Carboxy-benzimidazole GLP-1r modulating compounds

Abstract

To provide a method for treating a disease.SOLUTION: The present disclosure provides GLP-1R agonists, and compositions, methods, and kits thereof. Such compounds are generally useful for treating a GLP-1R mediated disease or condition in a human. As described and demonstrated in detail herein, the present invention surprisingly achieves a remarkable effect that could not have been readily anticipated by the man skilled in the art from the prior art.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 63 / 177,775, filed April 21, 2021, and U.S. Provisional Application No. 63 / 285,410, filed December 2, 2021, which are hereby incorporated by reference in their entireties for all purposes.

[0002] The present disclosure relates to compounds that bind to and act as agonists or modulators of the glucagon-like peptide-1 receptor (GLP-1R) and act as agonists or modulators of the GLP-1R. The disclosure further relates to the use of the compounds for the treatment and / or prevention of diseases and / or conditions. [Background technology]

[0003] Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted by enteroendocrine cells in the intestine in response to a meal. GLP-1 is thought to play a role in regulating postprandial blood glucose by directly enhancing meal-induced insulin secretion from pancreatic β cells and in promoting satiety by slowing food transit through the intestine. GLP-1 belongs to a family of G protein-coupled receptors present on cell membranes and mediates intracellular signaling through the GLP-1 receptor (GLP-1R), which upon activation can lead to the accumulation of the second messenger cyclic adenosine monophosphate (cAMP). Non-alcoholic steatohepatitis (NASH) can be associated with features of metabolic syndrome, including obesity, type 2 diabetes, insulin resistance, and cardiovascular disease.

[0004] GLP-1R agonists are currently being investigated in relation to diabetes, obesity, and NASH. GLP-1R agonists include peptides such as exenatide, liraglutide, and dulaglutide, which are approved for the management of type 2 diabetes. Such peptides are primarily administered by subcutaneous injection. Oral GLP-1 agonists are also being investigated for the treatment of type 2 diabetes. Some GLP-1R agonists, such as liraglutide, dulaglutide, and exenatide, are resistant to rapid degradation by dipeptidyl peptidase 4, resulting in a longer half-life than endogenous GLP-1.

[0005] There remains a need for compounds, such as agonists of GLP-1R, with desirable therapeutic properties, metabolic properties, and / or ease of administration in the treatment of metabolic and related diseases, including, but not limited to, NASH, obesity, and type 2 diabetes. Summary of the Invention

[0006] In one embodiment, the present disclosure provides a compound of formula (I):

[0007] [ka] [In the formula, R 1 teeth, i) 1 to 4 R 4 5-membered heteroaryl optionally substituted with ii) a 5-membered heteroaryl fused to a heteroaryl or aryl to form a heteroaryl ring system, wherein the heteroaryl ring system is fused to 1 to 4 R 4 5-membered heteroaryl optionally substituted with iii) Two R's attached to adjacent ring atoms 4 group and one or two further R 4 a 5-membered heteroaryl optionally substituted with two R 4 The groups, in combination with the atoms to which they are attached, are one to four R 6C, each optionally substituted with 5~10 5-membered heteroaryl, forming a cycloalkyl or heterocyclyl; iv) a 6-membered heteroaryl or phenyl substituted with a C2-alkynyl, wherein the 6-membered heteroaryl or phenyl is selected from the group consisting of 1 to 3 R 4 and C2-alkynyl is substituted with -C(CH3)2SO2CH3, aryl, heteroaryl, or heterocyclyl, and the aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 4 R 5 6-membered heteroaryl or phenyl optionally substituted with v) -C(O)NR a R b a 6-membered heteroaryl or phenyl substituted with 1 to 4 R 4 a 6-membered heteroaryl or phenyl optionally substituted with vi) a 6-membered heteroaryl or phenyl, wherein the 6-membered heteroaryl or phenyl is heteroaryl, C 3~10 substituted with cycloalkyl or heterocycle and 1 to 3 R 4 and optionally substituted with heteroaryl, C 3~10 The cycloalkyl or heterocycle is each C 3~10 Cycloalkyl, heterocyclyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 1~6 Alkyl-heterocyclyl, or C 1~6 Alkyl-heteroaryl substituted, C 3~10 Cycloalkyl, heterocyclyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 1~6 Alkyl-heterocyclyl, or C 1~6 The alkyl-heteroaryl is selected from 1 to 4 R 6 6-membered heteroaryl or phenyl optionally substituted with and X 1 , X 2 , and X 3are each independently -C(H)= or -C(R 8 )=, Each ring A is independently C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 1 to 3 Z's that are haloalkoxy, halogen, -OH, or -CN; 1a each optionally substituted with a group;

[0008] [ka] and Ring B is 1 to 4 R 4 C, each optionally substituted with 6~10 is aryl or heteroaryl, V is -C(O)-, -O-, -N(R 6a )- or -C(R 6b )(R 6c )- and R 2 is H, C 1~6 Alkyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~10 cycloalkyl, or heterocyclyl; Alkyl, alkynyl, cycloalkyl, or heterocyclyl may have 1 to 4 Z 1 and each Z 1 independently, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -OH, -CN, C 1~6 Alkyl-CN, -OC 3~6 Cycloalkyl, heterocyclyl, C 3~10 Cycloalkyl or heteroalkyl each independently represents C 1~6 Alkyl, C 1~6 Alkoxy, halogen, -CN, C1~6 Haloalkyl, or C 1~6 optionally substituted with 1 to 4 groups that are haloalkoxy; R 3 is -C(O)OR 3a and R 3a is H, C 1~4 Alkyl-N(R 9a )(R 9b ), -C 1~4 Alkyl-N(R 9a )C(O)-OC 1~4 Alkyl-OP(O)(OR 9c )2, C 1~4 Alkyl-C(O)N(R 9a )(R 9b ), -C 1~4 Alkyl-OC(O)-C 1~4 Alkyl, -C 1~4 Alkyl-OC(O)-OC 1~4 Alkyl, -C 1~4 Alkyl-OC(O)-C 1~4 Alkyl-N(R 9a )(R 9b ), -C 1~4 Alkyl-OC(O)-C 1~4 Alkyl-OP(O)(OR 9c )2, -CH2CH(N(R 9a )2)C(O)OR 9b , -P(O)(OR 9c )2, -OP(O)(OR 9c )2, -CH2P(O)(OR 9c )2, -CH2OP(O)(OR 9c )2, -OCH2P(O)(OR 9c )2, C(O)OCH2P(O)(OR 9c )2, -P(O)(R 9c )(OR 9d ), -OP(O)(R 9c )(OR 9d ), -CH2P(O)(R 9c )(OR 9d ), -OCH2P(O)(R 9c )(OR 9d ), -C(O)OCH2P(O)(R 9c )(OR9d ), -P(O)(N(R 9c )2)2, -OP(O)(N(R 9c )2)2, -CH2P(O)(N(R 9c )2)2, -OCH2P(O)(N(R 9c )2)2, -C(O)OCH2P(O)(N(R 9c )2)2, -P(O)(N(R 9c )2)(OR 9d ), -OP(O)(N(R 9c )2)(OR 9d ), -CH2P(O)(N(R 9c )2)(OR 9d ), -OCH2P(O)(N(R 9c )2)(OR 9d ), -C(O)OCH2P(O)(N(R 9c )2)(OR 9d ), -P(O)(R 9c )(N(R 9d )2), -OP(O)(R 9c )(N(R 9d )2), -CH2P(O)(R 9c )(N(R 9d )2), -OCH2P(O)(R 9c )(N(R 9d )2), -C(O)OCH2P(O)(R 9c )(N(R 9d )2) or C 1~6 alkyl-heterocyclyl, alkyl or heterocyclyl are each optionally substituted with 1 to 4 halogens; Each R 4 independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -NO2, -N3, -CN, -OR 10a , -C(O)R 10a, -C(O)OR 10a , -C(O)-N(R 10a )(R 10b ), -N(R 10a )(R 10b ), -N(R 10a )2(R 10b ) + , -N(R 10a )C(O)-R 10b , -N(R 10a )C(O)OR 10b , -N(R 10a )C(O)N(R 10b )(R 10c ), -N(R 10a )S(O)2(R 10b ), -NR 10a S(O)2N(R 10b )(R 10c ), -NR 10a S(O)2O(R 10b ), -OC(O)R 10a , -OC(O)OR 10a , -OC(O)-N(R 10a )(R 10b ), -SR 10a , -S(O)R 10a , -S(O)(NH)R 10a , -S(O)2R 10a , -S(O)2N(R 10a )(R 10b ), -S(O)(NR 10a )R 10b , or -Si(R 10a )3, Each alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be selected from 1 to 4 R 5 and optionally substituted with Each R 5 independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, halogen, C3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -NO2, -N3, -CN, -OR 10a , -C(O)-R 10a , -C(O)OR 10a , -C(O)N(R 10a )(R 10b ), -N(R 10a )(R 10b ), -N(R 10a )C(O)R 10b , -N(R 10a )C(O)OR 10b , -N(R 10a )C(O)N(R 10b )(R 10c ), -N(R 10a )S(O)2(R 10b ), -NR 10a S(O)2N(R 10b )(R 10c ), -NR 10a S(O)2O(R 10b ), -OC(O)R 10a , -OC(O)OR 10a , -OC(O)-N(R 10a )(R 10b ), -SR 10a , -S(O)R 10a , -S(O)(NH)R 10a , -S(O)2R 10a , -S(O)2N(R 10a )(R 10b ), -S(O)(NR 10a )R 10b , or -Si(R 10a )3, Each alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be selected from 1 to 4 R 6 and optionally substituted with Each R 6 and R 8 independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 -Cycloalkyl), -O(heterocyclyl), -O(C 6~10 aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(heterocyclyl), -NH(C 6~10 aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 1~8 haloalkyl)2, -N(C 2~6 alkenyl)2, -N(C 2~6 alkynyl)2, -N(C 3~15 -N(cycloalkyl)2, -N(heterocyclyl)2, -N(C 6~10 aryl), -N(heteroaryl), -N(C 1~9 Alkyl)(C 1~8 haloalkyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 alkyl)(heterocyclyl), -N(C 1~9 Alkyl)(C 6~10 aryl), -N(C 1~9 alkyl)(heteroaryl), -C(O)(C 1~9 alkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 2~6alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 -C(O)(cycloalkyl), -C(O)(heterocyclyl), -C(O)(C 6~10 aryl), -C(O)(heteroaryl), -C(O)O(C 1~9 alkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(heterocyclyl), -C(O)O(C 6~10 aryl), -C(O)O(heteroaryl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 1~8 haloalkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -C(O)NH(C 3~15 cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(C 6~10 aryl), -C(O)NH(heteroaryl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C 6~10 aryl), -C(O)N(heteroaryl), -NHC(O)(C 1~9 alkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 2~6 alkenyl), -NHC(O)(C 2~6 alkynyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6~10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C1~8 haloalkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1~9 alkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(heterocyclyl), -NHC(O)NH(C 6~10 aryl), -NHC(O)NH(heteroaryl), -NHS(O)( C 1~9 alkyl), -N(C 1~9 alkyl)(S(O)(C 1~9 alkyl), -S(C 1~9 alkyl), -S(C 1~8 haloalkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 -S(cycloalkyl), -S(heterocyclyl), -S(C 6~10 -S(aryl), -S(heteroaryl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(C 1~8 haloalkyl), -S(O)(C 2~6 alkenyl), -S(O)(C 2~6 alkynyl), -S(O)(C 3~15 -S(O)(cycloalkyl), -S(O)(heterocyclyl), -S(O)(C 6~10 aryl), -S(O)(heteroaryl), -S(O)2(C 1~9 alkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C3~15 cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(C 6~10 aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1~9 alkyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, Each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may have 1 to 3 C 1~9 Alkyl, C 1~8 Haloalkyl, halogen, -OH, -NH2, CO2H, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 3~15 -cycloalkyl), -O(heterocyclyl), -O(aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C 3~15 -cycloalkyl), -NH(heterocyclyl), -NH(aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1~9 alkyl), S(O)2(C 1~9 alkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 3~15-cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)(NH)(C 1~9 alkyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 optionally substituted with alkyl; alkyl or heterocyclyl are each optionally substituted with 1 to 4 halogens; R 6a is H, C 1~6 Alkyl, C 3~10 Cycloalkyl, heterocyclyl, -S(O)2R 6a1 , or -S(O)N(R 6a1 )(NR 6a2 ) and cycloalkyl or heterocyclyl is C 1~6 each optionally substituted with alkyl, F, or —CN; Each R 6b and R 6c are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkoxyalkyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, -C 1~6 Alkyl-N(R 9a )(R 9b ), -CN, -OR 6c1 , or -N(R 6c2 )(R 6c3 ) and Alkyl, cycloalkyl, or heterocyclyl may have 1 to 4 R 6b1 each optionally substituted with R 6b and R 6c are combined with the atoms to which they are attached to form 1 to 4 R 6b1 C, each optionally substituted with 3~10 forming a cycloalkyl or heterocyclyl; or R 6a or R 6c is one R 4 In combination with the groups and the atoms to which they are attached, one to four R10 C, each optionally substituted with 5~10 forming a cycloalkyl or heterocyclyl, each R6 b1 and R 10 independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C1 ~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, COR 3e , -NO2, or -C(O)N(R 2a )(R 2b ) and Heterocyclyl or heteroaryl is C 1~6 Alkyl, C 1~6 Haloalkyl or C 1~6 optionally substituted with haloalkoxy; Each R 6a1 , R 6a2 , R 6c1 , R 6c2 , and R 6c3 are independently H, C 1~6 Alkyl or C 3~10 is cycloalkyl, Each R 9a and R 9b are independently H, C 1~6 Alkyl or C 1~6 haloalkyl, or R 9a and R 9b together form a 6-membered heterocyclyl, Each R 9c , R 9d , R 10a , R 10b , and R 10c are independently H, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15Cycloalkyl, heterocyclyl, C 6~10 aryl or heteroaryl; Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from 1 to 4 R 6 each optionally substituted with R a and R b are independently H, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 aryl, or heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from 1 to 4 R 6 each optionally substituted with Optionally, R a and R b are combined with the atoms to which they are attached to form 1 to 4 R 6 forming a 5- or 6-membered heterocyclyl optionally substituted with Each R 2a , R 2b , R 12a , R 12b , and R 12c are independently H, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 aryl or heteroaryl; Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from 1 to 4 R 6 each optionally substituted with Each R 3e are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, -C 1~4 Alkyl-N(R 9a )(R 9b ), -C 1~4Alkyl-C(O)N(R 9a )(R 9b ), -C 1~4 Alkyl-OC(O)-C 1~4 Alkyl, -C 1~4 Alkyl-OC(O)-OC 1~4 Alkyl, -C 1~4 Alkyl-OC(O)-C 1~4 Alkyl-N(R 9a )(R 9b ), -C 1~4 Alkyl-C 3~8 Cycloalkyl, -C 1~4 Alkyl-heterocyclyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -P(O)(OR 9c )2, -CH2P(O)(OR 9c )2, -OCH2P(O)(OR 9c )2, -C(O)OCH2P(O)(OR 9c )2, -P(O)(R 9c )(OR 9d ), -OP(O)(R 9c )(OR 9d ), -CH2P(O)(R 9c )(OR 9d ), -C(O)OCH2P(O)(R 9c )(OR 9d ), -P(O)(N(R 9c )2)2, -CH2P(O)(N(R 9c )2)2, -C(O)OCH2P(O)(N(R 9c )2)2, -P(O)(N(R 9c )2)(OR 9d ), -CH2P(O)(N(R 9c )2)(OR 9d ), -C(O)OCH2P(O)(N(R 9c )2)(OR 9d ), -P(O)(R 9c )(N(R 9d )2), -CH2P(O)(R 9c )(N(R 9d )2), or -C(O)OCH2P(O)(R 9c )(N(R 9d )2) and Alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is a group consisting of 1 to 4 R 6 each optionally substituted with: each heterocyclyl has 3 to 12 ring members and 1 to 4 heteroatoms, each independently N, O, or S; Each heteroaryl has 5 to 12 ring members and is independently N, O, or S. 1 to 4 heteroatoms] or a pharmaceutically acceptable salt thereof.

[0009] In another embodiment, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0010] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof has the structure of a compound in Table 2.

[0011] In vivo metabolic products of the compounds described herein are also disclosed to the extent that such products are novel and unobvious based on the prior art. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily through enzymatic processes. Accordingly, novel and unobvious compounds are included that are produced by a process comprising contacting the compound with a mammal for a time sufficient to yield metabolic products. Such products are typically identified by preparing a radiolabeled (e.g., 14C or 3H) compound, parenterally administering it to an animal, such as a rat, mouse, guinea pig, monkey, or human, at a detectable dose (e.g., about 0.5 mg / kg), and isolating the transformation products from urine, blood, or other biological samples over a period of time sufficient for metabolism to occur (typically about 30 seconds to 30 hours). Because these products are labeled, they can be readily isolated (others are isolated by the use of antibodies capable of binding to epitopes surviving in the metabolite). The structures of the metabolites are determined by conventional methods, such as MS or NMR analysis. In general, analysis of metabolites can be performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. Conversion products may be useful in diagnostic assays for therapeutic dosing of compounds even if they have no GLP-1R activity of their own unless otherwise found in vivo.

[0012] Recipes and methods for determining the stability of compounds in surrogate gastrointestinal secretions are known. A compound is defined herein as stable in the gastrointestinal tract if less than about 50 mole percent of the protecting groups are deprotected in surrogate intestinal or gastric fluids upon incubation at 37° C. for 1 hour. Just because a compound is stable to the gastrointestinal tract does not mean that it is in This does not mean that it cannot be hydrolyzed in vivo. Prodrugs are typically stable in the digestive system, but can be substantially hydrolyzed to the parent drug in the digestive lumen, liver, lungs or other metabolic organs, or generally intracellularly. As used herein, a prodrug is understood to be a compound that is chemically designed to effectively release the parent drug after overcoming the biological barrier to oral delivery. [Brief explanation of the drawings]

[0013] [Figure 1] 1 is a graph showing plasma concentrations as a function of time in cynomolgus monkeys. DETAILED DESCRIPTION OF THE INVENTION

[0014] I. Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. A dash at the front or end of a chemical group is for convenience to indicate the point of attachment to the parent moiety, and chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. "C u~v " or "C u ~C v " indicates that the following group has u to v carbon atoms, where u and v are integers. For example, "C 1~6 "Alkyl" or "C1-C6 alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms.

[0015] "Alkyl" refers to a monovalent or divalent straight-chain or branched saturated hydrocarbon radical. For example, an alkyl group may be one having 1 to 10 carbon atoms (i.e., C 1-10 alkyl) or 1 to 8 carbon atoms (i.e., C 1-8 alkyl) or 1 to 6 carbon atoms (i.e., C 1-6 alkyl) or 1 to 4 carbon atoms (i.e., C 1-4Examples of alkyl groups include methyl (Me, -CH), ethyl (Et, -CHCH), 1-propyl (n-Pr, n-propyl, -CHCHCH), 2-propyl (i-Pr, i-propyl, -CH(CH)), 1-butyl (n-Bu, n-butyl, -CHCHCHCHCH), 2-methyl-1-propyl (i-Bu, i-butyl, -CHCH(CH)), 2-butyl (s-Bu, s-butyl, -CH(CH)CHCH). , 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2 -Methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH (-C(CH)(CHCH)), 2-methyl-3-pentyl (-CH(CHCH)CH(CH)), 2,3-dimethyl-2-butyl (-C(CH)CH(CH)), 3,3-dimethyl-2-butyl (-CH(CH)C(CH)), and octyl (-(CH)CH). Alkyl groups can be unsubstituted or substituted.

[0016] "Alkoxy" refers to an -O-alkyl group, where alkyl is as defined above. For example, C 1~4 Alkoxy refers to an -O-alkyl group having 1 to 4 carbons. The alkoxy group can be unsubstituted or substituted.

[0017] An "alkoxyalkyl" is an alkoxy group attached to an alkyl as defined above such that the alkyl is divalent. For example, C 2~6 Alkoxyalkyl includes -CH2-OMe, -CH2-O-iPr, -CH2-CH2-OMe, -CH2-CH2-O-CH2-CH3, and -CH2-CH2-O-tBu. Alkoxyalkyl groups can be unsubstituted or substituted.

[0018] A "hydroxyalkyl" is a hydroxy group attached to an alkyl as defined above such that the alkyl is divalent. For example, C 1~6 Hydroxyalkyl includes -CH2-OH and -CH2-CH2-OH. Hydroxyalkyl groups can be unsubstituted or substituted.

[0019] "Alkenyl" refers to a monovalent or divalent straight-chain or branched hydrocarbon radical having at least one carbon-carbon double bond. For example, an alkenyl group can be an alkyl group having 2 to 8 carbon atoms (i.e., C 2-8 alkenyl) or 2 to 6 carbon atoms (i.e., C 2-6 alkenyl) or 2 to 4 carbon atoms (i.e., C 2-4 Examples of alkenyl groups include, but are not limited to, ethenyl (-CH=CH), allyl (-CHCH=CH), and -CH-CH=CH-CH. Alkenyl groups can be unsubstituted or substituted.

[0020] "Alkynyl" refers to a monovalent or divalent straight-chain or branched hydrocarbon radical having at least one carbon-carbon triple bond. For example, an alkynyl group can be an alkyl group having 2 to 8 carbon atoms ( That is, C 2~8 alkynyl) or 2 to 6 carbon atoms (i.e., C 2~6 alkynyl) or 2 to 4 carbon atoms (i.e., C 2~4Examples of alkynyl groups include, but are not limited to, acetylenyl (-C≡CH), propargyl (-CHC≡CH), and -CH-C≡C-CH. Alkynyl groups can be unsubstituted or substituted.

[0021] "Halogen" refers to fluoro (-F), chloro (-Cl), bromo (-Br) and iodo (-I).

[0022] "Haloalkyl" is an alkyl, as defined herein, in which one or more hydrogen atoms of the alkyl are independently replaced by a halogen, which may be the same or different, such that the alkyl is divalent. The alkyl group and halogen may be any of those described above. In some embodiments, the haloalkyl defines the number of carbon atoms in the alkyl portion, e.g., C 1~4 Haloalkyl includes CF3, CH2F, CHF2, CH2CF3, CH2CH2CF3, CCl2CH2CH2CH3, and C(CH3)2(CF2H). Haloalkyl groups can be unsubstituted or substituted.

[0023] "Haloalkoxy" is an alkoxy as defined herein, wherein one or more hydrogen atoms of the alkyl in the alkyloxy are independently replaced by a halogen, which may be the same or different, such that the alkyl is divalent. The alkoxy group and halogen may be any of those described above. In some embodiments, the haloalkoxy defines the number of carbon atoms in the alkyl portion, e.g., C 1~4 Haloalkoxy includes OCF3, OCH2F, OCH2CF3, OCH2CH2CF3, OCCl2CH2CH2CH3, and OC(CH3)2(CF2H). A haloalkoxy group can be unsubstituted or substituted.

[0024] "Cycloalkyl" refers to a monovalent or divalent single all-carbocyclic ring or all-carbocyclic fused polycyclic ring system, in each case where the ring is a non-aromatic saturated or unsaturated ring. For example, in some embodiments, the cycloalkyl group has 3 to 12 carbon atoms, 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, 3 to 5 carbon atoms, or 3 to 4 carbon atoms. Exemplary single-ring cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. Cycloalkyl also includes fused polycyclic ring systems (e.g., ring systems containing two rings) having about 7 to 12 carbon atoms. The rings of a fused polycyclic ring system can be connected to each other through fused, spiro, or bridged bonds, if permitted by valence requirements. Exemplary multicyclic cycloalkyl groups include octahydropentalene, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[2.2.2]oct-2-ene, and spiro[2.5]octane. Cycloalkyl groups can be unsubstituted or substituted.

[0025] "Alkylcycloalkyl" refers to an alkyl, as defined herein, in which one or more hydrogen atoms of the alkyl are independently replaced by a cycloalkyl group, which can be the same or different. The alkyl and cycloalkyl groups can be any of those described above. In some embodiments, the number of carbon atoms in the alkyl and cycloalkyl portions can be specified separately (e.g., C 1~6 Alkyl-C 3~12 Cycloalkyl). An alkylcycloalkyl group can be unsubstituted or substituted.

[0026] As used herein, "aryl" refers to a monovalent or divalent single all-carbon aromatic ring or all-carbon fused polycyclic ring system in which the ring is aromatic. For example, in some embodiments, aryl groups are those having 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms. Aryl includes the phenyl radical. Aryl also includes fused polycyclic ring systems (e.g., ring systems containing 2, 3, or 4 rings) having about 9 to 20 carbon atoms in which multiple rings are aromatic. The rings of fused polycyclic ring systems can be connected to each other through fused, spiro, or bridged bonds, if permitted by valence requirements. When referring to a particular atom-range-membered aryl (e.g., a 6- to 10-membered aryl), it is also understood that the atom range is based on the total ring atoms of the aryl. For example, a 6-membered aryl would include phenyl, and a 10-membered aryl would include naphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like. Aryl groups can be unsubstituted or substituted.

[0027] "Alkylaryl" refers to an alkyl, as defined herein, in which one or more hydrogen atoms of the alkyl are independently replaced by an aryl group, which may be the same or different. The alkyl and aryl groups may be any of those described above, such that the alkyl is divalent. In some embodiments, the alkylaryl group has 7 to 24 carbon atoms, 7 to 16 carbon atoms, 7 to 13 carbon atoms, or 7 to 11 carbon atoms. An alkylaryl group defined by the number of carbon atoms refers to the total number of carbon atoms present in the constituent alkyl and aryl groups combined. For example, C7 alkylaryl refers to benzyl, while C7 alkylaryl refers to benzyl. 11 Alkylaryl includes 1-methylnaphthyl and n-pentylphenyl. In some embodiments, the number of carbon atoms in the alkyl and aryl portions may be specified separately (e.g., C 1~6 Alkyl-C 6~10 aryl). Non-limiting examples of alkylaryl groups include, but are not limited to, benzyl, 2,2-dimethylphenyl, n-pentylphenyl, 1-methylnaphthyl, 2-ethylnaphthyl, etc. Alkylaryl groups can be unsubstituted or substituted.

[0028] As used herein, "heterocyclyl" or "heterocycle" or "heterocycloalkyl" refers to a single saturated or partially unsaturated non-aromatic ring or non-aromatic polycyclic ring system having at least one heteroatom within the ring (i.e., at least one cyclic (i.e., ring-shaped) heteroatom selected from oxygen, nitrogen, and sulfur). Unless otherwise specified, a heterocyclyl group has 3 to about 20 ring atoms, e.g., 3 to 12 ring atoms, e.g., 4 to 12 ring atoms, 4 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 3 to 5 ring atoms, or 4 to 6 ring atoms, or 4 to 5 ring atoms. Thus, the term includes a single saturated or partially unsaturated ring (e.g., a 3-, 4-, 5-, 6-, or 7-membered ring) having about 1 to 6 ring carbon atoms and about 1 to 3 ring heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. The rings of fused polycyclic (e.g., bicyclic heterocyclyl) systems can be connected to each other via fused, spiro, and bridged bonds, if permitted by valence requirements. Heterocycles include azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, thietane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinacridine, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, Heterocyclyl groups include, but are not limited to, 2-thia-6-azaspiro[3.3]heptan-6-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2-azabicyclo[3.1.0]hexan-2-yl, 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[2.1.1]hexanyl, 2-azabicyclo[2.2.1]heptan-2-yl, 4-azaspiro[2.4]heptanyl, 5-azaspiro[2.4]heptanyl, etc. Heterocyclyl groups can be unsubstituted or substituted.

[0029] "Alkylheterocyclyl" refers to an alkyl, as defined herein, in which one or more hydrogen atoms of the alkyl are independently replaced by a heterocyclyl group, which is the same as or may be different. The alkyl group and heterocyclyl group can be any of those described above, such that the alkyl is divalent. In some embodiments, the number of atoms in the alkyl and heterocyclyl portions may be specified separately (e.g., C 16 having 1-3 heteroatoms, each independently N, O, or S). 1~6 Alkyl-3 to 12-membered heterocyclyl). The alkylheterocyclyl group can be unsubstituted or substituted.

[0030] "Heteroaryl" refers to a single aromatic ring having at least one atom other than carbon within the ring, the atom being selected from the group consisting of oxygen, nitrogen, and sulfur; "heteroaryl" also encompasses multiple condensed ring systems having at least one such aromatic ring, which are further described below. Thus, "heteroaryl" includes a single aromatic monocyclic ring of about 1 to 6 carbon atoms and about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The sulfur and nitrogen atoms may be present in oxidized form, provided the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. "Heteroaryl" also includes fused polycyclic ring systems (e.g., ring systems containing 2, 3, or 4 rings), where a heteroaryl group, as defined above, is fused with one or more rings selected from heteroaryl (e.g., to form 1,8-naphthyridinyl) and aryl (e.g., to form benzimidazolyl or indazolyl) to form a fused polycyclic ring system. Thus, a heteroaryl (single aromatic ring or fused polycyclic ring system) can have about 1 to 20 carbon atoms and about 1 to 6 heteroatoms in the heteroaryl ring. For example, tetrazolyl has one carbon atom and four nitrogen heteroatoms in the ring. The rings of a fused polycyclic ring system can be connected to each other via fused, spiro, or bridged bonds, if permitted by valence requirements. It is understood that the individual rings of a multiple fused ring system can be connected to each other in any order. It is understood that the point of attachment of a heteroaryl or heteroaryl fused polycyclic ring system can be at any suitable atom (e.g., nitrogen) of the heteroaryl or heteroaryl fused polycyclic ring system, including carbon atoms and heteroatoms. It is also understood that when referring to a particular atom range-membered heteroaryl (e.g., a 5- to 10-membered heteroaryl), the atom range is for the total ring atoms of the heteroaryl and includes carbon atoms and heteroatoms. It is also understood that fused polycyclic rings can include an aryl ring fused to a saturated or partially unsaturated heterocyclic ring (e.g., a 3-, 4-, 5-, 6-, or 7-membered ring) having about 1 to 6 ring carbon atoms and about 1 to 3 ring heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring.For example, a 5-membered heteroaryl includes thiazolyl, and a 10-membered heteroaryl includes quinolinyl. Exemplary heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, and tetrazolyl. Heteroaryl groups can be unsubstituted or substituted.

[0031] "Alkylheteroaryl" is an alkyl, as defined herein, in which one or more hydrogen atoms of the alkyl are independently replaced by a heteroaryl group, which can be the same or different, such that the alkyl is divalent. The alkyl group and heteroaryl group can be any of those described above. In some embodiments, the number of atoms in the alkyl and heteroaryl portions are specified separately (e.g., C 16 alkyl, C 26 alkyl, C 36 alkyl, C 46 alkyl, C 56 alkyl, C 66 alkyl, C 76 alkyl, C 86 alkyl, C 96 alkyl, C 106 alkyl, C 126 alkyl, C 146 alkyl, C 166 alkyl, C 18 ... 1~6 Alkyl-5 to 10 membered heteroaryl). The alkylheteroaryl group can be unsubstituted or substituted.

[0032] As used herein, "oxo" refers to =O.

[0033] As used herein, "substituted" refers to one or more hydrogen atoms of a group being independently replaced with one or more substituents (e.g., 1, 2, 3, or 4 or more) as indicated.

[0034] "Compounds of the disclosure" include compounds disclosed herein, for example, compounds of the disclosure include compounds of formula (I), including compounds of the Examples. In some embodiments, "compounds of the disclosure" include compounds of formula (I).

[0035] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, filler, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for use in humans or veterinary medicine.

[0036] As used herein, a "therapeutically effective amount" or "effective amount" refers to an amount effective to elicit a desired biological or medical response when administered to a subject to treat a disease, including an amount of a compound sufficient to effect such treatment of the disease. The effective amount will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject being treated. An effective amount may include a range of amounts. As understood in the art, an effective amount may be one or more doses, i.e., a single dose or multiple doses may be required to achieve a desired therapeutic endpoint. An effective amount may be considered in relation to the administration of one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount when a desired or beneficial result can be or is achieved in combination with one or more other agents. The suitable dose of any co-administered compound may optionally be reduced due to the combined effects (e.g., additive or synergistic effects) of the compounds.

[0037] As used herein, "co-administration" refers to administration of a unit dose of a compound disclosed herein before or after administration of a unit dose of one or more additional therapeutic agents, e.g., administration of a compound disclosed herein within seconds, minutes, or hours of administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed within seconds or minutes by a unit dose of a compound disclosed herein. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed several hours (e.g., 1-12 hours) later by a unit dose of one or more additional therapeutic agents. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed several hours (e.g., 1-12 hours) later by a unit dose of a compound disclosed herein. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein with one or more additional therapeutic agents such that a therapeutically effective amount of each agent is present in the subject's body.

[0038] Pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other substances that are useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0039] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts, or, where appropriate, as free bases. Pharmaceutically acceptable salts are non-toxic salts of the free base form of the compounds that possess the desired pharmacological activity of the free base. These salts may be inorganic or Pharmaceutically acceptable salts may be derived from organic acids or inorganic or organic bases. For example, compounds containing a basic nitrogen can be prepared as pharmaceutically acceptable salts by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyl phosphate ... Suitable pharmaceutically acceptable salts include benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0040] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein also include alkali metal (e.g., sodium, potassium), alkaline earth metal (e.g., magnesium), ammonium, and N(C≡C alkyl) 4+ Also included are salts derived from appropriate bases such as HCl, ...

[0041] Also provided are compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, in which 1 to n hydrogen atoms bonded to a carbon atom may be replaced by deuterium atoms or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such compounds may have enhanced resistance to metabolism and may therefore be useful for increasing the half-life of the compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, when administered to a mammal. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced with deuterium.

[0042] Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I can also be mentioned. 11 C. 18 F, 15 O, and 13Substitution with positron-emitting isotopes, such as N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the Examples below, using an appropriate isotopically labeled reagent in place of a previously used non-labeled reagent.

[0043] The compounds of the embodiments disclosed herein, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers and may therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms which may be defined, with respect to absolute stereochemistry, as (R)- or (S)-, or for amino acids, as (D)- or (L)-. The present disclosure provides all such The term "enantiomers" is intended to include all possible isomers, such as (R)- and (S)-, or (D)- and (L)-isomers, as well as their racemic and optically pure forms. Optically active (+)- and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, these compounds are intended to include both E- and Z-geometric isomers. Likewise, all tautomeric forms are also intended to be included. When compounds are represented in their chiral form, it is understood that the embodiment encompasses, but is not limited to, the specific diastereomerically or enantiomerically enriched forms. Where chirality is not specified, it is understood that the embodiment is directed to either a particular diastereomerically or enantiomerically enriched form, or to a racemic or scalemic mixture of such a compound. As used herein, a "scalemic mixture" is a mixture of stereoisomers in a ratio other than 1:1.

[0044] As used herein, "stereoisomers" refer to compounds made up of the same atoms connected by the same bonds but with different, not interchangeable, three-dimensional structures. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0045] As used herein, "tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. In some embodiments, the present disclosure includes tautomers of the compounds.

[0046] As used herein, "solvate" refers to the result of the interaction of a solvent with a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0047] As used herein, "hydrate" refers to a compound of the present disclosure that is chemically associated with one or more molecules of water.

[0048] "Prevention" or "preventing" means any treatment of a disease or condition that results in the non-development of clinical symptoms of the disease or condition. In some embodiments, the compounds may be administered to subjects (including humans) who are at risk or have a family history of the disease or condition.

[0049] As used herein, "prodrug" refers to a derivative of a drug that, upon administration to the human body, is converted into the parent drug by some chemical or enzymatic pathway. In some embodiments, a prodrug is a biologically inactive derivative of a drug that, upon administration to the human body, is converted into the biologically active parent drug by some chemical or enzymatic pathway.

[0050] As used herein, "treatment" or "treating" or "treating" refers to an approach for obtaining a beneficial or desired result. For purposes of this disclosure, a beneficial or desired result includes, but is not limited to, alleviating symptoms and / or reducing the severity of symptoms and / or preventing the worsening of symptoms associated with a disease or condition. In one embodiment, "treatment" or "treating" refers to a) inhibiting a disease or condition (e.g., reducing one or more symptoms resulting from a disease or condition, and / or preventing the disease or condition from worsening). The therapeutic effects of the present invention include one or more of the following: a) reducing the severity of the condition; b) delaying or halting the onset of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition); and c) alleviating the disease or condition, e.g., causing regression of clinical symptoms, ameliorating pathology, delaying disease progression, improving quality of life, and / or prolonging survival. As used herein, "individual at risk" refers to an individual who is at risk of developing the condition being treated. An "at risk" individual may or may not have a detectable disease or condition and may or may not exhibit detectable disease prior to treatment with the methods described herein. "At risk" means that an individual has one or more so-called risk factors, which are measurable parameters that correlate with the development of a disease or condition and are known in the art. Individuals who have one or more of these risk factors have a higher probability of developing the disease or condition than individuals without these risk factors.

