[0635] Step 4. To a solution of methyl 2-(6-chloropyridazin-3-yl)-2-methylpropanoate (4.45 g, 20.7 mmol, 1.00 eq.) in acetic acid (35 mL) was added sodium acetate (3.47 g, 42.3 mmol, 2.04 eq.). The mixture was stirred at 100 °C for 4 h under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to remove acetic acid. The residue was diluted with water (100 mL) and adjusted to pH = 10 with IM aqueous sodium hydroxide solution at 0 °C. The mixture was extracted with ethyl acetate (4 x 100 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford methyl 2-(6-hydroxypyridazin-3-yl)-2-methylpropanoate (2.6 g, 13.1 mmol, 63% yield) as a yellow solid.

[0636] Step 5. To a solution of methyl 2-(6-hydroxypyridazin-3-yl)-2-methylpropanoate (500 mg, 2.55 mmol, 1.00 eq.) in A,7V-dimethylformamide (6 mL) was added caesium carbonate (2.49 g, 7.65 mmol, 3.00 eq.) and sodium 2-chloro-2,2-difluoro-acetate (777 mg, 5.10 mmol, 2.00 eq.). The mixture was stirred at 100 °C for 1 h under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-20% ethyl acetate / petroleum ether) to afford methyl 2-(6-(difluoromethoxy)pyridazin-3-yl)-2-methylpropanoate (380 mg, 1.53 mmol, 60% yield) as a yellow oil.

[0637] Step 6. To a solution of methyl 2-(6-(difluoromethoxy)pyridazin-3-yl)-2-methylpropanoate (380 mg, 1.54 mmol, 1.00 eq.) in methanol (3 mL) was added a solution of sodium hydroxide (309 mg, 7.72 mmol, 5.00 eq.) in water (3 mL). The mixture was stirred at 25 °C for 2 h. The reaction mixture was adjusted to pH = 8 with IM hydrochloric acid. Then it was concentrated under reduced pressure to remove methanol and lyophilized to afford sodium 2-(6-(difluoromethoxy)pyridazin- 3-yl)-2-methylpropanoate (850 mg, crude) as a white solid.

[0638] Step 7. To a solution of sodium 2-(6-(difluoromethoxy)pyridazin-3-yl)-2-methylpropanoate (350 mg, 551 pmol, 1.00 eq.) in dimethylformamide (6 mL) was added 2-chloro-l-methyl-pyridin-l-ium iodide (169 mg, 661 pmol, 1.20 eq.) and N,N-diisopropylethylamine (214 mg, 1.65 mmol, 3.00 eq.) at 0 °C. The mixture was stirred at 25 °C for 0.5 h. Then l-(4-(aminomethyl)-2,6-dichlorophenyl)dihydropyrimidine-2, 4(1 / 7, 37 / )-dione hydrochloride (107 mg, 330 pmol, 0.60 eq.) was added. The mixture was stirred at 25 °C for 1.5 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: C18 150 × 30 mm; mobile phase:

[0639] [water (formic acid) - acetonitrile]; gradient: 25%-55% B over 7 min) and lyophilized to afford N-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-l(277)-yl)benzyl)-2-(6- (difluorom ethoxy )pyridazin-3-yl)-2-methylpropanamide (101 mg, 199 pmol, 36% yield) as a white solid. ’H NMR (400 MHz, DMSO-6) d = 10.58 (s, 1H), 8.26 (t, J = 6.0 Hz, 1H), 8.10 - 7.69 (m, 2H), 7.49 (d, J= 9.2 Hz, 1H), 7.34 (s, 2H), 4.27 (d, J= 6.0 Hz, 2H), 3.60 (t, J= 6.8 Hz, 2H), 2.75 (t, J = 6.8 Hz, 2H), 1.61 (s, 6H). MS (ESI) m / z 503.7 [M+H]+

[0640] Synthesis of Compound 42

[0641]

[0642] Step 1. To a solution of 2, 5 -dibromopyrazine (10.0 g, 42.0 mmol, 1.00 eq.) in dimethyl sulfoxide (60 mL) were added caesium carbonate (27.4 g, 84.1 mmol, 2.00 eq.) and tert-butyl methyl malonate (11.0 g, 63.1 mmol, 1.50 eq.). The mixture was stirred at 80 °C for 5 h. The mixture was diluted with water (80 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (2 x 100 mL) and brine (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0~6% ethyl acetate / petroleum ether) to give 1 -(tert-butyl) 3-methyl 2-(5-bromopyrazin-2-yl) malonate (15.0 g, 40.8 mmol, 97% yield) as a yellow oil.

[0643] Step 2. To a solution of 1 -(tert-butyl) 3-methyl 2-(5-bromopyrazin-2-yl)malonate (15.0 g, 45.3 mmol, 1.00 eq.) in di chloromethane (20 mL) was added trifluoroacetic acid (20 mL) in one portion at 25 °C. The mixture was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure and diluted with dichloromethane (40 mL). The mixture was washed with saturated sodium bicarbonate (3 x 40 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 2-(5-bromopyrazin-2-yl) acetate (8.29 g, 34.5 mmol, 76% yield) as a colourless oil. Step 3. To a solution of methyl 2-(5-bromopyrazin-2-yl) acetate (8.29 g, 35.9 mmol, 1.00 eq.) in tetrahydrofuran (60 mL) was added sodium hydride (4.31 g, 108 mmol, 60% purity, 3.00 eq.) at 0 °C under nitrogen atmosphere. After addition, the mixture was stirred at 25 °C for 30 min under nitrogen atmosphere, and then methyl iodide (22.0 mL, 353 mmol, 9.85 eq.) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with saturated ammonium chloride solution (80 mL) at 0 °C and diluted with ethyl acetate (100 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0~8% ethyl acetate / petroleum ether) to give methyl 2-(5-bromopyrazin-2-yl)-2-methylpropanoate (6.76 g, 23.5 mmol, 65% yield) as a yellow oil.

[0644] Step 4. A mixture of methyl 2-(5-bromopyrazin-2-yl)-2-methylpropanoate (6.76 g, 26.1 mmol, 1.00 eq.), [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (955 mg, 1.30 mmol, 0.05 eq.), potassium trifluoro(vinyl)borate (6.99 g, 52.2 mmol, 2.00 eq.), and caesium carbonate (17.0 g, 52.2 mmol, 2.00 eq.) in dioxane (15 mL) and water (15 mL) was degassed and purged with nitrogen 3 times. Then the mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature and filtered through a plug of Celite. The filtrate was diluted with water (50 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0~9% ethyl acetate / petroleum ether) to give methyl 2-methyl-2-(5-vinylpyrazin-2-yl)propanoate (4.78 g, 22.3 mmol, 85% yield) as a colourless oil.

[0645] Step 5. To a solution of methyl 2-methyl-2-(5-vinylpyrazin-2-yl)propanoate (4.78 g, 23.2 mmol, 1.00 eq.) in tetrahydrofuran (100 mL) and water (10 mL) was added osmium(VIII) oxide (1.00 g, 3.93 mmol, 0.17 eq.) in tetrahydrofuran (5 mL) at 0 °C under nitrogen atmosphere. Then a solution of sodium periodate (12.4 g, 57.9 mmol, 2.50 eq.) in water (40 mL) was added to the mixture at 0 °C under nitrogen atmosphere. The mixture was stirred at 25 °C under nitrogen atmosphere for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-12% ethyl acetate / petroleum ether) to give methyl 2-(5-formylpyrazin-2-yl)-2-methylpropanoate (3.69 g, 16.0 mmol, 69% yield) as a yellow oil.

[0646] Step 6. To a solution of methyl 2-(5-formylpyrazin-2-yl)-2-methylpropanoate (500 mg, 2.40 mmol, 1.00 eq.) in dichloromethane (5 mL) was added bis(2-methoxyethyl)aminosulfurtrifluoride (1.58 mL, 7.20 mmol, 3.00 eq.) at 0 °C. The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched by addition of saturated sodium bicarbonate solution (10 mL) at 0 °C, and then diluted with water (50 mL) and extracted with dichloromethane (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-20% ethyl acetate / petroleum ether) to afford methyl 2-(5-(difluoromethyl)pyrazin-2-yl)-2-methylpropanoate (480 mg, 2.00 mmol, 83% yield) as a light-yellow oil.

[0647] Step 7. To a solution of methyl 2-(5-(difluoromethyl)pyrazin-2-yl)-2-methylpropanoate (480 mg, 2.09 mmol, 1.00 eq.) in methanol (10 mL) and water (5 mL) was added sodium hydroxide (167 mg, 4.17 mmol, 2.00 eq.) at 0 °C. The mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with water (20 mL), and then the aqueous phase was adjusted to pH = 8 by addition of IM hydrochloric acid, followed by lyophilization to afford sodium 2-(5-(difluoromethyl)pyrazin-2-yl)-2-methylpropanoate (730 mg, crude) as a white solid.

[0648] Step 8. To a solution of sodium 2-(5-(difluoromethyl)pyrazin-2-yl)-2-methylpropanoate (200 mg, 546 pmol, 1.00 eq.) in dimethylformamide (4 mL) was added 7V-ethyl-7V-isopropylpropan-2-amine (380 pL, 2.18 mmol, 4.00 eq.) and 2-chloro-l-methyl-pyridin-l-ium iodide (167 mg, 655 pmol, 1.20 eq.) at 0 °C. The mixture was stirred at 25 °C for 1 h. Then l-(4-(aminomethyl)-2,6-dichlorophenyl)dihydropyrimidine-2, 4(1 / 7, 37 / )-dione hydrochloride (88.6 mg, 273 pmol, 0.50 eq.) was added to the mixture. The mixture was stirred at 25 °C for 1 h. The reaction was quenched by addition of water (2 mL) at 0 °C, and then diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: YMC-Actus Triart C18 150 × 30 mm × 7 μm; mobile phase:

[0649] [water (formic acid) - acetonitrile]; gradient: 30%-60% B over 10 min) and lyophilized to afford 7V-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-l(277)-yl)benzyl)-2-(5-(difluoromethyl)pyrazin-2-yl)-2-methylpropanamide (109 mg, 221 pmol, 41% yield) as a white solid. ’H NMR (400 MHz, DMSO-6) = 10.60 (s, 1H), 8.92 (s, 1H), 8.87 (d, J= 1.2 Hz, 1H), 8.23 (t, J = 6.0 Hz, 1H), 7.38 (s, 2H), 7.30 - 7.00 (m, 1H), 4.29 (d, J = 6.0 Hz, 2H), 3.61 (t, J = 6.8 Hz, 2H), 2.76 (t, J= 6.8 Hz, 2H), 1.62 (s, 6H). MS (ESI) m / z 486.1 [M+H]+

[0650] Synthesis of Compound 43

[0651]

[0652] Step 1. To a solution of lithium diisopropylamide (2 M in tetrahydrofuran, 20.0 mL, 2.16 eq.) in tetrahydrofuran (15 mL) was added 2, 5 -dimethylpyrazine (2.00 g, 18.5 mmol, 1.00 eq.) in tetrahydrofuran (8 mL) at -65 °C under nitrogen atmosphere. The reaction mixture was stirred at -65 °C for 0.5 h. Then diethyl carbonate (1.95 g, 16.5 mmol, 0.89 eq.) in tetrahydrofuran (8 mL) was added dropwise to the mixture, the reaction mixture was stirred at -65 °C for 2 h. The reaction was quenched with saturated ammonium chloride solution (20 mL) at 0 °C. The reaction mixture was diluted with ethyl acetate (20 mL) and water (10 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 × 15 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (eluent of 0-50% ethyl acetate / petroleum ether) to afford ethyl 2-(5-methylpyrazin-2-yl)acetate (1.14 g, 5.50 mmol, 30% yield) as a yellow oil.

[0653] Step 2. To a solution of ethyl 2-(5-methylpyrazin-2-yl)acetate (1.10 g, 6.10 mmol, 1.00 eq.) in tetrahydrofuran (20 mL) was added sodium hydride (620 mg, 15.5 mmol, 60% purity, 2.54 eq.) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 0.5 h, then methyl iodide (2.00 mL, 32.1 mmol, 5.26 eq.) was added dropwise to the mixture at 0 °C, and the reaction mixture was stirred at 25 °C for 1.5 h. The reaction was quenched by pouring the reaction mixture into saturated ammonium chloride solution (15 mL) at 0 °C. The reaction mixture was diluted with ethyl acetate (15 mL) and water (5 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with brine (25 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (eluent of 0-45% ethyl acetate / petroleum ether) to afford ethyl 2-methyl-2-(5-methylpyrazin-2-yl)propanoate (600 mg, 2.82 mmol, 46% yield) as a yellow oil.

[0654] Step 3. To a solution of ethyl 2-methyl-2-(5-methylpyrazin-2-yl)propanoate (290 mg, 1.39 mmol, 1.00 eq.) in methanol (2 mL) was added sodium hydroxide (280 mg, 7.00 mmol, 5.03 eq.) in water (2 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h, then it was diluted with ethyl acetate (15 mL) and water (10 mL). The layers were separated, and the aqueous phase was acidified to pH=5 with IM hydrochloric acid. The aqueous phase was extracted with ethyl acetate (20 mL). The organic layer was washed with brine (15 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 2-methyl-2-(5-methylpyrazin-2-yl)propanoic acid (130 mg, 714 pmol, 51% yield) as a colourless oil.

[0655] Step 4. To a solution of 2-methyl-2-(5-methylpyrazin-2-yl)propanoic acid (130 mg, 721 pmol, 1.00 eq.) and / V,7V-diisopropylethylamine (280 mg, 2.16 mmol, 3.00 eq.) in dimethylformamide (3 mL) was added 2-chloro-l-methyl-pyridin-l-ium iodide (200 mg, 783 pmol, 1.09 eq.) at 0 °C. The reaction mixture was stirred at 25 °C for 0.5 h. Then l-(4-(aminomethyl)-2,6-dichlorophenyl)dihydropyrimidine-2, 4(1 / 7, 37 / )-dione hydrochloride (150 mg, 462 pmol, 0.64 eq.) was added, and the reaction was stirred at 25 °C for 1.5 h. The reaction mixture was diluted with ethyl acetate (20 mL) and water (10 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (column: YMC-Actus Triart C18 150 × 30mm × 7μm; mobile phase:

[0656] [water (formic acid) - acetonitrile]; gradient:25%-55% B over 10 min) and lyophilized to afford 7V-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-l(277)-yl)benzyl)-2-methyl-2-(5-methylpyrazin-2-yl)propanamide (85.08 mg, 187 pmol, 26% yield) as a white solid. ’H NMR (400 MHz, DMSO- / / 6) d = 10.59 (s, 1H), 8.57 (d, J= 1.6 Hz, 1H), 8.50 (d, J = 0.8 Hz, 1H), 8.11 (s, 1H), 7.36 (s, 2H), 4.26 (d, J = 6.0 Hz, 2H), 3.60 (t, J = 6.8 Hz, 2H), 2.75 (t, J = 6.8 Hz, 2H), 2.49 (s, 3H), 1.56 (s, 6H). MS (ESI) m / z 450.3 [M+H]+

[0657] Synthesis of Compound 48

[0658]

[0659] Step 1. To a mixture of ethyl 2-(5-bromopyrimidin-2-yl)-2-methylpropanoate (2.00 g, 7.32 mmol, 1.00 eq.) and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.60 g, 8.05 mmol, 1.10 eq.) in dioxane (40 mL) and water (10 mL) were added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (268 mg, 366 / / mol, 0.05 eq.) and potassium carbonate (3.04 g, 22.0 mmol, 3.00 eq.) in one portion at 25 °C. The mixture was stirred at 90 °C under nitrogen atmosphere for 12 h. The mixture was poured into water (50 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent of 0-15% ethyl acetate / petr oleum ether gradient @ 20 mL / min) to give ethyl (£)-2-(5-(2-ethoxyvinyl)pyrimidin-2-yl)-2-methylpropanoate (1.97 g, 6.93 mmol, 94% yield) as a light-yellow oil. Step 2. To a solution of ethyl (£)-2-(5-(2-ethoxyvinyl)pyrimidin-2-yl)-2-methylpropanoate (1.97 g, 7.45 mmol, 1.00 eq.) in tetrahydrofuran (120 mL) was added hydrochloric acid (4 M, 40 mL) dropwise at 25 °C. The mixture was stirred at 80 °C under nitrogen atmosphere for 1 h. The mixture was poured into saturated aqueous sodium bicarbonate (50 mL) to adjusted pH = 7-8 and extracted with ethyl acetate (5 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was used into the next step without purification to give ethyl 2-methyl-2-(5-(2-oxoethyl)pyrimidin-2-yl)propanoate (2.20 g, crude) as a light-yellow oil.

