Carboxy-benzimidazole GLP-1r modulating compounds

Abstract

To provide methods for treating diseases.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 thoroughly described and specifically demonstrated herein, it is surprising that the present invention delivers remarkable effects, which could not have been easily anticipated by those skilled in the art based on conventional technology.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 177,778, filed April 21, 2021, and U.S. Provisional Application No. 63 / 286,475, filed December 6, 2021, which are incorporated herein 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 that 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 the cell membrane 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] or a pharmaceutically acceptable salt thereof, wherein: R 1 but, i) each of which has 1 to 4 R 4 C, optionally substituted with 6~10 aryl or 6-membered heteroaryl, or ii) a 6-membered heteroaryl, wherein the heteroaryl is fused to a 5- or 6-membered ring having 0-3 heteroatoms, each independently N, O, or S, to form a fused ring system, the fused ring system comprising 1-4 R 5 is a 6-membered heteroaryl optionally substituted with Ring A is

[0008] [ka] and each of them contains 1 to 3 R A and each R A But independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, halogen, —OH, —CN, or —N(R 10a )(R 10b ) and Ring B is (I C 6~10 aryl or heteroaryl, each of which is selected from 1 to 4 R B and each R B But independently, C 1~9 Alkyl, C 1~8 Haloalkyl, 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, -NO2, -CN, -N3, -OR 10a , -C(O)R 10a , -C(O)OR 10a , -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(R10a )(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, or (ii) C 6~10 aryl or heteroaryl, each of which is fused to a 5- or 6-membered ring system having 0-4 heteroatoms, each of which is independently N, O, or S, to form a fused ring system, said fused ring system comprising 1-5 R B and each R B But independently, C 1~9 Alkyl, C 1~8 Haloalkyl, 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, -NO2, -CN, -N3, -OR 10a , -C(O)R 10a , -C(O)OR 10a , -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 ), -NR10a 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, aryl or heteroaryl, V is -C(R 11a )(R 11b )- and X 1 , X 2 , and X 3 are each independently -C(H)= or -C(R 8 )=, R 2 but, I C 3~10 cycloalkyl or heterocyclyl, each of which is selected from the group consisting of 1 to 4 Z 1 and each Z 1 But 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, oxo, -OH, -CN, C 1~6 Alkyl-CN, -C(O)R 10a , -C(O)OR 10a , -C(O)NH2, -C(O)NH(C 1~9 alkyl), -N(R 10a )(R 10b ), -N(R 10a )C(O)OR 10b , -N(R 10a )C(O)-R 10b, -S(O)2R 10a , -S(O)2(C 1~9 alkyl), -OC 3~6 is cycloalkyl or heteroaryl; Each-OC 3~6 cycloalkyl or heteroaryl is 1 to 4 Z 1a groups, and each Z 1a But independently, C 1~6 Alkyl, C 1~6 Alkoxy, halogen, C 1~6 Haloalkyl or C 1~6 haloalkoxy, cycloalkyl or heterocyclyl, or (ii)

[0009] [ka] wherein: R 2a But C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 2-6 Alkoxyalkyl, C 1~6 Haloalkyl, C 1~6 Alkyl-CN, -C 3~6 cycloalkyl or heteroaryl Each alkyl, cycloalkyl, or heteroaryl is independently C 1~6 Alkyl, C 1~6 Alkoxy, halogen, C 1~6 Haloalkyl, or C 1~6 optionally substituted with 1 to 4 groups that are haloalkoxy; R 2b But H, C 1~3 Alkyl, or C 1~3 is haloalkyl, R 2c But H, C 1~3 Alkyl, or C 1~3 is haloalkyl, R 3 But -C(O)OR 3a and R 3a But H, C1~4 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 )(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(R9c )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)OCHP(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, each alkyl or heterocyclyl optionally substituted with 1 to 4 halogens; Each R 4 But independently, C 1~6 Alkyl, C 1~8 Haloalkyl, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 10a , -C(O)R 10a , -C(O)OR 10a , -N(R 10a )(R 10b ), -N(R 10a )2(R 10b ) + , -N(R 10a )-C(O)R 10b, -N(R 10a )C(O)O(R 10b ), -N(R 10a )C(O)N(R 10b )(R 10c ), -N(R 10a )S(O)2(R 10b ), -N(R 10a )S(O)2-N(R 10b )(R 10c ), -N(R 10a )S(O)2O(R 10b ), -OC(O)R 10a、 -OC(O)OR 10a , -OC(O)-N(R 10a )(R10 b ), -S-R10 a , -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, or aryl is selected from 1 to 4 R 5 is replaced by Each alkyl, cycloalkyl, heterocyclyl, or heteroaryl is selected from 1 to 4 R 12 and optionally substituted with Each R 5 But 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 )(R10b ), -N(R 10a )(R 10b ), -N(R 10a )2(R 10b ) + , -N(RR 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 is selected from 1 to 4 R 6 and optionally substituted with Each R 6 But 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 is selected from 1 to 4 R 7 and optionally substituted with Each R 7 and R 8 But independently, C 1~9 Alkyl, C 1~6 Alkoxy, C 2~6 Alkoxyalkyl, C 1~8 Haloalkyl, C2~6 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)(C 1~8 haloalkyl), -C(O)(C2~6 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 6~10 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 Shik -S(C(alkyl), -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 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 1~8 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; each alkyl or heterocyclyl optionally substituted with 1 to 4 halogens; Each R 9a and R 9b However, independently, H, C 1~6 Alkyl or C 1~6 haloalkyl or R 9a and R 9b together form a six-membered heterocyclyl, Each R 9c , R 9d , R 10a , R 10b , and R 10c However, 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, each of which is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each of which is 1 to 4 R 6 and optionally substituted with Each R 11a and R 11b But independently, -H, C 1~6 alkyl, oxo, or halogen; Each R 12 But C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, 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(C3~15 -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 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 2~6 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 2~6alkenyl), -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(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 1~9alkyl), -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(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 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 1~8 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; each alkyl or heterocyclyl optionally substituted with 1 to 4 halogens; each heteroaryl has 3 to 12 ring members and 1 to 4 heteroatoms, each independently N, O, or S; Each heterocyclyl has 5 to 12 ring members and 1 to 4 heteroatoms, each independently N, O, or S, or a pharmaceutically acceptable salt thereof.

[0010] The present disclosure further provides pharmaceutical compositions, methods, and uses comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof. The present disclosure further provides pharmaceutical compositions, methods, and uses comprising a compound of formula (IA-1), or a pharmaceutically acceptable salt thereof. For example, the compounds of the present disclosure are generally useful in methods for treating GLP-1R-mediated diseases or conditions. [Brief explanation of the drawings]

[0011] [Figure 1] 1 is a graph showing plasma concentrations as a function of time in cynomolgus monkeys. [Figure 2] 1 is a graph showing plasma concentrations as a function of time in cynomolgus monkeys. DETAILED DESCRIPTION OF THE INVENTION

[0012] 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.

[0013] "Alkyl" refers to a monovalent or divalent straight-chain or branched saturated hydrocarbon radical. For example, an alkyl group may contain 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 1~4 Examples 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(CH)), 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(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3, and octyl (-(CH 27 Alkyl groups include, but are not limited to, alkyl groups such as aryl, ...

[0014] "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.

[0015] 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.

[0016] 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.

[0017] "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.

[0018] "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 alkynyl group having 2 to 8 carbon atoms (i.e., 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 2~4 Examples 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.

[0019] "Halogen" refers to fluoro (-F), chloro (-Cl), bromo (-Br) and iodo (-I).

[0020] "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.

[0021] "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 1~4Haloalkoxy includes OCF3, OCH2F, OCH2CF3, OCH2CH2CF3, OCCl2CH2CH2CH3, and OC(CH3)2(CF2H). A haloalkoxy group can be unsubstituted or substituted.

[0022] "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.

[0023] "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 An alkylcycloalkyl group can be unsubstituted or substituted.

[0024] 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, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms. Aryl includes phenyl radicals. 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 via fused, spiro, or bridged bonds, if permitted by valence requirements. It is also understood that when a particular atom-range-membered aryl (e.g., a 6- to 10-membered aryl) is referenced, 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. An aryl group can be unsubstituted or substituted.

[0025] "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 6~10aryl). 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.

[0026] 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 a fused polycyclic ring system can be connected to each other via fused, spiro, or 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]heptane. Heterocyclyl groups include 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.

[0027] "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 may be the same or different. The alkyl group and heterocyclyl group may 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.

[0028] "Heteroaryl" refers to a single aromatic ring having at least one atom other than carbon in 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 multiple condensed ring systems are defined below. As further explained below. Thus, "heteroaryl" includes an 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 may 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 relative to the total ring atoms of the heteroaryl and includes carbon atoms and heteroatoms. It is also understood that the rings of a fused polycyclic ring system 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.

[0029] "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.

[0030] As used herein, "oxo" refers to =O.

[0031] 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.

[0032] "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).

[0033] "Pharmaceutically acceptable excipients" include, but are not limited to, those that are suitable for human or domestic animal use. The present invention includes any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / coloring agent, 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 the preparation of pharmaceutical compositions.

[0034] 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.

[0035] 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 the 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.

[0036] 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.

[0037] 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 a compound that possesses the desired pharmacological activity of the free base. These salts can be derived from inorganic or organic acids or inorganic or organic bases. For example, compounds containing 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, bisulfite, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, 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, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfone, and the like. Suitable pharmaceutically acceptable salts include phenylacetate, 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.

[0038] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include salts derived from appropriate bases, such as alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium, and N(C≡Calkyl) . Base addition salts, such as sodium or potassium salts, are also included.

[0039] 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, e.g., 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.

[0040] 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.

[0041] The compounds of the embodiments disclosed herein, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, with respect to absolute stereochemistry, as (R)- or (S)-, or for amino acids, as (D)- or (L)-. The present disclosure is meant to include all such possible 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, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or separation by, for example, chiral high-pressure liquid chromatography (HPLC). This includes resolution of the racemate (or racemate of a salt or derivative) using chromatography (e.g., HPLC). When the compounds described herein contain an olefinic double bond or other center 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 isomeric. It is intended to include. Where compounds are represented in their chiral form, it is understood that embodiments include, but are not limited to, the specific diastereomerically or enantiomerically enriched forms. Where chirality is not specified, it is understood that embodiments are directed to either the specific diastereomerically or enantiomerically enriched form, or racemic or scalemic mixtures of such compounds. As used herein, a "scalemic mixture" is a mixture of stereoisomers in a ratio other than 1:1.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] As used herein, "hydrate" refers to a compound of the present disclosure that is chemically associated with one or more molecules of water.

[0046] "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.

[0047] 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.

[0048] 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 worsening of symptoms associated with a disease or condition. In one embodiment, "treatment" or "treating" includes one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms resulting from the disease or condition and / or reducing the severity of the disease or 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, slowing 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, slowing 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 individual "at risk" 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 the individual has one or more so-called risk factors, which are measures that correlate with the development of a disease or condition. These are possible parameters and are known in the art. Individuals with one or more of these risk factors have a higher probability of developing the disease or condition than individuals without these risk factors.