[0051] II. Compounds In some embodiments, compounds of the present disclosure have formula (I):

[0052] [ka] [In the formula, R 1 teeth, i) 1 to 4 R 4 5-membered heteroaryl optionally substituted with ii) a 5-membered heteroaryl fused to a heteroaryl or aryl to form a heteroaryl ring system, wherein the heteroaryl ring system is fused to 1 to 4 R 4 5-membered heteroaryl optionally substituted with iii) Two R's attached to adjacent ring atoms 4 group and one or two further R 4 a 5-membered heteroaryl optionally substituted with two R4 The groups, in combination with the atoms to which they are attached, are one to four R 6 C, each optionally substituted with 5~10 5-membered heteroaryl, forming a cycloalkyl or heterocyclyl; iv) a 6-membered heteroaryl or phenyl substituted with a C2-alkynyl, wherein the 6-membered heteroaryl or phenyl is selected from the group consisting of 1 to 3 R 4 and C2-alkynyl is substituted with -C(CH3)2SO2CH3, aryl, heteroaryl, or heterocyclyl, and the aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 4 R 5 6-membered heteroaryl or phenyl optionally substituted with v) -C(O)NR a R b a 6-membered heteroaryl or phenyl substituted with 1 to 4 R 4 a 6-membered heteroaryl or phenyl optionally substituted with vi) a 6-membered heteroaryl or phenyl, wherein the 6-membered heteroaryl or phenyl is heteroaryl, C 3~10 substituted with cycloalkyl or heterocycle and 1 to 3 R 4 and wherein the heteroaryl, C cycloalkyl, or heterocycle is each optionally substituted with C 3~10 Cycloalkyl, heterocyclyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 1~6 Alkyl-heterocyclyl, or C 1~6 Alkyl-heteroaryl substituted, C 3~10 Cycloalkyl, heterocyclyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 1~6 Alkyl-heterocyclyl, or C 1~ 6 alkyl-heteroaryl is 1 to 4 R 6 6-membered heteroaryl or phenyl optionally substituted with and X 1 , X 2 , and X 3 are each independently -C(H)= or -C(R 8 )=, Each ring A is independently C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 1 to 3 Z's that are haloalkoxy, halogen, -OH, or -CN; 1a each optionally substituted with a group;

[0053] [ka] and Ring B is 1 to 4 R 4 C, each optionally substituted with 6~10 is aryl or heteroaryl, V is -C(O)-, -O-, -N(R 6a )- or -C(R 6b )(R 6c )- and R 2 is H, C 1~6 Alkyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~10 cycloalkyl, or heterocyclyl; Alkyl, alkynyl, cycloalkyl, or heterocyclyl may have 1 to 4 Z 1 and each Z 1 independently, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -OH, -CN, C 1~6 Alkyl-CN, -OC 3~6 Cycloalkyl, heterocyclyl, C 3~10 cycloalkyl, or heteroaryl, each independently C1~6 Alkyl, C 1~6 Alkoxy, halogen, -CN, C 1~6 Haloalkyl, or C 1~6 optionally substituted with 1 to 4 groups that are haloalkoxy; R 3 is -C(O)OR 3a and R 3a is H, C 1~4 Alkyl-N(R 9a )(R 9b ), -C 1~4 Alkyl-N(R 9a )C(O)-OC 1~4 Alkyl-OP(O)(OR 9c )2, C 1~4 Alkyl-C(O)N(R 9a )(R 9b ), -C 1~4 Alkyl-OC(O)-C 1~4 Alkyl, -C 1~4 Alkyl-OC(O)-OC 1~4 Alkyl, -C 1~4 Alkyl-OC(O)-C 1~4 Alkyl-N(R 9a )(R 9b ), -C 1~4 Alkyl-OC(O)-C 1~4 Alkyl-OP(O)(OR 9c )2, -CH2CH(N(R 9a )2)C(O)OR 9b , -P(O)(OR 9c )2, -OP(O)(OR 9c )2, -CH2P(O)(OR 9c )2, -CH2OP(O)(OR 9c )2, -OCH2P(O)(OR 9c )2, C(O)OCH2P(O)(OR 9c )2, -P(O)(R 9c )(OR 9d ), -OP(O)(R 9c )(OR 9d ), -CH2P(O)(R 9c )(OR 9d ), -OCH2P(O)(R 9c )(OR9d ), -C(O)OCH2P(O)(R 9c )(OR 9d ), -P(O)(N(R 9c )2)2, -OP(O)(N(R 9c )2)2, -CH2P(O)(N(R 9c )2)2, -OCH2P(O)(N(R 9c )2)2, -C(O)OCH2P(O)(N(R 9c )2)2, -P(O)(N(R 9c )2)(OR 9d ), -OP(O)(N(R 9c )2)(OR 9d ), -CH2P(O)(N(R 9c )2)(OR 9d ), -OCH2P(O)(N(R 9c )2)(OR 9d ), -C(O)OCH2P(O)(N(R 9c )2)(OR 9d ), -P(O)(R 9c )(N(R 9d )2), -OP(O)(R 9c )(N(R 9d )2), -CH2P(O)(R 9c )(N(R 9d )2), -OCH2P(O)(R 9c )(N(R 9d )2), -C(O)OCH2P(O)(R 9c )(N(R 9d )2) or C 1~6 alkyl-heterocyclyl, The alkyl or heterocyclyl are each optionally substituted with 1 to 4 halogens. the law of nature, Each R 4 independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10Aryl, heteroaryl, oxo, -NO2, -N3, -CN, -OR 10a , -C(O)R 10a , -C(O)OR 10a , -C(O)-N(R 10a )(R 10b ), -N(R 10a )(R 10b ), -N(R 10a )2(R 10b ) + , -N(R 10a )C(O)-R 10b , -N(R 10a )C(O)OR 10b , -N(R 10a )C(O)N(R 10b )(R 10c ), -N(R 10a )S(O)2(R 10b ), -NR 10a S(O)2N(R 10b )(R 10c ), -NR 10a S(O)2O(R 10b ), -OC(O)R 10a , -OC(O)OR 10a , -OC(O)-N(R 10a )(R 10b ), -SR 10a , -S(O)R 10a , -S(O)(NH)R 10a , -S(O)2R 10a , -S(O)2N(R 10a )(R 10b ), -S(O)(NR 10a )R 10b , or -Si(R 10a )3, Each alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be selected from 1 to 4 R 5 and optionally substituted with Each R 5 independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -NO2, -N3, -CN, -OR 10a , -C(O)-R 10a , -C(O)OR 10a , -C(O)N(R 10a )(R 10b ), -N(R 10a )(R 10b ), -N(R 10a )C(O)R 10b , -N(R 10a )C(O)OR 10b , -N(R 10a )C(O)N(R 10b )(R 10c ), -N(R 10a )S(O)2(R 10b ), -NR 10a S(O)2N(R 10b )(R 10c ), -NR 10a S(O)2O(R 10b ), -OC(O)R 10a , -OC(O)OR 10a , -OC(O)-N(R 10a )(R 10b ), -SR 10a , -S(O)R 10a , -S(O)(NH)R 10a , -S(O)2R 10a , -S(O)2N(R 10a )(R 10b ), -S(O)(NR 10a )R 10b , or -Si(R 10a )3, Each alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be selected from 1 to 4 R 6 and optionally substituted with Each R 6 and R 8 independently, C 1~9Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 -Cycloalkyl), -O(heterocyclyl), -O(C 6~10 aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(heterocyclyl), -NH(C 6~10 aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 1~8 haloalkyl)2, -N(C 2~6 alkenyl)2, -N(C 2~6 alkynyl)2, -N(C 3~15 -N(cycloalkyl)2, -N(heterocyclyl)2, -N(C 6~10 aryl), -N(heteroaryl), -N(C 1~9 Alkyl)(C 1~8 haloalkyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 alkyl)(heterocyclyl), -N(C 1~9 Alkyl)(C 6~10 aryl), -N(C 1~9 alkyl)(heteroaryl), -C(O)(C 1~9 alkyl), -C(O)(C1~8 haloalkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 -C(O)(cycloalkyl), -C(O)(heterocyclyl), -C(O)(C 6~10 aryl), -C(O)(heteroaryl), -C(O)O(C 1~9 alkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(heterocyclyl), -C(O)O(C 6~10 aryl), -C(O)O(heteroaryl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 1~8 haloalkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -C(O)NH(C 3~15 cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(C 6~10 aryl), -C(O)NH(heteroaryl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C 6~10 aryl), -C(O)N(heteroaryl), -NHC(O)(C 1~9 alkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 2~6 alkenyl), -NHC(O)(C 2~6 alkynyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6~10aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1~9 alkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(heterocyclyl), -NHC(O)NH(C 6~10 aryl), -NHC(O)NH(heteroaryl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)(S(O)(C 1~9 alkyl), -S(C 1~9 alkyl), -S(C 1~8 haloalkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 -S(cycloalkyl), -S(heterocyclyl), -S(C 6~10 -S(aryl), -S(heteroaryl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(C 1~8 haloalkyl), -S(O)(C 2~6 alkenyl), -S(O)(C 2~6 alkynyl), -S(O)(C 3~15 -S(O)(cycloalkyl), -S(O)(heterocyclyl), -S(O)(C 6~10 aryl), -S(O)(heteroaryl), -S(O)2(C 1~9 alkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(C 6~10 aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1~9 alkyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, Each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may have 1 to 3 C 1~9 Alkyl, C 1~8 Haloalkyl, halogen, -OH, -NH2, CO2H, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 3~15 -cycloalkyl), -O(heterocyclyl), -O(aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C 3~15 -cycloalkyl), -NH(heterocyclyl), -NH(aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1~9 alkyl) , S(O)2(C 1~9 alkyl), -S(O)2(C 1~8haloalkyl), -S(O)2(C 3~15 -cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)(NH)(C 1~9 alkyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 optionally substituted with alkyl; alkyl or heterocyclyl are each optionally substituted with 1 to 4 halogens; R 6a is H, C 1~6 Alkyl, C 3~10 Cycloalkyl, heterocyclyl, -S(O)2R 6a1 , or -S(O)N(R 6a1 )(NR 6a2 ) and cycloalkyl or heterocyclyl is C 1~6 each optionally substituted with alkyl, F, or —CN; Each R 6b and R 6c are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkoxyalkyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, -C 1~6 Alkyl-N(R 9a )(R 9b ), -CN, -OR 6c1 , or -N(R 6c2 )(R 6c3 ) and Alkyl, cycloalkyl, or heterocyclyl may have 1 to 4 R 6b1 each optionally substituted with R 6b and R 6c are combined with the atoms to which they are attached to form 1 to 4 R 6b1 C, each optionally substituted with 3~10 forming a cycloalkyl or heterocyclyl; or R 6a or R 6c is one R 4In combination with the groups and the atoms to which they are attached, one to four R 10 C, each optionally substituted with 5~10 forming a cycloalkyl or heterocyclyl, each R6 6b1 and R 10 independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, COR 3e , -NO2, or -C(O)N(R 2a )(R 2b ) and Heterocyclyl or heteroaryl is C 1~6 Alkyl, C 1~6 Haloalkyl, or C 1~6 optionally substituted with haloalkoxy; Each R 6a1 , R 6a2 , R 6c1 , R 6c2 , and R 6c3 are independently H, C 1~6 Alkyl, or C 3~10 is cycloalkyl, Each R 9a and R 9b are independently H, C 1~6 Alkyl, or C 1~6 haloalkyl, or R 9a and R 9b together form a 6-membered heterocyclyl, Each R 9c , R 9d , R 10a , R 10b , and R 10c are independently H, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C3~15 Cycloalkyl, heterocyclyl, C 6~10 aryl or heteroaryl; Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from 1 to 4 R 6 each optionally substituted with R a and R b are independently H, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 aryl, or heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from 1 to 4 R 6 each optionally substituted with Optionally, R a and R b are combined with the atoms to which they are attached to form 1 to 4 R 6 forming a 5- or 6-membered heterocyclyl optionally substituted with Each R 2a , R 2b , R 12a , R 12b , and R 12c are independently H, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 aryl or heteroaryl; Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or Heteroaryl is a group consisting of 1 to 4 R 6 each optionally substituted with Each R 3e are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, -C 1~4 Alkyl-N(R 9a )(R 9b), -C 1~4 Alkyl-C(O)N(R 9a )(R 9b ), -C 1~4 Alkyl-OC(O)-C 1~4 Alkyl, -C 1~4 Alkyl-OC(O)-OC 1~4 Alkyl, -C 1~4 Alkyl-OC(O)-C 1~4 Alkyl-N(R 9a )(R 9b ), -C 1~4 Alkyl-C 3~8 Cycloalkyl, -C 1~4 Alkyl-heterocyclyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -P(O)(OR 9c )2, -CH2P(O)(OR 9c )2, -OCH2P(O)(OR 9c )2, -C(O)OCH2P(O)(OR 9c )2, -P(O)(R 9c )(OR 9d ), -OP(O)(R 9c )(OR 9d ), -CH2P(O)(R 9c )(OR 9d ), -C(O)OCH2P(O)(R 9c )(OR 9d ), -P(O)(N(R 9c )2)2, -CH2P(O)(N(R 9c )2)2, -C(O)OCH2P(O)(N(R 9c )2)2, -P(O)(N(R 9c )2)(OR 9d ), -CH2P(O)(N(R 9c )2)(OR 9d ), -C(O)OCH2P(O)(N(R 9c )2)(OR 9d ), -P(O)(R 9c )(N(R 9d )2), -CH2P(O)(R 9c )(N(R 9d )2), or -C(O)OCH2P(O)(R 9c )(N(R9d )2) and Alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is a group consisting of 1 to 4 R 6 each optionally substituted with each heteroaryl has 5 to 12 ring members and 1 to 4 heteroatoms, each independently N, O, or S; each heterocyclyl has 3 to 12 ring members and 1 to 4 heteroatoms, each independently N, O, or S; Each heteroaryl has 5 to 12 ring members and 1 to 4 heteroatoms, each independently N, O, or S. or a pharmaceutically acceptable salt thereof.

[0054] In some embodiments of the compounds of Formula (I) or pharmaceutically acceptable salts thereof, R 1 teeth, i) 1 to 4 R 4 5-membered heteroaryl optionally substituted with ii) a 5-membered heteroaryl fused to a heteroaryl or aryl to form a heteroaryl ring system, wherein the heteroaryl ring system is fused to 1 to 4 R 4 a 5-membered heteroaryl optionally substituted with iii) Two R's attached to adjacent ring atoms 4 group and one or two further R 4 a 5-membered heteroaryl optionally substituted with two R 4 The groups, in combination with the atoms to which they are attached, are one to four R 6 C, each optionally substituted with 5~10 5-membered heteroaryl, forming a cycloalkyl or heterocyclyl; is.

[0055] In some embodiments, R 1 is 1 to 4 R 4pyrrolyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, benzoxazolyl, indazolyl, benzofuranyl, benzimidazolyl, pyrrolo[2,3-b]pyridinyl, triazolyl, tetrazolyl, thiazolo[5,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrazinyl, or 1λ optionally substituted by 2 -thieno[3,2-d]pyrazolyl; or 2 to 4 R 4 a 5-membered heteroaryl substituted with two R attached to adjacent ring atoms; 4 The groups, in combination with the atoms to which they are attached, are one to four R 6 C, each optionally substituted with 5~6 It is a 5-membered heteroaryl, forming a cycloalkyl or heterocyclyl. In the embodiment, R 1 is 1 to 4 R 4 pyrazolyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, benzimidazolyl, triazolyl, thiazolo[5,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrazinyl, or 1λ optionally substituted by 2 -thieno[3,2-d]pyrazolyl; or 2 to 4 R 4 and wherein two R are attached to adjacent pyrazolyl atoms. 4 The groups, in combination with the atoms to which they are attached, are one to four R 6 C, each optionally substituted with 5~6 It is pyrazolyl, forming a cycloalkyl or heterocyclyl.

[0056] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, R1 is 1 to 4 R 4 In some embodiments, R is a 5-membered heteroaryl optionally substituted with 1 is 1 to 4 R 4 In some embodiments, R is pyrrolyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, triazolyl, or tetrazolyl, optionally substituted with 1 is 1 to 4 R 4 In some embodiments, R is thiazolyl, pyrrolyl, imidazolyl, oxazolyl, or triazolyl optionally substituted with 1 is 1 to 4 R 4 In some embodiments, R is pyrrolyl optionally substituted with 1 is 1 to 4 R 4 In some embodiments, R is imidazolyl optionally substituted with 1 is 1 to 4 R 4 In some embodiments, R is oxazolyl optionally substituted with 1 is 1 to 4 R 4 In some embodiments, R is triazolyl optionally substituted with 1 is 1 to 4 R 4 In some embodiments, R is thiazolyl optionally substituted with 1 is one or two R 4 In some embodiments, R 1 is one or two R 4 In some embodiments, R 1 is one R 4 In some embodiments, R 1 is one R 4 In some embodiments, R 1 is non-substituted.

[0057] In some embodiments, R 1is one R 4 are respectively replaced by

[0058] [ka] is.

[0059] In some embodiments, R 1 teeth,

[0060] [ka]

[0061] [ka]

[0062] [ka] is.

[0063] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, R 1 teeth,

[0064] [ka] is.

[0065] In some embodiments, R 1 teeth,

[0066] [ka] is.

[0067] In some embodiments, R 1 teeth,

[0068] [ka] is.

[0069] In some embodiments, R 1 teeth,

[0070] [ka] is.

[0071] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, R 1 is a 5-membered heteroaryl fused to a heteroaryl or aryl to form a heteroaryl ring system, the heteroaryl ring system being fused to 1-4 R 4 In some embodiments, R 1 is 1 to 4 R 4 benzothiazolyl, benzoxazolyl, indazolyl, benzofuranyl, benzimidazolyl, pyrrolo[2,3-b]pyridinyl, thiazolo[5,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrazinyl, or 1λ optionally substituted by 2 -thieno[3,2-d]pyrazolyl. In some embodiments, R 1 is one or two R 4 In some embodiments, R 1 is one R 4 In some embodiments, R 1 is one R 4 In some embodiments, R 1 is unsubstituted. In some embodiments, R 1 teeth,

[0072] [ka] is.

[0073] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, R 1 represents two Rs attached to adjacent ring atoms. 4 group and one or two further R 4 and wherein two R are attached to adjacent ring atoms. 4 The groups, in combination with the atoms to which they are attached, are one to four R 6 C, each optionally substituted with 5~10 In some embodiments, R 1 represents two Rs attached to adjacent ring atoms. 4 group and one or two further R 4 and wherein two R are attached to adjacent ring atoms. 4 The groups, in combination with the atoms to which they are attached, are one to four R 6 In some embodiments, R 1 represents two Rs attached to adjacent ring atoms. 4 group and one or two further R 4 and wherein two R are attached to adjacent ring atoms. 4 The groups, in combination with the atoms to which they are attached, may be one or two R 6 In some embodiments, R 1 teeth,

[0074] [ka] is.

[0075] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, R 1is a 6-membered heteroaryl or phenyl substituted with a C2-alkynyl, and the 6-membered heteroaryl or phenyl is 4 and C2-alkynyl is substituted with -C(CH3)2SO2CH3, aryl, heteroaryl, or heterocyclyl, and the aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 4 R 5 In some embodiments, R 1 is pyridyl, pyrazinyl, pyrimidinyl, or phenyl substituted with C2-alkynyl, and the pyridyl, pyrazinyl, pyrimidinyl, or phenyl is selected from the group consisting of 1 to 3 R 4 and C2-alkynyl is substituted with -C(CH3)2SO2CH3, aryl, heteroaryl, or heterocyclyl, and the aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 4 R 5 In some embodiments, the pyridyl, pyrazinyl, pyrimidinyl, or phenyl is optionally substituted with one or two R 4 In some embodiments, pyridyl, pyrazinyl, pyrimidinyl, or phenyl is optionally substituted with one R 4 In some embodiments, pyridyl, pyrazinyl, pyrimidinyl, or phenyl is optionally substituted with one R 4 In some embodiments, the pyridyl, pyrazinyl, pyrimidinyl, or phenyl is unsubstituted. In some embodiments, R 1 teeth,

[0076] [ka]

[0077] [ka] is.

[0078] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, R1 is -C(O)NR a R b and the heteroaryl or phenyl is a 6-membered heteroaryl or phenyl substituted with 1 to 4 R 4 In some embodiments, R 1 is -C(O)NR a R b and the pyridyl, pyrazinyl, pyrimidinyl, or phenyl is substituted with 1 to 4 R 4 Some embodiments are optionally substituted with R 1 is -C(O)NR a R b and the pyridyl, pyrazinyl, or phenyl is substituted with 1 to 4 R 4 In some embodiments, the pyridyl, pyrazinyl, or phenyl is optionally substituted with one or two R 4 In some embodiments, pyridyl, pyrazinyl, or phenyl is optionally substituted with one R 4 In some embodiments, pyridyl, pyrazinyl, or phenyl is optionally substituted with one R 4 In some embodiments, the pyridyl, pyrazinyl, or phenyl is unsubstituted. In some embodiments, R 1 teeth,

[0079] [ka]

[0080] [ka] is.

[0081] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, R 1is a 6-membered heteroaryl or phenyl, and the 6-membered heteroaryl or phenyl is a heteroaryl, C 3~10 substituted with cycloalkyl or heterocycle and 1 to 3 R 4 and optionally substituted with heteroaryl, C 3~10 cycloalkyl, or heterocycle, each of which is C 3~10 Cycloalkyl, heterocyclyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 1~6 Alkyl-heterocyclyl, or C 1~6 Alkyl-heteroaryl substituted, C 3~10 Cycloalkyl, heterocyclyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 1~6 Alkyl-heterocyclyl, or C 1~6 The alkyl-heteroaryl is selected from 1 to 4 R 6 is optionally substituted with

[0082] In some embodiments, R 1 is pyridyl, pyrazinyl, pyrimidinyl, or phenyl, and pyridyl, pyrazinyl, pyrimidinyl, or phenyl is heteroaryl, C 3~10 substituted with cycloalkyl or heterocycle and 1 to 3 R 4 and optionally substituted with heteroaryl, C 3~10 cycloalkyl, or heterocycle, each of which is C 1~6 Alkyl, C 3~10 substituted with cycloalkyl or heterocyclyl, C 1~6 Alkyl, C 3~10 Cycloalkyl or heterocyclyl is 1 to 4 R 6 In some embodiments, R 1 is pyridyl or phenyl, and the pyridyl or phenyl is heteroaryl, C 3~10 substituted with cycloalkyl or heterocycle and 1 to 3 R 4 and optionally substituted with heteroaryl, C 3~10cycloalkyl, or heterocycle, each of which is C 1~6 Alkyl, C 3~10 substituted with cycloalkyl or heterocyclyl, C 1~6 Alkyl, C 3~10 Cycloalkyl or heterocyclyl is 1 to 4 R 6 In some embodiments, R 1 is pyridyl, pyrazinyl, pyrimidinyl, or phenyl, wherein the pyridyl, pyrazinyl, pyrimidinyl, or phenyl is substituted with heteroaryl, and 1 to 3 R 4 and the heteroaryl is optionally substituted with C 1~6 Alkyl, C 3~10 substituted with cycloalkyl or heterocyclyl, C 1~6 Alkyl, C 3~10 Cycloalkyl or heterocyclyl is 1 to 4 R 6 In some embodiments, R 1 teeth,

[0083] [ka] is.

[0084] In an embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X, X 2 , and X 3 are each independently -CH=, -C(F)=, -C(Cl)=, -C(Br)=, or -C(CN)=. In some embodiments, X 1 , X 2 , and X 3 are each independently -CH= or -C(F)=. In some embodiments, X 1 , X 2 , and X 3 In some embodiments, two of the groups are -CH= and one is -C(F)=. is X 1 is -C(F)=X 2 and X 3are each -CH=. In some embodiments, X 2 is -C(F)=X 1 and X 3 are each -CH=. In some embodiments, X 1 and X 2 are -CH=, and X 3 is -C(F)=. In some embodiments, X 1 , X 2 , and X 3 are -CH=, respectively.

[0085] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, ring A is 1 to 3 Zs 1a each optionally substituted with a group

[0086] [ka] is. In some embodiments, ring A is selected from the group consisting of 1 to 3 Z 1a each optionally substituted with a group;

[0087] [ka] is.

[0088] In some embodiments, ring A is 1 to 3 Zs 1a optionally substituted with a group

[0089] [ka] is.

[0090] In some embodiments, ring A is optionally substituted with 1 halogen.

[0091] [ka] In some embodiments, ring A is substituted with one halogen.

[0092] [ka] In some embodiments, ring A is Substituted with F or Cl

[0093] [ka] In some embodiments, ring A is Substituted with F

[0094] [ka] In some embodiments, ring A is Substituted with Cl

[0095] [ka] In some embodiments, ring A is unsubstituted

[0096] [ka] is.

[0097] In some embodiments, ring A is 1 Z 1a optionally substituted with a group

[0098] [ka] In some embodiments, ring A is optionally substituted with one halogen

[0099] [ka] In some embodiments, ring A is unsubstituted

[0100] [ka] is.

[0101] In some embodiments, ring A is selected from the group consisting of one Z 1a In some embodiments, ring A is optionally substituted with one halogen. In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, ring B is C 6~10 aryl, or a 5- to 10-membered heteroaryl having 1 to 3 heteroatoms, each independently N, O, or S; and the aryl or heteroaryl is selected from 1 to 4 R 4 In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, ring B is optionally substituted with C having 1 to 3 heteroatoms, each independently being N, O, or S. 6~10 aryl, wherein the aryl is selected from 1 to 4 R 4 In some embodiments, Ring B is optionally substituted with 1 to 3 R. In some embodiments, Ring B is phenyl or 5-6 membered heteroaryl having 1 to 3 heteroatoms, each independently N, O, or S. In some embodiments, Ring B is phenyl. In some embodiments, Ring B is optionally substituted with 1 to 3 R 4 In some embodiments, ring B is phenyl optionally substituted with one or two R 4 In some embodiments, ring B is phenyl optionally substituted with three R 4 In some embodiments, ring B is phenyl optionally substituted with two R 4 In some embodiments, ring B is phenyl optionally substituted with one R 4 In some embodiments, ring B is phenyl optionally substituted with two R 4In some embodiments, ring B is phenyl substituted with two R 4 is replaced by .

[0102] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, V is —O— or —C(R 6b )(R 6c In some embodiments, V is —O—. In some embodiments, V is —C(R 6b )(R 6c )-. In some embodiments, V is -CH2-.

[0103] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, R 2 is C 1~6 alkyl or heterocyclyl, wherein the alkyl or heterocyclyl is selected from 1 to 4 Z 1 and each Z 1 independently, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -OH, -CN, C 1~6 Alkyl-CN, -OC 3~6 Cycloalkyl, heterocyclyl, C 3~10 cycloalkyl, or heteroaryl, each independently C 1~6 Alkyl, C 1~6 Alkoxy, halogen, -CN, C 1~6 Haloalkyl, or C 1~6 In some embodiments, R is optionally substituted with 1 to 4 groups that are haloalkoxy. 2 is C 1~6 alkyl or heterocyclyl, wherein the alkyl or heterocyclyl is selected from 1 to 4 Z 1 and each Z 1 independently, C 1~6 Alkyl, C 1~6In some embodiments, each Z is alkoxy or heterocyclyl. 1 independently, C 1~6 Alkyl, C 1~6 Alkoxy, heterocyclyl, or C 3~10 In some embodiments, R 2 teeth,

[0104] [ka] is.

[0105] In some embodiments, R 2 teeth,

[0106] [ka] is.

[0107] In some embodiments, R 2 teeth,

[0108] [ka] is.

[0109] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, R 3 is —C(O)OH.

[0110] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, each R 4 independently, C 1~9 In some embodiments, each R 4 is independently halogen. In some embodiments, each R 4 is independently methyl or F. In some embodiments, each R 4 is F.

[0111] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, each R 5 independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -NO2, -N3, -CN, -OR 10a , -C(O)-R 10a , -C(O)OR 10a , -C(O)N(R 10a )(R 10b ), -N(R 10a )(R 10b ), -N(R 10a )C(O)R 10b , -N(R 10a )C(O)OR 10b , -N(R 10a )C(O)N(R 10b )(R 10c ), -N(R 10a )S(O)2(R 10b ), -NR 10a S(O)2N(R 10b )(R 10c ), -NR 10a S(O)2O(R 10b ), -OC(O)R 10a , -OC(O)OR 10a , -OC(O)-N(R 10a )(R 10b ), -SR 10a , -S(O)R 10a , -S(O)(NH)R 10a , -S(O)2R 10a , -S(O)2N(R 10a )(R 10b ), -S(O)(NR 10a )R 10b , or -Si(R 10a)3, and each alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from 1 to 4 R 6 is optionally substituted with

[0112] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, each R 6 or R 8 independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 -Cycloalkyl), -O(heterocyclyl), -O(C 6~10 aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(heterocyclyl), -NH(C 6~10 aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 1~8 haloalkyl)2, -N(C 2~6 alkenyl)2, -N(C 2~6 alkynyl)2, -N(C 3~15 -N(cycloalkyl)2, -N(heterocyclyl)2, -N(C 6~10 aryl), -N(heteroaryl), -N(C 1~9 Alkyl)(C 1~8 haloalkyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C1~9 Alkyl)(C 2~6 alkynyl), -N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 alkyl)(heterocyclyl), -N(C 1~9 Alkyl)(C 6~10 aryl), -N(C 1~9 alkyl)(heteroaryl), -C(O)(C 1~9 alkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 -C(O)(cycloalkyl), -C(O)(heterocyclyl), -C(O)(C 6~10 aryl), -C(O)(heteroaryl), -C(O)O(C 1~9 alkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(heterocyclyl), -C(O)O(C 6~10 aryl), -C(O)O(heteroaryl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 1~8 haloalkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -C(O)NH(C 3~15 cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(C 6~10 aryl), -C(O)NH(heteroaryl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C 6~10aryl), -C(O)N(heteroaryl), -NHC(O)(C 1~9 alkyl), -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 2~6 alkenyl), -NHC(O)(C 2~6 alkynyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6~10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 1~8 haloalkyl), -NHC(O)O(C 2~6 alkenyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(C 6~10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1~9 alkyl), -NHC(O)NH(C 1~8 haloalkyl), -NHC(O)NH(C 2~6 alkenyl), -NHC(O)NH(C 2~6 alkynyl), -NHC(O)NH(C 3~15 cycloalkyl), -NHC(O)NH(heterocyclyl), -NHC(O)NH(C 6~10 aryl), -NHC(O)NH(heteroaryl), -NHS(O)(C 1~9 alkyl), -N(C 1~9 alkyl)(S(O)(C 1~9 alkyl), -S(C 1~9 alkyl), -S(C 1~8 haloalkyl), -S(C 2~6 alkenyl), -S(C 2~6 alkynyl), -S(C 3~15 -S(cycloalkyl), -S(heterocyclyl), -S(C 6~10 -S(aryl), -S(heteroaryl), -S(O)N(C 1~9 alkyl)2, -S(O)(C 1~9 alkyl), -S(O)(C 1~8haloalkyl), -S(O)(C 2~6 alkenyl), -S(O)(C 2~6 alkynyl), -S(O)(C 3~15 -S(O)(cycloalkyl), -S(O)(heterocyclyl), -S(O)(C 6~10 aryl), -S(O)(heteroaryl), -S(O)2(C 1~9 alkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 2~6 alkenyl), -S(O)2(C 2~6 alkynyl), -S(O)2(C 3~15 cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(C 6~10 aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1~9 alkyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, and each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from 1 to 3 C 1~9 Alkyl, C 1~8 Haloalkyl, halogen, -OH, -NH2, CO2H, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 3~15 -cycloalkyl), -O(heterocyclyl), -O(aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C 3~15 -cycloalkyl), -NH(heterocyclyl), -NH(aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 3~15 cycloalkyl)2, -NHC(O)(C 1~8 haloalkyl), -NHC(O)(C 3~15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1~9 alkyl), -NHC(O)O(C 1~8haloalkyl), -NHC(O)O(C 2~6 alkynyl), -NHC(O)O(C 3~15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1~9 alkyl), S(O)2(C 1~9 alkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 3~15 -cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)(NH)(C 1~9 alkyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, and the alkyl or heterocyclyl are each optionally substituted with 1 to 4 halogens.

[0113] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, R 6a is H, C 1~6 Alkyl, C 3~10 Cycloalkyl, heterocyclyl, -S(O)2R 6a1 , or -S(O)N(R 6a1 )(NR 6a2 ) and cycloalkyl or heterocyclyl is C 1~6 Each is optionally substituted with alkyl, F, or —CN.

[0114] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, each R 6b and R 6c are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkoxyalkyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, -C 1~6 Alkyl-N(R 9a )(R 9b ), -CN, -OR 6c1 , or -N(R6c2 )(R 6c3 ) and the alkyl, cycloalkyl, or heterocyclyl is selected from 1 to 4 R 6b1 each optionally substituted with

[0115] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, R 6b and R 6c are combined with the atoms to which they are attached to form 1 to 4 R 6b1 C, each optionally substituted with 3~10 It forms a cycloalkyl or heterocyclyl.

[0116] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, R 6a or R 6c is one R 4 In combination with the groups and the atoms to which they are attached, one to four R 10 C, each optionally substituted with 5~10 It forms a cycloalkyl or heterocyclyl.

[0117] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, each R 6b1 and R 10 independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, COR 3e , -NO2, or -C(O)N(R 2a )(R 2b ) wherein the heterocyclyl or heteroaryl is C 1~6 Alkyl, C 1~6 Haloalkyl, or C 1~6Optionally substituted with haloalkoxy.

[0118] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, each R 6a1 , R 6a2 , R 6c1 , R 6c2 , and R 6c3 are independently H, C 1~6 Alkyl or C 3~10 It is cycloalkyl.

[0119] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, each R 9a and R 9b are independently H, C 1~6 Alkyl or C 1~6 haloalkyl, or R 9a and R 9b together form a 6-membered heterocyclyl.

[0120] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, each R 9 c , R 9d , R 10a , R 10b , and R 10c are independently H, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 aryl, or heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from 1 to 4 R 6 each optionally substituted with

[0121] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, R a and R b are independently H, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6Alkynyl, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 aryl, or heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from 1 to 4 R 6 each optionally substituted with

[0122] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R a and R b are combined with the atoms to which they are attached to form 1 to 4 R 6 to form a 5- or 6-membered heterocyclyl optionally substituted by

[0123] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, each R 2a , R 2b , R 12a , R 12b , and R 12c are independently H, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 aryl, or heteroaryl, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from 1 to 4 R 6 each optionally substituted with

[0124] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, each R 3e are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, -C 1~4 Alkyl-N(R 9a )(R 9b ), -C 1~4 Alkyl-C(O)N(R 9a )(R 9b ), -C 1~4 Alkyl-OC(O)-C 1~4Alkyl, -C 1~4 Alkyl-OC(O)-OC 1~4 Alkyl, -C 1~4 Alkyl-OC(O)-C 1~4 Alkyl-N(R 9a )(R 9b ), -C 1~4 Alkyl-C 3~8 Cycloalkyl, -C 1~4 Alkyl-heterocyclyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -P(O)(OR 9c )2, -CH2P(O)(OR 9c )2, -OCH2P(O)(OR 9c )2, -C(O)OCH2P(O)(OR 9c )2, -P(O)(R 9c )(OR 9d ), -OP(O)(R 9c )(OR 9d ), -CH2P(O)(R 9c )(OR 9d ), -C(O)OCH2P(O)(R 9c )(OR 9d ), -P(O)(N(R 9c )2)2, -CH2P(O)(N(R 9c )2)2, -C(O)OCH2P(O)(N(R 9c )2)2, -P(O)(N(R 9c )2)(OR 9d ), -CH2P(O)(N(R 9c )2)(OR 9d ), -C(O)OCH2P(O)(N(R 9c )2)(OR 9d ), -P(O)(R 9c )(N(R 9d )2), -CH2P(O)(R 9c )(N(R 9d )2), or -C(O)OCH2P(O)(R 9c )(N(R 9d )2) wherein alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from 1 to 4 R 6wherein each heteroaryl has 5 to 12 ring members and 1 to 4 heteroatoms that are each independently N, O, or S; and each heterocyclyl has 3 to 12 ring members and 1 to 4 heteroatoms that are each independently N, O, or S.

[0125] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, each heteroaryl has 5 to 12 ring members and 1 to 4 heteroatoms, each independently N, O, or S.

[0126] In some embodiments, a compound of formula (II):

[0127] [ka] [In the formula, R 1 is R 4 is thiazolyl optionally substituted with X 1 -C(H)= or -C(R 8 )=, X 4 is -C(H)=, -C(R 8 )= or N, Each R B independently, C 1~9 Alkyl, C 1~8 haloalkyl or halogen; Each R 8 are independently halogen; n is 0, 1, 2, or 3. or a pharmaceutically acceptable salt thereof.

[0128] In some embodiments, the compound of formula (I) is a compound according to formula (II).

