Inhibitors of receptor-interacting protein kinase I for the treatment of diseases

Abstract

Disclosed herein are compounds, pharmaceutical compositions, and methods for treating RIPK1-mediated diseases, such as neurodegenerative disorders, inflammatory disorders, and cancer, that inhibit RIPK1.

Description

[Technical Field]

[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 62 / 983,356, filed February 28, 2020, which is incorporated herein by reference in its entirety. [Background technology]

[0002] The role of receptor-interacting protein kinase I (RIPKI) in regulating apoptotic or necroptotic cell death pathways has been reported, and its novel role in mediating responses to inflammatory signaling in several cell types and contexts is emerging. RIPKI consists of an N-terminal kinase domain, an RHIM (RIP homotypic interacting motif) domain, and a death domain, which collectively undergo extensive post-translational modifications in response to signaling through various receptors, such as tumor necrosis factor α receptor (TNFR), Toll-like receptors, and NOD-like receptors. RIPKI has been most extensively studied in the context of TNF-RI signaling, where it is recruited to the C-terminal domain of the receptor via the protein TRADD (TNF receptor-associated death domain protein). There, RIPKI is ubiquitinated by the E3 ubiquitin ligases TNF receptor-associated factor 2 (TRAF2) or TRAF5 and the cellular inhibitor of apoptosis proteins (cIAPs), cIAP and cIAP2. This molecular assembly is known as complex I. Cylindromatosis (CYLD) then mediates the deubiquitination of RIPKI, allowing the assembly of complex IIb, also known as the necrosome. The necrosome consists of the RIPKI homolog RIPK3 and the pseudokinase MLKL. Necrosome assembly and function are inhibited by caspase-8, and the necrosome is functional only when caspase-8 activity is blocked. In this context, the necrosome triggers necroptosis, an inflammatory form of programmed cell death in which membrane lysis leads to the release of cellular contents into the extracellular space.

[0003] RIPKI can also regulate apoptosis and inflammation in different contexts. When cIAPs are inhibited to prevent RIPKI ubiquitination, RIPKI is involved in apoptosis. Ubiquitinated RIPKI can also recruit NF-KB essential modulator (NEMO) and TAKI-binding protein 2 or 3 (TAB2 / 3), leading to activation of inhibitor of kappa B (IKB), inhibitor of kinase β (IKK), and transforming growth factor β (TGF)-activated kinase 1 (TAKI), which in turn promotes NF-KB pro-inflammatory or pro-survival gene expression programs. Given its role in inflammation, RIPK1 has been implicated in many diseases characterized by chronic and acute inflammatory signaling, including viral infection, sepsis, retinal degeneration, traumatic brain injury, ischemic stroke, intracerebral hemorrhage, amyotrophic lateral sclerosis, acute kidney injury, myocardial reperfusion injury, Alzheimer's disease, ulcerative colitis, and osteoarthritis. In animal models of these diseases, RIPK1 kinase inhibitors such as necrostatin-1 have been shown to be effective, leading to the development of such molecules for clinical trials in several conditions. Summary of the Invention [Means for solving the problem]

[0004] As used herein, compounds of structural formula (I): [ka] (In the formula, W is CH, CR 5 and N; R 1 is selected from CN, halo, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (aryl)alkyl, and (heteroaryl)alkyl, any one of which may be selected from one or more R 6 optionally substituted with; R 2 and R 3are independently selected from H, halo, cyano, alkyl, (alkyl)oxy, (alkyl)thio, (alkyl)sulfonimidoyl, (alkyl)sulfonyl, cycloalkyl, and (cycloalkyl)oxy, any one of which may be selected from one or more R 7 optionally substituted with, or R 2 and R 3 together with the two intervening carbons, join to form a 5- to 7-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, any one of which may be joined by one or more R 8 and optionally fused to a 6-membered aryl or heteroaryl ring, said 6-membered aryl or heteroaryl ring being optionally substituted with one or more R 9 optionally substituted with; R 4 is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (aryl)alkyl, and (heteroaryl)alkyl, any one of which may be selected from one or more R 10 optionally substituted with; R 5 is selected from H, CN, halo, hydroxy, alkyl and (alkyl)oxy; Each R 6 , R 7 , R 8 and R 9 are independently selected from CN, halo, hydroxy, NH2, oxo, alkyl, and (alkyl)oxy; Each R 10is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)CH, (heterocycloalkyl)CH, (aryl)CH, (heteroaryl)CH, (alkyl)SO, (cycloalkyl)SO, (heterocycloalkyl)SO, (aryl)SO, (heteroaryl)SO, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (aryl)NH, (heteroaryl)NH, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R 11 optionally substituted with; Each R 11 is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, alkylsulfonyl, haloalkylsulfonyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (alkylsulfonyl)oxy, (haloalkylsulfonyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (alkylsulfonyl)NH, (haloalkylsulfonyl)NH, (aryl)NH, and (heteroaryl)NH, any one of which may be selected from one or more R 12 is optionally replaced by The Two R's 11 is combined with C 5~7 can form a cycloalkyl or a 5- to 7-membered heterocycloalkyl; and Each R 12 is selected from CN, halo, hydroxy, alkyl, (alkyl)oxy and oxo or a salt or tautomer thereof.

[0005] In certain embodiments, W is CH, CR 5 and N; R 1is selected from CN, halo, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (aryl)alkyl, and (heteroaryl)alkyl, any one of which may be selected from one or more R 6 optionally substituted with; R 2 and R 3 are independently selected from H, halo, cyano, alkyl, (alkyl)oxy, cycloalkyl, and (cycloalkyl)oxy, any one of which may be selected from one or more R 7 optionally substituted with, or R 2 and R 3 together with the two intervening carbons, join to form a 5- to 7-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, any one of which may be joined by one or more R 8 and optionally fused to a 6-membered aryl or heteroaryl ring, said 6-membered aryl or heteroaryl ring being optionally substituted with one or more R 9 optionally substituted with; R 4 is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (aryl)alkyl, and (heteroaryl)alkyl, any one of which may be selected from one or more R 10 optionally substituted with; R 5 is selected from H, CN, halo, hydroxy, alkyl and (alkyl)oxy; Each R 6 , R 7 , R 8 and R 9 are independently selected from CN, halo, hydroxy, oxo, alkyl, and (alkyl)oxy; Each R 10are independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R 11 optionally substituted with; Each R 11 is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, alkylsulfonyl, haloalkylsulfonyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (alkylsulfonyl)oxy, (haloalkylsulfonyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (alkylsulfonyl)NH, (haloalkylsulfonyl)NH, (aryl)NH, and (heteroaryl)NH, any one of which may be selected from one or more R 12 optionally substituted with; and Each R 12 is selected from CN, halo, hydroxy, alkyl, (alkyl)oxy and oxo.

[0006] Pharmaceutical compositions comprising one or more compounds, salts, or tautomers disclosed herein together with a pharmaceutically acceptable carrier, as well as methods for making and using the compounds, salts, or tautomers and compositions, are also provided. Certain embodiments provide methods for inhibiting RIPK1. Certain embodiments provide methods for treating a RIPK1-mediated disorder in a patient in need of treatment, comprising administering to the patient a therapeutically effective amount of a compound, or a salt or tautomer thereof, or a composition disclosed herein. Also provided is the use of certain compounds, salts, or tautomers disclosed herein for use in the manufacture of a pharmaceutical agent for the treatment of a disease or condition ameliorated by inhibition of RIPK1.

[0007] As used herein, compounds of structural formula (Ia): [ka] (In the formula, R 1 is selected from CN, halo, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (aryl)alkyl, and (heteroaryl)alkyl, any one of which may be selected from one or more R 6 optionally substituted with; R 2 and R 3 are independently selected from H, halo, cyano, alkyl, (alkyl)oxy, (alkyl)thio, (alkyl)sulfonimidoyl, (alkyl)sulfonyl, cycloalkyl, and (cycloalkyl)oxy, any one of which may be selected from one or more R 7 optionally substituted with, or R 2 and R 3 together with the two intervening carbons, join to form a 5- to 7-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, any one of which may be joined by one or more R 8 and optionally fused to a 6-membered aryl or heteroaryl ring, said 6-membered aryl or heteroaryl ring being optionally substituted with one or more R 9 optionally substituted with; R 4 is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (aryl)alkyl, and (heteroaryl)alkyl, any one of which may be selected from one or more R 10 optionally substituted with; Each R 6 , R 7 , R 8 and R 9 are independently selected from CN, halo, hydroxy, NH2, oxo, alkyl, and (alkyl)oxy; Each R 10is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)CH, (heterocycloalkyl)CH, (aryl)CH, (heteroaryl)CH, (alkyl)SO, (cycloalkyl)SO, (heterocycloalkyl)SO, (aryl)SO, (heteroaryl)SO, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (aryl)NH, (heteroaryl)NH, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R 11 optionally substituted with; Each R 11 is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, alkylsulfonyl, haloalkylsulfonyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (alkylsulfonyl)oxy, (haloalkylsulfonyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (alkylsulfonyl)NH, (haloalkylsulfonyl)NH, (aryl)NH, and (heteroaryl)NH, any one of which may be selected from one or more R 12 is optionally replaced by The Two R's 11 is combined with C 5~7 can form a cycloalkyl or a 5- to 7-membered heterocycloalkyl; and Each R 12 is selected from CN, halo, hydroxy, alkyl, (alkyl)oxy and oxo or a salt or tautomer thereof.

[0008] In certain embodiments, R 1is selected from CN, halo, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (aryl)alkyl, and (heteroaryl)alkyl, any one of which may be selected from one or more R 6 optionally substituted with; R 2 and R 3 are independently selected from H, halo, cyano, alkyl, (alkyl)oxy, cycloalkyl, and (cycloalkyl)oxy, any one of which may be selected from one or more R 7 optionally substituted with, or R 2 and R 3 together with the two intervening carbons, join to form a 5- to 7-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, any one of which may be joined by one or more R 8 and optionally fused to a 6-membered aryl or heteroaryl ring, said 6-membered aryl or heteroaryl ring being optionally substituted with one or more R 9 optionally substituted with; R 4 is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (aryl)alkyl, and (heteroaryl)alkyl, any one of which may be selected from one or more R 10 optionally substituted with; R 5 is selected from H, CN, halo, hydroxy, alkyl and (alkyl)oxy; Each R 6 , R 7 , R 8 and R 9 are independently selected from CN, halo, hydroxy, oxo, alkyl, and (alkyl)oxy; Each R 10are independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R 11 optionally substituted with; Each R 11 is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, alkylsulfonyl, haloalkylsulfonyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (alkylsulfonyl)oxy, (haloalkylsulfonyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (alkylsulfonyl)NH, (haloalkylsulfonyl)NH, (aryl)NH, and (heteroaryl)NH, any one of which may be selected from one or more R 12 optionally substituted with; and Each R 12 is selected from CN, halo, hydroxy, alkyl, (alkyl)oxy and oxo.

[0009] In certain embodiments, R 4 is C 1~6 Alkyl, C 3~7 Cycloalkyl, 4-11 membered heterocycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, (C 3~7 Cycloalkyl)C 1~6 Alkyl, (4-11 membered heterocycloalkyl)C 1~6 Alkyl, (C 6~10 Aryl)C 1~6 Alkyl and (5-14 membered heteroaryl)C 1~6 alkyl, any one of which is selected from one or more R 10 In certain embodiments, R 4 is C 1~6 Alkyl, C 3~7Cycloalkyl, 4-11 membered heterocycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, (C 3~7 cycloalkyl)methyl, (4- to 11-membered heterocycloalkyl)methyl, (C 6~10 (aryl)methyl, (5- to 14-membered heteroaryl)methyl, any one of which is selected from one or more R 10 In certain embodiments, R 4 is C 1~6 alkyl, cyclopropyl, cyclobutyl, phenyl, 2,3,4,5-tetrahydro-1H-benzo[b]azepinyl, 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepinyl, 2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl, 2,3,4,5-tetrahydro-1H-pyrido[3,4-b]azepin-3-yl, and 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-6-yl, any one of which may be selected from one or more R 10 is optionally replaced by

[0010] In certain embodiments, R 4 is one, two or three R 10 In certain embodiments, R 4 is one or two R 10 In certain embodiments, R 4 is one or two R 10 is replaced by .

[0011] In certain embodiments, R 4 teeth, [ka] is.

[0012] In certain embodiments, R 4 teeth, [ka] Selected from; Each V is CH, C(R 10 ) and N are independently selected; W 3 is selected from CH2, NH, O and S; R 10g is selected from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any one of which may be selected from one or more R 11 optionally substituted with; Each R 10 is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)CH, (heterocycloalkyl)CH, (aryl)CH, (heteroaryl)CH, (alkyl)SO, (cycloalkyl)SO, (heterocycloalkyl)SO, (aryl)SO, (heteroaryl)SO, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (aryl)NH, (heteroaryl)NH, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R 11 optionally substituted with; Each R 11 is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, alkylsulfonyl, haloalkylsulfonyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (alkylsulfonyl)oxy, (haloalkylsulfonyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (alkylsulfonyl)NH, (haloalkylsulfonyl)NH, (aryl)NH, and (heteroaryl)NH, any one of which may be selected from one or more R 12 is optionally replaced by The Two R's 11 is combined with C 5~7can form a cycloalkyl or a 5- to 7-membered heterocycloalkyl; and Each R 12 is selected from CN, halo, hydroxy, alkyl, (alkyl)oxy and oxo.

[0013] In certain embodiments, R 4 teeth, [ka] Selected from; Each V is CH, C(R 10 ) and N are independently selected; W 3 is selected from CH2, NH, O and S; R 10g is selected from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any one of which may be selected from one or more R 11 optionally substituted with; Each R 10 are independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R 11 optionally substituted with; Each R 11 is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, alkylsulfonyl, haloalkylsulfonyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (alkylsulfonyl)oxy, (haloalkylsulfonyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (alkylsulfonyl)NH, (haloalkylsulfonyl)NH, (aryl)NH, and (heteroaryl)NH, any one of which may be selected from one or more R12 optionally substituted with; and Each R 12 is selected from CN, halo, hydroxy, alkyl, (alkyl)oxy and oxo.

[0014] In certain embodiments, R 4 teeth, [ka] Selected from; R 10g is selected from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any one of which may be selected from one or more R 11 optionally substituted with; Each R 10 is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)CH, (heterocycloalkyl)CH, (aryl)CH, (heteroaryl)CH, (alkyl)SO, (cycloalkyl)SO, (heterocycloalkyl)SO, (aryl)SO, (heteroaryl)SO, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (aryl)NH, (heteroaryl)NH, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R 11 optionally substituted with; Each R 11is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, alkylsulfonyl, haloalkylsulfonyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (alkylsulfonyl)oxy, (haloalkylsulfonyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (alkylsulfonyl)NH, (haloalkylsulfonyl)NH, (aryl)NH, and (heteroaryl)NH, any one of which may be selected from one or more R 12 is optionally replaced by The Two R's 11 is combined with C 5~7 can form a cycloalkyl or a 5- to 7-membered heterocycloalkyl; and Each R 12 is selected from CN, halo, hydroxy, alkyl, (alkyl)oxy and oxo.

[0015] In certain embodiments, R 4 teeth, [ka] Selected from; R 10g is selected from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any one of which may be selected from one or more R 11 optionally substituted with; Each R 10 are independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R 11 optionally substituted with; Each R 11is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, alkylsulfonyl, haloalkylsulfonyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (alkylsulfonyl)oxy, (haloalkylsulfonyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (alkylsulfonyl)NH, (haloalkylsulfonyl)NH, (aryl)NH, and (heteroaryl)NH, any one of which may be selected from one or more R 12 optionally substituted with; and Each R 12 is selected from CN, halo, hydroxy, alkyl, (alkyl)oxy and oxo.

[0016] In certain embodiments, R 4 teeth, [ka] Selected from; R 10g is selected from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any one of which may be selected from one or more R 11 optionally substituted with; Each R 10is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)CH, (heterocycloalkyl)CH, (aryl)CH, (heteroaryl)CH, (alkyl)SO, (cycloalkyl)SO, (heterocycloalkyl)SO, (aryl)SO, (heteroaryl)SO, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (aryl)NH, (heteroaryl)NH, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R 11 optionally substituted with; Each R 11 is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, alkylsulfonyl, haloalkylsulfonyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (alkylsulfonyl)oxy, (haloalkylsulfonyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (alkylsulfonyl)NH, (haloalkylsulfonyl)NH, (aryl)NH, and (heteroaryl)NH, any one of which may be selected from one or more R 12 is optionally replaced by The Two R's 11 is combined with C 5~7 can form a cycloalkyl or a 5- to 7-membered heterocycloalkyl; and Each R 12 is selected from CN, halo, hydroxy, alkyl, (alkyl)oxy and oxo.

[0017] In certain embodiments, R 4 teeth, [ka] Selected from; R 10g is selected from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any one of which may be selected from one or more R 11 optionally substituted with; Each R 10 are independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R 11 optionally substituted with; Each R 11 is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, alkylsulfonyl, haloalkylsulfonyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (alkylsulfonyl)oxy, (haloalkylsulfonyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (alkylsulfonyl)NH, (haloalkylsulfonyl)NH, (aryl)NH, and (heteroaryl)NH, any one of which may be selected from one or more R 12 optionally substituted with; and Each R 12 is selected from CN, halo, hydroxy, alkyl, (alkyl)oxy and oxo.

[0018] In certain embodiments, R 10g is selected from H and alkyl. In certain embodiments, R 10g is H and C 1~4 In certain embodiments, R 10g is selected from H, CH, CD, CHCH, CH(CH) and C(CH). 10g is selected from H, CH, and CD. In certain embodiments, R 10gis CH3.

[0019] In certain embodiments, R 10g is selected from H, methyl, ethyl, and 2-propyl. In certain embodiments, R 10g is selected from H, methyl, and methyl-d3. In certain embodiments, R 10g is methyl.

[0020] In certain embodiments, R 4 teeth, [ka] In certain embodiments, R 4 teeth, [ka] is.

[0021] In certain embodiments, R 4 teeth, [ka] is selected from.

[0022] In certain embodiments, R 4 teeth, [ka] is selected from.

[0023] As used herein, compounds of structural formula (II): [ka] (In the formula, m is selected from 0, 1 and 2; W is CH, CR 5 and N; R 1is selected from CN, halo, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (aryl)alkyl, and (heteroaryl)alkyl, any one of which may be selected from one or more R 6 optionally substituted with; R 2 and R 3 are independently selected from H, halo, cyano, alkyl, (alkyl)oxy, (alkyl)thio, (alkyl)sulfonimidoyl, (alkyl)sulfonyl, cycloalkyl, and (cycloalkyl)oxy, any one of which may be selected from one or more R 7 optionally substituted with, or R 2 and R 3 together with the two intervening carbons, join to form a 5- to 7-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, any one of which may be joined by one or more R 8 and optionally fused to a 6-membered aryl or heteroaryl ring, said 6-membered aryl or heteroaryl ring being optionally substituted with one or more R 9 optionally substituted with; R 4a is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any one of which may be selected from one or more R 10 optionally substituted with; Each R 4b is independently selected from H and alkyl; R 5 is selected from H, CN, halo, hydroxy, alkyl and (alkyl)oxy; Each R 6 , R 7 , R 8 and R 9 are independently selected from CN, halo, hydroxy, NH2, oxo, alkyl, and (alkyl)oxy; Each R 10is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)CH, (heterocycloalkyl)CH, (aryl)CH, (heteroaryl)CH, (alkyl)SO, (cycloalkyl)SO, (heterocycloalkyl)SO, (aryl)SO, (heteroaryl)SO, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (aryl)NH, (heteroaryl)NH, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R 11 optionally substituted with; Each R 11 is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, alkylsulfonyl, haloalkylsulfonyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (alkylsulfonyl)oxy, (haloalkylsulfonyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (alkylsulfonyl)NH, (haloalkylsulfonyl)NH, (aryl)NH, and (heteroaryl)NH, any one of which may be selected from one or more R 12 is optionally replaced by The Two R's 11 is combined with C 5~7 can form a cycloalkyl or a 5- to 7-membered heterocycloalkyl; and Each R 12 is selected from CN, halo, hydroxy, alkyl, (alkyl)oxy and oxo or a salt or tautomer thereof.

[0024] As used herein, compounds of structural formula (II): [ka] (In the formula, m is selected from 0, 1 and 2; W is CH, CR 5 and N; R 1 is selected from CN, halo, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (aryl)alkyl, and (heteroaryl)alkyl, any one of which may be selected from one or more R 6 optionally substituted with; R 2 and R 3 are independently selected from H, halo, cyano, alkyl, (alkyl)oxy, cycloalkyl, and (cycloalkyl)oxy, any one of which may be selected from one or more R 7 optionally substituted with, or R 2 and R 3 together with the two intervening carbons, join to form a 5- to 7-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, any one of which may be joined by one or more R 8 and optionally fused to a 6-membered aryl or heteroaryl ring, said 6-membered aryl or heteroaryl ring being optionally substituted with one or more R 9 optionally substituted with; R 4a is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any one of which may be selected from one or more R 10 optionally substituted with; Each R 4b is independently selected from H and alkyl; R 5 is selected from H, CN, halo, hydroxy, alkyl and (alkyl)oxy; Each R 6 , R 7 , R 8 and R 9 are independently selected from CN, halo, hydroxy, oxo, alkyl, and (alkyl)oxy; Each R 10 are independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R 11 optionally substituted with; Each R 11 is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, alkylsulfonyl, haloalkylsulfonyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (alkylsulfonyl)oxy, (haloalkylsulfonyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (alkylsulfonyl)NH, (haloalkylsulfonyl)NH, (aryl)NH, and (heteroaryl)NH, any one of which may be selected from one or more R 12 optionally substituted with; and Each R 12 is selected from CN, halo, hydroxy, alkyl, (alkyl)oxy and oxo or a salt or tautomer thereof.

[0025] In certain embodiments, R 4a is C 1~6 Alkyl, C 3~7 Cycloalkyl, 4-11 membered heterocycloalkyl, C 6~14 aryl and 5- to 14-membered heteroaryl, any one of which is selected from one or more R 10 In certain embodiments, R 4a is C 1~6and 1H-benzo[d]thiazolyl, 1H-benzo[d]imidazolyl, and 1H-benzo[d][1,4]triazolyl, any one of which is selected from alkyl, cyclopropyl, cyclobutyl, 2,3,4,5-tetrahydro-1H-benzo[b]azepinyl, 2,3,4,5-tetrahydro-benzo[b][1,4]oxazepinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl, indolinyl, acridinyl, pyrazolo[1,5-a]pyridinyl, benzo[d]thiazolyl, 1H-benzo[d]imidazolyl, and 1H-benzo[d][1,2,3]triazolyl, any one of which is selected from one or more R 10 In certain embodiments, R 4a is selected from 2,3,4,5-tetrahydro-1H-benzo[b]azepinyl, 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazoyl, 1,2,3-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl, indolinyl, acridinyl, pyrazolo[1,5-a]pyridinyl, benzo[d]thiazolyl, 1H-benzo[d]imidazolyl, and 1H-benzo[d][1,2,3]triazolyl, any one of which may be selected from one or more R 10 is optionally replaced by

[0026] In certain embodiments, R 4a teeth, [ka] Selected from; Each V is CH, C(R 10 ) and N are independently selected; W 3 is selected from CH2, NH, O and S; R10g is selected from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any one of which may be selected from one or more R 11 optionally substituted with; Each R 10 is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)CH, (heterocycloalkyl)CH, (aryl)CH, (heteroaryl)CH, (alkyl)SO, (cycloalkyl)SO, (heterocycloalkyl)SO, (aryl)SO, (heteroaryl)SO, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (aryl)NH, (heteroaryl)NH, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R 11 optionally substituted with; Each R 11 is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, alkylsulfonyl, haloalkylsulfonyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (alkylsulfonyl)oxy, (haloalkylsulfonyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (alkylsulfonyl)NH, (haloalkylsulfonyl)NH, (aryl)NH, and (heteroaryl)NH, any one of which may be selected from one or more R 12 is optionally replaced by The Two R's 11 is combined with C 5~7 can form a cycloalkyl or a 5- to 7-membered heterocycloalkyl; and Each R 12 is selected from CN, halo, hydroxy, alkyl, (alkyl)oxy and oxo.

[0027] In certain embodiments, R 4a teeth, [ka] Selected from; Each V is CH, C(R 10 ) and N are independently selected; W 3 is selected from CH2, NH, O and S; R 10g is selected from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any one of which may be selected from one or more R 11 optionally substituted with; Each R 10 are independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R 11 optionally substituted with; Each R 11 is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, alkylsulfonyl, haloalkylsulfonyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (alkylsulfonyl)oxy, (haloalkylsulfonyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (alkylsulfonyl)NH, (haloalkylsulfonyl)NH, (aryl)NH, and (heteroaryl)NH, any one of which may be selected from one or more R 12 optionally substituted with; and Each R 12 is selected from CN, halo, hydroxy, alkyl, (alkyl)oxy and oxo.

[0028] In certain embodiments, R 4a teeth, [ka] Selected from; R 10g is selected from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any one of which may be selected from one or more R 11 optionally substituted with; Each R 10 is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)CH, (heterocycloalkyl)CH, (aryl)CH, (heteroaryl)CH, (alkyl)SO, (cycloalkyl)SO, (heterocycloalkyl)SO, (aryl)SO, (heteroaryl)SO, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (aryl)NH, (heteroaryl)NH, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R 11 optionally substituted with; Each R 11 is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, alkylsulfonyl, haloalkylsulfonyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (alkylsulfonyl)oxy, (haloalkylsulfonyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (alkylsulfonyl)NH, (haloalkylsulfonyl)NH, (aryl)NH, and (heteroaryl)NH, any one of which may be selected from one or more R 12 is optionally replaced by The Two R's 11 is combined with C 5~7can form a cycloalkyl or a 5- to 7-membered heterocycloalkyl; and Each R 12 is selected from CN, halo, hydroxy, alkyl, (alkyl)oxy and oxo.

[0029] In certain embodiments, R 4a teeth, [ka] Selected from; R 10g is selected from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any one of which may be selected from one or more R 11 optionally substituted with; Each R 10 are independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R 11 optionally substituted with; Each R 11 is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, alkylsulfonyl, haloalkylsulfonyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (alkylsulfonyl)oxy, (haloalkylsulfonyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (alkylsulfonyl)NH, (haloalkylsulfonyl)NH, (aryl)NH, and (heteroaryl)NH, any one of which may be selected from one or more R 12 optionally substituted with; and Each R 12 is selected from CN, halo, hydroxy, alkyl, (alkyl)oxy and oxo.

[0030] In certain embodiments, R 10g is selected from H and alkyl. In certain embodiments, R 10g is H and C 1~4 In certain embodiments, R 10g is selected from H, CH, CD, CHCH, CH(CH) and C(CH). 10g is selected from H, CH, and CD. In certain embodiments, R 10g is CH3.

[0031] In certain embodiments, R 10g is selected from H, methyl, ethyl, and 2-propyl. In certain embodiments, R 10g is selected from H, methyl, and methyl-d3. In certain embodiments, R 10g is methyl.

[0032] As used herein, compounds of structural formula (III): [ka] (In the formula, m is selected from 0, 1 and 2; W is CH, CR 5 and N; W 2 is CHR 10a , C.R. 10a , N.R. 10a , N, O and S; W 3 is CHR 10b , C.R. 10b , N.R. 10b , N, O and S; W 4 is a bond, CHR 10c , C.R. 10c , N.R. 10c , N, O and S; W 5 is CHR 10d , C.R. 10d , N.R. 10d, N, O and S; W 6 is CHR 10e , C.R. 10e , N.R. 10e , N, O and S; W 7 is CHR 10f , C.R. 10f , N.R. 10f , N, O and S; W 2 , W 3 , W 4 , W 5 , W 6 and W 7 together with the intervening carbons attached to form a 6- or 7-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 1 is selected from CN, halo, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (aryl)alkyl, and (heteroaryl)alkyl, any one of which may be selected from one or more R 6 optionally substituted with; R 2 and R 3 are independently selected from H, halo, cyano, alkyl, (alkyl)oxy, (alkyl)thio, (alkyl)sulfonimidoyl, (alkyl)sulfonyl, cycloalkyl, and (cycloalkyl)oxy, any one of which may be selected from one or more R 7 optionally substituted with, or R 2 and R 3 together with the two intervening carbons, join to form a 5- to 7-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, any one of which may be joined by one or more R 8 and optionally fused to a 6-membered aryl or heteroaryl ring, said 6-membered aryl or heteroaryl ring being optionally substituted with one or more R 9 optionally substituted with; Each R 4bis independently selected from H and alkyl; R 5 is selected from H, CN, halo, hydroxy, alkyl and (alkyl)oxy; Each R 6 , R 7 , R 8 and R 9 are independently selected from CN, halo, hydroxy, NH2, oxo, alkyl, and (alkyl)oxy; R 10a and R 10b can be joined together with the two intervening atoms to form a 5-, 6-, or 7-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any one of which may be joined by one or more R 10 optionally substituted with; R 10c and R 10d can be joined together with the two intervening atoms to form a 5-, 6-, or 7-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any one of which may be joined by one or more R 10 optionally substituted with; R 10e and R 10f can be joined together with the two intervening atoms to form a 5-, 6-, or 7-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any one of which may be joined by one or more R 10 optionally substituted with; R 10a and R 10e can be linked to form an alkylene, which can be joined to one or more R 10 optionally substituted with; Each R 10is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)CH, (heterocycloalkyl)CH, (aryl)CH, (heteroaryl)CH, (alkyl)SO, (cycloalkyl)SO, (heterocycloalkyl)SO, (aryl)SO, (heteroaryl)SO, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (aryl)NH, (heteroaryl)NH, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R 11 optionally substituted with; R 10a , R 10b , R 10c , R 10d , R 10e and R 10f are, unless otherwise defined, independently selected from H, CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R 11 optionally substituted with; Each R 11 is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, alkylsulfonyl, haloalkylsulfonyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (alkylsulfonyl)oxy, (haloalkylsulfonyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (alkylsulfonyl)NH, (haloalkylsulfonyl)NH, (aryl)NH, and (heteroaryl)NH, any one of which may be selected from one or more R 12 is optionally replaced by The Two R's11 is combined with C 5~7 can form a cycloalkyl or a 5- to 7-membered heterocycloalkyl; and Each R 12 is selected from CN, halo, hydroxy, alkyl, (alkyl)oxy and oxo or a salt or tautomer thereof.

[0033] As used herein, compounds of structural formula (III): [ka] (In the formula, m is selected from 0, 1 and 2; W is CH, CR 5 and N; W 2 is CHR 10a , C.R. 10a , N.R. 10a , N, O and S; W 3 is CHR 10b , C.R. 10b , N.R. 10b , N, O and S; W 4 is a bond, CHR 10c , C.R. 10c , N.R. 10c , N, O and S; W 5 is CHR 10d , C.R. 10d , N.R. 10d , N, O and S; W 6 is CHR 10e , C.R. 10e , N.R. 10e , N, O and S; W 7 is CHR 10f , C.R. 10f , N.R. 10f , N, O and S; W 2 , W 3 , W 4 , W 5 , W6 and W 7 together with the intervening carbons attached to form a 6- or 7-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 1 is selected from CN, halo, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (aryl)alkyl, and (heteroaryl)alkyl, any one of which may be selected from one or more R 6 optionally substituted with; R 2 and R 3 are independently selected from H, halo, cyano, alkyl, (alkyl)oxy, cycloalkyl, and (cycloalkyl)oxy, any one of which may be selected from one or more R 7 optionally substituted with, or R 2 and R 3 together with the two intervening carbons, join to form a 5- to 7-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, any one of which may be joined by one or more R 8 and optionally fused to a 6-membered aryl or heteroaryl ring, said 6-membered aryl or heteroaryl ring being optionally substituted with one or more R 9 optionally substituted with; Each R 4b is independently selected from H and alkyl; R 5 is selected from H, CN, halo, hydroxy, alkyl and (alkyl)oxy; Each R 6 , R 7 , R 8 and R 9 are independently selected from CN, halo, hydroxy, oxo, alkyl, and (alkyl)oxy; R 10a and R 10bcan be joined together with the two intervening atoms to form a 5-, 6-, or 7-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any one of which may be joined by one or more R 10 optionally substituted with; R 10c and R 10d can be joined together with the two intervening atoms to form a 5-, 6-, or 7-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any one of which may be joined by one or more R 10 optionally substituted with; R 10e and R 10f can be joined together with the two intervening atoms to form a 5-, 6-, or 7-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any one of which may be joined by one or more R 10 optionally substituted with; R 10a and R 10e can be linked to form an alkylene, which can be joined to one or more R 10 optionally substituted with; Each R 10 are independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R 11 optionally substituted with; R 10a , R 10b , R 10c , R 10d , R 10e and R 10fare, unless otherwise defined, independently selected from H, CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R 11 optionally substituted with; Each R 11 is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, alkylsulfonyl, haloalkylsulfonyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (alkylsulfonyl)oxy, (haloalkylsulfonyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (alkylsulfonyl)NH, (haloalkylsulfonyl)NH, (aryl)NH, and (heteroaryl)NH, any one of which may be selected from one or more R 12 optionally substituted with; and Each R 12 is selected from CN, halo, hydroxy, alkyl, (alkyl)oxy and oxo or a salt or tautomer thereof.

[0034] In certain embodiments, W 7 is C=O.

[0035] In certain embodiments, W 6 is selected from NH and N(CH3).

[0036] In certain embodiments, R 10c and R 10d together with the two intervening atoms, combine to form a phenyl or a 5- or 6-membered heteroaryl, any one of which may be selected from one or more R 10 In certain embodiments, R 10c and R 10dtogether with the two intervening atoms to form a phenyl or a 6-membered heteroaryl, any one of which may be selected from one or more R 10 In certain embodiments, R 10c and R 10d together with the two intervening atoms to form phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, any one of which may be joined by one or two R 10 In certain embodiments, R 10c and R 10d together with the two intervening atoms to form a phenyl or pyridinyl, any one of which may be joined by one or two R 10 is optionally replaced by

[0037] In certain embodiments, each R 4b is H and C 1~6 In certain embodiments, each R 4b is independently selected from H, methyl, and ethyl. In certain embodiments, each R 4b is independently selected from H and methyl. In certain embodiments, at most one R 4b is not H. In certain embodiments, R 4b is H.

[0038] In certain embodiments, m is selected from 0 and 1. In certain embodiments, m is 0.

[0039] In certain embodiments, R 10a , R 10b , R 10c , R 10d , R 10e and R 10f H, CN, halo, hydroxy, oxo, C 1~6 Alkyl, C 3~7 Cycloalkyl, 5-14 membered heterocycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, (C 1~6 alkyl)oxy, (C 3~7cycloalkyl)oxy, (5- to 14-membered heterocycloalkyl)oxy, (C 6~14 (aryl)oxy and (5- to 14-membered heteroaryl)oxy, any one of which is independently selected from one or two R 11 In certain embodiments, R 10a , R 10b , R 10c , R 10d , R 10e and R 10f are independently selected from H, CN, halo, hydroxy, oxo, methyl, ethyl, cyclopropyl, and cyclobutyl, any one of which may be selected from one or two R 11 is optionally replaced by

[0040] In certain embodiments, R 10a , R 10b , R 10c , R 10d , R 10e and R 10f is one R 11 In certain embodiments, R 10a , R 10b , R 10c , R 10d , R 10e and R 10f At most one of 11 is replaced by .

[0041] In certain embodiments, R 10a , R 10b , R 10c , R 10d , R 10e and R 10f Exactly one of the R 11 is replaced by .

[0042] In certain embodiments, R 10a , R 10b , R 10c , R 10d , R 10e and R 10f Both of these are R 11 is not replaced by

[0043] In certain embodiments, R 10a , R 10b , R 10c , R 10d , R 10e and R 10f are independently selected from H, CN, halo, hydroxy, oxo, and methyl.

[0044] In certain embodiments, W 4 is CHR 10c , C.R. 10c , N.R. 10c , N, O and S.

[0045] In certain embodiments, [ka] teeth, [ka] is selected from.

[0046] In certain embodiments, [ka] teeth, [ka] is selected from.

[0047] In certain embodiments, [ka] teeth, [ka] [ka] is selected from.