[0660] Step 3. To a solution of ethyl 2-methyl-2-(5-(2-oxoethyl)pyrimidin-2-yl)propanoate (2.20 g, 9.31 mmol, 1.00 eq.) in di chloromethane (40 mL) was added l,l,l-trifluoro-7V,7V-bis(2-methoxyethyl)- -sulfanamine (4.12 g, 18.6 mmol, 2.00 eq.) dropwise at 0 °C. The mixture was stirred at 25 °C for 1 h. The mixture was poured into saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (5 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent of 0-25% ethyl acetate / petroleum ether gradient @ 25 mL / min). The residue was purified by Prep-NPLC (column: Welch Ultimate XB-CN 250 mm × 70 mm × 10 μm; mobile phase: [hexane-ethanol]; gradient: 1%-35% B over 15 min) then concentrated under reduced pressure to give ethyl 2-(5-(2,2-difluoroethyl)pyrimidin-2-yl)-2-methylpropanoate (550 mg, 2.13 mmol, 22% yield) as a light yellow oil.

[0661] Step 4. To a solution of ethyl 2-(5-(2,2-difluoroethyl)pyrimidin-2-yl)-2-methylpropanoate (500 mg, 1.94 mmol, 1.00 eq.) in methanol (5 mL) and water (5 mL) was added sodium hydroxide (2 M, 1.94 mL, 2.00 eq.) in one portion at 25 °C. The mixture was stirred at 25 °C for 12 h. The mixture was poured into water (10 mL) and adjusted pH = 7-8 with 2 N hydrochloric acid then lyophilized to give sodium 2-(5-(2,2-difluoroethyl)pyrimidin-2-yl)-2-methylpropanoate (680 mg, crude) as a yellow solid.

[0662] Step 5. To a mixture of sodium 2-(5-(2,2-difluoroethyl)pyrimidin-2-yl)-2-methylpropanoate (250 mg, crude) and 2-chloro-l-methyl-pyridin-l-ium;iodide (152 mg, 595 / / mol, 1.20 eq.) in dimethylformamide (4 mL) was added diisopropylethylamine (256 mg, 1.98 mmol, 4.00 eq.) dropwise at 25 °C. The mixture was stirred at 25 °C for 0.5 h, then l-(4-(aminomethyl)-2,6-dichlorophenyl)dihydropyrimidine-2, 4(1 / 7, 37 / )-dione (145 mg, 446 mol, 0.90 eq., hydrochloride) was added. The mixture was stirred at 25 °C for 1 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: YMC-Actus Triart C18 150 mm × 30 mm × 7 μm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 30%-60% B over 10 min) then lyophilized to give 7V-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-l(2J7)-yl)benzyl)-2-(5-(2, 2-difluoroethyl)pyrimi din-2 -yl)-2-methylpropanamide (46.3 mg, 91.7 / / mol, 18% yield) as a white solid.

[0663] ’H NMR (400 MHz, DMSO ) d = 10.59 (s, 1H), 8.75 (s, 2H), 8.18 (t, J= 6.0 Hz, 1H), 7.51 (s, 2H), 6.52 - 6.14 (m, 1H), 4.30 (d, J = 6.0 Hz, 2H), 3.61 (t, J= 6.8 Hz, 2H), 3.30 - 3.21 (m, 2H), 2.75 (t, J= 6.8 Hz, 2H), 1.55 (s, 6H). MS (ESI) m / z 500.1 [M+H]+

[0664] Synthesis of Compound 50

[0665]

[0666] (methyl sulfmyl)methane (30 mL) was added tert-butyl methyl malonate (4.39 g, 25.2 mmol, 1.20 eq.) and caesium carbonate (20.6 g, 63.1 mmol, 3.00 eq.). The mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with water (100 mL) and extracted with di chloromethane (3 x 100 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-20% ethyl acetate / petroleum ether) to give -(tert- butyl) 3-methyl 2-(6-bromopyridazin-3-yl)malonate (5.00 g, 14.5 mmol, 69% yield) as a yellow solid.

[0667] Step 2. To a solution of 1 -(tert-butyl) 3-methyl 2-(6-bromopyridazin-3-yl)malonate (5.00 g, 15.1 mmol, 1.00 eq.) in di chloromethane (25 mL) was added trifluoroacetic acid (5 mL). The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (100 mL) and extracted with di chloromethane (3 x 100 mL). The combined organic layers were washed with brine (120 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-30% ethyl acetate / petroleum ether) to give methyl 2-(6-bromopyridazin-3-yl)acetate (2.50 g, 10.6 mmol, 70% yield) as a yellow oil.

[0668] Step 3. To a solution of methyl 2-(6-bromopyridazin-3-yl)acetate (2.50 g, 10.8 mmol, 1.00 eq.) in acetonitrile (20 mL) was added iodomethane (6.74 mL, 108 mmol, 10.0 eq.) and caesium carbonate (10.6 g, 32.5 mmol, 3.00 eq.). The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (eluent of 0-10% ethyl acetate / petroleum ether) to give 2-(6-bromopyridazin-3-yl)-2-methylpropanoate (1.90 g, 7.26 mmol, 67% yield) as a yellow oil.

[0669] Step 4. To a solution of 2-(6-bromopyridazin-3-yl)-2-methylpropanoate (1.50 g, 5.79 mmol, 1.00 eq.) in dioxane (20 mL) was added tributyl(l -ethoxy vinyl)stannane (2.35 mL, 6.95 mmol, 1.20 eq.) and bis(triphenylphosphine)-palladium(II) chloride (406 mg, 579 pmol, 0.10 eq.). The mixture was degassed and purged with nitrogen three times, and then stirred at 100 °C for 16 h under nitrogen atmosphere. The mixture was cooled to room temperature and acidified to pH = 3 with hydrochloric acid (2 M), and then stirred for 0.5 h at 25 °C. The mixture was poured into potassium fluoride (50 mL) and diluted with water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-10% ethyl acetate / petroleum ether) to give methyl 2-(6-acetylpyridazin-3-yl)-2-methylpropanoate (970 mg, 3.97 mmol, 69% yield) as a yellow oil.

[0670] Step 5. To a solution of methyl 2-(6-acetylpyridazin-3-yl)-2-methylpropanoate (970 mg, 3.97 mmol, 1.00 eq.) in di chloromethane (10 mL) was added 1,1,1 -trifluoro- / ' / , 7V-bi s(2-methoxy ethyl)- A4-sulfanamine (4.35 mL, 19.9 mmol, 5.00 eq.) at 0 °C under nitrogen atmosphere. The mixture was stirred at 40 °C for 42 h. The reaction mixture was quenched with ice water (50 mL) and extracted with di chloromethane (3 x 50 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-10% ethyl acetate / petroleum ether) to afford ethyl 2-(6-(l,l-difluoroethyl)pyridazin-3-yl)-2-methylpropanoate (820 mg, 3.26 mmol, 82% yield) as a yellow oil.

[0671] Step 6. To a solution of methyl 2-(6-(l,l-difluoroethyl)pyridazin-3-yl)-2-methylpropanoate (300 mg, 1.23 mmol, 1.00 eq.) in methanol (3 mL) was added a solution of sodium hydroxide (246 mg, 6.14 mmol, 5.00 eq.) in water (3 mL). The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (20 mL) and washed with dichloromethane (20 mL). The aqueous phase was adjusted to pH = 8 with IM hydrochloric acid and lyophilized to give sodium 2-(6-( 1, 1 -difluoroethyl)pyridazin-3-yl)-2-methylpropanoate (510 mg, crude) as a white solid.

[0672] Step 7. To a solution of sodium 2-(6-(l,l-difluoroethyl)pyridazin-3-yl)-2-methylpropanoate (160 mg, 381 pmol, 1.00 eq.) in

[0673]

[0674] methylformamide (5 mL) was added 2-chl oro-1 -methyl-pyridin- 1-ium iodide (117 mg, 457 pmol, 1.20 eq.) and N,N-diisopropylethylamine (148 mg, 1.14 mmol, 199 pL, 3.00 eq.) at 0 °C. The mixture was stirred at 25 °C for 0.5 h. Then 1-(4-(aminomethyl)-2,6-dichlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (98.8 mg, 305 pmol, 0.800 eq.) was added at this temperature. After addition, the mixture was stirred at 25 °C for 1.5 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: C18 150 × 30 mm; mobile phase: [water (formic acid) -acetonitrile]; gradient: 32%-62% B over 7 min) and lyophilized to afford A- 3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-l(2 / / )-yl)benzyl)-2-(6-(l, l-difluoroethyl)pyridazin-3-yl)-2-methylpropanamide (102 mg, 202 pmol, 53% yield) as a white solid.

[0675] ’H NMR (400 MHz, DMSO-6) d = 10.58 (s, 1H), 8.30 (t, J = 6.0 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.88 (d, J= 8.8 Hz, 1H), 7.35 (s, 2H), 4.29 (d, J= 6.0 Hz, 2H), 3.60 (t, J= 6.8 Hz, 2H), 2.75 (t, J= 6.8 Hz, 2H), 2.15 (t, J= 19.2 Hz, 3H), 1.65 (s, 6H). MS (ESI) m / z 500.1 [M+H]+ Synthesis of Compound 51

[0676]

[0677] Step 1. To a solution of 2-bromo-5-fluoropyrazine (500 mg, 2.83 mmol, 1.00 eq.) and oxetane-3-carbonitrile (235 mg, 2.83 mmol, 1.00 eq.) in toluene (10 mL) was added lithium bis(trimethylsilyl)amide (1 M, 3.40 mL, 1.20 eq.) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 20 °C for 16 h. The mixture was added to a saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (20 mL). The layers were separated, and the organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-20% ethyl acetate / petroleum ether) to afford 3-(5-bromopyrazin-2-yl)oxetane-3-carbonitrile (130 mg, 536 μmol, 19% yield) as a yellow solid.

[0678] Step 2. Sodium hydride (125 mg, 3.13 mmol, 60% purity, 5.00 eq.) was added to tetrahydrofuran (3 mL) and methanol (1 mL) at 0 °C under nitrogen atmosphere. The reaction was stirred at 0 °C for 10 min. Then a solution of 3-(5-bromopyrazin-2-yl)oxetane-3-carbonitrile (150 mg, 625 pmol, 1.00 eq.) in tetrahydrofuran (2 mL) was added at 0 °C. The mixture was stirred for 10 min, then it was added to water (20 mL) and extracted with ethyl acetate (20 mL). The organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-20% ethyl acetate / petroleum ether) to afford 3-(5-methoxypyrazin-2-yl)oxetane-3-carbonitrile (80.0 mg, 389 μmol, 62% yield) as a yellow solid.

[0679] Step 3. To a solution of 3 -(5-methoxypyrazin-2-yl)oxetane-3 -carbonitrile (80.0 mg, 418 pmol, 1.00 eq.) in ethanol (5 mL) was added a solution of sodium hydroxide (67.0 mg, 1.68 mmol, 4.00 eq.) in water (2.5 mL). The reaction mixture was stirred at 100 °C for 4 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were washed with brine (30 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 3-(5-methoxypyrazin-2-yl)oxetane-3 -carboxylic acid (78.0 mg, 348 pmol, 83% yield) as a white solid.

[0680] Step 4. To a solution of 3-(5-methoxypyrazin-2-yl)oxetane-3-carboxylic acid (78.0 mg, 371 pmol, 1.00 eq.) in dimethylformamide (10 mL) were added 2-chloro-l-methyl-pyridin-l-ium iodide (115 mg, 450 μmol, 1.22 eq.) and N,N-diisopropylethylamine (200 pL, 1.15 mmol, 3.10 eq.). The mixture was stirred at 20 °C for 0.5 h. Then l-(4-(aminomethyl)-2,6-dichlorophenyl)dihydropyrimidine-2, 4(1 / 7, 37 / )-dione hydrochloride (120 mg, 370 pmol, 1.00 eq.) was added to the mixture and the mixture was stirred at 20 °C for 1.5 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by / c -HPLC (column: YMC-Actus Triart Cl 8 150 x 30 mm x 7 / m; mobile phase: [water (formic acid) - acetonitrile]; gradient:23%-53% B over 10 min) and lyophilized to afford 7V-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-l(277)-yl)benzyl)-3-(5-methoxypyrazin-2-yl)oxetane-3-carboxamide (93.19 mg, 192 pmol, 52% yield) as a white solid.

[0681] ’H NMR (400 MHz, DMSO-d₆) δ = 10.61 (s, 1H), 8.56 (t, J = 6.0 Hz, 1H), 8.37 (d, J= 1.2 Hz, 1H), 8.35 (d, J= 1.2 Hz, 1H), 7.32 (s, 2H), 5.08 (d, J= 6.4 Hz, 2H), 4.95 (d, J= 6.4 Hz, 2H), 4.34 (d, J= 6.0 Hz, 2H), 3.94 (s, 3H), 3.60 (t, J= 6.8 Hz, 2H), 2.75 (t, J= 6.8 Hz, 2H). MS (ESI) m / z 480.0 [M+H]+

[0682]

[0683] Step 1. To a solution of 2-bromo-5-methoxy-pyridine (12.0 g, 63.8 mmol, 1.00 eq.) in dichloromethane (200 mL) was added 3-chlorobenzoperoxoic acid (15.6 g, 76.6 mmol, 85% purity, 1.20 eq.) in portions at 25 °C. The mixture was stirred at 25 °C for 12 h. The mixture was poured into ice water (100 mL) and extracted with dichloromethane (4 x 100 mL). The combined organic layers were washed with 10% sodium sulfite solution (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-10% methanol / ethyl acetate) to give 2-bromo-5-methoxypyridine 1-oxide (12.5 g, 60.7 mmol, 95% yield) as a white solid.

[0684] Step 2. Solution A (2-bromo-5-methoxypyridine 1-oxide (12.5 g, 61.3 mmol, 1.00 eq.) in sulfuric acid (75 mL), 2.99 mL / min) and solution B (fuming nitric acid (38.6 g, 613 mmol, 10.0 eq.), 1.00 mL / min) was reacted at 60 °C in a flow reaction for 30 min. The mixture was poured into ice water (100 mL) and the resulting precipitate was filtered. The solid was washed with water (2 × 10 mL) then collected and dried in vacuo to give 2-bromo-5-methoxy-4-nitropyridine 1-oxide (16.0 g, crude) as a yellow solid.

[0685] Step 3. To a mixture of 2-bromo-5-methoxy-4-nitropyridine 1-oxide (16.0 g, 64.3 mmol, 1.00 eq.) and ammonium chloride (3.44 g, 64.3 mmol, 1.00 eq.) in ethanol (160 mL) and water (160 mL) was added ferrous powder (25.1 g, 450 mmol, 7.00 eq.) in portions at 25 °C. The mixture was stirred at 80 °C for 1 h. The mixture was cooled to 25 °C then concentrated under reduced pressure to remove of ethanol. The residue was filtered, and the filter cake was washed with ethyl acetate (2 x 20 mL). The filtrate was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-35% ethyl acetate / petroleum ether) to give 2-bromo-5-methoxypyridin-4-amine (4.85 g, 23.2 mmol, 36% yield) as a white solid.