[0129] In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt thereof, R 1 are C 1~8substituted with haloalkyl,

[0130] [ka] is.

[0131] In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt thereof, R 1 teeth,

[0132] [ka] is.

[0133] In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt thereof, R 8 is F or Cl.

[0134] In some embodiments, the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, has the structure of the compound in Table 2.

[0135] In vivo metabolic products of the compounds described herein are also disclosed to the extent that such products are novel and unobvious based on the prior art. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily through enzymatic processes. Accordingly, novel and unobvious compounds are included that are produced by a process comprising contacting the compound with a mammal for a time sufficient to yield metabolic products. Such products are typically identified by preparing a radiolabeled (e.g., 14C or 3H) compound, parenterally administering it to an animal, such as a rat, mouse, guinea pig, monkey, or human, at a detectable dose (e.g., about 0.5 mg / kg), and isolating the transformation products from urine, blood, or other biological samples over a period of time sufficient for metabolism to occur (typically about 30 seconds to 30 hours). Because these products are labeled, they can be readily isolated (others are isolated by the use of antibodies capable of binding to epitopes surviving in the metabolite). The structures of the metabolites are determined by conventional methods, such as MS or NMR analysis. In general, analysis of metabolites can be performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. Conversion products may be useful in diagnostic assays for therapeutic dosing of compounds even if they have no GLP-1R activity of their own unless otherwise found in vivo.

[0136] Recipes and methods for determining the stability of compounds in surrogate gastrointestinal secretions are known. A compound is defined herein as stable in the gastrointestinal tract if less than about 50 mole percent of the protecting groups are deprotected in surrogate intestinal or gastric fluids upon incubation at 37° C. for 1 hour. Just because a compound is stable to the gastrointestinal tract does not mean that it is in This does not mean that it cannot be hydrolyzed in vivo. Prodrugs are typically stable in the digestive system, but can be substantially hydrolyzed to the parent drug in the digestive lumen, liver, lungs or other metabolic organs, or generally intracellularly. As used herein, a prodrug is understood to be a compound that is chemically designed to effectively release the parent drug after overcoming the biological barrier to oral delivery.

[0137] III. Methods for Preparing Compounds The compounds of the present disclosure can be prepared by any method known in the art. The following exemplary general methods illustrate routes that can be used to obtain the compounds of the present disclosure.

[0138] [ka]

[0139] Intermediate 1.3 can be prepared by reacting intermediate 1.1 (where X is halogen and R is alkyl, alkylaryl, or aryl) with an amine in the presence of a suitable base (e.g., DIPEA, KOtBu, etc.) to give intermediate 1.2, which can be reduced using suitable reduction conditions (e.g., H2 with Pd / C, Fe with HCl, etc.). , which can be converted to intermediate 1.3.

[0140] [ka]

[0141] Compounds of formula (I) having the structure of compounds of formula 2.9 can be prepared by reacting intermediate 2.1, 21 and X 22

[0049] Intermediate 2.3 can be obtained by first coupling heteroatom-containing intermediate 2.2 (where Y = O, NH, or S) with a suitable base (e.g., DIPEA, KOtBu, etc.) or by metal-mediated cross-coupling using a suitable palladium catalyst. Intermediate 2.4 (where M = Li, MgBr, MgCl, or MgI, commercially available or obtained by metallation of the corresponding halide) can be combined with intermediate 2.3 using a suitable palladium catalyst to provide intermediate 2.5. After conversion to acid intermediate 2.6 using standard conditions (e.g., LiOH, LiI-pyridine, etc.), intermediate 1.3 can be added using standard amide bond-forming conditions (e.g., DIPEA with HATU, etc.) to provide intermediate 2.7, which is then converted to the corresponding benzimidazole intermediate 2.8 under the influence of an acid catalyst (e.g., HCl, AcOH, etc.). This intermediate can be converted to a compound of formula (I) using standard ester hydrolysis conditions (eg, LiOH, LiI and pyridine).

[0142] Although Scheme 2 above is illustrated using intermediate 2.1 as the dihalopyridine, any dihalogenated A-ring starting material can be used to provide analogous compounds of formula (I).

[0143] [ka]

[0144] In some embodiments, compounds of formula (I) having the structure of compounds of formula 2.9 can be prepared by conversion of intermediate 3.1, wherein X 31 is Cl, Br, or I] with intermediate 1.3 [where R = alkyl, alkylaryl, or aryl] (Scheme 3). Treatment with a suitable acid catalyst (e.g., HCl, AcOH, etc.) can provide intermediate 3.3. -X31 Halogen metal exchange of -M can be achieved using a suitable reagent (e.g., iPrMgBr, etc.) or transition metal coupling using a suitable palladium catalyst and metal source (e.g., B2Pin2, Bu6Sn2, etc.) to provide intermediate 2.8, which can be converted to compounds of formula (I) using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine, etc.).

[0145] [ka]

[0146] In some embodiments, compounds of formula 2.9 can be formed by first converting intermediate 2.3 to the metallated intermediate 4.1 using a suitable palladium catalyst and metal source, such as B2Pin2, Bu6Sn2, etc. (Scheme 4). Intermediate 4.1 can be coupled to intermediate 3.3 using a suitable palladium catalyst to provide intermediate 2.8, which can then be converted to compounds of formula (I) using standard ester hydrolysis conditions, such as LiOH, LiI, and pyridine.

[0147] [ka]

[0148] Compounds of Formula (IA-1) and / or Formula (I) having the structure of compounds of Formula 5.3 can be constructed by first coupling intermediate 5.1 to halogen-X (where X is Cl, Br, or I) using a suitable coupling partner and palladium catalyst to give intermediate 5.2, which is then converted to compounds of Formula 5.3 using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine, etc.) (Scheme 5).

[0149] [ka]

[0150] Intermediate 2.9 can be reacted with sulfonamides under suitable coupling conditions (such as EDCI and DMAP) to provide compounds of formula (I) having the structure of compounds of formula 6.1 (Scheme 6).

[0151] [ka]

[0152] Compounds of formula (I) having the structure of compounds of formula 7.3 can be constructed by first coupling the halogen-X of intermediate 7.1 using a suitable coupling partner and palladium catalyst to give intermediate 7.2, which is then converted to compounds of formula 7.3 using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine) (Scheme 7).

[0153] [ka]

[0154] Compounds of formula (I) having the structure of compounds of formula 2.9 can be constructed via initial cross-coupling of intermediate 3.4 with intermediate 2.1 using a suitable transition metal catalyst (e.g., palladium, etc.) (Scheme 8). This can then be coupled with heteroatom-containing intermediate 2.2 (where Y = O, N, or S) via metal-mediated cross-coupling using a suitable base (e.g., DIPEA, KOtBu, etc.) or a suitable palladium catalyst to afford intermediate 2.8. Intermediate 2.8 can be converted to compounds of formula (I) having the structure of compounds of formula 2.9 using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine, etc.).

[0155] [ka]

[0156] Compounds of Formula (I) having the structure of compounds of Formula 2.9 can be constructed via initial cross-coupling of intermediate 3.4 with intermediate 9.1 using a suitable transition metal catalyst (e.g., palladium, etc.) (Scheme 9). The benzyl ether can then be removed by reduction using H and a suitable catalyst (e.g., Pd / C) to give intermediate 9.2. Then, with a suitable base (e.g., KCO, CsCO, AgCO, etc.), intermediate 9.3 [wherein X 91 Intermediate 9.2 can be alkylated using an appropriate electrophile represented by the formula [wherein -O- can be -Cl, -Br, I, or -OTs]. Using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine), intermediate 2.8 can be converted to a compound of formula (I) having the structure of a compound of formula 2.9.

[0157] [ka]

[0158] Using a suitable base (e.g., K2CO3, Cs2CO3, Ag2CO3), intermediate 9.2 can be converted to intermediates of type 10.1, where X 101 and X 102 are each independently -Cl, -Br, -I, -OTs, or -OTf, and Y 1 , Y 2 , Y 3 , and Y 4 are each independently -CH= or -N=], the compound of formula (I) having the structure of the compound of formula 10.4 can be constructed by first alkylating intermediate 10.2 with an appropriate transition metal catalyst (e.g., palladium, etc.). Intermediate 10.2 is then converted to intermediate 10.3 using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine, etc.). ) can be used to convert intermediate 10.3 to a compound of formula (I) having the structure of a compound of formula 10.4.

[0159] IV. Pharmaceutical Preparations In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0160] In some embodiments of the present disclosure, pharmaceutical compositions comprise a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, as described more fully below.

[0161] Pharmaceutical compositions containing the compounds disclosed herein, or pharmaceutically acceptable salts thereof, can be prepared using one or more pharmaceutically acceptable excipients, which can be selected according to conventional practice. Tablets may contain excipients, including lubricants, fillers, binders, etc. Aqueous compositions can be prepared in sterile form and, if intended for delivery by other than oral administration, may generally be isotonic. In some embodiments, the compositions may contain excipients such as those described in Rowe et al., Handbook of Pharmaceutical Excipients, 6th edition, American Pharmacists Association, 2009. Excipients can include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, and stearic acid. In some embodiments, the compositions are provided as solid dosage forms, including solid oral dosage forms.

[0162] The compositions include those suitable for various routes of administration, including oral administration. The compositions may be presented in unit dosage form and may be prepared by any of the methods known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient (e.g., a compound of the present disclosure, or a pharmaceutical salt thereof) with one or more pharmaceutically acceptable excipients. The compositions may be prepared by uniformly and intimately bringing into association the active ingredient with liquid excipients, or finely divided solid excipients, or both, and then, if necessary, shaping the product. Techniques and formulations are generally described in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0163] Compositions described herein suitable for oral administration may be presented as discrete units (unit dosage forms) including, but not limited to, capsules, sachets, or tablets, each containing a predetermined amount of the active ingredient. In one embodiment, the pharmaceutical composition of the present disclosure is a tablet.

[0164] Pharmaceutical compositions disclosed herein comprise one or more compounds disclosed herein, or pharmaceutically acceptable salts thereof, together with pharmaceutically acceptable excipients and, optionally, other therapeutic agents. Pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended method of administration. For example, when used for oral administration, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs may be prepared. Compositions intended for oral administration may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more excipients, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation. Tablets containing the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients include, for example, calcium carbonate or sodium carbonate, lactose, lactose monohydrate, cereals such as cereals containing glutamic acid, ... Inert diluents such as roscarmelose sodium, povidone, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used alone or with a wax.

[0165] The amount of active ingredient that can be combined with inactive ingredients to produce a dosage form can vary depending on the intended therapeutic subject and mode of administration. For example, in some embodiments, a dosage form for oral administration to humans can contain about 1 to 1000 mg of active agent, formulated with an appropriate and convenient amount of pharmaceutically acceptable excipients. In some embodiments, the pharmaceutically acceptable excipients can vary from about 5 to about 95% (weight:weight) of the total composition.

[0166] In some embodiments, compositions comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in one variation, do not contain an agent that affects the rate at which the active ingredient is metabolized. Thus, in one aspect, it is understood that a composition comprising a compound of the present disclosure does not contain an agent that affects (e.g., slows, inhibits, or prevents) the metabolism of the compound of the present disclosure, or any other active ingredient that is administered separately, sequentially, or simultaneously with the compound of the present disclosure. In one aspect, it is also understood that none of the methods, kits, articles of manufacture, etc. detailed herein contain an agent that affects (e.g., slows, inhibits, or prevents) the metabolism of the compound of the present disclosure, or any other active ingredient that is administered separately, sequentially, or simultaneously with the compound of the present disclosure.

[0167] In some embodiments, the pharmaceutical compositions are for human or animal use.

[0168] The present disclosure further includes compounds of the present disclosure for administration as the sole active ingredient of a pharmaceutically acceptable composition which can be prepared by conventional methods known in the art, e.g., by combining or mixing the active ingredient with pharmaceutically acceptable, therapeutically inert organic and / or inorganic carriers or excipients.

[0169] In one aspect, provided herein is the use of a compound of the present disclosure as a second or other active ingredient that has a synergistic effect with another active ingredient in a known drug, or the co-administration of a compound of the present disclosure with such a drug.

[0170] The compounds of the present disclosure may also be used in the form of prodrugs or other suitably modified forms that release the active ingredient in vivo.

[0171] V. Route of Administration The compounds of the present disclosure (also referred to herein as active ingredients) can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intratumoral, intrathecal, and epidural), etc. It will be understood that the preferred route may vary depending, for example, on the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0172] The compounds of the present disclosure may be administered for a desired period or duration, such as at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or more. The compound may then be administered to the individual according to an effective dosing regimen. In one variation, the compound is administered on a daily or intermittent schedule for the duration of the individual's life.

[0173] The dosage or frequency of administration of a compound of the present disclosure may be adjusted over the course of treatment, based on the judgment of the administering physician.

[0174] The compound can be administered to an individual (e.g., a human) in an effective amount. In some embodiments, the compound is administered once daily.

[0175] The compound can be administered by any useful route and means, such as oral or parenteral (e.g., intravenous) administration. A therapeutically effective amount of the compound can be from about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, for example, from about 0.0001 mg / kg body weight per day to about 10 mg / kg body weight per day, or from about 0.001 mg / kg body weight per day to about 1 mg / kg body weight per day, or from about 0.01 mg / kg body weight per day to about 1 mg / kg body weight per day, or from about 0.05 mg / kg body weight per day to about 0.5 mg / kg body weight per day, or from about 0.3 mg to about 30 mg per day, or from about 30 mg to about 300 mg per day.

[0176] The compounds of the present disclosure can be combined with one or more additional therapeutic agents at any dosage of the compound of the present disclosure (e.g., 1 mg to 1000 mg of compound). Therapeutically effective amounts can include about 1 mg per dose to about 1000 mg per dose, e.g., about 50 mg per dose to about 500 mg per dose, or e.g., about 100 mg per dose to about 400 mg per dose, or e.g., about 150 mg per dose to about 350 mg per dose, or e.g., about 200 mg per dose to about 300 mg per dose. Other therapeutically effective amounts of the compounds of the present disclosure are about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or about 500 mg per dose. Other therapeutically effective amounts of the compounds of the present disclosure are about 100 mg per dose, or about 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, or about 500 mg per dose. A single dose can be administered hourly, daily, or weekly. For example, a single dose can be administered once every 1, 2, 3, 4, 6, 8, 12, 16 hours, or once every 24 hours. A single dose can also be administered once every 1, 2, 3, 4, 5, 6 days, or once every 7 days. A single dose can also be administered once every 1, 2, 3 weeks, or once every 4 weeks. In some embodiments, a single dose can be administered once weekly. A single dose can also be administered once monthly.

[0177] Also included in the present disclosure are kits comprising a compound of the present disclosure, or an enantiomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing any of the above. In one embodiment, the kit further comprises instructions for use. In one aspect, the kit comprises a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and a label and / or instructions for use of the compound in treating an indication, such as a disease or condition described herein. In one embodiment, a kit is provided that comprises a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., 1, 2, 3, 4, 1 or 2, or 1 to 3, or 1 to 4) additional therapeutic agents.

[0178] Also provided herein is an article of manufacture comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, in a suitable container, which can be a vial, bottle, ampoule, pre-filled syringe, and infusion bag.

[0179] VI. Combination Therapy In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be combined with a therapeutically effective amount of one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents. In some embodiments, the additional therapeutic agents include an apoptotic signal-regulating kinase (ASK-1) inhibitor, a farnesoid X receptor (FXR) agonist, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, fish oil, an acetyl-coA carboxylase (ACC) inhibitor, a TGFβ antagonist, an LPA R antagonists, SGLT2 inhibitors, Tp12 inhibitors, or GLP-1 agonists, and combinations thereof.

[0180] The advantage of the combination can be enhanced efficacy and / or reduced side effects for the components, as the dose of the components can be adjusted to reduce their side effects while benefiting from their enhanced efficacy due to the efficacy of the compounds of the present disclosure.

[0181] In some embodiments, the therapeutic agent or combination of therapeutic agents is an ACE inhibitor, a 2-acylglycerol O-acyltransferase 2 ( ... 2, DGAT2 inhibitor, acetaldehyde dehydrogenase inhibitor, acetyl CoA Carboxylase inhibitor, adrenergic receptor agonist, Alstrom syndrome protein 1 (ALMS1) / PKC alpha protein Protein interaction inhibitors, apelin receptor agonists, diacylglycerol O-acyltransferase 2 inhibitors, adenosine A3 receptor agonists, adenosine A3 receptor antagonists, adiponectin receptor agonists, aldehyde dehydrogenase 2 stimulators, AKT protein kinase inhibitors, AMP-activated protein kinase (AMPK), AMP kinase activators, ATP citrate lyase inhibitors, AMP-activated protein kinase stimulators, endothelial nitric oxide synthase stimulators, NAD-dependent deacetylase sirtuin-1 stimulators, adrenergic receptor antagonists, androgen receptor agonists, amylin receptor agonists, angiotensin II AT-1 receptor antagonists, apical sodium-dependent bile acid transport inhibitors, autophagy protein modulators, autotaxin inhibitors, Axl tyrosine kinase receptor inhibitors, Bax protein stimulators, β-catenin inhibitors, bioactive lipids, calcitonin agonists, cannabinoid receptor modulators, caspase inhibitors, caspase-3 stimulators, cathepsin inhibitors, caveolin-1 inhibitors, CCK receptor antagonists, CCL26 gene inhibitors, CCR2 chemokine antagonists, CCR2 chemokine antagonists, angiotensin II AT-1 receptor antagonists, CCR3 chemokine antagonists, CCR5 chemokine antagonists, CD3 antagonists, CDGSH iron-sulfur domain protein modulators, chitinase inhibitors, chloride channel stimulators, chitotriosidase 1 inhibitors, CNR1 inhibitors, connective tissue growth factor ligand inhibitors, COT protein kinase inhibitors, cyclin D1 inhibitors, cytochrome P450 7A1 inhibitors, cytochrome P450 reductase inhibitors, DGAT1 / 2 inhibitors, diacylglycerol O acyltransferase 1 inhibitors (DGAT1), cytochrome P450 2E1 inhibitors (Cytochrome P450 2E1 inhibitors)inhibitor, CYP2E1), CXCR3 chemokine antagonist, CXCR4 chemokine antagonist, dihydroceramide δ4 desaturase inhibitor, dihydroorotate dehydrogenase inhibitor, dipeptidyl peptidase IV inhibitor, endosialin modulator, eotaxin ligand inhibitor, extracellular matrix protein modulator, farnesoid X receptor agonist, fatty acid synthase inhibitor, FGF1 receptor agonist, fibroblast growth factor (FGF-15, FGF-19, F GF-21 ligand, fibroblast activation protein inhibitor, free fatty acid receptor 1 agonist, galectin-3 inhibitor, GDNF family receptor α-like agonist, glucagon receptor agonist, glucagon-like peptide 1 agonist, glucocorticoid receptor antagonist, glucose 6-phosphate 1-dehydrogenase inhibitor, G-protein-coupled bile acid receptor 1 agonist, G-protein-coupled receptor-119 agonist, G-protein-coupled receptor 84 antagonist, hedgehog (Hh) modulator, hepatitis C virus NS3 protease inhibitor, hepatocyte nuclear factor 4 alpha modulator (HNF4A), hepatocyte growth factor modulator, histone deacetylase inhibitor, STAT-3 modulator, HMG CoA reductase inhibitor, HSD17B13 gene inhibitor, 5-HT 2a receptor antagonist, hydrolase inhibitor, hypoxia-inducible factor-2α inhibitor, IL-10 agonist, IL-17 antagonist, IL-22 agonist, ileal sodium bile acid cotransporter inhibitor, insulin sensitizer, insulin ligand agonist, insulin receptor agonist, integrin modulator, integrin antagonist, integrin α-V / β-1 antagonist, integrin α-V / β-6 antagonist, interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, IL-6 receptor agonist, interleukin-17 ligand inhibitor, Jak2 tyrosine kinase inhibitor, Jun N-terminal kinase-1 inhibitor, Kelch-like ECH-associated protein 1 modulator, ketohexokinase (KHK) inhibitor, Klotho β-agonists, leukotriene A4 hydrolase inhibitors, 5-lipoxygenase inhibitors, lipoprotein lipase inhibitors, liver X receptor, LPL gene stimulators, lysophosphatidate-1 receptor antagonists, lysyl oxidase homolog 2 inhibitors, LXR inverse agonists, macrophage mannose receptor 1 modulators, matrix metalloproteinase (Matrixmetalloproteinase (MMP) inhibitor, MEKK- 5 protein kinase inhibitors, MCH receptor-1 antagonists, membrane copper amine oxidase (VAP-1) inhibitors, methionine aminopeptidase-2 inhibitors, methyl-CpG binding protein 2 modulators, microRNA-132 (microRNA-132, miR-132) antagonists, microRNA-21 (microRNA-21, miR-21) inhibitors, mitochondrial kinase inhibitors, and mitochondrial kinase inhibitors. Chondriac uncouplers, mixed lineage kinase-3 inhibitors, motile sperm domain protein 2 inhibitors, myelin basic protein stimulators, NACHT LRR PYD domain protein 3 (NLRP3) inhibitors, NAD-dependent deacetylase inhibitors Sirtuin stimulators, NADPH oxidase inhibitors (NOX), NFE2L2 gene inhibitors, nicotinic acid receptor 1 agonists, opioids P2Y13 purinergic receptor μ antagonists, P2Y13 purinergic receptor stimulators, nuclear erythroid 2-related factor 2 stimulators, nuclear receptor modulators, nuclear transport of transcription factors, P2X7 purinergic receptor modulators, PACAP type I receptor agonists, PDE3 inhibitors, PDE4 inhibitors, PDE5 inhibitors, PDGF receptor β modulators, phenylalanine hydroxylase stimulators, phospholipase C inhibitors, phosphodiester hydrolase inhibitors, PPARα agonists, PPARδ agonists, PPARγ agonists, peptidyl-prolyl cis-trans isomerase A inhibitors, PNPLA3 gene inhibitors, PPARγ modulators, protease-activated receptor-2 antagonists, protein kinase modulators, protein NOV homolog modulators, PTGS2 gene inhibitors, renin inhibitors, resistin / CAP1 (adenylyl cyclase associated protein 1), adenylyl cyclase associated protein Rho-associated protein 1 interaction inhibitors, Rho-associated protein kinase inhibitors, RNA polymerase inhibitors, S-nitrosoglutathione reductase (GSNOR) enzyme inhibitors, sodium glucose transporter-2 inhibitors, sphingolipids δ4 desaturase DES1 inhibitors, SREBP transcription factor inhibitors, STAT-1 inhibitors, stearoyl-CoA desaturase-1 inhibitors, STK25 inhibitors, inhibitors of cytokine signaling-1 stimulators, inhibitors of cytokine signaling-3 stimulators, taste receptor type 2 agonists, telomerase stimulators, TERT gene modulators, TGFβ(T GFB1 ligand inhibitors, TNF antagonists, transforming growth factor β (TGF-β), transforming growth factor β activated kinase 1 (TAK1), thyroid hormone receptor β agonists, TLR-4 antagonists, transglutaminase inhibitors, tyrosine kinase receptor modulators, GPCR modulators, nuclear hormone receptor modulators, TLR-9 antagonists, VDR agonists, vitamin D3 receptor modulators, WNT modulators, YAP / TAZ modulators or zonulin inhibitors, and combinations thereof.

[0182] Non-limiting examples of the one or more additional therapeutic agents include: -ACE inhibitors, such as enalapril - acetaldehyde dehydrogenase inhibitors, such as ADX-629, - acetyl-CoA carboxylase (ACC) inhibitors such as NDI-010976 (filsocostat), DRM-01, gemcabene, GS-834356, PF-05175157, QLT-091382, and PF-05221304; - acetyl-CoA carboxylase / diacylglycerol O-acyltransferase 2 inhibitors, such as PF-07055341; - adenosine receptor agonists, such as CF-102 (namodenoson), CF-101 (piclidenoson), CF-502, CGS21680, - adenosine A3 receptor antagonists, such as FM-101, - adiponectin receptor agonists such as ADP-355, ADP-399, and ALY668-SR, -Adrenergic receptor antagonists such as bromocriptine, phentermine, and VI-0521 - aldehyde dehydrogenase 2 stimulators such as FP-045, - amylin / calcitonin receptor agonists such as KBP-042, KBP-089, -AMP-activated protein kinase stimulators such as C-455, PXL-770, and O-304, -AMP kinase activators / ATP citrate lyase inhibitors such as bempedoic acid (ETC-1002, ESP-55016), -AMP-activated protein kinase / endothelial nitric oxide synthase / NAD-dependent deacetylase sirtuin-1 stimulators such as NS-0200 (leucine + metformin + sildenafil), - androgen receptor agonists such as LPCN-1144, LPCN-1148, and testosterone prodrugs, -Angiotensin II AT-1 receptor antagonists such as irbesartan, angiopoietin-related protein-3 inhibitors (IONIS-ANGPTL3-LRx) such as bupanorsen, -Apelin receptor agonists such as CB-5064 and MBT-2, - apical sodium-dependent bile acid transport inhibitors such as A-3907, -autophagy protein modulators such as A-2906, GM-90194, - Autotaxin (ectonucleotide pyrophosphatase / phosphodiesterase 2 (NPP2 or ENPP2)) inhibitors such as FP10.47, PAT-505, PAT-048, GLPG-1690, X-165, PF-8380, TJC-0265, TJC-0316, AM-063, and BBT-877; -Axl tyrosine kinase receptor inhibitors such as bemcentinib (BGB-324, R-428), Bax protein stimulators, such as CBL-514, -bioactive lipids such as DS-102, -Cannabinoid receptor modulators such as nimacimab, GWP-42004, REV-200, CRB-4001, INV-101, and SCN-002; -Caspase inhibitors such as emricasan, - Pan-cathepsin B inhibitors, such as VBY-376, pan-cathepsin inhibitors, such as VBY-825; -CCK receptor antagonists such as proglumide, -CCL26 gene inhibitors such as mocedipimod and KDDF-201410-10 - CCR2 / CCR5 chemokine antagonists such as BMS-687681, cenicriviroc, maraviroc, CCX-872, leronlimab, and WXSH-0213; -CCR2 / CCR5 chemokine antagonists and FXR agonists, such as LJC-242 (tropifexor + cenicriviroc), -CCR2 chemokine antagonists such as propagermanium, -CCR2 chemokine / angiotensin II AT-1 receptor antagonists such as DMX-200, DMX-250, -CCR3 chemokine antagonists such as bertilimumab, -CD3 antagonists such as NI-0401 (foralumab), - CDGSH iron-sulfur domain protein modulators, such as EYP-002, -chitinase inhibitors such as OATD-01, - chitotriosidase 1 inhibitors, such as OAT-2068, chloride channel stimulators such as cobiprostone and lubiprostone, - Casein kinase-1 (CK1) delta / epsilon inhibitors such as PF-05006739; -Connective tissue growth factor ligand inhibitors, such as PBI-4050, -COT protein kinase inhibitors such as GS-4875, GS-5290, -CXCR4 chemokine antagonists such as AD-214, - cytochrome P450 reductase inhibitors, such as SNP-630, -Diglyceride acyltransferase 2 (DGAT2) inhibitors such as IONIS-DGAT2Rx and PF-06865571; -Diglyceride acyltransferase 1 (DGAT1) inhibitors, such as GSK-3008356; -Diacylglycerol O-acyltransferase 1 (DGAT1) / cytochrome P450 2E1 inhibitors (CYP2E1 inhibitors), such as SNP-610 P2E1), -Dihydroorotate dehydrogenase inhibitors such as bidofludimus, -Dipeptidyl peptidase IV inhibitors such as linagliptin and evogliptin, -Eotaxin ligand inhibitors such as bertilimumab and CM-101, -extracellular matrix protein modulators, such as CNX-024, -AGN-242266, AGN-242256, ASC-42, EDP-297 (EP-024297), RDX-023, BWL-200, AKN-083, EDP-305, GNF-5120, cilofexor tromethamine (GS-9674), HPG-1860, IOT-022, LMB-763, obeticholic acid, Px-102, Px-1 Farnesoid X receptor (FXR) agonists such as 03, M790, M780, M450, M-480, MET-409, MET-642, PX20606, SYHA-1805, bonafexor (EYP-001), TERN-101, TC-100, INT-2228, TQA-3526, ZG-5266, HPD-001, and alendronate; -farnesoid X receptor (FXR) / G protein-coupled bile acid receptor 1 (TGR5) agonists, such as INT-767; -fatty acid synthase inhibitors such as TVB-2640 and FT8225, -Fibroblast growth factor 19 (GF19), such as aldafermin (NGM-282) rhFGF19) / cytochrome P450 (CYP) 7A1 inhibitor, - Fibroblast growth factor 21 (FGF-21) ligand modulators, such as AP-025, BMS-986171, B-1654, BIO89-100, BOS-580, pegbelfermin (BMS-986036), B-1344, and NN-9499; - fibroblast growth factor 21 (FGF-21) / glucagon-like peptide 1 (GLP-1) agonists such as YH-25723 (YH-25724; YH-22241) and effluxifermin (AKR-001); -FGF receptor agonists / Klotho β stimulators such as BFKB-8488A (RG-7992), -Free fatty acid receptor 1 agonists, such as SCO-267, Galectin-3 inhibitors such as Bellapectin (GR-MD-02), GB-1107 (Gal-300), GB-1211 (Gal-400), and IMT-001; GDNF family receptor alpha-like agonists, such as NGM-395; - Glucagon-like peptide 1 (GLP1R) inhibitors such as ALT-801, AC-3174, liraglutide, cotadutide (MEDI-0382), SAR-425899, LY-3305677, HM-15211, YH-25723, YH-GLP1, RPC-8844, PB-718, PF-06882961, and semaglutide Gonist, -glucagon receptor agonists such as glucagon-like peptide 1 agonists, oxyntomodulin ligands, and efinopegdutide, Gastric inhibitory polypeptide / glucagon-like peptide-1 (GIP / Glucagon-like peptide-1), such as tirzepatide (LY-3298176) GLP-1 receptor co-agonist, -PEGylated long-acting glucagon-like peptide-1 / glucagon (GLP-1R / GCGR), such as DD-01 Receptor dual agonists, - glucagon / GLP1 receptor agonists such as BI-456906 and NN-6177, - glucocorticoid receptor antagonists such as CORT-118335 (milicolinant), -glucose 6-phosphate 1-dehydrogenase inhibitors, such as ST001; -Glucokinase stimulators such as dorzagliatin and sinogliatin (RO-5305552) -G protein-coupled bile acid receptor 1 (TGR5) agonists, such as RDX-009, INT-777, and HY-209; -G protein-coupled receptor 84 antagonists, such as PBI-4547, -G protein-coupled receptor-119 agonists, such as DA-1241, -Heat shock protein 47 (HSP47) inhibitors such as ND-L02-s0201, hedgehog protein TGFβ ligand inhibitors, such as -Oxy-210; -Histone deacetylase inhibitors / STAT-3 modulators, such as SFX-01; -HMG CoA reductase inhibitors, such as atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin; -HSD17B13 gene inhibitors such as ALN-HSD and ARO-HSD, -hydrolase inhibitors such as ABD-X, -Hypoxia-inducible factor-2α inhibitors, such as PT-2567, IL-10 agonists such as -peg-ilodecakin, -Odebixibat (A-4250), Borixibat potassium ethanolate hydrate (SHP-262), GSK2330672, CJ-14199, Elobixibat (A-3 ileal sodium bile acid cotransporter inhibitors such as 309), - insulin sensitizers such as KBP-042, azemiglitazone potassium (MSDC-0602K), ION-224, MSDC-5514, Px-102, RG-125 (AZD4076), trimidone, VVP-100X, CB-4211, and ETI-101; -insulin ligands / ds insulin receptor agonists, such as ORMD-0801; -integrin antagonists such as IDL-2965, -IL-6 receptor agonists, such as KM-2702, - Dual integrin α-V / β-6 and α-V / β-1 inhibitors, such as PLN-74809; -Interleukin-17 ligand inhibitors, such as netakimab -Jak1 / 2 tyrosine kinase inhibitors, such as baricitinib; Jun N-terminal kinase-1 inhibitors, such as CC-90001; -Kelch-like ECH-associated protein 1 modulators, such as α-cyclodextrin-stabilized sulforaphane, - ketohexokinase (KHK) inhibitors such as PF-06835919, LY-3478045, and LY-3522348; - β Klotho (KLB)-FGF1c agonists such as MK-3655 (NGM-313), - leukotriene A4 hydrolase inhibitors, such as LYS-006; - 5-lipoxygenase inhibitors such as tipelukast (MN-001), epereuton (DS-102, (AF-102), etc. - Lipoprotein lipase inhibitors, such as CAT-2003, -LPL gene stimulators such as alipogene tiparvovec, -Liver X receptor (LXR) inhibitors such as PX-665, PX-L603, PX-L493, BMS-852927, T-0901317, GW-3965, and SR-9238; - Lysophosphatidic acid-1 receptor antagonists such as BMT-053011, UD-009 (CP-2090), AR-479, ITMN-10534, BMS-986020, and KI-16198; -Lysyl oxidase homolog 2 inhibitors, such as simtuzumab and PXS-5382A (PXS-5338), - macrophage mannose receptor 1 modulators such as tilmanocept-Cy3 (technetium Tc 99m tilmanocept); -matrix metalloproteinase inhibitors, such as ALS-L1023, - membrane copper amine oxidase (VAP-1) inhibitors, such as TERN-201 and TT-01025; - MEKK-5 protein kinase (ASK-1) inhibitors such as CJ-16871, CS-17919, selonsertib (GS-4997), SRT-015, GS-444217, GST-HG-151, and TERN-301; - MCH receptor-1 antagonists such as CSTI-100 (ALB-127158), - Semicarbazide-Sensitive Amine Oxidase / Vascular Adhesion Protein-1 (SSAO / VAP-1) inhibitors such as PXS-4728A (BI-1467335), - methionine aminopeptidase-2 inhibitors such as ZGN-1061, ZGN-839, and ZN-1345; -methyl-CpG binding protein 2 modulators, such as mercaptamines, -Mineralocorticoid receptor antagonists (MCRA), such as MT-3995 (aparalenone), -mitochondrial uncouplers such as 2,4-dinitrophenol, HU6, and Mito-99-0053; - mixed lineage kinase-3 inhibitors, such as URMC-099-C, -Motile sperm domain protein 2 inhibitors, such as VB-601; -Myelin basic protein stimulators such as olesoxime, -myeloperoxidase inhibitors such as PF-06667272, AZM-198, - NADPH oxidase inhibitors such as GKT-831, GenKyoTex, APX-311, and setanaxib, - Nicotinic acid receptor 1 agonists, such as ARI-3037MO, - NACHT LRR PYD domain protein 3 (NLRP3) inhibitors such as KDDF-201406-03, NBC-6, IFM-514, and JT-194 (JT-349); - NFE2L2 gene inhibitors, such as GeRP-amiR-144, -nuclear transport of transcription factor modulators such as AMTX-100, - nuclear receptor modulators, such as DUR-928 (DV-928); -Opioid receptor μ antagonists, such as methylnaltrexone, - P2X7 purinergic receptor modulators, such as SGM-1019, - P2Y13 purinergic receptor agonists, such as CER-209, -PDE 3 / 4 inhibitors, such as tipelukast (MN-001), -PDE 5 inhibitors such as sildenafil, MSTM-102, -PDGF receptor beta modulators such as BOT-191 and BOT-509, - peptidyl-prolyl cis-trans isomerase inhibitors such as CRV-431 (CPI-432-32), NVP-018, and NV-556 (NVP-025); - Phenylanine hydroxylase stimulators such as HepaStem, -phosphodiester hydrolase inhibitors such as ZSP-1601, - PNPLA3 gene inhibitors, such as AZD-2693, - tiglitazar, elafibranor (GFT-505), seladelparridine (MBX-8025), deuterated pioglitazone R-enantiomer, pioglitazone, PXL-065 (DRX-065), saroglitazar, lanifibranor (IVA-337), CHS-131, pemafibrate (K-877), ZG-0588, ZSP-0678, ZSYM-008; - protease-activated receptor-2 antagonists, such as PZ-235, - protein kinase modulators, such as CNX-014, - protein NOV homologue modulators such as BLR-200, -PTGS2 gene inhibitors such as STP-705 and STP-707, -renin inhibitors such as PRO-20, - resistin / CAP1 (adenylyl cyclase-associated protein 1) interaction inhibitors, such as DWJ-211; -Rev protein modulators such as ABX-464, - Rho-associated protein kinase (ROCK) inhibitors such as REDX-10178 (REDX-10325), KD-025, RXC-007, and TDI-01; -RNA polymerase inhibitors such as rifaximin, - S-nitrosoglutathione reductase (GSNOR) enzyme inhibitors, such as SL-891; -Sodium glucose transporter-2 (SGLT2) inhibitors such as ipragliflozin, remogliflozin etabonate, ertugliflozin, dapagliflozin, tofogliflozin, and sotagliflozin; -Sodium glucose transporter-1 / 2 (SGLT1 / 2) inhibitors, such as licogliflozin bis(prolinate) (LIK-066); -SREBP transcription factor inhibitors such as CAT-2003, HPN-01, and MDV-4463, -Stearoyl CoA desaturase-1 inhibitors, such as aramchol, - taste receptor type 2 agonists such as ARD-101, - thyroid hormone receptor beta agonists such as ALG-009, ASC-41, CNPT-101101, CNPT-101207, CS-27186, KY-41111, resmetirom (MGL-3196), MGL-3745, TERN-501, VK-2809, and HP-515; -TLR-2 / TLR-4 antagonists such as VB-201 (CI-201), -TLR-4 antagonists such as JKB-121, JKB-122, and naltrexone; -tyrosine kinase receptor modulators such as CNX-025 and GFE-2137 (repurposed nitazoxanide); -TLR-9 antagonists such as GNKS-356, AVO-101; TNF antagonists, such as ALF-421, -GPCR modulators such as CNX-023, -nuclear hormone receptor modulators such as Px-102, -VDR agonists such as CK-15, -xanthine oxidase inhibitors, such as ACQT-1127, -xanthine oxidase / urate anion exchanger 1 (URAT1) inhibitors, such as RLBN-1001 and RLBN-1127; or -Zonulin inhibitors, such as larazotide acetate (INN-202).