[0048] As used herein, compounds of structural formula (IV): [ka] (In the formula, V 1 is a bond, CH, CR 10 , N, N.H., N.R. 10 , O and S; V 2 , V 3 and V 4 , CH, CR 10 , N, N.H., N.R. 10 , independently selected from O and S; V 1 , V 2 , V 3 and V 4 together with the two intervening carbons, join to form a 5- or 6-membered aryl or heteroaryl; W is CH, CR 5 and N; W 2 and W 3 CH2, CHR 10 , NH, O, and S; R 1 is selected from CN, halo, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (aryl)alkyl, and (heteroaryl)alkyl, any one of which may be selected from one or more R 6 optionally substituted with; R 2 and R 3 are independently selected from H, halo, cyano, alkyl, (alkyl)oxy, (alkyl)thio, (alkyl)sulfonimidoyl, (alkyl)sulfonyl, cycloalkyl, and (cycloalkyl)oxy, any one of which may be selected from one or more R 7 optionally substituted with, or R 2 and R 3 together with the two intervening carbons, join to form a 5- to 7-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, any one of which may be joined by one or more R 8and optionally fused to a 6-membered aryl or heteroaryl ring, said 6-membered aryl or heteroaryl ring being optionally substituted with one or more R 9 optionally substituted with; R 5 is selected from H, CN, halo, hydroxy, alkyl and (alkyl)oxy; Each R 6 , R 7 , R 8 and R 9 are independently selected from CN, halo, hydroxy, NH2, oxo, alkyl, and (alkyl)oxy; R 10g is selected from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any one of which may be selected from one or more R 11 optionally substituted with; Each R 10 is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)CH, (heterocycloalkyl)CH, (aryl)CH, (heteroaryl)CH, (alkyl)SO, (cycloalkyl)SO, (heterocycloalkyl)SO, (aryl)SO, (heteroaryl)SO, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (aryl)NH, (heteroaryl)NH, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R 11 optionally substituted with; Each R 11is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, alkylsulfonyl, haloalkylsulfonyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (alkylsulfonyl)oxy, (haloalkylsulfonyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (alkylsulfonyl)NH, (haloalkylsulfonyl)NH, (aryl)NH, and (heteroaryl)NH, any one of which may be selected from one or more R 12 is optionally replaced by The Two R's 11 is combined with C 5~7 can form a cycloalkyl or a 5- to 7-membered heterocycloalkyl; and Each R 12 is selected from CN, halo, hydroxy, alkyl, (alkyl)oxy and oxo or a salt or tautomer thereof.

[0049] As used herein, compounds of structural formula (IV): [ka] (In the formula, V 1 is a bond, CH, CR 10 , N, N.H., N.R. 10 , O and S; V 2 , V 3 and V 4 , CH, CR 10 , N, N.H., N.R. 10 , independently selected from O and S; V 1 , V 2 , V 3 and V 4 together with the two intervening carbons, join to form a 5- or 6-membered aryl or heteroaryl; W is CH, CR 5 and N; W 2 and W 3 CH2, CHR 10 , NH, O, and S; R 1 is selected from CN, halo, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (aryl)alkyl, and (heteroaryl)alkyl, any one of which may be selected from one or more R 6 optionally substituted with; R 2 and R 3 are independently selected from H, halo, cyano, alkyl, (alkyl)oxy, cycloalkyl, and (cycloalkyl)oxy, any one of which may be selected from one or more R 7 optionally substituted with, or R 2 and R 3 together with the two intervening carbons, join to form a 5- to 7-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, any one of which may be joined by one or more R 8 and optionally fused to a 6-membered aryl or heteroaryl ring, said 6-membered aryl or heteroaryl ring being optionally substituted with one or more R 9 optionally substituted with; R 5 is selected from H, CN, halo, hydroxy, alkyl and (alkyl)oxy; Each R 6 , R 7 , R 8 and R 9 are independently selected from CN, halo, hydroxy, oxo, alkyl, and (alkyl)oxy; R 10g is selected from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any one of which may be selected from one or more R 11 optionally substituted with; Each R 10are independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R 11 optionally substituted with; Each R 11 is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, alkylsulfonyl, haloalkylsulfonyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (alkylsulfonyl)oxy, (haloalkylsulfonyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (alkylsulfonyl)NH, (haloalkylsulfonyl)NH, (aryl)NH, and (heteroaryl)NH, any one of which may be selected from one or more R 12 optionally substituted with; and Each R 12 is selected from CN, halo, hydroxy, alkyl, (alkyl)oxy and oxo or a salt or tautomer thereof.

[0050] In certain embodiments, W 2 is CH(R 10 In certain embodiments, W 2 is CH2.

[0051] In certain embodiments, W 2 is NH. In certain embodiments, W 2 is O. In certain embodiments, W 2 is S.

[0052] In certain embodiments, W 3 is CH(R 10 In certain embodiments, W 3 is CH2.

[0053] In certain embodiments, W 3 is NH. In certain embodiments, W 3 is O. In certain embodiments, W 3 is S.

[0054] As used herein, compounds of structural formula (IVa): [ka] (In the formula, V 1 is a bond, CH, CR 10 , N, N.H., N.R. 10 , O and S; V 2 , V 3 and V 4 , CH, CR 10 , N, N.H., N.R. 10 , independently selected from O and S; V 1 , V 2 , V 3 and V 4 together with the two intervening carbons, join to form a 5- or 6-membered aryl or heteroaryl; W is CH, CR 5 and N; R 1 is selected from CN, halo, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (aryl)alkyl, and (heteroaryl)alkyl, any one of which may be selected from one or more R 6 optionally substituted with; R 2 and R 3 are independently selected from H, halo, cyano, alkyl, (alkyl)oxy, cycloalkyl, and (cycloalkyl)oxy, any one of which may be selected from one or more R 7 optionally substituted with, or R 2 and R 3together with the two intervening carbons, join to form a 5- to 7-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, any one of which may be joined by one or more R 8 and optionally fused to a 6-membered aryl or heteroaryl ring, said 6-membered aryl or heteroaryl ring being optionally substituted with one or more R 9 optionally substituted with; R 5 is selected from H, CN, halo, hydroxy, alkyl and (alkyl)oxy; Each R 6 , R 7 , R 8 and R 9 are independently selected from CN, halo, hydroxy, oxo, alkyl, and (alkyl)oxy; R 10g is selected from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any one of which may be selected from one or more R 11 optionally substituted with; Each R 10 are independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R 11 optionally substituted with; Each R 11is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, alkylsulfonyl, haloalkylsulfonyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (alkylsulfonyl)oxy, (haloalkylsulfonyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (alkylsulfonyl)NH, (haloalkylsulfonyl)NH, (aryl)NH, and (heteroaryl)NH, any one of which may be selected from one or more R 12 optionally substituted with; and Each R 12 is selected from CN, halo, hydroxy, alkyl, (alkyl)oxy and oxo or a salt or tautomer thereof.

[0055] As used herein, compounds of structural formula (IVb): [ka] (In the formula, V 1 is a bond, CH, CR 10 , N, N.H., N.R. 10 , O and S; V 2 , V 3 and V 4 , CH, CR 10 , N, N.H., N.R. 10 , independently selected from O and S; V 1 , V 2 , V 3 and V 4 together with the two intervening carbons, join to form a 5- or 6-membered aryl or heteroaryl; W is CH, CR 5 and N; R 1is selected from CN, halo, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (aryl)alkyl, and (heteroaryl)alkyl, any one of which may be selected from one or more R 6 optionally substituted with; R 2 and R 3 are independently selected from H, halo, cyano, alkyl, (alkyl)oxy, cycloalkyl, and (cycloalkyl)oxy, any one of which may be selected from one or more R 7 optionally substituted with, or R 2 and R 3 together with the two intervening carbons, join to form a 5- to 7-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, any one of which may be joined by one or more R 8 and optionally fused to a 6-membered aryl or heteroaryl ring, said 6-membered aryl or heteroaryl ring being optionally substituted with one or more R 9 optionally substituted with; R 5 is selected from H, CN, halo, hydroxy, alkyl and (alkyl)oxy; Each R 6 , R 7 , R 8 and R 9 are independently selected from CN, halo, hydroxy, oxo, alkyl, and (alkyl)oxy; R 10g is selected from H, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any one of which may be selected from one or more R 11 optionally substituted with; Each R 10are independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R 11 optionally substituted with; Each R 11 is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, alkylsulfonyl, haloalkylsulfonyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (alkylsulfonyl)oxy, (haloalkylsulfonyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (alkylsulfonyl)NH, (haloalkylsulfonyl)NH, (aryl)NH, and (heteroaryl)NH, any one of which may be selected from one or more R 12 optionally substituted with; and Each R 12 is selected from CN, halo, hydroxy, alkyl, (alkyl)oxy and oxo or a salt or tautomer thereof.

[0056] In certain embodiments, R 10g is selected from H and alkyl. In certain embodiments, R 10g is H and C 1~4 In certain embodiments, R 10g is selected from H, CH, CD, CHCH, CH(CH) and C(CH). 10g is selected from H, CH, and CD. In certain embodiments, R 10g is CH3.

[0057] In certain embodiments, R 10gis selected from H, methyl, ethyl, and 2-propyl. In certain embodiments, R 10g is selected from H, methyl, and methyl-d3. In certain embodiments, R 10g is methyl.

[0058] In certain embodiments, R 10g is H.

[0059] In certain embodiments, V 1 , V 2 , V 3 and V 4 , CH, CR 10 and N are independently selected from V 1 , V 2 , V 3 and V 4 together with the two intervening carbons, join to form a 6-membered aryl or heteroaryl.

[0060] In certain embodiments, V 1 , V 2 , V 3 and V 4 is independently selected from CH and N.

[0061] In certain embodiments, V 1 , V 2 , V 3 and V 4 Exactly one of is N.

[0062] In certain embodiments, V 1 , V 2 , V 3 and V 4 Exactly two of them are N.

[0063] In certain embodiments, V 1 , V 2 , V 3 and V 4 CH and CR 10 selected from; and V 1, V 2 , V 3 and V 4 together with the two intervening carbons, join to form a six-membered aryl.

[0064] In certain embodiments, V 1 is a bond; V 2 , V 3 and V 4 , CH, CR 10 , N, N.H., N.R. 10 , independently selected from O and S; and V 2 , V 3 and V 4 together with the two intervening carbons, join to form a 5-membered heteroaryl.

[0065] In certain embodiments, V 2 , V 3 and V 4 is selected from O and S.

[0066] In certain embodiments, V 2 , V 3 and V 4 , CH, CR 10 , N, NH and NR 10 are independently selected from

[0067] In certain embodiments, V 2 , V 3 and V 4 Exactly one of N, NH, and NR 10 is selected from.

[0068] In certain embodiments, V 2 , V 3 and V 4 Exactly two of these are N, NH, and NR 10 is selected from.

[0069] In certain embodiments, [ka] teeth, [ka] is selected from.

[0070] In certain embodiments, [ka] teeth, [ka] is selected from.

[0071] In certain embodiments, [ka] teeth, [ka] is selected from.

[0072] In certain embodiments, [ka] teeth, [ka] is selected from.

[0073] In certain embodiments, each R 10 are independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R 11 is optionally replaced by

[0074] In certain embodiments, each R 10 CN, halo, hydroxy, oxo, C1~6 Alkyl, C 3~7 Cycloalkyl, 5-14 membered heterocycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, (C 3~7 cycloalkyl)CH2, (5-14 membered heterocycloalkyl)CH2, (C 6~14 aryl)CH2 and (5- to 14-membered heteroaryl)CH2, (C 1~6 alkyl)SO2, (C 3~7 cycloalkyl)SO2, (5-14 membered heterocycloalkyl)SO2, (C 6~14 aryl)SO2, (5-14 membered heteroaryl)SO2, (C 1~6 alkyl)NH, (C 3~7 cycloalkyl)NH, (5- to 14-membered heterocycloalkyl)NH, (C 6~14 aryl)NH, (5- to 14-membered heteroaryl)NH, (C 1~6 alkyl)oxy, (C 3~7 cycloalkyl)oxy, (5- to 14-membered heterocycloalkyl)oxy, (C 6~14 (aryl)oxy and (5- to 14-membered heteroaryl)oxy, any one of which is independently selected from one or two R 11 is optionally replaced by

[0075] In certain embodiments, each R 10 is C 1~6 Alkyl, C 3~7 Cycloalkyl, 5-14 membered heterocycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, (C 3~7 cycloalkyl)CH2, (5-14 membered heterocycloalkyl)CH2, (C 6~14 aryl)CH2 and (5- to 14-membered heteroaryl)CH2, (C 1~6 alkyl)SO2, (C 3~7 cycloalkyl)SO2, (5-14 membered heterocycloalkyl)SO2, (C 6~14 aryl)SO2, (5-14 membered heteroaryl)SO2, (C 1~6 alkyl)NH, (C 3~7 cycloalkyl)NH, (5- to 14-membered heterocycloalkyl)NH, (C6~14 (aryl)NH and (5- to 14-membered heteroaryl)NH, (C 1~6 alkyl)oxy, (C 3~7 cycloalkyl)oxy, (5- to 14-membered heterocycloalkyl)oxy, (C 6~14 (aryl)oxy and (5- to 14-membered heteroaryl)oxy, any one of which is independently selected from one or two R 11 is optionally replaced by

[0076] In certain embodiments, each R 10 is C 1~6 Alkyl, C 3~7 Cycloalkyl, 5-14 membered heterocycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, (C 1~6 alkyl)oxy, (C 3~7 cycloalkyl)oxy, (5- to 14-membered heterocycloalkyl)oxy, (C 6~14 (aryl)oxy and (5- to 14-membered heteroaryl)oxy, any one of which is independently selected from one or two R 11 is optionally replaced by

[0077] In certain embodiments, each R 10 is C 1~6 Alkyl, C 3~7 Cycloalkyl, 5-14 membered heterocycloalkyl, C 6~14 aryl and 5- to 14-membered heteroaryl, any one of which is independently selected from one or two R 11 is optionally replaced by

[0078] In certain embodiments, each R 10 is C 1~6 Alkyl, C 3~7 cycloalkyl and 5- to 14-membered heterocycloalkyl, any one of which is independently selected from one or two R 11 is optionally replaced by

[0079] In certain embodiments, each R 10 is one R11 is optionally replaced by

[0080] In certain embodiments, each R 10 is one R 11 is replaced by .

[0081] In certain embodiments, each R 10 is R 11 is not replaced by

[0082] In certain embodiments, each R 10 are H, CH3, CD3, F, Cl, Br, CN, CF3, OCH3, [ka] are independently selected from

[0083] In certain embodiments, each R 10 is independently selected from CN, halo, hydroxy, and oxo. In certain embodiments, each R 10 is independently selected from CN and halo. In certain embodiments, each R 10 is independently selected from F and Cl.

[0084] In certain embodiments, each R 10 is independently selected from F, Cl, Br, CN, CH, CHCH, CH(CH), C(CH), OCH, and CF. In certain embodiments, each R 10 are independently selected from CH3 and CH2CH3.

[0085] As used herein, compounds of structural formula (V): [ka] (In the formula, W is CH, CR 5 and N; W 2 is CR 10a and N; W 3 is CR10b and N; W 5 is CR 10d and N; W 6 is CR 10e and N; W 7 is CR 10f and N; R 1 is selected from CN, halo, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (aryl)alkyl, and (heteroaryl)alkyl, any one of which may be selected from one or more R 6 optionally substituted with; R 2 and R 3 are independently selected from H, halo, cyano, alkyl, (alkyl)oxy, (alkyl)thio, (alkyl)sulfonimidoyl, (alkyl)sulfonyl, cycloalkyl, and (cycloalkyl)oxy, any one of which may be selected from one or more R 7 optionally substituted with, or R 2 and R 3 together with the two intervening carbons, join to form a 5- to 7-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, any one of which may be joined by one or more R 8 and optionally fused to a 6-membered aryl or heteroaryl ring, said 6-membered aryl or heteroaryl ring being optionally substituted with one or more R 9 optionally substituted with; R 5 is selected from H, CN, halo, hydroxy, alkyl and (alkyl)oxy; Each R 6 , R 7 , R 8 and R 9 are independently selected from CN, halo, hydroxy, NH2, oxo, alkyl, and (alkyl)oxy; R 10a, R 10b , R 10d , R 10e and R 10f are, unless otherwise defined, independently selected from H, CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R 11 optionally substituted with; Each R 11 is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, alkylsulfonyl, haloalkylsulfonyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (alkylsulfonyl)oxy, (haloalkylsulfonyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (alkylsulfonyl)NH, (haloalkylsulfonyl)NH, (aryl)NH, and (heteroaryl)NH, any one of which may be selected from one or more R 12 is optionally replaced by The Two R's 11 is combined with C 5~7 can form a cycloalkyl or a 5- to 7-membered heterocycloalkyl; and Each R 12 is selected from CN, halo, hydroxy, alkyl, (alkyl)oxy and oxo or a salt or tautomer thereof.

[0086] As used herein, compounds of structural formula (V): [ka] (In the formula, W is CH, CR 5 and N; W 2 is CR 10aand N; W 3 is CR 10b and N; W 5 is CR 10d and N; W 6 is CR 10e and N; W 7 is CR 10f and N; R 1 is selected from CN, halo, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (aryl)alkyl, and (heteroaryl)alkyl, any one of which may be selected from one or more R 6 optionally substituted with; R 2 and R 3 are independently selected from H, halo, cyano, alkyl, (alkyl)oxy, cycloalkyl, and (cycloalkyl)oxy, any one of which may be selected from one or more R 7 optionally substituted with, or R 2 and R 3 together with the two intervening carbons, join to form a 5- to 7-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, any one of which may be joined by one or more R 8 and optionally fused to a 6-membered aryl or heteroaryl ring, said 6-membered aryl or heteroaryl ring being optionally substituted with one or more R 9 optionally substituted with; R 5 is selected from H, CN, halo, hydroxy, alkyl and (alkyl)oxy; Each R 6 , R 7 , R 8 and R 9 are independently selected from CN, halo, hydroxy, oxo, alkyl, and (alkyl)oxy; R 10a, R 10b , R 10d , R 10e and R 10f are, unless otherwise defined, independently selected from H, CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R 11 optionally substituted with; Each R 11 is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, alkylsulfonyl, haloalkylsulfonyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (alkylsulfonyl)oxy, (haloalkylsulfonyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (alkylsulfonyl)NH, (haloalkylsulfonyl)NH, (aryl)NH, and (heteroaryl)NH, any one of which may be selected from one or more R 12 optionally substituted with; and Each R 12 is selected from CN, halo, hydroxy, alkyl, (alkyl)oxy and oxo or a salt or tautomer thereof.

[0087] In certain embodiments, W is selected from N, CH, and C(Cl). In certain embodiments, W is selected from CH and CR. 5 In certain embodiments, R 5 H, CN, halo, hydroxy, C 1~6 Alkyl and (C 1~6 In certain embodiments, R 5 is selected from H, CN, F, Cl, Br, and hydroxy. In certain embodiments, R 5is selected from H and Cl. In certain embodiments, R 5 is H. In certain embodiments, W is N.

[0088] In certain embodiments, R 10a , R 10b , R 10d , R 10e and R 10f H, CN, halo, hydroxy, oxo, C 1~6 Alkyl, C 3~7 Cycloalkyl, 5-14 membered heterocycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, (C 1~6 alkyl)oxy, (C 3~7 cycloalkyl)oxy, (5- to 14-membered heterocycloalkyl)oxy, (C 6~14 (aryl)oxy and (5- to 14-membered heteroaryl)oxy, any one of which is independently selected from one or two R 11 In certain embodiments, R 10a , R 10b , R 10d , R 10e and R 10f is H, C 1~6 Alkyl, C 3~7 Cycloalkyl, 5-14 membered heterocycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, (C 1~6 alkyl)oxy, (C 3~7 cycloalkyl)oxy, (5- to 14-membered heterocycloalkyl)oxy, (C 6~14 (aryl)oxy and (5- to 14-membered heteroaryl)oxy, any one of which is independently selected from one or two R 11 In certain embodiments, R 10a , R 10b , R 10d , R 10e and R 10f H, CN, halo, hydroxy, C 1~6 Alkyl, C 3~7 Cycloalkyl, 5-14 membered heterocycloalkyl, C 6~14aryl and 5- to 14-membered heteroaryl, any one of which is independently selected from one or two R 11 In certain embodiments, R 10a , R 10b , R 10d , R 10e and R 10f is H, C 1~6 Alkyl, C 3~7 cycloalkyl and 5- to 14-membered heterocycloalkyl, any one of which is independently selected from one R 11 is optionally replaced by

[0089] In certain embodiments, R 10a , R 10b , R 10d , R 10e and R 10f Both of these are R 11 is not replaced by

[0090] In certain embodiments, R 10a , R 10b , R 10d , R 10e and R 10f is independently selected from H, CN, halo, hydroxy and oxo.

[0091] In certain embodiments, R 10a , R10 b , R10 d , R10 e and R10 f At least one of R is not H. In certain embodiments, 10a , R10 b , R10 d , R10 e and R10 f At least two of them are not H.

[0092] In certain embodiments, R 10a , R 10b , R 10d , R 10e and R 10f At least one of R is halo. 10a, R 10b , R 10d , R 10e and R 10f At least two of them are halos.

[0093] In certain embodiments, R 10a , R 10b , R 10d , R 10e and R 10f At least one of is Cl.

[0094] In certain embodiments, R 10a , R 10b , R 10d , R 10e and R 10f At least one of is Br.

[0095] In certain embodiments, W 2 , W 3 , W 5 , W 6 and W 7 None of these are N.

[0096] In certain embodiments, W 2 , W 3 , W 5 , W 6 and W 7 At least one of is N. In certain embodiments, W 2 , W 3 , W 5 , W 6 and W 7 is N. In certain embodiments, W 2 , W 3 , W 5 , W 6 and W 7 Exactly two of are N.

[0097] In certain embodiments, W 2 is N.

[0098] In certain embodiments, W 3 is N.

[0099] In certain embodiments, W 5 is N.

[0100] In certain embodiments, R 10a , R 10b , R 10d , R 10e and R 10f H, CN, halo, hydroxy, C 1~6 Alkyl, C 3~7 is independently selected from cycloalkyl and 5- to 14-membered heterocycloalkyl.

[0101] In certain embodiments, R 10a is selected from F, Cl, Br, and CH. In certain embodiments, R 10a is F.

[0102] In certain embodiments, R 10b is selected from F, Cl, Br, and CH. In certain embodiments, R 10b is Cl.

[0103] As used herein, compounds of structural formula (VI): [ka] (In the formula, V 4 is selected from CH and N; R 1 is selected from CN, halo, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (aryl)alkyl, and (heteroaryl)alkyl, any one of which may be selected from one or more R 6 optionally substituted with; R 2 is selected from H, halo, cyano, alkyl, (alkyl)oxy, (alkyl)thio, (alkyl)sulfonimidoyl, (alkyl)sulfonyl, cycloalkyl, and (cycloalkyl)oxy, any one of which may be selected from one or more R 7 optionally substituted with; Each R 6 and R 7 are independently selected from CN, halo, hydroxy, NH2, oxo, alkyl, and (alkyl)oxy; R 10g is selected from H and alkyl; R 10h is selected from H, F, Cl and CN; R 10j is H or is selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)CH, (heterocycloalkyl)CH, (aryl)CH, (heteroaryl)CH, (alkyl)SO, (cycloalkyl)SO, (heterocycloalkyl)SO, (aryl)SO, (heteroaryl)SO, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (aryl)NH, (heteroaryl)NH, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R 11 optionally substituted with; Each R 11 is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, alkylsulfonyl, haloalkylsulfonyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (alkylsulfonyl)oxy, (haloalkylsulfonyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (alkylsulfonyl)NH, (haloalkylsulfonyl)NH, (aryl)NH, and (heteroaryl)NH, any one of which may be selected from one or more R 12 is optionally replaced by The Two R's 11 is combined with C 5~7 can form a cycloalkyl or a 5- to 7-membered heterocycloalkyl; and Each R12 is selected from CN, halo, hydroxy, alkyl, (alkyl)oxy and oxo or a salt or tautomer thereof.

[0104] As used herein, compounds of structural formula (VI): [ka] (In the formula, V 4 is selected from CH and N; R 1 is selected from CN, halo, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (aryl)alkyl, and (heteroaryl)alkyl, any one of which may be selected from one or more R 6 optionally substituted with; R 2 is selected from H, halo, cyano, alkyl, (alkyl)oxy, (alkyl)thio, (alkyl)sulfonimidoyl, (alkyl)sulfonyl, cycloalkyl, and (cycloalkyl)oxy, any one of which may be selected from one or more R 7 optionally substituted with; Each R 6 and R 7 are independently selected from CN, halo, hydroxy, oxo, alkyl, and (alkyl)oxy; R 10g is selected from H and alkyl; R 10h is selected from H, F, Cl and CN; R 10j is H or is selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R 11 optionally substituted with; Each R 11 is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, alkylsulfonyl, haloalkylsulfonyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (alkylsulfonyl)oxy, (haloalkylsulfonyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (alkylsulfonyl)NH, (haloalkylsulfonyl)NH, (aryl)NH, and (heteroaryl)NH, any one of which may be selected from one or more R 12 is optionally replaced by The Two R's 11 is combined with C 5~7 can form a cycloalkyl or a 5- to 7-membered heterocycloalkyl; and Each R 12 is selected from CN, halo, hydroxy, alkyl, (alkyl)oxy and oxo or a salt or tautomer thereof.

[0105] In certain embodiments, R 10h and R 10j At least one of is H.

[0106] In certain embodiments, R 10h is H. In certain embodiments, R 10h is selected from F, Cl, and CN. In certain embodiments, R 10h is selected from H, F and Cl.

[0107] In certain embodiments, R 10j is H.

[0108] In certain embodiments, R 10j is H or C 1~6 Alkyl, C 3~7 Cycloalkyl, 5-10 membered heterocycloalkyl, C 6~10Aryl, 5- to 7-membered heteroaryl, (C 3~7 cycloalkyl)CH2, (5-10 membered heterocycloalkyl)CH2, (C 6~10 aryl)CH2, (5- to 7-membered heteroaryl)CH2, (C 1~6 alkyl)SO2, (C 3~7 cycloalkyl)SO2, (5-10 membered heterocycloalkyl)SO2, (C 6~10 aryl)SO2, (5- to 7-membered heteroaryl)SO2, (C 1~6 alkyl)NH, (C 3~7 cycloalkyl)NH, (5-10 membered heterocycloalkyl)NH, (C 6~10 aryl)NH, (5- to 7-membered heteroaryl)NH, (C 1~6 alkyl)oxy, (C 3~7 cycloalkyl)oxy, (5-10 membered heterocycloalkyl)oxy, (C 6~10 (aryl)oxy and (5- to 7-membered heteroaryl)oxy, any one of which is selected from one or more R 11 is optionally replaced by

[0109] In certain embodiments, R 10j is H, or [ka] is selected from.

[0110] In certain embodiments, Each R 11 CN, halo, hydroxy, oxo, C 1~6 Alkyl, C 3~7 Cycloalkyl, 4-11 membered heterocycloalkyl, C 1~6 Alkyl sulfonyl, halo C 1~6 Alkyl sulfonyl, C 6~10 Aryl, 5- to 14-membered heteroaryl, (C 1~6 alkyl)oxy, (C 3~7 cycloalkyl)oxy, (4- to 11-membered heterocycloalkyl)oxy, (C 1~6 alkylsulfonyl)oxy, (haloC 1~6alkylsulfonyl)oxy, (C 6~10 (aryl)oxy, (5-14 membered heteroaryl)oxy, (C 1~6 alkyl)NH, (C 3~7 cycloalkyl)NH, (4- to 11-membered heterocycloalkyl)NH, (C 1~6 Alkyl sulfonyl)NH, (haloC 1~6 alkylsulfonyl)NH, (C 6~10 (aryl)NH and (5- to 14-membered heteroaryl)NH, any one of which is independently selected from one or two R 12 is optionally substituted with, and The Two R's 11 is combined with C 5~7 It can form a cycloalkyl or a 5- to 7-membered heterocycloalkyl.

[0111] In certain embodiments, each R 11 CN, halo, hydroxy, oxo, C 1~6 Alkyl, C 3~7 Cycloalkyl, 4-11 membered heterocycloalkyl, C 1~6 Alkyl sulfonyl, halo C 1~6 Alkyl sulfonyl, C 6~10 Aryl, 5- to 14-membered heteroaryl, (C 1~6 alkyl)oxy, (C 3~7 cycloalkyl)oxy, (4- to 11-membered heterocycloalkyl)oxy, (C 1~6 alkylsulfonyl)oxy, (haloC 1~6 alkylsulfonyl)oxy, (C 6~10 (aryl)oxy, (5-14 membered heteroaryl)oxy, (C 1~6 alkyl)NH, (C 3~7 cycloalkyl)NH, (4- to 11-membered heterocycloalkyl)NH, (C 1~6 Alkyl sulfonyl)NH, (haloC 1~6 alkylsulfonyl)NH, (C 6~10 (aryl)NH and (5- to 14-membered heteroaryl)NH, any one of which is independently selected from one or two R 12 is optionally replaced by

[0112] In certain embodiments, Each R 11 is C 1~6 Alkyl, C 3~7 Cycloalkyl, 4-11 membered heterocycloalkyl, C 1~6 Alkyl sulfonyl, halo C 1~6 Alkylsulfonyl, C 6~10 Aryl, 5- to 14-membered heteroaryl, (C 1~6 alkyl)oxy, (C 3~7 cycloalkyl)oxy, (4- to 11-membered heterocycloalkyl)oxy, (C 1~6 alkylsulfonyl)oxy, (haloC 1~6 alkylsulfonyl)oxy, (C 6~10 (aryl)oxy and (5- to 14-membered heteroaryl)oxy, any one of which is independently selected from one or two R 12 is optionally substituted with, and The Two R's 11 is combined with C 5~7 It can form a cycloalkyl or a 5- to 7-membered heterocycloalkyl.

[0113] In certain embodiments, each R 11 is C 1~6 Alkyl, C 3~7 Cycloalkyl, 4-11 membered heterocycloalkyl, C 1~6 Alkyl sulfonyl, halo C 1~6 Alkylsulfonyl, C 6~10 Aryl, 5- to 14-membered heteroaryl, (C 1~6 alkyl)oxy, (C 3~7 cycloalkyl)oxy, (4- to 11-membered heterocycloalkyl)oxy, (C 1~6 alkylsulfonyl)oxy, (haloC 1~6 alkylsulfonyl)oxy, (C 6~10 (aryl)oxy and (5- to 14-membered heteroaryl)oxy, any one of which is independently selected from one or two R 12 is optionally replaced by

[0114] In certain embodiments, Each R 11 is C 1~6 Alkyl, C 3~7 Cycloalkyl, 4-11 membered heterocycloalkyl, C 1~6 Alkyl sulfonyl, halo C 1~6 Alkylsulfonyl, C 6~10 aryl and 5- to 14-membered heteroaryl, any one of which is independently selected from one or two R 12 is optionally substituted with, and The Two R's 11 is combined with C 5~7 It can form a cycloalkyl or a 5- to 7-membered heterocycloalkyl.

[0115] In certain embodiments, each R 11 is C 1~6 Alkyl, C 3~7 Cycloalkyl, 4-11 membered heterocycloalkyl, C 1~6 Alkyl sulfonyl, halo C 1~6 Alkylsulfonyl, C 6~10 aryl and 5- to 14-membered heteroaryl, any one of which is independently selected from one or two R 12 is optionally replaced by

[0116] In certain embodiments, Each R 11 is C 1~6 Alkyl, C 3~7 Cycloalkyl, 4-11 membered heterocycloalkyl, C 6~10 aryl and 5- to 14-membered heteroaryl, any one of which is independently selected from one or two R 12 is optionally substituted with, and The Two R's 11 is combined with C 5~7 It can form a cycloalkyl or a 5- to 7-membered heterocycloalkyl.

[0117] In certain embodiments, each R 11 is C 1~6 Alkyl, C 3~7Cycloalkyl, 4-11 membered heterocycloalkyl, C 6~10 aryl and 5- to 14-membered heteroaryl, any one of which is independently selected from one or two R 12 is optionally replaced by

[0118] In certain embodiments, two R 11 When bonded directly to the same carbon atom, C 5~7 They can combine to form a 5- to 7-membered heterocycloalkyl having a heteroatom selected from N, O, and S. In certain embodiments, two R 11 When directly attached to the same carbon atom, they can be joined to form a 5- to 7-membered heterocycloalkyl having one or two heteroatoms selected from N, O, and S. In certain embodiments, two R 11 When directly attached to the same carbon atom, they can be joined to form a 5- to 7-membered heterocycloalkyl having one heteroatom selected from N, O, and S. In certain embodiments, two R 11 when directly attached to the same carbon atom, can be joined to form a 5- to 7-membered heterocycloalkyl having one heteroatom selected from N and O.

[0119] In certain embodiments, two R 11 can be linked to form a 5-7 membered heterocycloalkyl having heteroatoms selected from N, O, and S. In certain embodiments, two R 11 can be linked to form a 5-7 membered heterocycloalkyl having one or two heteroatoms selected from N, O, and S. In certain embodiments, two R 11 can be linked to form a 5-7 membered heterocycloalkyl having one heteroatom selected from N, O, and S. In certain embodiments, two R 11 can be linked to form a 5-7 membered heterocycloalkyl having one heteroatom selected from N and O. In certain embodiments, two R11 can be linked to form a 5- to 7-membered heterocycloalkyl selected from piperidine, pyrrolidine, tetrahydrofuran, and tetrahydro-2H-pyran.

[0120] In certain embodiments, each R 11 is one R 12 In certain embodiments, R 11 is one R 12 is replaced by .

[0121] In certain embodiments, each R 12 CN, halo, hydroxy, C 1~6 Alkyl, (C 1~6 In certain embodiments, each R 12 is selected from CN, halo, hydroxy, and oxo. In certain embodiments, each R 12 is selected from CN and halo.

[0122] In certain embodiments, each R 11 is R 12 is not replaced by

[0123] In certain embodiments, each R 11 is independently selected from CN, halo, hydroxy, and oxo. In certain embodiments, each R 11 is independently selected from CN and halo.

[0124] In certain embodiments, R 1 is C 1~6 Alkyl, C 3~7 Cycloalkyl, 4-11 membered heterocycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, (C 3~7 Cycloalkyl)C 1~6 Alkyl, (4-11 membered heterocycloalkyl)C 1~6 Alkyl, (C 6~14 Aryl)C 1~6 Alkyl and (5-14 membered heteroaryl)C 1~6alkyl, any one of which is selected from one or more R 6 is optionally replaced by

[0125] In certain embodiments, R 1 is C 1~6 Alkyl, C 3~7 Cycloalkyl, 4-11 membered heterocycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, (C 3~7 cycloalkyl)methyl, (4- to 11-membered heterocycloalkyl)methyl, (C 6~14 (aryl)methyl and (5- to 14-membered heteroaryl)methyl, any one of which is selected from one or more R 6 is optionally replaced by

[0126] In certain embodiments, R 1 is C 1~6 Alkyl, C 3~7 Cycloalkyl, 4-11 membered heterocycloalkyl, C 6~14 aryl and 5- to 14-membered heteroaryl, any one of which is selected from one or more R 6 is optionally replaced by

[0127] In certain embodiments, R 1 is C 1~6 Alkyl, C 3~7 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- or 6-membered heteroaryl, any one of which is selected from one or more R 6 is optionally replaced by

[0128] In certain embodiments, R 1 is selected from phenyl, pyridyl, pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl, and one or more R 6 is optionally replaced by

[0129] In certain embodiments, R 1 is one or two R 6In certain embodiments, R 1 is one R 6 In certain embodiments, R 1 is one R 6 is replaced by .

[0130] In certain embodiments, R 1 teeth, [ka] is selected from.

[0131] In certain embodiments, R 1 ,Br, [ka] is selected from.

[0132] In certain embodiments, R 1 teeth, [ka] is selected from.

[0133] In certain embodiments, R 1 teeth, [ka] is selected from.

[0134] In certain embodiments, R 1 teeth, [ka] is selected from.