[0686] Step 4. To a solution of 2-bromo-5-methoxypyridin-4-amine (4.85 g, 23.9 mmol, 1.00 eq.), triethylamine (7.25 g, 71.7 mmol, 3.00 eq.) and A,7V-dimethylpyridin-2-amine (292 mg, 2.39 mmol, 0.10 eq.) in dichloromethane (50 mL) was added di-tert-butyl dicarbonate (13.0 g, 59.7 mmol, 2.50 eq.) dropwise at 25 °C. The mixture was stirred at 25 °C for 12 h. The mixture was poured into water (10 mL) and the organic layer was separated. The aqueous phase was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-30% ethyl acetate / petroleum ether) to give tert-butyl N-(2-bromo-5-methoxy-4-pyridyl)-N-tert-butoxycarbonyl-carbamate (4.48 g, 10.8 mmol, 45% yield) as a white solid.

[0687] Step 5. To a mixture of tert-butyl N-(2-bromo-5-methoxy-4-pyridyl)-N-tert-butoxycarbonyl-carbamate (1.10 g, 2.73 mmol, 1.00 eq.) and difluorozinc (282 mg, 2.73 mmol, 1.00 eq.) in N,N-dimethylformamide (11 mL) were added (l-methoxy-2-methyl-prop-l-enoxy)-trimethyl-silane (951 mg, 5.46 mmol, 2.00 eq.) and palladium tritert-butylphosphane (139 mg, 272 pmol, 0.10 eq.) in one portion at 25 °C. The mixture was stirred at 100 °C under nitrogen atmosphere for 12 h. The mixture was cooled to 20 °C, then diluted with ethyl acetate (20 mL) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-25% ethyl acetate / petroleum ether) to give methyl 2-(4-(bis(tert-butoxycarbonyl)amino)-5-methoxy-2-pyridyl)-2-methyl-propanoate (670 mg, 1.52 mmol, 13% yield) as a white solid.

[0688] Step 6. A solution of methyl 2-(4-(bis(tert-butoxycarbonyl)amino)-5-methoxy-2-pyridyl)-2-methyl-propanoate (670 mg, 1.58 mmol, 1.00 eq.) in hydrogen chloride / ethyl acetate (2 M, 10 mL) was stirred at 20 °C for 12 h. The mixture was filtered, and the filter cake was dried under vacuum to give methyl 2-(4-amino-5-methoxypyridin-2-yl)-2-methylpropanoate hydrochloride (250 mg, 958 pmol, 60% yield) as a white solid.

[0689] Step 7. To a solution of methyl 2-(4-amino-5-methoxypyridin-2-yl)-2-methylpropanoate (250 mg, 1.11 mmol, 1.00 eq.) in water (1 mL) and methanol (3 mL) was added sodium hydroxide (223 mg, 5.57 mmol, 5.00 eq.). The mixture was stirred at 20 °C for 12 h. The mixture was diluted with water (10 mL) and dichloromethane (10 mL). The aqueous phase was separated and washed with dichloromethane (10 mL). The pH of aqueous phase was adjusted to 7 with hydrochloric acid (1 M). The mixture was lyophilized to give 2-(4-amino-5-methoxypyridin-2-yl)-2-methylpropanoic acid (700 mg, 998 pmol, 89 % yield, 30% purity) as a white solid. The crude product was used in the next step without purification.

[0690] Step 8. To a solution of 2-(4-amino-5-methoxypyridin-2-yl)-2-methylpropanoic acid (600 mg, 856 pmol, 1.00 eq.) in

[0691]

[0692] methylformamide (5 mL) were added N,N-diisopropylethylamine (450 μL, 2.58 mmol, 3.02 eq.) and 2-chloro-l-methyl-pyridin-l-ium iodide (262 mg, 1.03 mmol, 1.20 eq.). The mixture was stirred at 20 °C for 0.5 h. Then l-(4-(aminomethyl)-2,6-dichlorophenyl)dihydropyrimidine-2, 4(1 / / , 3 / 7)-dione hydrochloride (300 mg, 927 pmol, 1.08 eq.) was added to the mixture and the mixture was stirred at 20 °C for 1.5 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Phenomenex luna Cl 8 150 x 25mm x 10 pm; mobile phase: [water (formic acid) - acetonitrile]; gradient: 32%-62% B over 9 min). The pH of the desired fractions was adjusted to 7 with sodium hydroxide and lyophilized. The residue was triturated with acetonitrile (20 mL) for 2 h at 20 °C to give 2-(4-amino-5-methoxypyridin-2-yl)-N-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzyl)-2-methylpropanamide (70.0 mg, 141 μmol, 16% yield) as a white solid.

[0693] Step 9. To a solution of 2-(4-amino-5-methoxypyridin-2-yl)-N-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzyl)-2-methylpropanamide (80.0 mg, 166 μmol, 1.00 eq.) in trifluoroborane hydrofluoride (3 mL) was added sodium nitrite (23.0 mg, 333 pmol, 2.00 eq.) at 0 °C. The mixture was stirred at 60 °C for 2 h. The mixture was diluted with water (10 mL), and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Phenomenex luna C18 150 x 25mm x 10 pm; mobile phase:

[0694] [water (formic acid) - acetonitrile]; gradient: 30%-60% B over 9 min) and lyophilized to give N-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-l(2J7)-yl)benzyl)-2-(4-fluoro-5-methoxypyridin-2-yl)-2-methylpropanamide (11.79 mg, 23.9 pmol, 14% yield) as a yellow solid.

[0695] ’H NMR (400 MHz, DMSO-tL) d = 10.60 (s, 1H), 8.45 (d, J= 10.8 Hz, 1H), 7.99 (t, J= 6.0 Hz, 1H), 7.39 - 7.30 (m, 3H), 4.25 (d, J= 6.0 Hz, 2H), 3.94 (s, 3H), 3.60 (t, J= 6.8 Hz, 2H), 2.75 (t, J = 6.8 Hz, 2H), 1.50 (s, 6H). MS (ESI) m / z 483.1 [M+H]+

[0696] Synthesis of Compound 54

[0697]

[0698] Step 1. To a solution of 5-bromo-4-fluoro-2-methoxypyridine (500 mg, 2.43 mmol, 1.00 eq.) and sodium 2-cyanoacetate (519 mg, 4.85 mmol, 2.00 eq.) in mesitylene (15 mL) were added allylpalladium(II)chloride dimer (88.0 mg, 242 μmol, 0.10 eq.) and 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (199 mg, 485 μmol, 0.20 eq.). The reaction was stirred at 130 °C for 12 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure, then it was diluted with water (30 mL) and extracted with ethyl acetate (30 mL). The organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 10 g sepa flash® silica flash column, eluent of 0-10% ethyl acetate / petroleum ether gradient @ 40 mL / min) to give 2-(4-fluoro-6-methoxypyridin-3-yl)acetonitrile (240 mg, 1.33 mmol, 54% yield) as a yellow solid. Step 2. To a solution of 2-(4-fluoro-6-methoxypyridin-3-yl)acetonitrile (200 mg, 1.20 mmol, 1.00 eq.) in tetrahydrofuran (10 mL) was added sodium hydride (144 mg, 3.61 mmol, 60% purity, 3.00 eq.) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 1 h. Then methyl iodide (3.61 mmol, 220 pL, 3.00 eq.) was added at 0 °C, and the reaction was stirred at 25 °C for 3 h. The mixture was added to hydrochloric acid (0.5 M, 15 mL) and extracted with ethyl acetate (15 mL). The organic phase was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g sepa flash® silica flash column, eluent of 0-15% ethyl acetate / petroleum ether gradient @ 25 mL / min) to give 2-(4-fluoro-6-methoxypyridin-3-yl)-2-methylpropanenitrile (170 mg, 831 μmol, 69% yield) as a yellow oil.

[0699] Step 3. To a solution of 2-(4-fluoro-6-methoxypyridin-3-yl)-2-methylpropanenitrile (220 mg, 1.13 mmol, 1.00 eq.) in methanol (5 mL) was added sulfuric acid (2 mL) at 0 °C. The reaction mixture was stirred at 70 °C for 24 h. The reaction mixture was diluted with ethyl acetate (10 mL) and water (10 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (15 × 10 mL) and dichloromethane (5 × 10 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by Prep-TLC (petroleum ether / ethyl acetate = 5 / 1) to afford methyl 2-(4-fluoro-6-methoxypyridin-3-yl)-2-methylpropanoate (50.0 mg, 154 μmol, 14% yield) as a colourless oil.

[0700] Step 4. To a solution of methyl 2-(4-fluoro-6-methoxypyridin-3-yl)-2-methylpropanoate (50.0 mg, 220 pmol, 1.00 eq.) in methanol (3 mL) was added sodium hydroxide (88.0 mg, 2.20 mmol, 10.0 eq.) in water (3 mL). The reaction was stirred at 50 °C for 4 h. The reaction mixture was diluted with ethyl acetate (10 mL) and water (10 mL). The layers were separated, and the aqueous phase was acidified to pH=5 with IM hydrochloric acid. The aqueous phase was extracted with ethyl acetate (15 mL). The organic layer was washed with brine (15 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 2-(4-fluoro-6-methoxypyri din-3 -yl)-2-methylpropanoic acid (30 mg, crude) as a colourless oil.

[0701] Step 5. To a solution of 2-(4-fluoro-6-methoxypyridin-3-yl)-2-methylpropanoic acid (30.0 mg, 141 pmol, 1.00 eq.) and N,N-diisopropylethylamine (55.0 mg, 426 μmol, 3.02 eq.) in dimethylformamide (1 mL) was added 2-chloro-1-methyl-pyridin-1-ium iodide (39.0 mg, 153 μmol, 1.08 eq.). The reaction mixture was stirred at 15 °C for 1 h. Then l-(4-(aminomethyl)-2- chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (50.0 mg, 172 μmol, 1.22 eq.) was added. The reaction was stirred at 15 °C for 2 h. The reaction mixture was diluted with ethyl acetate (15 mL) and water (15 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (15 mL). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by Prep-HPLC (column: YMC-Actus Triart C18 150 x 30mm x 7^m; mobile phase: [water (formic acid) - acetonitrile]; gradient: 28%-58% B over 10 min) followed by Prep-HPLC (column: Waters Xbridge 150 x 25mm x 5^m; mobile phase: [water (ammonium hydrogen carbonate) -acetonitrile]; gradient: 18%-48% B over 9 min) and lyophilized to afford N-(3-chloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzyl)-2-(4-fluoro-6-methoxypyridin-3-yl)-2-methylpropanamide (8.38 mg, 18.5 μmol, 13% yield) as a white solid.

[0702] ’H NMR (400 MHz, DMSO-6) d = 10.45 (s, 1H), 8.19 (d, J= 11.2 Hz, 1H), 8.02 (t, J= 6.0 Hz, 1H), 7.40 (d,.7= 8.0 Hz, 1H), 7.31 (d, J= 1.6 Hz, 1H), 7.19 (dd, J= 1.6, 8.0 Hz, 1H), 6.71 (d, J= 12.4 Hz, 1H), 4.22 (d, J= 6.0 Hz, 2H), 3.87 (s, 3H), 3.68 (d, J= 7.2 Hz, 1H), 3.57 (d, J= 6.4 Hz, 1H), 2.79 - 2.68 (m, 2H), 1.49 (s, 6H). MS (ESI) m / z 449.1 [M+H]+

[0703]

[0704] Step 1. To a solution of 5-bromopyrazin-2(1H)-one (10.0 g, 57.2 mmol, 1.00 eq.) in toluene (70 mL) were added (bromomethyl)benzene (84.2 mmol, 10.0 mL, 1.47 eq.) and silver carbonate (31.5 g, 114 mmol, 2.00 eq.) at 25 °C. The mixture was stirred at 25 °C for 16 h. The mixture was filtered. The filtrate was diluted with water (100 mL), extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water (150 mL) and brine (150 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO ®; 120 g Sepa Flash ® Silica Flash Column, Eluent of 0~l% Ethyl acetate / Petroleum ether gradient @100 mL / min) to give 2-(benzyloxy)-5-bromopyrazine (11.6 g, 39.4 mmol, 69% yield) as a white solid.

[0705] Step 2. To a solution of 2-(benzyloxy)-5-bromopyrazine (11.6 g, 43.8 mmol, 1.00 eq.) in dioxane (50 mL) were added cuprous iodide (6.67 g, 35.0 mmol, 0.80 eq.), dimethyl malonate (219 mmol, 25.1 mL, 5.00 eq.), caesium carbonate (28.5 g, 87.5 mmol, 2.00 eq.) and pyridine-2-carboxylic acid (2.15 g, 17.5 mmol, 0.40 eq.) at 25 °C under nitrogen atmosphere. The mixture was stirred at 100 °C for 48h in a 100 mL sealed tube. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with water (400 mL) and brine (300 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO ®; 120 g Sepa Flash ® Silica Flash Column, Eluent of 0-17% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give dimethyl 2-(5-(benzyloxy) pyrazin-2-yl) malonate (2.06 g, 5.86 mmol, 13% yield) as a colourless oil.

[0706] Step 3. To a solution of dimethyl 2-(5-(benzyloxy)pyrazin-2-yl)malonate (2.36 g, 7.46 mmol, 1.00 eq.) in dimethyl sulfoxide (10 mL) and water (1 mL) was added lithium chloride (1.27 g, 29.8 mmol, 4.00 eq.) at 25 °C. The reaction was stirred at 100 °C for 16 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO ®; 20 g Sepa Flash ® Silica Flash Column, Eluent of 0-13% Ethyl acetate / Petr oleum ether gradient @ 80 mL / min) to give methyl 2-(5-(benzyloxy) pyrazin-2-yl) acetate (1.11 g, 3.87 mmol, 52% yield) as a yellow oil.

[0707] Step 4. To a solution of methyl 2-(5-(benzyloxy)pyrazin-2-yl)acetate (600 mg, 2.32 mmol, 1.00 eq.) in tetrahydrofuran (10 mL) was added lithium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 11.6 mL, 4.99 eq.) at 0 °C under nitrogen atmosphere. It was stirred at 0 °C for 30 min. Then methyl iodide (11.6 mmol, 720 μL, 4.98 eq.) was added at 0 °C under nitrogen atmosphere. The reaction was stirred at 25 °C under nitrogen atmosphere for 1 h, then it was quenched with saturated ammonium chloride solution (20 mL) at 0 °C and diluted with ethyl acetate (30 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO ®; 12 g Sepa Flash ® Silica Flash Column, Eluent of 0-7% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to give methyl 2-(5-(benzyloxy)pyrazin-2-yl)-2-methylpropanoate (510 mg, 1.60 mmol, 69% yield) as a yellow oil.

[0708] Step 5. Palladium on Carbon (100 mg, 10% purity) and methyl 2-(5-(benzyloxy) pyrazin-2-yl)-2-methylpropanoate (700 mg, 2.44 mmol, 1.00 eq.) were suspended in ethyl acetate (10 mL), and the reaction was stirred under hydrogen (15 psi) at 25 °C for 1 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give methyl 2-(5-hydroxypyrazin-2-yl)-2-methylpropanoate (520 mg, 2.39 mmol, 98% yield) as a yellow oil. Step 6. To a solution of methyl 2-(5-hydroxypyrazin-2-yl)-2-methylpropanoate (500 mg, 2.55 mmol, 1.00 eq.) and tetrabutylammonium bromide (41.1 mg, 127 μmol, 0.05 eq.) in N, N-dimethylformamide (10 mL) was added sodium hydride (155 mg, 3.88 mmol, 60% purity, 1.52 eq.) at 0 °C under nitrogen. The mixture was stirred at 20 °C for 2 h, then it was cooled to -30 °C, and dibromo(difluoro)methane (10.2 mmol, 950 μL, 4.00 eq.) was added at -30 °C. The mixture was carefully warmed to 20 °C and stirred at 20 °C for 12 h. The reaction was quenched with saturated ammonium chloride (50 mL) at 0 °C under nitrogen and extracted with petroleum ether (50 mL). The organic layer was washed with water (2 x 50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® Silica Flash Column, Eluent of 0~5% Ethyl acetate / Petroleum ether gradient @ 18 mL / min) to give methyl 2-(5-(bromodifluoromethoxy)pyrazin-2-yl)-2-methylpropanoate (100 mg, 292 μmol, 11% yield) as a colourless oil.