[0183] In certain specific embodiments, the one or more additional therapeutic agents are A-4250, AC-3174, acetylsalicylic acid, AK-20, alipogen tiparvovec, AMX-342, AN-3015, anti-CXCR3 antibody, anti-TAGE antibody, aramchol, ARI-3037MO, ASP-8232, AXA-1125, bertilimumab, betaine anhydrous, BI-1467335, BMS-986036, BMS-986171, BMT-0 53011, BOT-191, BTT-1023, budesonide, BX-003, CAT-2003, cenicriviroc, CBW-511, CER-209, CF-102, CGS21680, CNX-014, CNX-023, CNX-024, CNX-025, cobiprostone, colesevelam, dabigatran etexilate methanesulfonate, dapagliflozin, DCR-LIV1, deuterated pioglitazone R-enantiomer, 2,4-Dinitrophenol, DRX-065, DS-102, DUR-928, edaravone (TTYP-01), EDP-305, elafibranor (GFT-505), emricasan, enalapril, ertugliflozin, evogliptin, F-351, fluasterone (ST-002), FT-4101, GDD-3898, GH-509, GKT-831, GNF-5120, GRI-0621, GR-MD-02, GS-300, GS-499 7, GS-9674, GS-4875, GS-5290, HEC-96719, HTD-1801, HS-10356, HSG-4112, HST-202, HST-201, HU-6, hydrochlorothiazide, icosabtate (PRC-4016), icosapentaenoic acid ethyl ester, IMM-124-E, INT-767, INV-240, ION-455, IONIS-DGAT2Rx, ipragliflozin, irbesarta, propagermanium, IVA-337, J2H-1702, JKB-121, KB-GE-001, KBLP-004, KBLP-009, KBP-042, KD-025, M790, M780, M450, metformin, sildenafil, LB-700, LC-280126, linagliptin, liraglutide, (LJN-452) tropifexor, LM-011, LM-002 (CVI-LM-002), LMB-763, LYN-100, MB-N-008, MBX- 8025, MDV-4463, mercaptamine, MGL-3196, MGL-3745, MP-301, MSDC-0602K, namacizumab, NC-101, NDI-010976, ND-L02-s0201 (BMS-986263), NGM-282, NGM-313, NGM-386, NGM-395, NP-011, NP-135, NP-160, norursodeoxycholic acid, NV-422, NVP-022, O-304, obeticol, Acid (obeticholic acid, OCA), 25HC3S, olesoxime, PAT-505, P AT-048, peg-ilodecaquin, pioglitazone, pirfenidone, PRI-724, PX20606, Px-102, PX-L603, PX-L493, PXS-4728A, PZ-235, PZH-2109, RCYM-001, RDX-009, remogliflozin etabonate, RG-125 (AZD4076), RP-005, R PI-500, S-723595, saroglitazar, SBP-301, semaglutide, SH-2442, SHC-028, SHC-023, simtuzumab, solithromycin, sotagliflozin, statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), TCM-606F, TEV -45478, TQA-3526, TQA-3563, tipelukast (MN-001), TLY-012, TRX-318, TVB-2640, TXR-611, TXR-612, TS-20004, UD-009, UN-03, ursodeoxycholic acid, VBY-376, VBY-825, VK-2809, vismodegib, vorixib, ethanolol potassium phosphate hydrate (SHP-626), VVP-100X, WAV-301, WNT-974, WXSH-0038, WXSH-0078, XEN-103, XRx-117, XTYW-003, XW-003, XW-004, XZP-5610, ZGN-839, ZG-5216, ZSYM-008, or ZYSM-007.

[0184] In some embodiments, the compounds of the present disclosure are selected from the group consisting of peptide YY or analogs thereof, neuropeptide Y receptor type 2 (NPYR2) agonists, NPYR1 agonists, NPYR5 antagonists, cannabinoid receptor type 1 (CB1R) antagonists, lipase inhibitors (e.g., orlistat), human proislet peptide (HIP), melanocortin receptor 4 agonists (melanocortin-4 receptor, MC4R) (e.g., setomelanotide), melanin-concentrating hormone receptor 1 antagonists, farnesoid X receptor (FXR) agonists (e.g., obeticholic acid), apoptosis signal-regulating kinase (ASK-1) inhibitors, zonisamide, phentermine (alone or in combination with topiramate), norepinephrine / dopamine reuptake inhibitors (e.g., buproprion), opioid receptor antagonists (e.g., naltophenone), lexon), combinations of norepinephrine / dopamine reuptake inhibitors and opioid receptor antagonists (e.g., combinations of buproprion and naltrexone), GDF-15 analogs, sibutramine, cholecystokinin agonists, amylin and its analogs (e.g., pramlintide), leptin and its analogs (e.g., metroleptin), serotonergic agents (e.g., lorcaserin), methionine aminopeptidase 2 (MMA), 2, MetAP2 inhibitors (e.g., beloranib or ZGN-1061), phen dimetrazine, diethylpropion, benzphetamine, SGLT2 inhibitors (e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, or ertugliflozin), SGLTL1 inhibitors, dual SGLT2 / SGLT1 inhibitors, fibroblast growth factor receptor (FGFR) modulators, AMP-activated protein kinase (AMPK) activators, biotin, MAS receptor modulators, or glucagon receptor agonists (alone or in combination with another GLP-1 R agonist, e.g., liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, or semaglutide), insulin sensitizers such as thiazolidinedione (TZD), peroxisome proliferator-activated Peroxisome proliferator-activated receptor alpha (PPARα) agonist, fish oil, acetyl-coA carboxylase (ACC) ) inhibitor, transforming growth factor beta (TGFβ) antagonist, GDNF family receptor alpha like (GFRAL) agonist, melanocortin-4 receptor (MCR4) agonists (specifically named drugs, including but not limited to MC4R agonists) The compounds are combined with one or more therapeutic agents selected from anti-obesity agents (including pharmaceutically acceptable salts and pharmaceutically acceptable salts of such agents and salts).

[0185] VII. Treatment method In some embodiments, compounds of Formula (I), or pharmaceutically acceptable salts thereof, are useful in methods for treating and / or preventing GLP-1R-mediated diseases or conditions. In some embodiments, the methods for treating and / or preventing GLP-1R-mediated diseases or conditions comprise administering a pharmaceutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment and / or prevention. In some embodiments, compounds of the present disclosure have desirable properties, including, for example, favorable pharmacokinetic properties, physicochemical properties such as liver uptake properties, and / or bile salt export pump (BSEP) inhibitory properties. In one embodiment, compounds of the present disclosure have desirable pharmacokinetic properties, such as prolonged exposure and / or higher oral bioavailability. In one embodiment, compounds of the present disclosure have desirable liver uptake properties, such as reduced transporter-mediated liver uptake. In one embodiment, compounds of the present disclosure demonstrate desirable BSEP inhibition.

[0186] In some embodiments, the disease or condition is a liver disease or related disease or condition, such as liver fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cirrhosis, compensated liver fibrosis, degenerative liver fibrosis, hepatocellular carcinoma, primary biliary cirrhosis, In some embodiments, the disease or condition comprises a metabolic disease or related disease or condition, such as diabetes, obesity, or cardiometabolic disease.

[0187] GLP-1R agonists are currently being investigated in relation to certain disorders and conditions, including diabetes. GLP-1 analogs that are DPP4 resistant and have a longer half-life than endogenous GLP-1 have been reported to be associated with weight loss and improved insulin action. Liraglutide, a peptide GLP-1R agonist approved for the treatment of diabetes, has been reported to show favorable improvement in outcomes in NASH subjects.

[0188] In some embodiments, the present disclosure relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prevention and / or treatment of a disease or condition mediated by GLP-1R, such as a liver disease or a metabolic disease. In some embodiments, the present disclosure relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prevention and / or treatment of a disease or condition mediated by GLP-1R, such as a liver disease or a metabolic disease. For example, some embodiments are directed to the treatment of chronic intrahepatic or certain forms of extrahepatic cholestatic conditions, liver fibrosis, acute intrahepatic cholestatic conditions, obstructive or chronic inflammatory diseases resulting from inadequate bile composition, gastrointestinal conditions associated with reduced intake of dietary fat and fat-soluble dietary vitamins, inflammatory bowel disease, lipid and lipoprotein disorders, type II diabetes and clinical complications of types I and II diabetes, conditions and diseases resulting from chronic fatty and fibrotic degeneration of organs due to forced lipid and specifically triglyceride accumulation and subsequent activation of pro-fibrotic pathways, obesity and metabolic syndrome (dyslipidemia, diabetes and abnormally high body-mass index), and conditions and diseases resulting from chronic fatty and fibrotic degeneration of organs due to forced lipid and specifically triglyceride accumulation and subsequent activation of pro-fibrotic pathways. acute myocardial infarction, acute stroke, thrombosis occurring as an end point of chronic obstructive atherosclerosis, persistent infection with intracellular bacteria or parasitic protozoa, non-malignant hyperproliferative disorders such as colon adenocarcinoma and hepatocellular carcinoma, fatty liver and related syndromes, liver failure or liver dysfunction as a result of chronic liver disease or surgical liver resection, cholestatic and fibrotic effects associated with hepatitis B infection, hepatitis C infection and / or alcohol-induced cirrhosis or virally mediated forms of hepatitis, type 1 diabetes, prediabetes, idiopathic type 1 diabetes, latent autoimmune diabetes, adult-onset diabetes, early-onset diabetes Early-onset diabetes, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral fat accumulation, obesity, eating disorders, sleep apnea, weight gain, sugar craving, dyslipidemia, hyperinsulinemia, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, post-angioplasty Provided is a compound of formula (I), or a pharmaceutically acceptable salt thereof, or use of either for the treatment and / or prevention of restenosis, intermittent claudication, postprandial dyslipidemia, metabolic acidosis, ketosis, arthritis, left ventricular hypertrophy, Parkinson's disease, peripheral arterial disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, angina pectoris, premenstrual syndrome, thrombosis, atherosclerosis, glucose metabolism disorders, or vascular restenosis.

[0189] In some embodiments, the method for treating and / or preventing non-alcoholic fatty liver disease (NAFLD) comprises administering to a subject in need thereof a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0190] The present disclosure also relates to a compound according to formula (I), or a pharmaceutical composition comprising said compound, for the prevention and post-traumatic treatment of cardiovascular disorders, such as acute myocardial infarction, acute stroke, or thrombosis, which occur as an end point of chronic obstructive atherosclerosis. In some embodiments, the method for treating and / or preventing cardiovascular disorders comprises administering a compound of formula (I) to a subject in need thereof.

[0191] The present disclosure further relates to compounds or pharmaceutical compositions for the treatment and / or prevention of obesity and related disorders such as metabolic syndrome (a combined condition of dyslipidemia, diabetes, and abnormally high body mass index), which can overcome GLP1R-mediated lowering of serum triglycerides, blood glucose, and increased insulin sensitivity and GLP1R-mediated weight loss. In some embodiments, a method for treating and / or preventing a metabolic disorder comprises administering a compound of Formula (I) to a subject in need of such treatment and / or prevention. In some embodiments, a method for treating and / or preventing a metabolic disorder comprises administering a compound of Formula (I) to a subject in need of such treatment and / or prevention.

[0192] In further embodiments, the compounds or pharmaceutical compositions of the present disclosure are useful in preventing and / or treating clinical complications of type I diabetes and type II diabetes. Examples of such complications include diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, or peripheral arterial occlusive disease (PAOD). Other clinical complications of diabetes are also encompassed by the present disclosure. In some embodiments, a method for treating and / or preventing complications of type I diabetes and type II diabetes comprises administering a compound of Formula (I) to a subject in need of such treatment and / or prevention. In some embodiments, a method for treating and / or preventing complications of type I diabetes and type II diabetes comprises administering a compound of Formula (I) to a subject in need of such treatment and / or prevention.

[0193] Furthermore, conditions and diseases resulting from chronic fatty and fibrotic degeneration of organs due to forced lipid and / or triglyceride accumulation and subsequent activation of pro-fibrosis pathways can also be prevented and / or treated by administering a compound or pharmaceutical composition of the present disclosure. Such conditions and diseases can include NASH and chronic cholestatic conditions in the liver, glomerulosclerosis and diabetic nephropathy in the kidney, macular degeneration and diabetic retinopathy in the eye, and neurodegenerative diseases such as Alzheimer's disease in the brain, or neuropathy in the peripheral nervous system. In some embodiments, a method for treating and / or preventing conditions and diseases resulting from chronic fatty and fibrotic degeneration of organs due to forced lipid and / or triglyceride accumulation and subsequent activation of pro-fibrosis pathways comprises administering a compound of Formula (I) to a subject in need of such treatment and / or prevention. In some embodiments, the forced lipid and / or triglyceride accumulation can be prevented and / or treated by administering a compound of Formula (I) to a subject in need of such treatment and / or prevention. Methods for treating and / or preventing conditions and diseases resulting from chronic fatty and fibrotic degeneration of organs due to glyceride accumulation and subsequent activation of pro-fibrosis pathways include administering a compound of Formula (I) to a subject in need of such treatment and / or prevention. In some embodiments, methods for treating and / or preventing NASH include administering a compound of Formula (I) to a subject in need of such treatment and / or prevention. In some embodiments, methods for treating and / or preventing NASH include administering a compound of Formula (I) to a subject in need of such treatment and / or prevention.

[0194] Further provided herein is a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a GLP-1R mediated disease or condition described herein.

[0195] The present disclosure also describes the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament in treating a GLP-1R-mediated disease or condition. The medicaments referred to herein can be prepared by conventional processes comprising combining a compound according to the present disclosure with a pharmaceutically acceptable carrier.

[0196] Also disclosed are compounds of the present disclosure, or pharmaceutically acceptable salts thereof, for the treatment of GLP-1R mediated diseases or conditions. Also disclosed are compounds of the present disclosure, or pharmaceutically acceptable salts thereof, for the prevention of GLP-1R mediated diseases or conditions. VIII. Working Examples [Example]

[0197] Many general references are available that provide generally known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds (see, for example, Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th edition, Wiley-Interscience, 2013).

[0198] The compounds described herein can be purified by any of the means known in the art, including chromatographic means such as high-performance liquid chromatography (HPLC), preparative thin-layer chromatography, flash column chromatography, and ion-exchange chromatography. Any suitable stationary phase can be used, including normal and reverse phase and ionic resins. For example, the disclosed compounds can be purified via silica gel and / or alumina chromatography. See, for example, "Introduction to Modern Liquid Chromatography," 2nd ed., ed. L.S. Snyder and J.J. Kirkland, John Wiley and Sons, 1979, and "Thin Layer Chromatography," E. Stahl (ed.), Springer-Verlag, New York, 1969.

[0199] During any of the processes for preparing the target compounds, it may be desirable to protect sensitive or reactive groups on any of the molecules involved. This can be achieved by conventional protecting groups, as described in standard works such as T.W. Greene and P.G.M. Buts, "Protective Groups in Organic Synthesis," 4th ed., Wiley, New York 2006. The protecting groups can be removed at a convenient subsequent stage using methods known in the art.

[0200] Exemplary chemicals useful in the methods of the embodiments are now described in their general terms herein. This description is illustrated by reference to exemplary synthetic schemes for the general preparation of the compounds of the present invention and the specific examples below. To obtain the various compounds herein, the skilled artisan will recognize that starting materials can be appropriately selected to obtain the desired product, such that the ultimately desired substituents are carried through the reaction schemes, with or without protection as necessary. Alternatively, it may be desirable to use, in place of the ultimately desired substituent, a suitable group that can be carried through the reaction schemes and appropriately replaced with the desired substituent. Furthermore, one skilled in the art will recognize that the transformations shown in the following schemes can be carried out in any order compatible with the functionality of the pendant groups. Each of the reactions shown in the general schemes can be carried out at a temperature from about 0° C. to the reflux temperature of the organic solvent used.

[0201] The examples provided herein describe the synthesis of the compounds disclosed herein, as well as the intermediates used to prepare the compounds. It is understood that the individual steps described herein can be combined. It is also understood that separate batches of compounds can be combined and then carried forward to the next synthetic step.

[0202] In the following description of examples, specific embodiments are described. These embodiments are described in sufficient detail to enable those skilled in the art to practice certain embodiments of the present disclosure. Other embodiments may be utilized, and logical and other changes may be made without departing from the scope of the present disclosure. Embodiments are also directed to processes and intermediates useful for preparing the subject compounds, or pharmaceutically acceptable salts thereof. Therefore, the following description is not intended to limit the scope of the present disclosure.

[0203] In some embodiments, the present disclosure generally provides a particular enantiomer or diastereomer as the desired product, but the stereochemistry of the enantiomer or diastereomer has not been determined in all cases. When the stereochemistry of a particular stereocenter in an enantiomer or diastereomer is not determined, the compound is derived without indicating the stereochemistry at that particular stereocenter, even though the compound may be substantially enantiomerically or diastereomerically pure.

[0204] Representative syntheses of compounds of the present disclosure are described in the schemes below and in the examples below.

[0205] The compounds detailed in the Examples were synthesized according to the general synthetic methods described below. Compounds were named using ChemDraw version 18.1.0.535 (PerkinElmer Informatics, Inc.) unless otherwise indicated.

[0206] Abbreviation Certain abbreviations and acronyms are used in describing the experimental details. While most of these will be understood by those skilled in the art, Table 1 contains a list of many of these abbreviations and acronyms.

[0207] [Table 1-1]

[0208] [Table 1-2]

[0209] A. Synthesis of Intermediates Preparation of Intermediate I-1

[0210] [ka]

[0211] Methyl 4-amino-3-(2-methoxyethylamino)benzoate (I-1): Methyl 3-fluoro-4-nitrobenzoate (50.0 g, 2 mL) in THF (400 mL) To a solution of 51 mmol of methyl 3-(2-methoxyethylamino)-4-nitrobenzoate (20.0 g, 78.7 mmol) was added diisopropylethylamine (70.0 mL, 402 mmol) and 2-methoxyethylamine (34.9 mL, 402 mmol). The resulting solution was heated to 55° C. for 6 h. Upon completion, the solvent was removed and the resulting residue was taken up in EtOAc (150 mL), washed with brine (30 mL), concentrated, and carried forward without further purification. Methyl 3-(2-methoxyethylamino)-4-nitrobenzoate (20.0 g, 78.7 mmol) was then dissolved in 1:1 EtOAc:EtOH (140 mL), after which 10% palladium on carbon (5.02 g, 4.72 mmol) was then added. The resulting suspension was stirred under a hydrogen balloon at room temperature for 16 h. The reaction mixture was filtered through Celite, washed with EtOAc (100 mL), and concentrated to give the desired compound without further purification. ES / MS: 225.2 (M+H + ).

[0212] Preparation of Intermediate I-2

[0213] [ka]

[0214] Methyl 4-{[2-(4-bromo-2-fluorophenyl)acetyl]amino}-3-(2-methoxyethylamino)benzoate: To a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (1.00 g, 4.29 mmol) in DMF (20.0 mL), methyl 4-amino-3-(2-methoxyethylamino)benzoate (1.18 g, 5.28 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.96 g, 5.15 mmol) were added, followed by N,N-diisopropylethylamine (3.74 mL, 21.5 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, and the residue was taken up in EtOAc and washed once with water and once with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Assuming complete conversion, the crude residue was carried forward without further purification. ES / MS m / z: 441.2 (M+H + ).

[0215] Methyl 2-[(4-bromo-2-fluoro-phenyl)methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (I-2): The crude product from the previous step, methyl 4-{[2-(4-bromo-2-fluoro-phenyl)acetyl]amino}-3-(2-methoxyethylamino)benzoate (1.89 g, 4.29 mmol), was dissolved in AcOH (40.0 mL) and the reaction mixture was heated to 60 °C for 2 h. The reaction mixture was concentrated in vacuo, and the crude residue was taken up in DCM and washed with saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with DCM (2 times). The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by column chromatography (0-100% EtOAc in hexanes) to give the title compound. ES / MS m / z: 421.9 (M+H + ).

[0216] Preparation of Intermediate I-3

[0217] [ka]

[0218] 4-[(6-Bromo-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile (I-3): To a dried 100 mL RBF was added 3-fluoro-4-(hydroxymethyl)benzonitrile (2 g, 13.2 mmol). The material was dissolved in dry THF (20 mL) at 0 °C under a nitrogen atmosphere. Sodium hydride (60% dispersion in mineral oil, 0.507 g, 13.2 mmol) was added in one portion, and the mixture was stirred at 0 °C under N for 30 minutes. 2,6-Dibromopyridine (3.13 g, 13.2 mmol) was then added, and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc (100 mL) and water (20 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 30 mL). The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: EtOAc / hexane) to give intermediate I-6. ES / MS: 307.058 (M+H + ); 1 H NMR (400 MHz, chloroform-d) δ 7.72-7.63 (m, 1H), 7.52-7.46 (m, 2H), 7.41 (dd, J = 9.2, 1.5 Hz, 1H), 7.14 (dd, J = 7.5, 0.7 Hz, 1H), 6.79 (dd, J = 8.2, 0.7 Hz, 1H), 5.50 (t, J = 0.9 Hz, 2H).

[0219] Preparation of Intermediate I-4

[0220] [ka]

[0221] Methyl (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoate (I-4): Following the procedure of intermediate I-1, using (S)-oxetan-2-ylmethanamine instead of 2-methoxyethylamine, methyl (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoate was prepared. ES / MS: 237.2 (M+H + ).

[0222] Preparation of Intermediate I-5

[0223] [ka]

[0224] Ethyl 3,5-difluoro-4-nitrobenzoate: Ethyl 4-amino-3,5-difluorobenzoate (5.00 g, 24.9 mmol) was taken up in acetic acid (50.0 mL), and sulfuric acid (12.1 M, 2.05 mL, 24.9 mmol) and hydrogen peroxide (30% aqueous solution, 46.7 mL, 74.6 mmol) were added sequentially. The mixture was heated to 100 °C for 1 h. The mixture was then cooled to room temperature and then slowly poured into 300 mL of ice water with swirling. The mixture was then diluted with EtOAc (200 mL), transferred to a separatory funnel, and the organic phase was collected. The aqueous phase was extracted with EtOAc (2 × 100 mL), and the combined organics were dried over MgSO and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc / hexane gradient) to give the product.

[0225] Ethyl (S)-3-fluoro-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoate: Ethyl 3,5-difluoro-4-nitro-benzoate (2.50 g, 10.8 mmol) and (S)-oxetan-2-ylmethanamine (989 mg, 11.4 mol) were taken up in tetrahydrofuran (12.0 mL) and N,N-dimethylformamide (6.0 mL), and N,N-diisopropylethylamine (9.42 mL, 54.1 mmol) was added. The mixture was heated to 50 °C for 16 h. Following this time, the mixture was concentrated in vacuo, and the residue was purified by column chromatography (eluent: 0-25% EtOAc / hexanes) to give the product. ES / MS: 299.2 (M+H + ).

[0226] Ethyl (S)-4-amino-3-fluoro-5-(((oxetan-2-ylmethyl)amino)benzoate (I-5): Ethyl (S)-3-fluoro-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoate (2.20 g, 7.38 mmol) was taken up in ethanol (10 mL) and tetrahydrofuran (5 mL), and the mixture was sparged with nitrogen for 5 minutes. Palladium on carbon (10 wt. % loading, 785 mg, 0.74 mmol) was then added and the mixture was sparged. ng) was continued for 5 min. Hydrogen was then bubbled through the solution for 1 min, and the mixture was then placed under a balloon hydrogen atmosphere for 21 h. Following this time, the reaction was stopped and the mixture was filtered through Celite. The filter was washed with EtOAc (2 x 20 mL) and methanol (2 x 10 mL), and the filtrate was concentrated in vacuo to give ethyl (S)-4-amino-3-fluoro-5-((oxetan-2-ylmethyl)amino)benzoate (I-5). ES / MS: 269.2 (M+H + ); 1 H NMR (400 MHz, chloroform) δ 7.44-7.30 (m, 2H), 5 .13(qd,J=7.1,3.4 Hz,1H),4.72(ddd,J=8.7,7.4,6.0 Hz,1H),4.62(dt,J=9.1,6.1 Hz,1H),4.33(q,J=7.1 Hz,2H),3.58-3.30(m,2H),2.76(dtd,J=11.4,8.0,6.1 Hz,1H),2.56(ddt,J=11.3,9.0,7.1 Hz,1H),1.37(t,J=7.1Hz,3H).

[0227] Preparation of Intermediate I-6

[0228] [ka]

[0229] Tert-butyl 3-((2-methoxyethyl)amino)-4-nitrobenzoate: To a 500 mL RBF was added tert-butyl 3-fluoro-4-nitrobenzoate (10 g, 41.5 mmol). The material was dissolved in THF (150 mL) and 2-methoxyethanamine (7.2 mL, 82.9 mmol) and N,N-diisopropylethylamine (21.7 mL, 124 mmol) were added. The mixture was stirred at 50° C. overnight. The mixture was then concentrated to remove most of the THF and the crude material was dissolved in EtOAc (400 mL). The organics were washed with 50% NH4Cl (2 x 100 mL) and brine (1 x 50 mL). The organics were then dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was carried forward without further purification. ES / MS: 297.1 (M+H) + ); 1 H NMR(400 MHz,chloroform-d)δ8.21(d,J=8.9 Hz,1H),7.55(d,J=1.7 Hz,1H),7.20(dd,J=8.9,1.7 Hz,1H),3.72(dd,J=5.8,4.8 Hz,2H),3.57(q,J=5.2 Hz, 2H), 3.46 (s, 3H), 1.62 (s, 9H).

[0230] Tert-butyl 4-amino-3-((2-methoxyethyl)amino)benzoate (I-6): To a 1 L RBF was added tert-butyl 3-((2-methoxyethyl)amino)-4-nitrobenzoate (13 g, 43.9 mmol), ethanol (100 mL), and EtOAc (50 mL). The mixture was stirred and sonicated until all material was dissolved. Nitrogen was bubbled through the mixture for 5 minutes, and then palladium on carbon (10 wt%, 2.33 g, 2.19 mmol) was added. Hydrogen was bubbled through the mixture for 5 minutes, and the mixture was stirred under a hydrogen balloon overnight. Nitrogen was then bubbled through the flask for 10 minutes, and then the mixture was filtered through Celite to remove the catalyst. The filtrate was concentrated under reduced pressure and used without further purification. ES / MS: 267.2 (M+H + ).

[0231] Preparation of Intermediate I-7

[0232] [ka]

[0233] Methyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorophenyl)acetate: A suspension of methyl 2-(4-bromo-2,5-difluorophenyl)acetate (10.5 g, 39.6 mmol), bis(neopentyl glycol)diboron (17.9 g, 79.2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); PdCl2 (2.94 g, 3.96 mmol), and potassium propionate (15.6 g, 139 mmol) in dioxane (50 mL) was degassed with Ar for 20 minutes. The mixture was sealed and heated at 100 °C for 2 hours. Sodium carbonate (2.0 M, 39.6 mL, 79.2 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); PdCl2(dppf) (1.47 g, 1.98 mmol) and I-3 (14 g, 45.6 mmol) were added, and the mixture was degassed with Ar for 10 min, then sealed and heated at 100 °C for 1 h. The reaction mixture was diluted with EtOAc and washed with brine. The organic extract was dried over sodium sulfate and chromatographed (eluent: EtOAc / hexane) to give the title product. ES / MS: 413.2 (M+H + ).

[0234] 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorophenyl)acetic acid (I-7). A solution of methyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorophenyl)acetate (12.5 g, 30.3 mmol) and lithium hydroxide (0.2 M, 19.7 mL, 39.4 mmol) in CHCN (50 mL) was heated at 50 °C for 2 h. The mixture was acidified with 1 N hydrochloride to pH = 6-7. The material was crushed and filtered through a filter funnel. The solid was washed with water and dried overnight to give the product. ES / MS: 399.2 (M+H). + ); 1H NMR (400 MHz, methanol-d₄) δ 7.83–7.77 (m, 1H), 7.78–7.65 (m, 2H), 7.64–7.59 (m, 2H), 7.58–7.51 (m, 1H), 7.26–7.14 (m, 1H), 6.91 (d, J = 8.2 Hz, 1H), 5.63 (s, 2H), 3.73 (d, J = 1.2 Hz, 2H).

[0235] Preparation of Intermediate I-8

[0236] [ka]

[0237] Methyl (S)-2-(4-bromo-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (I-8): Following the procedure of intermediate I-2, using I-4 instead of I-1, and using 2-(4-bromo-2,5-difluorophenyl)acetic acid instead of 2-(4-bromo-2-fluorophenyl)acetic acid, methyl (S)-2-(4-bromo-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate was prepared. ES / MS: 451.0, 453.0 (M+H + ).

[0238] Preparation of Intermediate I-9

[0239] [ka]

[0240] Methyl (S)-2-(4-(6-(benzyloxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate: Methyl (S)-2-(4-bromo-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (I-8) (450 mg, 0.997 mmol), Pd(dppf)Cl (74.0 mg, 0.100 mmol), potassium propionate (336 mg, 2.99 mmol), and bis(pinacolato)diboron (304 mg, 2.99 mmol) were taken in 1,4-dioxane (4.00 mL), and the mixture was sparged with argon for 5 min. The mixture was then heated to 110 °C for 1 h. Following this time, complete conversion to the intermediate boronic ester was observed. The mixture was cooled to room temperature, and aqueous sodium carbonate (2.0 M, 0.997 mL, 1.99 mmol) was added. The mixture was stirred for 5 min, then 2-(benzyloxy)-6-bromopyridine (290 mg, 1.10 mmol) and Pd(dppf)Cl (37.0 mg, 0.050 mmol) were added, and the mixture was heated to 90 °C for 1 h. The mixture was then loaded directly onto SiO for purification using normal phase column chromatography (eluent: EtOAc / CHCl gradient), affording the desired product. The product was obtained. ES / MS: 556.2 (M+H + ).

[0241] Methyl (S)-2-(2,5-difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (I-9): Methyl (S)-2-(4-(6-(benzyloxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (426.0 mg, 0.767 mmol) was taken up in ethanol (6.0 mL) and tetrahydrofuran (3.0 mL), and the solution was sparged with nitrogen for 5 minutes. Pd / C (408 mg, 0.383 mmol) was added, and nitrogen was bubbled through the suspension for an additional 5 minutes. Hydrogen was then bubbled through the solution for 5 minutes before the reaction was placed under a balloon hydrogen atmosphere. The mixture was stirred at room temperature for 30 minutes. Following this time, the suspension was filtered through Celite and washed with EtOAc (3 x 10 mL). The filtrate was concentrated in vacuo to give methyl (S)-2-(2,5-difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (I-9). ES / MS: 466.2 (M+H). + ).

[0242] Preparation of Intermediate I-10

[0243] [ka]

[0244] In a vial, methyl 2-[[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (I-10): In a vial, methyl 2-[(4-bromo-2-fluoro-phenyl)methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (I-2) (200 ml) g, 0.475 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (145 mg, 0.570 mmol), (1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (33.6 mg, 0.0475 mmol), and potassium acetate (0.140 g, 1.42 mmol) were added. 1,4-Dioxane (4.80 mL) was then added, and the mixture was heated to 100 °C for 24 h. The reaction mixture was filtered through Celite, eluting with DCM, and the filtrate was concentrated in vacuo. The crude residue was purified by column chromatography (0-100% EtOAc in hexanes) to give methyl 2-[[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (I-10). ES / MS m / z: 469.4 (M+H). + ).

[0245] Preparation of Intermediate I-11

[0246] [ka]

[0247] tert-Butyl 2-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (I-11): Prepared as described for intermediate I-10 using 2-(4-bromo-2,5-difluorophenyl)acetic acid instead of 2-(4-bromo-2-fluorophenyl)acetic acid. tert-Butyl 4-amino-3-((2-methoxyethyl)amino)benzoate (I-6) was used instead of methyl 4-amino-3-(2-methoxyethylamino)benzoate to prepare tert-butyl 2-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate. ES / MS: 529.3 (M+H + ); 1 H NMR (400 MHz, DMSO-d 6 )δ8.13(s,1H),7.74(dd,J=8.4,1.6 Hz,1H),7.56(d,J=8.4 Hz,1H),7.33(dd,J=9.3,4.6 Hz,1H),7.17(dd,J=9.1,5.5 Hz,1H),4.54(t,J=5.1 Hz,2H),4.39(s,2H),3.65(t,J=5.1 Hz,2H),3.20(s,3H),1.57(s,9H),1.31(s,12H).

[0248] Preparation of Intermediate I-12

[0249] [ka]

[0250] Tert-Butyl 2-[[4-(6-chloropyridin-2-yl)-2,5-difluorophenyl]methyl]-3-(2-methoxyethyl)-1,3-benzodiazole-5-carboxylate (I-12): Tert-butyl 2-[[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3-(2-methoxyethyl)-1,3-benzodiazole-5-carboxylate (I-11) (30.0 g, 56.7 mmol, 1.00 equiv) and 2-bromo-6-chloropyridine (14.2 g, 73.8 mmol, 1.30 equiv) were dissolved in 1,4-dioxane (600 mL) and HO (60 mL). To the solution was added Pd(dppf)Cl (4.15 g, 5.68 mmol, 0.1 equiv.) and KCO (15.7 g, 114 mmol, 2.0 equiv.). The resulting solution was heated to 90 °C overnight under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / EtOAc (2 / 1) to give tert-butyl 2- [[4-(6-chloropyridin-2-yl)-2,5-difluorophenyl]methyl]-3-(2-methoxyethyl)-1,3-benzodiazole-5-carboxylate (I-12) was obtained. ES / MS: 513.8 (M+H + ); 1 H NMR (400 MHz, DMSO-d 6 )δ 8.14(s,1H),8.02(t,J=7.9Hz,1H),7.87(d,J=7.7Hz,1H),7.78 -7.69(m,2H),7.59(d,J=8.2Hz,2H),7.41(dd,J=11.4,6.0Hz,1H),4.58(t, J=5.1Hz,2H),4.44(s,2H),3.68(t,J=5.1Hz,2H),3.22(s,3H),1.58(s,9H).

[0251] Preparation of Intermediate I-13

[0252] [ka]

[0253] Ethyl (S)-4-(2-(4-bromo-2-fluorophenyl)acetamido)-3-fluoro-5-((oxetan-2-ylmethyl)amino)benzoate: A solution of I-5 (500 mg, 1.86 mmol) and 2-(4-bromo-2-fluorophenyl)acetic acid (521 mg, 2.24 mmol) in MeCN (9.0 mL) was cooled to 0 °C and 1-methylimidazole (765 mg, 0.74 mL, 9.32 mmol) was added, followed by N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (732 mg, 2.61 mmol). The mixture was allowed to warm to room temperature and stirred for 30 minutes. The crude mixture was concentrated in vacuo and then partitioned between water and EtOAc. The organic layer was isolated and washed with an additional portion of water and then brine. The isolated organic layer was dried over sodium sulfate, isolated by vacuum filtration, concentrated in vacuo, and purified by silica gel column chromatography (eluent: EtOAc / hexanes) to give ethyl (S)-4-(2-(4-bromo-2-fluorophenyl)acetamido)-3-fluoro-5-((oxetan-2-ylmethyl)amino)benzoate. ES / MS: 483.0, 485.0 [M+H] + .