[0049] II. Compounds In one embodiment, the present disclosure provides a compound of formula (I):

[0050] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 but, i) each of which has 1 to 4 R 4 C, optionally substituted with 6~10 aryl or 6-membered heteroaryl, or ii) a 6-membered heteroaryl, wherein the heteroaryl is fused to a 5- or 6-membered ring having 0-3 heteroatoms, each independently N, O, or S, to form a fused ring system, the fused ring system comprising 1-4 R 5 is a 6-membered heteroaryl optionally substituted with Ring A is

[0051] [ka] and each of them contains 1 to 3 R A and each R A But independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, halogen, —OH, —CN, or —N(R 10a )(R 10b ) and Ring B is (I C 6~10 aryl or heteroaryl, each of which is selected from 1 to 4 R B and each R B But independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~10Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 10a , -C(O)R 10a , -C(O)OR 10a , -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, or (ii) C 6~10 aryl or heteroaryl, each of which is fused to a 5- or 6-membered ring system having 0-4 heteroatoms, each of which is independently N, O, or S, to form a fused ring system, the fused ring system being fused to a 5- or 6-membered ring system having 1-5 R B Optionally substituted with Each R B But independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C1~6 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, -NO2, -CN, -N3, -OR 10a , -C(O)R 10a , -C(O)OR 10a , -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, aryl or heteroaryl, V is -C(R 11a )(R 11b )- and X 1 , X 2 , and X 3are each independently -C(H)= or -C(R 8 )=, R 2 but, I C 3~10 cycloalkyl or heterocyclyl, each of which is selected from the group consisting of 1 to 4 Z 1 and each Z 1 But 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, oxo, -OH, -CN, C 1~6 Alkyl-CN, -C(O)R 10a , -C(O)OR 10a , -C(O)NH2, -C(O)NH(C 1~9 alkyl), -N(R 10a )(R 10b ), -N(R 10a )C(O)OR 10b , -N(R 10a )C(O)-R 10b , -S(O)2R 10a , -S(O)2(C 1~9 alkyl), -OC 3~6 is cycloalkyl or heteroaryl; Each-OC 3~6 cycloalkyl or heteroaryl is 1 to 4 Z 1a groups, and each Z 1a But independently, C 1~6 Alkyl, C 1~6 Alkoxy, halogen, C 1~6 Haloalkyl or C 1~6 haloalkoxy, cycloalkyl or heterocyclyl, or (ii)

[0052] [ka] wherein: R 2a But C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 2-6 Alkoxyalkyl, C 1~6 Haloalkyl, C 1~6 Alkyl-CN, -C 3~6 is cycloalkyl or heteroaryl; Each alkyl, cycloalkyl, or heteroaryl is independently C 1~6 Alkyl, C 1~6 Alkoxy, halogen, C 1~6 Haloalkyl, or C 1~6 optionally substituted with 1 to 4 groups that are haloalkoxy; R 2b But H, C 1~3 Alkyl, or C 1~3 is haloalkyl, R 2c But H, C 1~3 Alkyl, or C 1~3 is haloalkyl, R 3 But -C(O)OR 3a and R 3a But 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 Al Kill-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)(OR9c )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 )(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)(R9c )(N(R 9d )2), -C(O)OCH2P(O)(R 9c )(N(R 9d )2) or C 1~6 alkyl-heterocyclyl, each alkyl or heterocyclyl optionally substituted with 1 to 4 halogens; Each R 4 But independently, C 1~6 Alkyl, C 1~8 Haloalkyl, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 10a , -C(O)R 10a , -C(O)OR 10a , -N(R 10a )(R 10b ), -N(R 10a )2(R 10b ) + , -N(R 10a )-C(O)R 10b , -N(R 10a )C(O)O(R 10b ), -N(R 10a )C(O)N(R 10b )(R 10c ), -N(R 10a )S(O)2(R 10b ), -N(R 10a )S(O)2-N(R 10b )(R 10c )、 -N(R 10a )S(O)2O(R 10b ), -OC(O)R 10a , -OC(O)OR 10a , -OC(O)-N(R 10a )(R10 b ), -S-R10 a , -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, or aryl is selected from 1 to 4 R 5 and optionally substituted with Each alkyl, cycloalkyl, heterocyclyl, or heteroaryl is selected from 1 to 4 R 12 and optionally substituted with Each R 5 But 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(RR 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)R10a , -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 is selected from 1 to 4 R 6 and optionally substituted with Each R 6 But 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 10aS(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 is selected from 1 to 4 R 7 and optionally substituted with Each R 7 and R 8 But independently, C 1~9 Alkyl, C 1~6 Alkoxy, C 2~6 Alkoxyalkyl, 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(C3~15 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 2~6 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 1~8haloalkyl), -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 )2, -C(O)N(heteroaryl)2, -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(C6~10 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(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 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 1~8 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; each alkyl or heterocyclyl optionally substituted with 1 to 4 halogens; Each R 9a and R 9b However, independently, H, C 1~6 Alkyl or C 1~6 haloalkyl or R 9a and R 9b together form a six-membered heterocyclyl, Each R 9c , R 9d, R 10a , R 10b , and R 10c However, independently, H, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, hetero Cyclyl, C 6~10 aryl, or heteroaryl, each of which is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each of which is 1 to 4 R 6 and optionally substituted with Each R 11a and R 11b But independently, -H, C 1~6 alkyl, oxo, or halogen; Each R 12 But C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, 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(C6~10 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 2~6 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(C2~6 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(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(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, 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 1~8haloalkyl), -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; each alkyl or heterocyclyl optionally substituted with 1 to 4 halogens; each heteroaryl has 3 to 12 ring members and 1 to 4 heteroatoms, each independently N, O, or S; Each heterocyclyl has 5 to 12 ring members and 1 to 4 heteroatoms, each independently N, O, or S, or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, R 1 is C 6~10 aryl or 6-membered heteroaryl, each of which optionally contains 1 to 4 R 4 is optionally substituted with

[0054] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, R 1is phenyl or 6-membered heteroaryl, each of which is selected from 1 to 4 R 4 In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, R 1 teeth,

[0055] [ka] and 1 to 4 R 4 is optionally substituted with

[0056] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, R 1 is a 6-membered heteroaryl, each of which is selected from 1 to 4 R 4 In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, R 1 teeth,

[0057] [ka] and 1 to 4 R 4 is optionally substituted with

[0058] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, R 1 is three R 4 In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, R 1 is two R 4 In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, R 1 is one R 4 may be substituted with

[0059] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, R 1is a 6-membered heteroaryl, wherein the heteroaryl is fused to a 5- or 6-membered ring having 0-3 heteroatoms, each independently N, O, or S, to form a fused ring system, wherein the fused ring system is fused to a 5- or 6-membered ring having 0-3 heteroatoms, each independently N, O, or S, and wherein the fused ring system is fused to a 5- or 6-membered ring having 1-4 R 5 is optionally substituted with

[0060] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, ring A is

[0061] [ka] each of which contains 1 to 3 R A is optionally substituted with

[0062] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, ring A is

[0063] [ka] and 1 to 3 R A is optionally substituted with

[0064] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, ring A is

[0065] [ka] each of which contains 1 to 3 R A is optionally substituted with

[0066] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, ring A is

[0067] [ka] and 1 to 3 R AIn some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, ring A is optionally substituted with

[0068] [ka] and 1 to 2 R A In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, ring A is optionally substituted with

[0069] [ka] and one R A is optionally substituted with

[0070] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, ring A is

[0071] [ka] and 1 to 3 R A In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, ring A is optionally substituted with

[0072] [ka] and 1 to 2 R A In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, ring A is optionally substituted with

[0073] [ka] and one R A is optionally substituted with

[0074] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, each R Aindependently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, halogen, —OH, —CN, or —N(R 10a )(R 10b )

[0075] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, ring B is C 6~10 aryl or heteroaryl, each of which is selected from 1 to 4 R B is optionally substituted with

[0076] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, Ring B is phenyl or a 5-6 membered heteroaryl, and the phenyl or heteroaryl is selected from 1 to 4 R B is optionally substituted with

[0077] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, ring B is

[0078] [ka] and 1 to 4 R B is optionally substituted with

[0079] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, ring B is

[0080] [ka] and 1 to 4 R B In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, ring B is optionally substituted with three R B In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, ring B may be substituted with two R BIn some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, ring B may be substituted with one R B may be substituted with

[0081] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, ring B is phenyl or a 5-6 membered heteroaryl, each of which is fused to a 5- or 6-membered ring having 0-4 heteroatoms, each of which is independently N, O, or S, to form a fused ring system, the fused ring system comprising 1-5 R B is optionally replaced by 。

[0082] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, ring B is

[0083] [ka] and 1 to 5 R B is optionally substituted with

[0084] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, each R B independently, C 1~9 Alkyl, C 1~8 haloalkyl, halogen, heteroaryl, oxo, or -N(R 10a )(R 10b )

[0085] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, V is —CH—, —C(O)—, —C(F)—, —CH(F)—, or —CH(CH)—.

[0086] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, X 1 , X 2 , and X 3are each independently -CH=, -C(Br)=, -C(C≡CCH2CH2CH3)=, or -C(C≡CC(CH3)(CH3)(CH2(OH)))=. In an embodiment of Formula (I), or a pharmaceutically acceptable salt thereof, X 1 , 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 Two of X are -CH= and one is -C(F)=. In some embodiments, X 1 is -C(F)=X 2 and X 3 are 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 each -CH=. In some embodiments, X 1 , X 2 , and X 3 are each independently -CH= or -C(Cl)=. In some embodiments, X 1 , X 2 , and X 3 Two of X are -CH= and one is -C(Cl)=. In some embodiments, X 1 is -C(Cl)=X 2 and X 3 are each -CH=. In some embodiments, X 2 is -C(Cl)=X 1 and X 3are each -CH=. In some embodiments, X 1 and X 2 are -CH=, and X 3 is -C(Cl)=. In some embodiments, X 1 , X 2 , and X 3 are -CH=, respectively.

[0087] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, R 2 is C 3~10 cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl is selected from 1 to 4 Z 1 is optionally substituted with

[0088] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, R 2 teeth,

[0089] [ka] and each contains 1 to 4 Z 1 is optionally substituted with

[0090] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, R 2 teeth,

[0091] [ka] and each contains 1 to 4 Z 1 is optionally substituted with

[0092] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, R 2 teeth,

[0093] [ka] and each contains 1 to 4 Z 1In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, R 2 teeth,

[0094] [ka] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 2 teeth,

[0095] [ka] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 2 teeth,

[0096] [ka] is.

[0097] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, R 2 teeth,

[0098] [ka] is.

[0099] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, R 2 teeth,

[0100] [ka] wherein: R 2a is C 1~6 Alkyl or C 1~6 Is it a haloalkyl? R 2b is H or C 1~3 Is it alkyl? R2c is H or C 1~3 alkyl, or Alternatively, R 2b and R 2c can be bonded to each other to form a ring.

[0101] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, R 2 teeth,

[0102] [ka] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 2 teeth,

[0103] [ka] is.