[0709] Step 7. Silver tetrafluoroborate (120 mg, 615 μmol, 2.00 eq.) was added in portions to the solution of methyl 2-(5-(bromodifluoromethoxy)pyrazin-2-yl)-2-methylpropanoate (100 mg, 308 μmol, 1.00 eq.) in dichloromethane (5 mL) at -70 °C. The mixture was warmed to 20 °C and stirred for 2 h in darkness. The mixture was quenched with saturated sodium bicarbonate (10 mL) and extracted with dichloromethane (10 mL). The organic layer was washed with water (2 × 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 5 g SepaFlash® Silica Flash Column, Eluent of 0~5% Ethyl acetate / Petroleum ether gradient @ 18 mL / min) to give methyl 2-methyl-2-(5-(trifluoromethoxy)pyrazin-2-yl)propanoate (60.0 mg, 204 μmol, 66% yield) as a colourless oil.

[0710] Step 8. To a solution of methyl 2-methyl-2-(5-(trifluoromethoxy)pyrazin-2-yl)propanoate (50.0 mg, 189 μmol, 1.00 eq.) in water (1 mL), tetrahydrofuran (1 mL) and Zc / V-butanol (1 mL) was added sodium hydroxide (37.9 mg, 946 μmol, 5.00 eq.). The mixture was stirred at 20 °C for 16 h. The mixture was acidified with hydrochloric acid (1 M) until pH = 4 at 0 °C, then extracted with di chloromethane (3 x 5 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 2-methyl-2-(5-(trifluoromethoxy)pyrazin-2-yl)propanoic acid (50.0 mg, crude) as a yellow oil.

[0711] Step 9. To a solution of 2-methyl-2-(5-(trifluoromethoxy)pyrazin-2-yl)propanoic acid (65.0 mg, 260 μmol, 1.00 eq.) in N,N-dimethylformamide (3 mL) were added 2-chl oro-1 -methyl-pyri din- 1- ium iodide (79.7 mg, 312 μmol, 1.20 eq.) and N,N-diisopropylethylamine (100 mg, 779 μmol, 3.00 eq.). The mixture was stirred at 10 °C for 0.5 h. Then l-(4-(aminomethyl)-2,6-dichlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (67.5 mg, 208 μmol, 0.80 eq.) was added to the mixture. The mixture was stirred at 10 °C for 1 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with water (2 x 20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Welch Xtimate C18 150 * 25 mm * 5 / m; mobile phase: [water (formic acid) - acetonitrile]; gradient: 35% - 55% B over 10 min). The desired fraction was collected and lyophilized under vacuum to give N-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzyl)-2-methyl-2-(5-(trifluoromethoxy)pyrazin-2-yl)propanamide (57.99 mg, 110 μmol, 42% yield) as a white solid.

[0712] ’H NMR (400 MHz, DMSO-6) d = 10.59 (s, 1H), 8.69 (d, J= 1.2 Hz, 1H), 8.55 (d, J= 1.2 Hz, 1H), 8.14 (t, J= 6.0 Hz, 1H), 7.35 (s, 2H), 4.26 (d, J= 6.0 Hz, 2H), 3.60 (t, J= 6.8 Hz, 2H), 2.75 (t, J= 6.8 Hz, 2H), 1.59 (s, 6H). MS (ESI) m / z 520.1 [M+H]+

[0713] Synthesis of Compound 60

[0714]

[0715] Step 1. A solution of acetic acid (1.43 g, 23.8 mmol, 1.00 eq.) and pyridin-1-ium 4-methylbenzenesulfonate (597 mg, 2.38 mmol, 0.10 eq.) in dichloromethane (20 mL) was cooled to 0 °C. Then a solution of 3,4-dihydro-2H-pyran (2.00 g, 23.8 mmol, 2.17 mL, 1.00 eq.) in dichloromethane (10 mL) was added dropwise to the mixture at 0 °C. Once the addition was complete, the solution was warmed to 20 °C and stirred for 12 h. The mixture was diluted with water (20 mL) and the layers were separated. The organic layer was washed with saturated sodium bicarbonate (3 x 20 mL) and brine (3 x 20 mL), dried over sodium sulfate, filtered, and concentrated to give tetrahydro-2H-pyran-2-yl acetate (2.30 g, 14.4 mmol, 60% yield) as a yellow oil.

[0716] Step 2. To a solution of tetrahydro-2H-pyran-2-yl acetate (200 mg, 1.39 mmol, 1.00 eq.) and ((1-methoxy-2-methylprop-l-en-l-yl)oxy)trimethylsilane (725 mg, 4.16 mmol, 3.00 eq.) in di chloromethane (10 mL) was added boron trifluoride diethyl etherate (1.80 mmol, 222 μL, 1.30 eq.) at -70 °C. The reaction mixture was gradually warmed to 20 °C and stirred at 20 °C for 16 h. The reaction was quenched with saturated sodium bicarbonate (10 mL) and diluted with di chloromethane (10 mL). The organic layer was separated, washed with water (10 mL) and brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 5 g Sepa Flash® Silica Flash Column, Eluent of 0~5% Ethyl acetate / Petroleum ether gradient @ 18 mL / min) to give methyl 2-methyl-2-(tetrahydro-2H-pyran-2-yl)propanoate (160 mg, 816 μmol, 59% yield) as a colourless oil.

[0717] Step 3. To a solution of methyl 2-methyl-2-(tetrahydro-2H-pyran-2-yl)propanoate (160 mg, 859 μmol, 1.00 eq.) in water (1 mL), methanol (1 mL) and tetrahydrofuran (1 mL) was added sodium hydroxide (172 mg, 4.30 mmol, 5.00 eq.). The reaction was stirred at 60 °C for 5 h. The mixture was acidified with aqueous hydrochloric acid (2 M) until pH = 3 and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 2-methyl-2-(tetrahydro-2H-pyran-2-yl)propanoic acid (150 mg, 784 μmol, 91% yield) as a yellow solid.

[0718] Step 4. To a solution of 2-methyl-2-(tetrahydro-2H-pyran-2-yl)propanoic acid (103 mg, 600 μmol, 1.50 eq.) in N,N-dimethylformamide (3 mL) were added 2-chloro-1-methyl-pyridin-1-ium iodide (133 mg, 521 μmol, 1.30 eq.) and N,N-diisopropylethylamine (1.20 mmol, 210 μL, 3.00 eq.). The mixture was stirred at 20 °C for 0.5 h. Then l-(4-(aminomethyl)-2,6-dichlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (130 mg, 400 μmol, 1.00 eq.) was added, and the reaction was stirred at 20 °C for 1 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with water (2 x 20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (formic acid) - acetonitrile]; gradient: 28% - 58% B over 10 min) and lyophilized under vacuum to give N-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzyl)-2-methyl-2-(tetrahydro-2H-pyran-2-yl)propanamide (114.72 mg, 257 μmol, 64% yield) as a white solid. ’H NMR (400 MHz, DMSO-6) d = 10.59 (s, 1H), 8.07 (t, J = 6.0 Hz, 1H), 7.43 (s, 2H), 4.37 -4.20 (m, 2H), 3.97 (dd, J= 2.0, 10.8 Hz, 1H), 3.61 (t, J = 6.8 Hz, 2H), 3.43 - 3.34 (m, 2H), 2.75 (t,.7= 6.8 Hz, 2H), 1.80 (d, J= 4.4 Hz, 1H), 1.54 - 1.35 (m, 4H), 1.29 - 1.15 (m, 1H), 1.07 (d, J= 9.6 Hz, 6H). MS (ESI) m / z 442.2 [M+H]+

[0719] Synthesis of Compound 61

[0720]

[0721] Step 1. To a solution of tert-butyl methyl malonate (27.4 g, 157 mmol, 1.50 eq.) in dimethylsulfoxide (150 mL) were added caesium carbonate (68.4 g, 210 mmol, 2.00 eq.) and 2,5-dibromopyrazine (25.0 g, 105 mmol, 1.00 eq.) in portions at 25 °C. The mixture was stirred at 80 °C for 2.5 h. The mixture was cooled to 25 °C, then poured into water (200 mL) and extracted with ethyl acetate (3 * 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 120 g Sepa Flash® Silica Flash Column, eluent of 0~6% ethyl acetate / petroleum ether gradient @ 120 mL / min) to give 1-(tert-butyl) 3-methyl 2-(5-bromopyrazin-2-yl)malonate (35.0 g, 96.1 mmol, 91% yield) as a yellow oil.

[0722] Step 2. To a solution of l-(tert-butyl) 3-methyl 2-(5-bromopyrazin-2-yl)malonate (35.0 g, 105 mmol, 1.00 eq.) in dichloromethane (50 mL) was added trifluoroacetic acid (50 mL) dropwise at 25 °C. The mixture was stirred at 25 °C for 2 h. The reaction was quenched with saturated aqueous sodium bicarbonate (200 mL) and solid sodium bicarbonate was added in portions until pH = 7-8. The mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 120 g Sepa Flash® Silica Flash Column, eluent of 0-18% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give methyl 2-(5-bromopyrazin-2-yl)acetate (17.0 g, 69.9 mmol, 66% yield) as a yellow oil.

[0723] Step 3. To a solution of methyl 2-(5-bromopyrazin-2-yl)acetate (2.00 g, 8.66 mmol, 1.00 eq.) in N,N-dimethylformamide (30 mL) was added sodium hydride (1.10 g, 27.5 mmol, 60% purity, 3.18 eq.) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 30 min under nitrogen. Then 1-chloro-2-(chloromethoxy)ethane (1.23 g, 9.52 mmol, 1.10 eq.) was added dropwise at 0 °C, and the reaction was stirred at 25 °C for 1 h. The mixture was poured into saturated ammonium chloride solution (40 mL) at 0 °C and extracted with ethyl acetate (2 x 40 mL). The aqueous layer was adjusted to pH = 3 with hydrochloric acid (2 M). The mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed phase column (Cl 8, 80 g, flow: 50 mL / min; gradient: from 60 - 100% water (0.1% formic acid) in acetonitrile over 0.5 h) followed by Prep-NPLC (column: YMC-Gel SiL-HG 250 mm × 70 mm × 10 μm; mobile phase: [Hexane-ethanol]; gradient: 1% - 20% B over 15 min) and concentrated under reduced pressure to give 3-(5-bromopyrazin-2-yl)tetrahydrofuran-3-carboxylic acid (220 mg, 588 μmol, 7% yield) as a white solid.

[0724] Step 4. To a solution of methanol (2 mL) in tetrahydrofuran (8 mL) was added sodium hydride (110 mg, 2.75 mmol, 60% purity, 5.14 eq.) at 0 °C under nitrogen. The reaction was stirred at 0 °C for 30 min, then 3-(5-bromopyrazin-2-yl)tetrahydrofuran-3-carboxylic acid (200 mg, 535 μmol, 1.00 eq.) in tetrahydrofuran (2 mL) was added at 0 °C. The reaction was stirred at 50 °C for 20 h under nitrogen. The reaction was quenched by dropwise addition to hydrochloric acid (1 M) at 0 °C under nitrogen. The reaction mixture was diluted with ethyl acetate (20 mL) and water (15 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (15 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (formic acid) - acetonitrile]; gradient: 13% - 43% B over 1 min) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 3-(5-methoxypyrazin-2-yl)tetrahydrofuran-3-carboxylic acid formate (80.0 mg, 293 μmol, 55% yield) as a colourless oil.

[0725] Step 5. To a solution of 3-(5-methoxypyrazin-2-yl)tetrahydrofuran-3-carboxylic acid formate (70.0 mg, 259 μmol, 1.00 eq.) in N,N-dimethylformamide (4 mL) were added 2-chloro-1-methylpyridin-1-ium iodide (80.0 mg, 313 μmol, 1.21 eq.) and N,N-diisopropylethylamine (180 μL, 1.04 mmol, 4.00 eq.) at 0 °C. The mixture was stirred at 25 °C for 0.5 h. Then l-(4-(aminomethyl)-2,6-dichlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (76.0 mg, 234 μmol, 0.90 eq.) was added, the resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Welch Xtimate C18 150 × 25 mm × 5 μm; mobile phase: [water (formic acid) - acetonitrile]; gradient: 15% - 45% B over 10 min) and lyophilized to give N-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzyl)-3-(5-methoxypyrazin-2-yl)tetrahydrofuran-3-carboxamide (62.8 mg, 126 μmol, 49% yield) as a white solid.

[0726] 'H NMR (400 MHz, DMSO-6) 8 = 10.59 (s, 1H), 8.33 (t, J= 6.0 Hz, 1H), 8.30 (d, J= 0.8 Hz, 1H), 8.28 (d, J= 0.8 Hz, 1H), 7.24 (s, 2H), 4.39 (d, J= 8.8 Hz, 1H), 4.26 (d, J= 6.0 Hz, 2H), 4.06 (d, J= 8.8 Hz, 1H), 3.91 (s, 3H), 3.89 - 3.78 (m, 2H), 3.59 (t, J= 6.8 Hz, 2H), 2.82 - 2.68 (m, 3H), 2.49 - 2.41 (m, 1H). MS (ESI) m / z 494.0 [M+H]+ Synthesis of Compound 62

[0727]

[0728] Step 1. To a suspension of 3-chloro-4-fluorobenzonitrile (5.00 g, 32.1 mmol, 1.00 eq.) and dihydropyrimidine-2,4(1H,3H)-dione (5.50 g, 48.2 mmol, 1.50 eq.) in

[0729]

[0730] methylformamide (150 mL) was added caesium carbonate (21.0 g, 64.5 mmol, 2.01 eq.). The mixture was stirred at 25 °C for 60 h. (The reaction was carried out in 2 batches in parallel.') The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with methanol (60 mL) for 30 min at 25°C, then filtered and concentrated under reduced pressure. The trituration was repeated with methanol (60 mL) then a third time with ethyl acetate (100 mL) for 30 min at 25°C. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 50-70% Ethyl acetate + dichloromethane / Petroleum ether gradient @ 150 mL / min) to afford 3-chloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzonitrile (410 mg, 1.63 mmol, 3% yield) as a yellow solid.

[0731] Step 2. To a solution of 3-chloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzonitrile (410 mg, 1.64 mmol, 1.00 eq.) in tetrahydrofuran (10 mL) and

[0732]

[0733] methylformamide (10 mL) were added di-tert-butyl dicarbonate (0.74 mL, 3.22 mmol, 1.96 eq.) and triethylamine (0.34 mL, 2.44 mmol, 1.49 eq.). Then Raney nickel (320 mg, 3.74 mmol, 2.27 eq.) was added to the mixture under nitrogen atmosphere. The suspension was degassed and purged with hydrogen 3 times. The mixture was stirred under hydrogen atmosphere (15 psi) at 60 °C for 48 h. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with methanol (30 mL) and A, A-di methylformamide (30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 60-70% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to afford tert-butyl (3-chloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzyl)carbamate (380 mg, 1.06 mmol, 65% yield) as a white solid.

[0734] Step 3. A mixture of tert-butyl (3-chloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzyl)carbamate (450 mg, 1.27 mmol, 1.00 eq.) in hydrogen chloride (2 M in ethyl acetate, 5 mL) was stirred at 25 °C for 1 h. The resulting precipitate was filtered, washed with ethyl acetate (40 mL), and dried under reduced pressure to afford 1-(4-(aminomethyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (330 mg, 1.09 mmol, 86% yield) as a white solid.

[0735] ¹H NMR (400 MHz, DMSO-d₆) d = 10.51 (s, 1H), 8.50 (s, 3H), 7.76 (s, 1H), 7.56 - 7.49 (m, 2H), 4.05 (d, J= 3.6 Hz, 2H), 3.78 - 3.67 (m, 1H), 3.63 - 3.51 (m, 1H), 2.78 - 2.71 (m, 2H). MS (ESI) m / z 254.0 [M+H]+

[0736] Step 4. To a solution of sodium hydride (1.00 g, 25.0 mmol, 60% purity, 3.90 eq.) in tetrahydrofuran (20 mL) was added a solution of 2-(6-methoxypyridin-3-yl)acetonitrile (950 mg, 6.41 mmol, 1.00 eq.) dissolved in tetrahydrofuran (5 mL) dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 30 min. Then iodomethane (1.60 mL, 25.7 mmol, 4.01 eq.) was added, and the mixture was stirred at 25 °C for 30 min. The reaction mixture was added dropwise to a saturated ammonium chloride solution (30 mL) under nitrogen atmosphere at 0 °C. Then the mixture was diluted with ethyl acetate (30 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-20% ethyl acetate / petroleum ether) to afford 2-(6-methoxypyridin-3-yl)-2-methylpropanenitrile (1.00 g, 5.62 mmol, 87% yield) as a colourless oil.