[0254] Ethyl (S)-2-(4-bromo-2-fluorobenzyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (I-13): To a solution of ethyl (S)-4-(2-(4-bromo-2-fluorophenyl)acetamido)-3-fluoro-5-((oxetan-2-ylmethyl)amino)benzoate (530 mg, 1.10 mmol) in DCE (12.0 mL) was added acetic acid (1.88 mL, 32.9 mmol). The mixture was heated to 60° C. for 12 h. The mixture was concentrated and partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer was isolated, dried over sodium sulfate, isolated by vacuum filtration, concentrated in vacuo, and purified by silica gel column chromatography (eluent: EtOAc / hexanes) to give ethyl (S)-4-(2-(4-bromo-2-fluorophenyl)acetamido)-3-fluoro-5-((oxetan-2-ylmethyl)amino)benzoate (530 mg, 1.10 mmol). -2-(4-bromo-2-fluorobenzyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (I-13) was obtained. ES / MS: 465.0, 467.0 [M+H] + .

[0255] Preparation of intermediate I-14

[0256] [ka]

[0257] Ethyl (S)-2-(4-bromo-2,5-difluorobenzyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (I-14): Ethyl (S)-2-(4-bromo-2,5-difluorobenzyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate was prepared by the method described for intermediate I-13, using 2-(4-bromo-2,5-difluorophenyl)acetic acid instead of 2-(4-bromo-2-fluorophenyl)acetic acid. ES / MS: 483.0, 485.0 (M+H + ).

[0258] Preparation of Intermediate I-15

[0259] [ka]

[0260] Ethyl (S)-2-(2,5-difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (I-15): Ethyl (S)-2-(2,5-difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate was prepared in the manner described for intermediate I-9, substituting I-14 for I-8. ES / MS: 498.2 (M+H + ).

[0261] Preparation of Intermediate I-16

[0262] [ka]

[0263] Methyl (S)-2-(4-(6-chloropyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (I-16): Methyl (S)-2-(4-(6-chloropyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate was prepared in the manner described for intermediate I-12, substituting I-4 for I-6. ES / MS: 484.0 (M+H + ).

[0264] Preparation of intermediate 17

[0265] [ka]

[0266] tert-Butyl 2-(2,5-difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (I-17): Prepared tert-butyl 2-(2,5-difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate by the method described for intermediate I-9, substituting tert-butyl 2-(4-bromo-2,5-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (prepared by the method described for intermediate I-2, substituting 2-(4-bromo-2,5-difluorophenyl)acetic acid for 2-(4-bromo-2-fluorophenyl)acetic acid), and substituting I-6 for I-1. ES / MS: 496.9 (M+H + ).

[0267] Preparation of Intermediate I-18

[0268] [ka]

[0269] tert-Butyl 2-(4-(6-((4-bromo-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (I-18): To a solution of tert-butyl 2-[[2,5-difluoro-4-(6-hydroxy-2-pyridyl)phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (I-17) (500 mg, 1.0 mmol) in toluene (5 mL) was added 4-bromo-1-(bromomethyl)-2-fluoro-benzene (406 mg, 1.5 mmol) and silver carbonate (835 mg, 3 mmol). The solution was stirred at 70 °C for 8 h, cooled, and filtered. The solution was concentrated and purified by silica gel column chromatography (eluent: EtOAc / hexane) to give tert-butyl 2-(4-(6-((4-bromo-2-fluorobenzyl)propan-1-yl)-2-methylpropan-1-yl)-4-oxo-2-methylpropan-1-yl)-4 ...oxo-2-methylpropan-1-yl) (2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (I-18) was obtained: ES / MS: 683.2, 684.1 (M+H + ).

[0270] Preparation of Intermediate I-19

[0271] [ka]

[0272] Methyl (S)-2-(4-(6-((4-bromo-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (I-19): Methyl (S)-2-(4-(6-((4-bromo-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate was prepared in the manner described for intermediate I-18, substituting I-9 for I-17. ES / MS: 652.3 (M+H + ).

[0273] Preparation of Intermediate I-20

[0274] [ka]

[0275] Ethyl (S)-2-(4-(6-((4-bromo-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (I-20): Ethyl (S)-2-(4-(6-((4-bromo-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate was prepared in the manner described for intermediate I-18, substituting I-15 for I-17. ES / MS: 684.2 (M+H + ).

[0276] Preparation of Intermediate I-21

[0277] [ka]

[0278] Methyl (S)-2-(4-(6-((5-bromothiazol-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (I-21). To a solution of methyl (S)-2-(2,5-difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (I-9) (500 mg, 1.07 mmol) in acetonitrile (15 mL) was added cesium carbonate (560 mg, 1.72 mmol) and 5-bromo-2-(bromomethyl)thiazole (290 mg, 1.13 mmol), and the resulting mixture was stirred at 50 °C for 1 h. Upon completion, the crude reaction mixture was filtered through Celite and rinsed with DCM. The filtrate was concentrated, and the crude residue was purified by silica gel column chromatography (eluent: EtOAc / hexanes) to give methyl (S)-2-(4-(6-((5-bromothiazol-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (I-21). ES / MS: 643.0 (M+H + ).

[0279] Preparation of Intermediate I-22

[0280] [ka]

[0281] Ethyl (S)-2-(4-(6-((5-bromothiazol-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (I-22): Ethyl (S)-2-(4-(6-((5-bromothiazol-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate was prepared in the manner described for intermediate I-21, substituting I-15 for I-17. ES / MS: 673.0 (M+H + ).

[0282] Preparation of Intermediate I-23

[0283] [ka]

[0284] Methyl (S)-2-(4-(6-((6-chloro-4-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (I-23): Methyl (S)-2-(4-(6-((6-chloro-4-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (I-23) may be prepared in the manner described for intermediate I-19, using 5-(bromomethyl)-2-chloro-4-fluoropyridine in place of 4-bromo-1-(bromomethyl)-2-fluoro-benzene. Xetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate was prepared. ES / MS: 609.2 (M+H + ).

[0285] Preparation of Intermediate I-24

[0286] [ka]

[0287] Methyl (S)-2-(4-(6-((6-bromo-4-chloropyridin-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (I-24): Methyl (S)-2-(4-(6-((6-bromo-4-chloropyridin-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate was prepared in the manner described for intermediate I-19, using 2-bromo-5-(bromomethyl)-4-chloropyridine instead of 4-bromo-1-(bromomethyl)-2-fluoro-benzene. ES / MS: 654.0, 656.0 (M+H + ).

[0288] Preparation of Intermediate I-25

[0289] [ka]

[0290] Methyl 4-amino-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)benzoate (I-25): Methyl 4-amino-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)benzoate was prepared as described for intermediate I-1, using (±)-4,4-dimethyltetrahydrofuran-3-amine instead of 2-methoxyethylamine, with the following modification: To a solution of methyl 3-fluoro-4-nitrobenzoate (3.94 g, 19.8 mmol) and 4,4-dimethyltetrahydrofuran-3-amine hydrochloride (3.00 g, 19.8 mmol) in 2-methyltetrahydrofuran (40 mL) was added DIPEA (17.2 mL, 98.9 mmol) under argon. The resulting solution was refluxed at 80 °C for 3 days. The mixture was concentrated in vacuo and partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc. The combined organic phase was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was redissolved in EtOH (52 mL) and tetrahydrofuran (26 mL) under argon, then redissolved in 10% palladium on carbon (2.1 g, 1.98 mmol). The mixture was cycled between argon and vacuum, then placed under a hydrogen atmosphere, and stirred at room temperature for 18 hours. The mixture was filtered through Celite and concentrated in vacuo. The crude material was purified by silica gel flash column chromatography (EtOAc / hexane gradient) to give methyl 4-amino-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)benzoate (Intermediate I-25). ES / MS: 265.2 (M+H + ).

[0291] Preparation of Intermediate I-26

[0292] [ka]

[0293] tert-Butyl (R)-4-amino-3-((2-methoxypropyl)amino)benzoate (I-26): tert-Butyl (R)-4-amino-3-((2-methoxypropyl)amino)benzoate was prepared as described for intermediate I-6, using (R)-2-methoxypropan-1-amine instead of 2-methoxyethylamine. ES / MS: 281.1 (M+H + ).

[0294] Preparation of Intermediate I-27

[0295] [ka]

[0296] Methyl 5-(((6-bromopyridin-2-yl)oxy)methyl)picolinate: To a solution of 6-bromopyridin-2-ol (3.00 g, 17 mmol) in acetonitrile (100 mL) was added silver carbonate (10.2 g, 37 mmol) and methyl 5-(bromomethyl)pyridine-2-carboxylate (5.00 g, 22 mmol), and the resulting mixture was heated to 60° C. for 3 h. Upon completion, the reaction mixture was filtered through Celite, concentrated, and purified by silica gel column chromatography (eluent: EtOAc / hexanes) to give the desired product. ES / MS: 325.2 (M+H + ).

[0297] 5-(((6-Bromopyridin-2-yl)oxy)methyl)picolinic acid I-27): To a solution of methyl 5-(((6-bromopyridin-2-yl)oxy)methyl)picolinate (5.57 g, 17 mmol) in acetonitrile (75 mL) was added lithium hydroxide (2.17 g, 51.7 mmol) as a solution in water (25 mL), and the mixture was stirred at room temperature for 1 h. The pH was adjusted to approximately 6 with 1 N HCl, after which the reaction mixture was diluted with EtOAc (200 mL), and the layers were separated. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to afford 5-(((6-bromopyridin-2-yl)oxy)methyl)picolinic acid (I-27) without further purification. ES / MS: 309.1 (M+H) + ).

[0298] Preparation of Intermediate I-28

[0299] [ka]

[0300] 5-(((6-Bromopyridin-2-yl)oxy)methyl)-N-(1-cyanocyclopropyl)picolinamide (I-28): To a solution of 5-(((6-bromopyridin-2-yl)oxy)methyl)picolinic acid (I-27) (5.32 g, 17 mmol) in DMF (80 mL) was added 1-aminocyclopropanecarbonitrile hydrochloride (3.14 g, 26 mmol), HATU (9.62 g, 25 mmol), and diisopropylethylamine (12 mL, 69 mmol) sequentially. The resulting solution was stirred at room temperature for 30 min. Upon completion, the contents of the mixture were diluted with EtOAc (250 mL), washed with water (2×50 mL), brine (1×40 mL), dried over MgSO4, filtered, and concentrated to afford 5-(((6-bromopyridin-2-yl)oxy)methyl)-N-(1-cyanocyclopropyl)picolinamide (I-28) without further purification. ES / MS: 375.1 (M+H + ).

[0301] The following intermediates were synthesized in a similar manner as described for intermediate I-28:

[0302] [ka]

[0303] Preparation of Intermediates I-29 and I-30

[0304] [ka]

[0305] tert-Butyl 4-amino-3-(((3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl)amino)benzoate (I-29 and I-30): tert-Butyl 3-(((3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl)amino)-4-nitrobenzoate: A solution of tert-butyl 3-fluoro-4-nitrobenzoate (0.150 g, 0.622 mmol), (3aS,6aR)-2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-amine (0.0984 g, 0.762 mmol), and N-ethyl-N-isopropyl-propan-2-amine (0.325 mL, 1.87 mmol) in NMP (4 mL) was heated at 90° C. overnight. The mixture was diluted with EtOAc and washed with 5% LiCl and brine. The organic extract was dried over sodium sulfate and purified by flash chromatography (eluent: EtOAc / hexanes) to give tert-butyl 3-(((3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl)amino)-4-nitrobenzoate as an inseparable mixture of two compounds. ES / MS: 351.0 (M+H + ).

[0306] tert-Butyl 4-amino-3-(((3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl)amino)benzoate (I-29 and I-30): A solution of tert-butyl 3-[[(3aS,6aR)-2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-yl]amino]-4-nitro-benzoate (156 mg, 0.445 mmol) in EtOH (15 mL) was degassed three times by cycling the mixture between argon and vacuum. Pd / C (10.0%, 47.4 mg, 0.0445 mmol) was added to the solution, and the solution was then degassed once by cycling the mixture between argon and vacuum and stirred overnight at room temperature with a hydrogen balloon. The reaction mixture was filtered through a plug of Celite and rinsed with EtOAc. Concentration and purification by flash chromatography (eluent: 30–40% EtOAc / hexanes) afforded two different isomers of tert-butyl 4-amino-3-(((3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl)amino)benzoate (I-29 and I-30).

[0307] Isomer 1 (less polar, first eluting), I-29 ES / MS: 321.0 (M+H + ). 1H NMR (400MHz, chloroform-d)δ 7.45(dd,J=8.1,1.8Hz,1H),7.37(d,J=1.8Hz,1H),6.74(d,J=8.1Hz,1H),5.87(d,J=5.1Hz,1H),4.32-4.06(m,2H),4.05-3.81(m,2H),3.6 6(t,J=8.7Hz,1H),3.24(tt,J=8.7,4.2Hz,1H),2.03-1.90(m,1H),1.90-1.79(m,1H),1.60(s,9H).

[0308] Isomer 2 (more polar, second eluting), I-30 ES / MS: 321.0 (M+H +). 1H NMR (400MHz, chloroform-d)δ 7.45(dd,J=8.1,1.8Hz,1H),7.38(d,J=1.8Hz,1H),6.75(d,J=8.0Hz,1H),5.87(d,J=5.1Hz,1H),4.34-4.05( m,2H),4.02-3.82(m,2H),3.67(t,J=8.6Hz,1H),3.24(tt,J=8.6,4.2Hz,1H),2.02-1.81(m,2H),1.60(s,9H).

[0309] Preparation of Intermediate I-31

[0310] [ka]

[0311] (5-Bromo-3-fluoropyridin-2-yl)methyl 4-methylbenzenesulfonate (I-31): (5-Bromo-3-fluoro-2-pyridyl)methanol (200 mg, 0.97 mmol), p-toluenesulfonic anhydride (350 mg, 1.1 mmol), diisopropylethylamine (0.34 mL, 1.9 mmol), and DCM (10 mL) were combined and stirred at ambient temperature for 16 h. Upon completion, the reaction mixture was washed with saturated aqueous NaHCO (5 mL) and brine (5 mL), dried over MgSO, filtered, and concentrated to afford (5-bromo-3-fluoropyridin-2-yl)methyl 4-methylbenzenesulfonate (I-31), which was used without further purification.

[0312] The following intermediates were prepared in a similar manner as described for intermediate I-31.

[0313] [ka]

[0314] Preparation of Intermediate I-32

[0315] [ka]

[0316] (5-Chloropyrazin-2-yl)methyl 4-methylbenzenesulfonate (I-32): (5-Chloropyrazin-2-yl)methyl 4-methylbenzenesulfonate was prepared as described for intermediate I-31, using (5-chloropyrazin-2-yl)methanol instead of (5-bromo-3-fluoro-2-pyridyl)methanol.

[0317] Preparation of Intermediate I-33

[0318] [ka]

[0319] tert-Butyl 2-[[4-[6-[(5-bromo-3-fluoro-2-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (I-33): To a solution of tert-butyl 2-[[2,5-difluoro-4-(6-hydroxy-2-pyridyl)phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (I-17) (400 mg, 0.80 mmol) and (5-bromo-3-fluoro-2-pyridyl)methyl 4-methylbenzenesulfonate (I-31) (350 mg, 0.97 mmol) in 15 mL of acetonitrile, CsCO (400 mg, 1.20 mmol) was added. The solution was then heated to 50 °C for 30 min. The solution was cooled to room temperature, filtered, and concentrated. The crude material was purified by silica gel column chromatography (eluent: EtOAc / hexane) to give tert-butyl 2-[[4-[6-[(5-bromo-3-fluoro-2-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (I-33): product. ES / MS: 686.0 (M+H + ).

[0320] Preparation of Intermediate I-34

[0321] [ka]

[0322] tert-Butyl 2-[[4-[6-[(5-chloropyrazin-2-yl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (I-34): Prepared tert-butyl 2-[[4-[6-[(5-chloropyrazin-2-yl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate in the manner described for intermediate I-33, substituting I-31 for I-32. ES / MS: 566.0 (M+H + ).

[0323] Preparation of Intermediate I-35

[0324] [ka]

[0325] 4-Fluoro-5-(hydroxymethyl)thiophene-2-carbonitrile: (5-bromo-3-fluoro-2-thienyl)methanol (220 mg, 1.04 mmol), zinc cyanide (182 mg, 1.55 mmol), zinc powder (3 mg, 0.05 mmol), and Pd(PPh) (300 mg, 0.26 mmol) in DMF (10 mL) were degassed by bubbling argon through for 1 minute, sealed, and heated to 100 °C for 20 h. Upon completion, the contents of the mixture were poured into HO (10 mL) and extracted with EtOAc (2 × 20 mL). The organic layers were combined, washed with brine (5 mL), dried over MgSO, filtered, concentrated, and purified by flash chromatography (eluent: EtOAc / hexanes) to give 4-fluoro-5-(hydroxymethyl)thiophene-2-carbonitrile. ES / MS:158.2[M+1].

[0326] 5-(Bromomethyl)-4-fluoro-thiophene-2-carbonitrile (I-35): Carbon tetrabromide (111 mg, 0.34 mmol) was added to a solution of 4-fluoro-5-(hydroxymethyl)thiophene-2-carbonitrile (48 mg, 0.31 mmol), triphenylphosphine (88 mg, 0.34 mmol) in DCM (3 mL) at room temperature. The mixture was stirred for 30 minutes at room temperature. Upon completion, the mixture was concentrated and purified by flash chromatography (eluent: EtOAc / hexanes) to give 5-(bromomethyl)-4-fluoro-thiophene-2-carbonitrile (I-35). ES / MS: 221.2 [M+1].

[0327] Preparation of Intermediate I-36

[0328] [ka]

[0329] [5-(Difluoromethyl)thiazol-2-yl]methanol: To a solution of [5-(difluoromethyl)thiazole-2-carbonyl]oxysodium (200 mg, 1.08 mmol) in DCM (5 mL) at room temperature was added oxalyl chloride (2.0 M in DCM, 0.65 mL, 1.3 mmol). After stirring at room temperature for 1 hour, MeOH (1 mL) was added, and the mixture was stirred for an additional 30 minutes before being poured into HO (10 mL) and extracted with EtOAc (2 x 20 mL). The organic layers were combined, washed with brine (5 mL), dried over MgSO, filtered, and concentrated. The residue was redissolved in THF (5 mL) and cooled to 0 °C. Diisobutylaluminum hydride (1.0 M in DCM, 3.3 mL, 3.3 mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 1 hour. Upon completion, the reaction was quenched with 2M NaOH (0.4 mL), HO (0.4 mL), and diluted with EtOAc (10 mL). The mixture was then filtered through a plug of Celite. The organic layers were combined, washed with brine (5 mL), dried over MgSO, filtered, concentrated, and purified by flash chromatography (eluent: EtOAc / hexanes) to give the desired product. ES / MS: 166.2 [M+1].

[0330] 2-(Bromomethyl)-5-(difluoromethyl)thiazole (I-36): To [5-(difluoromethyl)thiazol-2-yl]methanol (88 mg, 0.53 mmol), triphenylphosphine (150 mg, 0.56 mmol) in DCM (3 mL) was added carbon tetrabromide (190 mg, 0.56 mmol) at room temperature. The mixture was stirred at room temperature for 30 minutes. Upon completion, the mixture was concentrated and purified by flash chromatography (eluent: EtOAc / hexanes) to give I-36. ES / MS: 229.2 [M+1].

[0331] Preparation of Intermediate I-37

[0332] [ka]

[0333] [5-(2,2-Difluoroethoxy)thiazol-2-yl]methanol: A suspension of methyl 5-hydroxythiazole-2-carboxylate (200 mg, 1.3 mmol), 2,2-difluoroethyl trifluoromethanesulfonate (300 mg, 1.4 mmol), and cesium carbonate (610 mg, 1.9 mmol) in MeCN (5 mL) was stirred at room temperature for 16 hours. Upon completion, the mixture was filtered through a plug of Celite and concentrated. The residue was redissolved in THF (5 mL) and cooled to 0 °C. Diisobutylaluminum hydride (1.0 M in DCM, 2.8 mL, 2.8 mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 1 hour. Upon completion, the reaction was quenched with 2 M NaOH (0.4 mL), HO (0.4 mL), and diluted with EtOAc (10 mL). The mixture was then filtered through a plug of Celite. The organic layers were combined, washed with brine (5 mL), dried over MgSO.sub.4, filtered, concentrated, and purified by flash chromatography (eluent: EtOAc / hexanes) to give the desired product.

[0334] 2-(Bromomethyl)-5-(2,2-difluoroethoxy)thiazole (I-37): To [5-(2,2-difluoroethoxy)thiazol-2-yl]methanol (91 mg, 0.47 mmol), triphenylphosphine (125 mg, 0.48 mmol) in DCM (5 mL) was added carbon tetrabromide (160 mg, 0.48 mmol) at room temperature. The mixture was stirred for 30 minutes at room temperature. Upon completion, the mixture was concentrated and purified by flash chromatography (eluent: EtOAc / hexanes) to give I-37. ES / MS: 258.2 [M+1].

[0335] Preparation of Intermediate I-38

[0336] [ka]

[0337] 2-(Bromomethyl)-5-(2,2,2-trifluoroethoxy)thiazole (I- 38): 2-(bromomethyl)-5-(2,2,2-trifluoroethoxy)thiazole was prepared by the method described for intermediate I-37, using 2,2-difluoroethyl trifluoromethanesulfonate instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate. ES / MS: 277.2 [M+1].

[0338] Preparation of Intermediate I-39

[0339] [ka]

[0340] Methyl (S)-2-(4-(6-((5-bromothiophen-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (I-39): Methyl (S)-2-(4-(6-((5-bromothiophen-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate was prepared in the manner described for intermediate I-19, using 5-(bromomethyl)-2-chloro-4-fluoropyridine instead of 2-bromo-5-(bromomethyl)thiophene. ES / MS: 642.0 (M+H + ).

[0341] Preparation of Intermediate I-40

[0342] [ka]

[0343] Methyl (S)-2-(4-(6-((5-bromo-3-fluorothiophen-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (I-40): Methyl (S)-2-(4-(6-((5-bromo-3-fluorothiophen-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate was prepared in the manner described for intermediate I-19, using 5-(bromomethyl)-2-chloro-4-fluoropyridine instead of 5-bromo-2-(bromomethyl)-3-fluorothiophene. ES / MS: 660.0 (M+H + ).

[0344] Preparation of Intermediate I-41

[0345] [ka]

[0346] Methyl 2-[[4-[6-[(5-bromo-1,3,4-thiadiazol-2-yl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (I-41): Methyl 2-[[4-[6-[(5-bromo-1,3,4-thiadiazol-2-yl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate was prepared as described for intermediate I-19, using 5-(bromomethyl)-2-chloro-4-fluoropyridine instead of 2-bromo-5-(bromomethyl)-1,3,4-thiadiazole. ES / MS: 660.0 (M+H + ).

[0347] Preparation of Intermediate I-42

[0348] [ka]

[0349] Thiazolo[5,4-b]pyridin-2-ylmethanol: Methyl thiazolo[5,4-b]pyridine-2-carboxylate (100 mg, 0.52 mmol) in THF (5 mL) was cooled to 0 °C. Diisobutylaluminum hydride (1.0 M in DCM, 1.5 mL, 1.5 mmol) was added, and the mixture was warmed to room temperature and stirred for 1 h. Upon completion, the reaction was quenched with 2 M NaOH (0.4 mL), HO (0.4 mL), and diluted with EtOAc (10 mL). The mixture was then filtered through a plug of Celite. The organic layers were combined, washed with brine (5 mL), dried over MgSO, filtered, concentrated, and purified by flash chromatography (eluent: EtOAc / hexanes) to give the title product. ES / MS: 167.2 [M+1].

[0350] Thiazolo[5,4-b]pyridin-2-ylmethyl 4-methylbenzenesulfonate (I-42): To a solution of thiazolo[5,4-b]pyridin-2-ylmethanol (40 mg, 0.24 mmol), triethylamine (0.07 mL, 0.5 mmol) in DCM (5 mL) was added toluene-4-sulfonyl chloride (46 mg, 0.24 mmol) at room temperature. The mixture was stirred at room temperature for 20 hours. Upon completion, the mixture was concentrated and purified by flash chromatography (eluent: EtOAc / hexanes) to give the title product. ES / MS: 321.2 [M+1].

[0351] Preparation of Intermediate I-43

[0352] [ka]

[0353] 2-Bromo-6-[(1-methylimidazol-4-yl)methoxy]pyridine (I-43): To a solution of 2-bromo-6-fluoro-pyridine (90.7 mg, 0.52 mmol) and (1-methylimidazol-4-yl)methanol (75.1 mg, 0.67 mmol) in 2.0 mL of acetonitrile was added CsCO (338 mg, 1.04 mmol). The solution was then heated to 50 °C for 30 min. The solution was cooled to room temperature, filtered, and concentrated. The crude material was purified by normal phase chromatography (1-12% DCM / MeOH). The product-containing fractions were combined and concentrated to give the title product. ES / MS m / z: 268.0, 270.2 (M+H). + ).

[0354] The following intermediates were synthesized using the method described for intermediate I-43.

[0355] [ka]

[0356] Preparation of Intermediate I-44

[0357] [ka]

[0358] 2-Bromo-6-[[1-(difluoromethyl)-2-methyl-imidazol-4-yl]methoxy]pyridine (I-44): This intermediate was prepared as described for intermediate I-43, using [1-(difluoromethyl)-2-methyl-imidazol-4-yl]methanol instead of (1-methylimidazol-4-yl)methanol. ES / MS m / z: 318.2 (M+H + ).

[0359] Preparation of Intermediate I-45

[0360] [ka]

[0361] Methyl 2-[(7-bromo-1,3-dihydroisobenzofuran-4-yl)methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (I-45): This intermediate was prepared as described for intermediate I-13, using 2-(7-bromo-1,3-dihydroisobenzofuran-4-yl)acetic acid instead of 2-(4-bromo-2-fluorophenyl)acetic acid. ES / MS m / z: 447.1 (M+H). + ).

[0362] Preparation of Intermediate I-46

[0363] [ka]

[0364] tert-Butyl (3R,4R)-3-(2-amino-5-methoxycarbonyl-anilino)-4-fluoro-pyrrolidine-1-carboxylate (I-46): This intermediate was prepared as described for intermediate I-6, using tert-butyl (3R,4R)-3-amino-4-fluoro-pyrrolidine-1-carboxylate instead of 2-methoxyethanamine. ES / MS m / z: 418.4 (M+Na + ).

[0365] Preparation of Intermediate I-47

[0366] [ka]

[0367] tert-Butyl N-tert-butoxycarbonyl-N-(6-chloro-2-methylsulfanyl-pyrimidin-4-yl)carbamate: A solution of methylsulfanyl-pyrimidin-4-amine (1 g, 5.7 mmol), tert-butoxycarbonyl tert-butyl carbonate (2.61 g, 12 mmol), ethyldiisopropylamine (3 mL, 17.1 mmol), and 4-dimethylaminopyridine (140 mg, 1.14 mmol) in 20 mL of DCM was stirred overnight. The mixture was washed with HO and brine. The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by column chromatography (0–50% EtOAc in hexanes) to give the title compound: ES / MS m / z: 375.2 (M+H+).

[0368] tert-Butyl N-tert-butoxycarbonyl-N-[6-chloro-2-[(4-cyano-2-fluoro-phenyl)methoxy]pyrimidin-4-yl]carbamate (I-47): A solution of tert-butyl N-tert-butoxycarbonyl-N-(6-chloro-2-methylsulfanyl-pyrimidin-4-yl)carbamate (0.5 g, 1.33 mmol) and 3-chloroperoxybenzoic acid (0.6 g, 2.7 mmol, 77%) in 5 mL of DCM was stirred overnight. The mixture was washed with HO and brine. The solvent was removed, and the resulting residue was dried in vacuo. The crude product was dissolved in 3 mL of DMF. 3-Fluoro-4-(hydroxymethyl)benzonitrile (220 mg, 1.46 mmol) and potassium carbonate (366 mg, 2.65 mmol) were added to this solution, and the mixture was allowed to stand at room temperature for 2 hours. After 2 h, the resulting solution was diluted with EtOAc (50 mL) and washed with HO. The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by column chromatography (0-50% EtOAc in hexanes) to give the title compound: ES / MS m / z: 479.1 (M+H+). Preparation of Intermediate I-48

[0369] [ka]

[0370] 2-[(2,6-Dichloro-4-pyridyl)oxymethoxy]ethyl-trimethyl-silane: To a solution of 2,6-dichloropyridin-4-ol (1 g, 6.1 mmol) and 2-(chloromethoxy)ethyl-trimethyl-silane (1.07 g, 6.4 mmol) in THF (10 mL) was added lithium bis(trimethylsilyl)amide (6.4 mL, 6.4 mmol) and stirred overnight. The solution was washed with HO and brine. The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by column chromatography (0-50% EtOAc in hexanes) to give the title compound. ES / MS m / z: 294.1 (M+H+).

[0371] 4-[(6-Chloro-4-hydroxy-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile (I-48): To a solution of 2-[(2,6-dichloro-4-pyridyl)oxymethoxy]ethyl-trimethylsilane (1.0 g, 3.4 mmol) in 5 mL of DMF was added 3-fluoro-4-(hydroxymethyl)benzonitrile (0.77 g, 5.1 mmol) and potassium carbonate (0.94 g, 6.8 mmol). The solution was heated to 120 °C for 6 h. Upon completion, the solution was diluted with EtOAc (50 mL) and washed with HO. The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude product was dissolved in 2 mL of THF. To the resulting solution was added tetrabutylammonium fluoride (4.0 mL, 4 mmol). The mixture was stirred for 3 h. The solvent was removed and the resulting residue was purified by column chromatography (0-80% EtOAc in hexanes) to give the title compound: ES / MS m / z: 279.2 (M+H+).

[0372] Preparation of Intermediate I-49

[0373] [ka]

[0374] 4-[[6-Chloro-4-(difluoromethyl)-2-pyridyl]oxymethyl]-3-fluoro-benzonitrile (I-49): To a solution of 2,6-dichloro-4-(difluoromethyl)pyridine (927 mg, 4.68 mmol) in 10 mL of DMF was added 3-fluoro-4-(hydroxymethyl)benzonitrile (708 mg, 4.68 mmol) and potassium carbonate (971 mg, 7 mmol). The mixture was heated to 60 °C overnight, diluted with EtOAc (50 mL), and washed with water. The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The solvent was removed, and the resulting residue was purified by column chromatography (0–60% EtOAc in hexanes) to give the title compound: ES / MS m / z: 313.1 (M+H+).

[0375] Preparation of Intermediate I-50

[0376] [ka]

[0377] Methyl 6-(4-cyclopropyltriazol-1-yl)pyridine-3-carboxylate: A suspension of methyl 6-chloropyridine-3-carboxylate (300 mg, 1.75 mmol) and sodium azide (227 mg, 3.5 mmol) in THF was added to 60 mL of The mixture was heated to °C for 5 h. Upon completion, the mixture was diluted with EtOAc and washed with a saturated solution of sodium bicarbonate (20 mL) and brine. The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. To the crude residue was added ethynylcyclopropane (145 mg, 2.2 mmol) in tert-butanol (5 mL). To the resulting mixture was added a solution of sodium ascorbate (0.19 mmol, 38 mg) in water (2.5 mL) and a solution of copper sulfate pentahydrate (0.19 mmol, 48 mg) in HO (2.5 mL), successively. The reaction mixture was stirred at room temperature for 18 h. Upon completion, the mixture was diluted with 5 mL of 1 M aqueous NH4OH and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (0-100% EtOAc in hexanes) to give the title compound: ES / MS m / z: 245.2 (M+H+).

[0378] [6-(4-Cyclopropyltriazol-1-yl)-3-pyridyl]methyl 4-methylbenzenesulfonate (I-50): To a solution of methyl 6-(4-cyclopropyltriazol-1-yl)pyridine-3-carboxylate (300 mg, 1.23 mmol) in 2 mL of THF was added 0.92 mL of 2 N lithium borohydride in THF. The resulting solution was stirred for 8 h, diluted with 50 mL of EtOAc, and washed with H2O and brine. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The resulting crude product was dissolved in 5 mL of DCM. Next, p-tolylsulfonyl 4-methylbenzenesulfonate (365 mg, 1.12 mmol) and ethyldiisopropylamine (0.37 mL, 2.13 mmol) were added to the solution. The mixture was stirred overnight. Upon completion, the resulting solution was diluted with 20 mL of DCM and washed with H2O and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (0-100% EtOAc in hexanes) to give the title compound: ES / MS m / z: 371.2 (M+H+).

[0379] Preparation of Intermediate I-51

[0380] [ka]

[0381] Methyl 6-(3-cyclopropyl-1,2,4-triazol-1-yl)pyridine-3-carboxylate: A suspension of methyl 6-chloropyridine-3-carboxylate (300 mg, 1.75 mmol), 3-cyclopropyl-1H-1,2,4-triazole (191 mg, 1.75 mmol), and potassium carbonate (483 mg, 3.5 mmol) in THF was heated at reflux for 8 h. The solution was then diluted with EtOAc and washed with a saturated solution of sodium bicarbonate (20 mL) and brine. The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (0–100% EtOAc in hexanes) to give the title compound: ES / MS m / z: 245.2 (M+H+).

[0382] [6-(3-Cyclopropyl-1,2,4-triazol-1-yl)-3-pyridyl]methyl 4-methylbenzenesulfonate (I-51): To a solution of methyl 6-(3-cyclopropyl-1,2,4-triazol-1-yl)pyridine-3-carboxylate (300 mg, 1.23 mmol) in 2 mL of THF was added 0.92 mL of 2 N lithium borohydride in THF. The solution was stirred overnight, diluted with 50 mL of EtOAc, and washed with water and brine. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was dissolved in 5 mL of DCM, and 4-methylbenzenesulfonyl chloride (241 mg, 1.26 mmol) and triethylamine (0.34 mL, 2.4 mmol) were added to the solution. The mixture was stirred overnight, diluted with 20 mL of DCM, and then washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (0-100% EtOAc in hexanes) to give I-51: ES / MS m / z: 371.1 (M+H+).

[0383] Preparation of Intermediate I-52

[0384] [ka]

[0385] [2-Fluoro-4-(2-trimethylsilylethynyl)phenyl]methyl 4-methylbenzenesulfonate: (2-Fluoro-4-iodophenyl)methanol (2 g, 7.94 mmol), ethynyl(trimethyl)silane (1.17 g, 11.9 mmol), copper iodide (75.6 mg, 0.4 mmol), bis(triphenylphosphine)palladium chloride (280 mg, 0.4 mmol), and triethylamine (3.3 mL, 23.8 mmol) were suspended in THF (15 mL). The mixture was degassed with nitrogen and stirred at ambient temperature for 16 h. After this time, the mixture was filtered through Celite and washed three times with 20 mL of DCM. The solvent was removed, and the resulting crude product was dried under vacuum. The crude product was then dissolved in 20 mL of DCM, followed by the addition of p-tolylsulfonyl 4-methylbenzenesulfonate (2.58 g, 7.92 mmol) and ethyldiisopropylamine (2.76 mL, 15.8 mmol). The mixture was stirred for 5 hours and checked by LC / MS. The mixture was then diluted with 20 mL of DCM and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (0-50% EtOAc in hexanes) to give the title compound: ES / MS m / z: 377.1 (M+H+).

[0386] Methyl 2-[[4-[6-[(4-ethynyl-2-fluoro-phenyl)methoxy]- [2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (I-52): Potassium carbonate (742 mg, 5.37 mmol) was added to a solution of methyl 2-[[2,5-difluoro-4-(6-hydroxy-2-pyridyl)phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (500 mg, 1.07 mmol) and [2-fluoro-4-(2-trimethylsilylethynyl)phenyl]methyl 4-methylbenzenesulfonate (420 mg, 1.12 mmol) in DMF (5 mL) and stirred for 3 h. Then, 50 mL of water was added to the solution, and the aqueous phase was extracted twice with EtOAc. The combined organic phase was dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude product was dissolved in MeOH (20 mL) and potassium carbonate (51.6 mg, 0.37 mmol) was added to the solution. After 2 h, the solution was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (0-80% EtOAc in hexanes) to give I-52. ES / MS m / z: 598.2 (M+H+).

[0387] Preparation of intermediate I-53

[0388] [ka]

[0389] N-(1-cyanocyclopropyl)-4-methoxy-5-methyl-pyridine-2-carboxamide: N,N-diisopropylethylamine (2.14 mL, 12.3 mmol) was added to a solution of 4-methoxy-5-methyl-pyridine-2-carboxylic acid (500 mg, 2.46 mmol), 1-aminocyclopropanecarbonitrile (349 mg, 2.95 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1373 mg, 3.61 mmol) in DMF (10 mL). The mixture was stirred overnight at room temperature. The mixture was then diluted with EtOAc and washed with 5% LiCl, saturated NaHCO3, and brine. The organic extract was dried over sodium sulfate and purified by flash chromatography (eluent: EtOAc / hexane) to give the title compound.