[0104] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, 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, oxo, -OH, -CN, C 1~6 Alkyl-CN, -C(O)R 10a , -C(O)OR 10a , -C(O)NH2, -C(O)NH(C 1~9 alkyl), -N(R 10a (R 10b ), -N(R 10a C(O)OR 10b , -N(R 10a C(O)-R 10b , -S(O)2R 10a , -S(O)2(C 1~9 alkyl).

[0105] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, each Z 1 independently, C 1~6 Alkyl, C 1~6 Alkoxy, halogen, oxo, -C(O)R 10a , -C(O)OR 10a , -C(O)NH2, -C(O)NH(C 1-9 alkyl), -N(R 10a (R 10b ), -N(R 10a C(O)OR 10b , -N(R 10a C(O)-R 10b -S(O)2R 10a , or -S(O)2(C 1~9 alkyl).

[0106] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, each Z 1 independently, C 1~6 Alkyl, C 1~6 Alkoxy, halogen, or C 1~6 It is haloalkyl.

[0107] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, each Z 1 is independently methyl, ethyl, or propyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, each Z 1 is independently methyl or ethyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, each Z 1 is independently methyl.

[0108] In some embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, R 3 is —C(O)OH.

[0109] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, each R 4 independently, C 1~9 Alkyl, C1~8 Haloalkyl, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 10a , -C(O)R 10a , -C(O)OR 10 R 10a , -N(R 10a (R 10b , -N(R 10a )2(R 10b ) + , -N(R 10a )-C(O)R 10b , -N(R 10a S(O)2-N(R 10b (R 10c ), -S(O)R 10a , or -S(O)(NR 10a R 10b -S(O)2R 10a is.

[0110] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, each R 4 independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, halogen, C 3~10 cycloalkyl, heteroaryl, or -C(O)R 10a is.

[0111] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, each R 4 are independently -F, -Cl, -CN, C 1~9 Alkyl, C 3~10 cycloalkyl, heteroaryl, or -C(O)R 10a In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, each R 4is independently -F, -Cl, -CN, or heteroaryl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, each R 4 is independently -F, -Cl, or -CN. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, each R 4 is independently -F, -Cl, or heteroaryl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, each R 4 Heteroaryl is pyrrole, imidazole In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, each R 4 Heteroaryl is imidazole or triazole. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, each R 4 The heteroaryl is a triazole.

[0112] 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, halogen, C 3~15 Cycloalkyl, heterocyclyl, heteroaryl, C 6~10 Aryl, heteroaryl, oxo, -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 R 10b )C(O)-R 10b , -N(R10a )C(O)OR 10b , -N(R 10a )C(O)N(R 10b )(R 10c ), -OC(O)-N(R 10a )(R 10b )

[0113] 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 2~6 Alkoxyalkyl, halogen, C 3~15 It is cycloalkyl, heteroaryl, or -CN.

[0114] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, each R 6 independently, C 1~9 Alkyl, C 1~6 Alkoxy, C 2~6 Alkoxyalkyl, C 1~8 Haloalkyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -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), or -NH (heteroaryl).

[0115] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, each R 6 independently, C 1~9 Alkyl, C 1~6 Alkoxy, C 2~6 Alkoxyalkyl, C 1~8 Haloalkyl, C 3~15 It is cycloalkyl, or halogen.

[0116] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, each R 7 independently, C 1~9 Alkyl, C 1~6 Alkoxy, C 2~6 Alkoxyalkyl, C 1~8 It is haloalkyl, oxo, -OH, -CN, -NH2, or halogen.

[0117] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, each R 7 is C 2~6 It is an alkoxyalkyl.

[0118] In some embodiments, the compound of formula (II):

[0119] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 is R 4 phenyl or 6-membered heteroaryl optionally substituted with X 1 -C(H)= or -C(R 8 )=, X 4 is -C(H)=, -C(R 8 )=, or N, Each R 4 are independently halogen or —CN, Each R B independently, C 1~9 Alkyl, C 1~8haloalkyl or halogen; Each R 8 are independently H or halogen; n is 0, 1, 2, or 3.

[0120] In some embodiments, the compound of formula (I) is a compound according to formula (II).

[0121] In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt thereof, R 1 is phenyl substituted with halogen or -CN.

[0122] In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt thereof, R 1 is substituted with halogen or -CN

[0123] [ka] is.

[0124] In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt thereof, R 1 teeth,

[0125] [ka] is.

[0126] In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt thereof, is B is methyl, ethyl, F, or Cl. In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt thereof, is B is methyl or F. In some embodiments, the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R B is F.

[0127] In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt thereof, R 8 is F or Cl.

[0128] In some embodiments, the compound of formula (III):

[0129] [ka] or a pharmaceutically acceptable salt thereof, wherein: X 1 -C(H)= or -C(R 8 )=, X 4 is -C(H)=, -C(R 8 )=, or N, X 5 is -C(H)= or N, Each R B independently, C 1~9 Alkyl, C 1~8 haloalkyl or halogen; Each R 4 are independently pyrrole, imidazole, triazole, or thiazole; Each R 8 are independently halogen; m is 0 or 1; n is 0, 1, 2, or 3.

[0130] In some embodiments, the compound of formula (I) is a compound according to formula (III).

[0131] In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt thereof, is B is methyl, ethyl, F, or Cl. In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt thereof, is B is methyl or F. In some embodiments, the compound of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R B is F.

[0132] In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt thereof, is 4 In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt thereof, is 4 is imidazole.

[0133] In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt thereof, is 4 teeth,

[0134] [ka] is.

[0135] In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt thereof, is 4 teeth,

[0136] [ka] is.

[0137] In some embodiments of the compound of Formula (II), or a pharmaceutically acceptable salt thereof, R 8 is F or Cl.

[0138] In some embodiments, Formula (I), Formula (II), or The compound of formula (III), or a pharmaceutically acceptable salt thereof, has the structure of the compound in Table 2.

[0139] The 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 the oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily by enzymatic processes. Thus, included are novel and unobvious compounds produced by a process comprising contacting a compound with a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically radiolabeled (e.g., 14 C or 3 H) Compounds are prepared and identified by parenterally administering a detectable dose (e.g., about 0.5 mg / kg) to animals, such as rats, mice, guinea pigs, monkeys, or humans, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours), and isolating the conversion products from urine, blood, or other biological samples. These products are labeled and therefore easily isolated (others are isolated by the use of antibodies capable of binding to epitopes surviving in the metabolites). Metabolite structures are determined in conventional manner, for example, by MS or NMR analysis. Metabolite analysis can generally 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 administration of compounds, even if they do not possess GLP-1R activity of their own unless otherwise found in vivo.

[0140] 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 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 within cells. As used herein, a prodrug is understood to be a compound chemically designed to efficiently release the parent drug after overcoming a biological barrier to oral delivery.

[0141] 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.

[0142] Scheme 1

[0143] [ka]

[0144] Intermediate 1.3 can be assembled by reacting an amine with intermediate 1.1 (X is halogen and R is alkyl, alkylaryl, or aryl) in the presence of a suitable base (e.g., DIPEA, KOtBu, etc.) to give intermediate 1.2. Intermediate 1.2 can be converted to intermediate 1.3 using suitable reduction conditions (e.g., H2 and Pd / C, Fe and HCl, etc.).

[0145] Scheme 2

[0146] [ka]

[0147] Compounds of formula (I) having the structure of compounds of formula 2.9 can be prepared by first converting intermediate 2.1 (X 2.9) into intermediate 2.1 (X 2.9) through a metal-mediated cross-coupling using a suitable base (e.g., DIPEA, KOtBu, etc.) or a suitable palladium catalyst. 21 and X 22 Intermediate 2.2 can be assembled by reacting a heteroatom containing intermediate 2.2 (where M = Li, MgBr, MgCl, or MgI, either purchased commercially or obtained through metallation of the corresponding halide) with intermediate 2.3 to yield intermediate 2.3 (Scheme 2). Intermediate 2.4 (where M = Li, MgBr, MgCl, or MgI, either purchased commercially or obtained through metallation of the corresponding halide) can be combined with intermediate 2.3 using a suitable palladium catalyst to deliver intermediate 2.5. After conversion to acid intermediate 2.6 using standard conditions (e.g., LiOH, LiI, and pyridine), intermediate 1.3 can be added using standard amide bond-forming conditions (e.g., DIPEA with HATU) to yield intermediate 2.7, which can then be converted to the corresponding benzimidazole intermediate 2.8 under the influence of an acid catalyst (e.g., HCl, AcOH, etc.) or a dehydrating agent (e.g., POCl, TfO / triphenylphosphine oxide, etc.). This intermediate can be converted to a compound of formula (I) using standard ester hydrolysis conditions (eg, LiOH, LiI, and pyridine).

[0148] 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).

[0149] Scheme 3

[0150] [ka]

[0151] In some embodiments, compounds of Formula (I) having the structure of a compound of Formula 2.9 can be assembled by first combining intermediate 3.1 (X31 is Cl, Br, or I) with intermediate 1.3 (R = alkyl, alkylaryl, or aryl) under standard amide bond forming conditions, such as DIPEA with HATU (Scheme 3). Treatment with a suitable acid catalyst (e.g., HCl, AcOH, etc.) or dehydrating agent (e.g., POCl3, Tf2O / triphenylphosphine oxide, etc.) can deliver intermediate 3.3. Halogen metal exchange of -X31 to -M can be achieved using transition metal coupling using a suitable reagent (e.g., iPrMgBr, etc.) or a suitable palladium catalyst and metal source (e.g., B2Pin2, Bu6Sn2, etc.) to give intermediate 2.8, which can be converted to a compound of Formula (I) using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine, etc.).

[0152] Scheme 4

[0153] [ka]

[0154] In some embodiments, compounds of formula 2.9 can be formed by first converting intermediate 2.3 to the metallated variant 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 deliver intermediate 2.8, which can then be converted to compounds of formula (I) using standard ester hydrolysis conditions, such as LiOH, LiI, and pyridine.

[0155] Scheme 5

[0156] [ka]

[0157] Compounds of Formula (IA-1) and / or Formula (I) having the structure of compounds of Formula 5.3 can be assembled via initial coupling of intermediate 5.1 to halogen-X (where X is Cl, Br, or I) using a suitable coupling partner and palladium catalyst to deliver intermediate 5.2, which can be converted to compounds of Formula 5.3 using standard ester hydrolysis conditions such as LiOH, LiI, and pyridine (Scheme 5).

[0158] Scheme 6

[0159] [ka]

[0160] Compounds of formula (I), having the structure of compounds of formula 6.1, can be obtained through reaction of intermediate 2.9 with sulfonamides under suitable coupling conditions (eg, EDCI and DMAP) (Scheme 6).

[0161] Scheme 7

[0162] [ka]

[0163] Compounds of formula (I) having the structure of compounds of formula 7.3 can be assembled via initial coupling of intermediate 7.1 to halogen-X using a suitable coupling partner and palladium catalyst to deliver intermediate 7.2, which can be converted to compounds of formula 7.3 using standard ester hydrolysis conditions such as LiOH, LiI, and pyridine (Scheme 7).