[0737] Step 5. A solution of 2-(6-methoxypyri din-3 -yl)-2-methylpropanenitrile (950 mg, 5.39 mmol, 1.00 eq.) in concentrated hydrochloric acid (12 M, 6 mL) was stirred at 60 °C forl6 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 2-(6-methoxypyridin-3-yl)-2-methylpropanoic acid (500 mg, 2.43 mmol, 45% yield) as a colourless oil.

[0738] Step 6. To a solution of 2-(6-methoxypyri din-3 -yl)-2-m ethylpropanoic acid (80.0 mg, 410 μmol, 1.00 eq.) in N,N-dimethylformamide (2 mL) were added 7V-ethyl-7V-isopropylpropan-2-amine (240 pL, 1.38 mmol, 3.36 eq.) and 2-chloro-l-methyl-pyridin-l-ium iodide (126 mg, 493 pmol, 1.20 eq.) at 0 °C. The mixture was stirred at 25 °C for 1 h. Then 1-(4-(aminomethyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (120 mg, 414 μmol, 1.01 eq.) was added at 25 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (formic acid) - acetonitrile]; gradient: 20%-50% B over 1 min) and lyophilized to afford N-(3-chloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzyl)-2-(6-methoxypyridin-3-yl)-2-methylpropanamide (41.4 mg, 95.1 μmol, 23% yield) as a white solid.

[0739] ’H NMR (400 MHz, DMSO-tL) d = 10.46 (s, 1H), 8.13 (d, J = 2.4 Hz, 1H), 8.07 (t, J = 6.0 Hz, 1H), 7.60 (dd, J= 2.4, 8.8 Hz, 1H), 7.38 (d, J= 8.0 Hz, 1H), 7.20 (d, J= 1.6 Hz, 1H), 7.15 (dd, J = 1.6, 8.0 Hz, 1H), 6.78 (d, J= 8.8 Hz, 1H), 4.23 (d, J= 6.0 Hz, 2H), 3.83 (s, 3H), 3.72 - 3.63 (m, 1H), 3.60 - 3.50 (m, 1H), 2.77 - 2.65 (m, 2H), 1.49 (s, 6H). MS (ESI) m / z 431.2 [M+H]+

[0740] Synthesis of Compound 65

[0741]

[0742] Step 1. To a mixture of ethyl 2-(5-bromopyrimidin-2-yl)acetate (1.00 g, 4.08 mmol, 1.00 eq.) in dimethylformamide (20 mL) was added sodium hydride (489 mg, 12.2 mmol, 60% purity, 3.00 eq.) in portions at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then iodomethane (1.74 g, 12.2 mmol, 3.00 eq.) was added, and the mixture was stirred at 20 °C for 1 h. The reaction was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give ethyl 2-(5-bromopyrimidin-2-yl)-2-methylpropanoate (1.18 g, 3.93 mmol, 96% yield) as a yellow oil.

[0743] Step 2. To a mixture of ethyl 2-(5-bromopyrimidin-2-yl)-2-methylpropanoate (5.50 g, 20.1 mmol, 1.00 eq.), trifluoro(vinyl)-λ4-borane, potassium salt (5.39 g, 40.2 mmol, 2.00 eq.) and caesium carbonate (13.1 g, 40.2 mmol, 2.00 eq.) in dioxane (20 mL) and water (20 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (736 mg, 1.01 mmol, 0.05 eq.) in portions at 25 °C. The mixture was stirred at 100 °C under nitrogen atmosphere for 2 h. The mixture was cooled to 25 °C and poured into water (50 mL), then it was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g Sepa Flash® Silica Flash Column, eluent of 0-10% ethyl acetate / petroleum ether gradient @ 40 mL / min). The residue was purified by n-Prep-HPLC (column: Welch Ultimate XB-CN 250 mm x 70 mm x 10 / m; mobile phase: [hexaneethanol (0.1% ammonia solution)]; gradient: l%-10% B over 25 min) then concentrated under reduced pressure to give ethyl 2-methyl-2-(5-vinylpyrimidin-2-yl)propanoate (3.30 g, 14.3 mmol, 71% yield) as a colourless oil.

[0744] Step 3. To a solution of ethyl 2-methyl-2-(5-vinylpyrimidin-2-yl)propanoate (1.50 g, 6.81 mmol, 1.00 eq.) in tetrahydrofuran (15 mL) and water (5 mL) was added a solution of osmium(VIII) oxide (242 mg, 953 μmol, 0.14 eq.) in tetrahydrofuran (5 mL) dropwise at 0 °C. Then a solution of sodium periodate (3.64 g, 17.0 mmol, 2.50 eq.) in water (10 mL) was added, and the mixture was stirred at 25 °C under nitrogen atmosphere for 2 h. The mixture was poured into water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g Sepa Flash® Silica Flash Column, eluent of 0-25% ethyl acetate / petroleum ether gradient @ 20 mL / min) to give ethyl 2-(5-formylpyrimidin-2-yl)-2-methylpropanoate (1.30 g, 5.79 mmol, 85% yield) as a colourless oil.

[0745] Step 4. To a solution of ethyl 2-(5-formylpyrimidin-2-yl)-2-methylpropanoate (500 mg, 2.25 mmol, 1.00 eq.) in methanol (10 mL) was added sodium borohydride (220 mg, 5.82 mmol, 2.58 eq.) in portions at 0 °C. The mixture was stirred at 0 °C under nitrogen atmosphere for 1 h. The reaction was quenched with saturated aqueous ammonium chloride (30 mL) at 0 °C and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give ethyl 2-(5-(hydroxymethyl)pyrimidin-2-yl)-2-methylpropanoate (500 mg, 2.21 mmol, 98% yield) as a colourless oil.

[0746] Step 5. To a solution of ethyl 2-(5-(hydroxymethyl)pyrimidin-2-yl)-2-methylpropanoate (1.00 g, 4.46 mmol, 1.00 eq.) in tetrahydrofuran (20 mL) was added sodium hydride (356 mg, 8.92 mmol, 60% purity, 2.00 eq.) in portions at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. Carbon disulfide (679 mg, 8.92 mmol, 2.00 eq.) was added, and the mixture was stirred at 0 °C for 0.5 h. Methyl iodide (1.27 g, 8.92 mmol, 2.00 eq.) was added, and the mixture was stirred at 25 °C under nitrogen atmosphere for 1 h. The reaction was quenched with saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 10 g Sepa Flash® Silica Flash Column, eluent of 0-15% ethyl acetate / petroleum ether gradient @ 20 mL / min) to give ethyl 2-methyl-2-(5- ((((methylthio)carbonothioyl)oxy)methyl)pyri-midin-2-yl)propanoate (850 mg, 2.54 mmol, 56% yield) as a colourless oil.

[0747] Step 6. To a solution of 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (3.09 g, 10.8 mmol, 4.00 eq.) in dichloromethane (24 mL) was added pyridine*hydrofluoride (2.68 g, 27.0 mmol, 10.0 eq.) dropwise at -60 °C. The mixture was stirred at -60 °C for 0.5 h, then a solution of ethyl 2-methyl-2-(5-((((methylthio)carbonothioyl)oxy)methyl)pyrimidin-2-yl)propanoate (850 mg, 2.70 mmol, 1.00 eq.) in di chloromethane (6 mL) was added, and the mixture was stirred at 0 °C under nitrogen atmosphere for 2 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 10 g Sepa Flash® Silica Flash Column, eluent of 0-14% ethyl acetate / petroleum ether gradient @ 20 mL / min) to give ethyl 2-methyl-2-(5-((trifluoromethoxy)methyl)-pyrimidin-2-yl)propanoate (450 mg, 1.49 mmol, 55% yield) as a colourless oil.

[0748] Step 7. To a mixture of ethyl 2-methyl-2-(5-((trifluoromethoxy)methyl)pyrimidin-2-yl)propanoate (50.0 mg, 171 / / mol, 1.00 eq.) in water (1 mL) and propan-2-ol (0.1 mL) was added sodium hydroxide (34.2 mg, 855 µmol, 5.00 eq.) in portions at 25 °C. The mixture was stirred at 25 °C for 15 h. The mixture was poured into water (10 mL) and adjusted to pH = 7-8 with 6% aqueous hydrochloric acid, then extracted with di chloromethane (3 x 10 mL). The aqueous layer was collected and lyophilized to give (2-methyl-2-(5-((trifluoromethoxy)-methyl)pyrimidin-2-yl)propanoyl)sodium (130 mg, crude) as a white solid.

[0749] Step 8. To a solution of (2-methyl-2-(5-((trifluoromethoxy)methyl)pyrimidin-2-yl)propanoyl)sodium (130 mg, 454 µmol, 1.00 eq.) and 2-chloro-1-methyl-pyridin-1-ium;iodide (92.8 mg, 363 µmol, 0.80 eq.) in dimethylformamide (2 mL) was added diisopropylethylamine (176 mg, 1.36 mmol, 3.00 eq.) dropwise at 25 °C. The mixture was stirred at 25 °C for 0.5 h, then 1-(4-(aminomethyl)-2,6-dichlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (73.7 mg, 227 µmol, 0.50 eq., hydrochloride) was added, and the mixture was stirred at 25 °C for 2 h. The mixture was poured into water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: YMC-Actus Triart C18 150 mm × 30 mm × 7 µm; mobile phase: [water (formic acid) -acetonitrile]; gradient: 35%-65% B over 10 min) then lyophilized to give N-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzyl)-2-methyl-2-(5-((trifluoromethoxy)methyl)pyrimidin-2-yl)propanamide (9.67 mg, 17.9 µmol, 3% yield) as a white solid.

[0750] ’H NMR (400 MHz, DMSO) 3 = 10.61 (br s, 1H), 8.91 (s, 2H), 8.19 (t, J= 6.0 Hz, 1H), 7.50 (s, 2H), 5.30 (s, 2H), 4.30 (d, J= 6.0 Hz, 2H), 3.61 (t, J= 6.8 Hz, 2H), 2.75 (t, J= 6.8 Hz, 2H), 1.56 (s, 6H). MS (ESI) m / z 534.0 [M+H]+ Synthesis of Compound 67

[0751]

[0752] Step 1. To a solution of (5-methylisoxazol-3-yl)methanol (2.00 g, 17.7 mmol, 1.00 eq.) in di chloromethane (10 mL) was added phosphorus tribromide (14.4 g, 53.1 mmol, 3.00 eq.) at 0 °C. The mixture was stirred at 25 °C for 2 h under nitrogen atmosphere. The reaction was quenched with saturated aqueous sodium bicarbonate (40 mL) and extracted with ethyl acetate (60 mL). The organic phase was washed with water (3 x 40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-(bromomethyl)-5-methylisoxazole (1.90 g, 9.72 mmol, 55% yield) as a colourless oil, and it was used directly in the next step.

[0753] Step 2. To a solution of 3-(bromomethyl)-5-methylisoxazole (2.20 g, 12.5 mmol, 1.00 eq.) and trimethyl silyl cyanide (18.8 mmol, 2.35 mL, 1.50 eq.) in tetrahydrofuran (20 mL) was added a solution of tetrabutylammonium fluoride (18.7 mL, 1.50 eq., IM in tetrahydrofuran) dropwise at 0 °C. The mixture was stirred at 25 °C for 1 h under nitrogen atmosphere, then it was poured into water (50 mL). The mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-40% ethyl acetate / petroleum ether) to give 2-(5-methylisoxazol-3-yl)acetonitrile (1.25 g, 9.21 mmol, 73% yield) as a colourless oil.

[0754] Step 3. Sodium hydride (980 mg, 24.5 mmol, 60% purity, 2.56 eq.) was suspended in tetrahydrofuran (5 mL). The mixture was degassed and purged with nitrogen 3 times. Then a solution of 2-(5-methylisoxazol-3-yl)acetonitrile (1.30 g, 9.58 mmol, 1.00 eq.) in tetrahydrofuran (15 mL) was added dropwise at 0 °C. It was stirred at 0 °C for 30 min. Then methyl iodide (4.08 g, 28.7 mmol, 3.00 eq.) was added, and the reaction was stirred at 0 °C for 1.5 h. The mixture was poured into saturated ammonium chloride (40 mL) and extracted with ethyl acetate (50 mL). The layers were separated, and the organic layer was washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 2-methyl-2-(5-methylisoxazol-3-yl)propanenitrile (1.60 g, 8.52 mmol, 88% yield) as a yellow oil. The crude product was used in the next step without purification.

[0755] Step 4. A solution of 2-methyl-2-(5-methylisoxazol-3-yl)propanenitrile (200 mg, 1.33 mmol, 1.00 eq.) in hydrochloric acid (6 M, 4 mL) was stirred at 60 °C for 12 h, then at 100 °C for 16 h. The mixture was diluted with water (40 mL) and ethyl acetate (35 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 ^ 35 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 2-methyl-2-(5-methylisoxazol-3-yl)propanoic acid (160 mg, 851 / mol, 63% yield) as a yellow oil. The crude product was used in the next step without purification.

[0756] Step 5. To a solution of 2-methyl-2-(5-methylisoxazol-3-yl)propanoic acid (250 mg, 738 pmol, 1.00 eq.) in N,N-dimethylformamide (3 mL) were added N,N-diisopropylethylamine (3.69 mmol, 650 pL, 5.00 eq.) and 2-chloro-l-methyl-pyridinium iodide (226 mg, 886 pmol, 1.20 eq.) at 0 °C. The reaction was stirred at 25 °C for 0.5 h. Then l-(4-(aminomethyl)-2,6- dichlorophenyl)dihydropyrimidine-2, 4(1 / 7, 37 / )-dione hydrochloride (100 mg, 308 pmol, 0.40 eq.) was added, and the reaction was stirred at 25 °C for 0.5 h. The mixture was diluted with ethyl acetate (20 mL) and water (20 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The combined extracts were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by / c -HPLC (column: Phenomenex luna C18 150 x 25 mm x 10 / m; mobile phase: [water (formic acid) - acetonitrile]; B%: 25% - 55%, 10 min) and lyophilize to give 7V-(3,5-dichloro-4- (2,4-dioxotetrahydropyrimidin-l(277)-yl)benzyl)-2-methyl-2-(5-methylisoxazol-3-yl)propanamide (88.43 mg, 201 pmol, 27% yield) as a white solid.

[0757] ’H NMR (400 MHz, DMSO-t / ,) 3 = 10.60 (s, 1H), 8.25 (t, J= 6.0 Hz, 1H), 7.35 (s, 2H), 6.20 (s, 1H), 4.27 (d, J= 6.0 Hz, 2H), 3.61 (t, J= 6.8 Hz, 2H), 2.75 (t, J= 6.8 Hz, 2H), 2.38 (s, 3H), 1.50 (s, 6H). MS (ESI) m / z 461.1 [M+Na]+ Synthesis of Compound 69

[0758]

[0759] Step 1. To a suspension of 3-chloro-4,5-difluorobenzonitrile (4.80 g, 27.7 mmol, 1.00 eq.) and dihydropyrimidine-2, 4(1 / 7, 3J7)-dione (3.16 g, 27.7 mmol, 1.00 eq.) in

[0760]

[0761] methylformamide (50 mL) was added caesium carbonate (36.1 g, 111 mmol, 4.00 eq.). The reaction was stirred at 25 °C for 16 h, then it was quenched with water (200 mL). The mixture was extracted with di chloromethane (3 x 200 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reversed phase column chromatography (Cl 8, 330 g, flow: 100 mL / min; gradient from: 12-12% water (0.1% formic acid) in acetonitrile over 2 h) and concentrated under reduced pressure to give 3-chloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluorobenzonitrile (2.30 g, 8.51 mmol, 31% yield) as a white solid.