[0390] 5-(Bromomethyl)-N-(1-cyanocyclopropyl)-4-methoxy-pyridine-2-carboxamide: To a suspension of N-(1-cyanocyclopropyl)-4-methoxy-5-methyl-pyridine-2-carboxamide (400 mg, 1.73 mmol) in CCl4 (10 mL) was added N-bromosuccinimide (403 mg, 2.26 mmol), followed by benzoyl peroxide (45.1 mg, 0.186 mmol). The resulting solution was heated at 90 °C for 1 h. Upon completion, the mixture was cooled to room temperature, diluted with 5 mL of hexane, and the suspension was filtered. The filtrate was concentrated and purified by flash chromatography (eluent: EtOAc / hexane) to give the title compound. ES / MS: 310, 312 (M +H + ).

[0391] 5-[(6-Bromo-2-pyridyl)oxymethyl]-N-(1-cyanocyclopropyl)-4-methoxy-pyridine-2-carboxamide (Intermediate I-53): A suspension of 5-(bromomethyl)-N-(1-cyanocyclopropyl)-4-methoxy-pyridine-2-carboxamide (112 mg, 0.36 mmol), 6-bromopyridin-2-ol (50 mg, 0.29 mmol), and silver carbonate (169 mg, 0.61 mmol) in CHCN (5 mL) was heated at 50 °C overnight. Upon completion, the mixture was diluted with EtOAc and the brine was filtered through a Celite frit. The reaction mixture was partitioned, and the organic phase was washed once more with brine. The resulting crude product was dried over sodium sulfate, concentrated, and purified by flash chromatography (eluent: EtOAc / hexanes) to give I-53. ES / MS: 403, 405 (M+H + ).

[0392] Preparation of intermediate I-54

[0393] [ka]

[0394] 3-(Bromomethyl)-1-cyclopropylpyrazole (I-54): Carbon tetrabromide (0.541 g, 0.00163 mol) was added to a solution of (1-cyclopropylpyrazol-3-yl)methanol (0.188 g, 1.36 mmol) and (4-diphenylphosphanylphenyl polymer-bound) (78.7%, 0.542 g, 0.00163 mol) in DCM (10 mL) at 0 °C. The mixture was gradually warmed to room temperature and stirred overnight. The resulting suspension was filtered, and the filtrate was diluted with DCM and washed with brine. The organic extract was dried over sodium sulfate, concentrated, and purified by flash chromatography (eluent: EtOAc / hexanes) to give I-54. ES / MS: 201.2, 203.2 (M+H + ).

[0395] The following intermediates were prepared as described for intermediate I-54:

[0396] [ka]

[0397] Preparation of Intermediate I-55

[0398] [ka]

[0399] [1-(oxetan-3-yl)pyrazol-3-yl]methanol: Diisobutylaluminum hydride (1000 mmol / L in DCM, 2.40 mL, 2.40 mmol) was added to a solution of methyl 1-(oxetan-3-yl)pyrazole-3-carboxylate (175 mg, 0.961 mmol) in THF (5 mL) at 0° C. and stirred for 1 hour. After this time, the mixture was diluted with 5 mL of EtO and cooled to 0° C. Upon completion, 0.100 mL of water, 0.100 mL of 15% NaOH, and 0.240 mL of water were added. The solution was allowed to warm to room temperature and stirred for 15 minutes. After this time, MgSO was added, and the solution was stirred for an additional 15 minutes and filtered to give the title product, which was used in the next step without further purification. ES / MS: 155.2 (M+H + ).

[0400] 3-(Bromomethyl)-1-(oxetan-3-yl)pyrazole (I-55): Carbon tetrabromide (0.281 g, 0.000848 mol) was added to a solution of [1-(oxetan-3-yl)pyrazol-3-yl]methanol (0.109 g, 0.707 mmol) and (4-diphenylphosphanylphenyl polymer-bound) (78.7%, 0.282 g, 0.000848 mol) in DCM (10 mL) at 0 °C. The mixture was gradually warmed to room temperature and stirred overnight. The resulting suspension was filtered, and the filtrate was diluted with DCM and washed with brine. The organic extract was dried over sodium sulfate, concentrated, and purified by flash chromatography (eluent: EtO / hexanes) to give I-55. ES / MS: 217.2, 219.2 (M+H + ).

[0401] Preparation of Intermediate I-56

[0402] [ka]

[0403] Methyl 1-(4-pyridyl)pyrazole-3-carboxylate: In a 40 mL reaction vial, a mixture of methyl 1H-pyrazole-3-carboxylate (472 mg, 3.74 mmol), 4-fluoropyridine hydrochloride (500 mg, 3.74 mmol), and potassium carbonate (1358 mg, 9.83 mmol) in NMP (10 mL) was heated at 120° C. for 48 h. After this time, the mixture was diluted with EtOAc and washed with 5% LiCl (2×) and brine. The organic extract was dried over sodium sulfate, concentrated, and purified by flash chromatography (eluent: EtOAc / hexanes) to give the title compound. ES / MS: 204.2 (M+H + ).

[0404] [1-(4-pyridyl)pyrazol-3-yl]methanol (I-56): To a solution of methyl 1-(4-pyridyl)pyrazole-3-carboxylate (106 mg, 0.520 mmol) in THF (5 mL) at 0 °C was added diisobutylaluminum hydride (1.0 M in DCM, 1.30 mL, 1.30 mmol). The solution was stirred for 1 h. After this time, the mixture was diluted with 5 mL of EtO and cooled to 0 °C. Upon completion of cooling, 0.05 mL of water, 0.05 mL of 15% NaOH, and 0.130 mL of water were added to the solution. The solution was then warmed to room temperature and stirred for 15 min, after which MgSO was added. The solution was stirred for an additional 15 min and then filtered. The crude product was purified by flash chromatography (eluent: EtOAc / hexanes) to give I-56. ES / MS: 176.2 (M+H + ).

[0405] Preparation of Intermediate I-57

[0406] [ka]

[0407] [1-(trifluoromethyl)pyrazol-3-yl]methanol: To a solution of 1-(trifluoromethyl)pyrazole-3-carboxylic acid (321 mg, 1.78 mmol) in THF (10 mL) at 0 °C was added lithium aluminum hydride (2.0 M in THF) (2.00 mmol / L, 980 mL, 1.96 mmol). The solution was gradually warmed to room temperature and stirred for 1 hour. After this time, the solution was diluted with EtO and cooled to 0 °C. Upon complete cooling, 0.075 mL of water, 0.075 mL of 15% aqueous NaOH, and 0.225 mL of water were added to the solution, which was warmed to room temperature and stirred for an additional 15 minutes. After stirring for an additional 15 minutes, MgSO was added, and the solution was stirred for an additional 15 minutes and filtered to give the title product, which was used in the next step without further purification. ES / MS: 167.2 (M+H + ).

[0408] 3-(Bromomethyl)-1-(trifluoromethyl)pyrazole (I-57): Carbon tetrabromide (0.465 g, 0.00140 mol) was added to a solution of [1-(trifluoromethyl)pyrazol-3-yl]methanol (0.194 g, 1.17 mmol) and (4-diphenylphosphanylphenyl polymer-bound) (78.7%, 0.465 g, 0.00140 mol) in DCM (10 mL) at 0 °C. The mixture was gradually warmed to room temperature and stirred overnight. The resulting suspension was filtered, and the filtrate was diluted with DCM and washed with brine. The organic extract was dried over sodium sulfate, concentrated, and purified by flash chromatography (eluent: EtO / hexanes) to give I-57. ES / MS: 230.2 (M+H + ).

[0409] Preparation of Intermediate I-58

[0410] [ka]

[0411] Methyl 3-(trifluoromethyl)isothiazole-5-carboxylate: To a solution of 3-(trifluoromethyl)isothiazole-5-carboxylic acid (303 mg, 1.54 mmol) in MeOH (3 mL) at 0 °C, thionyl chloride (0.125 mL, 1.69 mmol) was added. The resulting solution was gradually warmed to room temperature and stirred overnight. After this time, additional thionyl chloride (0.125 mL, 1.69 mmol) was added and stirred for 9 h. Upon completion, the mixture was concentrated and purified by flash chromatography (eluent: EtOAc / hexanes) to give the title compound. 1H NMR (400 MHz, chloroform-d) δ 8.01 (s, 1H), 4.01 (s, 3H).

[0412] [3-(trifluoromethyl)isothiazol-5-yl]methanol: TH at 0°C To a solution of methyl 3-(trifluoromethyl)isothiazole-5-carboxylate (136 mg, 0.644 mmol) in F (5 mL) was added diisobutylaluminum hydride (1.0 M in DCM, 1.61 mL, 1.61 mmol). The resulting solution was stirred for 3 h. At the completion of this time, the mixture was diluted with 5 mL of EtO and cooled to 0 °C. After the mixture was cooled, 0.064 mL of water, 0.064 mL of 15% NaOH, and 0.161 mL of water were added, and the solution was allowed to warm to room temperature and stirred for 15 min. After this time, MgSO was added, and the solution was stirred for an additional 15 min before being filtered. The crude product was purified by flash chromatography (eluent: EtOAc / hexanes) to give the title compound. ES / MS: 184.2 (M+H + ).

[0413] 5-(Bromomethyl)-3-(trifluoromethyl)isothiazole (I-58): To a solution of [3-(trifluoromethyl)isothiazol-5-yl]methanol (85 mg, 0.464 mmol) and (4-diphenylphosphanylphenyl polymer-bound) (78.7%, 185 mg, 0.557 mol) in DCM (10 mL) at 0 °C, carbon tetrabromide (185 mg, 0.557 mmol) was added. The mixture was gradually warmed to room temperature and stirred overnight. The resulting suspension was filtered, and the filtrate was diluted with DCM and washed with brine. The organic extract was dried over sodium sulfate, concentrated, and purified by flash chromatography (eluent: EtO / hexane) to give I-58. H NMR (400 MHz, chloroform-d) δ 7.49 (d, J = 0.8 Hz, 1H), 4.72 (d, J = 0.8 Hz, 2H).

[0414] Preparation of Intermediate I-59

[0415] [ka]

[0416] Methyl 4-nitro-3-(spiro[2.2]pentan-2-ylamino)benzoate: A solution of methyl 3-fluoro-4-nitrobenzoate (0.205 g, 1.03 mmol), spiro[2.2]pentan-2-amine; hydrochloride (0.151 g, 1.26 mmol), and N,N-diisopropylethylamine (0.538 mL, 3.09 mmol) in NMP (3 mL) was heated at 90° C. for 12 hours. After this time, the mixture was diluted with EtOAc and washed with 5% LiCl, brine, and water. The organic extract was dried over sodium sulfate, concentrated, and purified by flash chromatography (eluent: EtOAc / hexanes) to give the title compound. ES / MS: 263.2 (M+H +);1H NMR(400MHz,chloroform-d)δ 8.22(d,J=8.8Hz,1H),8.06(s,1H),7.79(d,J=1.8Hz,1H),7.29(dd,J=8.9,1.8Hz,1H),3.98(s,3H),3.01(dd,J=6. 3,3.1Hz,1H),1.54-1.42(m,1H),1.14(ddd,J=9.0,5.5,4.1Hz,1H),1.06-0.98(m,2H),0.95(td,J=8.5,4.7Hz,2H).

[0417] Methyl 4-amino-3-(spiro[2.2]pentan-2-ylamino)benzoate (I-59): A solution of methyl 4-nitro-3-(spiro[2.2]pentan-2-ylamino)benzoate (101 mg, 0.4385 mmol) in EtOAc (8 mL) The mixture was degassed by cycling between argon and vacuum three times. Platinum (1%), vanadium (2%) on carbon (50-70% wet) was added to the mixture, and I-59 was carried on to the next step without further purification. ES / MS: 233.2 (M+H) + ).

[0418] Preparation of Intermediates I-60 and I-61

[0419] [ka]

[0420] tert-Butyl 3-[(6-bromo-2-pyridyl)oxymethyl]pyrazole-1-carboxylate: A suspension of tert-butyl 3-(bromomethyl)pyrazole-1-carboxylate (946 mg, 3.6 mmol), 6-bromopyridin-2-ol (500 mg, 2.9 mmol), and silver carbonate (1694 mg, 6.1 mmol) in CHCN (15 mL) was heated at 50° C. for 15 hours. After this time, an additional 335 mg of 6-bromopyridin-2-ol and 5 mL of CHCN were added, and the solution was heated at 50° C. for 5 hours. Upon completion, 500 mg of 6-bromopyridin-2-ol was added, and heating was resumed for 2 hours. After this time, the mixture was diluted with EtOAc and brine. The mixture was filtered through a plug of Celite. The reaction mixture was partitioned, and the organic phase was washed with brine. The organic extract was dried over sodium sulfate, concentrated, and purified by flash chromatography (eluent: EtOAc / hexanes) to give the title compound. ES / MS: 298, 300 (M+H + ).

[0421] 2-Bromo-6-(1H-pyrazol-3-ylmethoxy)pyridine: A solution of tert-butyl 3-[(6-bromo-2-pyridyl)oxymethyl]pyrazole-1-carboxylate (456 mg, 1.3 mmol) and TFA (0.49 mL, 6.4 mmol) in DCM (5 mL) was stirred overnight at room temperature. After this time, the solution was diluted with DCM, washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, concentrated, and carried on to the next step without further purification. ES / MS: 254, 256 (M+H). + ).

[0422] 2-[3-[(6-Bromo-2-pyridyl)oxymethyl]pyrazol-1-yl]acetonitrile (I-60) and 2-[5-[(6-Bromo-2-pyridyl)oxymethyl]pyrazol-1-yl]acetonitrile (I-61): To a suspension of 2-bromo-6-(1H-pyrazol-3-ylmethoxy)pyridine (0.115 g, 0.453 mmol) and cesium carbonate (0.177 g, 0.543 mmol) in DMF (3 mL) was added 2-chloroacetonitrile (0.0314 mL, 0.498 mmol). The solution was stirred overnight at room temperature. After this time, the solution was warmed to 40 °C for 2 h, then diluted with EtOAc and washed with 5% LiCl (2x) and brine. The organic extract was dried over sodium sulfate, concentrated, and purified by flash chromatography (eluent: EtOAc / hexanes) to give I-60 and I-61.

[0423] 2-[3-[(6-bromo-2-pyridyl)oxymethyl]pyrazol-1-yl]acetonitrile (I-60): ES / MS: 293.2, 295.1 (M+H + );1H NMR (400 MHz, chloroform-d) δ 7.55 (d, J = 2.4 Hz, 1H), 7.45 (dd, J = 8.2, 7.5 Hz, 1H), 7.11 (dd, J = 7.5, 0.7 Hz, 1H), 6.76 (dd, J = 8.2, 0.7 Hz, 1H), 6.52 (d, J = 2.4 Hz, 1H), 5.39 (s, 2H), 5.10 (s, 2H).

[0424] 2-[5-[(6-bromo-2-pyridyl)oxymethyl]pyrazol-1-yl]acetonitrile (I-61): ES / MS: 293.2, 295.0 (M+H + );1H NMR(400MHz,chloroform-d)δ 7.57(d,J=1.9Hz,1H),7.50(dd,J=8.2,7.5Hz,1H),7.15(d,J=7.4Hz,1H),6.80(d,J=8.1Hz,1H),6.48(d,J=1.9Hz,1H),5.47(s,2H),5.35(s,2H).

[0425] Preparation of Intermediate I-62

[0426] [ka]

[0427] Ethyl 1-(1-methylpyrazol-4-yl)pyrazole-3-carboxylate: In a 40 mL reaction vial, a mixture of ethyl 1H-pyrazole-3-carboxylate (1000 mg, 7.14 mmol), 4-iodo-1-methyl-pyrazole (1484 mg, 7.14 mmol), cesium carbonate (5812 mg, 17.8 mmol), copper(I) oxide (60.0 mg, 0.419 mmol), and salicylaldoxime (120 mg, 0.875 mmol) in DMF (20 mL) was heated at 110° C. for 48 h. After this time, the mixture was diluted with EtOAc and washed with 5% LiCl, saturated sodium bicarbonate, and brine. The organic extract was dried over sodium sulfate and purified by flash chromatography (eluent: EtOAc / hexanes) to give the title compound. ES / MS: 221.2 (M+H + ).

[0428] [1-(1-methylpyrazol-4-yl)pyrazol-3-yl]methanol: To a solution of ethyl 1-(1-methylpyrazol-4-yl)pyrazole-3-carboxylate (287 mg, 1.30 mmol) in THF (6 mL) at 0 °C was added diisobutylaluminum hydride (1.0 M in DCM, 3.26 mL, 3.26 mmol). The solution was stirred for 1 hour while gradually warming to room temperature. After this time, the solution was diluted with EtO and cooled to 0 °C. Upon complete cooling, 0.130 mL of water, 0.130 mL of 15% aqueous NaOH, and 0.326 mL of water were added to the solution, and the resulting solution was allowed to warm to room temperature. After warming, the solution was stirred for 15 minutes, followed by the addition of MgSO, stirring for an additional 15 minutes, and filtering. The filtrate was concentrated and purified by flash chromatography (eluent: EtOAc / hexanes) to give the title compound. ES / MS: 179.2 (M+H + ).

[0429] 3-(Bromomethyl)-1-(1-methylpyrazol-4-yl)pyrazole (I-62): To a solution of [1-(1-methylpyrazol-4-yl)pyrazol-3-yl]methanol (136 mg, 0.762 mmol) and (4-diphenylphosphanylphenyl polymer-bound) (78.7%, 303 mg, 0.914 mmol) in DCM (10 mL) at 0 °C, carbon tetrabromide (303 mg, 0.914 mmol) was added. The mixture was gradually warmed to room temperature and stirred overnight. The resulting suspension was filtered, and the filtrate was diluted with DCM and washed with brine. The organic extract was dried over sodium sulfate, concentrated, and purified by flash chromatography (eluent: EtO / hexane) to give I-62. ES / MS: 241.2, 243.2 (M+H + ). 1H NMR (400 MHz, chloroform-d) δ 7.71 (s, 1H), 7.69 (d, J = 0.8 Hz, 1H), 7.61 (d, J = 2.4 Hz, 1H), 6.47 (d, J = 2.4 Hz, 1H), 4.56 (s, 2H), 3.96 (s, 3H).

[0430] The following intermediates were prepared in a similar manner as described for intermediate I-62:

[0431] [ka]

[0432] Preparation of Intermediate I-63

[0433] [ka]

[0434] 2-(Bromomethyl)thiazole-5-carbonitrile (I-63): To a solution of 2-methylthiazole-5-carbonitrile (200 mg, 1.61 mmol) in CCl4 (8 mL) was added N-bromosuccinimide (375 mg, 2.11 mmol), followed by benzoyl peroxide (42.0 mg, 0.173 mmol). The solution was heated at 90 °C for 9 h. After that, the mixture was cooled to room temperature, and 5 mL of hexane was added. The suspension was filtered, and the filtrate was concentrated and purified by flash chromatography (eluent: EtOAc / hexane) to give I-63. ES / MS: 203.0, 205.2 (M+H). + ). 1H NMR (400 MHz, chloroform-d) δ 8.23 ​​(s, 1H), 4.74 (s, 2H).

[0435] The following intermediates were prepared as described for intermediate I-63:

[0436] [ka]

[0437] Preparation of intermediate I-64

[0438] [ka]

[0439] 3-(Bromomethyl)-5-methoxy-1-methyl-1H-pyrazole (I-64): To a stirred solution of (5-methoxy-1-methyl-1H-pyrazol-3-yl)methanol (1.42 g, 10 mmol, 1.0 equiv) in DCM (15 mL) was added CBr (7.2 g, 21 mmol, 2.0 equiv) and triphenylphosphine (5.7 g, 21 mmol, 2.0 equiv) at room temperature. The mixture was stirred for an additional 16 h. Upon completion, the reaction mixture was diluted with water (150 mL), extracted with DCM (3 × 150 mL), washed with brine (50 mL), dried over NaSO, and concentrated to give the crude product, which was purified by column chromatography (0–2% MeOH-DCM) to give 3-(bromomethyl)-5-methoxy-1-methyl-1H-pyrazole (I-64).

[0440] The following intermediates were prepared as described for intermediate I-64:

[0441] [ka]

[0442] Preparation of Intermediate I-65

[0443] [ka]

[0444] (5,5-Difluoro-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)methanol (I-65-1): 5,5-Difluoro-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid (105 mg, 0.56 mmol) was dissolved in THF (3 mL) and stirred at 0 °C for 5 min. Next, a 1 M solution of borane (3.4 mL) was added dropwise to the reaction mixture at 0 °C over 30 min. The ice bath was removed, and stirring was continued at room temperature for 7 h. After this time, the reaction mixture was cooled in an ice bath and treated with 3 M HCl (5 mL). The solution was heated at 50 °C for 1 h. Upon completion, the solution was washed with EtOAc (2x), and the aqueous layer was cooled in an ice bath and neutralized with 3 M NaOH. The solution was extracted with EtOAc (3x) and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo to give (5,5-difluoro-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl ) methanol (I-65-1) was obtained.

[0445] 2-(Bromomethyl)-5,5-difluoro-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (I-65): The title compound was prepared in the manner described for intermediate I-64 using intermediate I-65-1. ES / MS m / z 237 (M+H + ).

[0446] Preparation of Intermediate I-66

[0447] [ka]

[0448] Methyl 2-[[4-[6-[(5-bromopyrimidin-2-yl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (I-66): Methyl 2-[[4-[6-[(5-bromopyrimidin-2-yl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate was prepared as described for intermediate I-21 to give I-66. ES / MS: 637.4 (M+H+).

[0449] Preparation of Intermediate I-67

[0450] [ka]

[0451] Methyl 2-[[4-[6-[(5-chloropyrazin-2-yl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (I-67): Methyl 2-[[4-[6-[(5-chloropyrazin-2-yl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate was prepared as described for intermediate I-21 to give I-67. ES / MS: 593 (M+H+).

[0452] Preparation of Intermediate I-68

[0453] [ka]

[0454] Methyl 3-bromo-5-((4,4-dimethyltetrahydrofuran-3-yl)amino-4-nitrobenzoate): Methyl 3-bromo-5-fluoro-4-nitrobenzoate (0.5 g, 1.8 mmol) was dissolved in a 100 mL round-bottom flask containing DMF (10 mL), then 4,4-dimethyltetrahydrofuran-3-amine hydrochloride (0.46 g, 3 mmol) and N,N-diisopropylethylamine (0.63 mL, 3.6 mmol) were added to the solution. The mixture was stirred at 50 °C overnight. The mixture was then concentrated to remove most of the THF, and the crude material was dissolved in EtOAc (40 mL). The organics were washed with 50% NH4Cl (2 × 10 mL) and brine (1 × 50 mL). The organics were then dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was carried forward without further purification: ES / MS: 374.2 (M+H+).

[0455] Methyl 4-amino-3-bromo-5-[(4,4-dimethyltetrahydrofuran-3-yl)amino]benzoate (I-68): To a 100 mL round-bottom flask was added methyl 3-bromo-5-((4,4-dimethyltetrahydrofuran-3-yl)amino-4-nitrobenzoate (0.58 g, 1.6 mmol), iron (0.43 g, 7.8 mmol), and acetic acid (10 mL). The mixture was stirred and heated at 100 °C for 1 h, after which the mixture was filtered through Celite to remove the catalyst. The filtrate was concentrated under reduced pressure to provide I-68, which was used without further purification: ES / MS: 344.2 (M+H).

[0456] Preparation of Intermediate I-69

[0457] [ka]

[0458] Methyl 3-bromo-4-[[2-[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]acetyl]amino]-5-[(4,4-dimethyltetrahydrofuran-3-yl)amino]benzoate: To a 0 °C cooled solution of I-68 (200 mg, 0.58 mmol) and I-7 (180 mg, 0.45 mmol) in MeCN (5 mL) was added 1-methylimidazole (239 mg, 0.23 mL, 2.9 mmol), followed by N,N,N',N'-tetramethylimidazole. Chloroformamidinium hexafluorophosphate (204 mg, 0.73 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. Upon completion of the 30 minutes, the crude mixture was concentrated in vacuo and partitioned with water and EtOAc. The organic layer was isolated and washed with an additional portion of water and then brine. The isolated organic layer was dried over sodium sulfate, isolated by vacuum filtration, concentrated in vacuo, and purified by silica gel column chromatography (eluent: EtOAc / hexanes) to give the desired product. ES / MS: 724.4 [M+H]+.

[0459] Methyl 7-bromo-2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-(4,4-dimethyltetrahydrofuran-3-yl)benzimidazole-5-carboxylate (I-69): A solution of methyl 3-bromo-4-[[2-[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]acetyl]amino]-5-[(4,4-dimethyltetrahydrofuran-3-yl)amino]benzoate (100 mg, 0.14 mmol) in acetic acid (2 mL) was heated to 80° C. for 5 days. The mixture was concentrated and partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic layer was isolated, dried over sodium sulfate, isolated by vacuum filtration, concentrated in vacuo, and purified by silica gel column chromatography (eluent: EtOAc / hexanes) to give I-69. ES / MS: 706.5 [M+H] + .

[0460] Preparation of intermediate I-70

[0461] [ka]

[0462] Methyl 2-(5-bromo-3-fluoropyridin-2-yl)acetate: To a suspension of NaH (60% in mineral oil, 1.3 g, 34 mmol) in DMF (20 mL) was added tert-butylmethyl malonate dropwise at 5° C. and the suspension was stirred for 5 minutes. 5-Bromo-2,3-difluoropyridine was then added dropwise and the resulting suspension was warmed to 60° C. and stirred at that temperature overnight. After this time, NH4Cl was added and the mixture was extracted with ether. The organic phase was rinsed with brine and concentrated. The residue was redissolved in DCM (10 mL). TFA (10 mL) was then added and the resulting solution was warmed to 40° C. and stirred for 5 hours. Upon completion, the mixture was concentrated and purified by flash chromatography (EtOAc / hexanes) to give the title product: ES / MS: 248.2 (M+H + ).

[0463] 5-Bromo-3-fluoro-2-(2-methoxy-2-oxoethyl)pyridine 1-oxide: MCPBA (3.51 g, 16 mmol) was dissolved in methyl 2-bromo-2-(2-methoxy-2-oxoethyl)pyridine 1-oxide in DCM (30 mL). The resulting solution was allowed to warm to room temperature and stirred overnight. The mixture was then diluted with hexane (20 mL) and filtered. The filtrate was concentrated and purified by flash chromatography (EtOAc / hexane) to give the title product: ES / MS: 265.2 (M+H). + ).

[0464] Methyl 2-(6-amino-5-bromo-3-fluoropyridin-2-yl)acetate: To a solution of 5-bromo-3-fluoro-2-(2-methoxy-2-oxoethyl)pyridine-1-oxide (1.24 g, 4.7 mmol), saccharin (6.3 g, 34 mmol), and DIPEA (6.5 mL, 38 mmol) in chloroform (5 mL) was added p-toluenesulfonic anhydride (1.5 g) over 1.5 hours. The resulting solution was stirred at room temperature for 2 hours. After this time, an additional amount of p-toluenesulfonic anhydride (1.3 g) was added and stirred for 1 hour. After 1 hour, an additional amount of p-toluenesulfonic anhydride (2.0 g) was added and stirred over the weekend. The reaction was quenched with Na2CO3 and filtered. The phases were separated, and the aqueous phase was extracted with DCM. The combined organics were washed with 10% citric acid, dried, filtered, concentrated, and purified by flash chromatography (EtOAc / hexanes). The resulting product was suspended in 2M H2SO4 (4 mL) and stirred at 90 °C for 18 h, then warmed to reflux and stirred for 24 h. The mixture was filtered, and the filtrate was washed with CHCl3. The aqueous phase was basified with NaOH to pH ∼7 and filtered. The filtrate was acidified to pH ∼5 and extracted with CHCl3 (3x). The organics were dried and concentrated to give the title product: ES / MS: 249.0 (M+H + ). 1 H NMR (400 MHz, chloroform-d) δ 7.59 (d, J = 7.7 Hz, 1H), 5.05 (s, 2H), 3.80 (d, J = 2.2 Hz, 2H). 19 F NMR (376 MHz, chloroform-d) δ −137.76 (d, J = 7.5 Hz).

[0465] 2-(6-Amino-5-bromo-3-fluoropyridin-2-yl)acetic acid: The title intermediate was prepared as described for intermediate I-7 (step 2) using methyl 2-(6-amino-5-bromo-3-fluoropyridin-2-yl)acetate instead of methyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorophenyl)acetate.

[0466] tert-Butyl 2-((6-amino-5-bromo-3-fluoropyridin-2-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate: The title compound was prepared in the manner described for intermediate I-2, using 2-(6-amino-5-bromo-3-fluoropyridin-2-yl)acetic acid instead of 2-(4-bromo-2-fluoro-phenyl)acetic acid and tert-butyl 4-amino-3-((2-methoxyethyl)amino)benzoate instead of methyl 4-amino-3-(2-methoxyethylamino)benzoate. ES / MS: 481.1 (M+H + ). 1 H NMR(400MHz,chloroform-d)δ 8.07(d,J=1.5Hz,1H),7.94(d,J=8.6Hz,1H),7.78(d,J=8.5Hz,1H),7.51(d,J=7.8Hz, 1H),4.79(s,2H),4.57-4.39(m,4H),3.70(t,J=5.3Hz,2H),3.30(s,3H),1.65(s,9H).

[0467] tert-Butyl 2-((2'-amino-6-((4-cyano-2-fluorobenzyl)oxy)-5'-fluoro-[2,3'-bipyridin]-6'-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (I-70): tert-butyl 2-((2'-amino-6-((4-cyano-2-fluorobenzyl)oxy)-5'-fluoro-[2,3'-bipyridin]-6'-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate was prepared in the manner described for intermediate I-7, using dichlorobis(di-tert-butylphenylphosphine)palladium(II) instead of Pd(dppf)Cl in step 1. I-70 was prepared by using methyl 2-(4-bromo-2,5-difluorophenyl)acetate instead of methyl 2-(4-bromo-2,5-difluorophenyl)acetate. ES / MS: 627.5 (M+H). + ).

[0468] Preparation of Intermediate I-71

[0469] [ka]

[0470] tert-Butyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (I-71): The title compound was prepared in the manner described for Intermediate I-2 using Intermediate I-6 and Intermediate I-7. ES / MS: 629.5 (M+H + ).

[0471] Preparation of Intermediate I-72

[0472] [ka]

[0473] Methyl 4-amino-3-iodo-5-((2-methoxyethyl)amino)benzoate: The title compound was prepared as described for Intermediate I-1. The reduction was carried out by stirring iron (603 mg, 10.8 mmol), acetic acid (12.0 mL, 1.8 mmol), and crude methyl 3-iodo-5-(2-methoxyethylamino)-4-nitro-benzoate (821 mg, 2.16 mmol) in methanol (5.0 mL) at reflux for 1 hour. The mixture was diluted with DCM, filtered, and the organics were dried, filtered, and concentrated to collect the crude product.

[0474] Methyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-iodo-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate: The title compound was prepared in a manner similar to that described for intermediate I-13 using methyl 4-amino-3-iodo-5-((2-methoxyethyl)amino)benzoate and intermediate I-7.

[0475] 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-7-iodo-3-(2-methoxyethyl)benzimidazole-5-carboxylic acid (I-72): In an 8 mL reaction vial, a solution of methyl 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-7-iodo-3-(2-methoxyethyl)benzimidazole-5-carboxylate (105 mg, 0.15 mmol) and lithium hydroxide monohydrate (25 mg, 0.59 mmol) in THF / water (2:1, 3 mL) was heated at 70 °C until completion (15 min). After the reaction was completed, trifluoroacetic anhydride (0.3 mL) was added and the solution was directly purified by RP-HPLC (eluent: MeCN / H2O) to give I-72. ES / MS: 699.1.

[0476] Preparation of Intermediate I-73

[0477] [ka]

[0478] tert-Butyl (R)-2-(4-(6-((5-bromothiazol-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(2-methoxypropyl)-1H-benzo[d]imidazole-6-carboxylate (I-73): tert-Butyl (R)-2-(4-(6-((5-bromothiazol-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(2-methoxypropyl)-1H-benzo[d]imidazole-6-carboxylate was prepared in the manner described for intermediate I-21, substituting I-26 for I-4. ES / MS: 686.8 (M+H + ).

[0479] Preparation of intermediate I-74:

[0480] [ka]

[0481] (1-Methylthieno[2,3-c]pyrazol-5-yl)methanol: To a solution of 1-methylthieno[2,3-c]pyrazole-5-carboxylic acid (140 mg, 0.77 mmol) in THF (6 mL) was added CDI (249 mg, 1.54 mmol), and the resulting slurry was stirred at ambient temperature for 2 h. After this time, NaBH4 (145 mg, 3.84 mmol) was added in portions, and the mixture was stirred overnight. Upon completion, MeOH was added (2 mL), and the crude mixture was directly concentrated. The crude residue was purified by silica gel column chromatography (eluent: EtOAc / hexanes) to give the desired product. ES / MS: 169.1 (M+H + ).

[0482] 5-[(6-bromo-2-pyridyl)oxymethyl]-1-methyl-thieno[2,3- c]Pyrazole (I-74): To a solution of 2-bromo-6-fluoro-pyridine (122 mg, 0.69 mmol) in acetonitrile (2 mL) was added (1-methylthieno[2,3-c]pyrazol-5-yl)methanol (106 mg, 0.63 mmol) and cesium carbonate (411 mg, 1.26 mmol), and the resulting mixture was stirred at 80 °C for 2 h. Upon completion, the reaction mixture was diluted with EtOAc (25 mL) and washed with water (5 mL) and brine (5 mL). The organic layer was dried over MgSO, filtered, concentrated, and purified by silica gel column chromatography (eluent: EtOAc / hexanes) to give I-74. ES / MS: 326.1 (M+H + ).

[0483] Preparation of Intermediate I-75

[0484] [ka]

[0485] Methyl 2-(4-(6-((4-bromo-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (I-75): Methyl 2-(4-(6-((4-bromo-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate was prepared in the manner described for intermediate I-19, substituting I-2 for I-96. ES / MS: 623.3 (M+H + ).

[0486] Preparation of Intermediate I-76

[0487] [ka]

[0488] Methyl 2-(4-(6-((6-chloro-4-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylate (I-76): Methyl 2-(4-(6-((6-chloro-4-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylate was prepared in the manner described for intermediate I-23, substituting I-25 for I-4. ES / MS: 638.0 (M+H + ).

[0489] Preparation of Intermediate I-77

[0490] [ka]

[0491] 2-Bromo-6-(1H-pyrazol-3-ylmethoxy)pyridine (I-77): To a solution of 6-bromopyridin-2-ol (180 mg, 1.0 mmol) in acetonitrile (4 mL), cesium carbonate (482 mg, 1.5 mmol) and tert-butyl 3-(bromomethyl)pyrazole-1-carboxylate (378 mg, 1.4 mmol) were added, and the reaction mixture was heated to 65 °C for 30 min. Upon completion, the reaction mixture was filtered through Celite, concentrated, and purified by silica gel column chromatography (eluent: EtOAc / hexanes) to give the desired product. The thus obtained tert-butyl 3-[(6-bromo-2-pyridyl)oxymethyl]pyrazole-1-carboxylate (343 mg, 0.97 mmol) was dissolved in DCM (4.4 mL) and TFA (1.1 mL) and stirred at ambient temperature for 2 h. Upon completion, the reaction mixture was diluted with EtOAc (25 mL), washed with saturated aqueous NaHCO3 until gas evolution ceased, dried over MgSO4, filtered, and concentrated to give I-77, which was used without further purification. ES / MS: 254.2, 256.2 (M+H + ).

[0492] Preparation of Intermediate I-78

[0493] [ka]

[0494] Methyl (S)-2-(4-(6-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (I-78): Methyl (S)-2-(4-(6-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate was prepared as described for intermediate I-21, using 5-bromo-3-(bromomethyl)-1-methyl-1H-pyrazole instead of 5-bromo-2-(bromomethyl)thiazole. ES / MS: 638.0, 640.0 (M+H + ).

[0495] Preparation of Intermediate I-79

[0496] [ka]

[0497] 2-[5-(hydroxymethyl)-2-methyl-pyrazol-3-yl]acetonitrile: To a solution of methyl 5-(bromomethyl)-1-methyl-pyrazole-3-carboxylate (750 mg, 3.22 mmol) in DMF (9.5 mL) and water (1.2 mL), sodium cyanide (241 mg, 4.83 mmol) was added, and the resulting mixture was stirred at room temperature for 3.5 hours. Upon completion, the reaction mixture was diluted with EtOAc (50 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography (eluent: EtOAc / hexanes) to give the desired product. The thus obtained methyl 5-(cyanomethyl)-1-methyl-pyrazole-3-carboxylate (328 mg, 1.83 mmol) was dissolved in THF (10 mL) and lithium borohydride (2.0 M in THF, 1.83 mL, 3.66 mmol) was added at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 6 h, at which point lithium borohydride (2.0 M in THF, 1.83 mL, 3.66 mmol) was added and the mixture was stirred for 2 h. Upon completion, the reaction was quenched by the addition of water (5 mL), diluted with EtOAc (50 mL), and the layers were separated. The organic layer was dried over MgSO, filtered, concentrated, and purified by silica gel column chromatography (eluent: EtOAc / hexanes) to give the desired product.