[0135] In certain embodiments, R 1 is R 6 is not replaced by

[0136] In certain embodiments, each R 6 CN, halo, hydroxy, oxo, C1~6 Alkyl and (C 1~6 In certain embodiments, each R 6 is independently selected from CN, F, Cl, Br, hydroxy, and CH. In certain embodiments, each R 6 is independently selected from F, Cl, and CH. In certain embodiments, each R 6 is independently selected from F and CH3.

[0137] In certain embodiments, R 2 and R 3 are independently selected from H, halo, cyano, alkyl, (alkyl)oxy, cycloalkyl, and (cycloalkyl)oxy, any one of which may be selected from one or more R 7 is optionally replaced by

[0138] In certain embodiments, R 2 and R 3 are independently selected from H, halo, cyano, alkyl, (alkyl)oxy, cycloalkyl, and (cycloalkyl)oxy, any one of which may be selected from one or more R 7 is optionally replaced by

[0139] In certain embodiments, R 2 is selected from alkyl, (alkyl)oxy, cycloalkyl, and (cycloalkyl)oxy, any one of which may be selected from one or more R 7 In certain embodiments, R 2 is selected from alkyl and cycloalkyl, any one of which may be selected from one or more R 7 In certain embodiments, R 2 is selected from H, halo, cyclopropyl, CH, CD, and cyano. In certain embodiments, R 2 is selected from Cl, CH3, and CD3. In certain embodiments, R 2 is selected from Cl and CH3.

[0140] In certain embodiments, R 3 is selected from alkyl, (alkyl)oxy, cycloalkyl, and (cycloalkyl)oxy, any one of which may be selected from one or more R 7 In certain embodiments, R 3 is selected from H, halo, and cyano. In certain embodiments, R 3 is H.

[0141] In certain embodiments, each R 7 CN, halo, hydroxy, oxo, C 1~6 Alkyl and (C 1~6 In certain embodiments, each R 7 is independently selected from CN, halo, and hydroxy.

[0142] In certain embodiments, R 2 and R 3 together with the two intervening carbons, join to form a 5- to 7-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, any one of which may be joined by one or more R 8 and optionally fused to a 6-membered aryl or heteroaryl ring, said 6-membered aryl or heteroaryl ring being optionally substituted with one or more R 9 In certain embodiments, R 2 and R 3 together with the two intervening carbons, form a 5- to 7-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, any one of which may be joined by one or two R 8 and fused to a 6-membered aryl or heteroaryl ring, said 6-membered aryl or heteroaryl ring being optionally substituted with one or two R 9 In certain embodiments, R 2 and R 3 together with the two intervening carbons, form a 5- to 7-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, any one of which may be joined by one R 8and optionally fused to a 6-membered aryl or heteroaryl ring, said 6-membered aryl or heteroaryl ring being optionally substituted with one or two R 9 In certain embodiments, R 2 and R 3 together with the two intervening carbons, form a 5- to 7-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, any one of which may be R 8 and is fused to a 6-membered aryl or heteroaryl ring, said 6-membered aryl or heteroaryl ring being fused to one or two R 9 In certain embodiments, R 2 and R 3 together with the two intervening carbons, form a 5- to 7-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, any one of which may be joined by one or two R 8 In certain embodiments, R 2 and R 3 together with the two intervening carbons, form a 5- to 7-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, any one of which may be joined by one R 8 In certain embodiments, R 2 and R 3 may be joined together with the two intervening carbons to form a 5- to 7-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, any of which may be R 8 is not replaced by

[0143] In certain embodiments, each R 9 CN, halo, hydroxy, oxo, C 1~6 Alkyl and (C 1~6 In certain embodiments, each R 9 is independently selected from CN, halo, and hydroxy.

[0144] In certain embodiments, each R 8CN, halo, hydroxy, oxo, C 1~6 Alkyl and (C 1~6 In certain embodiments, each R 8 is independently selected from CN, halo, and hydroxy.

[0145] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] Also provided is a compound selected from: or a salt or tautomer thereof.

[0146] Further embodiments are provided herein, any one or more of which may be combined with any of the embodiments described above, provided that the combinations are not mutually exclusive.

[0147] As used herein, two embodiments are "mutually exclusive" when one is defined as being different from the other. For example, an embodiment in which two groups are bonded to form a cycloalkyl is mutually exclusive from an embodiment in which one group is ethyl and the other group is hydrogen. Similarly, an embodiment in which one group is -CH- is mutually exclusive from an embodiment in which the same group is -NH-.

[0148] Also provided is a compound selected from the examples disclosed herein, or a salt or tautomer thereof.

[0149] Also provided are methods for inhibiting at least one RIPK1 function, comprising contacting RIPK1 with a compound described herein, or a salt or tautomer thereof. Cell phenotype, cell proliferation, RIPK1 activity, changes in biochemical outcomes resulting from active RIPK1, RIPK1 expression, or binding of RIPK1 to a natural binding partner can be monitored. Such methods can be disease treatment methods, biological assays, cellular assays, biochemical assays, etc.

[0150] Also provided herein is a method for treating a RIPK1-mediated disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a salt or tautomer thereof.

[0151] Also provided herein are methods for treating the inflammatory component of RIPK1-mediated diseases.

[0152] Also provided herein are methods for treating the apoptotic component of RIPK1-mediated diseases.

[0153] Also provided herein are methods for treating the necroptosis component of RIPK1-mediated diseases.

[0154] In certain embodiments, the disease is selected from a neurodegenerative disorder, an inflammatory disorder, and cancer.

[0155] In certain embodiments, the disease is cancer. In certain embodiments, cancer is treated by promoting an appropriate immune response against the tumor. In certain embodiments, an appropriate immune response against the tumor includes or results in one or more of the following: - an increase in the number or activity of cytotoxic T lymphocytes and / or natural killer cells or the degree of tumor infiltration; - an increase in the number or activity of M1 macrophages in the tumor microenvironment and / or a decrease in the number or activity of M2 macrophages in the tumor microenvironment; - a decrease in the number or activity of regulatory T cells; and - A decrease in the number or activity of myeloid-derived suppressor cells.

[0156] In certain embodiments, the disease is myelodysplastic syndrome (MDS). In certain embodiments, the myelodysplastic syndrome is selected from myelodysplastic syndrome with unilineage dysplasia, myelodysplastic syndrome with multilineage dysplasia, myelodysplastic syndrome with ringed sideroblasts, myelodysplastic syndrome associated with isolated del chromosomal abnormality, myelodysplastic syndrome type 1 with excess blasts, and myelodysplastic syndrome type 2 with excess blasts. In certain embodiments, the myelodysplastic syndrome is unclassifiable myelodysplastic syndrome.

[0157] In certain embodiments, the disease is acute myeloid leukemia (AML).

[0158] Also provided herein are compounds disclosed herein, or salts or tautomers thereof, for use as pharmaceutical agents.

[0159] Also provided herein are compounds disclosed herein, or salts or tautomers thereof, for use as pharmaceutical agents for the treatment of RIPK1-mediated diseases.

[0160] Also provided is the use of the compounds disclosed herein, or salts or tautomers thereof, as pharmaceutical agents.

[0161] There is also provided the use of a compound disclosed herein, or a salt or tautomer thereof, as a pharmaceutical agent for the treatment of a RIPK1-mediated disease.

[0162] Also provided is a compound disclosed herein, or a salt or tautomer thereof, for use in the manufacture of a medicament for the treatment of a RIPK1-mediated disease.

[0163] Also provided is the use of a compound disclosed herein, or a salt or tautomer thereof, for the treatment of a RIPK1-mediated disease.

[0164] Also provided herein is a method of inhibiting RIPK1, comprising contacting RIPK1 with a compound disclosed herein, or a salt or tautomer thereof.

[0165] Also provided herein are methods for achieving an effect in a patient, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a salt or tautomer thereof, wherein the effect is selected from cognitive enhancement.

[0166] Also provided is a method for modulating RIPK1-mediated function in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein, or a salt or tautomer thereof.

[0167] Also provided are pharmaceutical compositions comprising a compound disclosed herein, or a salt or tautomer thereof, in association with a pharmaceutically acceptable carrier.

[0168] In certain embodiments, the pharmaceutical composition is formulated for oral administration.

[0169] In certain embodiments, the oral pharmaceutical composition is selected from a tablet and a capsule.

[0170] Formula (I) [ka] or a salt or tautomer thereof, comprising reacting a compound of formula (IA) [ka] of formula (IB) [ka] contacting the compound with a base of (In the formula, W is CH, CR 5 and N; R 1 is selected from CN, halo, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (aryl)alkyl, and (heteroaryl)alkyl, any one of which may be selected from one or more R 6 optionally substituted with; R 2 and R 3 are independently selected from H, halo, cyano, alkyl, (alkyl)oxy, (alkyl)thio, (alkyl)sulfonimidoyl, (alkyl)sulfonyl, cycloalkyl, and (cycloalkyl)oxy, any one of which may be selected from one or more R 7 optionally substituted with, or R 2 and R 3 together with the two intervening carbons, join to form a 5- to 7-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, any one of which may be joined by one or more R 8 and optionally fused to a 6-membered aryl or heteroaryl ring, said 6-membered aryl or heteroaryl ring being optionally substituted with one or more R 9 optionally substituted with; R 4is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (aryl)alkyl, and (heteroaryl)alkyl, any one of which may be selected from one or more R 10 optionally substituted with; R 5 is selected from H, CN, halo, hydroxy, alkyl and (alkyl)oxy; Each R 6 , R 7 , R 8 and R 9 are independently selected from CN, halo, hydroxy, NH2, oxo, alkyl, and (alkyl)oxy; Each R 10 is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)CH, (heterocycloalkyl)CH, (aryl)CH, (heteroaryl)CH, (alkyl)SO, (cycloalkyl)SO, (heterocycloalkyl)SO, (aryl)SO, (heteroaryl)SO, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (aryl)NH, (heteroaryl)NH, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R 11 optionally substituted with; Each R 11is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, alkylsulfonyl, haloalkylsulfonyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (alkylsulfonyl)oxy, (haloalkylsulfonyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (alkylsulfonyl)NH, (haloalkylsulfonyl)NH, (aryl)NH, and (heteroaryl)NH, any one of which may be selected from one or more R 12 is optionally replaced by The Two R's 11 is combined with C 5~7 can form a cycloalkyl or a 5- to 7-membered heterocycloalkyl; and Each R 12 is selected from CN, halo, hydroxy, alkyl, (alkyl)oxy and oxo Also provided is a method comprising:

[0171] In certain embodiments, the amide coupling agent is selected from T3P and HATU.

[0172] In certain embodiments, the reaction is carried out in the presence of an amine base, hi certain embodiments, the amine base is selected from EtN and iPrNEt. DETAILED DESCRIPTION OF THE INVENTION

[0173] definition As used herein, the following terms have the indicated meanings.

[0174] When a range of values ​​is disclosed and the notation "n1... to n2" or "between n1... and n2" (where n1 and n2 are numbers) is used, unless otherwise specified, this notation is intended to include those numbers themselves and the range between those numbers. The range may be integer or continuous between the endpoints, and is inclusive. As an example, the range "2 to 6 carbons" is intended to include 2, 3, 4, 5, and 6 carbons, since carbon is an integer unit. Compare, as an example, the range "1 to 3 μM (micromolar)," which is intended to include 1 μM, 3 μM, and all significant digits of any number therebetween (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0175] As used herein, the term "about" is intended to indicate that the numerical value it modifies represents such value as a variable within a margin of error. In the absence of a specific margin of error, such as a standard deviation for an average value given in a chart or table of data, the term "about" should be understood to mean a range that may encompass the stated value, and also to mean a range that may be encompassed by rounding up or down to that number, taking into account significant digits.

[0176] The term "acyl," as used herein, alone or in combination, refers to a carbonyl bonded to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety, where the atom bonded to the carbonyl is carbon. An "acetyl" group refers to a -C(O)CH group. An "alkylcarbonyl" or "alkanoyl" group refers to an alkyl group bonded to the parent molecular moiety through a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl, and aroyl.

[0177] The term "alkenyl," as used herein, alone or in combination, refers to a straight- or branched-chain hydrocarbon group having one or more double bonds and containing 2 to 20 carbon atoms. In certain embodiments, the alkenyl can contain 2 to 6 carbon atoms. The term "alkenylene" refers to a carbon-carbon double bond system attached at two or more positions, such as ethenylene [(-CH=CH-),(-C::C-)]. Examples of suitable alkenyl groups include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl, and the like. Unless otherwise specified, the term "alkenyl" can include "alkenylene" groups.

[0178] The terms "alkoxy" and, interchangeably, "(alkyl)oxy," as used herein, alone or in combination, refer to an alkyl ether group, where the term alkyl is as defined below. Examples of suitable alkyl ether groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.

[0179] The term "alkyl," as used herein, alone or in combination, refers to a straight-chain or branched-chain alkyl group containing 1 to 20 carbon atoms. In certain embodiments, the alkyl can contain 1 to 10 carbon atoms. In certain embodiments, the alkyl can contain 1 to 8 carbon atoms. The alkyl group is optionally substituted as defined below. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, nonyl, and the like. The term "alkylene," as used herein, alone or in combination, refers to a straight-chain saturated hydrocarbon bonded at two or more positions, such as methylene (-CH-), ethylene (-CHCH-), and propylene (-CHCHCH-). Thus, "alkylene" refers to -(CH) n-(n is a positive integer). In some embodiments, n is selected from 1 to 20. In some embodiments, n is selected from 1 to 10. In some embodiments, n is selected from 1 to 8. In some embodiments, n is selected from 1 to 6. The term "alkyl" can include "alkylene" groups unless otherwise specified.

[0180] The term "alkylamino," as used herein, alone or in combination, refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups can be mono- or dialkyl-forming groups, such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-ethylmethylamino, and the like.

[0181] The term "alkylthio," as used herein, alone or in combination, refers to an alkyl thioether (RS-) group, where the term alkyl is as defined above and sulfur can be singly or doubly oxidized. Examples of suitable alkyl thioether groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

[0182] The term "alkynyl," as used herein, alone or in combination, refers to a straight- or branched-chain hydrocarbon group having one or more triple bonds and containing 2 to 20 carbon atoms. In certain embodiments, said alkynyl contains 2 to 6 carbon atoms. In certain embodiments, said alkynyl contains 2 to 4 carbon atoms. The term "alkynylene" refers to a carbon-carbon triple bond attached at two positions, such as ethynylene (-C:::C-, -C≡C-). Examples of alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, and the like. Unless otherwise specified, the term "alkynyl" can include "alkynylene" groups.

[0183] The terms "amido" and "carbamoyl," as used herein, alone or in combination, refer to an amino group, as described below, attached to the parent molecular moiety through a carbonyl group (or vice versa). The term "C-amido," as used herein, alone or in combination, refers to the group -C(O)N(RR'), where R and R' are as defined herein or as defined by a specifically enumerated designated "R" group. The term "N-amido," as used herein, alone or in combination, refers to the group RC(O)N(R')-, where R and R' are as defined herein or as defined by a specifically enumerated designated "R" group. The term "acylamino," as used herein, alone or in combination, includes an acyl group attached to the parent moiety through an amino group. An example of an "acylamino" group is acetylamino (CHC(O)NH-).

[0184] The term "amino," as used herein, alone or in combination, refers to -NRR', where R and R' are independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted. Additionally, R and R' may join to form a heterocycloalkyl, either of which may be optionally substituted.

[0185] The term "aryl," as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two, or three rings, where such polycyclic ring systems are fused. The term "aryl" encompasses aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl.

[0186] The terms "arylalkyl" or "aralkyl," as used herein, alone or in combination, refer to an aryl group attached to the parent molecular moiety through an alkyl group.

[0187] The terms "arylalkanoyl" or "aralkanoyl" or "aroyl," as used herein, alone or in combination, refer to an acyl group derived from an aryl-substituted alkanecarboxylic acid, such as benzoyl, naphthoyl, phenylacetyl, 3-phenylpropionyl(hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

[0188] The term aryloxy, as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an oxy.

[0189] The terms "benzo" and "benz," as used herein, alone or in combination, refer to the divalent group CH= derived from benzene. Examples include benzothiophene and benzimidazole.

[0190] The term "carbamate," as used herein, alone or in combination, refers to an ester of carbamic acid (-NHCOO-), which can be attached to the parent molecular moiety through either the nitrogen or the acid terminus, and is optionally substituted as defined herein.

[0191] The term "O-carbamyl," as used herein, alone or in combination, refers to an --OC(O)NRR' group, with R and R' as defined herein.

[0192] The term "N-carbamyl," as used herein, alone or in combination, refers to an ROC(O)NR'- group, with R and R' as defined herein.

[0193] The term "carbonyl" as used herein when alone includes formyl [-C(O)H] and when in combination is a -C(O)- group.

[0194] The terms "carboxyl" or "carboxy" as used herein refer to -C(O)OH or the corresponding "carboxylate" anion (such as in carboxylic acid salts). An "O-carboxy" group refers to a RC(O)O- group, where R is as defined herein. A "C-carboxy" group refers to a -C(O)OR group, where R is as defined herein.

[0195] The term "cyano," as used herein, alone or in combination, refers to --CN.

[0196] The term "cycloalkyl," or alternatively, "carbocycle," as used herein, alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic, or tricyclic alkyl group, wherein each cyclic moiety contains 3 to 12 carbon atom ring members, and may optionally be a benzo-fused ring system, optionally substituted as defined herein. In certain embodiments, the cycloalkyl may contain 5 to 7 carbon atoms. In certain embodiments, the cycloalkyl includes spiro ring systems. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl, and the like. As used herein, "bicyclic ring system" and "tricyclic ring system" are intended to include both fused ring systems, such as decahydronaphthalene, octahydronaphthalene, and the like, as well as polycyclic (multi-center) saturated or partially saturated types. Examples of the latter type of isomers include, in general, bicyclo-[1.1.1]pentane, camphor, adamantane, and bicyclo[3.2.1]octane.

[0197] The term "ester," as used herein, alone or in combination, refers to a carboxy group bridging two moieties joined at a carbon atom.

[0198] The term "ether," as used herein, alone or in combination, refers to an oxy group bridging two moieties joined at a carbon atom.

[0199] The terms "halo" or "halogen," as used herein, alone or in combination, refer to fluorine, chlorine, bromine, or iodine.

[0200] The term "haloalkoxy," as used herein, alone or in combination, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

[0201] The term "haloalkyl," as used herein, alone or in combination, refers to an alkyl group having the meaning defined above in which one or more hydrogen atoms have been replaced by halogen. Specifically, monohaloalkyl, dihaloalkyl, and polyhaloalkyl groups are encompassed. For example, a monohaloalkyl group may have an iodo, bromo, chloro, or fluoro atom within the group. Dihalo and polyhaloalkyl groups may have two or more of the same halo atoms or a combination of different halo groups. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. "Haloalkylene" refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF2-), chloromethylene (-CHCl-), and the like.

[0202] The term "heteroalkyl," as used herein, alone or in combination, refers to a stable linear, branched, or combination thereof, which is fully saturated or contains one to three degrees of unsaturation and consists of the specified number of carbon atoms and one, two, or three heteroatoms selected from N, O, and S, where the N and S atoms can be optionally oxidized, or the N heteroatom can be optionally quaternized. The heteroatoms can be placed at any interior position of the heteroalkyl group. Up to two heteroatoms can be consecutive, for example, -CH-NH-OCH.

[0203] The term "heteroaryl," as used herein, alone or in combination, refers to a 3- to 15-membered unsaturated heteromonocyclic ring or fused monocyclic, bicyclic, or tricyclic ring system, wherein at least one of the fused rings is aromatic containing at least one atom selected from N, O, and S. In certain embodiments, the heteroaryl can contain 1 to 4 heteroatoms as ring members. In certain embodiments, the heteroaryl can contain 1 to 2 heteroatoms as ring members. In certain embodiments, the heteroaryl can contain 5 to 7 atoms. The term also encompasses fused polycyclic groups in which a heterocyclic ring is fused to an aryl ring, a heteroaryl ring is fused to another heteroaryl ring, a heteroaryl ring is fused to a heterocycloalkyl ring, or a heteroaryl ring is fused to a cycloalkyl ring. Examples of heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

[0204] As used herein, the terms "heterocycloalkyl" and, interchangeably, "heterocycle," alone or in combination, refer to a saturated, partially unsaturated, or fully unsaturated (but non-aromatic) monocyclic; saturated, partially unsaturated, or fully unsaturated (but not fully aromatic) bicyclic; or saturated, partially unsaturated, or fully unsaturated (but not fully aromatic) tricyclic heterocyclic group, each containing at least one heteroatom as a ring member, where each of the heteroatoms may be independently selected from nitrogen, oxygen, and sulfur. This term includes polycyclic groups containing at least one non-aromatic ring, such as 1,2-dihydroquinoline, 5,6-dihydroquinoline, and 2,3-dihydrobenzofuran. This term excludes polycyclic groups in which all rings are non-aromatic, such as indole, quinoline, and acridine.

[0205] In certain embodiments, the heterocycloalkyl includes spirocyclic ring systems. In certain embodiments, the heterocycloalkyl can include 1 to 4 heteroatoms as ring members. In certain embodiments, the heterocycloalkyl can include 1 to 2 heteroatoms as ring members. In certain embodiments, the heterocycloalkyl can include 3 to 8 ring members in each ring. In certain embodiments, the heterocycloalkyl can include 3 to 7 ring members in each ring. In certain embodiments, the heterocycloalkyl can include 5 to 6 ring members in each ring. "Heterocycloalkyl" and "heterocycle" are intended to include sulfone, sulfoxide, N-oxide of tertiary nitrogen ring members, and carbocyclic fused and benzofused ring systems; further, both terms also include systems in which a heterocycle is fused to an aryl or heteroaryl group, as defined herein, or to an additional heterocyclic group. Examples of heterocyclic groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like.

[0206] The term "hydroxy," as used herein, alone or in combination, refers to --OH.

[0207] The term "hydroxyalkyl," as used herein, alone or in combination, refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.

[0208] The phrase "linear chain of atoms" refers to the longest linear chain of atoms independently selected from carbon, nitrogen, oxygen, and sulfur.

[0209] The term "lower", as used herein, alone or in combination, means, unless otherwise defined, containing 1 to 6 carbon atoms (ie, C1-C6 alkyl).

[0210] The term "lower cycloalkyl," as used herein, alone or in combination, means a monocyclic cycloalkyl having 3 to 6 ring members (i.e., C3-C6 cycloalkyl). A lower cycloalkyl can be unsaturated. Examples of lower cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0211] The term "lower heterocycloalkyl," as used herein, alone or in combination, means a monocyclic heterocycloalkyl (i.e., a C3-C6 heterocycloalkyl) having 3 to 6 ring members, of which 1 to 4 can be heteroatoms selected from N, O, and S. Examples of lower heterocycloalkyls include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl. Lower heterocycloalkyls can be unsaturated.

[0212] The term "lower amino," as used herein, alone or in combination, refers to -NRR', where R and R' are independently selected from hydrogen and lower alkyl, either of which is optionally substituted.

[0213] The term "nitro," as used herein, alone or in combination, refers to -NO2.

[0214] The terms "oxy" or "oxa," as used herein, alone or in combination, refer to --O--.

[0215] The term "oxo" as used herein, alone or in combination, refers to =0.

[0216] The term "perhaloalkoxy" refers to an alkoxy group in which all of the hydrogen atoms have been replaced by halogen atoms.

[0217] The term "perhaloalkyl," as used herein, alone or in combination, refers to an alkyl group in which all of the hydrogen atoms have been replaced by halogen atoms.

[0218] The term "spirocyclic ring system" refers to a polycyclic ring system containing two rings in which a single atom is common to both rings.

[0219] The terms "sulfonate," "sulfonic acid," and "sulfonic," as used herein, alone or in combination, refer to the -SO3H group and its anion (when the sulfonic acid is used in salt form).

[0220] The term "sulfanyl," as used herein, alone or in combination, refers to --S--.

[0221] The term "sulfinyl," as used herein, alone or in combination, refers to --S(O)--.

[0222] The term "sulfonyl," as used herein, alone or in combination, refers to -S(O)2-.

[0223] The term "N-sulfonamido" refers to a RS(=O)2NR'- group, where R and R' are as defined herein.

[0224] The term "S-sulfonamido" refers to a -S(=O)2NRR' group, where R and R' are as defined herein.

[0225] The terms "thia" and "thio," as used herein, alone or in combination, refer to an -S- group or an ether where the oxygen is replaced with a sulfur. The oxidized derivatives of the thio group, i.e., sulfinyl: -SO-, sulfonyl: -SO-, and sulfonimidoyl: -SO(NH)-, are included in the definition of thia and thio.

[0226] The term "thiol," as used herein, alone or in combination, refers to a --SH group.

[0227] The term "thiocyanato" refers to the group -CNS.

[0228] The term "trisubstituted silyl," as used herein, alone or in combination, refers to a silicone group in the definition of substituted amino, in which the three free valences have been replaced with a group listed herein. Examples include trimethylsilyl, tert-butyldimethylsilyl, triphenylsilyl, and the like.

[0229] Any definition herein can be used in combination with any other definition to describe a composite structural group. By convention, the latter element of any such definition is the element that is attached to the parent moiety. For example, the composite group alkylamido can represent an alkyl group attached to the parent molecule via an amide group, and the term alkoxyalkyl can represent an alkoxy group attached to the parent molecule via an alkyl group.

[0230] When a group is defined as "null," it is meant that said group is not present.

[0231] The term "optionally substituted" means that the preceding group can be substituted or unsubstituted. When substituted, the substituents of the "optionally substituted" group can include, but are not limited to, one or more substituents independently selected from the following groups or the set of specific specified groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloa Alkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamide, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N3, SH, SCH3, C(O)CH3, CO2CH3, CO2H, pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Where structurally feasible, two substituents may be joined together to form a fused 5-, 6-, or 7-membered carbocyclic or heterocyclic ring consisting of 0 to 3 heteroatoms, for example, to form methylenedioxy or ethylenedioxy. Optionally substituted groups can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between fully and monosubstituted (e.g., -CH2CF3). When a substituent is recited without qualification as to substitution, both substituted and unsubstituted forms are encompassed. When a substituent is qualified as "substituted," the substituted form is specifically intended. Furthermore, where appropriate, different optional substituent sets can be defined for a particular moiety; in these cases, the optional substitution will often be as defined immediately following the phrase "optionally substituted with."

[0232] The term R or R', appearing alone and without a number designation, unless otherwise defined, refers to a moiety selected from hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, and heterocycloalkyl, any of which is optionally substituted. Such R and R' groups should be understood to be optionally substituted as defined herein. Whether or not an R group has a number designation, R, R', and R n All R groups, including (where n = (1, 2, 3, ... n)), all substituents, and all terms should be understood to be independent of all others with respect to selection from a group. When any variable, substituent, or term (e.g., aryl, heterocycle, R, etc.) occurs more than one time in a formula or generic structure, its definition at each occurrence is independent of its definition at every other occurrence. Those skilled in the art will further recognize that certain groups may be attached to a parent molecule or may occupy a position in the chain of elements from either end as depicted. For example, an unsymmetrical group such as -C(O)N(R)- can be attached to the parent moiety at either the carbon or the nitrogen.

[0233] Asymmetric centers exist in the compounds, salts, and tautomers disclosed herein. These centers are designated by the symbol "R" or "S," depending on the configuration of substituents around the chiral carbon atom. It should be understood that the present invention encompasses all stereochemical isomers, including diastereomeric, enantiomeric, and epimeric forms, as well as d- and l-isomers, and mixtures thereof. Individual stereoisomers of the compounds, salts, and tautomers can be prepared synthetically from commercially available starting materials containing chiral centers, or by preparing a mixture of enantiomeric products followed by separation, such as conversion to a diastereomeric mixture, followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on a chiral chromatographic column, or any other suitable method known in the art. Starting compounds, salts, and tautomers of particular stereochemistry are commercially available or can be made and resolved by techniques known in the art. Furthermore, the compounds, salts, and tautomers disclosed herein may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (opposite sides) (E) and zusammen (same sides) (Z) isomers as well as the appropriate mixtures thereof.

[0234] The term "tautomers," as used herein, alone or in combination, refers to a pair of compounds that differ in the arrangement of hydrogen bonds and double bonds and that rapidly interconvert in conventional media. Tautomeric pairs recognized by those skilled in the art include, but are not limited to, keto / enol tautomers, 2-hydroxypyridine / 2-pyridone tautomers, lactam / lactim tautomers, and imine / enamine tautomers.

[0235] The compounds disclosed herein can exist as tautomers; all tautomers are provided in this disclosure. For example, 2-hydroxypyridine can exist in the following equilibrium: [ka] It is recognized by those skilled in the art that 2-pyridones exist in tautomeric equilibrium with the corresponding 2-pyridone, as represented by:

[0236] A similar equilibrium exists with 4-hydroxypyridine. The relative amounts of 2-hydroxypyridine and 2-pyridone (and 4-hydroxypyridine and 4-pyridone, respectively) are controlled by the various groups around the heteroaryl ring and the details of the solvent medium. Those skilled in the art will understand that compounds that exist in tautomeric equilibria, including but not limited to the above equilibria, generally are not isolated in either of the two tautomeric forms, but rather exist as a mixture.

[0237] Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. In general, the solvated forms are considered equivalent to the unsolvated forms.

[0238] The term "bond" refers to a covalent bond between two atoms, or between two moieties when the atoms joined by the bond are considered to be part of a larger substructure. The bond may be a single, double, or triple bond, unless otherwise specified. A dashed line between two atoms in a molecular drawing indicates that an additional bond may or may not be present at that position.

[0239] As used herein, the term "disease" is generally intended to be synonymous with, and used interchangeably with, the terms "disorder," "syndrome," and "condition" (as in pathology), all of which refer to an abnormal condition of the human or animal body or one of its organs that impairs normal function, is usually manifested by noticeable signs and symptoms, and causes a decrease in the lifespan or quality of life of the human or animal.

[0240] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in this disclosure. Such administration includes the co-administration of these therapeutic agents substantially simultaneously (e.g., in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient). Furthermore, such administration also includes the sequential use of each type of therapeutic agent. In either case, the treatment regimen will provide the beneficial effect of the drug combination in treating the condition or disorder described herein.

[0241] As used herein, a "RIPK1-binding agent" refers to a compound that binds to RIPK1 with a K for RIPK1 of about 100 μM or less, more typically about 50 μM or less, as measured in a RIPK1 binding assay generally described herein. d The RIPK1 binding assay refers to a compound or a salt or tautomer thereof that exhibits the K d The dissociation constant (K) is measured. Certain compounds disclosed herein, or salts or tautomers thereof, have been found to bind to RIPK1. In certain embodiments, the compounds, or salts or tautomers thereof, have a K for RIPK1 of about 10 μM or less when measured in the RIPK1 assay described herein. d In certain embodiments, the compound or a salt or tautomer thereof has a K for RIPK1 of about 1 μM or less. d In certain embodiments, the compound, or salt or tautomer thereof, exhibits a Kd of about 0.1 μM or less for RIPK1; in certain embodiments, the compound, or salt or tautomer thereof, exhibits a Kd of about 10 nM or less for RIPK1.

[0242] The phrase "therapeutically effective" is intended to qualify the amount of active ingredient used in the treatment of a disease or disorder or in achieving a clinical endpoint.

[0243] The term "therapeutically acceptable" refers to a compound (or a salt or tautomer thereof) that is suitable for use in contact with the tissues of a patient without undue toxicity, irritation, or allergic response, commensurate with a reasonable benefit / risk ratio, and that is effective for its intended use.

[0244] As used herein, reference to "treatment" of a patient is intended to include prophylaxis. Treatment may be proactive in nature, i.e., include prevention of disease. Prevention of disease may include complete protection from disease, such as in the case of preventing infection by a pathogen, or may include prevention of disease progression. For example, prevention of disease may not mean complete elimination of all effects associated with the disease at any level, but instead may mean preventing disease symptoms to a clinically significant or detectable level. Prevention of disease may also mean preventing a disease from progressing to a late stage of disease.

[0245] The term "patient" is generally synonymous with the term "subject" and includes all mammals, including humans. Examples of patients include humans, domestic animals such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

[0246] Salts and Polymorphs The compounds disclosed herein can exist as therapeutically acceptable salts. The present invention includes the above compounds and their tautomers in the form of salts, including acid addition salts. Suitable salts include salts formed with both organic and inorganic acids. Such acid addition salts will usually be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be useful in the preparation and purification of the compound in question. Base addition salts may also be formed and may be pharmaceutically acceptable. For a more complete discussion of salt preparation and selection, see Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich, Wiley-VCHA, Zurich, Switzerland, 2002).

[0247] As used herein, the term "therapeutically acceptable salt" refers to a water- or oil-soluble or dispersible salt or zwitterionic form of a compound disclosed herein that is therapeutically acceptable as defined herein. Salts can be prepared by reacting the free base form of the appropriate compound with a suitable acid, either during the final isolation and purification of the compound or separately. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, malonate, and the like. The salts include methyl, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), and undecanoate. Basic groups in the compounds disclosed herein can also be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfate; decyl chlorides, bromides, and iodides, lauryl, myristyl, and steryl; and benzyl and phenethyl bromides. Examples of acids that can be used to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. Salts can also be formed by coordination of a compound with an alkali metal or alkaline earth metal ion. Thus, the present invention contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, as well as tautomers thereof, and the like.

[0248] Base addition salts can be prepared during the final isolation and purification of the compounds by reacting the carboxyl group with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a metal cation, or ammonia, or an organic primary, secondary, or tertiary amine. Therapeutically acceptable salt cations include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as non-toxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-phenamine, and N,N'-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[0249] While it may be possible for the compounds, salts, and tautomers of the present invention to be administered as the raw chemical, they can also be provided as pharmaceutical formulations. Accordingly, provided herein are pharmaceutical formulations comprising one or more of the specific compounds disclosed herein, or one or more pharmaceutically acceptable salts or tautomers thereof, together with one or more pharmaceutically acceptable carriers thereof, and optionally one or more other therapeutic ingredients. A carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Appropriate formulations depend on the route of administration chosen. Any well-known techniques, carriers, and excipients may be used, as appropriate and understood in the art. The pharmaceutical compositions disclosed herein can be prepared by any method known in the art, for example, by conventional mixing, dissolving, granulating, dragee-making, gelatinizing, emulsifying, encapsulating, entrapping, or compressing processes.

[0250] formulation Formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal, and topical (including dermal, buccal, sublingual, and ocular) administration, although the most suitable route may depend, for example, on the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. In general, these methods include the step of bringing into association a compound, salt, or tautomer of the invention, or a pharmaceutically acceptable salt or tautomer thereof (the "active ingredient"), with the carrier, which constitutes one or more accessory ingredients. Generally, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation.

[0251] Formulations of the compounds disclosed herein, or salts or tautomers thereof, suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary, or paste.

[0252] Pharmaceutical preparations that can be used orally include tablets, push-fit capsules made of gelatin, and sealed soft capsules made of gelatin and a plasticizer (such as glycerol or sorbitol). Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, inert diluent, or lubricant, surfactant, or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound or a salt or tautomer thereof moistened with an inert liquid diluent. Tablets can optionally be coated or scored and can also be formulated so as to provide sustained or controlled release of the active ingredient therein. All preparations for oral administration should be in dosages suitable for such administration. Push-fit capsules can contain the active ingredient in admixture with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compound or its salt or tautomer can be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers can be added. Dragee cores are provided with a suitable coating. For this purpose, concentrated sugar solutions can be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to tablets or dragee coatings for identification or to characterize different combinations of active compound doses or their salts or tautomers.

[0253] The compound or its salts or tautomers can be formulated for parenteral administration by injection, e.g., bolus injection or continuous infusion. Injectable formulations can be provided in unit dosage form, e.g., in ampoules or multi-dose containers, with added preservatives. The compositions can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. The formulations can be provided in single-dose or multi-dose containers, e.g., sealed ampoules and vials, and can be stored in powder form or freeze-dried (lyophilized) condition, requiring only the addition of a sterile liquid carrier, e.g., saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the type described above.