[0164] Scheme 8

[0165] [ka]

[0166] Compounds of formula (I) having the structure of a compound of formula 2.9 can be assembled through initial cross-coupling of intermediate 2.1 with intermediate 3.4 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 give intermediate 2.8. Intermediate 2.8 can be converted to a compound of formula (I) having the structure of a compound of formula 2.9 using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine, etc.).

[0167] Scheme 9

[0168] [ka]

[0169] Compounds of Formula (I) having the structure of compounds of Formula 2.9 can be assembled through an 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 via reduction using H and a suitable catalyst (e.g., Pd / C) to give intermediate 9.2. Intermediate 9.2 can then be reacted with a suitable base (e.g., KCO, CsCO, AgCO, etc.), X to afford intermediate 9.3. 91 can be alkylated using a suitable electrophile represented by intermediate 9.3, which can be -Cl, -Br, I, or -OTs. Intermediate 2.8 can be converted to a compound of formula (I) having the structure of a compound of formula 2.9 using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine).

[0170] Scheme 10

[0171] [ka]

[0172] Compounds of formula (I) having the structure of compounds of formula 10.4 can be assembled by first alkylation of intermediate 9.2 with intermediates of type 10.1 using a suitable base (K2CO3, Cs2CO3, Ag2CO3, etc.), 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=. Intermediate 10.2 is then converted to intermediate 10.3 using a suitable transition metal catalyst (e.g., palladium, etc.). Intermediate 10.3 can be converted to a compound of Formula (I) having the structure of a compound of Formula 10.4 using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine, etc.).

[0173] 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.

[0174] 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.

[0175] Pharmaceutical compositions containing the compounds disclosed herein, or pharmaceutically acceptable salts thereof, can be prepared with 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, can generally be isotonic. In some embodiments, the compositions can 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.

[0176] 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 administering one or more active ingredients (e.g., a compound of the present disclosure, or a pharmaceutical salt thereof) to a patient. The method includes bringing the active ingredient into association with the above pharmaceutically acceptable excipients. The compositions can be prepared by uniformly and intimately bringing the active ingredient into association with liquid excipients, finely divided solid excipients, or both, and then, if necessary, shaping the product. Techniques and formulations can generally be found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0177] 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.

[0178] The 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 may be, for example, inert diluents such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium 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. 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.

[0179] 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.

[0180] 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.

[0181] In some embodiments, the pharmaceutical compositions are for human or animal use.

[0182] 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.

[0183] In one aspect, provided herein is the use of a compound of the present disclosure as a second or other active ingredient in a known drug that has a synergistic effect with that other active ingredient, or the co-administration of a compound of the present disclosure with such a drug.

[0184] 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.

[0185] 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 being 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.

[0186] The compounds of the present disclosure can be administered to an individual according to an effective dosing regimen 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, hi one variation, the compounds are administered on a daily or intermittent schedule for the duration of the individual's life.

[0187] 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.

[0188] 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.

[0189] 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.

[0190] 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 compounds of the present disclosure are about 100 mg per dose, or about 125, 150, 175, 200, 225, 250 mg per dose. , 275, 300, 350, 400, 450, or about 500 mg. 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.

[0191] 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 ill health 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.

[0192] 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.

[0193] 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 are an apoptotic signal-regulating kinase (ASK-1) inhibitor, a farnesoid X receptor (FXR) agonist, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, fish oil, acetyl-coA carboxylase inhibitor, or a combination thereof. Enzyme (acetyl-coA carboxylase, ACC) inhibitor, TGFβ antagonist, LPA R antagonists, SGLT2 inhibitors, Tpl2 inhibitors, or GLP-1 agonists, and combinations thereof.

[0194] The benefit of the combination can be increased efficacy and / or reduced side effects for one component, as the dose of that component can be adjusted downward to reduce its side effects while benefiting from its enhanced efficacy due to the efficacy of the compounds of the present disclosure.

[0195] 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 Stimulators of the dependent deacetylase sirtuin-1, adrenergic receptor antagonists, androgen receptor agonists, amylin receptor agonists, angiotensin II AT-1 receptor antagonists, apical sodium-dependent bile acid transporter inhibitors, autophagy protein modulators, autotaxin inhibitors, Axl tyrosine kinase receptor inhibitors, Bax protein stimulators, beta-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, angiotensin II AT-1 receptor antagonist, CCR3 chemokine antagonist, CCR5 chemokine antagonist, CD3 antagonist, CDGSH iron-sulfur domain protein modulator, chitinase inhibitor, chloride channel stimulator, chitotriosidase 1 inhibitor, CNR1 inhibitor, connective tissue growth factor ligand inhibitor, COT protein kinase inhibitor, cyclin D1 inhibitor, cytochrome P450 7A1 inhibitor, DGAT1 / 2 inhibitor, diacylglycerol O acyltransferase 1 inhibitor (DGAT1), cytochrome P450 2E1 inhibitors (Cytochrome P450 2E1 inhibitors, CYP2E1), CXCR3 chemokine antagonists, CXCR4 chemokine antagonists, dihydroceramide δ4 desaturase inhibitors, dihydroorotate dehydrogenase inhibitors, dipeptidyl peptidase IV inhibitors, endosialin modulators, eotaxin ligand inhibitors, extracellular matrix protein modulators, farnesoid X receptor agonists, fatty acid synthase inhibitors, FGF1 receptor agonists, fibroblast growth factor (FGF) receptor agonists, factor, FGF-15, FGF-19, FGF-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 modulator, HNF4A), hepatocyte growth factor modulator, histone deacetylase inhibitors, STAT-3 modulators, HMG CoA reductase inhibitors, HSD17B13 gene inhibitors, 5-HT2a receptor antagonists, hydrolase inhibitors, hypoxia-inducible factor-2α inhibitors, IL-10 agonists, IL-17 antagonists, IL-22 agonists, ileal sodium bile acid cotransporter inhibitors, insulin sensitizers, insulin ligand agonists, insulin receptor agonists, integrin modulators, integrin antagonists, integrin α-V / β-1 antagonists, integrin α-V / β-6 antagonists, interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors, IL-6 receptor agonists, interleukin-17 ligand inhibitors, Jak2 tyrosine kinase inhibitors, Jun N-terminal kinase-1 inhibitors, Kelch-like ECH-associated protein 1 modulators, ketohexokinase (KHK) inhibitors, Klotho β stimulators, 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 (MMP) inhibitors, 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 deacetylase inhibitors Conjugates, 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 Chewing stimulant, NADPH oxidase inhibitor (NOX ), NFE2L2 gene inhibitors, nicotinic acid receptor 1 agonists, opioid receptor μ antagonists, P2Y13 purinergic receptor stimulators, nuclear erythroid 2-associated factor 2 stimulators, nuclear receptor modulators, nuclear transporter modulators 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-related 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 and combinations thereof.

[0196] 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, CF-502, and 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, 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 such as bupanorsen (IONIS-ANGPTL3-LRx), -Apelin receptor agonists such as CB-5064 and MBT-2, - apical sodium-dependent bile acid transporter 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 namacizumab (nimasimab), 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, such as DMX-200 and DMX-250 AT-1 receptor antagonists, -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 (Diglycer ide acyltransferase 1 (DGAT1) inhibitor, -Diacylglycerol O acyltransferase 1 (DGAT1) / cytochrome P450 2E1 inhibitors, such as SNP-610 (CYP2E1), -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 FT-8225, -Fibroblast growth factor 19 (rhFGF19) / cytochrome P450 (CYP) 7A1 inhibitors, such as aldafermin (NGM-282); - 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 / Klothoβ 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), 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 agonist, -glucagon receptor agonists such as glucagon-like peptide 1 agonists, oxyntomodulin ligands, and efinopegdutide, Gastric inhibitory polypeptide / glucagon-like peptide-1 (GIP), such as tirzepatide (LY-3298176) / GLP-1) receptor co-agonist, -PEGylated long-acting glucagon-like peptide-1 / glucagon, such as DD-01 (GLP-1R / GCGR ) Receptor dual agonist, -glucagon / GLP1 receptor agonists such as BI-456906 and NN-6177, - Glucocorticoid receptor antagonists such as CORT-118335 (milicorilant) Gonist, -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 (ND-L02-s0201) 47, HSP47) inhibitors, -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, - ileal sodium bile acid cotransporter inhibitors such as odebixibat (A-4250), borixibat potassium ethanolate hydrate (SHP-262), GSK2330672, CJ-14199, and elobixibat (A-3309); - 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 oxidases such as simtuzumab and PXS-5382A (PXS-5338) homolog 2 inhibitors, - 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 modulators of transcription factors, 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, - PPAR agonists such as 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, - a xanthine oxidase / urate anion exchanger 1 (URAT1) inhibitor such as RLBN-1001, RLBN-1127, or -Zonulin inhibitors such as lorazotide acetate (INN-202).

[0197] 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, B I-1467335, BMS-986036, BMS-986171, BMT-053011, 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, cobiprost 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-5 09, GKT-831, GNF-5120, GRI-0621, GR-MD-02, GS-300, GS-4997, GS-9674, GS-4875, GS-5290, HEC-96719, HTD-1801, HS-10356, HSG-4112, HST-202, HST-201, HU-6, hydrochlorothiazide, icosabutate (PRC-4016), icosapentaenoic acid ethyl ester, IMM-124-E, INT-767, INV-240, ION-455, IONIS-DGAT2 Rx, 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, obeticholic acid (OCA), 25HC3S, olesoxime, PAT-505 , PAT-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, RPI-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, TE V-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 potassium benzoate 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.

[0198] In some embodiments, the compounds of the present disclosure are selected from the group consisting of peptide YY or an analog thereof, a neuropeptide Y receptor type 2 (NPYR2) agonist, an NPYR1 agonist, an NPYR5 antagonist, a cannabinoid receptor type 1 (CB1R) antagonist, a lipase inhibitor (e.g., orlistat), a human proislet peptide (HIP), a melanocortin-4 receptor (MC4R) agonist (e.g., setomelanotide), a melanin-concentrating hormone receptor 1 antagonist, a farnesoid X receptor (FXR) agonist (e.g., obeticholic acid), an apoptosis signal-regulating kinase (ASK-1) inhibitor, zonisamide, phentermine (alone or in combination with topiramate), a norepinephrine / dopamine reuptake inhibitor (e.g., bupromethazine), a steroid hormone receptor antagonist ... prion), opioid receptor antagonists (e.g., naltrexone), 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 2, MetAP2 inhibitors (e.g., beloranib or ZGN-1061), phen insulin-sensitizing agents such as 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), thiazolidinedione (TZD), etc. agents, peroxisome proliferator-activated receptor alpha (PPARα) agonists, fish oil, acetyl-coA carboxylase (ACC) inhibitors, transforming growth factor beta (TGFβ) antagonists, GDNF family receptor alpha like (GFRAL) agonists, melanocortin- The compounds are combined with one or more therapeutic agents selected from anti-obesity agents, including, but not limited to, melanocortin-4 receptor (MC4R) agonists (including pharmaceutically acceptable salts of the specifically named agents and pharmaceutically acceptable salts of such agents and salts).