[0498] 2-[5-(Bromomethyl)-2-methyl-pyrazol-3-yl]acetonitrile (I-79): 2-[5-(hydroxymethyl)-2-methyl-pyrazol-3-yl]acetonitrile (100 mg, 0.662 mmol) was taken up in dichloromethane (2.65 mL) and triphenylphosphine (0.208 g, 0.794 mmol) was added, followed by carbon tetrabromide (0.263 g, 0.794 mmol). The reaction mixture was stirred at room temperature for 5 minutes, at which point the reaction was quenched by the addition of water (5 mL), diluted with EtOAc (25 mL), and the layers were separated. The organic layer was dried over MgSO, filtered, concentrated, and purified by silica gel column chromatography (eluent: EtOAc / hexanes) to give I-79. ES / MS: 214.0, 216.0 (M+H).+ ).

[0499] Preparation of Intermediates I-80 and I-81 (Method 1)

[0500] [ka]

[0501] Methyl 4-amino-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)benzoate (I-80, I-81): Methyl 4-amino-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)benzoate, as a mixture of two stereoisomers, was separated by chiral SFC (SFC IB column, EtOH co-solvent) to give two distinct stereoisomers.

[0502] Methyl (S)-4-amino-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)benzoate Isomer 1 (I-80): Isolated by chiral SFC (4.6 x 100 mm 5 μm IB column, 10% EtOH in CO) as the faster of the two stereoisomers. ES / MS: 265.2 (M+H) + ).

[0503] Methyl (R)-4-amino-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)benzoate, isomer 2 (I-81): Isolated by chiral SFC (4.6 x 100 mm 5 μm IB column, 10% EtOH in CO) as the later eluting of the two isomers. ES / MS: 265.2 (M+H + ).

[0504] Preparation of Intermediate I-80 (Method 2) Methyl 4-amino-3-[[(3S)-4,4-dimethyltetrahydrofuran-3-yl]amino]benzoate isomer 2 (I-80): A solution of methyl 3-[[(3S)-4,4-dimethyltetrahydrofuran-3-yl]amino]-4-nitro-benzoate (Intermediate I-100, 17.8 g, 60.5 mmol) in EtOAc (380 mL) was degassed three times with argon and then in vacuo. Palladium on carbon (10.0%, 6.07 g, 5.70 mmol) was added. The mixture was degassed three times with argon and then in vacuo and stirred at room temperature under a hydrogen atmosphere until complete. The suspension was filtered through a plug of Celite and rinsed with EtOAc. The mixture was concentrated to give methyl 4-amino-3-[[(3S)-4,4-dimethyltetrahydrofuran-3-yl]amino]benzoate, which was carried on to the next step without further purification. ES / MS:265.0(M+H+). 1H NMR (400MHz, chloroform-d)δ 7.49(dd,J=8.0,1.8Hz,1H),7.35(d,J=1.8Hz,1H),6.73(d,J=8.1Hz,1H),4.36(dd,J=9.1,6.4Hz,1H) ,3.89(s,3H),3.76(t,J=5.9Hz,1H),3.72-3.63(m,2H),3.63-3.59(m,1H),1.22(s,3H),1.15(s,3H).

[0505] Preparation of Intermediates I-82 and I-83 (Method 1)

[0506] [ka]

[0507] Methyl 2-(4-bromo-2,5-difluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylate (I-82, I-83): I-82 and I-83 were prepared separately as described for intermediate I-8, substituting I-80 (for intermediate I-82) and I-81 (for intermediate I-83) for I-4.

[0508] Methyl (S)-2-(4-bromo-2,5-difluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylate Isomer 1 (I-82): ES / MS: 479.0, 481.0 (M+H + ).

[0509] Methyl (R)-2-(4-bromo-2,5-difluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylate isomer 2 (I-83): ES / MS: 479.0, 481.0 (M+H + ).

[0510] Preparation of Intermediate I-82 (Method 2): Methyl 2-[(4-bromo-2,5-difluorophenyl)methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]benzimidazole-5-carbohydrate Xylate (Intermediate I-82): To a solution of 2-(4-bromo-2,5-difluorophenyl)acetic acid (3301 mg, 13.2 mmol), methyl 4-amino-3-[[(3S)-4,4-dimethyltetrahydrofuran-3-yl]amino]benzoate (Intermediate I-80, 3.16 g, 12.0 mmol), and o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (6360 mg, 16.7 mmol) in DMF (20 mL) and CHCN (20 mL) was added N,N-diisopropylethylamine (10.2 mL, 58.4 mmol). The solution was stirred overnight at room temperature. Next, 0.2 equivalents of 2-(4-bromo-2,5-difluorophenyl)acetic acid (600 mg, 2.39 mmol) and o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (930 mg, 2.39 mmol) were added to the mixture, and stirring was continued until complete conversion to the product. The crude reaction mixture was diluted with 200 mL of EtOAc and washed with saturated NH4Cl (200 mL), 5% LiCl (100 mL), saturated NaHCO3 (100 mL), and brine (100 mL). The organic extract was dried over sodium sulfate to give methyl 4-[[2-(4-bromo-2,5-difluorophenyl)acetyl]amino]-3-[[(3S)-4,4-dimethyltetrahydrofuran-3-yl]amino]benzoate.

[0511] A solution of methyl 4-[[2-(4-bromo-2,5-difluoro-phenyl)acetyl]amino]-3-[[(3S)-4,4-dimethyltetrahydrofuran-3-yl]amino]benzoate (5.96 g, 12.0 mmol) in AcOH (60 mL) was heated to 180 °C for 90 min in a microwave reactor. The mixture was concentrated, diluted with EtOAc, and washed with saturated NaHCO3 and brine. The mixture was dried over sodium sulfate and purified by silica gel column chromatography (eluent: EtOAc / hexane) to give methyl 2-[(4-bromo-2,5-difluoro-phenyl)methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]benzimidazole-5-carboxylate (Intermediate I-82). ES / MS: 478.6, 480.6 (M+H). + ). 1H NMR (400MHz, chloroform-d)δ 8.55(s,1H),8.02(dd,J=8.5,1.5Hz,1H),7.78(d,J=8.5Hz,1H),7.37(dd,J=8.7,5.6Hz,1H),7.12(dd,J=8.4,6.3Hz,1H),4.5 9(d,J=10.5Hz,2H),4.40(dd,J=11.1,7.3Hz,1H),4.31(s,2H),3.97(s,4H),3.80(d,J=8.8Hz,1H),1.35(s,3H),0.67(s,3H).

[0512] Preparation of Intermediate I-84

[0513] [ka]

[0514] 2-[(6-Bromo-2-pyridyl)oxymethyl]thiazole-5-carbonitrile (I-84): To a solution of 6-bromopyridin-2-ol (500 mg, 2.9 mmol) in acetonitrile (10 mL) was added 2-(bromomethyl)thiazole-5-carbonitrile (I-63) (584 mg, 2.9 mmol) and cesium carbonate (1.34 g, 4.1 mmol), and the resulting mixture was stirred at 65 °C for 1 h. Upon completion, the reaction mixture was filtered through Celite, concentrated, and purified by silica gel column chromatography (eluent: EtOAc / hexanes) to give I-84. ES / MS: 296.0, 298.0 (M+H + ).

[0515] Preparation of Intermediate I-85

[0516] [ka]

[0517] Methyl 2-[[4-[6-[(6-chloro-4-methoxy-3-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (I-85): Methyl 2-[[4-[6-[(6-chloro-4-methoxy-3-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate was prepared by the method described for intermediate I-23, using 5-(bromomethyl)-2-chloro-4-methoxypyridine instead of 5-(bromomethyl)-2-chloro-4-fluoropyridine. ES / MS: 621.2 (M+H + ).

[0518] Preparation of Intermediate I-86

[0519] [ka]

[0520] 5-(Bromomethyl)-4-methoxy-N-methylpicolinamide (I-86): 5-(Bromomethyl)-4-methoxy-N-methylpicolinamide was prepared by the method described for intermediate I-53, using methylamine HCl instead of 1-aminocyclopropane-1-carbonitrile. ES / MS: 259.2, 261.2 (M+H + ).

[0521] Preparation of Intermediate I-87

[0522] [ka]

[0523] 5-(Bromomethyl)-4-chloro-N-methylpicolinamide (I-87): Prepare 5-(bromomethyl)-4-chloro-N-methylpicolinamide by the method described for intermediate I-53, using methylamine HCl instead of 1-aminocyclopropane-1-carbonitrile and 4-chloro-5-methylpicolinic acid instead of 4-methoxy-5-methylpicolinic acid. ES / MS: 263.0, 265.0 (M+H + ).

[0524] Preparation of Intermediate I-88

[0525] [ka]

[0526] tert-Butyl 2-[[2,5-difluoro-4-[6-[[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy]-2-pyridyl]phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (I-88): tert-Butyl 2-[[4-[6-[(4-bromo-2-fluorophenyl)phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate in 1,4-dioxane (20 mL) To a solution of [fluoro-phenyl]methoxy-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (300 mg, 0.44 mmol) was added bis(pinacolato)diboron (179 mg, 0.70 mmol), Pd(dppf)Cl2 (33 mg, 0.044 mmol), and potassium propionate (148 mg, 1.3 mmol). Argon was bubbled through the reaction mixture for 1 minute, after which the reaction vessel was sealed and heated to 110 °C in a microwave reactor for 45 minutes. Upon completion, the reaction mixture was directly concentrated and purified by silica gel column chromatography (eluent: EtOAc / hexanes) to give I-88. ES / MS: 730.8 (M+H + ).

[0527] Preparation of Intermediate I-89

[0528] [ka]

[0529] (3S,4R)-4-(5-Methoxycarbonyl-2-nitro-anilino)tetrahydrofuran-3-carboxylic acid: To a solution of methyl 3-fluoro-4-nitro-benzoate (700 mg, 3.52 mmol) and (3S,4R)-4-aminotetrahydrofuran-3-carboxylic acid; hydrochloride salt (648 mg, 17.6 mmol) in DMF (2.5 mL) and THF (5 mL) was added diisopropylethylamine (3.1 mL, 17.6 mmol), and the resulting solution was heated to 70 °C for 3 days. Upon completion, the reaction mixture was diluted with EtOAc (50 mL), washed with water (10 mL), brine (10 mL), dried over MgSO, filtered, and concentrated to give the desired product, which was used without further purification. ES / MS: 311.2 (M+H) + ).

[0530] Methyl 3-[[(3R,4S)-4-(methylcarbamoyl)tetrahydrofuran-3-yl]amino]-4-nitrobenzoate: (3S,4R)-4-(5-methoxycarbonyl-2-nitroanilino)tetrahydrofuran-3-carboxylic acid (370 mg, 0.00119 mol), 1-hydroxybenzotriazole hydrate (0.192 g, 0.00125 mol), and methylamine (2000 mmol / L in THF, 1.19 mL, 0.00239 mol) were taken up in tetrahydrofuran (8.00 mL), and triethylamine (0.151 g, 0.00149 mol) was added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.251 g, 0.00131 mol). The mixture was stirred at room temperature overnight. Upon completion, the mixture was diluted with EtOAc (50 mL), washed with water (10 mL), brine (10 mL), dried over MgSO, filtered, and concentrated to give the desired product, which was used without further purification. ES / MS: 324.2 (M+H + ).

[0531] Methyl 4-amino-3-[[(3R,4S)-4-(methylcarbamoyl)tetrahydrofuran-3-yl]amino]benzoate (I-89): To a solution of methyl 3-[[(3R,4S)-4-(methylcarbamoyl)tetrahydrofuran-3-yl]amino]-4-nitro-benzoate (168 mg, 0.52 mmol) in EtOH (2 mL) and THF (1 mL) was added palladium on carbon (10%, 111 mg, 0.10 mmol). The reaction mixture was purged with H gas and stirred under 1 atmosphere of H for 1 hour. Upon completion, the reaction mixture was filtered through Celite, concentrated, and the crude residue I-89 was used without further purification. ES / MS: 294.2 (M+H + ).

[0532] Preparation of Intermediate I-90

[0533] [ka]

[0534] Methyl 4-amino-3-(((3R,4S)-4-(dimethylcarbamoyl)tetrahydrofuran-3-yl)amino)benzoate (I-90): Methyl 4-amino-3-(((3R,4S)-4-(dimethylcarbamoyl)tetrahydrofuran-3-yl)amino)benzoate was prepared by the method described for intermediate I-89, using dimethylamine instead of methylamine. ES / MS: 308.2 (M+H + ).

[0535] Preparation of Intermediate I-91

[0536] [ka]

[0537] 4-Bromo-1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]pyrazole: To a solution of 4-bromo-1H-pyrazole (100 mg, 0.68 mmol) in 2-Me tetrahydrofuran (2 mL) was added potassium bis(trimethylsilyl)amide (204 mg, 1.0 mmol) and 1-[2-(2-bromoethoxy)ethoxy]-2-methoxyethane (309 mg, 1.4 mmol) and heated to 50° C. for 2 h. Upon completion, the reaction mixture was diluted with EtOAc (25 mL), washed with water (5 mL), brine (5 mL), dried over MgSO, filtered, and concentrated to give the desired product, which was used without further purification. ES / MS: 293.3 (M+H) + ).

[0538] 1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (I-91): Using the procedure described for intermediate I-88, 4-bromo-1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]pyrazole was converted to 1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (I-91). ES / MS: 341.1 (M+H + ).

[0539] Preparation of Intermediate I-92

[0540] [ka]

[0541] tert-Butyl 2-(4-(6-((6-chloropyridin-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6- (I-92): Prepared tert-butyl 2-(4-(6-((6-chloropyridin-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6- in the manner described for intermediate I-18, using 5-(bromomethyl)-2-chloropyridine instead of 4-bromo-1-(bromomethyl)-2-fluoro-benzene. ES / MS: 621.2 (M+H + ).

[0542] Preparation of Intermediate I-93

[0543] [ka]

[0544] Methyl (S)-2-(4-(6-((6-bromo-4-fluoropyridin-3-yl) (S)-2-(4-(6-((6-bromo-4-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (I-93): Methyl (S)-2-(4-(6-((6-bromo-4-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate was prepared in the manner described for intermediate I-19, using 2-bromo-5-(bromomethyl)-4-fluoropyridine instead of 4-bromo-1-(bromomethyl)-2-fluoro-benzene. ES / MS: 654.0, 656.0 (M+H + ).

[0545] Preparation of Intermediate I-94

[0546] [ka]

[0547] 4-[(4-Bromopyrimidin-2-yl)oxymethyl]-3-fluoro-benzonitrile (I-94): 4-Bromo-2-chloro-pyrimidine (1.7 g, 8.8 mmol), 3-fluoro-4-(hydroxymethyl)benzonitrile (1.46 g, 9.7 mmol), potassium hydroxide (542 mg, 9.7 mmol), 18-crown-6 (116 mg, 0.44 mmol), and toluene (20 mL) were combined and heated to 110 °C for 2 h. Upon completion, the reaction mixture was diluted with EtOAc (100 mL), washed with water (25 mL), washed with brine (25 mL), dried over MgSO, filtered, concentrated, and purified by silica gel chromatography (eluent: EtOAc / hexanes) to give I-94. ES / MS: 309.2 (M+H + ).

[0548] Preparation of Intermediate I-95

[0549] [ka]

[0550] Methyl 2-(4-(6-chloropyridin-2-yl)-2,5-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (I-95): Methyl (S)-2-(4-(6-chloropyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate was prepared in the manner described for intermediate I-12, substituting I-1 for I-6. ES / MS: 472.8 (M+H + ).

[0551] Preparation of Intermediate I-96

[0552] [ka]

[0553] Methyl 2-(4-bromo-2,5-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (I-96). Methyl 2-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate was prepared by the method described for intermediate I-2, using 2-(4-bromo-2,5-difluorophenyl)acetic acid instead of 2-(4-bromo-2-fluorophenyl)acetic acid. ES / MS: 439.8 (M+H + ).

[0554] Preparation of Intermediate I-97:

[0555] [ka]

[0556] (5-Chloro-1-methyl-pyrazol-3-yl)methanol: 5-Chloro-1-methyl-pyrazole-3-carboxylic acid (700 mg, 4.36 mmol) was taken up in THF (20.0 mL) and 1,1'-carbonyldiimidazole (1.41 g, 8.72 mmol) was added. The mixture was stirred at room temperature for 2 hours. Upon completion, the mixture was cooled to 0°C and a solution of sodium borohydride (0.825 g, 21.8 mmol) in water (3.30 mL) was slowly added, after which the mixture was allowed to warm to room temperature over 40 minutes. Upon completion, methanol (5 mL) was added and the reaction mixture was directly concentrated and purified by flash chromatography (eluent: EtOAc / hexanes) to give the desired product.

[0557] 3-(Bromomethyl)-5-chloro-1-methyl-pyrazole (I-97): (5-Chloro-1-methyl-pyrazol-3-yl)methanol (550 mg, 3.75 mmol) was taken in DCM (25.0 mL) and (4-diphenylphosphanylphenyl) polymer-bound (78.7%, 1.50 g, 0.00450 mol) was added. The reaction mixture was cooled to 0 °C and carbon tetrabromide (1.49 g, 0.00450 mol) was added in one portion. The mixture was stirred at room temperature for 16 h. Upon completion, the mixture was filtered, concentrated, and purified by flash chromatography (eluent: EtOAc / hexanes) to give I-97. ES / MS: 209.0, 211.0 (M+H + ).

[0558] The following intermediates were prepared using the method described for intermediate I-97:

[0559] [ka]

[0560] Preparation of Intermediate I-98

[0561] [ka]

[0562] 5-(Hydroxymethyl)-N-methyl-pyridine-2-carboxamide: 5-(hydroxymethyl)pyridine-2-carboxylic acid (400 mg, 2.61 mmol), methanamine hydrochloride (194 mg, 2.87 mmol), and o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1192 mg, 3.14 mmol) were taken up in DMF (5.00 mL), N,N-diisopropylethylamine (2.27 mL, 13.1 mmol) was added, and the reaction mixture was stirred for 30 min. Upon completion, the reaction mixture was diluted with EtOAc (50 mL), washed with water (10 mL), washed with brine (10 mL), dried over MgSO, filtered, concentrated, and purified by silica gel chromatography (eluent: MeOH / EtOAc / hexanes) to give the desired product. ES / MS: 167.2 (M+H + ).

[0563] 5-(Bromomethyl)-N-methyl-pyridine-2-carboxamide (I-98): 5-(Hydroxymethyl)-N-methyl-pyridine-2-carboxamide (106 mg, 0.638 mmol) and triphenylphosphine (0.167 g, 0.638 mmol) were taken up in dichloromethane (2.60 mL) and carbon tetrabromide (0.212 g, 0.638 mmol) was added. The reaction mixture was stirred for 15 minutes. Upon completion, the reaction mixture was filtered, concentrated, and purified by flash chromatography (eluent: EtOAc / hexanes) to give I-98. ES / MS: 229.0 (M+H + ).

[0564] The following intermediates were prepared using the method described for intermediate I-98:

[0565] [ka]

[0566] Preparation of Intermediate I-99

[0567] [ka]

[0568] (R)-4,4-Dimethyl-2-oxotetrahydrofuran-3-yl trifluoromethanesulfonate (I-99-1): A round-bottom flask was charged with (D)-(−)-pantolactone (4.20 g, 32.3 mmol, 1.0 equiv). Anhydrous dichloromethane (20 mL) and pyridine (3.39 mL, 42.0 mmol, 1.30 equiv) were added, and the resulting solution was cooled to −78° C. A solution of trifluoromethanesulfonic anhydride (5.96 mL, 35.4 mmol, 1.10 equiv) in dichloromethane (100 mL) was added slowly via an addition funnel to the reaction mixture while stirring at −78° C. After the addition, the mixture was maintained at −78° C. with stirring for 30 minutes, after which the cooling bath was removed. The mixture was stirred at room temperature for an additional 3 hours. The solvent was removed in vacuo, and the residue was dissolved in ethyl ether (200 mL) and washed with 10% aqueous sodium bicarbonate (100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give (R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl trifluoromethanesulfonate. 1H NMR (500 MHz, CDCl3) δ = 5.10 (s, 1 H), 4.13 (d, J = 9.5 Hz, 1 H), 4.07 (d, J = 9.5 Hz, 1 H), 1.28 (s, 3 H), 1.18 (s, 3 H).

[0569] (S)-3-Azido-4,4-dimethyldihydrofuran-2(3H)-one (I-99-2): A round-bottom flask was charged with tetrabutylammonium azide (10.5 g, 36.8 mmol, 1.15 equiv). Anhydrous toluene (50 mL) was added, and the resulting solution was cooled to 0 °C. A solution of (R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl trifluoromethanesulfonate (8.40 g, 32 mmol, 1.0 equiv) in toluene (50 mL) was added slowly via addition funnel at 0 °C. After maintaining the mixture at 0 °C for 30 minutes, the cooling bath was removed, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl ether (200 mL) and washed with 10% aqueous sodium bicarbonate (200 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give (S)-3-azido-4,4-dimethyldihydrofuran-2(3H)-one. The crude material was carried on immediately to the next step without purification.

[0570] 3-Azido-4,4-dimethyltetrahydrofuran-2-ol (I-99-3): 3-Azido-4,4-dimethyldihydrofuran-2(3H)-one (4.16 g, 26.8 mmol) was taken up in dichloromethane (40 mL) and cooled to -78 °C. Diisobutylaluminum hydride (1.0 M in toluene) (32.2 mL, 32.2 mmol, 1.2 equiv.) was then slowly added at the same temperature. The mixture was stirred at -78 °C for 2 hours until the starting material disappeared. A saturated solution of sodium potassium tartrate (100 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (3 × 50 mL). The organic extract was dried over anhydrous NaSO and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel) to give 3-azido-4,4-dimethyltetrahydrofuran-2-ol. Ta. 1H NMR (400MHz, CDCl3) δ=5.58-5.29(m,1 H),3.93-3.76(m,2 H),3.66-3.50(m,2 H),1.19-1.08(m,6 H.

[0571] 4-Azido-3,3-dimethyltetrahydrofuran (I-99-4): 3-Azido-4,4-dimethyltetrahydrofuran-2-ol was taken up in dichloromethane (80 mL) and cooled to -78 °C. BF EtO (3.6 mL, 28.7 mmol, 1.5 equiv.) was slowly added, followed by triethylsilane (6.1 mL, 2.0 mmol) at the same temperature. The mixture was stirred at 0 °C for 4 h until the starting material was consumed. Water (100 mL) was then added to the reaction mixture. The resulting phases were separated, and the aqueous phase was extracted with dichloromethane (2 × 50 mL). The organic extract was dried over anhydrous NaSO and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel) to give (S)-4-azido-3,3-dimethyltetrahydrofuran. 1H NMR (400MHz, CDCl3) = 4.17 (dd, J = 6.1, 9.8 Hz, 1 H), 3.77 (dd, J = 3.9, 9.8 Hz, 1 H), 3.65 (dd, J = 3.9, 6.1 Hz, 1 H), 3.58-3.50 (m, 2 H), 1.13 (d, J = 6.1 Hz, 6 H).

[0572] 4,4-Dimethyltetrahydrofuran-3-amine (I-99): To 4-azido-3,3-dimethyltetrahydrofuran (1.89 g, 13.4 mmol) dissolved in ethyl acetate (50 mL) was added 10% palladium on carbon (2.14 g, 2.0 mmol, 0.15 equiv.). The mixture was stirred under 1 atmosphere of hydrogen at room temperature for 16 hours and then filtered through a plug of Celite. The solution was acidified with 4 M HCl in methanol (5.0 mL) and then concentrated in vacuo to give (S)-4,4-dimethyltetrahydrofuran-3-amine as the hydrochloride salt. 1H NMR (400MHz, CDCl3) = 4.09-4.05(m,1H),3.72-3.68(m,1H),3.59-3.56(m,1H),3.44-3.42(m,1H),3.35(m,1H),1.07(s,6H).

[0573] Preparation of Intermediate I-100

[0574] [ka]

[0575] Methyl 3-[[(3S)-4,4-dimethyltetrahydrofuran-3-yl]amino]-4-nitrobenzoate (I-100): To a suspension of methyl 3-fluoro-4-nitrobenzoate (15.0 g, 75.3 mmol) and (3S)-4,4-dimethyltetrahydrofuran-3-amine hydrochloride (Intermediate I-99, 12.6 g, 82.9 mmol) in THF (100 mL) and DMF (50 mL) was added N,N-diisopropylethylamine (65.6 mL, 377 mmol). The resulting solution was heated at 80 °C overnight. The crude reaction mixture was diluted with EtOAc (300 mL) and washed with 5% LiCl (250 mL) and brine (250 mL). The organic extract was dried over sodium sulfate and purified by silica gel column chromatography (eluent: EtOAc / hexane) to give methyl 3-[[(3S)-4,4-dimethyltetrahydrofuran-3-yl]amino]-4-nitrobenzoate. 1H NMR (400 MHz, chloroform-d) δ 8.24 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 1.6 Hz, 1H), 7.27 (dd, J = 8.9, 1.7 Hz, 1H), 4.41 (dd, J = 9.2, 6.8 Hz, 1H), 4.0 (dd, J = 9.2, 6.8 Hz, 1H). .02(s,1H),3.97(s,3H),3.76-3.64(m,3H),1.26(s,3H),1.18(s,3H). ES / MS:295.0(M+H+).

[0576] Preparation of Intermediate I-101

[0577] [ka]

[0578] 2-(Bromomethyl)-5-(trifluoromethyl)thiazole (I-101). Under argon, [5-(trifluoromethyl)thiazol-2-yl]methanol (100 mg, 0.546 mmol) was added with DCM (5.5 mL). The mixture was cooled to 0 °C. Triphenylphosphine (150 mg, 0.573 mmol) was then added, followed by carbon tetrabromide (190 mg, 0.573 mmol). The cooling bath was removed, and the mixture was stirred at 20 °C for 30 min. The mixture was directly purified by silica gel flash column chromatography (hexanes in EtOAc gradient) to give 2-(bromomethyl)-5-(trifluoromethyl)thiazole (Intermediate I-101). 1H NMR (400 MHz, chloroform-d) δ 8.04 (d, J = 1.2 Hz, 1H), 4.72 (s, 2H).

[0579] Preparation of Intermediate I-102

[0580] [ka]

[0581] 2-[(6-Bromo-3-fluoro-2-pyridyl)oxymethyl]-5-(trifluoromethyl)thiazole (Intermediate I-102). 6-Bromo-2-chloro-3-fluoro-pyridine (3.00 g, 14.3 mmol) was taken up in acetonitrile (20.0 mL), followed by the addition of [5-(trifluoromethyl)thiazol-2-yl]methanol (1.52 mL, 14.7 mmol) and cesium carbonate (9.29 g, 28.5 mmol). The mixture was heated to 60 °C until all starting material was consumed, as determined by LCMS. The mixture was filtered to remove CsCO, washed with EtOAc, and concentrated in vacuo. Silica gel flash column chromatography (EtOAc gradient in hexanes) afforded 2-[(6-bromo-3-fluoro-2-pyridyl)oxymethyl]-5-(trifluoromethyl)thiazole (Intermediate I-102). ES / MS m / z: 358 (M+H + ).

[0582] Preparation of Intermediate I-103

[0583] [ka]

[0584] Methyl (S)-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)-5-fluoro-4-nitrobenzoate (Intermediate I-103): To a solution of methyl 3,5-difluoro-4-nitrobenzoate (2.21 g, 10.2 mmol) and (S)-4,4-dimethyltetrahydrofuran-3-amine hydrochloride (Intermediate I-99, 1.70 g, 11.2 mmol) in tetrahydrofuran (12.5 mL) and N,N-dimethylformamide (6.0 mL) was added N,N-diisopropylethylamine (8.86 mL, 50.9 mmol). The mixture was stirred at 70 °C overnight and then cooled to room temperature. The mixture was diluted with water, extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound, which was carried on to the next step without further purification. ES / MS m / z: 313.3 (M+H+).

[0585] Preparation of Intermediate I-104

[0586] [ka]

[0587] Methyl (S)-4-amino-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)-5-fluorobenzoate (Intermediate I-104): Methyl (S)-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)-5-fluoro-4-nitrobenzoate (Intermediate I-103, 2.88 g, 10.2 mmol) was dissolved in EtOAc and placed under argon. To this mixture was added 10% palladium on carbon (1.08 g, 1.02 mmol), and the mixture was then placed under hydrogen gas. The mixture was stirred overnight, and then the mixture was filtered through Celite and concentrated in vacuo. Purification by silica gel flash column chromatography (EtOAc / hexane gradient) gave methyl (S)-4-amino-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)-5-fluorobenzoate (Intermediate I-104). ES / MS m / z: 283.2 (M+H). + .

[0588] Preparation of Intermediate I-105

[0589] [ka]

[0590] Methyl (S)-4-(2-(4-bromo-2,5-difluorophenyl)acetamido)-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)-5-fluorobenzoate (I-105-1): To a solution of methyl (S)-4-amino-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)-5-fluorobenzoate (Intermediate I-104, 2000 mg, 7.08 mmol) and 2-(4-bromo-2,5-difluoro-phenyl)acetic acid (1867 mg, 7.44 mmol) in MeCN (10.0 mL) was cooled to 0 °C, after which 1-methylimidazole (2.91 g, 2.82 mL, 35.4 mmol) was added, followed by N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (2.39 g, 8.50 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes, and the mixture was concentrated in vacuo to give methyl (S)-4-(2-(4-bromo-2,5-difluorophenyl)acetamido)-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)-5-fluorobenzoate (I-105-1), which was carried on to the next step without further purification.

[0591] Methyl 2-[(4-bromo-2,5-difluorophenyl)methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]-7-fluorobenzimidazole-5-carboxylate (Intermediate I-105): To methyl (S)-4-(2-(4-bromo-2,5-difluorophenyl)acetamido)-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)-5-fluorobenzoate (I-105-1, 2.2 g, 4.3 mmol) in 21 mL of 1,2-dichloroethane was added phosphoryl trichloride (2.6 g, 17 mmol, 1.6 mL). The solution was heated to 80 °C for 24 h and then cooled to room temperature. A 20 mL aliquot of water was added and stirred for 1 h, after which aqueous sodium hydroxide (26 mL, 51 mmol, 2 M) was added. The mixture was diluted with DCM, the layers were separated, and the organic phase was washed with brine, dried over MgSO4, filtered, and concentrated. Purification by silica chromatography (EtOAc / hexane gradient) gave methyl 2-[(4-bromo-2,5-difluorophenyl)methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]-7-fluorobenzimidazole-5-carboxylate (Intermediate I-105). ES / MS m / z: 497.0 (M+H). + .

[0592] Preparation of intermediate I-106.

[0593] [ka]

[0594] Methyl 2-[[2,5-difluoro-4-[5-fluoro-6-[[5-(trifluoromethyl)thiazol-2-yl]methoxy]-2-pyridyl]phenyl]methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]-7-fluoro-benzimidazole-5-carboxylate (intermediate I-106). To a vial was added methyl (S)-2-(4-bromo-2,5-difluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate I-105, 50 mg, 0.101 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.6 mg, 0.010 mmol), bis(pinacolato)diboron (28 mg, 0.111 mmol), and potassium propionate (34 mg, 0.302 mmol), followed by 1,4-dioxane (1.5 mL). Argon was bubbled through the solution for 3 min, and the mixture was then heated to 120 °C for 60 min. To the mixture was added aqueous sodium carbonate (2.00 M, 0.10 mL, 0.20 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.8 mg, 0.050 mmol), and 2-[(6-bromo-3-fluoro-2-pyridyl)oxymethyl]-5-(trifluoromethyl)thiazole (Intermediate I-102, 40 mg, 0.111 mmol). Argon was bubbled through the solution for 3 minutes, and the mixture was heated to 110 °C for 60 minutes. The reaction mixture was filtered through Celite, eluting with DCM, and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel flash column chromatography (EtOAc / Hex gradient) to give methyl 2-[[2,5-difluoro-4-[5-fluoro-6-[[5-(trifluoromethyl)thiazol-2-yl]methoxy]-2-pyridyl]phenyl]methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]-7-fluoro-benzimidazole-5-carboxylate (Intermediate I-106). ES / MS m / z: 694.2 (M+H + ).

[0595] Preparation of Intermediate I-107

[0596] [ka]

[0597] 2-[(6-Bromo-2-pyridyl)oxymethyl]-5-(trifluoromethyl)thiazole (I-107): A round-bottom flask was charged with [5-(trifluoromethyl)thiazol-2-yl]methanol (570 mg, 3.1 mmol, 1.1 equiv), 2-bromo-6-fluoropyridine (500 mg, 2.8 mol, 1.0 equiv), and cesium carbonate (1.3 g, 4.0 mmol, 1.4 equiv). Anhydrous acetonitrile (10 mL) was added, and the resulting mixture was heated to reflux and stirred for 12 h. After cooling to room temperature, the mixture was filtered through a plug of Celite and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (EtOAc / hexane gradient) to give the title compound. ES / MS m / z: 339.8 (M+H). + .

[0598] Preparation of Intermediate I-108

[0599] [ka]

[0600] Ethyl (S)-2-(4-bromo-2,5-difluorobenzyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate I-108). A round-bottom flask was charged with 2-(4-bromo-2,5-difluorophenyl)acetic acid (3.37 g, 13.4 mmol, 1.2 equiv.), ethyl 4-amino-3-fluoro-5-[[(2S)-oxetan-2-yl]methylamino]benzoate (Intermediate I-5, 3.00 g, 11.2 mmol, 1.0 equiv.), and 1-methylimidazole (2.7 mL, 33 mmol, 3.0 equiv.). Anhydrous acetonitrile (40 mL) was added, and the mixture was cooled to 0 °C. TCFH (3.76 g, 13.4 mmol, 1.2 equiv) was added slowly, and the mixture was allowed to warm to room temperature and stirred for 2 h before being diluted with EtOAc (100 mL) and water (100 mL). The layers were separated, and the combined organic extracts were washed with saturated aqueous NH4Cl (100 mL), saturated aqueous NaHCO3 (100 mL), and brine (50 mL), respectively. The resulting solution was dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was dissolved in dichloroethane (60 mL), followed by the addition of acetic acid (10 mL). The mixture was heated to 60 °C and stirred for 48 h. After cooling to room temperature, the solution was concentrated and purified by silica gel column chromatography (EtOAc / hexane gradient) to give ethyl (S)-2-(4-bromo-2,5-difluorobenzyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate I-108). ES / MS m / z: 483.6 (M+H). + .

[0601] Preparation of Intermediate I-109

[0602] [ka]

[0603] Ethyl (S)-2-(2,5-difluoro-4-(6-((5-(trifluoromethyl)thiazol-2-yl)methoxy)pyridin-2-yl)benzyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate I-109): In a 25 mL microwave vial, add methyl 2-[(4-bromo-2,5-difluoro-phenyl)methyl]-3- [(3S)-4,4-Dimethyltetrahydrofuran-3-yl]benzimidazole-5-carboxylate (Intermediate I-108, 1.3 g, 2.70 mmol, 1.0 equiv.), PdCl(dppf) (300 mg, 0.400 mmol, 0.15 equiv.), potassium propionate (900 mg, 8.07 mmol, 3.0 equiv.), and B2Pin (820 mg, 3.23 mol, 1.2 equiv.) were added. Anhydrous 1,4-dioxane (15 mL) was added, and the resulting mixture was purged with argon for 2 minutes. The mixture was sealed, heated to 120 °C in a microwave, and stirred for 1 hour. After cooling to room temperature, 2-[(6-bromo-2-pyridyl)oxymethyl]-5-(trifluoromethyl)thiazole (Intermediate I-107, 1100 mg, 3.23 mmol, 1.2 equiv.), PdCl(dppf) (100 mg, 0.134 mmol, 0.05 equiv.), and 2 M aqueous NaCO (3.4 mL, 6.72 mmol, 2.5 equiv.) were added. The resulting mixture was heated to 100 °C under argon and stirred for 3 h, then cooled to room temperature and filtered through a plug of Celite and MgSO. The filtrate was concentrated and purified by silica gel column chromatography (EtOAc / hexane gradient) to give ethyl (S)-2-(2,5-difluoro-4-(6-((5-(trifluoromethyl)thiazol-2-yl)methoxy)pyridin-2-yl)benzyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate I-109). ES / MS m / z: 662.6 (M+H). + .

[0604] Preparation of Intermediate I-109a

[0605] [ka]

[0606] 4-[(6-Bromo-3-fluoro-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile (Intermediate I-109a): To a solution of 6-bromo-2-chloro-3-fluoro-pyridine (4.90 g, 23.3 mmol) and 3-fluoro-4-(hydroxymethyl)benzonitrile (3.87 g, 25.6 mmol) in acetonitrile (40 mL) was added cesium carbonate (15.2 g, 25.6 mmol). The mixture was stirred at 60 °C overnight and then cooled to room temperature. The mixture was diluted with water, extracted three times with EtOAc, washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by silica gel flash column chromatography (EtOAc gradient in hexanes) afforded 4-[(6-bromo-3-fluoro-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile (Intermediate I-109a). ES / MS m / z: 326.1 (M+H). + .