[0254] Preparations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound or its salts or tautomers, which may contain antioxidants, buffers, bacteriostats, and solutes that render the preparation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound or its salts or tautomers, allowing for the preparation of highly concentrated solutions.

[0255] In addition to the above-mentioned formulations, the compound or its salt or tautomer can be formulated as a depot preparation. Such long-acting preparations can be administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Thus, for example, the compound or its salt or tautomer can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as a sparingly soluble derivative, for example, as a sparingly soluble salt.

[0256] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in a conventional manner. Such compositions may comprise the active ingredient in a flavored base such as sucrose and acacia or tragacanth.

[0257] The compounds or salts or tautomers thereof may also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

[0258] Certain compounds disclosed herein, or their salts or tautomers, can be administered locally, i.e., by non-systemic administration. This includes external application of a compound disclosed herein, or its salts or tautomers, to epithelia or the buccal cavity, as well as instillation of such a compound, or its salts or tautomers, into the ears, eyes, and nose, so that the compound, or its salts or tautomers, do not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0259] Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation, such as gels, liniments, lotions, creams, ointments, or pastes, as well as drops suitable for administration to the eye, ear, or nose. The active ingredient for topical administration may, for example, comprise 0.001% to 10% w / w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10% w / w. In other embodiments, it may comprise less than 5% w / w. In certain embodiments, the active ingredient may comprise 2% w / w to 5% w / w. In other embodiments, it may comprise 0.1% to 1% w / w of the formulation.

[0260] For administration by inhalation, the compound or its salt or tautomer can be conveniently delivered from an insufflator, a nebulizer pressurized pack, or other means convenient for delivering an aerosol spray. The pressurized pack can contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compound according to the present invention or its salt or tautomer can be in the form of a dry powder composition, for example, a powder mix of the compound or its salt or tautomer with a suitable powder base, such as lactose or starch. The powder composition can be presented in unit dosage form, for example, in capsules, cartridges, gelatin, or blister packs, from which the powder can be administered using an inhaler or insufflator.

[0261] Preferred unit dosage forms are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient.

[0262] It should be understood that in addition to the ingredients particularly listed above, the above formulations may include other agents conventional in the art having regard to the type of formulation; for example, those suitable for oral administration may include flavoring agents.

[0263] Administration and Treatment The compounds or their salts or tautomers can be administered orally or by injection at a dose of 0.1 to 500 mg / kg per day. The dose range for adults is generally 5 mg to 2 g per day. Tablets or other presentation forms provided in discrete units can conveniently contain one or more compounds or their salts or tautomers in an amount that is effective in such a dosage or a multiple thereof; for example, a unit contains 5 mg to 500 mg, usually about 10 mg to 200 mg.

[0264] The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

[0265] The compound or its salt or tautomer can be administered in various modes, for example, orally, topically, or by injection. The exact amount of the compound or its salt or tautomer administered to a patient can be the responsibility of the attending physician. The specific dose level for any particular patient can depend on a variety of factors, including the activity of the specific compound or its salt or tautomer used, age, body weight, overall health, sex, diet, time of administration, route of administration, excretion rate, drug combinations, the exact disorder being treated, and the severity of the symptom or condition being treated. The route of administration can also vary depending on the condition and its severity.

[0266] In certain instances, it may be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt or tautomer thereof) in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient when receiving a compound described herein, or one of its salts or tautomers, is high blood pressure, it may be appropriate to administer an antihypertensive drug in combination with the first therapeutic agent. Alternatively, by way of example only, the therapeutic effectiveness of a compound described herein, or one of its salts or tautomers, may be enhanced by the administration of an adjunct agent (i.e., the adjunct agent may have only minimal therapeutic benefit by itself, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Alternatively, by way of example only, the benefit experienced by a patient may be increased by administering a compound described herein, or one of its salts or tautomers, with another therapeutic agent (including a therapeutic regimen) that also has therapeutic benefit. By way of example only, in the treatment of diabetes involving the administration of a compound described herein, or one of its salts or tautomers, an enhanced therapeutic benefit may occur by also providing the patient with another therapeutic agent for diabetes. In either case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may simply be the additive benefit of the two therapeutic agents, or the patient may experience a synergistic benefit.

[0267] Specific, non-limiting examples of possible combination therapies include the use of certain compounds of the invention or salts or tautomers thereof with donepezil, rivastigmine, galantamine, and memantine. Further examples include anti-amyloid antibodies and vaccines, anti-Ab antibodies and vaccines, anti-tau antibodies and vaccines, β-secretase inhibitors, 5-HT4 agonists, 5-HT6 antagonists, 5-HT1a antagonists, α7 nicotinic receptor agonists, 5-HT3 receptor antagonists, PDE4 inhibitors, O-GlycNcase inhibitors, and other medications approved for the treatment of Alzheimer's disease. Further examples include metformin, minocycline, tissue plasminogen activator, and other therapeutic agents that improve neuronal survival.

[0268] In either case, the multiple therapeutic agents (at least one of which is a compound disclosed herein or a salt or tautomer thereof) can be administered in any order or simultaneously. If simultaneously, the multiple therapeutic agents can be provided in a single, unified form or in multiple forms (by way of example only, either as a single tablet or as two separate tablets). One of the therapeutic agents can be given in multiple doses, or both can be given as multiple doses. If not simultaneously, the timing between the multiple doses can be any period ranging from a few minutes to four weeks.

[0269] Accordingly, in another aspect, certain embodiments provide methods for treating a RIPK1-mediated disorder in a human or animal subject in need of such treatment, comprising administering to the subject an amount of a compound disclosed herein, or a salt or tautomer thereof, in combination with at least one additional agent known in the art for treating said disorder, effective to reduce or prevent said disorder in the subject. In a related aspect, certain embodiments provide therapeutic compositions comprising at least one compound disclosed herein, or a salt or tautomer thereof, in combination with one or more additional agents for treating a RIPK1-mediated disorder.

[0270] For use in cancer and neoplastic diseases, RIPK1 inhibitors may be optimally used in conjunction with one or more of the following non-limiting examples of anti-cancer drugs: 1) Inhibitors or modulators of proteins involved in one or more DNA damage repair (DDR) pathways, e.g., a.PARP1 / 2, including but not limited to olaparib, niraparib, and rucaparib; b. Checkpoint kinase 1 (CHK1), including but not limited to UCN-01, AZD7762, PF477736, SCH900776, MK-8776, LY2603618, V158411, and EXEL-9844; c. Checkpoint kinase 2 (CHK2), including but not limited to PV1019, NSC109555, and VRX0466617; d. Dual CHK1 / CHK2, including but not limited to XL-844, AZD7762, and PF-473336; e. WEE1, including but not limited to MK-1775 and PD0166285; f. ATMs, including but not limited to KU-55933; g. DNA-dependent protein kinases, including but not limited to NU7441 and M3814; and h.Another protein involved in DDR; 2) Inhibitors or modulators of one or more immune checkpoints, including but not limited to: PD-1 inhibitors such as nivolumab (OPDIVO), pembrolizumab (KEYTRUDA), pidilizumab (CT-011), and AMP-224 (AMPLIMMUNE); b. PD-L1 inhibitors such as atezolizumab (TECENTRIQ), avelumab (BAVENCIO), durvalumab (IMFINZI), MPDL3280A (Tecentriq), BMS-936559, and MEDI4736; c. Anti-CTLA-4 antibodies such as ipilimumab (YERVOY) and CP-675,205 (TREMELIMUMAB); inhibitor of dT-cell immunoglobulin and mucin domain 3 (Tim-3); eV-domain Ig suppressor of T cell activation (Vista) inhibitor; fB and T lymphocyte attenuator (BTLA) inhibitors; g. Lymphocyte activation gene 3 (LAG3) inhibitors; and hInhibitor of T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT); 3) telomerase inhibitors or telomeric DNA binding compounds; 4) Alkylating agents, including but not limited to chlorambucil (LEUKERAN), oxaliplatin (ELOXATIN), streptozocin (ZANOSAR), dacarbazine, ifosfamide, lomustine (CCNU), procarbazine (MATULAN), temozolomide (TEMODAR), and thiotepa; 5) DNA cross-linking agents, including but not limited to carmustine, chlorambucil (LEUKERAN), carboplatin (PARAPLATIN), cisplatin (PLATIN), busulfan (MYLERAN), melphalan (ALKERAN), mitomycin (MITOSOL), and cyclophosphamide (ENDOXAN); 6) Antimetabolites, including but not limited to cladribine (LEUSTATIN), cytabine, (ARA-C), mercaptopurine (PURINETHOL), thioguanine, pentostatin (NIPENT), cytosine arabinoside (cytarabine, ARA-C), gemcitabine (GEMZAR), fluorouracil (5-FU, CARAC), capecitabine (XELODA), leucovorin (FUSILEV), methotrexate (RHEUMATREX), and raltitrexed; 7) Antimitotic agents (which are often plant alkaloids and terpenoids) or derivatives thereof, including but not limited to taxanes such as docetaxel (TAXITERE), paclitaxel (ABRAXANE, TAXOL), vinca alkaloids such as vincristine (ONCOVIN), vinblastine, vindesine, and vinorelbine (NAVELBINE); 8) Topoisomerase inhibitors, including but not limited to amacrine, camptothecin (CTP), genistein, irinotecan (CAMPTOSAR), topotecan (HYCAMTIN), doxorubicin (ADRIAMYCIN), daunorubicin (CERUBIDINE), epirubicin (ELLENCE), ICRF-193, teniposide (VUMON), mitoxantrone (NOVANTRONE), and etoposide (EPOSIN); 9) DNA replication inhibitors, including but not limited to fludarabine (FLUDARA), aphidicolin, ganciclovir, and cidofovir; 10) Ribonucleoside diphosphate reductase inhibitors, including but not limited to hydroxyurea; 11) Transcription inhibitors, including but not limited to actinomycin D (dactinomycin, COSMEGEN) and plicamycin (mithramycin); 12) DNA cleaving agents, including but not limited to, bleomycin (BLENOXANE), idarubicin; 13) Cytotoxic antibiotics, including but not limited to actinomycin D (dactinomycin, COSMEGEN); 14) Aromatase inhibitors, including but not limited to aminoglutethimide, anastrozole (ARIMIDEX), letrozole (FEMARA), vorozole (RIVIZOR), and exemestane (AROMASIN); 15) Angiogenesis inhibitors, including but not limited to, genistein, sunitinib (SUTENT), and bevacizumab (AVASTIN); 16) Antisteroids and antiandrogens, including but not limited to aminoglutethimide (CYTADREN), bicalutamide (CASODEX), cyproterone, flutamide (EULEXIN), nilutamide (NILANDRON); 17) Tyrosine kinase inhibitors, including but not limited to imatinib (GLEEVEC), erlotinib (TARCEVA), lapatinib (TYKERB), sorafenib (NEXAVAR), and axitinib (INLYTA); 18) mTOR inhibitors, including but not limited to everolimus, temisirolimus (TORISEL), and sirolimus; 19) Monoclonal antibodies, including but not limited to trastuzumab (HERCEPTIN) and rituximab (RITUXAN); 20) Apoptotic derivatives such as cordycepin; 21) Protein synthesis inhibitors, including but not limited to clindamycin, chloramphenicol, streptomycin, anisomycin, and cycloheximide; 22) Antidiabetic drugs, including but not limited to metformin and phenformin; 23) but not limited to: a. Tetracyclines, such as but not limited to doxycycline; b. Erythromycin, such as but not limited to azithromycin; c. Glycylglycines, such as but not limited to tigecycline; d. Antiparasitic drugs such as, but not limited to, pyrvinium pamoate; e. β-lactams, such as, but not limited to, penicillins and cephalosporins; f. Anthracycline antibiotics, such as, but not limited to, daunorubicin and doxorubicin; g. Other antibiotics, such as, but not limited to, chloramphenicol, mitomycin C, and actinomycin Antibiotics, including; 24) Antibody therapeutics, including but not limited to muromonab-CD3, infliximab (REMICADE), adalimumab (HUMIRA), omalizumab (XOLAIR), daclizumab (ZENAPAX), rituximab (RITUXAN), ibritumomab (ZEVALIN), tositumomab (BEXXAR), cetuximab (ERBITUX), trastuzumab (HERCEPTIN), ADCETRIS, alemtumab (CAMPATH-1H), Lym-1 (ONCOLYM), ipilimumab (YERVOY), vitaxin, bevacizumab (AVASTIN), and abciximab (REOPRO); and 25) Bacillus Calmette-Guerin (BCG) vaccine; buserelin (etilamide); chloroquine (aralen); clodronate, pamidronate, and other bisphosphonates; colchicine; demethoxyviridine; dichloroacetate; estramustine; filgrastim (neupogen); fludrocortisone (flourine); goserelin (zoladex); interferon; leucovorin; leuprolide (lupron); levamisole; lonidamine; mesna; metformin; mitotane (o,p'-ddd, ly SODREN); nocodazole; octreotide (SANDOSTATIN); perifosine; porfimer (especially in combination with phototherapy and radiation therapy); suramin; tamoxifen; titanocene dichloride; tretinoin; anabolic steroids such as fluoxymesterone (HALOTESTIN); estrogens such as estradiol, diethylstilbestrol (DES), and dienestrol; progestins such as medroxyprogesterone acetate (MPA) and megestrol; and other agents such as testosterone.

[0271] RIPK1 inhibitors can be optimally used in conjunction with one or more of the following treatments for myelodysplastic syndromes: (1) growth factors such as epoetin (EPOGEN®, PROCRIT®), darbepoetin alfa (ARANESP®), luspatercept (REBLOZYL®), filgrastim (NEUPOGEN®), pegfilgrastim (NEULASTA®), romiplostim (NPLATE®), eltrombopag (PROMACTA®), and oprelvekin (NEUMEGA); (2) hypomethylating agents such as azacitidine (ONUREG®, VIDAZA®); (3) Antineoplastic agents such as idarubicin (IDAMYCIN®) and daunorubicin (CERUBIDINE®).

[0272] RIPK1 inhibitors may be optimally used in conjunction with one or more of the following non-limiting examples of CNS agents: (1) Catecholamine drugs such as L-DOPA; (2) acetylcholinesterase inhibitors such as donepezil (ARICEPT®); (3) edaravone (RADICAVA®); (4) riluzole (RILUTEK®); (5) Glaucoma treatment drugs, including: a.Beta blockers such as timolol; b. Alpha agonists such as brimonidine (ALPHAGAN®) and apraclonidine (IOPIDINE®); c. Rho kinase inhibitors such as netarsudil (RHOPRESSA®, RHOKINSA®); and d. Carbonic anhydrase inhibitors such as dorzolamide (TRUSOPT®), brinzolamide (AZOPT®), acetazolamide (DIAMOX®), and methazolamide (NEPTAZANE®); (6) Multiple sclerosis medications, including: a. Immunomodulatory agents such as glatiramer (COPAXONE®), ofatumumab (KESIMPTA®) and interferon and its derivatives; b. Monoclonal antibodies such as alemtuzumab (LEMTRADA®), ocrelizumab (OCREVUS®), and natalizumab (TYSABRI®); and c. Other medications such as teriflunomide (Aubagio®), monomethyl fumarate (BAFIERTAM™), dimethyl fumarate (TECFIDERA®), fingolimod (GILENYA®), cladribine (MAVENCLAD®), siponimod (MAYZENT®), diroximel (VUMERITY®), ozanimod (ZEPOSIA®), and mitoxantrone (NOVANTRONE®); (7) Epilepsy / anticvulsants, including brivaracetam (BRIVIACT®), carbamazepine (CARBATROL®), diazepam (VALIUM®), lorazepam (ATIVAN®), clonazepam (KLONOPIN®), eslicarbazepine (APTIOM®), ethosuximide (ZARONTIN®), felbamate (FELBATOL®), fenfluramine (FINTEPLA®), lacosamide (VIMPAT®), lamotrigine (LAMICTAL®), levetiracetam (KEPPRA®), oxcarbazepine (OXTELLAR®), perampanel (FYCOMPA®), and phenobarbital.

[0273] In certain embodiments, the compounds, salts or tautomers, compositions, and methods disclosed herein may be useful for treating disorders associated with an inflammatory component of cellular stress, in certain embodiments, the disorder is selected from glutamic expansion disorders such as multiple sclerosis, Niemann-Pick disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, dementia with Lewy bodies, frontotemporal dementia, Huntington's disease, Kennedy disease, and spinocerebellar ataxia.

[0274] In certain embodiments, the compounds, salts, tautomers, compositions and methods disclosed herein may be useful for treating neuropathy, hi certain embodiments, the neuropathy is selected from diabetic neuropathy and chemotherapy-induced neuropathy.

[0275] In certain embodiments, the compounds, salts, tautomers, compositions and methods disclosed herein may be useful for treating retinal diseases, hi certain embodiments, the retinal diseases are selected from macular degeneration and retinitis.

[0276] In certain embodiments, the compounds, salts, tautomers, compositions and methods disclosed herein may be useful for treating CNS injuries, in certain embodiments, the injuries are selected from traumatic brain injury and stroke.

[0277] In certain embodiments, the compounds, salts, tautomers, compositions and methods disclosed herein may be useful in treating an autoimmune disorder, in certain embodiments, the autoimmune disorder is selected from ulcerative colitis, rheumatoid arthritis, psoriasis, lupus, and inflammatory bowel disease.

[0278] In certain embodiments, the compounds, salts, tautomers, compositions and methods disclosed herein may be useful in the treatment of viral infections.

[0279] In certain embodiments, the compounds, salts, tautomers, compositions and methods disclosed herein may be useful in the treatment of sepsis.

[0280] In certain embodiments, the compounds, salts, tautomers, compositions and methods disclosed herein may be useful in the treatment of retinal degeneration.

[0281] In certain embodiments, the compounds, salts, tautomers, compositions and methods disclosed herein may be useful in the treatment of ischemic stroke.

[0282] In certain embodiments, the compounds, salts, tautomers, compositions and methods disclosed herein may be useful in the treatment of intracerebral hemorrhage.

[0283] In certain embodiments, the compounds, salts, tautomers, compositions and methods disclosed herein may be useful for the treatment of amyotrophic lateral sclerosis.

[0284] In certain embodiments, the compounds, salts, tautomers, compositions and methods disclosed herein may be useful for the treatment of acute kidney injury.

[0285] In certain embodiments, the compounds, salts, tautomers, compositions and methods disclosed herein may be useful for the treatment of myocardial reperfusion injury.

[0286] In certain embodiments, the compounds, salts, tautomers, compositions and methods disclosed herein may be useful for the treatment of Alzheimer's disease.

[0287] In certain embodiments, the compounds, salts, tautomers, compositions and methods disclosed herein may be useful for the treatment of ulcerative colitis.

[0288] In certain embodiments, the compounds, salts, tautomers, compositions and methods disclosed herein may be useful for the treatment of osteoarthritis.

[0289] In certain embodiments, the compounds, salts, tautomers, compositions, and methods disclosed herein may be useful for treating myelodysplastic syndrome. In certain embodiments, the compounds, salts, tautomers, compositions, and methods disclosed herein may be useful for treating myelodysplastic syndrome at any stage of the disease and delaying disease progression, including progression to acute myeloid leukemia. In certain embodiments, the compounds, salts, tautomers, compositions, and methods disclosed herein may be effective in maintaining disease in complete or partial remission after treatment for remission, such as bone marrow transplantation or chemotherapy.

[0290] In certain embodiments, the compounds, salts, tautomers, compositions and methods disclosed herein may be useful for treating one or more subclassifications of myelodysplastic syndromes as defined by either the FAB classification or the WHO classification, including refractory anemia with or without ringed sideroblasts, 5q-syndrome with or without ringed sideroblasts, refractory anemia with multilineage dysplasia with or without ringed sideroblasts, refractory anemia with excess blasts I and II, refractory anemia with excess blasts in transformation, chronic myelomonocytic leukemia, and unclassifiable myelodysplastic syndrome.

[0291] In certain embodiments, the compounds, salts, tautomers, compositions, and methods disclosed herein may be useful for treating patients who fall into one of the categories defined by the International Prognostic System, including the low-risk category, the intermediate-1 risk category, the intermediate-2 risk category, and the high-risk category. In certain embodiments, the compounds, salts, tautomers, compositions, and methods disclosed herein may be particularly beneficial for treating patients who fall into the intermediate-risk and high-risk categories and who are at high risk of death or disease progression to acute myeloid leukemia.

[0292] In certain embodiments, the compounds, salts, tautomers, compositions, and methods disclosed herein may be useful for treating acute myeloid leukemia. In certain embodiments, the compounds, salts, tautomers, compositions, and methods disclosed herein may be useful for both treating active disease and maintaining the disease in complete or partial remission after treatment for such remission, such as bone marrow transplantation or chemotherapy.

[0293] In certain embodiments, the compounds, salts, tautomers, compositions and methods disclosed herein are directed to the treatment of minimally differentiated myeloid leukemia (MO), immature acute myeloid leukemia (M1), mature acute myeloid leukemia (M2), mature acute myeloid leukemia with t(8;21), acute promyelocytic leukemia (M3), hypergranular acute myeloid leukemia, microgranular acute myeloid leukemia, acute myelomonocytic leukemia (M4), acute myelomonocytic leukemia with bone marrow eosinophilia (M4EO), acute monocytic leukemia (M5), acute monoblastic leukemia (M5a), mature acute monocytic leukemia (M5b), acute monoblastic leukemia (M5c), acute monoblastic leukemia (M5d), acute monocytic leukemia (M5e), acute monoblastic leukemia (M5f), acute monoblastic leukemia (M5g), acute monoblastic leukemia (M5g), acute monoblastic leukemia (M5h), acute monoblastic leukemia (M5h), acute monoblastic leukemia (M5i ...b), acute monoblastic leukemia (M5c), acute monoblastic leukemia (M5d), acute monoblastic leukemia (M5i), acute monoblastic leukemia (M5i), acute monoblastic leukemia (M5i), acute monoblastic leukemia (M5i), acute monoblastic leukemia (M5i), acute monoblastic le It may be useful for the treatment of one or more subclassifications of acute myeloid leukemia as defined by either the FAB classification or the WHO classification, including leukemia (M5b), erythroleukemia, erythroid / myeloid leukemia (M6a), pure erythroleukemia (M6b), acute megakaryoblastic leukemia (M7), acute megakaryoblastic leukemia with t(1;22), acute basophilic leukemia, acute myelofibrosis (acute myelodysplasia with myelofibrosis), acute leukemia and transient myeloproliferative disorder in Down's syndrome, hypocellular acute myeloid leukemia, and myeloid sarcoma.

[0294] In certain embodiments, the compounds, salts, tautomers, compositions and methods disclosed herein may be co-administered with another therapeutic agent.

[0295] In addition to being useful for human treatment, the salts, tautomers and formulations of certain compounds disclosed herein may also be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, etc. More preferred animals include horses, dogs and cats.

[0296] List of abbreviations Ac2O = acetic anhydride; AcCl = acetyl chloride; AcOH = acetic acid; AIBN = azobisisobutyronitrile; aq. = aqueous; BAST = bis(2-methoxyethyl)aminosulfur trifluoride; BPD = bis(pinacolato)diboron = 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane; Bu = butyl; Bu3SnH = tributyltin hydride; CD3OD = deuterated methanol; CDCl3 = deuterated chloroform; CDI = 1,1'-carbonyldiimide Dazol; DAST = (diethylamino)sulfur trifluoride; dba = dibenzylideneacetone; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; DCE = 1,2-dichloroethane; DCM = dichloromethane; DEAD = diethyl azodicarboxylate; DtBAD = di-t-butyl azodicarboxylate; DHP = 3,4-dihydro-2H-pyran; DIBAL-H = di-isobutylaluminum hydride; DIEA = DIPEA = N,N-diisopropylethylamine; DMAP = 4-dimethylaminopyridine; DMF = N,N-dimethylformamide amide; DMFDMA = dimethylformamide dimethyl acetal; DMSO-d6 = deuterated dimethyl sulfoxide; DMSO = dimethyl sulfoxide; DPPA = diphenylphosphoryl azide; dppp = 1,3-bis(diphenylphosphino)propane; dppf = 1,1'-bis(diphenylphosphino)ferrocene; EDC·HCl = EDCI·HCl = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; Et = ethyl; Et2O = diethyl ether; EtOAc = ethyl acetate; EtOH = ethanol; h = hour; HATU = 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium; HMDS = hexamethyldisilazane; HOBT = 1-hydroxybenzotriazole; iPr = i-Pr = isopropyl; iPrOH = i-PrOH = isopropanol; LAH = lithium aluminum hydride; LDA = lithium diisopropylamide; LiHMDS = lithium bis(trimethylsilyl)amide; MeCN = acetonitrile; MeI = methyl iodide; MeOH = methanol;MP-carbonate resin = macroporous triethylammonium methyl polystyrene carbonate resin; MsCl = mesyl chloride; MTBE = methyl tert-butyl ether; n-Buli = n-butyllithium; NaHMDS = sodium bis(trimethylsilyl)amide; NaOEt = sodium ethoxide; NaOMe = sodium methoxide; NaOtBu = sodium t-butoxide; NBS = N-bromosuccinimide; NCS = N-chlorosuccinimide; NIS = N-iodosuccinic acid Imide; NMP = N-methyl-2-pyrrolidone; Pd(Ph3)4 = tetrakis(triphenylphosphine)palladium(0); Pd2(dba)3 = tris(dibenzylideneacetone)-dipalladium(0); PdCl2(PPh3)2 = bis(triphenylphosphine)palladium(II) dichloride; PG = protecting group; Ph = phenyl; Prep HPLC = preparative high-performance liquid chromatography; PMB = para-methoxybenzyl; PMBCl = para-methoxybenzyl chloride; PMBOH = para-methoxybenzyl Dimethyl alcohol; PyBop = (benzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate; Pyr = pyridine; RT = room temperature; RuPhos = 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; sat. = saturated; ss = saturated solution; tBu = t-Bu = tert-butyl 1,1-dimethylethyl; TBAF = tetrabutylammonium fluoride; TBDPS = t-butyldiphenylsilyl; t-BuOH = tBuOH = tert-butyl nol; T3P = propylphosphonic anhydride; TEA = Et3N = triethylamine; TFA = trifluoroacetic acid; TFAA = trifluoroacetic anhydride; THF = tetrahydrofuran; TIPS = triisopropylsilyl; Tol = toluene; TsCl = tosyl chloride; Trt = trityl (triphenyl)methyl; Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; XPhos = 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[0297] General synthetic methods for preparing compounds The following scheme can be used to practice the present invention.

[0298] [ka] Example 1 and similar compounds can be synthesized by using the general synthetic procedure shown in Scheme I. Carboxylic acid I-01 is coupled with primary amine I-02 using HATU or another suitable coupling agent known in the art, such as T3P, to give amide I-03. The synthesis of specific compounds involves coupling of the group R 1 , R 2 , R 3 and R 4 may include one or more deprotection steps of

[0299] [ka] Example 1 and similar compounds can be synthesized using the general synthetic procedure shown in Scheme II. Carboxaldehyde II-01 is reacted with vinyl Grignard II-02 to give secondary alcohol II-03. Allylic rearrangement affords ketone II-04. Condensation with amide acetal II-05 affords enone II-06, which is further reacted with acetamidine to give pyrimidine II-07. Oxidation of the activated 2-methyl group affords carboxylic acid II-08, suitable for incorporation into Scheme I. The synthesis of specific compounds involves the addition of the group R to the carboxylic acid II-08 using methods known in the art. 1 , R 2 , R 3 and R 4 may include one or more deprotection steps of

[0300] The present invention is further illustrated by the following examples.

[0301] Intermediate A-1 [ka] 4-(3-fluoro-4-methylphenyl)-5-methylpyrimidine-2-carboxylic acid [ka] 1-(3-fluoro-4-methyl-phenyl)prop-2-en-1-ol To a solution of 3-fluoro-4-methyl-benzaldehyde (15 g, 108.59 mmol, 13.27 mL, 1 eq) in THF (200 mL) was added vinylmagnesium bromide (1 M, 119.45 mL, 1.1 eq) dropwise at 0 °C. After stirring under N at 25 °C for 16 h, the reaction was quenched with 1 N HCl (20 mL) and diluted with HO (50 mL) and EtOAc (50 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over NaSO, filtered, and concentrated to give a residue that was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: 0–15% EtOAc / PE gradient at 30 mL / min) to give the title compound (11 g, 66 mmol, 61% yield) as a pale yellow oil. 1 H NMR(400MHz,CDCl3)δ=7.25-7.13(m,2H),7.04-6.95(m,1H),6.11-5.99(m,1H),5.41-5.32(m,1H),5.26-5.12(m,2H),2.29(d,J=1.6Hz,3H).

[0302] [ka] 1-(3-fluoro-4-methyl-phenyl)propan-1-one To a solution of the product from the previous step (7 g, 42.12 mmol, 1 eq) in THF (60 mL) was added n-BμLi (2.5 M, 18.53 mL, 1.1 eq) at 0° C. and the mixture was stirred for 30 min at 0° C. To this mixture was added a solution of tris(triphenylphosphine)rhodium(I) chloride (1.95 g, 2.11 mmol, 0.05 eq) in THF (20 mL) at 0° C. After stirring at 60° C. under N for 16 h, the mixture was poured into water (50 mL), extracted with EtOAc (50 mL×3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent of 0-10% EtOAc / PE gradient at 30 mL / min) to give 1-(3-fluoro-4-methyl-phenyl)propan-1-one (3.5 g, 21.06 mmol, 50% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ=7.87-7.83(m,1H),7.83-7.77(m,1H),7.10-7.03(m,1H ),3.04-2.94(m,2H),2.36-2.31(d,3H,J=2.0Hz),1.26-1.19(t,3H,J=2.0Hz).

[0303] [ka] (Z)-3-(Dimethylamino)-1-(3-fluoro-4-methyl-phenyl)-2-methyl-prop-2-en-1-one To a solution of the product from the previous step (3.5 g, 21.06 mmol, 4.55 mL, 1 eq) in DMF (20 mL) was added DMFDMA (10.0 g, 84.24 mmol, 11.19 mL, 4 eq). After stirring at 160 °C for 2 h, the mixture was poured into water (20 mL), extracted with EtOAc (20 mL), dried over Na SO , filtered, and concentrated under reduced pressure to give the title compound as a yellow solid, which was used directly without further purification. MS(ES+)C 13 H 16ONF theoretical value: 221, measured value: 222 [M+H] + .

[0304] [ka] 4-(3-fluoro-4-methyl-phenyl)-2,5-dimethyl-pyrimidine To a solution of acetamidine HCl (2.99 g, 31.59 mmol, 1.5 eq) in THF (30 mL) was added t-BuOK (3.54 g, 31.59 mmol, 1.5 eq). The mixture was stirred at 70 °C for 1 h. To this mixture was then added a solution of the product from the previous step (4.66 g, 21.06 mmol, 1 eq) in THF (10 mL). After stirring at 60 °C for 16 h, the mixture was poured into water (50 mL), extracted with EtOAc (50 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: 0-10% EtOAc / PE gradient at 30 mL / min) to give the title compound (2.1 g, 9.13 mmol, 43% yield) as a pale yellow oil. MS (ES+) C 13 H 13 N2F theoretical value: 216, measured value: 217 [M+H] + .

[0305] [ka] 4-(3-fluoro-4-methyl-phenyl)-5-methyl-pyrimidine-2-carboxylic acid To a solution of the product from the previous step (2.1 g, 9.71 mmol, 1 eq) in pyridine (15 mL) was added SeO (3.77 g, 33.99 mmol, 3.70 mL, 3.5 eq). The mixture was stirred at 120 °C for 16 h. The mixture was adjusted to pH 13 by the addition of aqueous NaOH (1 M) and extracted with EtOAc (10 mL). The aqueous phase was adjusted to pH 1 by the addition of HCl (1 M), then extracted with EtOAc (10 mL), washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue which was triturated with EtOAc at 25 °C for 30 min to give the title compound (1.47 g, 5.85 mmol, 60% yield) as a brown solid. MS(ES+)C 13 H 11 N2FO2 theoretical value: 246, measured value: 247 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=8.90-8.84(s,1H),7.69-7.64(m,1H),7.62-7.56(m,1H),7.35-7.27(m,1H),2.45-2.38(s,3H),2.35-2.30(s,3H).

[0306] Intermediate A-2 [ka] 5-Methyl-4-(piperidin-1-yl)pyrimidine-2-carboxylic acid [ka] 2-chloro-5-methyl-4-(1-piperidyl)pyrimidine To a solution of 2,4-dichloro-5-methylpyrimidine (3 g, 18.40 mmol, 1 eq) in dioxane (3 mL) was added a solution of piperidine (3.13 g, 36.81 mmol, 3.64 mL, 2 eq) in dioxane (3 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h. The mixture was poured into water (20 mL), extracted with EtOAc (20 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® silica flash column, eluent: 0-10% EtOAc / PE gradient at 30 mL / min) to give the title compound (2.6 g, 12.28 mmol, 66% yield) as a colorless oil. MS (ES+) C 10 H 14 ClN3 theoretical value: 211, measured value: 212 [M+H] + .

[0307] [ka] 5-Methyl-4-(1-piperidyl)pyrimidine-2-carbonitrile To a solution of the product from the previous step (2 g, 9.45 mmol, 1 eq) in DMSO (10 mL) was added NaCN (694.55 mg, 14.17 mmol, 1.5 eq) and DABCO (211.95 mg, 1.89 mmol, 207.79 μL, 0.2 eq). The mixture was stirred at 120 °C for 16 h. Water (70 mL) was added to the mixture, which was extracted with EtOAc (100 mL × 3). The organic phase was washed with brine (100 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO2, petroleum ether / EtOAc = 20 / 1 to 5 / 1) to give the title compound (1.2 g, 5.87 mmol, 62% yield) as a white solid. MS(ES+)C 11 H 14 N4 theoretical value: 202, actual value: 203 [M+H] + . 1H NMR(400MHz, CDCl3)δ=7.99(s,1H),3.46-3.44(m,4H),2.2(s,3H),1.67-1.57(m,6H).

[0308] [ka] 5-Methyl-4-(1-piperidyl)pyrimidine-2-carboxylic acid To a solution of the product from the previous step (1.2 g, 5.87 mmol, 1 eq) in dioxane (7 mL) was added a solution of NaOH (704.80 mg, 17.62 mmol, 3 eq) in HO (21 mL). The mixture was stirred at 60 °C for 2 h. Aqueous HCl was added to the mixture to adjust the pH to 7, and it was concentrated under reduced pressure to give a residue that was purified by preparative HPLC (column: Phenomenex luna C18 (250 × 70 mm, 15 μm); mobile phase: [water (0.1% TFA)-CHCN]; B%: 1 CHCN% to 30 CHCN%, 30 min). The eluent was concentrated and then lyophilized to give the title compound (1.16 g, 5.23 mmol, 89% yield) as a white solid. MS(ES+)C 11 H 15 N3O2 theoretical value: 221, measured value: 222 [M+H] + . 1 H NMR(400MHz, CDCl3)δ=8.3(s,1H),3.96-3.91(m,4H),2.43(s,3H),1.83-1.75(m,6H).

[0309] Intermediate A-3 [ka] 5-chloro-4-(3-fluoro-4-methylphenyl)pyrimidine-2-carboxylic acid [ka] 2,5-Dichloro-4-(3-fluoro-4-methylphenyl)pyrimidine To a solution of 2,4,5-trichloropyrimidine (1 g, 5.45 mmol) in dioxane (20 mL) was added (3-fluoro-4-methylphenyl)boronic acid (1.007 g, 6.54 mmol), CsCO (5.33 g, 16.36 mmol), and PdCl(dppf)-CHCl adduct (0.445 g, 0.545 mmol), and the resulting mixture was stirred at 60 °C overnight. The reaction mixture was filtered through CELITE®, the filter pad was washed with MeOH, and the combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 70% EtOAc in hexanes) to give the title compound (947 mg, 3.68 mmol, 67.6% yield) as a pale yellow liquid.