[0199] 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.

[0200] 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, decompensated 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 a cardiometabolic disease.

[0201] GLP-1R agonists are currently being investigated in relation to certain disorders and conditions, including, for example, 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 subjects with NASH.

[0202] 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 type I and type II diabetes, chronic fatty and fibrotic degeneration of organs due to forced lipid and specifically triglyceride accumulation and subsequent activation of pro-fibrotic pathways. conditions and diseases arising from obesity and metabolic syndrome (a combined condition of dyslipidemia, diabetes and an abnormally high body mass index), acute myocardial infarction, acute stroke, thrombosis occurring as an end point of chronic obstructive atherosclerosis, persistent infection with intracellular bacteria or protozoan parasites, non-malignant hyperproliferative disorders such as colon adenocarcinoma and hepatocellular carcinoma, fatty liver and related syndromes, liver failure or dysfunction as a result of chronic liver disease or surgical liver resection, hepatitis B infection, hepatitis C infection and / or alcohol-induced cirrhosis or Cholestatic and fibrotic effects associated with virally mediated forms of hepatitis, type 1 diabetes, prediabetes, idiopathic type 1 diabetes, latent autoimmune diabetes, adult-onset diabetes, early-onset diabetes of the young, 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 deposition, obesity, eating disorders, sleep apnea, weight gain, sugar craving, dyslipidemia, hyperinsulinemia, congestive heart failure, myocardial Provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof, or use thereof for the treatment and / or prevention of infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, 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.

[0203] 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.

[0204] 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.

[0205] 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 an abnormally high body mass index), which can be overcome by GLP-1R-mediated lowering of serum triglycerides, blood glucose, and increased insulin sensitivity, as well as GLP-1R-mediated weight loss. In some embodiments, the method for treating and / or preventing a metabolic disease comprises administering to a subject in need thereof a compound of Formula (I). In some embodiments, the method for treating and / or preventing a metabolic disease comprises administering to a subject in need thereof a compound of Formula (I).

[0206] 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.

[0207] 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, methods 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 comprise 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 comprise 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 comprise administering a compound of Formula (I) to a subject in need of such treatment and / or prevention.

[0208] 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.

[0209] 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.

[0210] 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. [Example]

[0211] Many general references are available that provide generally known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds (e.g., Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7 th edition, Wiley-Interscience, 2013).

[0212] 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.

[0213] 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.

[0214] Exemplary chemicals useful in the methods of the embodiments will now be described by reference to exemplary synthetic schemes for their general preparation herein and the specific examples below. To obtain the various compounds herein, the skilled artisan will recognize that starting materials can be suitably selected to yield the desired product such that the ultimately desired substituent is carried through the reaction scheme, 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 scheme 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 temperatures from about 0° C. to the reflux temperature of the organic solvent used.

[0215] 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.

[0216] 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.

[0217] In some embodiments, the present disclosure generally provides a particular enantiomer or diastereomer as the desired product, although 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 has not been determined, the compound is depicted without showing the stereochemistry at that particular stereocenter, even though the compound may be substantially enantiomerically or diastereomerically pure.

[0218] Representative syntheses of compounds of the present disclosure are described in the schemes below and in the examples below.

[0219] 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.

[0220] 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.

[0221] [Table 1-1]

[0222] [Table 1-2]

[0223] A. Synthesis of Intermediates Preparation of intermediate I-1:

[0224] [ka]

[0225] Methyl 4-amino-3-(2-methoxyethylamino)benzoate (I-1): To a solution of methyl 3-fluoro-4-nitrobenzoate (50.0 g, 251 mmol) in THF (400 mL) was added diisopropylethylamine (70.0 mL, 402 mmol) and 2 3-Methoxyethylamine (34.9 mL, 402 mmol) was added. The resulting solution was heated to 55° C. for 6 hours. 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 EtOAc:EtOH (1:1, 140 mL), after which 10% palladium on carbon (5.02 g, 4.72 mmol) was then added. The resulting suspension was stirred at room temperature under a hydrogen balloon for 16 hours. The 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 + ).

[0226] Preparation of intermediate I-2:

[0227] [ka]

[0228] 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 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 + ).

[0229] 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 mixture was heated to 60 °C for 2 h. The 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 (2x). 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 + ).

[0230] Preparation of intermediate I-3:

[0231] [ka]

[0232] 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 mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc (100 mL) and HCl (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).

[0233] Preparation of intermediate I-4:

[0234] [ka]

[0235] Methyl (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoate (I-4): Methyl (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoate was prepared according to the procedure of Intermediate I-1, substituting 2-methoxyethylamine for (S)-oxetan-2-ylmethanamine. ES / MS: 237.2 (M+H + ).

[0236] Intermediate I-5

[0237] [ka]

[0238] 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 was added. 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 MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc / hexane gradient) to give the product.

[0239] (S)-3-Fluoro-4-nitro-5-((oxetan-2-ylmethyl)amino)ethyl 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 + ).

[0240] 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 % supported, 785 mg, 0.74 mmol) was then added, and the sparging was continued for 5 minutes. The reaction mixture was stirred for 1 minute. Hydrogen was then bubbled through the solution for 1 minute, and the mixture was then placed under a balloon hydrogen atmosphere for 21 hours. Following this time, the reaction was stopped and the mixture was filtered through Celite. The filter was washed with EtOAc (2×20 mL) and methanol (2×10 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 (400MHz, chloroform) δ7.44-7.30(m,2H),5.13(qd,J=7.1,3.4Hz,1H),4.72(ddd,J=8.7,7.4,6.0Hz,1H),4.62(dt,J=9.1,6.1Hz,1H),4 .33(q,J=7.1Hz,2H),3.58-3.30(m,2H),2.76(dtd,J=11.4,8.0,6.1Hz,1H),2.56(ddt,J=11.3,9.0,7.1Hz,1H),1.37(t,J=7.1Hz,3H).

[0241] Preparation of intermediate I-6:

[0242] [ka]

[0243] 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. Then, The mixture was 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 (400MHz, chloroform-d) δ8.21(d,J=8.9Hz,1H),7.55(d,J=1.7Hz,1H),7.20(dd,J=8.9,1 .7Hz,1H),3.72(dd,J=5.8,4.8Hz,2H),3.57(q,J=5.2Hz,2H),3.46(s,3H),1.62(s,9H).

[0244] 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-benzoate (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 + ).

[0245] Preparation of intermediate I-7:

[0246] [ka]

[0247] 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 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 + ).

[0248] 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorophenyl)acetic acid (I-7). Methyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorophenyl)acetate (12.5 g, 30.3 mmol) and hydroxide in CHCN (50 mL). A solution of lithium (0.2 M, 19.7 mL, 39.4 mmol) was heated at 50° C. for 2 hours. 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 + ); 1 H NMR (400MHz, methanol-d4) δ7.83-7.77(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=8.2Hz,1H),5.63(s,2H),3.73(d,J=1.2Hz,2H).

[0249] Preparation of intermediate I-8:

[0250] [ka]

[0251] (S)-2-(4-Bromo-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (I-8): (S)-2-(4-Bromo-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate was prepared according to the procedure of intermediate I-2, substituting I-4 for I-1 and 2-(4-bromo-2,5-difluorophenyl)acetic acid for 2-(4-bromo-2-fluoro-phenyl)acetic acid. ES / MS: 451.0, 453.0 (M+H + ).

[0252] Preparation of Intermediate I-9:

[0253] [ka]

[0254] (S)-2-(4-(6-(Benzyloxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate: (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 minutes. The mixture was then heated to 110°C for 1 hour. 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 minutes, then 2-(benzyloxy)-6-bromopyridine (290 mg, 1.10 mmol) and 1,2-dimethyl-2,4-dibromopyridine (2.0 M, 0.997 mL, 1.99 mmol) were added. 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 / CH Cl gradient) to give the desired product. ES / MS: 556.2 (M+H). + )

[0255] (S)-2-(2,5-Difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (I-9): (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 mixture 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 (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). + ) Preparation of intermediate I-10:

[0256] [ka]

[0257] 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): A vial was charged with 200 mg of 2-[(4-bromo-2-fluoro-phenyl)methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (I-2) (0.475 mg). To the reaction mixture was added 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). 1,4-Dioxane (4.80 mL) was then added, and the mixture was heated to 100 °C for 24 h. The 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). + )

[0258] Preparation of intermediate I-11:

[0259] [ka]

[0260] 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): 2-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-(2-methoxyethyl)-1H- tert-Butyl benzo[d]imidazole-6-carboxylate was prepared in the manner described for intermediate I-10, substituting 2-(4-bromo-2,5-difluorophenyl)acetic acid for 2-(4-bromo-2-fluorophenyl)acetic acid and tert-butyl 4-amino-3-((2-methoxyethyl)amino)benzoate (I-6) for methyl 4-amino-3-(2-methoxyethylamino)benzoate. ES / MS: 529.3 (M+H + ); 1 H NMR (400 MHz, DMSO-d 6 )δ8.13(s,1H),7.74(dd,J=8.4,1.6Hz,1H),7.56(d,J=8.4Hz,1H),7.33(dd,J=9.3,4.6Hz,1H),7.17(dd,J=9.1 ,5.5Hz,1H),4.54(t,J=5.1Hz,2H),4.39(s,2H),3.65(t,J=5.1Hz,2H),3.20(s,3H),1.57(s,9H),1.31(s,12H).

[0261] Preparation of intermediate I-12:

[0262] [ka]

[0263] 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 2-[[4-(6-chloropyridine)-2-(4-methyl-2-propanol]-2-yl]propanol]. tert-Butyl 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 )δ8.14(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).

[0264] Preparation of intermediate I-13:

[0265] [ka]

[0266] (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 warmed 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 followed by 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 provide (S)-4-(2-(4-bromo-2-fluorophenyl)acetamido)-3-fluoro-5-((oxetan-2-ylmethyl)amino)ethyl benzoate. ES / MS: 483.0, 485.0 [M+H] + .

[0267] (S)-2-(4-Bromo-2-fluorobenzyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (I-13): To a solution of (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. Purification by chromatography (eluent: EtOAc / hexane) gave (S)-ethyl 2-(4-bromo-2-fluorobenzyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (I-13). ES / MS: 465.0, 467.0 [M+H] + .

[0268] Preparation of intermediate I-14:

[0269] [ka]

[0270] (S)-2-(4-bromo-2,5-difluorobenzyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (1-14): (S)-2-(4-bromo-2,5-difluorobenzyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate was prepared in the manner described for intermediate 1-13, substituting 2-(4-bromo-2,5-difluorophenyl)acetic acid for 2-(4-bromo-2-fluorophenyl)acetic acid. ES / MS: 483.0, 485.0 (M+H + ).

[0271] Preparation of intermediate I-15:

[0272] [ka]

[0273] (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): (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 + ).

[0274] Preparation of intermediate I-16:

[0275] [ka]

[0276] (S)-2-(4-(6-chloropyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (I-16): (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 + ).