[0762] Step 2. To a suspension of Raney nickel (1.70 g) in N,N-dimethylformamide (25 mL) and tetrahydrofuran (25 mL) were added 3-chloro-4-(2,4-dioxohexahydropyrimidin-l-yl)-5-fluoro- benzonitrile (2.3 g, 8.59 mmol, 1 eq.), di-tert-butyl dicarbonate (17.4 mmol, 4.00 mL, 2.03 eq.) and triethylamine (12.9 mmol, 1.80 mL, 1.50 eq.). The system was purged with argon 3 times. The mixture was stirred at 60 °C for 48 h under hydrogen (15 psi) atmosphere. After cooling to 25 °C, the mixture was filtered through a pad of Celite. The filter cake was washed with N, N-dimethylformamide (20 mL) and dichloromethane (20 mL). The filtrate was concentrated under reduced pressure. The crude product was distilled azeotropically with ethyl acetate (50 mL) at 45 °C under 0.1 MPa. The mixture was concentrated under reduced pressure to remove ethyl acetate. The solid was triturated with a solution of petroleum ether / ethyl acetate = 1 / 2 (50 mL) at 25 °C for 1 h. The mixture was filtered, and the filter cake was washed with petroleum ether (20 mL). The filter cake was collected and dried in vacuo to give tert-butyl (3-chloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluorobenzyl)carbamate (1.65 g, 4.26 mmol, 50% yield) as a white solid.

[0763] Step 3. A mixture of tert-butyl (3-chloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluorobenzyl)carbamate (1.76 g, 4.73 mmol, 1.00 eq.) in hydrogen chloride / ethyl acetate (50 mL) (2 M) was stirred at 25 °C for 3 h. The mixture was filtered, and the filter cake was washed with ethyl acetate (20 mL). The filter cake was collected and dried in vacuo to give 1-(4-(aminomethyl)-2-chloro-6-fluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (1.42 g, 4.33 mmol, 92% yield) as a white solid.

[0764] ’H NMR (400 MHz, DMSO-t / ,) d = 10.66 (s, 1H), 8.69 (s, 3H), 7.68 (s, 1H), 7.60 (d, J= 10.0 Hz, 1H), 4.07 (d, J = 5.2 Hz, 2H), 3.72 - 3.57 (m, 2H), 2.84 - 2.65 (m, 2H). MS (ESI) m / z 2 \ [M+H]+

[0765] Step 4. To a solution of methyl 2-(6-chl oropyri din-3 -yl)acetate (2.00 g, 10.8mmol, 1.0 eq.) in tetrahydrofuran (30 mL) was added lithium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 32 mL, 3.00 eq.) at 0 °C under nitrogen atmosphere. It was stirred at 0 °C for 30 min. Then methyl iodide (43.1 mmol, 2.7 mL, 4.00 eq.) was added, and the reaction was stirred at 25 °C for 30 min. The reaction was quenched by pouring into saturated ammonium chloride (30 mL) at 0 °C, and the mixture was extracted with ethyl acetate (30 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (3 × 30 mL). Combined extracts were washed with brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 20 g sepa flash® silica flash column, eluent of 0-20% ethyl acetate / petroleum ether gradient @ 80 mL / min) to give methyl 2-(6-chloropyridin-3-yl)-2-methylpropanoate (2.10 g, 8.85 mmol, 82% yield) as a colourless oil.

[0766] Step 5. A mixture of methyl 2-(6-chloropyridin-3-yl)-2-methylpropanoate (1.00 g, 4.68 mmol, 1.00 eq.) and caesium carbonate (3.81 g, 11.7 mmol, 2.50 eq.) in toluene (15 mL) was degassed and purged with nitrogen 3 times, then palladium(II) acetate (105 mg, 468 µmol, 0.10 eq.), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (112 mg, 234 µmol, 0.05 eq.) and ethyl alcohol (647 mg, 14.0 mmol, 3.00 eq.) were added to the mixture. The reaction was stirred at 110 °C for 36 h under nitrogen atmosphere, then it was concentrated in vacuo. Ethyl acetate (25 mL) and water (20 mL) were added to the residue, and the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The combined extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 12 g Sepa flash® silica flash column, eluent of 0-20% ethyl acetate / petroleum ether gradient @ 40 mL / min) to give methyl 2-(6-ethoxypyridin-3-yl)-2-methylpropanoate (500 mg, 2.00 mmol, 43% yield) as a colourless oil.

[0767] Step 6. To a solution of methyl 2-(6-ethoxypyridin-3-yl)-2-methylpropanoate (200 mg, 895 µmol, 1.00 eq.) in methanol (2 mL) and water (2 mL) was added sodium hydroxide (179 mg, 4.48 mmol, 5.00 eq.). The reaction was stirred at 25 °C for 30 min, then it was diluted with water (15 mL). The pH of the mixture was adjusted to 4 using IN hydrochloric acid at 0 °C, and it was extracted with dichloromethane (3 x 15 mL). The combined extracts were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-(6-ethoxypyridin-3-yl)-2-methylpropanoic acid (160 mg, 688 µmol, 77% yield) as a white solid.

[0768] Step 7. To a solution of 2-(6-ethoxypyridin-3-yl)-2-methylpropanoic acid (70.0 mg, 334 pmol, 1.00 eq.) in N,N-dimethylformamide (3 mL) were added N,N-diisopropylethylamine (1.67 mmol, 290 µL, 5.00 eq.) and 2-chloro-l-methyl-pyridinium iodide (102 mg, 401 pmol, 1.20 eq.) at 0 °C. The reaction was stirred at 20 °C for 0.5 h. Then 1-(4-(aminomethyl)-2-chloro-6-fluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (82.0 mg, 267 µmol, 0.80 eq.) was added, and the reaction was stirred at 20 °C for 0.5 h. The mixture was diluted with ethyl acetate (20 mL) and water (20 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The combined extracts were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 µm; mobile phase: [water (formic acid) - acetonitrile]; B%: 25% - 55%, 10 min) and lyophilized to give N-(3-chloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluorobenzyl)-2-(6-ethoxypyridin-3-yl)-2-methylpropanamide (67.42 mg, 144 µmol, 43% yield) as a white solid.

[0769] ’H NMR (400 MHz, DMSO-6) d = 10.61 (s, 1H), 8.13 (d, J = 2.4 Hz, 1H), 8.09 (t, J = 6.0 Hz, 1H), 7.60 (dd, J= 2.8, 8.8 Hz, 1H), 7.10 (s, 1H), 7.05 (d, J= 10.4 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 4.34 - 4.26 (m, 2H), 4.26 - 4.20 (m, 2H), 3.70 - 3.54 (m, 2H), 2.83 - 2.63 (m, 2H), 1.51 (s, 6H), 1.31 (t, J = 7.2 Hz, 3H). MS (ESI) m / z 463.1 [M+H]+

[0770] Synthesis of Compound 70

[0771]

[0772] Step 1. To a solution of tert-butyl methyl mal onate (27.4 g, 157 mmol, 1.50 eq.) in dimethylsulfoxide (150 mL) were added caesium carbonate (68.4 g, 210 mmol, 2.00 eq.) and 2,5-dibromopyrazine (25.0 g, 105 mmol, 1.00 eq.) in portions at 25 °C. The mixture was stirred at 80 °C for 2.5 h. The mixture was cooled to 25 °C then poured into water (200 mL). The mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 120 g Sepa Flash® Silica Flash Column, eluent of 0~6% ethyl acetate / petroleum ether gradient @ 120 mL / min) to give 1-(tert-butyl) 3-methyl 2-(5-bromopyrazin-2-yl)malonate (35.0 g, 96.1 mmol, 91% yield) as a yellow oil. Step 2. To a solution of 1-(tert-butyl) 3-methyl 2-(5-bromopyrazin-2-yl)malonate (35.0 g, 105 mmol, 1.00 eq.) in dichloromethane (50 mL) was added trifluoroacetic acid (50 mL) dropwise at 25 °C. The mixture was stirred at 25 °C for 2 h. The reaction was quenched with saturated aqueous sodium bicarbonate (200 mL), and solid sodium bicarbonate was added in portions until pH = 7-8. The mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 120 g Sepa Flash® Silica Flash Column, eluent of 0-18% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give methyl 2-(5-bromopyrazin-2-yl)acetate (17.0 g, 69.9 mmol, 66% yield) as a yellow oil.

[0773] Step 3. To a mixture of sodium hydride (8.83 g, 220 mmol, 60% purity, 3.00 eq.) in tetrahydrofuran (180 mL) was added a solution of methyl 2-(5-bromopyrazin-2-yl)acetate (17.0 g, 73.5 mmol, 1.00 eq.) in tetrahydrofuran (20 mL) dropwise at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then iodomethane (52.2 g, 367 mmol, 5.00 eq.) was added, and the mixture was stirred at 25 °C under nitrogen atmosphere for 1 h. The reaction was quenched with saturated aqueous ammonium chloride (200 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 120 g Sepa Flash® Silica Flash Column, eluent of 0-13% ethyl acetate / petroleum ether gradient @ 120 mL / min) to give methyl 2-(5-bromopyrazin-2-yl)-2-methylpropanoate (15.0 g, 57.9 mmol, 55% yield) as a colourless oil.

[0774] Step 4. Sodium hydride (385 mg, 9.65 mmol, 60% purity, 5.00 eq.) was added into ethanol (20 mL) in portions at 0 °C. The mixture was stirred at 25 °C for 10 min, then a solution of methyl 2-(5-bromopyrazin-2-yl)-2-methylpropanoate (500 mg, 1.93 mmol, 1.00 eq.) in ethanol (5 mL) was added. The mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. The mixture was cooled to 25 °C and concentrated in vacuo. The residue was poured into water (20 mL) and adjusted to pH = 3-4 with 6% aqueous hydrochloric acid. The mixture was extracted with di chloromethane (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2-(5-ethoxypyrazin-2-yl)-2-methylpropanoic acid (370 mg, 1.41 mmol, 72% yield) as a yellow solid. Step 5. To a solution of 2-(5-ethoxypyrazin-2-yl)-2-methylpropanoic acid (110 mg, 418 µmol, 1.00 eq.) and diisopropylethylamine (162 mg, 1.26 mmol, 3.00 eq.) in dimethylformamide (1 mL) was added 2-chloro-1-methyl-pyridin-1-ium; iodide (128 mg, 502 µmol, 1.20 eq.) in one portion at 25 °C. The mixture was stirred at 25 °C for 0.5 h, then 1-(4-(aminomethyl)-2-chloro-6-fluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (128 mg, 418 µmol, 1.00 eq., hydrochloride) was added. The mixture was stirred at 25 °C for 1 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: YMC-Actus Triart C18 150 mm × 30 mm × 7 µm; mobile phase: [water (formic acid) - acetonitrile]; gradient:33%-63% B over 10 min) then lyophilized to give N-(3-chloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluorobenzyl)-2-(5-ethoxypyrazin-2-yl)-2-methylpropanamide (111 mg, 238 µmol, 56% yield) as a white solid.

[0775] ’H NMR (400 MHz, DMSO- / / 6) d = 10.61 (s, 1 H), 8.23 (q, J= 1.6 Hz, 2 H), 8.02 (t, J= 6.0 Hz, 1 H), 7.20 (s, 1 H), 7.13 (dd, J= 10.4, 1.6 Hz, 1 H), 4.34 (q, J= 7.2 Hz, 2 H), 4.24 (d, J= 6.0 Hz, 2 H), 3.54 - 3.71 (m, 2 H), 2.63 - 2.82 (m, 2 H), 1.54 (s, 6 H), 1.34 (t, J= 7.2 Hz, 3 H). MS (ESI) m / z 464.1 [M+H]+ Synthesis of Compound 73

[0776]

[0777] Step 1. To a solution of 2-aminopyri din-3 -ol (1.00 g, 9.08 mmol, 1.00 eq.) in ethanol (15 mL) was added ethyl 3 -ethoxy-3 -imino-propanoate hydrochloride (1.95 g, 9.99 mmol, 1.10 eq.) in one portion at 25 °C. The solution was stirred at 80 °C for 40 h. The mixture was cooled to 20 °C and poured into saturated aqueous sodium bicarbonate (20 mL). The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® Silica Flash Column, eluent of 0-45% ethyl acetate / petroleum ether gradient @ 20 mL / min) to give ethyl 2-(oxazolo[4,5-b]pyridin-2-yl)acetate (560 mg, 2.69 mmol, 29% yield) as a light-yellow oil.

[0778] Step 2. To a mixture of ethyl 2-(oxazolo[4,5-b]pyri din-2 -yl)acetate (500 mg, 2.42 mmol, 1.00 eq.) and caesium carbonate (2.37 g, 7.27 mmol, 3.00 eq.) in acetonitrile (10 mL) was added iodomethane (860 mg, 6.06 mmol, 2.50 eq.) dropwise at 25 °C. The reaction was stirred at 25 °C for 12 h. The mixture was diluted with ethyl acetate (20 mL), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® Silica Flash Column, eluent of 0-40% ethyl acetate / petroleum ether gradient @ 20 mL / min) to give ethyl 2-methyl-2-(oxazolo[4,5-b]pyridin-2-yl)propanoate (450 mg, 1.82 mmol, 75% yield) as a light-yellow oil. Step 3. To a mixture of ethyl 2-methyl-2-(oxazolo[4,5-b]pyridin-2-yl)propanoate (100 mg, 427 pmol, 1.00 eq.) in methanol (2 mL) and water (2 mL) was added sodium hydroxide (85.4 mg, 854 pmol, 2.00 eq.) in one portion at 25 °C. The reaction was stirred at 25 °C for 2 h. The mixture was poured into water (20 mL) and adjusted to pH = 7-8 with 2N hydrochloric acid, then lyophilized to give sodium 2-methyl-2-(oxazolo[4,5-b]pyridin-2-yl)propanoate (200 mg, 219 pmol, 51% yield, 25% purity) as a white solid.

[0779] Step 4. To a mixture of sodium 2-methyl-2-(oxazolo[4,5-b]pyridin-2-yl)propanoate (200 mg, 219 pmol, 1.00 eq., 25% purity) and 2-chloro-l-methyl-pyridin-l-ium iodide (67.7 mg, 263 pmol, 1.20 eq.) in dimethylformamide (3 mL) was added diisopropylethylamine (113 mg, 877 pmol, 4.00 eq.) dropwise at 25 °C. The mixture was stirred at 25 °C for 0.5 h, then l-(4-(aminomethyl)-2,6-dichlorophenyl)dihydropyrimidine-2,4(lH,3H)-dione hydrochloride (56.9 mg, 175 pmol, 0.80 eq.) was added. The reaction was stirred at 25 °C for 1 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (column: Waters Xbridge 150 mm

[0780]

[0781] mobile phase: [water (ammonium bicarbonate)-acetonitrile]; gradient: 10%-40% B over 15 min) then lyophilized to give N-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)benzyl)-2-methyl-2-(oxazolo[4,5-b]pyridin-2-yl)propanamide (51.9 mg, 107 pmol, 48% yield) as a white solid.