[0310] [ka] 5-chloro-4-(3-fluoro-4-methylphenyl)-2-methylpyrimidine A mixture of the product from the previous step (430 mg, 1.673 mmol), K2CO3 (462 mg, 3.35 mmol), and Pd(Ph3P)4 (193 mg, 0.167 mmol) in dioxane (8,363 μL) was degassed with N2 for 5 min. 2,4,6-Trimethyl-1,3,5,2,4,6-trioxatriborinane (252 mg, 2.007 mmol) was added. The reaction mixture was heated to 100 °C and stirred for 16 h. H2O was added, and the layers were separated. The aqueous phase was extracted with EtOAc (3x), and the combined organic layers were washed with saturated NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0–50% EtOAc in hexanes) to give the title compound (140 mg, 0.592 mmol, 35.4% yield) as an orange oil.

[0311] [ka] 5-chloro-4-(3-fluoro-4-methylphenyl)pyrimidine-2-carboxylic acid To a solution of the product from the previous step (140 mg, 0.592 mmol) in pyridine (657 μl) was added SeO (164 mg, 1.479 mmol), and the resulting mixture was stirred at 120° C. for 48 h. The reaction mixture was filtered through CELITE®, the filter pad was washed with MeOH, and the combined filtrates were concentrated under reduced pressure to give the title compound (127 mg, 0.476 mmol, 81% yield).

[0312] Intermediate A-4 [ka] 5-chloro-4-(4-fluoro-3-methylphenyl)pyrimidine-2-carboxylic acid This compound was obtained using a procedure similar to that used for intermediate A-3.

[0313] Intermediate A-5 [ka] 5-chloro-4-(2-fluorophenyl)pyrimidine-2-carboxylic acid [ka] 2,5-Dichloro-4-(2-fluorophenyl)pyrimidine To a solution of 2,4,5-trichloropyrimidine (3 g, 16.36 mmol, 1 eq) in THF (30 mL) and HO (6 mL) was added (2-fluorophenyl)boronic acid (2.29 g, 16.36 mmol, 1 eq), NaCO (3.47 g, 32.71 mmol, 2 eq), PPh (214.50 mg, 817.78 μmol, 0.05 eq), and Pd(OAc) (183.60 mg, 817.78 μmol, 0.05 eq) under N. After stirring at 60 °C for 12 h, the mixture was diluted with water (30 mL), extracted with EtOAc (30 mL × 3), dried over NaSO, filtered, and concentrated under N. The residue was purified by chromatography on silica gel (eluent: EtOAC / petroleum ether = 2% to 20%) to give the title compound (3.8 g, 15.63 mmol, 95% yield) as a pale yellow oil. MS(ES+)C 10 H5Cl2FN2 Theoretical values: 242 and 244, Found values: 243 and 245 [M+H] +

[0314] [ka] 5-chloro-4-(2-fluorophenyl)-2-methylpyrimidine To a solution of the product from the previous step (3.8 g, 12.51 mmol, 80% purity, 1 eq), AlMe3 (1.35 g, 18.76 mmol, 9 mL, 2 M in toluene, 1.5 eq) in THF (38 mL) under N2, Pd(PPh3)4 (1.45 g, 1.25 mmol, 0.1 eq) was added. After stirring at 60 °C for 16 h, the mixture was quenched with saturated aqueous NH4Cl, diluted with water (30 mL), extracted with EtOAc (30 mL × 3), washed with brine (20 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: EtOAC / petroleum ether = 10% to 50% eluent) to give the title compound (1.9 g, 8.41 mmol, 67% yield) as a pale yellow solid. MS (ES+) C 11 H8ClFN2 Theoretical values: 222 and 224, Found values: 223 and 225 [M+H] +

[0315] [ka] 5-chloro-4-(2-fluorophenyl)pyrimidine-2-carboxylic acid To a solution of the product from the previous step (1.9 g, 8.53 mmol, 1 eq) in pyridine (25 mL) and HO (2.5 mL) was added SeO (9.47 g, 85.34 mmol, 10 eq). After stirring at 120 °C for 48 h, the mixture was filtered, and the filtrate was concentrated, diluted with HO (20 mL), basified with NaOH (10%) to pH 8–10, and extracted with EtOAc (20 mL × 2). The aqueous layer was acidified with HCl (1 N) to pH 3–5, and the suspension was filtered and washed with HO (15 mL × 2). The filter cake was triturated with MeOH (5 mL), filtered, and concentrated to give the title compound (1.8 g, 7.13 mmol, 83% yield) as a pale yellow solid. MS(ES+)C 11 H6ClFN2O2 Theoretical values: 252 and 254, Measured values: 253 and 255 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=14.44-13.35(br s,1H),9.21(s,1H),7.71-7.57(m,2H),7.49-7.37(m,2H).

[0316] The following pyrimidine-2-carboxylic acids were obtained by a procedure similar to that used for intermediate A-5.

[0317] [Table 1]

[0318] [Table 2]

[0319] [Table 3]

[0320] [Table 4]

[0321] Intermediate A-19 [ka] 5-chloro-4-(3-fluorophenyl)pyrimidine-2-carboxylic acid [ka] 2,5-Dichloro-4-(3-fluorophenyl)pyrimidine To a solution of 2,4,5-trichloropyrimidine (2 g, 10.90 mmol, 1 eq), (3-fluorophenyl)boronic acid (1.60 g, 11.45 mmol, 1.05 eq) in THF (80 mL), HO (20 mL) under N was added NaCO (1.81 g, 17.08 mmol, 1.57 eq), PPh (114.40 mg, 436.15 μmol, 0.04 eq), and Pd(OAc) (48.96 mg, 218.08 μmol, 0.02 eq) at 25 °C. After stirring at 60 °C for 6 h, the mixture was diluted with EtOAc (50 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (ISCO®; 25 g SepaFlash® silica flash column, elution with a 0-30% EtOAC / petroleum ether gradient at 40 mL / min) to give the title compound (2.4 g, 9.48 mmol, 87% yield) as a white solid. MS(ES+)C 10 H5Cl2FN2 Theoretical values: 242 and 244, Found values: 243 and 245 [M+H] + .

[0322] [ka] 5-chloro-4-(3-fluorophenyl)-2-methylpyrimidine To a solution of the product from the previous step (4.4 g, 18.10 mmol, 1 eq) in HO (10 mL) and dioxane (70 mL) under N was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (5.09 g, 20.27 mmol, 5.67 mL, 1.12 eq, 50% solution in THF), KCO (6.25 g, 45.26 mmol, 2.5 eq), and Pd(PPh) (418.36 mg, 362.04 μmol, 0.02 eq) at 25 °C. After stirring at 100 °C for 16 h, the mixture was diluted with EtOAc (50 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, elution with a 0-15% EtOAC / petroleum ether gradient at 100 mL / min) to give the title compound (2.7 g, 11.40 mmol, 63% yield) as a brown oil. MS(ES+)C 11 H8ClFN2 Theoretical values: 222 and 224, Found values: 223 and 225 [M+H] + .

[0323] [ka] 5-chloro-4-(3-fluorophenyl)pyrimidine-2-carboxylic acid To a solution of the product from the previous step (2.6 g, 11.68 mmol, 1 eq) in pyridine (50 mL) was added SeO (6.48 g, 58.39 mmol, 5 eq) at 25 °C. After stirring at 120 °C for 16 h, HO (4 mL) and SeO (3.89 g, 35.03 mmol, 3 eq) were added to the reaction mixture at 25 °C. After stirring at 120 °C for another 12 h, the mixture was cooled to 25 °C, basified with aqueous NaOH (1 M) to adjust the pH to 13, and extracted with EtOAc (50 mL × 3). The aqueous phase was acidified with HCl (1 M) to adjust the pH to 1, then extracted with EtOAc (50 mL × 3), washed with brine (20 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was triturated with petroleum ether: EtOAc (20:1, 20 mL) at 25°C for 1 h to give the title compound (1.21 g, 4.80 mmol, 41% yield) as a yellow solid. MS(ES+)C 11 H6ClFN2O2 Theoretical values: 252 and 254, Measured values: 253 and 255 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=13.85(br s,1H),9.18(s,1H),7.73-7.59(m,3H),7.65-7.45(m,1H).

[0324] The following pyrimidine-2-carboxylic acids were obtained by a procedure similar to that used for intermediate A-19.

[0325] [Table 5]

[0326] [Table 6]

[0327] Intermediate A-26 [ka] 4-(5-fluoropyridin-2-yl)-5-methylpyrimidine-2-carboxylic acid [ka] 5-Fluoro-2-(tributylstannyl)pyridine To a solution of 2-bromo-5-fluoro-pyridine (4 g, 22.73 mmol, 1 eq) in dioxane (40 mL) under N was added tributyl(tributylstannyl)stannane (15.82 g, 27.27 mmol, 13.64 mL, 1.2 eq), tricyclohexylphosphane (318.69 mg, 1.14 mmol, 368.43 μL, 0.05 eq), and Pd(dba) (1.04 g, 1.14 mmol, 0.05 eq). After stirring at 100 °C for 16 h, the mixture was concentrated under reduced pressure to give the title compound (8.8 g, crude) as a black oil, which was used as is. MS (ES+) C 17 H 30 NFSn theoretical value: 387, measured value: 388 [M+H] + .

[0328] [ka] 2,5-Dichloro-4-(5-fluoropyridin-2-yl)pyrimidine To a solution of the product from the previous step (8.8 g, 22.79 mmol, 1 eq) in toluene (60 mL) under N was added 2,4,5-trichloropyrimidine (4.18 g, 22.79 mmol, 2.61 mL, 1 eq), Pd(PPh3)4 (790.06 mg, 683.70 μmol, 0.03 eq), LiCl (1.93 g, 45.58 mmol, 933.49 μL, 2 eq), and CuI (868.07 mg, 4.56 mmol, 0.2 eq). After stirring at 100 °C for 16 h, the mixture was concentrated under reduced pressure, diluted with HO (50 mL), and extracted with EtOAc (50 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Synergi Max-RP 250 × 50 mm × 10 μm; mobile phase: [water (0.05% HCl)-CHCN]; B%: 25 CHCN% to 55 CHCN%, 23 min), and the eluent was concentrated under reduced pressure and lyophilized to give the title compound (300 mg, 1.23 mmol, 5% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ=9.06(s,1H),8.81-8.77(m,1H),8.10-8.04(m,1H),8.03-7.96(m,1H).

[0329] [ka] 4-(5-fluoropyridin-2-yl)-2,5-dimethylpyrimidine To a solution of the product from the previous step (250 mg, 1.02 mmol, 1 eq) in THF (10 mL) under N was added Pd(PPh) (118.37 mg, 102.44 μmol, 0.1 eq) and AlMe (2 M in toluene, 1.54 mL, 3 eq). After stirring at 80 °C for 16 h, the mixture was poured into HO (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure, and the residue was purified by preparative TLC (petroleum ether / EtOAc = 2 / 1) to give the title compound (90 mg, 403.02 μmol, 39% yield) as a white solid. MS(ES+)C 11 H 10 N3F Theoretical value: 203, Measured value: 204 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=8.72(d,J=2.9Hz,1H),8.66(s,1H),8.16(dd,J=4.7,8.8Hz,1H),7.96-7.89(m,1H),2.65(s,3H),2.46(s,3H).

[0330] [ka] 4-(5-fluoropyridin-2-yl)-5-methylpyrimidine-2-carboxylic acid To a solution of the product from the previous step (90 mg, 442.88 μmol, 1 eq) in pyridine (5 mL) and HO (0.5 mL) was added SeO (245.71 mg, 2.21 mmol, 5 eq). After stirring at 120 °C for 16 h, the mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (120 mg, crude) as a yellow oil, which was used as is. MS (ES+) C 11 H8N3FO2 theoretical value: 233, measured value: 234 [M+H] + .

[0331] Intermediate A-27 [ka] 5-chloro-4-(3-fluoropyridin-2-yl)pyrimidine-2-carboxylic acid [ka] 3-Fluoro-2-(tributylstannyl)pyridine A mixture of 2-bromo-3-fluoro-pyridine (10 g, 56.82 mmol, 1 eq), tricyclohexylphosphane (1.59 g, 5.68 mmol, 1.84 mL, 0.1 eq), tributyl(tributylstannyl)stannane (49.44 g, 85.23 mmol, 42.62 mL, 1.5 eq), and Pd(dba) (5.20 g, 5.68 mmol, 0.1 eq) in dioxane (100 mL) was degassed and purged with N three times. After stirring at 100 °C for 16 h, the mixture was filtered and concentrated under reduced pressure to give the title compound (64 g, crude) as a black oil, which was used directly without further purification. MS (ES+) C 17 H 30 NFSn theoretical values: 387 and 385, measured values: 388 and 386 [M+H] + .

[0332] [ka] 2,5-Dichloro-4-(3-fluoropyridin-2-yl)pyrimidine To a solution of the product from the previous step (78 g, 64.64 mmol, 32% purity, 1 eq) in toluene (150 mL) under N was added 2,4,5-trichloropyrimidine (11.86 g, 64.64 mmol, 1 eq), Pd(PPh3)4 (3.73 g, 3.23 mmol, 0.05 eq), LiCl (5.48 g, 129.28 mmol, 2.65 mL, 2 eq), and CuI (4.92 g, 25.86 mmol, 0.4 eq). After stirring at 100 °C for 16 h, the mixture was filtered, and the combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluent of 0-10% EtOAC / petroleum ether gradient at 50 mL / min) to give the title compound (6 g, 22.37 mmol, 34% yield) as a brown solid. MS(ES + ) C9H4N3Cl2F Theoretical values: 243 and 245, Found values: 244 and 246 [M+H] + . 1H NMR(400MHz, CDCl3)δ=8.77(s,1H),8.67-8.60(m,1H),7.69-7.59(m,1H),7.57-7.50(m,1H).

[0333] [ka] 5-chloro-4-(3-fluoropyridin-2-yl)-2-methylpyrimidine To a solution of the product from the previous step (5.3 g, 21.72 mmol, 1 eq) in THF (50 mL) under N was added Pd(PPh3)4 (2.51 g, 2.17 mmol, 0.1 eq) and AlMe3 (2 M in toluene, 16.29 mL, 1.5 eq). After stirring at 100 °C for 16 h, the mixture was poured into ice-water (60 mL) and extracted with EtOAc (60 mL × 3). The organic phase was washed with brine (60 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: 0–20% EtOAc / petroleum ether gradient at 50 mL / min) to give the title compound (2.6 g, 11.63 mmol, 53% yield) as a yellow solid. MS(ES + )C 10 H7N3ClF Theoretical values: 223 and 225, Measured values: 224 and 226 [M+H] + . 1 H NMR(400MHz, CDCl3)δ=8.75(s,1H),8.62(d,J=4.4Hz,1H),7.64-7.55(m,1H),7.53-7.45(m,1H),2.82(s,3H).

[0334] [ka] 5-chloro-4-(3-fluoropyridin-2-yl)pyrimidine-2-carboxylic acid To a solution of the product from the previous step (2.6 g, 11.63 mmol, 1 eq) in pyridine (20 mL) and HO (2 mL) was added SeO (5.16 g, 46.50 mmol, 4 eq). After stirring at 120 °C for 16 h, the mixture was poured into water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic phases were washed with brine (30 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was triturated with EtOAc at 25 °C for 30 min, and the filter cake was collected to give the title compound (2.1 g, 7.78 mmol, 66% yield) as a yellow solid. MS(ES + )C 10 H5ClFN3O2 Theoretical values: 253 and 255, Measured values: 254 and 256 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=8.94(s,1H),8.61(td,J=1.6,4.6Hz,1H),7.99(m,1H),7.75-7.66(m,1H).

[0335] Intermediate A-28 [ka] 5-chloro-4-(pyrazin-2-yl)pyrimidine-2-carboxylic acid [ka] 2,5-Dichloro-4-(pyrazin-2-yl)pyrimidine To a solution of 2,4,5-trichloropyrimidine (2 g, 10.90 mmol, 1.25 mL, 1 eq) in xylene (10 mL) under N2, Pd(PPh3)4 (630.00 mg, 545.19 μmol, 0.05 eq) and 2-(tributylstannyl)pyrazine (4.02 g, 10.90 mmol, 1 eq) were added. After stirring at 120 °C for 16 h, the mixture was quenched with saturated aqueous KF solution (40 mL) and extracted with EtOAc (40 mL × 2). The combined organic layers were concentrated and then purified by chromatography on silica gel (eluent: petroleum ether / EtOAc = 20 / 1) to give the title compound (280 mg, 1.17 mmol, 10% yield) as an orange solid. MS (ES) + ) C8H4N4Cl2 Theoretical values: 226 and 228, Found values: 227 and 229 [M+H] + .

[0336] [ka] 5-chloro-2-methyl-4-(pyrazin-2-yl)pyrimidine To a solution of the product from the previous step (280 mg, 1.23 mmol, 1 eq) in THF (6 mL) under N was added AlMe (2 M in toluene, 924.91 μL, 1.5 eq) and Pd(PPh) (71.25 mg, 61.66 μmol, 0.05 eq). After stirring at 60 °C for 16 h, the mixture was quenched with HO (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by preparative TLC (petroleum ether: EtOAc = 2:1) to give the title compound (100 mg, 479.11 μmol, 38% yield) as a yellow solid. MS (ES+) C9H7N4Cl Theoretical: 206 and 208, Found: 207 and 209 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=9.14(s,1H),9.00(s,1H),8.85-8.84(m,2H),2.72(s,3H).

[0337] [ka] 5-chloro-4-(pyrazin-2-yl)pyrimidine-2-carboxylic acid To a solution of the product from the previous step (100 mg, 483.95 μmol, 1 eq) in pyridine (2 mL) and HO (0.2 mL) was added SeO (268.50 mg, 2.42 mmol, 5 eq). After stirring at 120 °C for 16 h, the mixture was filtered, and the filtrate was concentrated, then diluted with HO (5 mL) and extracted with EtOAc (5 mL × 2). The aqueous phase was acidified with HCl (1 M) to adjust the pH to 2, then extracted with EtOAc (5 mL × 2). The combined organic layers were concentrated to give the title compound (30 mg, 106.50 μmol, 22% yield) as a yellow solid. MS (ES+) CHNOCl Calculated: 236 and 238, Found: 237 and 239 [M+H] + .

[0338] Intermediate A-29 [ka] 5-(hydroxymethyl)-4-phenylpyrimidine-2-carboxylic acid, and Intermediate A-30 [ka] 5-(((tert-butoxycarbonyl)amino)methyl)-4-phenylpyrimidine-2-carboxylic acid [ka] Methyl 5-chloro-4-phenylpyrimidine-2-carboxylate To a solution of 5-chloro-4-phenylpyrimidine-2-carboxylic acid (600 mg, 2.56 mmol, 1 eq) in MeOH (6 mL) was added H2SO4 (920.00 mg, 9.38 mmol, 0.5 mL, 3.67 eq). After stirring at 60 °C for 1 h, the mixture was concentrated to a yellow oil, diluted with HO (10 mL), and extracted with EtOAc (10 mL × 2). The combined organic layers were washed with brine (20 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (540 mg, 1.95 mmol, 76% yield) as a yellow oil. MS(ES+)C 12 H9N2ClO2 Theoretical values: 248 and 250, Measured values: 249 and 251 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=9.18(s,1H),7.93-7.77(m,2H),7.70-7.51(m,3H),3.94(s,3H).

[0339] [ka] Methyl 5-methyl-4-phenylpyrimidine-2-carboxylate To a solution of the product from the previous step (540 mg, 2.17 mmol, 1 eq) in THF (10 mL) under N was added Pd(PPh) (125.47 mg, 108.58 μmol, 0.05 eq) and AlMe (2 M in toluene, 2.71 mL, 2.5 eq). After stirring at 80 °C for 3 h, the mixture was quenched with HO (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (20 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (eluent: petroleum ether / EtOAc = 1 / 1) to give the title compound (260 mg, 797.38 μmol, 36% yield) as a white solid. MS(ES+)C 13 H 12 N2O2 theoretical value: 228, measured value: 229 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ=9.04(s,1H),7.85-7.80(m,2H),7.71-7.67(m,3H),4.04(s,3H),2.56(s,3H).

[0340] [ka] Methyl 5-(bromomethyl)-4-phenylpyrimidine-2-carboxylate To a solution of the product from the previous step (260 mg, 797.38 μmol, 70% purity, 1 eq) in DCE (6 mL) was added NBS (283.84 mg, 1.59 mmol, 2 eq) and AIBN (52.37 mg, 318.95 μmol, 0.4 eq). After stirring at 80 °C for 16 h, the mixture was diluted with HO (20 mL) and extracted with CHCl (20 mL × 2). The combined organic layers were washed with brine (20 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (eluent: petroleum ether / EtOAc = 1 / 1) to give the title compound (100 mg, 293.02 μmol, 36% yield) as a white solid. MS(ES+)C 13 H 11 N2O2Br Theoretical values: 306 and 308, Measured values: 307 and 309 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=9.19(s,1H),7.79-7.70(m,2H),7.65-7.58(m,3H),4.81(s,2H),3.93(s,3H).

[0341] [ka] 5-(Hydroxymethyl)-4-phenylpyrimidine-2-carboxylic acid (Intermediate A-29) A mixture of the product from the previous step (250 mg, 691.86 μmol, 1 eq) in THF (5 mL) and HO (5 mL) was stirred at 80° C. for 16 h, which was then concentrated under reduced pressure to give the title compound (300 mg, crude) as a yellow solid. MS(ES+)C12 H 10 N2O3 theoretical value: 230, measured value: 231 [M+H] + .

[0342] [ka] Methyl 5-(azidomethyl)-4-phenylpyrimidine-2-carboxylate To a solution of the product from the previous step (100 mg, 325.58 μmol, 1 eq) in DMF (2 mL) was added NaN (70 mg, 1.08 mmol, 3.31 eq). After stirring at 25 °C for 16 h, the mixture was diluted with HO (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were washed with brine (20 mL × 3), dried over NaSO, filtered, and concentrated to give the title compound (80 mg, crude) as a yellow oil. MS (ES+) C 13 H 11 N5O2 theoretical value: 269, measured value: 270 [M+H] + .

[0343] [ka] Methyl 5-(aminomethyl)-4-phenylpyrimidine-2-carboxylate To a solution of the product from the previous step (80 mg, 297.11 μmol, 1 eq) in THF (4 mL) was added PPh3 (155.86 mg, 594.23 μmol, 2 eq) and HO (0.4 mL). After stirring at 25 °C for 1 h, the mixture was concentrated to give the title compound (120 mg, crude) as a yellow oil. MS (ES+) C 13 H 13 N3O2 theoretical value: 243, measured value: 244 [M+H] + .

[0344] [ka] Methyl 5-(((tert-butoxycarbonyl)amino)methyl)-4-phenylpyrimidine-2-carboxylate To a solution of the product from the previous step (80 mg, 328.87 μmol, 1 eq) in THF (3 mL) was added BocO (143.55 mg, 657.73 μmol, 151.10 μL, 2 eq) and EtN (133.11 mg, 1.32 mmol, 183.10 μL, 4 eq). After stirring at 25 °C for 2 h, the mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (eluent: petroleum ether / EtOAc = 1 / 1) to give the title compound (30 mg, 61.16 μmol, 18% yield) as a colorless oil. MS (ES+) C 18 H 21 N3O4 theoretical value: 343, measured value: 344 [M+H] + .

[0345] [ka] 5-(((tert-butoxycarbonyl)amino)methyl)-4-phenylpyrimidine-2-carboxylic acid (Intermediate A-30) To a solution of the product from the previous step (30 mg, 87.37 μmol, 1 eq) in MeOH (1.5 mL) and HO (1.5 mL) was added LiOH·HO (7.33 mg, 174.74 μmol, 2 eq). After stirring at 25 °C for 1 h, the mixture was concentrated to give the title compound (40 mg, crude) as a white solid. MS (ES+) C 17 H 19 N3O4 theoretical value: 329, measured value: 330 [M+H] + .

[0346] Intermediate A-31 [ka] 4-(2,3-difluorophenyl)-5-methylpyrimidine-2-carboxylic acid [ka] 2-chloro-4-(2,3-difluorophenyl)-5-methylpyrimidine To a solution of 2,4-dichloro-5-methylpyrimidine (4.3 g, 26.38 mmol, 1 eq) in THF (50 mL) and HO (5 mL) was added (2,3-difluorophenyl)boronic acid (5.00 g, 31.66 mmol, 1.2 eq), Pd(OAc) (118.45 mg, 0.52 mmol, 0.02 eq), NaCO (2.80 g, 26.38 mmol, 1 eq) and PPh (276.76 mg, 1.06 mmol, 0.04 eq) under N. After stirring at 60 °C for 16 h, the reaction mixture was diluted with HO (50 mL), extracted with EtOAc (50 × 3 mL), washed with brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (80 g SepaFlash® silica flash column, eluent of 30-40% EtOAc / petroleum ether gradient at 100 mL / min) to give the title compound (5 g, 20.78 mmol, 78% yield) as a white solid. MS(ES+)C 11 H7ClF2N2 Theoretical value: 240, Measured value: 241 [M+H] + .

[0347] [ka] Methyl 4-(2,3-difluorophenyl)-5-methylpyrimidine-2-carboxylate To a solution of the product from the previous step (2 g, 8.31 mmol, 1 eq) in MeOH (20 mL) under N was added Pd(dppf)Cl (608.14 mg, 0.83 mmol, 0.1 eq) and EtN (2.52 g, 24.93 mmol, 3.47 mL, 3 eq). The suspension was degassed under vacuum and purged several times with CO. After stirring at 60 °C under CO (50 psi) for 16 h, the reaction mixture was filtered and concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (45 g SepaFlash® silica flash column, eluent: 40–50% EtOAc / petroleum ether gradient at 80 mL / min) to give the title compound (2 g, 7.49 mmol, 90% yield) as a white solid. MS (ES+) C 13 H10 F2N2O2 theoretical value: 264, measured value: 265 [M+H] + .

[0348] [ka] 4-(2,3-difluorophenyl)-5-methylpyrimidine-2-carboxylic acid To a solution of the product from the previous step (2 g, 7.57 mmol, 1 eq) in THF (20 mL) and HO (5 mL) was added LiOH·HO (953 mg, 22.71 mmol, 3 eq). After stirring at 25 °C for 16 h, the mixture was acidified with aqueous HCl to pH = 2 and concentrated under reduced pressure to give a residue that was triturated with water (40 mL) to give the title compound (2 g, 7.43 mmol, 98% yield) as a white solid. MS(ES+)C 12 H8F2N2O2 theoretical value: 250, actual value: 251 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=14.58-12.44(br s,1H),8.97(s,1H),7.70-7.59(m,1H),7.46-7.32(m,2H),2.26(s,3H).

[0349] The following pyrimidine-2-carboxylic acids were obtained using a procedure similar to that used for intermediate A-31.

[0350] [Table 7]

[0351] Intermediate A-37 [ka] 5-Methyl-4-(pyrazin-2-yl)pyrimidine-2-carboxylic acid [ka] 2-chloro-5-methyl-4-(pyrazin-2-yl)pyrimidine A mixture of tributyl(pyrazin-2-yl)stannane (2 g, 5.42 mmol, 1 eq), 2,4-dichloro-5-methylpyrimidine (883.18 mg, 5.42 mmol, 1 eq), Pd(PPh3)4 (626.10 mg, 541.81 μmol, 0.1 eq), CuI (412.75 mg, 2.17 mmol, 0.4 eq), and LiCl (459.39 mg, 10.84 mmol, 221.93 μL, 2 eq) in toluene (20 mL) was degassed and purged with N2 three times, then the mixture was stirred under N2 at 60 °C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (40 g SepaFlash® silica flash column, elution with a 30-50% EtOAc / petroleum ether gradient at 50 mL / min) to give the title compound (900 mg, 3.88 mmol, 71% yield) as a red solid. MS (ES+) C9H7ClN4 calculated: 206 and 208, found: 207 and 209 [M+H] +

[0352] [ka] Methyl 5-methyl-4-(pyrazin-2-yl)pyrimidine-2-carboxylate To a solution of the product from the previous step (900 mg, 4.36 mmol, 1 eq) in methanol (20 mL) under N was added Pd(dppf)Cl (318.70 mg, 435.56 μmol, 0.1 eq) and EtN (1.32 g, 13.07 mmol, 1.82 mL, 3 eq). The suspension was degassed under vacuum and purged with CO three times. After stirring at 70 °C under CO (50 psi) for 16 h, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (40 g SepaFlash® silica flash column, eluent: 50–80% EtOAc / petroleum ether gradient at 60 mL / min) to give the title compound (600 mg, 2.01 mmol, 46% yield) as a red solid. MS (ES+) C 11 H 10N4O2 theoretical value: 230, measured value: 231 [M+H] + .

[0353] [ka] 5-Methyl-4-(pyrazin-2-yl)pyrimidine-2-carboxylic acid To a solution of the product from the previous step (600 mg, 2.61 mmol, 1 eq) in THF (10 mL) and HO (2 mL) was added LiOH·HO (328.07 mg, 7.82 mmol, 3 eq). The mixture was stirred at 25 °C for 16 h, then acidified to pH = 6 with aqueous HCl (1 M) and concentrated under reduced pressure. The residue was triturated with water and the filter cake was collected. Deionized water (5 mL) was added to the filter cake, and the mixture was lyophilized to give the title compound (200 mg, 370.03 μmol, 14% yield) as a yellow solid. MS(ES+)C 10 H8N4O2 theoretical value: 216, measured value: 217 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=13.60(br s,1H),9.32(s,1H),9.00(s,1H),8.88-8.78(m,2H),2.60(s,3H).

[0354] Intermediate A-38 [ka] 4-(2,4-difluoro-6-methylphenyl)-5-methylpyrimidine-2-carboxylic acid [ka] 2-(2,4-difluoro-6-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a solution of the product from the previous step (1.5 g, 7.25 mmol, 1 eq) in dioxane (20 mL) under N was added BPD (3.68 g, 14.49 mmol, 2 eq), Pd(dppf)Cl (530.18 mg, 724.58 μmol, 0.1 eq), and KOAc (1.07 g, 10.87 mmol, 1.5 eq). After stirring at 120 °C for 16 h, the mixture was concentrated under reduced pressure to give a residue that was purified by column chromatography (SiO, petroleum ether / EtOAc = 100 / 1 to 50 / 1) to give the title compound (1 g, 3.74 mmol, 51% yield) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ=7.02-6.76(m,2H),2.39(s,3H),1.30(s,12H).

[0355] [ka] 2-Bromo-4-(2,4-difluoro-6-methylphenyl)-5-methylpyrimidine To a solution of the product from the previous step (1.6 g, 6.30 mmol, 1 eq) in dioxane (20 mL) and HO (5 mL) under N was added 2,4-dibromopyrimidine (1.50 g, 6.30 mmol, 1 eq), CsCO (6.16 g, 18.89 mmol, 3 eq), and Pd(dppf)Cl (230.39 mg, 314.86 μmol, 0.05 eq). After stirring at 100 °C for 16 h, the reaction mixture was diluted with HO (50 mL) and extracted with EtOAc (25 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, petroleum ether / EtOAc = 100 / 1 to 5 / 1) to give the title compound (1.2 g, 3.37 mmol, 53.47% yield, 80% purity) as a yellow solid. MS(ES+)C 11 H7F2BrN2 Theoretical values: 284 and 286, Measured values: 285 and 287 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ=8.90(d,J=5.1Hz,1H),7.84-7.82(m,1H),7.37-7.30(m,1H),7.25-7.20(m,1H),2.30(s,3H).

[0356] [ka] Methyl 4-(2,4-difluoro-6-methylphenyl)-5-methylpyrimidine-2-carboxylate To a solution of the product from the previous step (1.2 g, 4.21 mmol, 1 eq) in MeOH (30 mL) was added Pd(dppf)Cl (154.00 mg, 210.46 μmol, 0.05 eq) and EtN (851.86 mg, 8.42 mmol, 1.17 mL, 2 eq). After stirring at 60 °C under CO (50 psi) for 30 h, the mixture was concentrated, diluted with water (20 mL), and extracted with EtOAc (10 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by column chromatography (SiO, petroleum ether / EtOAc = 100 / 1 to 1 / 1) to give the title compound (730 mg, 2.76 mmol, 65% yield) as a white solid. MS(ES+)C 13 H 10 F2N2O2 theoretical value: 264, measured value: 265 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=9.11(d,J=5.1Hz,1H),7.89(dd,J=1.6,5.1Hz,1H),7.29(s,1H),7.19(dd,J=0.7,9.6Hz,1H),3.93(s,3H),2.23(s,3H).

[0357] [ka] 4-(2,4-difluoro-6-methylphenyl)-5-methylpyrimidine-2-carboxylic acid To a solution of the product from the previous step (730 mg, 2.76 mmol, 1 eq) in MeOH (10 mL) and HO (10 mL) was added LiOH·HO (348 mg, 8.29 mmol, 3 eq). After stirring at 25 °C for 2 h, the mixture was concentrated, the pH adjusted to 11 with NaOH (1 M), and extracted with EtOAc (10 mL). The aqueous layer was adjusted to pH 3 with HCl (1 M) and extracted with EtOAc (10 mL). The organic layer was dried over NaSO, filtered, and concentrated to give the title compound (670 mg, 2.68 mmol, 97% yield) as a white solid. MS(ES+)C 12 H8F2N2O2 theoretical value: 250, actual value: 251 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=13.68(s,1H),9.08(d,J=5.1Hz,1H),7.83(dd,J=1.6,5.1Hz,1H),7.34-7.23(m,1H),7.18(dd,J=0.7,9.6Hz,1H),2.22(s,3H).

[0358] Intermediate A-39 [ka] 2-chloro-5-methyl-4,5'-bipyrimidine To a solution of 2,4-dichloro-5-methyl-pyrimidine (2 g, 12.27 mmol, 1 eq) in THF (21 mL) and HO (7 mL) under N was added pyrimidin-5-ylboronic acid (1.67 g, 13.50 mmol, 1.1 eq), Pd(dppf)Cl (448.89 mg, 613.48 μmol, 0.05 eq), and NaCO (3.90 g, 36.81 mmol, 3 eq). After stirring at 70 °C for 16 h, the mixture was diluted with HO (50 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated and purified by silica gel chromatography (eluent: petroleum ether / EtOAc = 1:1) to give the title compound (3.8 g, crude) as an orange solid. 1H NMR(400MHz,DMSO-d6)δ=9.35(s,1H),9.15(s,2H),8.81(s,1H),2.40(s,3H).

[0359] [ka] Methyl 5-methyl-[4,5'-bipyrimidine]-2-carboxylate To a solution of the product from the previous step (3.8 g, 18.39 mmol, 1 eq) in MeOH (40 mL) was added EtN (3.72 g, 36.78 mmol, 5.12 mL, 2 eq) and Pd(dppf)Cl (672.81 mg, 919.51 μmol, 0.05 eq), the suspension was stirred under CO (45 psi) at 70 °C for 16 h, and the mixture was concentrated. The resulting brown solid was purified by chromatography on silica gel (eluent: petroleum ether / EtOAc = 0:1) to give the title compound (630 mg, 2.65 mmol, 14% yield) as a red solid. MS(ES+)C 11 H 10 N4O2 theoretical value: 230, measured value: 231 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=9.37(s,1H),9.17(s,2H),9.01(s,1H),3.93(s,3H),2.49(s,3H).

[0360] [ka] 5-methyl-[4,5'-bipyrimidine]-2-carboxylic acid To a solution of the product from the previous step (30 mg, 130.31 μmol, 1 eq) in MeOH (1 mL) and HO (1 mL) was added LiOH HO (8.20 mg, 195.46 μmol, 1.5 eq). After stirring at 25 °C for 10 min, the pH of the mixture was adjusted to 7 with 1 M aqueous HCl. The residue was concentrated under reduced pressure to give the title compound (30 mg, crude) as a yellow oil. MS(ES+)C 10H8N4O2 theoretical value: 216, measured value: 217 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=9.32(s,1H),9.18(s,2H),8.84(s,1H),2.41(s,3H).