[0277] Preparation of intermediate 17:

[0278] [ka]

[0279] tert-Butyl 2-(2,5-difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (I-17): tert-Butyl 2-(2,5-difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate was reacted with 2-(4-bromo-2,5- tert-Butyl (difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (prepared in the manner 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 + ).

[0280] Preparation of intermediate I-18:

[0281] [ka]

[0282] 2-(4-(6-((4-bromo-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d 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-fluorobenzene (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 provide 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): ES / MS: 683.2, 684.1 (M+H + ).

[0283] Preparation of intermediate I-19:

[0284] [ka]

[0285] (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): (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 + ).

[0286] Preparation of intermediate I-20:

[0287] [ka]

[0288] (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): (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-17 for I-15. ES / MS: 684.2 (M+H + ).

[0289] Preparation of intermediate I-21:

[0290] [ka]

[0291] (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 (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 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 provide (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). + ).

[0292] Preparation of intermediate I-22:

[0293] [ka]

[0294] (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): (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-17 for I-15. ES / MS: 673.0 (M+H + ).

[0295] Preparation of intermediate I-23:

[0296] [ka]

[0297] (S)-2-(4-(6-((6-cyano-4-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (I-23): (S)-2-(4-(6-((6-cyano-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, substituting 5-(bromomethyl)-2-chloro-4-fluoropyridine for 4-bromo-1-(bromomethyl)-2-fluoro-benzene. ES / MS: 609.2 (M+H). + ).

[0298] Preparation of intermediate I-24:

[0299] [ka]

[0300] (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): (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, substituting 4-bromo-1-(bromomethyl)-2-fluoro-benzene for 2-bromo-5-(bromomethyl)-4-chloropyridine. ES / MS: 654.0, 656.0 (M+H). + ).

[0301] Preparation of Intermediate I-25:

[0302] [ka]

[0303] 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 in the manner described for intermediate I-1, substituting (±)-4,4-dimethyltetrahydrofuran-3-amine for 2-methoxyethylamine, as follows: 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) under argon, DIPEA (17.2 mL, 98.9 mmol) was added. 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 extracted with additional EtOAc. The combined organic phase was washed with brine and evaporated over MgSO4 The mixture was dried at 77°C, 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 + ).

[0304] Preparation of intermediate I-26:

[0305] [ka]

[0306] tert-Butyl (R)-4-amino-3-((2-methoxypropyl)amino)benzoate (I-26): tert-Butyl (R)-4-amino-3-((2-methoxypropyl)amino)benzoate was prepared in the manner described for intermediate I-6, substituting 2-methoxyethylamine for (R)-2-methoxypropan-1-amine. ES / MS: 281.1 (M+H + ).

[0307] Preparation of intermediate I-27:

[0308] [ka]

[0309] 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 hours. Upon completion, the mixture was filtered through Celite, concentrated, and purified by silica gel column chromatography (eluent: EtOAc / hexanes) to provide the desired product. ES / MS: 325.2 (M+H + ).

[0310] 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 mixture was diluted with EtOAc (200 mL) and the layers separated. The organic layer was washed with brine, dried over MgSO4, filtered, concentrated and used without further purification to give 5-(((6-bromopyridin-2-yl)oxy)methyl)picolinate (I-28). )Oxy)methyl)picolinic acid (I-27) was obtained. ES / MS: 309.1 (M+H + ).

[0311] Preparation of intermediate I-28:

[0312] [ka]

[0313] 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 mixture was 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). + ).

[0314] The following intermediates were synthesized in a manner similar to that described for intermediate I-28:

[0315] [ka]

[0316] Preparation of Intermediates I-29 and I-30:

[0317] [ka]

[0318] 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 extracted 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 + ).

[0319] 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 by cycling the mixture between argon and vacuum three times. 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 balloon of hydrogen. The mixture was filtered over a plug of Celite and rinsed with EtOAc. Concentration and purification by flash chromatography (eluent: 30-40% EtOAc / hexanes) afforded two distinct isomers of tert-butyl 4-amino-3-(((3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl)amino)benzoate (I-29 and I-

[0320] Isoform 1 (low polarity, first elution), I-29 ES / MS: 321.0 (M+H + ). 1H NMR(400MHz, クロロホルム-d)δ7.45(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),4.32-4.0 6(m,2H),4.05-3.81(m,2H),3.66(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).

[0321] Isoform 2 (high polarity, second elution), I-30 ES / MS: 321.0 (M+H + ). 1H NMR (400MHz, クロロホルム-d)δ7.45(dd,J=8.1,1.8Hz,1H),7.38(d,J=1.8H z,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,2 H),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).

[0322] Preparation of intermediate I-31:

[0323]

change

[0324] (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 mixture was washed with saturated NaHCO (aq. 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. ES / MS

[0325] The following intermediates were prepared in the manner described for intermediate I-31.

[0326] [ka]

[0327] Preparation of intermediate I-32:

[0328] [ka]

[0329] (5-Chloropyrazin-2-yl)methyl 4-methylbenzenesulfonate (I-32): (5-Chloropyrazin-2-yl)methyl 4-methylbenzenesulfonate was prepared in the manner described for intermediate I-31, substituting (5-bromo-3-fluoro-2-pyridyl)methanol for (5-chloropyrazin-2-yl)methanol.

[0330] Preparation of intermediate I-33:

[0331] [ka]

[0332] 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 was added CsCO (400 mg, 1.20 mmol). The solution was then heated to 50 °C for 30 min. The solution was cooled to room temperature, filtered, and then concentrated. The crude material was purified by silica gel column chromatography (eluent: EtOAc / hexane) to provide 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 + ).

[0333] Preparation of intermediate I-34:

[0334] [ka]

[0335] 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): tert-Butyl 2-[[4-[6-[(5-chloropyrazin-2-yl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate was prepared in the manner described for intermediate I-33, substituting I-32 for I-31. ES / MS: 566.0 (M+H + ).

[0336] Preparation of intermediate I-35:

[0337] [ka]

[0338] 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) in DMF (10 mL). 34 ) (300 mg, 0.26 mmol) was degassed by bubbling argon for 1 minute, sealed, and heated to 100 °C for 20 h. Upon completion, the mixture was 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].

[0339]

[0047] 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 at room temperature for 30 min. 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].

[0340] Preparation of intermediate I-36:

[0341] [ka]

[0342] [5-(Difluoromethyl)thiazol-2-yl]methanol: To a solution of [5-(difluoromethyl)thiazol-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 diluted with 2M The reaction mixture was quenched with 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].

[0343] 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].

[0344] Preparation of intermediate I-37:

[0345] [ka]

[0346] [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.

[0347] 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 at room temperature for 30 minutes. Upon completion, the mixture was concentrated and purified by flash chromatography (eluent: EtOAc / hexanes) to give I-37. ES / MS: 258.2 [M+1].

[0348] Preparation of intermediate I-38:

[0349] [ka]

[0350] 2-(Bromomethyl)-5-(2,2,2-trifluoroethoxy)thiazole (1-38): 2-(Bromomethyl)-5-(2,2,2-trifluoroethoxy)thiazole was prepared in the manner described for intermediate 1-37, substituting 2,2-difluoroethyl trifluoromethanesulfonate for 2,2,2-trifluoroethyl trifluoromethanesulfonate. ES / MS: 277.2 [M+1].

[0351] Preparation of intermediate I-39:

[0352] [ka]

[0353] (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): (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, substituting 5-(bromomethyl)-2-chloro-4-fluoropyridine for 2-bromo-5-(bromomethyl)thiophene. ES / MS: 642.0 (M+H). + ).

[0354] Preparation of intermediate I-40:

[0355] [ka]

[0356] (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): (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, substituting 5-(bromomethyl)-2-chloro-4-fluoropyridine for 5-bromo-2-(bromomethyl)-3-fluorothiophene. ES / MS: 660.0 (M+H). + ).

[0357] Preparation of intermediate I-41:

[0358] [ka]

[0359] 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): 2-[[4-[6-[(5-bromo-1,3,4-thiadiazol-2-yl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[[(2S) Methyl-oxetan-2-yl]methyl]benzimidazole-5-carboxylate was prepared in the manner described for intermediate I-19, substituting 5-(bromomethyl)-2-chloro-4-fluoropyridine for 2-bromo-5-(bromomethyl)-1,3,4-thiadiazole. ES / MS: 660.0 (M+H + ).

[0360] Preparation of intermediate I-42:

[0361] [ka]

[0362] 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].

[0363] 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), trimethylamine (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].

[0364] Preparation of intermediate I-43:

[0365] [ka]

[0366] 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 with 1-12% DCM / MeOH. Product-containing fractions were combined and concentrated to give the title product. ES / MS m / z: 268.0, 270.2 (M+H). + ).

[0367] The following intermediates were synthesized in the manner described for intermediate I-43.

[0368] [ka]

[0369] Preparation of intermediate I-44:

[0370] [ka]

[0371] 2-Bromo-6-[[1-(difluoromethyl)-2-methyl-imidazol-4-yl]methoxy]pyridine (I-44): This intermediate was prepared in the manner described for intermediate I-43, substituting [1-(difluoromethyl)-2-methyl-imidazol-4-yl]methanol for (1-methylimidazol-4-yl)methanol. ES / MS m / z: 318.2 (M+H + ).

[0372] Preparation of intermediate I-45:

[0373] [ka]

[0374] Methyl 2-[(7-bromo-1,3-dihydroisobenzofuran-4-yl)methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (1-45): This intermediate was prepared in the manner described for intermediate 1-13, substituting 2-(4-bromo-2-fluorophenyl)acetic acid for 2-(7-bromo-1,3-dihydroisobenzofuran-4-yl)acetic acid. ES / MS m / z: 447.1 (M+H + ).

[0375] Preparation of intermediate I-46:

[0376] [ka]

[0377] tert-Butyl (3R,4R)-3-(2-amino-5-methoxycarbonyl-anilino)-4-fluoro-pyrrolidine-1-carboxylate (I-46): This intermediate was prepared in the manner described for intermediate I-6, substituting tert-butyl (3R,4R)-3-amino-4-fluoro-pyrrolidine-1-carboxylate for 2-methoxyethanamine. ES / MS m / z: 418.4 (M+Na + ).

[0378] Preparation of intermediate I-47:

[0379] [ka]

[0380] 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-butyl tert-butoxycarbonylcarbonate (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+).

[0381] tert-Butyl N-tert-butoxycarbonyl-N-[6-chloro-2-[(4-cyano-2-fluoro-phenyl)methoxy]pyrimidin-4-yl]carbamate (I-47): 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) in 5 mL of DCM. A solution of 1,3-dichloro-2,4-dichloro-1,4 ...

[0382] Preparation of intermediate I-48:

[0383] [ka]

[0384] 2-[(2,6-Dichloro-4-pyridyl)oxymethoxy]ethyl-trimethyl-silane: 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 10 mL of THF, lithium bis(trimethylsilyl)amide (6.4 mL, 6.4 mmol) was 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+).