[0782] ’H NMR (400 MHz, DMSO-6) d = 10.59 (br s, 1H), 8.59 - 8.50 (m, 2H), 8.17 (dd, J= 1.2, 8.0 Hz, 1H), 7.45 (dd, J= 4.8, 8.0 Hz, 1H), 7.37 (s, 2H), 4.30 (d, J= 6.0 Hz, 2H), 3.60 (t, J= 6.8 Hz, 2H), 2.74 (t, J= 6.8 Hz, 2H), 1.70 (s, 6H). MS (ESI) m / z 476.1 [M+H]+ Synthesis of Compound 77

[0783]

[0784] Step 1. To a solution of 5-bromo-2-(difluoromethoxy)pyridine (1.30 g, 5.80 mmol, 1.00 eq.) in dimethylsulfoxide (8 mL) and water (4 mL) were added 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoxazole (1.70 g, 8.71 mmol, 1.50 eq.) and potassium fluoride (1.01 g, 17.4 mmol, 3.00 eq.). Then [l,l'-bis(diphenylphosphino)ferrocene]di chloropalladium (II) (425 mg, 580 pmol, 0.10 eq.) was added. The reaction was stirred at 120 °C for 12 h under nitrogen atmosphere. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 * 30 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g Sepa Flash® Silica Flash Column, Eluent of 0 - 34% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to give 2-(6-(difluoromethoxy)pyridin-3-yl)acetonitrile (428 mg, 2.21 mmol, 38% yield) as a yellow oil. Step 2. To a solution of 2-(6-(difluorom ethoxy )pyri din-3 -yl)acetonitrile (595 mg, 3.23 mmol, 1.00 eq.) in tetrahydrofuran (5 mL) was added sodium hydride (388 mg, 9.69 mmol, 60% purity, 3.00 eq.) under nitrogen atmosphere. The reaction was stirred at 0 °C for 30 min, then the methyl iodide (1.38 g, 9.69 mmol, 3.00 eq.) was added. The reaction was stirred at 25 °C for 1 h, then it was quenched with saturated ammonium chloride (50 mL) at 0 °C and extracted with ethyl acetate (3 x 15 mL). The combined organic extracts were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® Silica Flash Column, Eluent of 0 - 25 % Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to give the 2-(6-(difluoromethoxy)pyridin-3-yl)-2-methylpropanenitrile (502 mg, 2.32 mmol, 72% yield) as a yellow oil.

[0785] Step 3. A solution of 2-(6-(difluoromethoxy)pyridin-3-yl)acetonitrile (200 mg, 943 pmol, 1.00 eq.) in hydrochloric acid (12 M, 3 mL) was stirred at 60 °C for 12 h. The mixture was diluted with water (30 mL) and the pH of the mixture was adjusted to 4 - 5 with saturated sodium bicarbonate. Then it was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the 2-(6-(difluorom ethoxy)pyri din-3 -yl)-2-m ethylpropanoic acid (205 mg, 860 pmol, 91% yield) as a yellow oil. It was used directly in the next step without purification.

[0786] Step 4. To a solution of 2-(6-(difluorom ethoxy )pyri din-3 -yl)-2-methylpropanoic acid (200 mg, 865 pmol, 1.50 eq.) in

[0787]

[0788] -di methyl formamide (3 mL) were added 2-chloro-l-methyl-pyridin-l-ium iodide (221 mg, 865 pmol, 1.50 eq.) and N,N-diisopropylethylamine (224 mg, 1.73 mmol, 3.00 eq.). The mixture was stirred at 25 °C for 30 min, then l-(4-(aminomethyl)-2,6-dichlorophenyl)dihydropyrimidine-2, 4(1 / 7, 37 / )-dione hydrochloride (187 mg, 577 pmol, 1.00 eq.) was added. The reaction was stirred at 25 °C for 1 h. The mixture was diluted with water (75 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with water (35 mL) and brine (35 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by / c -HPLC (column: Welch Xtimate C18 150 * 25 mm * 5 / / m; mobile phase: [water (formic acid) - acetonitrile]; gradient: 35% - 55% B over 10 min). It was collected and lyophilized to give the 7V-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimi din- l(2J7)-yl)benzyl)-2-(6-(difluoromethoxy)pyri din-3 -yl)-2-methylpropanamide (216.18 mg, 427 pmol, 74% yield) as a white solid.

[0789] ’H NMR (400 MHz, D SO-A) 3 = 10.61 (s, 1H), 8.23 (d, J= 2.4 Hz, 1H), 8.18 (t, J= 6.0 Hz, 1H), 7.91 - 7.45 (m, 2H), 7.25 (s, 2H), 7.05 (d, J= 8.4 Hz, 1H), 4.24 (d, J= 6.0 Hz, 2H), 3.59 (t, J= 6.8 Hz, 2H), 2.74 (t, J= 6.8 Hz, 2H), 1.53 (s, 6H). MS (ESI) m / z 501.1 [M+H]+ Synthesis of Compound 78

[0790]

[0791] Step 1. To a solution of (6-brom opyri din-3 -yl) methanol (2.00 g, 10.6 mmol, 1.00 eq.) in di chloromethane (30 mL) was added tert-butylchlorodimethylsilane (16.0 mmol, 1.96 mL, 1.50 eq.) and imidazole (1.45 g, 21.3 mmol, 2.00 eq.). The reaction mixture was stirred at 25 °C for 1 h. The mixture was diluted with water (30 mL) and extracted with dichloromethane (3 x 30 mL). The combined organic layers were washed with water (60 mL) and brine (60 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 2-brorno-5-((( / c / 7-butyldimethylsilyl)oxy)methyl)pyridine (3.50 g, 10.4 mmol, 98% yield) as a yellow oil.

[0792] Step 2. To a solution of dicyclohexylamine (12.4 mmol, 2.47 mL, 1.50 eq.) in toluene (30 mL) was added / / -butyl lithium (2.5 M in n-hexane, 5.00 mL, 1.51 eq.) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 15 min, then methyl isobutyrate (12.4 mmol, 1.42 mL, 1.50 eq.) was added to the mixture at 0 °C. The mixture was stirred at 25 °C for 15 min, then 2-bromo-5-(((te / 7-butyldimethylsilyl)oxy)methyl)pyridine (2.50 g, 8.27 mmol, 1.00 eq.), tri-Zc / 7-butylphosphane (426 / / mol, 0.40 mL, 25% purity, 0.05 eq.) and bis(dibenzylideneacetone)palladium(0) (238 mg, 414 / / mol, 0.05 eq.) were added, and the reaction was stirred at 25 °C under nitrogen atmosphere for 1 h. The reaction was quenched with water (30 mL) at 0 °C and stirred at 0 °C for 30 min. The mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with water (60 mL) and brine (60 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO ®; 12 g Sepa Flash ® Silica Flash Column, Eluent of 0-17% Ethyl acetate / Petroleum ether gradient @ 20 mL / min) to give methyl 2-(5-((( / c / 7-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-2-methylpropanoate (2.32 g, 5.74 mmol, 69% yield) as a yellow solid.

[0793] Step 3. To a solution of methyl 2-(5-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-2-methylpropanoate (2.20 g, 6.80 mmol, 1.00 eq.) in tetrahydrofuran (20 mL) was added tetrabutyl ammonium fluoride (IM tetrahydrofuran, 10.2 mL, 1.50 eq.) at 0 °C under nitrogen atmosphere. The mixture was stirred at 25 °C under nitrogen for 1 h. The mixture was adjusted to pH = 6 with IM hydrochloric acid, diluted with water (40 mL), and extracted with ethyl acetate (40 mL). The organic layer was washed with water (3 x 40 mL) and brine (40 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO ®; 12 g Sepa Flash ® Silica Flash Column, Eluent of 0-52% Ethyl acetate / Petroleum ether gradient @ 20 mL / min) to give methyl 2-(5-(hydroxymethyl)pyridin-2-yl)-2-methylpropanoate (730 mg, 3.31 mmol, 49% yield) as a colourless oil.

[0794] Step 4. To a solution of methyl 2-(5-(hydroxymethyl)pyridin-2-yl)-2-methylpropanoate (950 mg, 4.54 mmol, 1.00 eq.) in tetrahydrofuran (10 mL) was added sodium hydride (380 mg, 9.50 mmol, 60% purity, 2.09 eq.) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 0.5 h. Carbon disulfide (9.12 mmol, 0.55 mL, 2.01 eq.) was added dropwise, and the reaction was stirred at 0 °C under nitrogen atmosphere for 0.5 h. Then methyl iodide (9.08 mmol, 565 «L, 2.00 eq.) was added, and the reaction was stirred at 25 °C under nitrogen atmosphere for 1 h. The reaction was quenched with saturated ammonium chloride solution (20 mL) at 0 °C and diluted with ethyl acetate (20 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO ®; 12 g Sepa Flash ® Silica Flash Column, Eluent of 0-15% Ethyl acetate / Petroleum ether gradient @ 30 mL / min) to give methyl 2-methyl-2-(5-((((methylthio)carbonothioyl)oxy)methyl)pyridin-2-yl)propanoate (776 mg, 2.07 mmol, 46% yield) as a colourless oil.

[0795] Step 5. To a solution of l,3-dibromo-5,5-dimethylimidazolidine-2, 4-dione (2.94 g, 10.3 mmol, 4.00 eq.) in dichloromethane (15 mL) was added pyridine hydrofluoride (25.7 mmol, 3.31 mL, 70% purity, 10.0 eq.) at -60 °C under nitrogen atmosphere. The mixture was stirred at -60 °C for 0.5 h, then methyl 2-methyl-2-(5-((((methylthio)carbonothioyl)oxy)methyl)pyri din-2 -yl)propanoate (770 mg, 2.57 mmol, 1.00 eq.) in dichloromethane (3 mL) was added dropwise. The reaction was stirred at 0 °C under nitrogen atmosphere for 2 h. The reaction was quenched with saturated sodium bicarbonate (20 mL) at 0 °C and diluted with dichloromethane (20 mL). The layers were separated, and the aqueous phase was extracted with dichloromethane (2 x 20 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO ®; 12 g Sepa Flash ® Silica Flash Column, Eluent of 0-15% Ethyl acetate / Petroleum ether gradient @ 30 mL / min) to give methyl 2-methyl-2-(5-((trifluoromethoxy)methyl)pyri din-2 -yl)propanoate (207 mg, 658 / / mol, 25% yield) as a yellow oil.

[0796] Step 6. To a solution of methyl 2-methyl-2-(5-((trifluoromethoxy)methyl)pyridin-2-yl)propanoate (140 mg, 505 / / mol, 1.00 eq.) in tetrahydrofuran (1.5 mL) and water (1.5 mL) was added lithium hydroxide monohydrate (48.4 mg, 2.02 mmol, 4.00 eq.). The mixture was stirred at 25 °C for 6 h. The pH of the mixture was adjusted to 7 with IM hydrochloric acid and lyophilized to give 2-methyl-2-(5-((trifhioromethoxy)methyl)pyridin-2-yl)propanoic acid (107 mg, crude) as a white solid.

[0797] Step 7. To a solution of 2-methyl-2-(5-((trifluoromethoxy)methyl)pyridin-2-yl)propanoic acid (107 mg, crude) in TV, TV-dim ethyl formamide (4 mL) were added N,N-diisopropylethylamine (977 / / mol, 170 / / L, 3.00 eq.) and 2-chloro-l-methyl-pyridin-l-ium iodide (99.7 mg, 390 / / mol, 1.20 eq.). After addition, the mixture was stirred at 25 °C for 30 min, then 1-(4-(aminomethyl)-2,6-dichlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (52.8 mg, 163 / / mol, 0.50 eq.) was added. The reaction was stirred at 25 °C for 1 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with water (2 x 15 mL) and brine (15 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by / vc -HPLC [column: Welch Xtimate C 18 150 * 25 mm * 5 / / m; mobile phase: [water (formic acid) - acetonitrile]; gradient: 38% - 58% B over 10 min). The desired fraction was collected and lyophilized to give 7V-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-1 (277)-yl)benzyl)-2-methyl-2-(5-((tri fluoromethoxy )methyl)pyridin-2-yl) propanamide (21.01 mg, 39.0 / / mol, 12% yield) as a white solid. ’H NMR (400 MHz, DMSO-6) = 10.59 (s, 1H), 8.65 (d, J = 2.0 Hz, 1H), 8.10 (t, J = 6.0 Hz, 1H), 7.87 (dd, J= 2.4, 8.4 Hz, 1H), 7.48 (d, J= 8.4 Hz, 1H), 7.40 (s, 2H), 5.24 (s, 2H), 4.27 (d, J = 6.0 Hz, 2H), 3.60 (t, J= 6.8 Hz, 2H), 2.75 (t, J= 6.8 Hz, 2H), 1.53 (s, 6H). MS (ESI) m / z 533.1 [M+H]+

[0798] Synthesis of Compound 79

[0799]

[0800] Step 1. To a solution of 6-methylpyri din-3 -ol (5.00 g, 45.8 mmol, 1.00 eq.) in N, N-dimethylformamide (70 mL) was added 1H-imidazole (6.24 g, 91.6 mmol, 2.00 eq.) under nitrogen atmosphere. Then a solution of tert-butyldimethylsilyl chloride (9.32 g, 61.8 mmol, 1.35 eq.) in methylformamide (35 mL) was added slowly, and the reaction was stirred at 25 °C for 2 h under nitrogen atmosphere. The reaction was quenched with water (80 mL) and extracted with ethyl acetate (2 x 80 mL). The combined extracts were washed with water (100 mL) and brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 80 g Sepa flash® silica flash column, eluent of 0-20% ethyl acetate / petroleum ether gradient @ 130 mL / min) to give 5-(( / c / 7-butyldimethylsilyl)oxy)-2-methylpyridine (10.6 g, 37.9 mmol, 82% yield) as a colourless oil. Step 2. To a solution of 5-((terLbutyldimethylsilyl)oxy)-2-methylpyridine (2.00 g, 8.95 mmol, 1.00 eq.) in tetrahydrofuran (30 mL) at -70 °C was added slowly lithium diisopropyl amide (2 M in tetrahydrofuran, 18.0 mL, 4.00 eq.) under nitrogen atmosphere. It was stirred at -70 °C for 10 min. Then a solution of dimethyl carbonate (3.24 g, 35.9 mmol, 4.00 eq.) in tetrahydrofuran (10 mL) was added, and the reaction was stirred at -70 °C for 1 h. The reaction was quenched with saturated ammonium chloride solution (15 mL) at 0 °C and extracted with ethyl acetate (2 x 75 mL). The combined organic layers were washed with water (2 x 40 mL) and brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g Sepa flash® silica flash column, eluent of 0-40% ethyl acetate / petroleum ether gradient @ 50 mL / min) to give methyl 2-(5-((leri-butyldimethylsilyl)oxy)pyridin-2-yl)acetate (970 mg, 3.10 mmol, 34% yield) as a yellow oil. Step 3. To a solution of methyl 2-(5-((terLbutyldimethylsilyl)oxy)pyridin-2-yl)acetate (770 mg, 2.74 mmol, 1.00 eq.) in tetrahydrofuran (10 mL) was added lithium bis(trimethylsilyl)amide (IM in tetrahydrofuran, 8.2 mL, 3.00 eq.) at 0 °C under nitrogen atmosphere. It was stirred at 0 °C for 30 min, then methyl iodide (10.9 mmol, 680 μL, 4.00 eq.) was added, and the reaction was stirred at 25 °C for 1 h. The mixture was poured into saturated ammonium chloride (20 mL) and extracted with ethyl acetate (30 mL). The layers were separated, and the organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 4 g sepa flash® silica flash column, eluent of 0-20% ethyl acetate / petroleum ether gradient @ 50 mL / min) to give methyl 2-(5-((terLbutyldimethylsilyl)oxy)pyridin-2-yl)-2-methylpropanoate (750 mg, 2.18 mmol, 79% yield) as a yellow oil.

[0801] Step 4. To a solution of methyl 2-(5-((terLbutyldimethylsilyl)oxy)pyridin-2-yl)-2-methylpropanoate (650 mg, 2.10 mmol, 1.00 eq.) in tetrahydrofuran (8 mL) was added tetrabutyl ammonium fluoride (IM in tetrahydrofuran 2.27 mL, 1.08 eq.). The reaction was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (20 mL) and water (20 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (20 mL). The combined extracts were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 4 g sepa flash® silica flash column, eluent of 0-40% ethyl acetate / petroleum ether gradient @ 50 mL / min) to give methyl 2-(5-hydroxypyridin-2-yl)-2-methylpropanoate (300 mg, 1.38 mmol, 65% yield) as a white solid.

[0802] Step 5. To a solution of methyl 2-(5-hydroxypyridin-2-yl)-2-methylpropanoate (300 mg, 1.54 mmol, 1.00 eq.) in N,N-dimethylformamide (8 mL) were added caesium carbonate (1.00 g, 3.07 mmol, 2.00 eq.) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (535 mg, 2.31 mmol, 1.50 eq.). The reaction was stirred at 80 °C for 2 h. The mixture was diluted with ethyl acetate (20 mL) and water (20 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The combined extracts were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 4 g sepa flash® silica flash column, eluent of 0-30% ethyl acetate / petroleum ether gradient @ 50 mL / min) to give methyl 2-methyl-2-[5-(2,2,2-trifluoroethoxy)-2-pyridyl]propanoate (360 mg, 1.17 mmol, 76% yield) as a colourless oil.