[0361] Intermediate A-40 [ka] 5-Methoxy-4-phenylpyrimidine-2-carboxylic acid [ka] 2-chloro-5-methoxy-4-phenylpyrimidine To a solution of 2,4-dichloro-5-methoxypyrimidine (2 g, 11.17 mmol, 1 eq) in THF (20 mL) and HO (5 mL) was added phenylboronic acid (1.36 g, 11.17 mmol, 1 eq), Pd(OAc) (50.17 mg, 223.46 μmol, 0.02 eq), NaCO (2.37 g, 22.35 mmol, 2 eq), and PPh (117.22 mg, 446.92 μmol, 0.04 eq) under N. After stirring at 60 °C for 16 h, the mixture was diluted with HO (20 mL), extracted with EtOAc (20 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: petroleum ether / EtOAc=10 / -5 / 1) to give the title compound (1.9 g, 5.86 mmol, 52% yield) as a white solid. MS(ES+)C 11 H9ClNO Theoretical values: 220 and 222, Measured values: 221 and 223 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=8.66(s,1H),8.06-7.98(m,2H),7.57-7.48(m,3H),4.00(s,3H).

[0362] [ka] Methyl 5-methoxy-4-phenylpyrimidine-2-carboxylate To a solution of the product from the previous step (1.8 g, 8.16 mmol, 1 eq) in MeOH (40 mL) and DMF (8 mL) under N was added EtN (2.48 g, 24.47 mmol, 3.41 mL, 3.00 eq) and Pd(dppf)Cl (895.34 mg, 1.22 mmol, 0.15 eq). The suspension was degassed under vacuum and purged with CO three times. After stirring at 80 °C under CO (45 psi) for 16 h, the mixture was diluted with HO (50 mL), extracted with EtOAc (2 x 50 mL), and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether / EtOAc = 5 / 1 to 2 / 1) to give the title compound (1.7 g, 6.26 mmol, 76% yield) as a white solid. MS(ES+)C 13 H 12 N2O3 theoretical value: 244, measured value: 245 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=8.82(s,1H),8.09-8.02(m,2H),7.57-7.50(m,3H),4.08(s,3H),3.90(s,3H).

[0363] [ka] 5-Methoxy-4-phenylpyrimidine-2-carboxylic acid To a solution of the product from the previous step (1.7 g, 6.96 mmol, 1 eq) in MeOH (10 mL) and HO (10 mL) was added LiOH·HO (876.23 mg, 20.88 mmol, 3 eq). After stirring at 25 °C for 16 h, the mixture was diluted with water (50 mL), extracted with EtOAc (50 mL × 2), and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: petroleum ether / EtOAc = 10 / 1 to 2 / 1) to give the title compound (1.3 g, 5.65 mmol, 81% yield). MS(ES+)C 12 H 10N2O3 theoretical value: 230, measured value: 231 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=8.80(s,1H),8.10-8.05(m,2H),7.56-7.50(m,3H),4.07(s,3H).

[0364] Intermediate A-41 [ka] 4-(4-fluoro-2-methylphenyl)pyrimidine-2-carboxylic acid [ka] 2-Bromo-4-(4-fluoro-2-methylphenyl)pyrimidine To a solution of 2,4-dibromopyrimidine (5 g, 21.02 mmol, 1 eq) and (4-fluoro-2-methylphenyl)boronic acid (3.24 g, 21.02 mmol, 1 eq) in THF (60 mL) and HO (20 mL) was added NaCO (6.68 g, 63.06 mmol, 3 eq) and Pd(PPh) (1.21 g, 1.05 mmol, 0.05 eq) under N. After stirring at 60 °C for 16 h, the mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL × 2). The combined organic phase was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: petroleum ether / EtOAc = 100 / 1 to 5 / 1) to give the title compound (3.5 g, 11.79 mmol, 56% yield) as a white solid. MS(ES+)C 11 H8N2FBr Theoretical values: 266 and 268, Measured values: 267 and 269 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=8.77(d,J=5.1Hz,1H),7.82(d,J=5.1Hz,1H),7.61(dd,J=6.0,8.5Hz,1H),7.32-7.16(m,2H),2.43(s,3H).

[0365] [ka] Methyl 4-(4-fluoro-2-methylphenyl)pyrimidine-2-carboxylate To a solution of the product from the previous step (3.5 g, 13.10 mmol, 1 eq) in MeOH (50 mL) was added Pd(dppf)Cl (479.41 mg, 655.19 μmol, 0.05 eq) and EtN (2.65 g, 26.21 mmol, 3.65 mL, 2 eq). The suspension was stirred at 60 °C under CO (50 psi) for 16 h, and then the reaction was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: petroleum ether / EtOAc = 5 / 1) to give the title compound (2.8 g, 10.23 mmol, 78% yield) as a yellow solid. MS (ES+) C 13 H 11 FN2O2 theoretical value: 246, measured value: 247 [M+H] +

[0366] [ka] 4-(4-fluoro-2-methylphenyl)pyrimidine-2-carboxylic acid To a solution of the product from the previous step (400 mg, 1.54 mmol, 1 eq) in THF (10 mL) and HO (5 mL) was added LiOH·HO (122.94 mg, 3.07 mmol, 2 eq). After stirring at 25 °C for 2 h, the mixture was concentrated under reduced pressure to remove THF. The mixture was acidified with aqueous HCl (1 M) to adjust the pH to 2, diluted with water (5 mL), and extracted with EtOAc (5 mL × 3). The combined organic phases were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was triturated with EtOAc for 10 min at 25 °C, and the filter cake was collected and dried under reduced pressure to give the title compound (220 mg, 900.05 μmol, 58% yield) as a white solid. MS(ES+)C 12 H9N2O2F Theoretical value: 232, Measured value: 233 [M+H] +1H NMR(400MHz,DMSO-d6)δ=13.60(br s,1H),8.90(br d,J=5.0Hz,1H),7.73(d,J=5.1Hz,1H),7.59(dd,J=6.1,8.5Hz,1H),7.31-7.14(m,2H),2.42(s,3H).

[0367] Intermediate A-42 4-(2-fluorophenyl)-5-(methyl-d3)pyrimidine-2-carboxylic acid [ka] [ka] 2-chloro-4-(2-fluorophenyl)-5-methylpyrimidine To a solution of 2,4-dichloro-5-methylpyrimidine (6 g, 36.81 mmol, 1 eq) in THF (60 mL) and HO (20 mL) under N was added (2-fluorophenyl)boronic acid (5.15 g, 36.81 mmol, 1 eq), NaCO (7.80 g, 73.62 mmol, 2 eq), and Pd(dppf)Cl (807.99 mg, 1.10 mmol, 0.03 eq). After stirring at 70 °C for 16 h, the mixture was diluted with HO (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated and purified by silica gel chromatography (eluent: petroleum ether / EtOAc = 1:1) to give the title compound (8 g, crude) as a white solid. MS(ES+)C 11 H8N2ClF Theoretical values: 222 and 224, Measured values: 223 and 225 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=8.77(s,1H),7.64-7.58(m,1H),7.56-7.50(m,1H),7.42-7.36(m,2H),2.17(s,3H).

[0368] [ka] Methyl 4-(2-fluorophenyl)-5-methylpyrimidine-2-carboxylate To a solution of the product from the previous step (8 g, 35.93 mmol, 1 eq) in MeOH (80 mL) was added Pd(dppf)Cl (1.31 g, 1.80 mmol, 0.05 eq) and EtN (10.91 g, 107.79 mmol, 15.00 mL, 3 eq). The suspension was stirred at 70 °C under CO (45 psi) for 16 h. The mixture was concentrated to remove MeOH, then diluted with HO (200 mL) and extracted with EtOAc (200 mL × 2). The combined organic layers were washed with brine, dried over NaSO, and filtered. The filtrate was concentrated and purified by chromatography on silica gel (eluent: petroleum ether / EtOAc = 1:1) to give the title compound (6 g, 24.37 mmol, 67% yield) as a white solid. MS(ES+)C 13 H 11 N2FO2 theoretical value: 246, measured value: 247 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=8.97(s,1H),7.66-7.58(m,1H),7.56-7.50(m,1H),7.44-7.36(m,2H),3.91(s,3H),2.25(d,J=1.1Hz,3H).

[0369] [ka] Methyl 5-(bromomethyl)-4-(2-fluorophenyl)pyrimidine-2-carboxylate To a solution of the product from the previous step (500 mg, 2.03 mmol, 1 eq) in DCE (10 mL) was added AIBN (66.69 mg, 406.11 μmol, 0.2 eq) and NBS (542.11 mg, 3.05 mmol, 1.5 eq). After stirring at 80 °C for 16 h, the mixture was concentrated to remove DCE, then diluted with HO (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were washed with brine, dried over NaSO, and filtered. The filtrate was concentrated and purified by preparative TLC (eluent: petroleum ether / EtOAc = 1:1) to give the title compound (151 mg, 413.34 μmol, 20% yield) as a white solid. MS (ES+) C 13 H 10 N2O2FBr Theoretical values: 324 and 326, Measured values: 325 and 327 [M+H] + .

[0370] [ka] Methyl 4-(2-fluorophenyl)-5-(methyl-d3)pyrimidine-2-carboxylate To a solution of the product from the previous step (80 mg, 228.83 μmol, 93% purity, 1 eq) in DO (1 mL) and THF (1 mL) was added PPh (72.02 mg, 274.60 μmol, 1.2 eq). The mixture was stirred at 15 °C for 12 h. Next, KCN (0.03 g, 460.72 μmol, 2.01 eq) was added to the mixture, which was stirred at 50 °C for 13 h. The mixture was diluted with HO (5 mL) and extracted with EtOAc (5 mL × 2). The combined organic layers were washed with brine, dried over NaSO, and filtered. The filtrate was concentrated and purified by preparative TLC (eluent: petroleum ether / EtOAc = 1:2) to give the title compound (25 mg, 92.27 μmol, 40% yield) as a white solid. MS (ES+) C 13 H8D3N2O2F Theoretical value: 249, Measured value: 250 [M+H] + .

[0371] [ka] 4-(2-fluorophenyl)-5-(methyl-d3)pyrimidine-2-carboxylic acid To a solution of the product from the previous step (25 mg, 100.30 μmol, 1 eq) in MeOH (1.5 mL) and HO (1.5 mL) was added LiOH·HO (12.63 mg, 300.90 μmol, 3 eq). The mixture was stirred at 15 °C for 30 min. The pH of the mixture was adjusted to 7 with 1 M aqueous HCl, and it was concentrated to give the title compound (30 mg, crude) as a white solid. MS (ES+) C 12 H6D3N2O2F Theoretical value: 235, Measured value: 236 [M+H] + .

[0372] Intermediate A-43 [ka] 4-(4-cyanophenyl)-5-methylpyrimidine-2-carboxylic acid [ka] 4-(2-chloro-5-methylpyrimidin-4-yl)benzonitrile To a solution of 2,4-dichloro-5-methylpyrimidine (3 g, 18.40 mmol, 1 eq), (4-cyanophenyl)boronic acid (2.70 g, 18.40 mmol, 1 eq) in THF (40 mL) and HO (4 mL) under N was added Pd(OAc) (82.64 mg, 368.09 μmol, 0.02 eq), PPh (193.09 mg, 736.18 μmol, 0.04 eq), and NaCO (1.95 g, 18.40 mmol, 1 eq) at 25 °C. After stirring at 60 °C for 16 h, the mixture was diluted with HO (30 mL), extracted with EtOAc (50 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: petroleum ether / EtOAc = 0 to 20 / 1) to give the title compound (2.5 g, 10.12 mmol, 55% yield) as a white solid. MS(ES+)C 12H8ClN3 theoretical values: 229 and 231, observed values: 230 and 232 [M+H] + . 1 H NMR(400MHz, CDCl3)δ=8.59(s,1H),7.85-7.81(m,2H),7.80-7.74(m,2H),2.41(s,3H).

[0373] [ka] Methyl 4-(4-cyanophenyl)-5-methylpyrimidine-2-carboxylate To a solution of the product from the previous step (1.5 g, 6.53 mmol, 1 eq) in MeOH (20 mL) under N was added Pd(dppf)Cl (238.95 mg, 326.56 μmol, 0.05 eq) and EtN (1.32 g, 13.06 mmol, 1.82 mL, 2 eq). The suspension was degassed under vacuum and purged with CO several times. After stirring at 60 °C under CO (50 psi) for 20 h, the mixture was diluted with HO (30 mL), extracted with EtOAc (50 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether / EtOAc = 5 / 1 to 1 / 1) to give the title compound (300 mg, 1.15 mmol, 17% yield) as a red solid. MS(ES+)C 14 H 11 N3O2 theoretical value: 253, measured value 254 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=8.98(s,1H),8.04(d,J=8.4Hz,2H),7.90(d,J=8.4Hz,2H),3.92(s,3H),2.42(s,3H).

[0374] [ka] 4-(4-cyanophenyl)-5-methylpyrimidine-2-carboxylic acid To a solution of the product from the previous step (100 mg, 394.86 μmol, 1 eq) in THF (1 mL) and HO (0.1 mL) was added LiOH (9.46 mg, 394.86 μmol, 1 eq). After stirring at 25 °C for 3 h, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL), basified with aqueous NaOH (1 M) to adjust the pH to 10, and extracted with EtOAc (20 mL × 3). The aqueous phase was then acidified with aqueous HCl (1 M) to adjust the pH to 2, extracted with EtOAc (20 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (90 mg, 376.21 μmol, 95% yield) as a white solid. MS(ES+)C 13 H9N3O2 theoretical value: 239, measured value 240 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=8.75(br s,1H),8.02(d,J=8.3Hz,2H),7.87(d,J=8.4Hz,2H),2.34(s,3H).

[0375] Intermediate A-44 [ka] 4-(4-cyano-2-fluorophenyl)-5-methylpyrimidine-2-carboxylic acid [ka] 3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile To a solution of 4-bromo-3-fluorobenzonitrile (5 g, 25.00 mmol, 1 eq) in dioxane (50 mL) was added Pd(dppf)Cl (914.60 mg, 1.25 mmol, 0.05 eq), AcOK (4.91 g, 50.00 mmol, 2 eq), and BPD (7.62 g, 30.00 mmol, 1.2 eq) under N. After stirring at 110 °C for 16 h, the mixture was concentrated under reduced pressure to give the title compound (12 g, crude) as a crude black solid.

[0376] [ka] 4-(2-chloro-5-methylpyrimidin-4-yl)-3-fluorobenzonitrile To 2,4-dichloro-5-methylpyrimidine (3 g, 18.40 mmol, 1 eq) and the product from the previous step (5.46 g, 22.09 mmol, 1.2 eq) in THF (32 mL) and HO (8 mL) was added Pd(OAc) (82.64 mg, 368.09 μmol, 0.02 eq), PPh (193.09 mg, 736.18 μmol, 0.04 eq), and NaCO (3.90 g, 36.81 mmol, 2 eq) under N. After stirring at 60 °C for 16 h, the mixture was diluted with water (50 mL), extracted with EtOAc (50 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The mixture was purified by silica gel chromatography (eluent: petroleum ether / EtOAc = 0:1) and triturated with petroleum ether and EtOAc (60 mL, petroleum ether / EtOAc = 5:1). The mixture was filtered and the filter cake was collected to give the title compound (2.7 g, 10.90 mmol, 59% yield) as a white solid. MS(ES+)C 12 H7ClFN3 theoretical values: 247 and 249, observed values: 248 and 250 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=8.85(s,1H),8.12(dd,J=1.2,10.0Hz,1H),7.95-7.88(m,1H),7.84-7.75(m,1H),2.18(d,J=0.9Hz,3H).

[0377] [ka] Methyl 4-(4-cyano-2-fluorophenyl)-5-methylpyrimidine-2-carboxylate To a solution of the product from the previous step (2.7 g, 10.90 mmol, 1 eq) in MeOH (30 mL) under N was added Pd(dppf)Cl (398.86 mg, 545.11 μmol, 0.05 eq) and EtN (2.21 g, 21.80 mmol, 3.03 mL, 2 eq). After degassing and purging with CO for 5 min, the mixture was stirred at 70 °C under a CO atmosphere (50 psi) for 16 h. The mixture was then concentrated under reduced pressure to remove MeOH, then diluted with HO (50 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: petroleum ether / EtOAc=1:1) to give the title compound (650 mg, 1.75 mmol, 16% yield) as a yellow solid. MS(ES+)C 14 H 10 N3O2F Theoretical value: 271, Measured value: 272 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=9.03(s,1H),8.12(dd,J=1.2,9.9Hz,1H),7.92(dd,J=1.3,7.9Hz,1H),7.78(t,J=7.6Hz,1H),3.91(s,3H),2.26(s,3H).

[0378] [ka] 4-(4-cyano-2-fluorophenyl)-5-methylpyrimidine-2-carboxylic acid To a solution of the product from the previous step (600 mg, 1.61 mmol, 1 eq) in HO (6 mL) and MeOH (6 mL) was added LiOH·HO (203.28 mg, 4.84 mmol, 3 eq). After stirring at 15 °C for 1 h, the mixture was diluted with HO (20 mL), and the pH of the aqueous layer was adjusted to 6 with 1 M aqueous HCl. The mixture was extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (200 mg, crude) as an orange solid. MS (ES+) C 13 H8FN3O2 theoretical value: 257, actual value 258 [M+H] +

[0379] Intermediate A-45 [ka] 4-(bicyclo[2.2.2]octan-1-yl)-5-methylpyrimidine-2-carboxylic acid [ka] N-Methoxy-N-methylbicyclo[2.2.2]octane-1-carboxamide To a solution of bicyclo[2.2.2]octane-4-carboxylic acid (4.5 g, 29.18 mmol, 1 eq) in DMF (50 mL) was added N-methoxymethanamine hydrochloride (3.42 g, 35.02 mmol, 1.2 eq), HOBt (4.73 g, 35.02 mmol, 1.2 eq), EDCI (6.71 g, 35.02 mmol, 1.2 eq), and i-PrNEt (11.31 g, 87.55 mmol, 15.25 mL, 3 eq). After stirring at 15 °C for 2 h, the mixture was diluted with HO (200 mL), extracted with EtOAc (200 mL × 2), and washed with brine (100 mL × 3). The combined organic phases were dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (6.12 g, crude) as a colorless oil. MS(ES+)C 11 H 19 NO2 theoretical value: 197, actual value: 198 [M+H] +. 1 H NMR(400MHz,CDCl3)δ=3.58(s,3H),3.07(s,3H),1.84-1.69(m,6H),1.58-1.46(m,7H).

[0380] [ka] 1-(bicyclo[2.2.2]octan-1-yl)propan-1-one To a solution of the product from the previous step (6.12 g, 31.02 mmol, 1 eq) in THF (60 mL) under N was added EtMgBr (3 M, 11.38 mL, 1.1 eq) at 0 °C. After stirring at 25 °C for 4 h, the mixture was poured into 1 M HCl (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (eluent: petroleum ether / EtOAc = 20 / 1) to give the title compound (2.8 g, 15.16 mmol, 48% yield) as a yellow oil. 1 H NMR(400MHz,CD3OD)δ =2.49(q,J=7.3Hz,2H),1.73-1.58(m,13H),0.95(t,J=7.2Hz,3H).

[0381] [ka] (E)-1-(bicyclo[2.2.2]octan-1-yl)-3-(dimethylamino)-2-methylprop-2-en-1-one To 1-tert-butoxy-N,N,N',N'-tetramethyl-methanediamine (4.22 g, 24.21 mmol, 5 mL, 2.24 eq) was added the product from the previous step (1.8 g, 10.83 mmol, 1 eq). After stirring at 120 °C for 16 h, the residue was diluted with HO (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were dried over NaSO, filtered, and concentrated to give the title compound (2.3 g, crude) as a yellow solid. 1H NMR(400MHz,CD3OD)δ=7.41(s,1H),2.98(s,6H),1.80(s,3H),1.76-1.69(m,6H),1.57-1.49(m,7H).

[0382] [ka] 4-(bicyclo[2.2.2]octan-1-yl)-2,5-dimethylpyrimidine To a solution of acetamidine (905.33 mg, 15.59 mmol, 1.5 eq) in THF (30 mL) under N was added t-BuOK (1.75 g, 15.59 mmol, 1.5 eq). After stirring at 60 °C for 15 min, the product from the previous step (2.3 g, 10.39 mmol, 1 eq) was added to the mixture, which was stirred at 60 °C for 16 h. The mixture was diluted with HO (60 mL) and extracted with EtOAc (60 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (eluent: petroleum ether / EtOAc = 2 / 1) to give the title compound (0.8 g, 2.92 mmol, 28% yield) as a yellow solid. MS(ES+)C 14 H 20 N2 theoretical value: 216, measured value: 217 [M+H] + . 1 H NMR(400MHz,CD3OD)δ=8.23(s,1H),2.58(s,3H),2.46(s,3H),2.07-1.94(m,6H),1.78-1.67(m,7H).

[0383] [ka] 4-(bicyclo[2.2.2]octan-1-yl)-5-methylpyrimidine-2-carboxylic acid To a solution of the product from the previous step (800 mg, 2.92 mmol, 79% purity, 1 eq) in pyridine (10 mL) was added SeO2 (1.13 g, 10.23 mmol, 3.5 eq). After stirring at 120 °C for 48 h, the mixture was filtered, and the filtrate was concentrated. The residue was then purified by preparative HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (0.05% HCl)-CH3CN]; B%: 33%–63%, 10 min). The eluent was concentrated under reduced pressure and lyophilized to give the title compound (500.7 mg, 1.99 mmol, 68% yield) as a white solid. MS(ES+)C 14 H 18 N2O2 theoretical value: 246, measured value: 247 [M+H] + . 1 H NMR(400MHz,CD3OD)δ:8.54(s,1H),2.58(s,3H),2.14-1.99(m,6H),1.79-1.68(m,7H).

[0384] Intermediate A-46 [ka] 5-Methyl-4-(tetrahydro-2H-pyran-4-yl)pyrimidine-2-carboxylic acid [ka] N-Methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide To tetrahydro-2H-pyran-4-carboxylic acid (15 g, 115.26 mmol, 1 eq) and N-methoxymethanamine (13.49 g, 138.31 mmol, 1.20 eq, HCl) in DMF (150 mL) were added HATU (65.74 g, 172.89 mmol, 1.5 eq) and i-PrNEt (44.69 g, 345.78 mmol, 60.23 mL, 3 eq) at 25 °C. After stirring at 25 °C for 16 h, the mixture was poured into ice water (200 mL) and extracted with EtOAc (200 mL × 3). The combined organic phase was washed with brine (200 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ISCO®; 120 g SepaFlash® silica flash column, eluent of 20-50% EtOAC / petroleum ether gradient at 100 mL / min) to give the title compound (14 g, 80.83 mmol, 70% yield) as a pale yellow oil. MS(ES+)C8H 15 NO3 theoretical value: 173, actual value: 174 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=3.90-3.80(m,2H),3.68(s,3H),3.42-3.32(m,2H),3.09(s,3H),2.98-2.85(m,1H),1.63-1.52(m,4H).

[0385] [ka] 1-(tetrahydro-2H-pyran-4-yl)propan-1-one To a solution of the product from the previous step (13 g, 75.05 mmol, 1 eq) in THF (150 mL) under N was added EtMgBr (3 M, 27.52 mL, 1.1 eq) at 0 °C. After stirring at 25 °C for 4 h, the mixture was quenched with saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (200 mL × 3). The combined organic phases were washed with brine (200 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluent: 0–15% EtOAc / petroleum ether gradient at 50 mL / min) to afford the title compound (9.2 g, 64.70 mmol, 86% yield) as a colorless liquid. MS(ES+)C8H 14 O2 theoretical value: 142, measured value: 143 [M+H] + . 1 H NMR(400MHz,CDCl3)δ=4.03-3.96(m,2H),3.46-3.38(m,2H),2.60-2.43(m,3H),1.80-1.65(m,4H),1.05(t,J=7.2Hz,3H).

[0386] [ka] 3-(Dimethylamino)-2-methyl-1-(tetrahydro-2H-pyran-4-yl)prop-2-en-1-one To a solution of the product from the previous step (2.4 g, 16.88 mmol, 1 eq) in DMF (10 mL) was added DMFDMA (8.04 g, 67.51 mmol, 8.97 mL, 4 eq). After stirring at 160 °C for 2 h, the mixture was poured into water (50 mL), extracted with CHCl (50 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (3.33 g, 16.88 mmol, 100% yield) as a pale yellow oil.

[0387] [ka] 2,5-Dimethyl-4-(tetrahydro-2H-pyran-4-yl)pyrimidine To a solution of acetamidine hydrochloride (2.37 g, 25.09 mmol, 1.5 eq) in THF (20 mL) under N was added t-BuOK (2.82 g, 25.09 mmol, 1.5 eq). After stirring at 60 °C for 1 h, a solution of the product from the previous step (3.3 g, 16.73 mmol, 1 eq) in THF (10 mL) was added. After stirring at 60 °C for 16 h, the mixture was dried over Na SO , filtered, and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: 0–50% EtOAc / petroleum ether gradient at 30 mL / min) to give the title compound (320 mg, 1.66 mmol, 9% yield) as a brown solid. 1 H NMR(400MHz,CDCl3)δ=8.24(s,1H),4.16-4.07(m,2H),3.52-3.43(m,2H),3.01 -2.91(m,1H),2.59(s,3H),2.19(s,3H),2.10-1.93(m,2H),1.56-1.50(m,2H).

[0388] [ka] 5-Methyl-4-(tetrahydro-2H-pyran-4-yl)pyrimidine-2-carboxylic acid To a solution of the product from the previous step (320 mg, 1.66 mmol, 1 eq) in pyridine (6 mL) and HO (0.06 mL) was added SeO (646.40 mg, 5.83 mmol, 3.5 eq). After stirring at 120 °C for 16 h, the mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Zhongpu RD-C18 150 × 25 mm × 3 μm; mobile phase: [water (0.225% FA)-CHCN]; B%: 3%–33%, 10 min). The eluent was concentrated and lyophilized to give the title compound (70 mg, 314.97 μmol, 18% yield) as a white solid. 1H NMR(400MHz,CDCl3)δ=8.62(br s,1H),4.07 4.14-3.99(m,2H),3.58-3.42(m,2H),3.22-3.06(m,1H),2.39(s,3H),2.15-1.98(m,2H),1.69-1.49(m,2H).

[0389] Intermediate A-47 [ka] 4-(2-fluorophenyl)-5-methylpyrimidine-2-carboxylic acid [ka] 3-(Dimethylamino)-1-(2-fluorophenyl)-2-methylprop-2-en-1-one To a solution of 1-(2-fluorophenyl)propan-1-one (6 g, 39.43 mmol, 1 eq) in DMF (30 mL) was added DMFDMA (18.79 g, 157.72 mmol, 20.95 mL, 4 eq). The mixture was stirred at 160 °C for 2 h. Water (100 mL) was added to the mixture, which was then extracted with EtOAc (100 mL × 3). The organic phase was washed with brine (100 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: 0–100% EtOAc / petroleum ether gradient at 100 mL / min). The eluent was concentrated to give the title compound (7.47 g, 36.04 mmol, 91% yield) as a brown solid. MS(ES+)C 12 H 14 OFN theoretical value: 207, measured value: 208 [M+H] +1 H NMR(400MHz,DMSO-d6)δ=7.44-7.38(m,1H),7.27-7.18(m,3H),6.74(s,1H),3.02(s,6H),2.02(s,3H).

[0390] [ka] 4-(2-fluorophenyl)-2,5-dimethylpyrimidine To EtOH (10 mL) was added Na (1.33 g, 57.90 mmol, 3 eq). The mixture was stirred at 20 °C under N for 20 min. Next, a solution of acetamidine hydrochloride (2.74 g, 28.95 mmol, 1.5 eq) in EtOH (10 mL) was added to the mixture. The mixture was stirred at 0 °C under N for 20 min. Next, a solution of the product from the previous step (4 g, 19.30 mmol, 1 eq) in EtOH (10 mL) was added to the mixture. The mixture was stirred at 70 °C for 5 h. Water (80 mL) was added to the mixture, which was extracted with EtOAc (50 mL × 3). The organic phase was washed with brine (50 mL × 2), dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ISCO®; 25 g SepaFlash® silica flash column, eluent of 0-100% EtOAC / petroleum ether gradient at 50 mL / min), and the eluent was concentrated to give the title compound (3.16 g, 15.63 mmol, 80% yield) as a yellow oil. MS(ES+)C 12 H 11 N2F theoretical value: 202, measured value: 203 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=8.66(s,1H),7.59-7.53(m,1H),7.49-7.45(m,1H),7.38-7.33(m,2H),2.62(s,3H),2.11(s,3H).

[0391] [ka] 4-(2-fluorophenyl)-5-methylpyrimidine-2-carboxylic acid To a solution of the product from the previous step (1.5 g, 7.42 mmol, 1 eq) in pyridine (15 mL) was added SeO2 (4.94 g, 44.50 mmol, 6 eq). The mixture was stirred at 120 °C for 16 h. Water (20 mL) was added to the mixture, which was then extracted with EtOAc (20 mL × 3). The organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 (250 × 70 mm, 15 μm); mobile phase: [water (0.1% TFA)-CH3CN]; B%: 20 CH3CN% to 50 CH3CN%, 30 min). The eluent was concentrated and then lyophilized to give the title compound (360.7 mg, 1.55 mmol, 20% yield) as a yellow solid. MS(ES+)C 12 H9N2FO2 Theoretical value: 232, Measured value: 233 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=13.55(s,1H),8.94(s,1H),7.65-7.60(m,1H),7.57-7.53(s,1H),7.44-7.39(m,2H),2.25(s,3H).

[0392] Intermediate A-48 [ka] 5-chloro-4-(tetrahydro-2H-pyran-2-yl)pyrimidine-2-carboxylic acid [ka] 2,5-Dichloro-4-(tetrahydro-2H-pyran-2-yl)pyrimidine To a solution of 2,5-dichloropyrimidine (2.5 g, 16.78 mmol, 1 eq) in CHCN (40 mL) and HO (20 mL) was added tetrahydropyran (28.91 g, 335.62 mmol, 20 eq) and OXONE® (13.61 g, 50.34 mmol, 10.08 mL, 3 eq). After stirring at 120 °C under N for 6 h, the mixture was poured into water (30 mL), extracted with EtOAc (50 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: 0–10% EtOAc / petroleum ether gradient at 50 mL / min) to give the title compound (1.0 g, 4.29 mmol, 25% yield) as a colorless oil. MS(ES + )C9H 10 N2Cl2O Theoretical values: 232 and 234, Measured values: 233 and 235 [M+H] +1 H NMR(400MHz,CDCl3)δ=8.53(s,1H),4.77(dd,J=2.4,10.4Hz,1H),4.26-4.18(m,1H),4.16 -4.08(m,1H),4.07-3.98(m,1H),3.70-3.59(m,2H),3.59-3.41(m,1H),2.08-1.91(m,2H).

[0393] [ka] 5-chloro-4-(tetrahydro-2H-pyran-2-yl)-2-vinylpyrimidine To a solution of the product from the previous step (900 mg, 3.86 mmol, 1 eq) in dioxane (4 mL) and HO (0.4 mL) was added CsCO (2.52 g, 7.72 mmol, 2 eq), potassium (vinyl)trifluoroborate (620.46 mg, 4.63 mmol, 1.2 eq), Pd(OAc) (130.03 mg, 579.00 μmol, 0.15 eq), and PPh (303.81 mg, 1.16 mmol, 0.3 eq). After stirring at 105 °C for 16 h, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent of 0-10% EtOAC / petroleum ether gradient at 30 mL / min) to afford the title compound (300 mg, 1.34 mmol, 34% yield) as a colorless oil. MS(ES + )C 11 H 13 N2ClO Theoretical values: 224 and 226, Measured values: 225 and 227 [M+H] +1 H NMR(400MHz,CDCl3)δ=8.52(s,1H),6.86(dd,J=10.6,17.3Hz,1H),6.55(dd,J=1.7,17.3Hz,1H),5.67(dd,J=1. 7,10.6Hz,1H),4.78-4.67(m,1H),4.20-4.11(m,1H),3.64-3.54(m,1H),1.99-1.90(m,1H),1.87-1.49(m,5H).

[0394] [ka] 5-chloro-4-(tetrahydro-2H-pyran-2-yl)pyrimidine-2-carbaldehyde A stream of O3 was introduced into a solution of the product from the previous step (280 mg, 1.25 mmol, 1 eq) in CHCl (4 mL) and MeOH (4 mL) and bubbled for 10 min at −78 °C. After purging excess O3 with N, MeS (774.30 mg, 12.46 mmol, 915.25 μL, 10 eq) was added at 25 °C. After stirring for 2 h at 25 °C, the mixture was diluted with H0 (10 mL), extracted with EtOAc (10 mL × 3), and washed with brine (10 mL × 3). The combined organic phases were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: petroleum ether / EtOAc = 2 / 1) to give the title compound (200 mg, 882.38 μmol, 70% yield) as a colorless oil. MS(ES + )C 10 H 11 ClN2O2 theoretical values: 226 and 227, observed values: 227 and 228 [M+H] + . 1 H NMR(400MHz,CDCl3)δ=10.18(s,1H),8.90(s,1H),4.99-4.87(m,1H),4.31-4.25(m,1H),3.78-3.65(m,1H),1.96-1.68(m,6H).

[0395] [ka] 5-chloro-4-(tetrahydro-2H-pyran-2-yl)pyrimidine-2-carboxylic acid To a solution of the product from the previous step (180 mg, 794.14 μmol, 1 eq) in acetone (4 mL) and HO (1 mL) was added KMnO (125.50 mg, 794.14 μmol, 1 eq). After stirring at 25 °C for 1 h, the mixture was extracted with EtOAc (10 mL) and water (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Shim-pack C18 150 × 25 × 10 μm column; mobile phase: [water (0.225% FA)-CHCN]; B%: 15%–35%, 11 min). The eluent was concentrated and lyophilized to give the title compound (20 mg, 81.60 μmol, 10.27% yield, 99% purity) as a white solid. MS(ES + )C 10 H 11 N2ClO3 theoretical values: 242 and 244, observed values: 243 and 245 [M+H] + . 1 H NMR(400MHz,CDCl3)δ=8.81(s,1H),4.83(dd,J=2.3,10.4Hz,1H),4.21-4.09(m, 1H),3.67-3.56(m,1H),2.04-1.93(m,1H),1.92-1.82(m,1H),1.80-1.56(m,4H).

[0396] Intermediate A-49 [ka] 5-chloro-2'-methyl-[4,5'-bipyrimidine]-2-carboxylic acid [ka] 2,5-Dichloro-2'-methyl-4,5'-bipyrimidine To a solution of 2,4,5-trichloropyrimidine (2 g, 10.90 mmol, 1.25 mL, 1 eq) in THF (21 mL) and HO (7 mL) was added (2-methylpyrimidin-5-yl)boronic acid (1.50 g, 10.90 mmol, 1 eq), Pd(PPh)Cl (382.67 mg, 545.19 μmol, 0.05 eq), and NaCO (3.47 g, 32.71 mmol, 3 eq) under N. After stirring at 70 °C for 16 h, the mixture was diluted with HO (50 mL), extracted with EtOAc (50 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: petroleum ether / EtOAc=2 / 1) to give the title compound (2 g, 5.89 mmol, 54% yield) as a white solid. MS (ES+) C9H6Cl2N4 Calculated: 240 and 242, Found: 241 and 243 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=9.14(s,2H),9.08(s,1H),2.74(s,3H).

[0397] [ka] 5-chloro-2'-methyl-2-vinyl-4,5'-bipyrimidine To a solution of the product from the previous step (1.9 g, 5.60 mmol, 1 eq) and potassium (vinyl)trifluoroborate (899.46 mg, 6.71 mmol, 1.2 eq) in dioxane (40 mL) and HO (10 mL) under N was added Pd(dppf)Cl (204.72 mg, 279.79 μmol, 0.05 eq) and CsCO (5.47 g, 16.79 mmol, 3 eq). After stirring at 80 °C for 16 h, the mixture was diluted with HO (100 mL), extracted with EtOAc (100 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether / EtOAc = 2 / 1) to give the title compound (1.1 g, 4.02 mmol, 71% yield) as a white solid. MS(ES+)C11 H9N4Cl Theoretical values: 232 and 234, Measured values: 233 and 235 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=9.16(s,2H),9.03(s,1H),7.01-6.78(m,1H),6.62(d,J=17.2Hz,1H),5.87(d,J=10.4Hz,1H),2.73(s,3H).