[0385] 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-trimethyl-silane (1.0 g, 3.4 mmol) dissolved in 5 mL of DMF, 3-fluoro-4-(hydroxymethyl)benzonitrile (0.77 g, 5.1 mmol) and potassium carbonate (0.94 g, 6.8 mmol) were added. 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, tetrabutylammonium fluoride (4.0 mL, 4 mmol) was added. 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+).

[0386] Preparation of intermediate I-49:

[0387] [ka]

[0388] 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) dissolved in 10 mL of DMF was added 3-fluoro-4-(hydroxymethyl)benzonitrile (708 mg, 4.68 mmol) and potassium carbonate (971 mg, 7 mmol). This 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+).

[0389] Preparation of intermediate I-50:

[0390] [ka]

[0391] 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 heated to 60 °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 sequentially added a solution of sodium ascorbate (0.19 mmol, 38 mg) in water (2.5 mL) and copper sulfate pentahydrate (0.19 mmol, 48 mg) in HO (2.5 mL). The 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+).

[0392] [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, then 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+).

[0393] Preparation of intermediate I-51:

[0394] [ka]

[0395] 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 to reflux for 8 hours. Following this time, the solution 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. 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+).

[0396] [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 (Hexane). Purification by elution with hexane (0-100% EtOAc in hexane) gave I-51: ES / MS m / z: 371.1 (M+H+).

[0397] Preparation of intermediate I-52:

[0398] [ka]

[0399] [2-Fluoro-4-(2-trimethylsilylethynyl)phenyl]methyl 4-methylbenzenesulfonate: (2-Fluoro-4-iodo-phenyl)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 trimethylamine (3.3 mL, 23.8 mmol) were suspended in THF (15 mL). The mixture was degassed with nitrogen and stirred at room temperature for 16 hours. Following this, 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 in vacuo. 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 monitored via 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+).

[0400] 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 5 mL of DMF and stirred for 3 h. Following this time, 50 mL of water was added to the solution and the aqueous phase was extracted 2× with EtOAc. The combined organic phases were 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 To the solution was added I-52. 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+).

[0401] Preparation of intermediate I-53:

[0402] [ka]

[0403] 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. Following this time, the mixture was 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 / hexanes) to provide the title compound.

[0404] 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 + ).

[0405] 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 filtered over a Celite frit with brine. The mixture was partitioned, and the organic phase was washed once more with brine. The resulting crude was dried over sodium sulfate, concentrated, and purified by flash chromatography (eluent: EtOAc / hexanes) to give I-53. ES / MS: 403, 405 (M+H + ).

[0406] Preparation of intermediate I-54:

[0407] [ka]

[0408] 3-(Bromomethyl)-1-cyclopropyl-pyrazole (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 + ).

[0409] The following intermediates were prepared in the manner described for intermediate I-54.

[0410] [ka] Preparation of intermediate I-55:

[0411] [ka]

[0412] [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 h. Following this time, the mixture was diluted with 5 mL of EtO and cooled to 0° C. Then, 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 min. Following this time, MgSO was added and the solution was stirred for an additional 15 min and then filtered to give the title product, which was carried on to the next step without further purification. ES / MS: 155.2 (M+H) + ).

[0413] 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 + ).

[0414] Preparation of intermediate I-56:

[0415] [ka]

[0416] Methyl 1-(4-pyridyl)pyrazole-3-carboxylate: In a 40 mL glass vial, a mixture of 1H-methyl 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. Following 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 + ).

[0417] [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. Following 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, followed by the addition of MgSO. 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 + ).

[0418] Preparation of intermediate I-57:

[0419] [ka]

[0420] [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. Following this time, the solution was diluted with EtO and cooled to 0° C. Upon completion of 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 then warmed to room temperature and stirred for an additional 15 minutes. After an additional 15 minutes, MgSO was added, and the solution was stirred for an additional 15 minutes and then filtered to give the title product, which was carried on to the next step without further purification. ES / MS: 167.2 (M+H) + ).

[0421] 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 + ).

[0422] Preparation of intermediate I-58:

[0423] [ka]

[0424] 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 was added thionyl chloride (0.125 mL, 1.69 mmol). The resulting solution was gradually warmed to room temperature and stirred overnight. Following this time, additional thionyl chloride (0.125 mL, 1.69 mmol) was added and stirred for 9 h. At the completion of this time, the mixture was concentrated and purified by flash chromatography (eluent: EtOAc / hexanes) to provide the title compound. 1H NMR (400 MHz, chloroform-d) δ 8.01 (s, 1H), 4.01 (s, 3H).

[0425] [3-(trifluoromethyl)isothiazol-5-yl]methanol:THF at 0°C To a solution of methyl 3-(trifluoromethyl)isothiazole-5-carboxylate (136 mg, 0.644 mmol) in hexane (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 period, the mixture was diluted with 5 mL of EtO and cooled to 0 °C. After cooling the mixture, 0.064 mL of water, 0.064 mL of 15% NaOH, and 0.161 mL of water were added, and the solution was warmed to room temperature and stirred for 15 min. Following this period, MgSO was added, and the solution was stirred for an additional 15 min and then filtered. The crude product was purified by flash chromatography (eluent: EtOAc / hexane) to provide the title compound. ES / MS: 184.2 (M+H + ).

[0426] 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 / hexanes) 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).

[0427] Preparation of intermediate I-59:

[0428] [ka]

[0429] 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. Following 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) δ8.22(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).

[0430] Methyl 4-amino-3-(spiro[2.2]pentan-2-ylamino)benzoate (I-59): 4-nitro-3-(spiro[2.2]pentane-2-ylamino)benzoate in 8 mL of EtOAc A solution of methyl (-ylamino)benzoate (101 mg, 0.4385 mmol) was degassed by cycling the mixture between argon and vacuum three times. To the mixture was added platinum (1%), vanadium (2%) on carbon (50-70% wet), and I-59 was carried on to the next step without further purification. ES / MS: 233.2 (M+H). + );

[0431] Preparation of Intermediates I-60 and I-61:

[0432] [ka]

[0433] 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. Following this period, 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. At the completion of this period, 500 mg of 6-bromopyridin-2-ol was added, and heating was resumed for 2 hours. Following this period, the mixture was diluted with EtOAc and brine. The mixture was filtered over a plug of Celite. The 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 + ).

[0434] 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. Following this time, the solution was diluted with DCM, washed with saturated sodium bicarbonate solution, dried over sodium sulfate, concentrated, and carried on to the next step without further purification. ES / MS: 254, 256 (M+H). + ).

[0435] 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. Following this period, 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.

[0436] 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).

[0437] 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) δ7.57(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).

[0438] Preparation of intermediate I-62:

[0439] [ka]

[0440] Ethyl 1-(1-methylpyrazol-4-yl)pyrazole-3-carboxylate: In a 40 mL glass 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. Following 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 + ).

[0441] [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 resulting solution was stirred for 1 hour while gradually warming to room temperature. Following this period, the solution was diluted with EtO and cooled to 0° C. Upon completion of 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 then warmed to room temperature. After warming, the solution was stirred for 15 minutes, followed by the addition of MgSO4. The solution was stirred for an additional 15 minutes and then filtered. The filtrate was concentrated and purified by flash chromatography (eluent: EtOAc / hexanes) to give the title compound. ES / MS: 179.2 (M+H + ).

[0442] 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 was added carbon tetrabromide (303 mg, 0.914 mmol). 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-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).

[0443] The following intermediates were prepared in the manner described for intermediate I-62.

[0444] [ka]

[0445] Preparation of intermediate I-63:

[0446] [ka]

[0447] 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. Following this time, 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).

[0448] The following intermediates were prepared in the manner described for intermediate I-63.

[0449] [ka]

[0450] Preparation of intermediate I-64:

[0451] [ka]

[0452] 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) at room temperature was added CBr (7.2 g, 21 mmol, 2.0 equiv) and triphenylphosphine (5.7 g, 21 mmol, 2.0 equiv). The mixture was stirred for an additional 16 h. Upon completion, the 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).

[0453] The following intermediates were prepared in the manner described for intermediate I-64.

[0454] [ka]

[0455] Preparation of intermediate I-65:

[0456] [ka]

[0457] (5,5-Difluoro-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)methanol (I-65): 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 minutes. Then, a 1 M solution of borane (3.4 mL) was added dropwise at 0 °C over a period of 30 minutes. The ice bath was removed and stirring was continued at room temperature for 7 hours. Following this time, the mixture was cooled in an ice bath and treated with 3 M HCl (5 mL). The solution was heated at 50 °C for 1 hour. At the completion of this time, the solution was washed with EtOAc (2x), 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 (NaSO), and concentrated in vacuo. to give (5,5-difluoro-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)methanol (I-65).

[0458] Preparation of Intermediate I-66:

[0459] [ka]

[0460] 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 in the manner described for intermediate I-21 to provide I-66. ES / MS: 637.4 (M+H+).

[0461] Preparation of intermediate I-67:

[0462] [ka]

[0463] 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 in the manner described for intermediate I-21 to provide I-67. ES / MS: 593 (M+H+).

[0464] Preparation of intermediate I-68:

[0465] [ka]

[0466] 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). Next, 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 x 10 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: 374.2 (M+H+).

[0467] 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. Following this time, 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).

[0468] Preparation of intermediate I-69:

[0469] [ka]

[0470] 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 solution of I-68 (200 mg, 0.58 mmol) and I-7 (180 mg, 0.45 mmol) in MeCN (5 mL) cooled to 0 °C, 1-methylimidazole (239 mg, 0.23 mL, 2.9 mmol) was added, followed by N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (204 mg, 0.73 mmol). The mixture was allowed to warm to room temperature and stirred for 30 min. Upon completion of the 30 min reaction, 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 provide the desired product. ES / MS: 724.4 [M+H]+.

[0471] 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 provide I-69. ES / MS: 706.5 [M+H] + .

[0472] Preparation of intermediate I-70:

[0473] [ka]

[0474] Methyl 2-(5-bromo-3-fluoropyridin-2-yl)acetate: tert-Butylmethyl malonate was added dropwise to a suspension of NaH (60% in mineral oil, 1.3 g, 34 mmol) in DMF (20 mL) 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. Following this period, 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 of this period, the mixture was concentrated and purified by flash chromatography (EtOAc / hexanes) to give the title product: ES / MS: 248.2 (M+H + ).

[0475] 5-Bromo-3-fluoro-2-(2-methoxy-2-oxoethyl)pyridine 1-oxide: MCPBA (3.51 g, 16 mmol) was added to a solution of methyl 2-(5-bromo-3-fluoropyridin-2-yl)acetate (2.68 g, 11 mmol) in DCM (30 mL) at 0° C., and 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 + ).

[0476] Methyl 2-(6-amino-5-bromo-3-fluoropyridin-2-yl)acetate: p-Toluenesulfonic anhydride (1.5 g) was added 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) over 1.5 hours. The resulting solution was stirred at room temperature for 2 hours. Following this time, an additional amount of p-toluenesulfonic anhydride (1.3 g) was added and stirred for 1 hour. After 1 hour, a further 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, 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 + ). 1H 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).