[0803] Step 6. To a solution of methyl 2-methyl-2-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)propanoate (200 mg, 721 pmol, 1.00 eq.) in methanol (4 mL) was added a solution of sodium hydroxide (144 mg, 3.61 mmol, 5.00 eq.) in water (4 mL) at 0 °C. The reaction was stirred at 25 °C for 4 h. Water (5 mL) was added, then the pH of the mixture was adjusted to 4 with IN hydrochloric acid at 0 °C. The mixture was extracted with dichloromethane (2 x 5 mL). The combined organic phases were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give 2-methyl-2-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)propanoic acid (120 mg, 410 μmol, 57% yield) as a white solid.

[0804] Step 7. To a solution of 2-methyl-2-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)propanoic acid (100 mg, 380 pmol, 1.00 eq.) in N,N-dimethylformamide (1 mL) were added N, N-diisopropylethylamine (1.90 mmol, 330 pL, 5.00 eq.) and 2-chloro-l-methyl-pyridinium iodide (116 mg, 455 pmol, 1.20 eq.) at 0 °C. The reaction was stirred at 25 °C for 1 h. Then l-(4-(aminomethyl)-2,6-dichlorophenyl)dihydropyrimidine-2, 4(1 / 7, 3J7)-di one hydrochloride (80.0 mg, 246 pmol, 0.65 eq.) was added, and the reaction was stirred at 25 °C for 0.5 h. The mixture was diluted with ethyl acetate (20 mL) and water (20 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 20 mL). The combined extracts were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by / i / c -HPLC (column: Phenomenex luna C18 150 * 25 mm * 10 / m; mobile phase: [water (formic acid) - acetonitrile]; B%: 32% - 62%, 9 min). The desired fraction was collected and lyophilized to give 7V-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-l(2 / 7)-yl)benzyl)-2-methyl-2-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)propanamide (61.17 mg, 113 pmol, 29% yield) as a white solid.

[0805] ’H NMR (400 MHz, DMSO-6) d = 10.60 (s, 1H), 8.37 (d, J = 3.2 Hz, 1H), 8.02 (t, J = 6.0 Hz, 1H), 7.53 (dd, J= 3.2, 8.8 Hz, 1H), 7.40 (d, J= 8.8 Hz, 1H), 7.37 (s, 2H), 4.87 (q, J= 8.8 Hz, 2H), 4.26 (d, J= 6.0 Hz, 2H), 3.61 (t, J= 6.8 Hz, 2H), 2.75 (t, J= 6.8 Hz, 2H), 1.52 (s, 6H). MS (ESI) m / z 533.0 [M+H]+

[0806] Synthesis of Compound 81

[0807]

[0808] Step 1. To a solution of sodium hydride (6.00 g, 150 mmol, 60% purity, 2.45 eq.) in tetrahydrofuran (120 mL) was added dropwise ethyl 2-(5-bromopyrimidin-2-yl)acetate (15.0 g, 61.2 mmol, 1.00 eq.) in tetrahydrofuran (10 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 30 min, then iodomethane (15.0 mL, 240 mmol, 3.94 eq.) was added, and the reaction was stirred at 25 °C for 1.5 h. The reaction was quenched by adding it dropwise to saturated ammonium chloride (100 mL) at 0 °C under nitrogen atmosphere, then ethyl acetate (100 mL) was added. The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-10% ethyl acetate / petroleum ether) to give ethyl 2-(5-bromopyrimidin-2-yl)-2-methylpropanoate (11.2 g, 38.1 mmol, 62% yield) as a yellow oil.

[0809] Step 2. To a solution of ethyl 2-(5-bromopyrimidin-2-yl)-2-methylpropanoate (1.00 g, 3.66 mmol, 1.00 eq.) in dioxane (20 mL) and water (5 mL) were added [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (300 mg, 410 μmol, 0.10 eq.), caesium carbonate (2.50 g, 7.67 mmol, 2.10 eq.), and 4,4,5,5-tetramethyl-2-(prop-l-en-2-yl)-l,3,2-dioxaborolane (700 mg, 4.17 mmol, 1.14 eq.). The mixture was stirred at 100 °C for 1.5 h. The mixture was filtered, and the filtrate was diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-30% ethyl acetate / petroleum ether) to afford ethyl 2-methyl-2-(5-(prop-l-en-2-yl)pyrimidin-2-yl)propanoate (400 mg, 1.69 mmol, 46% yield) as a colourless oil.

[0810] Step 3. To a solution of palladium on carbon (100 mg, 10% purity) in ethyl acetate (5 mL) was added a solution of ethyl 2-methyl-2-(5-(prop-l-en-2-yl)pyrimidin-2-yl)propanoate (400 mg, 1.71 mmol, 1.00 eq.) in ethyl acetate (3 mL) under nitrogen atmosphere. The mixture was stirred at 25 °C under hydrogen (15 psi) for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to afford ethyl 2-(5-isopropylpyrimidin-2-yl)-2-methylpropanoate (400 mg, 1.68 mmol, 98% yield) as a colourless oil.

[0811] Step 4. To a solution of ethyl 2-(5-isopropylpyrimidin-2-yl)-2-methylpropanoate (200 mg, 846 μmol, 1.00 eq.) in methanol (3 mL) was added sodium hydroxide (200 mg, 5.00 mmol, 5.91 eq.) and water (2 mL). The reaction was stirred at 25 °C for 16 h. The mixture was diluted with water (10 mL) and dichloromethane (10 mL). The aqueous phase was separated and washed with di chloromethane (10 mL). The pH of the aqueous phase was adjusted to 6 with hydrochloric acid (I M) and extracted with di chloromethane (3 x 10 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 2-(5-isopropylpyrimidin-2-yl)-2 -methylpropanoic acid (100 mg, 475 μmol, 56% yield) as a white solid.

[0812] Step 5. To a solution of 2-(5-isopropylpyrimidin-2-yl)-2-methylpropanoic acid (100 mg, 480 pmol, 1.29 eq.) in dimethylformamide (3 mL) were added 2-chloro-l-methyl-pyridin-l-ium iodide (115 mg, 450 μmol, 1.21 eq.) and N,N-diisopropylethylamine (200 pL, 1.15 mmol, 3.10 eq.) at 0 °C. The mixture was stirred at 25 °C for 0.5 h, then l-(4-(aminomethyl)-2,6-dichlorophenyl)dihydropyrimidine-2, 4(1 / 7, 37 / )-dione hydrochloride (120 mg, 370 pmol, 1.00 eq.) was added, and the reaction was stirred at 25 °C for 1.5 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by / i / c -HPLC (column: Welch Xtimate Cl 8 150 x 25 mm x 5

[0813]

[0814] mobile phase: [water (formic acid) - acetonitrile]; gradient: 5%-55% B over 15 min) and lyophilized to afford 7V-(3,5-dichloro-4-(2,4-dioxotetrahydropyrimidin-l(2J7)-yl)benzyl)-2-(5-isopropylpyrimidin-2-yl)-2-methylpropanamide (109 mg, 227 μmol, 61% yield) as an off-white solid.

[0815] 1H NMR (400 MHz, DMSO-tL) d = 10.60 (s, 1H), 8.72 (s, 2H), 8.13 (s, 1H), 7.49 (s, 2H), 4.29 (s, 2H), 3.61 (s, 2H), 3.06 - 2.88 (m, 1H), 2.75 (s, 2H), 1.54 (s, 6H), 1.26 (d, J = 6.0 Hz, 6H). MS (ESI) m / z 478.2 [M+H]+

[0816] Synthesis of Compound 85

[0817]

[0818] Step 1. To a solution of 2, 5 -dibromopyrazine (10.0 g, 42.0 mmol, 1.00 eq.) in dimethyl sulfoxide (60 mL) were added caesium carbonate (27.4 g, 84.1 mmol, 2.00 eq.) and tert-butyl methyl malonate (11.0 g, 63.1 mmol, 1.50 eq.). The reaction was stirred at 80 °C for 5 h. The mixture was diluted with water (80 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (2 x 100 mL) and brine (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0~6% ethyl acetate / petroleum ether) to give 1 -(tert-butyl) 3-methyl 2-(5-bromopyrazin-2-yl) malonate (15.0 g, 40.8 mmol, 97% yield) as a yellow oil.

[0819] Step 2. To a solution of l-(tert-butyl) 3-methyl 2-(5-bromopyrazin-2-yl)malonate (15.0 g, 45.3 mmol, 1.00 e...

Claims

1. CLAIMS1. A compound having formula (I):

4. 6.or a pharmaceutically acceptable salt thereof; wherein:7.R1, R2a, and R2bare defined according to (A) and (B) below:8.(A)9.R1is:10.• heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o- 2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc;11.• heterocyclyl including 4-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc;12.• C3-7 cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc;13.• heterocycloalkenyl including 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc; or • Ce-io aryl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc; and14.each of R2aand R2bis independently selected from the group consisting of:15.• H;16.• Ci-2 alkyl optionally substituted with from 1-5 Ra;17.• C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb;18.• C1-4 alkoxy;19.• C1-4 haloalkoxy; or20.• cyano; or21.R2aand R2btaken together with the carbon atom to which each is attached forms:22.• C3-7 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb;23.• heterocyclyl including 4-7 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb;24.(B)25.R1taken together with (i) the carbon atom to which it is attached and (ii) and one of R2aand R2bforms:26.• C8-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc; or27.• heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc; and28.the other of R2aand R2bis H or C1-2 alkyl optionally substituted with from 1-5 Ra; R3is H; Ci-2 alkyl, which is optionally substituted with 1-5 fluoro; fluoro; or chloro;29.R4is chloro; bromo; or fluoro; optionally wherein it is provided that R4is fluoro when R3is chloro;30.each occurrence of Rais independently selected from the group consisting of: -OH; -halo; -NReRf; Ci-4 alkoxy; Ci-4haloalkoxy,; -C(=O)O(Ci-4alkyl); -C(=O)(Ci-4alkyl); -C(=O)OH; -CONR’R”; -S(O)I-2NR’R”; -S(O)1-2(C1-4alkyl); and cyano;31.each occurrence of Rbis independently selected from the group consisting of: halo; cyano; Ci-io alkyl which is optionally substituted with from 1-6 independently selected Ra; C2-6 alkenyl; C2-6 alkynyl; Ci-4alkoxy; -O(Ci-3 alkylene)-(C3-6 cycloalkyl); Ci-4haloalkoxy; -S(0)o-2(Ci-4alkyl); -NReRf; -OH; -S(O)I-2NR’R”; -NO2; -C(=0)(Ci-io alkyl); -C(=O)O(Ci-4alkyl); -C(=O)OH; and -C(=O)NR’R”;32.each occurrence of Rcis independently selected from the group consisting of:33.• C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb;34.• heterocyclyl or heterocycloalkenyl including 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and Rb;35.• heteroaryl including 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with from 1-4 Rb; and36.• Ce-io aryl optionally substituted with from 1-4 Rb;37.each occurrence of Rdis independently selected from the group consisting of: C1-6 alkyl optionally substituted with from 1-3 independently selected Ra; -C(O)(Ci-4alkyl); -C(O)O(Ci-4alkyl); -CONR’R”; -S(O)I-2NR’R”; -S(O)1-2(C1-4alkyl); -OH; and Ci-4alkoxy; and each occurrence of Reand Rfis independently selected from the group consisting of: H; Ci-6 alkyl; -C(O)(Ci-4alkyl); -C(O)O(Ci-4alkyl); -CONR’R”; -S(O)I-2NR’R”; -S(O)1-2(C1-4alkyl); -OH; and Ci-4alkoxy; and38.each occurrence of R’ and R” is independently selected from the group consisting of: H; and Ci-4alkyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1, R2a, and R2bare defined according to (A).

3. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R1is heteroaryl including 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

4. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R1has the formula:

45. 47.wherein each of X1, X2, X3, and X4is, independently, CH or N; and R11is H, Rb, or Rc, preferably wherein R1has the formula:

53.

5. The compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof, wherein R1has the formula:

57.

6. The compound of claims 4 or 5 or a pharmaceutically acceptable salt thereof, wherein R11is unsubstituted C1-3 alkyl.

7. The compound of claims 4 or 5 or a pharmaceutically acceptable salt thereof, wherein R11is CF3.

8. The compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof, wherein R1has the formula:

64.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein R11is CN.

10. The compound of any of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R1is heteroaryl including 9 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein R1is:

69.

12. The compound of any one of claims 1-3, wherein R1is heteroaryl including 5 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of Rband Rc.

13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein R1is:

74.

14. The compound of any one of claims 1-2 or a pharmaceutically acceptable salt thereof, wherein R1is heterocycloalkenyl including 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc.

15. The compound of any one of claims 1-2 or a pharmaceutically acceptable salt thereof, wherein R1is heterocyclyl including 4-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rband Rc.

16. The compound of any one of claims 1-2 or a pharmaceutically acceptable salt thereof, wherein R1is C3-7 cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, Rb, and Rc.

17. The compound of any one of claims 1-2 or a pharmaceutically acceptable salt thereof, wherein R1is:

80.

82.

84.

18. The compound of any one of claims 1-17 or a pharmaceutically acceptable salt thereof, wherein each of R2aand R2bis independently selected from the group consisting of H and C1-2 alkyl optionally substituted with from 1-5 Ra.

19. The compound of any one of claims 1-18 or a pharmaceutically acceptable salt thereof, wherein each of R2aand R2bis CH3.

20. The compound of any one of claims 1-17 or a pharmaceutically acceptable salt thereof, wherein R2aand R2btaken together with the carbon atom to which each is attached forms:89.• C3-7 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb;90.• heterocyclyl including 4-7 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rb.

21. The compound of claim 20 or a pharmaceutically acceptable salt thereof, wherein R2aand R2btaken together with the carbon atom to which each is attached forms:

93.

94.

22. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1, R2a, and R2bare defined according to (B).

23. The compound of any one of claims 1-22 or a pharmaceutically acceptable salt thereof, wherein R3is Cl.

24. The compound of any one of claims 1-23 or a pharmaceutically acceptable salt thereof, wherein R4is Cl.

25. The compound of any one of claims 1-20 or a pharmaceutically acceptable salt thereof, wherein the compound has the formula:

100.

26. The compound of any one of claims 1-7 or a pharmaceutically acceptable salt thereof, wherein the compound has the formula:

103.

27. The compound of any of claims 1-19 or a pharmaceutically acceptable salt thereof, wherein each of R2aand R2bis CD3.

28. A compound selected from those depicted in Table Cl, or a pharmaceutically acceptable salt thereof.

29. A compound having the structure:

109. 111.or a pharmaceutically acceptable salt thereof.

30. A compound having the structure:

114.

115.

31. A pharmaceutical composition comprising the compound of any one of claims 1- 30, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

32. A method of treating a disorder caused by or associated with NLRP3 inflammasome activation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-30 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 31.

33. The method of claim 32, wherein the disorder is selected from the group consisting of:118.(i) inflammatory reactions in the joints;119.(ii) hyperactive inflammation with underlying genetic mutations;120.(iii) autoimmune diseases;121.(iv) respiratory diseases;122.(v) kidney diseases;123.(vi) central nervous system diseases;124.(vii) ocular diseases;125.(viii) cardiovascular diseases;126.(ix) viral infections and subsequent immune hyperactivation;127.(x) diseases of the hematopoietic system;128.(xi) liver disease;129.(xii) inflammatory reactions in the skin;130.(xiii) metabolic diseases;131.(xiv) cancers;132.(xv) infectious diseases; and133.(xvi) allergic disease.

34. The method of claim 32, wherein the disorder is gout, for example wherein the disorder is a) acute or chronic gout, b) tophaceous gout or c) pseudo-gout, including calcium pyrophosphate deposition disease.

35. The method of claim 32, wherein the disorder is pericarditis, for example Dressier’s syndrome.

36. The method of claim 32, wherein the disorder is a lysosomal storage disease.

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