[0398] [ka] 5-chloro-2'-methyl-[4,5'-bipyrimidine]-2-carbaldehyde A stream of O was passed through a solution of the product from the previous step (1.1 g, 4.02 mmol, 1 eq) in CHCl (3 mL) and MeOH (1 mL) at −78 °C. After stirring at 25 °C for 10 min, MeS (3.45 g, 55.53 mmol, 4.08 mL, 13.82 eq) was added. The mixture was poured into water (20 mL), extracted with EtOAc (20 mL × 3), washed with brine (20 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: petroleum ether / EtOAc = 1 / 1) to give the title compound (870 mg, 3.45 mmol, 85% yield) as a white solid. MS (ES+) C 10 H7N4ClO Theoretical values: 234 and 236, Measured values: 235 and 237 [M+H] + .

[0399] [ka] 5-chloro-2'-methyl-[4,5'-bipyrimidine]-2-carboxylic acid To a solution of the product from the previous step (0.87 g, 3.71 mmol, 1 eq) in t-BuOH (8 mL) was added NaClO (1.01 g, 11.12 mmol, 3 eq) and NaHPO (355.88 mg, 2.97 mmol, 0.8 eq) in HO (2 mL). After stirring at 25 °C for 3 h, the mixture was quenched with saturated aqueous NaSO (10 mL), extracted with EtOAc (10 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (220 mg, 868.97 μmol, 23% yield). MS(ES+)C 10 H7N4O2Cl Theoretical values: 250 and 252, Measured values: 251 and 253 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=9.14(s,2H),8.97(s,1H),2.72(s,3H).

[0400] Intermediate A-50 [ka] 5-chloro-[4,5'-bipyrimidine]-2-carboxylic acid This compound was obtained using a procedure similar to that used for Intermediate A-49.

[0401] Intermediate A-51 [ka] 5-chloro-4-(3-methyl-1H-pyrazol-1-yl)pyrimidine-2-carboxylic acid [ka] 2,5-Dichloro-4-(3-methyl-1H-pyrazol-1-yl)pyrimidine To a solution of 2,4,5-trichloropyrimidine (3.58 g, 19.52 mmol, 1 eq) in CHCN (50 mL) was added 3-methyl-1H-pyrazole (1.60 g, 19.52 mmol, 1 eq) and KCO (4.05 g, 29.28 mmol, 1.5 eq) at 25 °C. After stirring at 25 °C for 16 h, the mixture was diluted with HO (30 mL), extracted with EtOAc (50 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: petroleum ether / EtOAc = 0 to 20 / 1) to give the title compound (2.5 g, 10.04 mmol, 51% yield) as a white solid. MS (ES+) C8H6N4Cl2 calculated: 228 and 230, found: 229 and 231 [M+H]. + . 1 H NMR(400MHz, CDCl3)δ=8.63(s,1H),8.45(d,J=2.7Hz,1H),6.35(d,J=2.7Hz,1H),2.41(s,3H).

[0402] [ka] 5-chloro-4-(3-methyl-1H-pyrazol-1-yl)-2-vinylpyrimidine To a solution of the product from the previous step (2.5 g, 10.91 mmol, 1 eq) in t-BuOH (30 mL) under N was added Pd(dppf)Cl (399.29 mg, 545.69 μmol, 0.05 eq), potassium (vinyl)trifluoroborate (1.75 g, 13.10 mmol, 1.2 eq), and EtN (1.66 g, 16.37 mmol, 2.28 mL, 1.5 eq) at 25 °C. After stirring at 60 °C for 16 h, the mixture was diluted with HO (30 mL), extracted with EtOAc (50 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether / EtOAc = 0 to 20 / 1) to give the title compound (1.5 g, 3.33 mmol, 30% yield). MS(ES+)C 10H9ClN4 Theoretical values: 220 and 222, Found values: 221 and 223 [M+H] + . 1 H NMR(400MHz,CDCl3)δ=8.74(s,1H),8.47(d,J=2.4Hz,1H),6.90-6.82(m,1H),6. 70-6.63(m,1H),6.35(d,J=2.8Hz,1H),5.81(dd,J=1.6,10.4Hz,1H),2.43(s,3H)

[0403] [ka] 5-chloro-4-(3-methyl-1H-pyrazol-1-yl)pyrimidine-2-carbaldehyde A stream of O3 was introduced into a solution of the product from the previous step (1.5 g, 3.33 mmol, 49% purity, 1 eq) in CHCl (15 mL) at −78 °C and bubbled for 0.5 h. After purging excess O3 with N, MeS (2.07 g, 33.31 mmol, 2.45 mL, 10 eq) was added at 25 °C. After stirring at 25 °C for 20 h, the mixture was diluted with H2O (30 mL), extracted with EtOAc (50 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: petroleum ether / EtOAc = 20 / 1 to 10 / 1) to give the title compound (400 mg, 1.51 mmol, 45% yield) as a yellow oil. MS (ES+) C9H7N4ClO Theoretical: 222 and 224, Found: 223 and 225 [M+H] + .

[0404] [ka] 5-chloro-4-(3-methyl-1H-pyrazol-1-yl)pyrimidine-2-carboxylic acid To a solution of the product from the previous step (400 mg, 1.80 mmol, 1 eq) in t-BuOH (2 mL), HO (0.5 mL), and dioxane (2 mL) was added NaHPO (172.45 mg, 1.44 mmol, 0.8 eq) and NaClO (487.49 mg, 5.39 mmol, 3 eq). After stirring at 25 °C for 3 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C). 18 The mixture was purified using a column chromatography column (250 × 50 mm × 15 μm; mobile phase: [water (0.225% FA)-CHCN]; B%: 18% to 48%, 10 min). The eluent was concentrated and lyophilized to give the title compound (100 mg, 419.06 μmol, 23% yield) as a white solid. MS (ES+) C9H7N4ClO2 Calculated: 238 and 240, Found: 239 and 241 [M+H] + . 1 H NMR(400MHz, CDCl3)δ=8.94(s,1H),8.62(d,J=2.8Hz,1H),6.42(d,J=2.8Hz,1H),2.44(s,3H).

[0405] Intermediate A-52 [ka] 2,5-Dichloro-4-(1,4-dioxan-2-yl)pyrimidine To a solution of 2,5-dichloropyrimidine (2.5 g, 16.78 mmol, 1 eq) and dioxane (29.57 g, 335.62 mmol, 28.71 mL, 20 eq) in CHCN (50 mL) was added OXONE® (13.61 g, 50.34 mmol, 10.08 mL, 3 eq) under N at 25 °C. After stirring at 120 °C for 16 h, the mixture was diluted with HO (30 mL), extracted with EtOAc (50 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether / EtOAc = 0 to 20 / 1) to give the title compound (2 g, 8.51 mmol, 50% yield) as a white solid. MS (ES+) C8H8N2Cl2O2 Calculated: 234 and 236, Found: 235 and 237 [M+H] + . 1 H NMR(400MHz,CDCl3)δ=8.50(s,1H),5.00(dd,J=2.6,9.8Hz,1H),4.00-3.95(m,1 H),3.95-3.83(m,2H),3.76(dd,J=2.3,8.1Hz,2H),3.68(dd,J=9.8,11.5Hz,1H)

[0406] [ka] 5-chloro-4-(1,4-dioxan-2-yl)-2-vinylpyrimidine To a solution of the product from the previous step (1.4 g, 5.96 mmol, 1 eq), potassium (vinyl)trifluoroborate (1.20 g, 8.93 mmol, 1.5 eq) in dioxane (15 mL) under N was added PPh (468.64 mg, 1.79 mmol, 0.3 eq), CsCO (3.88 g, 11.91 mmol, 2 eq), and Pd(OAc) (200.57 mg, 893.36 μmol, 0.15 eq) at 25 °C. After stirring at 60 °C for 16 h, the mixture was diluted with HO (30 mL), extracted with EtOAc (50 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: petroleum ether / EtOAc = 0 to 20 / 1) to give the title compound (1 g, 4.41 mmol, 74% yield) as a white solid. MS(ES+)C 10 H 11 N2ClO2 theoretical values: 226 and 228, observed values: 227 and 229 [M+H] +

[0407] [ka] 5-chloro-4-(1,4-dioxan-2-yl)pyrimidine-2-carbaldehyde A stream of O3 was introduced into a solution of the product from the previous step (1 g, 4.41 mmol, 100% purity, 1 eq) in CHCl (15 mL) and bubbled for 30 min at −78 °C. After purging excess O3 with N, MeS (2.74 g, 44.12 mmol, 3.24 mL, 10 eq) was added at 25 °C. After stirring for 20 h at 25 °C, the mixture was diluted with H0 (30 mL) and extracted with EtOAc (50 mL × 3). The combined organic phases were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: petroleum ether / EtOAc = 20 / 1 to 10 / 1) to give the title compound as a yellow oil. MS (ES+) C9H9N2ClO3 Calculated: 228 and 230, Found: 229 and 231 [M+H] + . 1H NMR(400MHz, CDCl3)δ=10.15(s,1H),8.93(s,1H),5.20(dd,J=2.7,9.7Hz,1H),4.14-4.05(m,4H),3.90-3.87(m,2H).

[0408] [ka] 5-chloro-4-(1,4-dioxan-2-yl)pyrimidine-2-carboxylic acid To a solution of the product from the previous step (120 mg, 524.86 μmol, 1 eq) in t-BuOH (1.2 mL), HO (0.3 mL) was added NaHPO (50.38 mg, 419.89 μmol, 0.8 eq) and NaClO (142.41 mg, 1.57 mmol, 3 eq) at 25 °C. After stirring at 50 °C for 16 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Synergi C 18 150×25 mm×10 μm; mobile phase: [water (0.1% TFA)-CH 3 CN]; B%: 8% to 38%, 10 min) to give the title compound (65 mg, 265.71 μmol, 50% yield) as a white solid. MS (ES+) C9H9N2ClO4 Calculated: 244 and 246, Found: 245 and 247 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=13.84(br s,1H),9.08(s,1H),4.99(dd,J=2.6,9.7Hz,1H),3.94(dt,J=2.5,11.2Hz,2H),3.84-3.74(m,3H),3.69-3.60(m,1H).

[0409] Intermediate A-53 [ka] 4-(1,4-dioxan-2-yl)-5-methylpyrimidine-2-carboxylic acid [ka] 2-chloro-4-(1,4-dioxan-2-yl)-5-methylpyrimidine To a solution of the product from the previous step (0.5 g, 3.89 mmol, 1 eq) in HO (5 mL) and CHCN (10 mL) under N was added dioxane (6.85 g, 77.78 mmol, 6.65 mL, 20 eq) and OXONE® (3.15 g, 11.67 mmol, 3 eq). After stirring at 120 °C for 16 h, the mixture was cooled to 25 °C, diluted with water (20 mL), and extracted with EtOAc (20 mL × 3). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ISCO®; 14 g SepaFlash® silica flash column, eluent: 0–20% EtOAc / petroleum ether gradient at 30 mL / min) to afford the title compound (400 mg, 1.86 mmol, 47% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ=8.33(s,1H),4.71(dd,J=2.8,9.8Hz,1H),3.94-3.87(m,2H),3.87-3.79(m,2H),3.76-3.68(m,2H),2.31(s,3H).

[0410] [ka] 4-(1,4-dioxan-2-yl)-5-methylpyrimidine-2-carboxylic acid To a mixture of the product from the previous step (400 mg, 1.86 mmol, 1 eq) in DMF (6 mL) and HO (1 mL) under N was added dppp (76.86 mg, 186.35 μmol, 0.1 eq), Pd(OAc) (41.84 mg, 186.35 μmol, 0.1 eq), and EtN (377.13 mg, 3.73 mmol, 518.75 μL, 2 eq). The suspension was degassed under vacuum and purged with CO three times. After stirring at 80 °C under CO (45 psi) for 16 h, the mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL), basified with 1 M aqueous NaOH to pH 13, and extracted with EtOAc (20 mL × 3). The aqueous phase was acidified with HCl (1 M) to adjust the pH to 1, then extracted with EtOAc (20 mL × 3), washed with brine (20 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (600 mg, crude) as a gray solid. MS(ES+)C 10 H 12 N2O4 theoretical value: 224, measured value: 225 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=12.90(br s,1H),8.78(s,1H),4.85(dd,J=2.4,9.7Hz,1H),4.07-3.71(m,5H),3.68-3.55(m,1H),2.43(s,3H).

[0411] Intermediate A-54 [ka] 4-(1H-benzo[d]imidazol-4-yl)-5-chloropyrimidine-2-carboxylic acid [ka] 4-Bromo-1-(p-toluenesulfonyl)-1H-benzo[d]imidazole To a solution of 4-bromo-1H-benzo[d]imidazole (4 g, 20.30 mmol, 1 eq) in THF (40 mL) was added NaH (1.22 g, 30.45 mmol, 60 wt% dispersion, 1.5 eq) at 0 °C. After stirring at 0 °C for 30 min under N2, 4-methylbenzenesulfonyl chloride (4.64 g, 24.36 mmol, 1.2 eq) was added to the reaction mixture. After stirring at 25 °C for 16 h, the reaction mixture was quenched with saturated aqueous NH4Cl (10 mL) and then extracted with EtOAc (50 mL × 3). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether / EtOAc = 0 to 20 / 1) to give the title compound (4 g, 11.39 mmol, 56% yield) as a white solid. MS(ES+)C 14 H 11 N2SO2Br Theoretical values: 350 and 352, Measured values: 351 and 353 [M+H + ]. 1 H NMR(400MHz,CDCl3)δ=8.37(s,1H),7.80(d,J=8.4Hz,2H),7.75(d,J=8.3Hz, 1H),7.48(d,J=7.9Hz,1H),7.25(d,J=8.3Hz,2H),7.21(s,1H),2.33(s,3H).

[0412] [ka] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(p-toluenesulfonyl)-1H-benzo[d]imidazole To a solution of the product from the previous step (2 g, 5.69 mmol, 1 eq) in dioxane (20 mL) was added BPD (1.74 g, 6.83 mmol, 1.2 eq), Pd(dppf)Cl (208.33 mg, 284.72 μmol, 0.05 eq), and AcOK (838.30 mg, 8.54 mmol, 1.5 eq) at 25 °C. After stirring at 120 °C under N for 16 h, the mixture was concentrated under reduced pressure to give the title compound (4.0 g, crude). MS(ES+)C20 H 23 N2SO4B Theoretical value: 398, Measured value: 399 [M+H] +

[0413] [ka] 4-(2,5-Dichloropyrimidin-4-yl)-1-(p-toluenesulfonyl)-1H-benzo[d]imidazole To a solution of the product from the previous step (4 g, 10.04 mmol, 1 eq), 2,4,5-trichloropyrimidine (1.84 g, 10.04 mmol, 1 eq) in THF (40 mL) and HO (4 mL) was added NaCO (1.06 g, 10.04 mmol, 1 eq) and Pd(PPh) (11.61 g, 10.04 mmol, 1 eq) at 25 °C. After stirring at 60 °C under N for 16 h, the mixture was diluted with HO (30 mL) and then extracted with EtOAc (50 mL × 3). The combined organic phases were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether / EtOAc = 0 to 20 / 1) to give the title compound (3.7 g, 7.59 mmol, 75% yield) as a yellow oil. MS (ES+) C 18 H 12 N4Cl2SO2 theoretical values: 418 and 420, observed values: 419 and 421 [M+H] + .

[0414] [ka] 4-(5-chloro-2-methylpyrimidin-4-yl)-1-(p-toluenesulfonyl)-1H-benzo[d]imidazole To a solution of the product from the previous step (3.7 g, 8.82 mmol, 1 eq) in THF (40 mL) was added Pd(PPh3)4 (509.87 mg, 441.23 μmol, 0.05 eq) and Al(CH3)3 (2 M toluene solution, 8.82 mL, 2 eq) at 25 °C. After stirring at 100 °C under N2 for 5 h, the mixture was diluted with HO (30 mL) and then extracted with EtOAc (50 mL × 3). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: petroleum ether / EtOAc = 0 to 20 / 1) to give the title compound (1.5 g, 3.01 mmol, 34% yield) as a yellow oil. MS(ES+)C 19 H 15 N4ClSO2MS (ES+) Theoretical values: 398 and 400, Found values: 399 and 401 [M+H + ]. 1 H NMR(400MHz,CDCl3)δ=8.73(s,1H),8.42(s,1H),8.01(dd,J=1.4,7.9Hz,1H),7.90(d,J=8.4H) z,2H),7.72-7.63(m,1H),7.57-7.53(m,1H),7.34(d,J=8.2Hz,2H),2.77(s,3H),2.41(s,3H).

[0415] [ka] 4-(5-chloro-2-methylpyrimidin-4-yl)-1H-benzo[d]imidazole To a solution of the product from the previous step (1.5 g, 3.76 mmol, 1 eq) in ethanol (15 mL) and HO (1.5 mL) was added NaOH (752.13 mg, 18.80 mmol, 5 eq) at 25 °C. After stirring at 60 °C for 1 h, the mixture was diluted with HO (30 mL) and then extracted with EtOAc (50 mL × 3). The combined organic phases were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: petroleum ether / EtOAc = 20 / 1 to 10 / 1) to give the title compound (630 mg, 2.32 mmol, 61% yield) as a white solid. MS(ES+)C 12 H9N4Cl Theoretical values: 244 and 246, Measured values: 245 and 247 [M+H] + . 1 H NMR(400MHz, CDCl3)δ=8.81-8.72(m,1H),8.35(d,J=7.8Hz,1H),8.28(s,1H),7.99(d,J=7.9Hz,1H),7.47-7.41(m,1H),2.85(s,3H).

[0416] [ka] 4-(5-chloro-2-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole To a solution of the product from the previous step (600 mg, 2.45 mmol, 1 eq) in THF (6 mL) was added NaH (147.13 mg, 3.68 mmol, 60% purity, 1.5 eq) at 0 °C. After stirring at 0 °C for 30 min, SEM-Cl (490.60 mg, 2.94 mmol, 520.80 μL, 1.2 eq) was added to the reaction mixture. After stirring at 25 °C for 16 h, the reaction mixture was quenched with saturated NH4Cl (5 mL) solution at 0 °C, diluted with HO (20 mL), and extracted with EtOAc (50 mL × 3). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether / EtOAc = 20 / 1 to 10 / 1) to give the title compound (700 mg, 1.59 mmol, 64% yield) as a yellow solid. MS(ES+)C 18 H 23 N4ClSiO Theoretical values: 374 and 376, Measured values: 375 and 377 [M+H] + . 1 H NMR(400MHz,CDCl3)δ=8.76(s,1H),8.18(s,1H),7.99(d,J=7.8Hz,1H),7.44(d,J=7.8Hz,1H), 7.42-7.38(m,1H),5.35(s,2H),3.14-3.07(m,2H),2.8(s,3H),0.67-0.60(m,2H),0.11(s,9H).

[0417] [ka] 5-chloro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)-pyrimidine-2-carboxylic acid To a solution of the product from the previous step (0.7 g, 1.87 mmol, 1 eq) in pyridine (7 mL) and HO (1.5 mL) was added SeO (725.06 mg, 6.53 mmol, 3.5 eq). After stirring at 120 °C for 144 h, the reaction mixture was concentrated under reduced pressure. The residue was diluted with HO (20 mL). The pH of the mixture was adjusted to 10 with aqueous NaOH (1 M). After washing with EtOAc (20 mL × 3), the pH of the aqueous phase was adjusted to 2 with aqueous HCl (1 M). The aqueous phase was extracted with EtOAc (20 mL × 3). The combined organic phase was dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (100 mg, 219.80 μmol, 11% yield) as a yellow solid. MS(ES+)C 18 H 21 N4ClO3Si Theoretical values: 404 and 406, Measured values: 405 and 407 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ =9.24(s,1H),8.43(s,1H),7.90(dd,J=1.2,7.8Hz,1H),7.48-7.44(m,1H),7.1 3-7.08(m,1H),5.38(s,2H),2.69-2.64(m,2H),1.23-1.19(m,2H),0.18(s,9H).

[0418] [ka] 4-(1H-benzo[d]imidazol-4-yl)-5-chloropyrimidine-2-carboxylic acid To a solution of the product from the previous step (100.00 mg, 246.96 μmol, 1 eq) in CHCl (1 mL) was added TFA (1.13 g, 9.88 mmol, 731.41 μL, 40 eq). After stirring at 25° C. for 16 h, the reaction mixture was concentrated under reduced pressure. The residue was triturated with EtOAc (1 mL) at 25° C. for 30 min, and the solid was removed by filtration to give the title compound (40 mg, 116.51 μmol, 47% yield) as a colorless solid. 1H NMR(400MHz,DMSO-d6)δ=10.92(br s,0.5H),10.64(br s,0.5H),9.28(s,1H),8.02(d,J=8.2Hz,1H),7.82(d,J=7.3Hz,1H),7.72-7.62(m,1H),7.11(s,1H).

[0419] Intermediate A-55 [ka] 5-(S-methylsulfonimidoyl)-4-phenylpyrimidine-2-carboxylic acid [ka] 2-chloro-5-(methylthio)-4-phenylpyrimidine To 2,4-dichloro-5-(methylthio)pyrimidine (4.7 g, 24.09 mmol, 1 eq) and phenylboronic acid (3.53 g, 28.91 mmol, 1.2 eq) in THF (50 mL) and HO (5 mL) under N was added NaCO (2.55 g, 24.09 mmol, 1 eq), PPh (252.78 mg, 963.76 μmol, 0.04 eq), and Pd(OAc) (108.19 mg, 481.88 μmol, 0.02 eq) at 25 °C. After stirring at 60 °C for 16 h, the mixture was diluted with HO (30 mL), extracted with EtOAc (50 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: ether / EtOAc = 0 to 20 / 1) to give the title compound (4.2 g, 14.73 mmol, 61% yield) as a yellow solid. MS(ES+)C 11 H9ClN2S Theoretical values: 236 and 238, Measured values: 237 and 239 [M+H + ]. 1 H NMR(400MHz, CDCl3)δ=8.49(s,1H),7.82-7.78(m,2H),7.54-7.50(m,3H),2.47(s,3H).

[0420] [ka] Methyl 5-(methylthio)-4-phenylpyrimidine-2-carboxylate To a solution of the product from the previous step (1.5 g, 6.34 mmol, 1 eq) in MeOH (20 mL) was added Pd(dppf)Cl (231.83 mg, 316.83 μmol, 0.05 eq) and EtN (1.28 g, 12.67 mmol, 1.76 mL, 2 eq) at 25 °C. The mixture was stirred at 60 °C under CO (45 psi) for 16 h, then diluted with HO (30 mL), extracted with EtOAc (50 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether / EtOAc = 0 to 20 / 1) to give the title compound (700 mg, 2.18 mmol, 34% yield) as a yellow solid. MS(ES+)C 13 H 12 N2O2S Theoretical value: 260, Measured value: 261 [M+H] + . 1 H NMR(400MHz,CDCl3)δ=8.61(s,1H),7.74-7.67(m,2H),7.47-7.39(m,3H),4.00-3.96(m,3H),2.47(s,3H)

[0421] [ka] Methyl 5-(S-methylsulfonimidoyl)-4-phenylpyrimidine-2-carboxylate To a solution of the product from the previous step (100 mg, 384.16 μmol, 1 eq) in MeOH (1 mL) and THF (20 mL) under N was added PhI(OAc) (247.47 mg, 768.31 μmol, 2 eq) and ammonium carbamate (89.97 mg, 1.15 mmol, 3 eq) at 25 °C. After stirring at 60 °C for 20 h, the mixture was diluted with HO (30 mL) and then extracted with EtOAc (50 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: petroleum ether / EtOAc = 20 / 1 to 10 / 1) to give the title compound (60 mg, 199.78 μmol, 52% yield) as a white solid. MS(ES+)C 13 H 13 N3SO3 theoretical value: 291, measured value: 292 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=9.51(s,1H),7.71-7.66(m,2H),7.62-7.52(m,3H),4.99(br s,1H),3.95(s,3H),2.92(s,3H).

[0422] [ka] 5-(S-methylsulfonimidoyl)-4-phenylpyrimidine-2-carboxylic acid To a solution of the product from the previous step (50 mg, 171.63 μmol, 1 eq) in THF (1 mL) and HO (0.5 mL) was added LiOH (8.22 mg, 343.26 μmol, 2 eq). After stirring at 25 °C for 1 h, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL), basified with aqueous NaOH (1 M) to adjust the pH to 10, and extracted with EtOAc (20 mL × 3). The aqueous phase was then acidified with aqueous HCl (1 M) to adjust the pH to 2, extracted with EtOAc (20 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (30 mg, 97.37 μmol, 56% yield) as a white solid. MS(ES+)C 12 H11 N3SO3 theoretical value: 277, actual value: 278 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=9.47(s,1H),7.72-7.66(m,2H),7.58-7.50(m,3H),4.94(br s,1H),2.92(s,3H).

[0423] Intermediate A-56 [ka] 4-(3-(((tert-butyldimethylsilyl)oxy)methyl)-2,4-difluorophenyl)-5-chloropyrimidine-2-carboxylic acid [ka] 3-(2,5-Dichloropyrimidin-4-yl)-2,6-difluorobenzaldehyde To a solution of (2,4-difluoro-3-formylphenyl)boronic acid (5 g, 26.89 mmol, 1 eq) and 2,4,5-trichloropyrimidine (4.93 g, 26.89 mmol, 3.08 mL, 1 eq) in THF (80 mL) and HO (20 mL) was added Pd(OAc) (120.75 mg, 537.86 μmol, 0.02 eq), PPh (282.15 mg, 1.08 mmol, 0.04 eq), and NaCO (5.70 g, 53.79 mmol, 2 eq) under N. After stirring at 60 °C for 16 h, the reaction mixture was concentrated to remove THF, then diluted with HO (100 mL), extracted with EtOAc (100 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: petroleum ether / EtOAc = 40 / 1) to give the title compound (2.6 g, 7.92 mmol, 29% yield) as a yellow oil. MS(ES+)C 11 H4F2ON2Cl2 Theoretical values: 288 and 290, Measured values: 289 and 291 [M+H] + .

[0424] [ka] (3-(2,5-dichloropyrimidin-4-yl)-2,6-difluorophenyl)methanol To a solution of the product from the previous step (2.3 g, 7.00 mmol, 1 eq) in THF (40 mL) under N was added DIBAL-H (1 M in toluene, 21.01 mL, 3 eq) at 0 °C. After stirring at 0 °C for 2 h, the mixture was quenched with HO (100 mL), extracted with EtOAc (100 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: petroleum ether / EtOAc = 5 / 1) to give the title compound (1.5 g, 4.07 mmol, 58% yield) as a colorless oil. MS (ES+) C 11 H6F2ON2Cl2 Theoretical values: 290 and 292, Found values: 291 and 293 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=9.09(s,1H),7.72-7.55(m,1H),7.41-7.24(m,1H),4.58(s,2H).

[0425] [ka] 4-(3-(((tert-butyldimethylsilyl)oxy)methyl)-2,4-difluorophenyl)-2,5-dichloropyrimidine To a solution of the product from the previous step (1.4 g, 3.80 mmol, 79% purity, 1 eq) in CHCl (20 mL) was added DMAP (92.84 mg, 759.93 μmol, 0.2 eq), EtN (768.96 mg, 7.60 mmol, 1.06 mL, 2 eq), and TBSCl (1.15 g, 7.60 mmol, 931.20 μL, 2 eq). After stirring at 25 °C for 16 h, the mixture was diluted with HO (50 mL), extracted with CHCl (50 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: petroleum ether / EtOAc = 2 / 1) to give the title compound (1.6 g, 3.75 mmol, 98% yield) as a colorless oil. MS(ES+)C 17 H 20 N2OF2Cl2Si Theoretical values: 404 and 406, Measured values: 405 and 407 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=9.01(s,1H),7.65-7.51(m,1H),7.27(t,J=8.6Hz,1H),4.71(s,2H),0.79-0.74(m,9H),0.00(s,6H).

[0426] [ka] 4-(3-(((tert-butyldimethylsilyl)oxy)methyl)-2,4-difluorophenyl)-5-chloro-2-methylpyrimidine To a solution of the product from the previous step (1.6 g, 3.95 mmol, 1 eq) in THF (20 mL) under N was added AlMe (2 M in toluene, 2.96 mL, 1.5 eq) and Pd(PPh) (228.07 mg, 197.36 μmol, 0.05 eq). After stirring at 60 °C under N for 16 h, the mixture was quenched with HO (50 mL), extracted with EtOAc (50 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: petroleum ether / EtOAc = 10 / 1) to give the title compound (1.2 g, 2.96 mmol, 75% yield) as a colorless oil. MS (ES+) C 18 H 23 N2OClF2Si Theoretical values: 384 and 386, Measured values: 385 and 387 [M+H] + .

[0427] [ka] 5-chloro-4-(2,4-difluoro-3-(hydroxymethyl)phenyl)pyrimidine-2-carboxylic acid To a solution of the product from the previous step (1.2 g, 3.12 mmol, 1 eq) in pyridine (10 mL) and HO (1 mL) was added SeO (1.73 g, 15.59 mmol, 5 eq). After stirring at 120 °C for 16 h, the mixture was filtered and the filtrate was concentrated. The residue was diluted with HO (50 mL), acidified with aqueous HCl (1 M) to adjust the pH to 2–3, and extracted with EtOAc (50 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated to give the title compound (1.86 g, crude) as a yellow oil. MS(ES+)C 12 H7N2O3ClF2 Theoretical values: 300 and 302, Measured values: 301 and 303 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=9.22(s,1H),7.68-7.58(m,1H),7.32(t,J=8.8Hz,1H),4.59(s,2H).

[0428] [ka] 4-(3-(((tert-butyldimethylsilyl)oxy)methyl)-2,4-difluorophenyl)-5-chloropyrimidine-2-carboxylic acid To a solution of the product from the previous step (1.86 g, 6.19 mmol, 1 eq) in CHCl (20 mL) was added DMAP (151.16 mg, 1.24 mmol, 0.2 eq), EtN (1.25 g, 12.37 mmol, 1.72 mL, 2 eq), and TBSCl (1.86 g, 12.37 mmol, 1.52 mL, 2 eq). After stirring at 25 °C for 16 h, the mixture was concentrated to remove CHCl, diluted with HO (40 mL), and extracted with EtOAc (40 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CHCl / methanol = 10 / 1) to give the title compound (600 mg, 1.45 mmol, 23% yield) as a white solid. MS(ES+)C 18 H 21N2O3ClF2Si Theoretical values: 414 and 416, Measured values: 415 and 417 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=8.96(s,1H),7.70-7.47(m,1H),7.32(t,J=8.6Hz,1H),4.78(s,2H),0.85(s,9H),0.08(s,6H).

[0429] Intermediate A-57 [ka] 5-chloro-4-(1H-indazol-4-yl)pyrimidine-2-carboxylic acid [ka] 4-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole To a solution of 4-bromo-1H-indazole (5 g, 25.38 mmol, 1 eq) in THF (40 mL) was added 4-methylbenzenesulfonic acid (436.99 mg, 2.54 mmol, 0.1 eq) and DHP (4.27 g, 50.75 mmol, 4.64 mL, 2 eq). After stirring at 70 °C for 16 h, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: 0–30% EtOAc / petroleum ether gradient at 30 mL / min) to afford the title compound (7 g, 24.90 mmol, 98% yield) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ=8.06(s,1H),7.57(d,J=8.4Hz,1H),7.40-7.31(m,1H),7.29-7.21(m,1H),5.73(dd,J=2 .8,9.2Hz,1H),4.09-3.95(m,1H),3.87-3.66(m,1H),2.68-2.47(m,1H),2.25-2.07(m,2H),1.94-1.60(m,3H).

[0430] [ka] 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole To a solution of the product from the previous step (7 g, 24.90 mmol, 1 eq) in dioxane (70 mL) under N2, BPD (9.48 g, 37.35 mmol, 1.5 eq), AcOK (7.33 g, 74.69 mmol, 3 eq), and Pd(dppf)Cl2·CHCl2 (1.02 g, 1.24 mmol, 0.05 eq) were added. After stirring at 100 °C for 3 h, the mixture was concentrated under reduced pressure to give the title compound (8.17 g, 24.89 mmol, 100% yield) as a black oil. MS (ES+) C 18 H 25 BN2O3 theoretical value: 328, measured value: 329 [M+H] +

[0431] [ka] To a solution of 1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (8.17 g, 24.89 mmol, 1 eq) in dioxane (80 mL) and HO (15 mL) was added 2,4,5-trichloropyrimidine (5.48 g, 29.87 mmol, 1.2 eq), Pd(dppf)Cl (1.82 g, 2.49 mmol, 0.1 eq), and KCO (10.32 g, 74.68 mmol, 3 eq) under N. After stirring at 60 °C for 16 h, the mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic phase was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent of 0-20% EtOAC / petroleum ether gradient at 50 mL / min) to give the title compound (7.9 g, 22.62 mmol, 90% yield) as a white solid. 1H NMR(400MHz,CDCl3)δ=8.75(s,1H),8.19(d,J=0.6Hz,1H),7.83(d,J=8.5Hz,1H),7.70(d,J=6.7Hz,1H),7.53(dd,J=7.3,8.4Hz, 1H),5.82(dd,J=2.8,9.0Hz,1H),4.08-4.01(m,1H),3.89-3.68(m,1H),2.74-2.48(m,1H),2.32-2.08(m,2H),1.89-1.58(m,3H).

[0432] [ka] 4-(5-chloro-2-vinylpyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole To a solution of the product from the previous step (3 g, 8.59 mmol, 1 eq) in dioxane (30 mL) and HO (6 mL) under N was added potassium (vinyl)trifluoroborate (1.38 g, 10.31 mmol, 1.2 eq), CsCO (5.60 g, 17.18 mmol, 2 eq), Pd(OAc) (289.30 mg, 1.29 mmol, 0.15 eq), and PPh (675.97 mg, 2.58 mmol, 0.3 eq). After stirring at 110 °C for 16 h, the mixture was diluted with water (50 mL), extracted with EtOAc (50 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent of 0-20% EtOAC / petroleum ether gradient at 50 mL / min) to give the title compound (0.9 g, 2.64 mmol, 30% yield) as a colorless oil. 1H NMR(400MHz,CDCl3)δ=8.82(s,1H),8.19(s,1H),7.79(d,J=8.5Hz,1H),7.69(d,J=7.2Hz,1H),7.53(dd,J=7.3,8.4Hz,1H),6.96(dd,J=10.5,17.3Hz, 1H),6.71(dd,J=1.6,17.3Hz,1H),5.87-5.76(m,2H),4.10-4.02(m,1H),3 .84-3.75(m,1H),2.74-2.55(m,1H),2.30-2.09(m,2H),1.91-1.65(m,3H).

[0433] [ka] 4-(5-chloro-2-vinylpyrimidin-4-yl)-1H-indazole To a solution of the product from the previous step (800 mg, 2.35 mmol, 1 eq) in CHCl (10 mL) was added TfOH (5 mL). After stirring at 25 °C for 2 h, the mixture was neutralized with saturated aqueous NaCO (20 mL), extracted with EtOAc (20 mL × 3), and the combined organic phases were washed with brine (50 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (1.7 g, crude) as a yellow solid. MS (ES+) C 13 H9N4Cl Theoretical values: 256 and 258, Measured values: 257 and 259 [M+H] + .

[0434] [ka] Benzyl 4-(5-chloro-2-vinylpyrimidin-4-yl)-1H-indazole-1-carboxylic acid To a solution of the product from the previous step (1.7 g, 6.62 mmol, 1 eq) in THF (10 mL) under N was added NaH (317.86 mg, 7.95 mmol, 60% in mineral oil, 1.2 eq) at 0 °C. After stirring at 0 °C for 0.5 h, CbzCl (1.69 g, 9.93 mmol, 1.41 mL, 1.5 eq) was added to the mixture. After stirring at 25 °C for 3 h, the mixture was quenched with saturated aqueous NH Cl (10 mL), which was extracted with EtOAc (10 mL × 3), and the combined organic phases were dried over Na SO , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ISCO®; 10 g SepaFlash® silica flash column, eluent of 0-20% EtOAC / petroleum ether gradient at 30 mL / min) to give the title compound (0.9 g, 2.30 mmol, 34% yield) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ=8.84(s,1H),8.44(d,J=8.5Hz,1H),8.38(s,1H),7.85(d,J=7.5Hz,1H),7.69(dd,J=7.5,8.3Hz,1H),7.61-7.5 6(m,2H),7.48-7.30(m,3H),6.95(dd,J=10.5,17.3Hz,1H),6.70(dd,J=1.6,17.4Hz,1H),5.83(dd,J=1.5,10.5Hz,1H),5.60(s,2H).