[0607] Preparation of Intermediate I-1001

[0608] [ka]

[0609] tert-butyl (1R,3R,5R)-3-[(2-amino-5-methoxycarbonyl-anilino)methyl]-2-azabicyclo[3.1.0]hexane-2-carboxylate was used in place of 2-methoxyethylamine in the manner described for intermediate I-1. [3.1.0]Hexane-2-carboxylate was prepared. ES / MS: 362.2 (M+H+). 1H NMR (400MHz, chloroform-d)δ 7.39(d,J=8.1Hz,1H),7.15(s,1H),6.63(d,J=8.1Hz,1H),4.58(t,J=11.0Hz,1H),3.87(s,3H),3.64(d,J=7.3Hz,1H),3.27-3.09(m ,1H),3.00(t,J=11.0Hz,1H),2.56(q,J=11.7Hz,1H),1.95-1.70(m,1H),1.53(s,10H),0.81(q,J=7.1Hz,1H),0.57(d,J=5.7Hz,1H).

[0610] Preparation of Intermediate I-1010

[0611] [ka]

[0612] 5-[(6-bromo-2-pyridyl)oxymethyl]-N-(2-cyanoethyl)pyridine-2-carboxamide was prepared by the method described for intermediate I-28, using 3-aminopropanenitrile instead of 1-aminocyclopropanecarbonitrile hydrochloride. ES / MS: 361.0, 363.0 (M+H+). 1H NMR (400MHz, chloroform-d)δ 8.68(d,J=2.0Hz,1H),8.46(d,J=6.7Hz,1H),8.20(d,J=8.0Hz,1H),7.98(dd,J=8.0,2.1Hz,1H),7.48(t,J=7.8 Hz,1H),7.13(d,J=7.5Hz,1H),6.79(d,J=8.1Hz,1H),5.48(s,2H),3.78(q,J=6.5Hz,2H),2.77(t,J=6.5Hz,2H).

[0613] Preparation of intermediate I-1011

[0614] [ka]

[0615] (4-Bromo-2-fluoro-3-methyl-phenyl)methanol: To a solution of methyl 4-bromo-2-fluoro-3-methyl-benzoate (500 mg, 2.02 mmol) in THF (10 mL) at 0 °C was added diisobutylaluminum hydride (1000 mmol / L, 5.06 mL, 5.06 mmol). The mixture was stirred for 1 hour. The reaction was diluted with 25 mL of EtO and cooled to 0 °C. 0.200 mL of water and 0.200 mL of 15% NaOH were added, followed by 0.500 mL of water. The mixture was allowed to warm to room temperature. After stirring for 15 min, MgSO4 was added and the mixture was stirred for 15 min, then filtered and rinsed with Et2O to give a crude residue, which was purified by chromatography (eluent: EtOAc / hexanes) to give the desired product. 1H NMR (400 MHz, chloroform-d) δ 7.37 (dd, J = 8.2, 1.3 Hz, 1H), 7.16 (t, J = 7.9 Hz, 1H), 4.73 (s, 2H), 2.36 (d, J = 2.5 Hz, 3H).

[0616] 1-Bromo-4-(bromomethyl)-3-fluoro-2-methyl-benzene: To a solution of (4-bromo-2-fluoro-3-methyl-phenyl)methanol (358 mg, 1.63 mmol) and (4-diphenylphosphanylphenyl)polymer-bound (78.7%, 651 mg, 1.966 mmol) in DCM (10 mL) at 0 °C, carbon tetrabromide (650 mg, 1.96 mmol) was added. The mixture was allowed to warm gradually to room temperature overnight. The suspension was filtered, diluted with DCM, and washed with brine. The organic extract was dried over sodium sulfate, concentrated, and purified by chromatography (eluent: EtOAc / hexanes) to give the desired product. 1H NMR (400 MHz, chloroform-d) δ 7.35 (dd, J = 8.3, 1.3 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H), 4.49 (d, J = 1.2 Hz, 2H), 2.37 (d, J = 2.5 Hz, 3H).

[0617] 2-(4-Bromo-2-fluoro-3-methyl-phenyl)acetonitrile: To a solution of 1-bromo-4-(bromomethyl)-3-fluoro-2-methyl-benzene (299 mg, 1.06 mmol) in DMSO (6 mL) at room temperature, potassium cyanide (138 mg, 2.12 mmol) was added. The mixture was stirred overnight at room temperature. The reaction was diluted with EtOAc and washed with 10% Na2CO3. The organic layer was then washed with brine. The mixture was dried over sodium sulfate to give the desired product. 1H NMR (400 MHz, chloroform-d) δ 7.41 (dd, J = 8.3, 1.4 Hz, 1H), 7.17 (t, J = 8.0 Hz, 1H), 3.73 (d, J = 1.0 Hz, 2H), 2.37 (d, J = 2.6 Hz, 3H).

[0618] 2-(4-Bromo-2-fluoro-3-methyl-phenyl)acetic acid (I-1011): A solution of 2-(4-bromo-2-fluoro-3-methyl-phenyl)acetonitrile (164 mg, 0.717 mmol) in concentrated HCl (2 mL) was heated at 100°C overnight. The reaction was cooled to room temperature, diluted with EtOAc, and carefully neutralized with NaOH (4 mL). The organic extract was dried over sodium sulfate, filtered, and concentrated to give the desired product. 1H NMR (400 MHz, methanol-d4) δ 7.35 (dd, J = 8.3, 1.3 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 3.64 (d, J = 1.8 Hz, 2H), 2.35 (d, J = 2.5 Hz, 3H).

[0619] Preparation of intermediate I-1012

[0620] [ka]

[0621] Using the method described for intermediate I-2, I-4 was used in place of I-1, and 2-(4-bromo-2-fluoro-3-methyl-phenyl)acetic acid (I-1011) was used in place of 2-(4-bromo-2-fluoro-phenyl)acetic acid to give methyl 2-[(4-bromo-2- Fluoro-3-methyl-phenyl)methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate was prepared. ES / MS: 447.0, 449.0 (M+H+). 1H NMR (400MHz, chloroform-d)δ 8.11(d,J=1.7Hz,1H),7.98(dd,J=8.5,1.6Hz,1H),7.75(d,J=8.5Hz,1H),7.29(dd,J=8.3,1.3Hz,1H),6.99(t,J=8.0Hz,1H),5.14(qd,J=6.8 ,2.9Hz,1H),4.72-4.51(m,1H),4.51-4.27(m,5H),3.96(s,3H),2.73( dtd,J=11.4,8.1,6.1Hz,1H),2.51-2.38(m,1H),2.35(d,J=2.6Hz,3H).

[0622] Preparation of intermediate I-1017

[0623] [ka]

[0624] Ethyl 2-[(6-bromo-2-pyridyl)oxymethyl]thiazole-4-carboxylate: A suspension of ethyl 2-(bromomethyl)thiazole-4-carboxylate (500 mg, 2.0 mmol), 6-bromopyridin-2-ol (350 mg, 2.0 mmol), and silver carbonate (1186 mg, 4.3 mmol) in CHCN (15 mL) was heated at 50 °C overnight. The reaction was diluted with EtOAc and brine. The mixture was filtered through a Celite frit. The layers were partitioned, and the organic layer was washed once more with brine. The mixture was dried over sodium sulfate, concentrated, and purified by chromatography (eluent: EtOAc / hexanes) to give the desired product. ES / MS: 343, 345 (M+H). 1H NMR (400 MHz, chloroform-d) δ 8.22 (s, 1H), 7.51 (dd, J = 8.2, 7.5 Hz, 1H), 7.17 (dd, J = 7.5, 0.7 Hz, 1H), 6.82 (dd, J = 8.2, 0.7 Hz, 1H), 5.73 (s, 2H), 4.46 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H).

[0625] 2-[(6-Bromo-2-pyridyl)oxymethyl]thiazole-4-carboxylic acid: A solution of ethyl 2-[(6-bromo-2-pyridyl)oxymethyl]thiazole-4-carboxylate (114 mg, 0.332 mmol) and lithium hydroxide monohydrate (43.3 mg, 1.03 mmol) in CH3CN (3 mL) and water (1 mL) was prepared. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc. The mixture was adjusted to pH 6 with 1 N HCl (1.05 mL). The organic layer was dried over sodium sulfate to give the desired product. ES / MS: 315, 317 (M+H+). 1H NMR (400MHz, methanol-d4) δ 8.40(d,J=1.0Hz,1H),7.71-7.57(m,1H),7.25(d,J=7.5Hz,1H),6.93(d,J=8.1Hz,1H),5.68(d,J=1.0Hz,2H).

[0626] 2-[(6-Bromo-2-pyridyl)oxymethyl]-N-methyl-thiazole-4-carboxamide (I-1017): 2-[(6-Bromo-2-pyridyl)oxymethyl]thiazole-4-carboxylic acid (47.7 mg, 0.151 mmol), methanamine; salt To a solution of the benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (26.0 mg, 0.385 mmol) and o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (84.6 mg, 0.223 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine (0.105 mL, 0.605 mmol). The mixture was stirred at room temperature overnight. The reaction was diluted with EtOAc and washed with 5% LiCl, saturated NaHCO3, and brine. The mixture was dried over sodium sulfate, concentrated, and purified by chromatography (eluent: EtOAc / hexane) to give the desired product. MR (400 MHz, chloroform-d) δ 8.13 (s, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.34 (s, 1H), 7.18 (d, J = 7.5 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 5.64 (s, 2H), 3.04 (d, J = 5.0 Hz, 3H).

[0627] Preparation of intermediate I-1018

[0628] [ka]

[0629] Methyl 2-(chloromethyl)-3-(4,4-dimethyltetrahydrofuran-3-yl)-7-fluoro-benzimidazole-5-carboxylate: To a solution of methyl 4-amino-3-[(4,4-dimethyltetrahydrofuran-3-yl)amino]-5-fluoro-benzoate (I-104) (1.13 g, 4.00 mmol) in CHCN (20 mL) was added p-toluenesulfonic acid monohydrate (0.0345 g, 0.200 mmol) and 2-chloro-1,1,1-trimethoxyethane (0.547 mL, 5.20 mmol). The mixture was heated at 60 °C overnight. To this was added 2-chloro-1,1,1-trimethoxyethane (0.547 mL, 5.20 mmol) and p-toluenesulfonic acid monohydrate (0.0345 g, 0.200 mmol), and the mixture was heated at 60° C. for 3 h. The reaction was diluted with EtOAc, washed with brine, dried over sodium sulfate, concentrated, and purified by chromatography (eluent: EtOAc / hexanes) to give the desired product. ES / MS: 341.2 (M+H+). 1H NMR (400MHz, chloroform-d)δ 8.41(s,1H),7.71(dd,J=10.6,1.4Hz,1H),4.96(d,J=12.6Hz,1H),4.90-4.76(m,2H),4.61(dd,J=11.2,1.9H z,1H),4.50(dd,J=11.2,7.0Hz,1H),3.97(d,J=1.2Hz,4H),3.83(d,J=9.3Hz,1H),1.43(s,3H),0.73(s,3H).

[0630] Methyl 2-[(4-bromo-5-fluoro-2-oxo-1-pyridyl)methyl]-3-(4,4-dimethyltetrahydrofuran-3-yl)-7-fluoro-benzimidazo Benzimidazole-5-carboxylate (I-1018): A suspension of 4-bromo-5-fluoro-1H-pyridin-2-one (115 mg, 0.599 mmol), methyl 2-(chloromethyl)-3-(4,4-dimethyltetrahydrofuran-3-yl)-7-fluoro-benzimidazole-5-carboxylate (205 mg, 0.602 mmol), and potassium carbonate (414 mg, 3.00 mmol) in DMF (3 mL) was heated at 60 °C for 24 h. The mixture was cooled to room temperature, diluted with EtOAc, filtered, and concentrated. The mixture was diluted with EtOAc and washed with 5% LiCl and brine. The mixture was dried over sodium sulfate, concentrated, and purified by chromatography (eluent: EtOAc / hexane) to give the desired product. Chiral SFC separation (SFC IG column, EtOH co-solvent) afforded two distinct stereoisomers. ES / MS:497, 499(M+H+). 1H NMR (400MHz, chloroform-d)δ 8.45(s,1H),7.82(d,J=3.9Hz,1H),7.72(dd,J=10.8,1.2Hz,1H),6.93(d,J=6.4Hz,1H),5.73(d,J=14.8Hz,1H),5.28( d,J=6.6Hz,1H),5.11(d,J=14.8Hz,1H),4.69-4.36(m,2H),3.97(s,3H),3.90-3.72(m,2H),1.43(s,3H),0.61(s,3H).

[0631] Preparation of Intermediates I-1019 and I-1020

[0632] [ka]

[0633] Methyl 2-[(4-bromo-5-fluoro-2-oxo-1-pyridyl)methyl]-3-(4,4-dimethyltetrahydrofuran-3-yl)-7-fluoro-benzimidazole-5-carboxylate was subjected to chiral SFC separation (SFC IG column, EtOH co-solvent) to give two different stereoisomers.

[0634] Methyl 2-[(4-bromo-5-fluoro-2-oxo-1-pyridyl)methyl]-3-(4,4-dimethyltetrahydrofuran-3-yl)-7-fluoro-benzimidazole-5-carboxylate (I-1019 isomer 1): RT 2.46 min. ES / MS: 496, 498 (M+H+). 1H NMR (400MHz, chloroform-d)δ 8.46(s,1H),7.82(d,J=3.9Hz,1H),7.73(dd,J=10.8,1.2Hz,1H),6.94(d,J=6.4Hz,1H),5.74(d,J=14.8Hz,1H),5.29( d,J=6.5Hz,1H),5.10(d,J=14.8Hz,1H),4.68-4.45(m,2H),3.97(s,3H),3.93-3.77(m,2H),1.44(s,3H),0.62(s,3H).

[0635] Methyl 2-[(4-bromo-5-fluoro-2-oxo-1-pyridyl)methyl]-3-(4,4-dimethyltetrahydrofuran-3-yl)-7-fluoro-benzimidazole-5-carboxylate (I-1020 isomer 2): RT 5.88 min. ES / MS: 496, 498 (M+H+). 1H NMR (400 MHz, chloroform-d) δ 8.46 (s, 1H), 7.82 (d, J = 3.9 Hz, 1H), 7.73 (dd, J = 10.8, 1.2 Hz, 1H), 6.94 (d, J = 6.4 Hz, 1H), 5.74 (d, J = 14.8 Hz, 1H), 5.29 (d, J = 6.5 Hz, 1H), 5.10 (d, J =14.8Hz,1H),4.68-4.45(m,2H),3.97(s,3H),3.93-3.77(m,2H),1.44(s,3H),0.62(s,3H).

[0636] Preparation of intermediate I-1023

[0637] [ka]

[0638] To a solution of 4-bromo-2-chloro-5-methyl-benzoic acid (996 mg, 3.99 mmol) in DCM (10 mL) at 0 °C, oxalyl dichloride (2000 mmol / L, 2.40 mL, 4.79 mmol) and DMF (5 drops) were added. The mixture was stirred for 1 h. Upon completion, 10 mL of MeOH was added, and the resulting mixture was stirred at room temperature overnight. The mixture was then diluted with DCM, washed with saturated NaHCO3, dried over sodium sulfate, concentrated, and purified by chromatography (eluent: EtOAc / hexanes) to give the desired product. 1H NMR (400 MHz, chloroform-d) δ 7.74 (s, 1H), 7.68 (d, J = 1.1 Hz, 1H), 3.94 (d, J = 1.2 Hz, 3H), 2.42 (s, 3H).

[0639] (4-Bromo-2-chloro-5-methyl-phenyl)methanol: To a solution of methyl 4-bromo-2-chloro-5-methyl-benzoate (931 mg, 3.53 mmol) in THF (15 mL) at 0 °C, diisobutylaluminum hydride (1000 mmol / L, 8.83 mL, 8.83 mmol) was added, and the resulting mixture was stirred for 1 hour. Upon completion, the mixture was diluted with 25 mL of EtO and cooled to 0 °C. 0.350 mL of water, 0.350 mL of 15% NaOH, and 0.900 mL of water were then added. The resulting mixture was allowed to warm to room temperature and stirred for 15 minutes. MgSO was then added and stirred for 15 minutes. The mixture was then filtered and rinsed with EtO to give a crude residue, which was purified by chromatography (eluent: EtOAc / hexanes) to give the desired product. 1H MR (400 MHz, chloroform-d) δ 7.56 (d, J = 1.4 Hz, 1H), 7.38 (s, 1H), 4.73 (s, 2H), 2.41 (d, J = 1.3 Hz, 4H).

[0640] 1-Bromo-4-(bromomethyl)-5-chloro-2-methyl-benzene: To a solution of (4-bromo-2-chloro-5-methyl-phenyl)methanol (639 mg, 2.71 mmol) and (4-diphenylphosphanylphenyl) polymer-bound (78.7%, 1081 mg, 3.26 mmol) in DCM (10 mL) at 0 °C, carbon tetrabromide (1080 mg, 3.26 mmol) was added. The mixture was allowed to warm gradually to room temperature overnight. The suspension was filtered, diluted with DCM, and washed with brine. The organic extract was dried over sodium sulfate, concentrated, and purified by chromatography (eluent: EtOAc / hexanes) to give the desired product. 1H NMR (400 MHz, chloroform-d) δ 7.60 (s, 1H), 7.32 (s, 1H), 4.53 (s, 2H), 2.39 (s, 3H).

[0641] 2-(4-Bromo-2-chloro-5-methyl-phenyl)acetonitrile: 1-Bromo-4-(bromomethyl)-5-chloro-2-methyl-benzene in DMSO (12 mL) To a solution of (721 mg, 2.42 mmol) at room temperature was added potassium cyanide (315 mg, 4.83 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with 10% Na2CO3. The organic extract was washed once more with brine and dried over sodium sulfate to give the desired product. 1H NMR (400 MHz, chloroform-d) δ 7.62 (s, 1H), 7.52-7.33 (m, 1H), 3.78 (s, 2H), 2.42 (s, 3H).

[0642] 2-(4-Bromo-2-chloro-5-methyl-phenyl)acetic acid (I-1023): A solution of 2-(4-bromo-2-chloro-5-methyl-phenyl)acetonitrile (179 mg, 0.732 mmol) in concentrated HCl (5 mL) was heated at 100 °C overnight. The mixture was cooled to room temperature, diluted with EtOAc, and carefully neutralized with 6 N NaOH (10 mL). The organic extract was dried over sodium sulfate to give the desired product. 1H NMR (400 MHz, methanol-d4) δ 7.59 (s, 1H), 7.29 (s, 1H), 3.71 (s, 2H), 2.37 (s, 3H).

[0643] Preparation of Intermediate I-1024

[0644] [ka]

[0645] Methyl 2-[(4-bromo-2-chloro-5-methyl-phenyl)methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (I-1024): Methyl 2-[(4-bromo-2-chloro-5-methyl-phenyl)methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate was prepared in the manner described for intermediate I-2, using I-4 instead of I-1 and 2-(4-bromo-2-chloro-5-methyl-phenyl)acetic acid (I-1023) instead of 2-(4-bromo-2-fluoro-phenyl)acetic acid. ES / MS: 463, 465 (M+H+). 1H NMR (400MHz, chloroform-d)δ 8.12(d,J=1.6Hz,1H),8.00(dd,J=8.5,1.4Hz,1H),7.78(d,J=8.5Hz,1H),7.62(s,1H),7.13(s,1H),5.13(dd,J=7.1,2.9Hz,1H), 4.77-4.59(m,1H),4.59-4.23(m,5H),3.97(d,J=1.0Hz,3H),2.74(ddt,J=14.1,11.7,6.6Hz,1H),2.52-2.35(m,1H),2.29(s,3H).

[0646] Preparation of Intermediate I-1026

[0647] [ka]

[0648] Ethyl 4-[[2-(4-bromo-2-chloro-5-methyl-phenyl)acetyl]amino]-3-fluoro-5-[[(2S)-oxetan-2-yl]methylamino]benzoate: To a solution of 2-(4-bromo-2-chloro-5-methyl-phenyl)acetic acid (501 mg, 1.90 mmol) and ethyl 4-amino-3-fluoro-5-[[(2S)-oxetan-2-yl]methylamino]benzoate (510 mg, 1.90 mmol) in CHCN (19 mL) at 0 °C, 1-methylimidazole (0.758 mL, 9.50 mmol) was added, followed by TCFH (640 mg, 2.28 mmol). The mixture was stirred overnight at room temperature. The mixture was diluted with EtOAc, washed with saturated NH4Cl, 1N NaOH, and brine, then dried over sodium sulfate, concentrated, and carried on to the next step below. ES / MS: 513, 515 (M+H+).

[0649] Ethyl 2-[(4-bromo-2-chloro-5-methyl-phenyl)methyl]-7-fluoro-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (I-1026): A solution of ethyl 4-[[2-(4-bromo-2-chloro-5-methyl-phenyl)acetyl]amino]-3-fluoro-5-[[(2S)-oxetan-2-yl]methylamino]benzoate (977 mg, 1.90 mmol) and acetic acid (3426 mg, 57.0 mmol) in DCE (15 mL) was heated at 60 °C overnight. The mixture was cooled to room temperature, diluted with EtOAc, and carefully neutralized with NaHCO (4.78 g). The organic layer was washed with brine, dried over sodium sulfate, and concentrated. Purification by chromatography (eluent: EtOAc / hexane) gave the desired product. ES / MS: 495, 497 (M+H+). 1H NMR (400 MHz, chloroform-d) δ 7.94 (d, J = 1.3 Hz, 1H), 7.69 (dd, J = 11.0, 1.3 Hz, 1H), 7.62 (s, 1H), 7.12 (s, 1H), 5.08 (qd, J = 6.9, 2.8 Hz, 1H), 4.74-4.59 (m, 1H), 4.59-4.24 (m, 8H), 2.73 (dtd, J = 11.4, 8.1, 6.1 Hz, 1H), 2.39 (ddt, J = 11.5, 9.0, 7.2 Hz, 1H), 2.29 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H).

[0650] Preparation of Intermediate I-1030

[0651] [ka]

[0652] Methyl 2-[(4-bromo-2-chloro-5-methyl-phenyl)methyl]-3-[( 3S)-4,4-Dimethyltetrahydrofuran-3-yl]benzimidazole-5-carboxylate (I-1030): Methyl 2-[(4-bromo-2-chloro-5-methyl-phenyl)methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]benzimidazole-5-carboxylate was prepared by the method described for intermediate I-2, using I-80 instead of I-1 and 2-(4-bromo-2-chloro-5-methyl-phenyl)acetic acid (I-1023) instead of 2-(4-bromo-2-fluoro-phenyl)acetic acid. ES / MS: 490.6, 492.6 (M+H+). 1H NMR (400 MHz, chloroform-d) δ 8.56 (s, 1H), 8.02 (dd, J = 8.5, 1.4 Hz, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.64 (s, 1H), 7.06 (s, 1H), 4.60-4.47 (m, 2H), 4.45-4.26 (m, 3H), 3.95 (d, J = 10.4 Hz, 5H), 3.78 (d, J = 8.8 Hz, 1H), 2.28 (s, 3H), 2.07 (s, 1H), 1.31 (s, 3H), 0.67 (s, 3H).

[0653] Preparation of intermediate I-1031

[0654] [ka]

[0655] Methyl 4-[[2-(4-bromo-2-chloro-5-methyl-phenyl)acetyl]amino]-3-[[[(3S)-4,4-dimethyltetrahydrofuran-3-yl]amino]-5-fluoro-benzoate: To a solution of 2-(4-bromo-2-chloro-5-methyl-phenyl)acetic acid (399 mg, 1.51 mmol) and methyl 4-amino-3-[[(3S)-4,4-dimethyltetrahydrofuran-3-yl]amino]-5-fluoro-benzoate (427 mg, 1.51 mmol) in CHCN (7 mL) at 0 °C, 1-methylimidazole (0.603 mL, 7.56 mmol) was added, followed by TCFH (509 mg, 1.82 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was then diluted with EtOAc and washed with saturated NH4Cl, 1 N NaOH, and brine. The mixture was then dried over sodium sulfate, concentrated and carried on to the next step below without purification: ES / MS: 527, 529 (M+H+).

[0656] Methyl 2-[(4-bromo-2-chloro-5-methyl-phenyl)methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]-7-fluoro-benzimidazole-5-carboxylate (I-1031): To a solution of methyl 4-[[2-(4-bromo-2-chloro-5-methyl-phenyl)acetyl]amino]-3-[[(3S)-4,4-dimethyltetrahydrofuran-3-yl]amino]-5-fluoro-benzoate (798 mg, 1.51 mmol) and triphenylphosphine oxide (1262 mg, 4.54 mmol) in DCM (15 mL) was added trifluoromethanesulfonic acid at 0 °C. Anhydride (1000 mmol / L, 2.27 mL, 2.27 mmol) was added. The mixture was gradually warmed to room temperature and stirred for 1 h. Upon completion, the mixture was diluted with DCM and washed with saturated aqueous NaHCO3 and brine. The mixture was then dried over sodium sulfate, concentrated, and purified by chromatography (eluent: EtOAc / hexanes) to give the desired product. ES / MS: 508.6, 510.6 (M+H+). 1H NMR (400MHz, chloroform-d)δ 8.38(s,1H),7.71(dd,J=10.8,1.2Hz,1H),7.64(s,1H),7.06(s,1H),4.55-4.42(m,2H),4.41(d,J=2.8Hz,2H),4.32(dd ,J=11.0,7.0Hz,1H),3.97(s,3H),3.92(d,J=8.8Hz,1H),3.77(d,J=8.8Hz,1H),2.27(s,3H),1.29(s,3H),0.64(s,3H).

[0657] Preparation of Intermediate I-1032

[0658] [ka]

[0659] Ethyl (S)-4-amino-3-fluoro-5-((oxetan-2-ylmethyl)amino)benzoate (I-1032): Ethyl (S)-4-amino-3-fluoro-5-((oxetan-2-ylmethyl)amino)benzoate was prepared by the method described for intermediate I-1, using ethyl 3,5-difluoro-4-nitrobenzoate instead of methyl 3-fluoro-4-nitrobenzoate. ES / MS:257.2(M+H+), 1H NMR(400MHz, CDCl3)δ 7.32(dd,J=10.8,1.7Hz,1H),7.20(t,J=1.4Hz,1H),4.35(q,J=7.1Hz,2H),3.78(s,3H),3. 68(dd,J=5.6,4.5Hz,2H),3.43(s,3H),3.35(dd,J=5.6,4.5Hz,2H),1.39(t,J=7.1Hz,3H).

[0660] Preparation of intermediate I-1033

[0661] [ka]

[0662] Ethyl 2-(4-bromo-2,5-difluorobenzyl)-4-fluoro-l-(2-methoxyethyl)-lH-benzo[d]imidazole-6-carboxylate (I-1033): Following the procedure described for intermediate I-2, ethyl 4-amino-3-fluoro-5-((2-methoxyethyl)amino)benzoate (I-1032) was used in place of I-1. Using the same procedure as above and substituting 2-(4-bromo-2,5-difluorophenyl)acetic acid for 2-(4-bromo-2-fluorophenyl)acetic acid, ethyl 2-(4-bromo-2,5-difluorobenzyl)-4-fluoro-l-(2-methoxyethyl)-lH-benzo[d]imidazole-6-carboxylate was prepared. ES / MS: 471.0, 473.0 (M+H+). 1H NMR(400MHz,CDCl3)δ 7.91(d,J=1.3Hz,1H),7.70(dd,J=10.8,1.3Hz,1H),7.34(dd,J=8.7,5.5Hz,1H),7.12(dd,J=8.6,6.3Hz,1H),4 .44(q,J=7.1Hz,2H),4.39(s,2H),4.37-4.29(m,2H),3.66(t,J=5.1Hz,2H),3.25(s,3H),1.45(t,J=7.1Hz,3H).

[0663] Preparation of intermediate I-1037

[0664] [ka]

[0665] Methyl 2-[(4-bromo-2,5-difluoro-phenyl)methyl]-7-chloro-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]benzimidazole-5-carboxylate (I-1037): Prepared in the manner described for intermediate I-1031, using 2-(4-bromo-2,5-difluoro-phenyl)acetic acid in place of 2-(4-bromo-2-chloro-5-methyl-phenyl)acetic acid and methyl 4-amino-3-chloro-5-[[( Using methyl 4-amino-3-[[(3S)-4,4-dimethyltetrahydrofuran-3-yl]amino]benzoate I-1038 instead of methyl 4-amino-3-[[(3S)-4,4-dimethyltetrahydrofuran-3-yl]amino]-5-fluoro-benzoate, methyl 2-[(4-bromo-2,5-difluoro-phenyl)methyl]-7-chloro-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]benzimidazole-5-carboxylate was prepared. ES / MS: 513.0, 514.9 (M+H+). 1H NMR (400MHz, chloroform-d)δ 8.50(s,1H),8.07(d,J=1.3Hz,1H),7.38(dd,J=8.7,5.6Hz,1H),7.23-7.07(m,1H),4.61-4.40(m,3H), 4.40-4.29(m,2H),3.97(s,3H),3.92(d,J=8.9Hz,1H),3.78(d,J=8.9Hz,1H),1.32(s,3H),0.63(s,3H).

[0666] Preparation of intermediate I-1038

[0667] [ka]

[0668] Methyl 4-amino-3-chloro-5-[[(3S)-4,4-dimethyltetrahydrofuran-3-yl]amino]benzoate (I-1038): Methyl 4-amino-3-chloro-5-[[(3S)-4,4-dimethyltetrahydrofuran-3-yl]amino]benzoate was prepared by the method described for intermediate I-68, using methyl 3-chloro-5-fluoro-4-nitrobenzoate instead of methyl 3-bromo-5-fluoro-4-nitrobenzoate. ES / MS: 299.2 (M+).

[0669] Preparation of Intermediate I-1039

[0670] [ka]

[0671] Methyl 5-bromo-3-fluoro-thiophene-2-carboxylate: To a suspension of 5-bromo-3-fluoro-thiophene-2-carboxylic acid (1000 mg, 4.44 mmol) in DCM (20 mL) at 0 °C, oxalyl dichloride (2000 mmol / L, 2.67 mL, 5.33 mmol) and 10 drops of DMF were added. The mixture was then stirred for 1 h. Upon completion, 10 mL of MeOH was added, and the resulting mixture was stirred at room temperature overnight. The mixture was then diluted with DCM, washed with saturated NaHCO3, dried over sodium sulfate, concentrated to dryness, and purified by chromatography (eluent: EtOAc / hexanes) to give the desired product. 1H NMR (400 MHz, chloroform-d) δ 6.91 (s, 1H), 3.89 (s, 3H).

[0672] (5-Bromo-3-fluoro-2-thienyl)methanol: To a solution of methyl 5-bromo-3-fluoro-thiophene-2-carboxylate (907 mg, 3.79 mmol) in THF (15 mL) at 0 °C was added diisobutylaluminum hydride (1000 mmol / L, 9.48 mL, 9.48 mmol). The mixture was gradually warmed to room temperature and stirred for 1 hour. The mixture was then diluted with 25 mL of EtO and cooled to 0 °C. 0.380 mL of water, 0.380 mL of 15% NaOH, and 0.948 mL of water were then added. The resulting mixture was warmed to room temperature and stirred for 15 minutes. MgSO4 was then added. The resulting mixture was stirred for 15 min. Upon completion, the mixture was filtered and rinsed with EtO to give a crude residue, which was purified by chromatography (eluent: EtOAc / hexanes) to give the desired product. 1H NMR (400 MHz, chloroform-d) δ 6.81 (s, 1H), 4.77-4.55 (m, 2H).

[0673] 4-Fluoro-5-(hydroxymethyl)thiophene-2-carbonitrile (I-1039): A suspension of (5-bromo-3-fluoro-2-thienyl)methanol (300 mg, 1.42 mmol), tetrakis(triphenylphosphine)palladium(0) (411 mg, 0.355 mmol), zinc cyanide (334 mg, 2.84 mmol), and zinc powder (4.65 mg, 0.0711 mmol) in DMF (3.5 mL) was degassed with argon and heated at 100° C. for 16 h. The mixture was concentrated to dryness and purified by chromatography (eluent: EtOAc / hexanes) to give the desired product. 1 H NMR (400MHz, CDCl3) δ 7.36-7.31 (m, 1H), 4.89 (s, 2H). 19 F NMR(376MHz, CDCl3)δ -129.96.

[0674] Preparation of Intermediate I-1040

[0675] [ka]

[0676] 5-[(4-Bromopyrimidin-2-yl)oxymethyl]-4-fluoro-thiophene-2-carbonitrile (I-1040): A solution of 4-bromo-2-fluoro-pyrimidine (40.0 mg, 0.226 mmol), 4-fluoro-5-(hydroxymethyl)thiophene-2-carbonitrile (37.3 mg, 0.237 mmol) and cesium carbonate (147 mg, 0.452 mmol) in CHCN (5 mL) was heated at 50° C. overnight. The mixture was diluted with EtOAc, washed with brine, dried over sodium sulfate, concentrated to dryness and purified by chromatography. ES / MS: 314, 316 (M+H). + ). 1H NMR (400MHz, chloroform-d) δ 8.35 (d, J = 5.2 Hz, 1H), 7.30-7.22 (m, 2H), 5.57 (d, J = 1.0 Hz, 2H). 19F NMR (377MHz, chloroform-d) δ -127.05.

[0677] Preparation of intermediate I-1041

[0678] [ka]

[0679] tert-Butyl 4-[[2-(4-bromo-2,5-difluorophenyl)acetyl]amino]-3-[[(3S)-4,4-dimethyltetrahydrofuran-3-yl]amino]benzoate: To a solution of 2-(4-bromo-2,5-difluorophenyl)acetic acid (575 mg, 2.29 mmol), tert-butyl 4-amino-3-[[(3S)-4,4-dimethyltetrahydrofuran-3-yl]amino]benzoate (696 mg, 2.27 mmol), and o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1292 mg, 3.40 mmol) in DMF (10 mL) was added N,N-diisopropylethylamine (1.22 mL, 6.98 mmol). The mixture was stirred at room temperature overnight. The mixture was then diluted with EtOAc, washed with 5% LiCl, saturated NaHCO3, and brine, dried over sodium sulfate, concentrated, and carried on to the next step below without purification. ES / MS: 539, 541 (M+H+).

[0680] tert-Butyl 2-[(4-bromo-2,5-difluorophenyl)methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]benzimidazole-5-carboxylate (I-1041): To a solution of tert-butyl 4-[[2-(4-bromo-2,5-difluorophenyl)acetyl]amino]-3-[[(3S)-4,4-dimethyltetrahydrofuran-3-yl]amino]-5-fluorobenzoate (1236 mg, 2.22 mmol) and triphenylphosphine oxide, 99% (1851 mg, 6.65 mmol) in DCM (20 mL) at 0 °C, trifluoromethanesulfonic anhydride (0.559 mL, 3.33 mmol) was added. The mixture was then gradually warmed to room temperature and stirred for 1 h. Upon completion, the mixture was diluted with DCM and washed with saturated NaHCO solution and brine. The mixture was then dried over sodium sulfate, concentrated, and purified by chromatography (eluent: EtOAc / hexanes) to give the desired product. ES / MS: 521, 523 (M+H). H NMR (400 MHz, chloroform-d) δ 8.55 (s, 1H), 7.97 (dd, J = 8.5, 1.5 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.37 (dd, J = 8.7, 5.5 Hz, 1H), 7.15 (t, J = 7.4 Hz, 1H), 4.59 (t, J = 8.9 Hz, 2H), 4.47-4.25 (m, 3H), 3.96 (d, J = 8.8 Hz, 1H), 3.81 (d, J = 8.8 Hz, 1H), 1.34 (s, 3H), 0.66 (s, 3H).

[0681] Preparation of Intermediate I-1042

[0682] [ka]

[0683] tert-Butyl 3-[[(3S)-4,4-dimethyltetrahydrofuran-3-yl]amino]-4-nitro-benzoate: tert-Butyl 3-fluoro-4-nitro- To a suspension of benzoate (3.50 g, 14.5 mmol), (3S)-4,4-dimethyltetrahydrofuran-3-amine hydrochloride (2.50 g, 16.5 mmol), and (3S)-4,4-dimethyltetrahydrofuran-3-amine hydrochloride (2.50 g, 16.5 mmol) in THF (30 mL) and DMF (15 mL) was added N,N-diisopropylethylamine (12.6 mL, 72.5 mmol). The solution was heated at 80° C. for 18 h. The crude reaction mixture was diluted with EtOAc (300 mL) and washed with 5% LiCl (250 mL) and brine (250 mL). The organic extract was dried over sodium sulfate and purified by...

Claims

[Claim 1] The invention described in the specification.

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