[0435] [ka] Benzyl 4-(5-chloro-2-formylpyrimidin-4-yl)-1H-indazole-1-carboxylate A stream of O3 was passed through a cooled (-78 °C) solution of the product from the previous step (900 mg, 2.30 mmol, 1 eq) in MeOH (3 mL) and CHCl (10 mL). After stirring at -78 °C for 15 min, the mixture was purged with N, and MeS (1.78 g, 28.65 mmol, 2.10 mL, 12.44 eq) was added to the mixture, which was then stirred at 25 °C for 3 h. The mixture was concentrated under reduced pressure, diluted with EtOAc (10 mL), washed with brine (10 mL x 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ISCO®; 10 g SepaFlash® silica flash column, eluting with a 0-50% EtOAc / petroleum ether gradient at 50 mL / min) to give the title compound (300 mg, crude) as a colorless oil. MS (ES+) C 20 H 13 N4ClO3 theoretical values: 392 and 394, observed values: 393 and 395 [M+H] +

[0436] [ka] 4-(1-((benzyloxy)carbonyl)-1H-indazol-4-yl)-5-chloropyrimidine-2-carboxylic acid To a solution of the product from the previous step (250 mg, 636.46 μmol, 1 eq) in t-BuOH (6 mL) and HO (1.5 mL) was added NaHPO (61.09 mg, 509.17 μmol, 0.8 eq) and sodium chlorite (172.69 mg, 1.91 mmol, 3 eq). After stirring at 25 °C for 3 h, the mixture was poured into water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic phases were concentrated under reduced pressure to give the title compound (100 mg, 244.62 μmol, 38% yield) as a white solid. 1H NMR(400MHz,CDCl3)δ=8.93-8.86(m,1H),8.46(d,J=2.1Hz,1H),8.32(dd,J=2.1,6. 8Hz,1H),7.78(d,J=7.1Hz,2H),7.61-7.53(m,2H),7.49-7.35(m,3H),5.56(s,2H).

[0437] [ka] 5-chloro-4-(1H-indazol-4-yl)pyrimidine-2-carboxylic acid To a solution of the product from the previous step (100 mg, 244.62 μmol, 1 eq) in CHCl (0.2 mL) was added TFA (2.79 g, 24.46 mmol, 1.81 mL, 100 eq). After stirring at 40° C. for 0.5 h, the mixture was concentrated under reduced pressure to give the trifluoroacetate salt of the title compound (90 mg, 231.55 μmol, 94% yield) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ=13.42(s,1H),9.10(s,1H),8.17(s,1H),7.77(br d,J=8.4Hz,1H),7.60(br d,J=7.0Hz,1H),7.57-7.48(m,1H).

[0438] Intermediate A-58 [ka] 5-chloro-4-(imidazo[1,2-a]pyridin-6-yl)pyrimidine-2-carboxylic acid [ka] 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine A mixture of 6-bromoimidazo[1,2-a]pyridine (5 g, 25.38 mmol, 1 eq), BPD (7.09 g, 27.91 mmol, 1.1 eq), Pd(dppf)Cl (1.86 g, 2.54 mmol, 0.1 eq), and AcOK (7.47 g, 76.13 mmol, 3 eq) in dioxane (50 mL) was degassed and purged with N three times, then the mixture was stirred under N at 90 °C for 6 h. The reaction mixture was filtered, and the filter cake was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure to give the title compound (6 g, crude) as a brown solid. MS (ES+) C 13 H 17 BN2O2 theoretical value: 162, measured value: 163 [M-pinacol + H] + ,

[0439] [ka] 6-(2,5-dichloropyrimidin-4-yl)imidazo[1,2-a]pyridine A mixture of 2,4,5-trichloropyrimidine (5.41 g, 29.50 mmol, 1.2 eq), the product from the previous step (6 g, 24.58 mmol, 1 eq), K2CO3 (10.19 g, 73.74 mmol, 3 eq), and Pd(dppf)Cl2 (1.80 g, 2.46 mmol, 0.1 eq) in water (10 mL) and dioxane (100 mL) was degassed and purged with N2 three times, then the mixture was stirred under N2 at 60 °C for 16 h. The mixture was diluted with EtOAc (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (80 g SepaFlash® silica flash column, eluent: 80-90% EtOAC / petroleum ether gradient at 100 mL / min) to give the title compound (700 mg, 2.11 mmol, 8% yield) as a yellow solid. MS(ES+)C 11 H6Cl2N4 Theoretical values: 264 and 266, Found values: 265 and 267 [M+H] + ,

[0440] [ka] Methyl 5-chloro-4-(imidazo[1,2-a]pyridin-6-yl)pyrimidine-2-carboxylate To a solution of the product from the previous step (200 mg, 754.44 μmol, 1 eq) in MeOH (4 mL) was added Pd(dppf)Cl (55.20 mg, 75.44 μmol, 0.1 eq) and EtN (229.02 mg, 2.26 mmol, 315.03 μL, 3 eq) under N. The suspension was degassed under vacuum and purged with CO three times. After stirring at 50 °C under CO (15 psi) for 5 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: [water (0.225% FA)-CHCN]; B%: 0%–10%, 7 min). The eluent was concentrated and lyophilized to give the title compound (80 mg, 271.57 μmol, 36% yield) as a white solid. MS(ES+)C 13 H9ClNO2 Theoretical values: 288 and 290, Measured values: 289 and 291 [M+H] + ,

[0441] [ka] 5-chloro-4-(imidazo[1,2-a]pyridin-6-yl)pyrimidine-2-carboxylic acid To a solution of the product from the previous step (50 mg, 173.20 μmol, 1 eq) in THF (1 mL) and HO (0.2 mL) was added LiOH·HO (21.80 mg, 519.59 μmol, 3 eq). After stirring at 20 °C for 2 h, the mixture was neutralized to pH = 6 with aqueous HCl (1 M) and concentrated under reduced pressure to give the title compound (50 mg, crude) as a white solid. MS (ES+) C 12 H7ClNO2 Theoretical values: 274 and 276, Measured values: 275 and 277 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ=9.35-9.30(m,1H),9.18(s,1H),8.27-8.23(m,1H),7.84-7.74(m,3H)

[0442] Intermediate A-59 [ka] 4-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-5-chloropyrimidine-2-carboxylic acid This compound was obtained using a procedure similar to that used for intermediate A-58.

[0443] Intermediate A-60 [ka] 4-(1-(tert-butoxycarbonyl)-4,4-difluoropiperidin-2-yl)-5-methylpyrimidine-2-carboxylic acid [ka] tert-Butyl 2-(2-chloro-5-methylpyrimidin-4-yl)-4-oxopiperidine-1-carboxylate An oven-dried 40 mL vial equipped with a magnetic stir bar was charged with 2,4-dichloro-5-methylpyrimidine (500 mg, 3.07 mmol, 1 eq), 1-tert-butoxycarbonyl-4-oxopiperidine-2-carboxylic acid (970.01 mg, 3.99 mmol, 1.3 eq), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (34.41 mg, 30.67 μmol, 0.01 eq), NiCl2·dtbbpy (61.04 mg, 153.37 μmol, 0.05 eq), Cs2CO3 (1.50 g, 4.60 mmol, 1.5 eq), and DMA (35 mL) under N2. The reaction mixture was then stirred and irradiated with two 34 W blue LED lamps (approximately 7 cm distance) to maintain the reaction temperature at 25 °C for 14 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (50 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (40 g SepaFlash® silica flash column, eluent: 10–25% EtOAc / petroleum ether gradient at 60 mL / min) to afford the title compound (390 mg, 1.20 mmol, 78% yield) as a yellow oil. MS(ES+)C 15 H 20 ClN3O3 theoretical values: 325 and 327, measured values: 326 and 328 [M+H] + . 1 H NMR(400MHz,CDCl3)δ=8.39(s,1H),5.88-5.45(m,1H),4.23-4.11(m,1H),3.70 -3.43(m,1H),2.75-2.64(m,3H),2.59-2.44(m,1H),2.35(s,3H),1.43(s,9H).

[0444] [ka] tert-Butyl 2-(2-chloro-5-methylpyrimidin-4-yl)-4,4-difluoropiperidine-1-carboxylate A solution of the product from the previous step (340 mg, 1.04 mmol, 1 eq) in DAST (3.66 g, 22.71 mmol, 3 mL, 21.76 eq) was stirred at -20 °C for 0.5 h. The mixture was warmed to 20 °C and stirred for 6 h. The reaction mixture was quenched by the addition of aqueous NaCO (100 mL, 1 M) at 0 °C and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (30 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20 g SepaFlash® silica flash column, eluent: 10–30% EtOAc / petroleum ether gradient at 30 mL / min) to give the title compound (100 mg, 287.53 μmol, 27% yield) as a yellow oil. MS (ES+) C 15 H 20 ClF2N3O2 theoretical value: 347 and 349, measured value: 348 and 350 [M+H] + .

[0445] [ka] Methyl 4-(1-(tert-butoxycarbonyl)-4,4-difluoropiperidin-2-yl)-5-methylpyrimidine-2-carboxylate To a solution of the product from the previous step (80 mg, 230.03 μmol, 1 eq) in MeOH (5 mL) under N was added Pd(dppf)Cl (16.83 mg, 23.00 μmol, 0.1 eq) and EtN (69.83 mg, 690.08 μmol, 96.05 μL, 3 eq). The suspension was degassed under vacuum and purged with CO several times. The mixture was stirred under CO (15 psi) at 50 °C for 6 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (10 g SepaFlash® silica flash column, eluent: 20–40% EtOAc / petroleum ether gradient at 30 mL / min) to give the title compound (80 mg, 202.49 μmol, 88% yield) as a yellow oil. MS (ES+) C 17 H 23 F2N3O4 theoretical value: 371, measured value 372 [M+H]+ . 1 H NMR(400MHz,CDCl3)δ=8.61(s,1H),5.54-5.37(m,1H),4.23-4.12(m,2H),4 .02(s,3H),2.51-2.43(m,2H),2.42(s,3H),2.22-2.07(m,2H),1.34(s,9H).

[0446] [ka] 4-(1-(tert-butoxycarbonyl)-4,4-difluoropiperidin-2-yl)-5-methylpyrimidine-2-carboxylic acid To a solution of the product from the previous step (40 mg, 107.71 μmol, 1 eq) in THF (1 mL) was added a solution of LiOH·HO (13.56 mg, 323.12 μmol, 3 eq) in HO (0.2 mL). After stirring at 20 °C for 2 h, the mixture was neutralized to pH = 7 with aqueous HCl (1 M) and concentrated under reduced pressure to give the title compound (crude) as a white solid. MS (ES+) C 16 H 21 F2N3O4 theoretical value: 357, actual value: 358 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=8.52(s,1H),5.44-5.30(m,1H),4.19-3.96(m,2H),2.48-2.30(m,5H),2.28-2.07(m,2H),1.28(s,9H).

[0447] Intermediate A-61 [ka] 5-methyl-4-(4-(trifluoromethyl)thiophen-2-yl)pyrimidine-2-carboxylic acid [ka] 4-(trifluoromethyl)thiophene-2-carbaldehyde To a solution of 4-iodothiophene-2-carbaldehyde (4.3 g, 18.06 mmol, 1 eq) in DMF (30 mL) under N was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (3.47 g, 18.06 mmol, 2.30 mL, 1 eq) and CuI (3.44 g, 18.06 mmol, 1 eq). After stirring at 100 °C for 16 h, the mixture was diluted with HO (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated to give the title compound (2.7 g, crude) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=9.97(d,J=1.2Hz,1H),8.80(d,J=1.0Hz,1H),8.32(t,J=1.3Hz,1H).

[0448] [ka] 4-(trifluoromethyl)thiophene-2-carboxylic acid To a solution of the product from the previous step (2.6 g, 14.43 mmol, 1 eq) in HO (20 mL) and MeOH (20 mL) was added KMnO (2.28 g, 14.43 mmol, 1 eq) and NaHPO (1.73 g, 14.43 mmol, 1 eq). After stirring at 15 °C for 2 h, the mixture was diluted with HO (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated to give the title compound (1.75 g, crude) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ=13.25(br s,1H),8.59-8.53(m,1H),7.93(d,J=1.1Hz,1H).

[0449] [ka] N-Methoxy-N-methyl-4-(trifluoromethyl)thiophene-2-carboxamide and 4-iodo-N-methoxy-N-methylthiophene-2-carboxamide To a solution of the product from the previous step (1.65 g, 8.41 mmol, 1 eq) and N-methoxymethanamine hydrochloride (902.60 mg, 9.25 mmol, 1.1 eq) in DMF (15 mL) was added EtN (2.55 g, 25.24 mmol, 3.51 mL, 3 eq) and HATU (4.80 g, 12.62 mmol, 1.5 eq). After stirring at 10 °C for 2 h, the mixture was diluted with HO (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated to give a mixture of N-methoxy-N-methyl-4-(trifluoromethyl)thiophene-2-carboxamide and 4-iodo-N-methoxy-N-methylthiophene-2-carboxamide (1.9 g, crude) as a yellow oil. MS (ES+) C8H8NO2SF3 calculated: 239, found: 240 [M+H] + MS(ES+)C7H8NO2SI Theoretical value: 297, Measured value: 298 [M+H] + .

[0450] [ka] N-Methoxy-N-methyl-4-(trifluoromethyl)thiophene-2-carboxamide To a solution of the above mixture (1.9 g, 6.39 mmol, 1 eq) in DMF (20 mL) under N was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.23 g, 6.39 mmol, 813.61 μL, 1 eq) and CuI (1.22 g, 6.39 mmol, 1 eq). After stirring at 100 °C for 32 h, the mixture was diluted with HO (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether / EtOAc = 1:1) to give the title compound (1.8 g) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ=8.58(s,1H),7.98(s,1H),3.80(s,3H),3.32(s,3H).

[0451] [ka] 1-(4-(trifluoromethyl)thiophen-2-yl)propan-1-one To a solution of the product from the previous step (1.7 g, 7.11 mmol, 1 eq) in THF (20 mL) under N was added EtMgBr (3 M in diethyl ether, 3.55 mL, 1.5 eq). After stirring at 0 °C for 1 h, the mixture was poured into 1 M aqueous HCl (40 mL) and extracted with EtOAc (40 mL × 2). The combined organic layers were washed with brine (40 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: petroleum ether / EtOAc = 5:1) to give the title compound (1 g, 4.80 mmol, 67% yield) as a white solid. MS(ES+)C8H7OSF3Theoretical value: 208, Found value: 209 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=8.71(s,1H),8.33(s,1H),3.12(q,J=7.2Hz,2H),1.15(t,J=7.2Hz,3H).

[0452] [ka] 3-(Dimethylamino)-2-methyl-1-(4-(trifluoromethyl)thiophen-2-yl)prop-2-en-1-one A mixture of DMFDMA (10 mL) and the product from the previous step (750 mg, 3.60 mmol, 1 eq) was stirred at 120 °C for 2 h. The mixture was concentrated under reduced pressure to give the title compound (950 mg, crude) as a yellow oil. MS (ES+) C 11 H 12 NOSF3 theoretical value: 263, actual value 264 [M+H] + .

[0453] [ka] 2,5-Dimethyl-4-(4-(trifluoromethyl)thiophen-2-yl)pyrimidine To a solution of acetamidine hydrochloride (511.72 mg, 5.41 mmol, 1.5 eq) in THF (10 mL) was added t-BuOK (607.34 mg, 5.41 mmol, 1.5 eq). The mixture was stirred at 60 °C for 15 min. Next, the product from the previous step (950 mg, 3.61 mmol, 1 eq) was added to the mixture, which was stirred at 60 °C for 6 h. The mixture was concentrated to remove THF, diluted with HO (30 mL), and extracted with EtOAc (30 mL × 2). The combined organic phases were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO, eluent: petroleum ether / EtOAc = 1:1) to give the title compound (40 mg, 122.36 μmol, 3% yield) as a yellow solid. MS (ES+) C 11 H9N2SF3 theoretical value: 258, measured value 259 [M+H] + . 5-methyl-4-[4-(trifluoromethyl)-2-thienyl]pyrimidine-2-carboxylic acid

[0454] [ka] 5-methyl-4-(4-(trifluoromethyl)thiophen-2-yl)pyrimidine-2-carboxylic acid To a solution of the product from the previous step (40 mg, 122.36 μmol, 1 eq) in pyridine (2 mL) and HO (0.2 mL) was added SeO (67.88 mg, 611.78 μmol, 66.55 μL, 5 eq). After stirring at 120 °C for 16 h, the mixture was filtered and the filtrate was concentrated to give the title compound (45 mg, crude) as a yellow oil. MS (ES+) C 11 H7N2O2SF3 theoretical value: 288, measured value 289 [M+H] + .

[0455] Intermediate A-62 [ka] 4-(5,5-Difluorotetrahydro-2H-pyran-2-yl)-5-methylpyrimidine-2-carboxylic acid [ka] 2-chloro-4-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5-methylpyrimidine To a solution of 2,4-dichloro-5-methylpyrimidine (75 mg, 0.46 mmol, 1 eq) in DMA (10 mL) was added 5,5-difluorotetrahydropyran-2-carboxylic acid (100 mg, 0.78 mmol, 1.3 eq), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (5.6 mg, 0.46 μmol, 0.01 eq), NiCl2·dtbpy (10 mg, 0.023 mmol, 0.05 eq), and Cs2CO3 (224.38 mg, 0.69 mmol, 1.5 eq) under N2. The mixture was then stirred and irradiated with two 34 W blue LED lamps (approximately 7 cm distance) from the light source, maintaining the reaction temperature at 25 °C for 14 h. Another batch photoreaction (75 mg scale) was set up under the same conditions, and the two batches were combined for testing. The combined reaction mixture was diluted with water (20 mL), extracted with EtOAc (20 mL × 3), washed with brine (20 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ISCO®; 10 g SepaFlash® silica flash column, eluent: 0–20% EtOAc / petroleum ether gradient at 50 mL / min) to afford the title compound (50 mg, 201.61 μmol, 21% yield) as a colorless oil. 1 H NMR(400MHz, CDCl3)δ=8.34(s,1H),4.54(dd,J=2.1,10.8Hz,1H),4.01-3.92(m, 1H),3.66-3.52(m,1H),2.43-2.30(m,4H),2.30-2.19(m,1H),2.10-1.89(m,2H)

[0456] [ka] Methyl 4-(5,5-difluorotetrahydro-2H-pyran-2-yl)-5-methylpyrimidine-2-carboxylate To a solution of the product from the previous step (50 mg, 201.08 μmol, 1 eq) in MeOH (1 mL) under N was added Pd(dppf)Cl (7.36 mg, 10.05 μmol, 0.05 eq) and EtN (40.69 mg, 402.16 μmol, 55.98 μL, 2 eq). The suspension was degassed under vacuum and purged several times with CO. After stirring at 60 °C under CO (15 psi) for 32 h, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent: 0–50% EtOAc / petroleum ether gradient at 30 mL / min) to give the title compound (30 mg, 110.19 μmol, 54% yield) as a white solid. MS (ES) + )C 12 H 14 N2O3F2 theoretical value: 272, measured value 273 [M+H] +

[0457] [ka] 4-(5,5-Difluorotetrahydro-2H-pyran-2-yl)-5-methylpyrimidine-2-carboxylic acid To a solution of the product from the previous step (25 mg, 91.83 μmol, 1 eq) in MeOH (1 mL) and HO (0.3 mL) was added LiOH·HO (11.56 mg, 275.48 μmol, 3 eq). After stirring at 25 °C for 16 h, the mixture was neutralized with aqueous HCl (1 M) to adjust the pH to 7 and concentrated under reduced pressure to give the title compound (40 mg, crude) as a white solid. MS (ES) + )C 11 H 12 N2O3F2 theoretical value: 258, measured value 259 [M+H] + .

[0458] The following compounds were obtained using procedures reported in the literature:

[0459] [Table 8]

[0460] Intermediate B-4 [ka] (S)-3-Amino-8-fluoro-5-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one [ka] tert-Butyl (S)-(3-(tert-butoxy)-1-((3,5-difluoropyridin-2-yl)amino)-1-oxopropan-2-yl)carbamate N-(tert-butoxycarbonyl)-O-(tert-butyl)-L-serine (5 g, 19.13 mmol, 1 eq) and 3,5-difluoropyridin-2-amine (4.98 g, 38.27 mmol, 2 eq) in CHCl (50 mL) were added to pyridine (4.54 g, 57.40 mmol, 4.63 mL, 3 eq). After stirring at 0 °C for 5 min, T3P (24.35 g, 38.27 mmol, 22.76 mL of 50% EtOAc solution, 2 eq) was added dropwise to the mixture and stirred at 0 °C for 1 h. The mixture was diluted with HO (200 mL) and extracted with CHCl (200 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (eluent: petroleum ether / EtOAc = 1 / 1) to give the title compound (7.5 g, 18.08 mmol, 94% yield) as a yellow oil. MS(ES+)C 17 H 25 N3O4F2 theoretical value: 373, measured value: 374 [M+H] + .

[0461] [ka] tert-Butyl (S)-(3-(tert-butoxy)-1-((3,5-difluoropyridin-2-yl)(methyl)amino)-1-oxopropan-2-yl)carbamate To a solution of the product from the previous step (3.5 g, 9.37 mmol, 1 eq) in THF (40 mL) was added KCO (2.10 g, 18.75 mmol, 2 eq) and CHI (2.66 g, 18.75 mmol, 1.17 mL, 2 eq). After stirring at 20 °C for 2 h, the mixture was diluted with HO (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (eluent: petroleum ether / EtOAc = 1 / 1) to give the title compound (2.7 g, 6.90 mmol, 73% yield) as a yellow oil. MS (ES+) C 18 H 27 N3O4F2 theoretical value: 387, measured value: 388 [M+H] + .

[0462] [ka] (S)-2-Amino-N-(3,5-difluoropyridin-2-yl)-3-hydroxy-N-methylpropanamide To HCl / EtOAc (4M, 30 mL, 17.22 eq) was added the product from the previous step (2.7 g, 6.97 mmol, 1 eq) at 0° C. After stirring at 0° C. for 2 h, the mixture was concentrated to give the HCl salt of the title compound (1.9 g) as a brown solid. MS (ES+) CH 11 N3O2F2 theoretical value: 231, measured value: 232 [M+H] + .

[0463] [ka] (S)-N-(3,5-difluoropyridin-2-yl)-3-hydroxy-N-methyl-2-(tritylamino)-propanamide To a solution of the HCl salt of the product from the previous step (1.8 g, 7.79 mmol, 1 eq) in chloroform (30 mL) was added [chloro(diphenyl)methyl]benzene (3.26 g, 11.68 mmol, 1.5 eq) and EtN (3.15 g, 31.14 mmol, 4.33 mL, 4 eq) at 0 °C. After stirring at 25 °C for 16 h, the mixture was dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: 0–50% EtOAc / petroleum ether gradient at 40 mL / min) to give the title compound (1.3 g, 2.75 mmol, 35% yield) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ=7.98(s,1H),7.37(br s,7H),7.28-7.07(m,9H),4.52(br d,J=3.4Hz,1H),4.07-3.91(m,1H),3.78-3.67(m,2H),3.51(s,3H).

[0464] [ka] (S)-8-Fluoro-5-methyl-3-(tritylamino)-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one To a solution of the product from the previous step (1.1 g, 2.32 mmol, 1 eq) in DMF (5 mL) was added Cs2CO3 (2.65 g, 8.13 mmol, 3.5 eq). After stirring at 110 °C for 16 h, the mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL × 3). The organic phase was washed with brine (50 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ISCO®; 25 g SepaFlash® silica flash column, eluent: 0–50% EtOAc / petroleum ether gradient at 50 mL / min) to afford the title compound (750 mg, 1.65 mmol, 71% yield) as a white solid. 1H NMR(400MHz,CDCl3)δ=8.03-7.97(m,1H),7.40-7.32(m,3H),7.32-7.29(m,3H),7.22-7.00(m,10 H),4.55-4.42(m,1H),4.39-4.29(m,1H),3.54-3.42(m,1H),3.29(d,J=8.4Hz,1H),2.88(s,3H).

[0465] [ka] (3S)-3-Amino-8-fluoro-5-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4-one To a solution of the product from the previous step (650 mg, 1.43 mmol, 1 eq) in dioxane (20 mL) and MeOH (2.25 mL) was added HCl / dioxane (4 M, 1.15 mL, 3.2 eq). After stirring at 25 °C for 16 h, the mixture was concentrated under reduced pressure. The residue was triturated with CHCl at 25 °C for 30 min to give the HCl salt of the title compound (250 mg, 879.93 μmol, 61% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ=8.35(d,J=2.6Hz,1H),7.72(dd,J=2.6,8.8Hz,1H),4.38(dd,J=7 .2,9.9Hz,1H),4.12(dd,J=10.0,11.5Hz,1H),3.70(dd,J=7.1,11.6Hz,1H),3.34(s,3H).

[0466] Intermediate B-5 [ka] (S)-3-Amino-8-chloro-5-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one [ka] tert-Butyl (S)-(3-(tert-butoxy)-1-((5-chloro-3-fluoropyridin-2-yl)amino)-1-oxopropan-2-yl)carbamate To a solution of 5-chloro-3-fluoropyridin-2-amine (14 g, 50.63 mmol, 53% purity, 1 eq) and N-(tert-butoxycarbonyl)-O-(tert-butyl)-L-serine (22.49 g, 86.07 mmol, 1.7 eq) in CHCl (150 mL) was added pyridine (12.01 g, 151.89 mmol, 12.26 mL, 3 eq) and T3P (64.44 g, 101.26 mmol, 60.22 mL of 50% EtOAc solution, 2 eq). After stirring at 25 °C for 16 h, the reaction mixture was diluted with water (100 mL) and extracted with CHCl (100 mL × 2). The combined organic phase was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: petroleum ether / EtOAc = 100 / 1 to 5 / 1) to give the title compound (6 g, 15.39 mmol, 30% yield) as a white solid. MS(ES+)C 17 H 25 N3FO4Cl Theoretical value: 389, Measured value: 390 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=10.36(s,1H),8.35(d,J=2.1Hz,1H),8.10(dd,J=2.1,9.6Hz,1 H),6.76-6.65(m,1H),4.42-4.26(m,1H),3.60-3.50(m,2H),1.39(s,9H),1.12(s,9H).

[0467] [ka] tert-Butyl (S)-(3-(tert-butoxy)-1-((5-chloro-3-fluoropyridin-2-yl)(methyl)amino)-1-oxopropan-2-yl)carbamate To a solution of the product from the previous step (6 g, 15.39 mmol, 1 eq) in THF (60 mL) was added KCO (8.51 g, 61.56 mmol, 4 eq) and MeI (8.74 g, 61.56 mmol, 3.83 mL, 4 eq). After stirring at 60 °C for 16 h, the mixture was concentrated under reduced pressure to remove THF. The residue was diluted with water (50 mL) and extracted with EtOAc (50 mL × 2). The combined organic phases were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: petroleum ether / EtOAc = 5 / 1) to give the title compound (5.9 g, 10.96 mmol, 71% yield) as a yellow oil.

[0468] [ka] (S)-2-Amino-N-(5-chloro-3-fluoropyridin-2-yl)-3-hydroxy-N-methylpropanamide To a solution of the product from the previous step (5.9 g, 14.61 mmol, 1 eq) in CHCl (30 mL) was added TFA (1.67 g, 14.61 mmol, 1.08 mL, 1 eq) at 0° C. After stirring at 25° C. for 16 h, the mixture was concentrated under reduced pressure to give the trifluoroacetate salt of the title compound (3 g, 12.11 mmol, 82% yield) as a yellow solid. MS (ES+) CH 11 N3FO2Cl Theoretical value: 247, Measured value: 248 [M+H]+

[0469] [ka] (S)-N-(5-chloro-3-fluoropyridin-2-yl)-3-hydroxy-N-methyl-2-(tritylamino)-propenamide To a solution of the TFA salt of the product from the previous step (3 g, 12.11 mmol, 1 eq) in CHCl (60 mL) was added [chloro(diphenyl)methyl]benzene (5.07 g, 18.17 mmol, 1.5 eq) and EtN (6.13 g, 60.57 mmol, 8.43 mL, 5 eq) at 0 °C. After stirring at 25 °C for 16 h, the mixture was concentrated under reduced pressure to remove CHCl. ​​The residue was diluted with water (50 mL) and extracted with EtOAc (25 mL × 2). The combined organic phases were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: petroleum ether / EtOAc = 100 / 1 to 1 / 1) to give the title compound (1.4 g, 2.57 mmol, 21% yield) as a yellow oil. 1 H NMR400MHz,DMSO-d6)δ=8.43-7.94(m,2H),7.57-7.15(m,15H),3.84-3.39(m,3H),2.88(s,3H).

[0470] [ka] (S)-8-Chloro-5-methyl-3-(tritylamino)-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one To a solution of the product from the previous step (1.4 g, 2.86 mmol, 1 eq) in DMF (30 mL) was added Cs2CO3 (3.26 g, 10.00 mmol, 3.5 eq). After stirring at 80 °C for 16 h, the mixture was diluted with water (50 mL) and extracted with EtOAc (25 mL × 2). The combined organic phases were washed with brine (50 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: petroleum ether / EtOAc = 100 / 1 to 10 / 1) to give the title compound (1 g, 1.92 mmol, 67% yield) as a yellow oil. 1H...

Claims

1. Structural formula (VI): 【Chemical 1】 (In the formula, V ４ is selected from CH and N; R １ is phenyl, said phenyl being selected from one or more R ６ optionally substituted with; R ２ is selected from H, halo, cyano, alkyl, (alkyl)oxy, (alkyl)thio, (alkyl)sulfonimidoyl, (alkyl)sulfonyl, cycloalkyl, and (cycloalkyl)oxy, any one of which may be selected from one or more R ７ optionally substituted with; R ５ is selected from H, CN, halo, hydroxy, alkyl and (alkyl)oxy; Each R ６ and R ７ is independently selected from CN, halo, hydroxy, oxo, alkyl, and (alkyl)oxy; R １０ｇ is H and C １～４ alkyl; R １０ｈ is selected from H, F, Cl and CN; R １０ｊ is H or is selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R １１ optionally substituted with; Each R １１ is independently selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, alkylsulfonyl, haloalkylsulfonyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (alkylsulfonyl)oxy, (haloalkylsulfonyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)NH, (cycloalkyl)NH, (heterocycloalkyl)NH, (alkylsulfonyl)NH, (haloalkylsulfonyl)NH, (aryl)NH, and (heteroaryl)NH, any one of which may be selected from one or more R １２ is optionally replaced by Two R's １１ is combined to form C ５～７ can form a cycloalkyl or a 5- to 7-membered heterocycloalkyl; and Each R １２ is selected from CN, halo, hydroxy, alkyl, (alkyl)oxy and oxo or a salt or tautomer thereof.

2. V ４ is N, or a salt or tautomer thereof.

3. R １０ｊ is selected from CN, halo, hydroxy, oxo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (alkyl)oxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, and (heteroaryl)oxy, any one of which may be selected from one or more R １１ 3. The compound of claim 1 or 2, or a salt or tautomer thereof, optionally substituted with:

4. Each R １１ is C １～６ Alkyl, C ３～７ cycloalkyl, 4- to 11-membered heterocycloalkyl, C １～６ Alkyl sulfonyl, halo C １～６ Alkylsulfonyl, C ６～１０ aryl, 5- to 14-membered heteroaryl, (C １～６ alkyl)oxy, (C ３～７ cycloalkyl)oxy, (4- to 11-membered heterocycloalkyl)oxy, (C １～６ alkylsulfonyl)oxy, (haloC １～６ alkylsulfonyl)oxy, (C ６～１０ (aryl)oxy and (5- to 14-membered heteroaryl)oxy, any one of which is independently selected from one or two R １２ is optionally substituted with, and Two R's １１ is combined to form C ５～７ The compound according to any one of claims 1 to 3, or a salt or tautomer thereof, which is capable of forming a cycloalkyl or a 5- to 7-membered heterocycloalkyl.

5. R １０ｊ The compound according to claim 1 or 2, wherein is H, or a salt or tautomer thereof.

6. R １０ｈ The compound according to any one of claims 1 to 5, or a salt or tautomer thereof, wherein is selected from H, F and Cl.

7. R ２ is Cl and CH ３ The compound according to any one of claims 1 to 6, or a salt or tautomer thereof, selected from:

8. Each R ６ is F and CH ３ 8. The compound according to any one of claims 1 to 7, or a salt or tautomer thereof, independently selected from:

9. R １ teeth, 【Chemistry 2】 9. The compound of claim 8, or a salt or tautomer thereof, wherein:

10. 【Chemical 3】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 or a salt or tautomer thereof.

11. A pharmaceutical agent comprising the compound according to any one of claims 1 to 10, or a salt or tautomer thereof.

12. Use of the compound according to any one of claims 1 to 10, or a salt or tautomer thereof, in the manufacture of a pharmaceutical agent for the prevention or treatment of a disease that is ameliorated by inhibition of RIPK1.

13. A pharmaceutical agent for use in treating a disease mediated by RIPK1, comprising the compound according to any one of claims 1 to 10, or a salt or tautomer thereof.

14. The pharmaceutical agent according to claim 13, wherein the disease is a neurological disease.

15. The pharmaceutical agent of claim 14, wherein the neurological disorder involves an inflammatory component of cellular stress.

16. The pharmaceutical agent according to claim 15, wherein the neurological disease is selected from multiple sclerosis, Niemann-Pick disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, dementia with Lewy bodies, frontotemporal dementia, and glutamine expansion disease.

17. The pharmaceutical agent according to claim 13, wherein the disease is neuropathy.

18. The pharmaceutical agent according to claim 17, wherein the neuropathy is selected from diabetic neuropathy and chemotherapy-induced neuropathy.

19. The pharmaceutical agent according to claim 13, wherein the disease is a retinal disease.

20. The pharmaceutical agent according to claim 19, wherein the retinal disease is selected from macular degeneration and retinitis.

21. The pharmaceutical agent of claim 13, wherein the disease is an autoimmune disorder.

22. 22. The pharmaceutical agent of claim 21, wherein the autoimmune disorder is selected from ulcerative colitis, rheumatoid arthritis, psoriasis, lupus, and inflammatory bowel disease.

23. The pharmaceutical agent according to claim 13, wherein the disease is an inflammatory disease.

24. 24. The pharmaceutical agent of claim 23, wherein the inflammatory disease is in one or more organs selected from the lung, heart, kidney, and liver.

25. The pharmaceutical agent according to claim 13, wherein the disease is cancer.

26. 26. The pharmaceutical agent of claim 25, wherein the cancer is treated by promoting an appropriate immune response against tumors.

27. The pharmaceutical agent according to claim 13, wherein the disease is myelodysplastic syndrome (MDS).

28. The pharmaceutical agent according to claim 13, wherein the disease is acute myeloid leukemia (AML).

29. A pharmaceutical agent for use in the treatment of injuries to the central nervous system (CNS), comprising a compound according to any one of claims 1 to 10, or a salt or tautomer thereof.

30. 30. The pharmaceutical agent of claim 29, wherein the injury is selected from traumatic brain injury and stroke.

31. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a salt or tautomer thereof, together with a pharmaceutically acceptable carrier.

32. A method for inhibiting RIPK1, comprising contacting RIPK1 with a compound according to any one of claims 1 to 10, or a salt or tautomer thereof, except when the method is carried out in the human body.

33. A pharmaceutical agent for use in a method for treating a RIPK1-mediated disease, comprising the compound according to any one of claims 1 to 10, or a salt or tautomer thereof, The method comprises: a. a therapeutically effective amount of the pharmaceutical agent; and b. Another therapeutic drug A pharmaceutical agent comprising administering

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