[0477] 2-(6-Amino-5-bromo-3-fluoropyridin-2-yl)acetic acid: The title intermediate was prepared in the manner described for intermediate I-7 (step 2), substituting methyl 2-(6-amino-5-bromo-3-fluoropyridin-2-yl)acetate for methyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorophenyl)acetate.

[0478] 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 1-2, 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) δ8.07(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).

[0479] 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): I-70 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 and tert-butyl 2-((6-amino-5-bromo-3-fluoropyridin-2-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate instead of methyl 2-(4-bromo-2,5-difluorophenyl)acetate. ES / MS: 627.5 (M+H + ).

[0480] Preparation of intermediate I-71:

[0481] [ka]

[0482] 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 + ).

[0483] Preparation of intermediate I-72:

[0484] [ka]

[0485] Methyl 4-amino-3-iodo-5-((2-methoxyethyl)amino)benzoate: The title compound was prepared in the manner 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-nitrobenzoate (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, concentrated, and carried forward crude.

[0486] 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 the manner described for intermediate I-13 using methyl 4-amino-3-iodo-5-((2-methoxyethyl)amino)benzoate and intermediate I-7.

[0487] 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 glass vial, 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) were dissolved in THF / water (2:1, 3 mL). The solution of I) was heated at 70°C until completion (15 min). After completion of the mixture, trifluoroacetic anhydride (0.3 mL) was added and the solution was directly purified by RP-HPLC (eluent: MeCN / HO) to give I-72. ES / MS: 699.1.

[0488] Preparation of intermediate I-73:

[0489] [ka]

[0490] (R)-tert-Butyl 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): (R)-tert-Butyl 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 + ).

[0491] Preparation of intermediate I-74:

[0492] [ka]

[0493] (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. Following this time, NaBH4 (145 mg, 3.84 mmol) was added portionwise, 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 provide the desired product. ES / MS: 169.1 (M+H + ).

[0494] 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 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 was obtained. ES / MS: 326.1 (M+H + ).

[0495] Preparation of intermediate I-75:

[0496] [ka]

[0497] 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-96 for I-2. ES / MS: 623.3 (M+H + ).

[0498] Preparation of intermediate I-76:

[0499] [ka]

[0500] 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 + ).

[0501] Preparation of intermediate I-77:

[0502] [ka]

[0503] 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) was added cesium carbonate (482 mg, 1.5 mmol) and tert-butyl 3-(bromomethyl)pyrazole-1-carboxylate (378 mg, 1.4 mmol), and the mixture was then heated to 65° C. for 30 minutes. Upon completion, the mixture was filtered through Celite, concentrated, and purified by silica gel column chromatography (eluent: EtOAc / hexane) to provide 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 hours. Upon completion, the mixture was diluted with EtOAc (25 mL), washed with saturated aqueous NaHCO until gas evolution ceased, dried over MgSO, filtered, and concentrated to give I-77, which was used without further purification. ES / MS: 254.2, 256.2 (M+H+ ).

[0504] Preparation of intermediate I-78:

[0505] [ka]

[0506] (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 (1-78): (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 in the manner described for intermediate 1-21, substituting 5-bromo-3-(bromomethyl)-1-methyl-1H-pyrazole for 5-bromo-2-(bromomethyl)thiazole. ES / MS: 638.0, 640.0 (M+H + ).

[0507] Preparation of intermediate I-79:

[0508] [ka]

[0509] 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 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 / hexane) to provide the desired product. The thus obtained 5-(cyanomethyl)- Methyl 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 mixture was allowed to warm to room temperature and stirred for 6 h, at which point additional 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 MgSO4, filtered, concentrated, and purified by silica gel column chromatography (eluent: EtOAc / hexanes) to provide the desired product.

[0510] 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 mixture was allowed to stir 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 provide I-79. ES / MS: 214.0, 216.0 (M+H + ).

[0511] Preparation of Intermediates I-80 and I-81 (Method 1):

[0512] [ka]

[0513] 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 with EtOH co-solvent) to give two distinct stereoisomers.

[0514] (S)-4-amino-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)benzoate, isomer 1 (I-80): Isolated by chiral SFC (4.6 × 100 mm 5 μm IB column, 10% EtOH in CO) as the earlier eluting of the two isomers. ES / MS: 265.2 (M+H + ).

[0515] 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 + ).

[0516] 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-nitrobenzoate (Intermediate I-100, 17.8 g, 60.5 mmol) in EtOAc (380 mL) was heated under argon The mixture was degassed three times under vacuum, then evacuated three times. Palladium on carbon (10.0%, 6.07 g, 5.70 mmol) was added. The mixture was degassed three times under argon, then vacuum, and stirred at room temperature under a hydrogen atmosphere until complete. The suspension was filtered over 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) δ7.49(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).

[0517] Preparation of Intermediates I-82 and I-83 (Method 1):

[0518] [ka]

[0519] 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 in the manner described for intermediate I-8, substituting I-80 (for intermediate I-82) and I-81 (for intermediate I-83) for I-4.

[0520] (S)-2-(4-bromo-2,5-difluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylate methyl isomer 1 (Intermediate I-82): ES / MS: 479.0, 481.0 (M+H + ).

[0521] (R)-2-(4-bromo-2,5-difluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylate methyl ester isomer 2 (Intermediate I-83): ES / MS: 479.0, 481.0 (M+H + ).

[0522] Preparation of Intermediate I-82 (Method 2): Methyl 2-[(4-bromo-2,5-difluorophenyl)methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]benzimidazole-5-carboxylate (Intermediate I-82): 2-(4-bromo-2,5-difluorophenyl)acetic acid (3301 mg, 13.2 mmol), 4-amino-3-[[(3S)-4,4 To a solution of methyl o-(dimethyltetrahydrofuran-3-yl)aminobenzoate (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), N,N-diisopropylethylamine (10.2 mL, 58.4 mmol) was added. The solution was stirred overnight at room temperature. The mixture was then treated with 0.2 equivalents of 2-(4-bromo-2,5-difluorophenyl)acetic acid (600 mg, 2.39 mmol) and o-(7-azabenzotriazoline). (N,N,N',N'-tetramethyluronium hexafluorophosphate (930 mg, 2.39 mmol) was added and stirring was continued until complete conversion to the product. The crude 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-difluoro-phenyl)acetyl]amino]-3-[[(3S)-4,4-dimethyltetrahydrofuran-3-yl]amino]benzoate.

[0523] 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, then diluted with EtOAc and washed with saturated NaHCO 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) δ8.55(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), 4.59(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).

[0524] Preparation of intermediate I-84:

[0525] [ka]

[0526] 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), 2-(bromomethyl)thiazole-5-carbonitrile (I-63) (584 mg, 2.9 mmol) and cesium carbonate (1.34 g, 4.1 mmol) were added, and the resulting mixture was stirred at 65 °C for 1 h. Upon completion, the mixture was filtered through Celite, concentrated, and purified by silica gel column chromatography (eluent: EtOAc / hexanes) to provide I-84. ES / MS: 296.0, 298.0 (M+H + ).

[0527] Preparation of Intermediate I-85:

[0528] [ka]

[0529] 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 in the manner described for intermediate I-23, substituting 5-(bromomethyl)-2-chloro-4-methoxypyridine for 5-(bromomethyl)-2-chloro-4-fluoropyridine. ES / MS: 621.2 (M+H + ).

[0530] Preparation of Intermediate I-86:

[0531] [ka]

[0532] 5-(Bromomethyl)-4-methoxy-N-methylpicolinamide (I-86): 5-(Bromomethyl)-4-methoxy-N-methylpicolinamide was prepared in the manner described for intermediate I-53, substituting methylamine HCl for 1-aminocyclopropane-1-carbonitrile. ES / MS: 259.2, 261.2 (M+H + ).

[0533] Preparation of intermediate I-87:

[0534] [ka]

[0535] 5-(Bromomethyl)-4-chloro-N-methylpicolinamide (I-87): 5-(Bromomethyl)-4-chloro-N-methylpicolinamide was prepared in the manner described for intermediate I-53, substituting 1-aminocyclopropane-1-carbonitrile for methylamine HCl and 4-methoxy-5-methylpicolinic acid for 4-chloro-5-methylpicolinic acid. ES / MS: 263.0, 265.0 (M+H + ).

[0536] Preparation of intermediate I-88:

[0537] [ka]

[0538] 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): 2-[[4-[6-[(4-bromo-2-fluoro-phenyl) To a solution of tert-butyl [methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (300 mg, 0.44 mmol), bis(pinacolato)diboron (179 mg, 0.70 mmol), Pd(dppf)Cl (33 mg, 0.044 mmol), and potassium propionate (148 mg, 1.3 mmol) were added. Argon was bubbled through the mixture for 1 minute, after which the reaction vial was sealed and heated to 110 °C in a microwave reactor for 45 minutes. Upon completion, the mixture was directly concentrated and purified by silica gel column chromatography (eluent: EtOAc / hexanes) to provide I-88. ES / MS: 730.8 (M+H + ).

[0539] Preparation of Intermediate I-89:

[0540] [ka]

[0541] (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 mixture was diluted with EtOAc (50 mL), washed with water (10 mL), brine (10 mL), dried over MgSO4, filtered, and concentrated to give the desired product, which was used without further purification. ES / MS: 311.2 (M+H) + ).

[0542] 3-[[(3R,4S)-4-(methylcarbamoyl)tetrahydrofuran-3-yl ]amino]-4-nitro-methylbenzoate: (3S,4R)-4-(5-methoxycarbonyl-2-nitro-anilino)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 + ).

[0543] 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-nitrobenzoate (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 mixture was then purged with H gas and stirred under 1 atmosphere of H for 1 hour. Upon completion, the mixture was filtered through Celite, concentrated, and the crude residue I-89 was used without further purification. ES / MS: 294.2 (M+H + ).

[0544] Preparation of intermediate I-90:

[0545] [ka]

[0546] 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 in the manner described for intermediate I-89, substituting methylamine for dimethylamine. ES / MS: 308.2 (M+H + ).

[0547] Preparation of intermediate I-91:

[0548] [ka]

[0549] 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 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) + ).

[0550] 1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (I-91): 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) in the manner described for intermediate I-88. ES / MS: 341.1 (M+H + ).

[0551] Preparation of Intermediate I-92:

[0552] [ka]

[0553] 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): Tert-butyl 2-(4-(6-((6-chloropyridin-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6- was prepared in the manner described for intermediate I-18, substituting 4-bromo-1-(bromomethyl)-2-fluoro-benzene for 5-(bromomethyl)-2-chloropyridine. ES / MS: 621.2 (M+H + ).

[0554] Preparation of intermediate I-93:

[0555] [ka]

[0556] (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): (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, substituting 4-bromo-1-(bromomethyl)-2-fluoro-benzene for 2-bromo-5-(bromomethyl)-4-fluoropyridine. ES / MS: 654.0, 656.0 (M+H). + ).

[0557] Preparation of intermediate I-94:

[0558] [ka]

[0559] 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 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 + ).

[0560] Preparation of Intermediate I-95:

[0561] [ka]

[0562] Methyl 2-(4-(6-chloropyridin-2-yl)-2,5-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (I-95): (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-6 for I-1. ES / MS: 472.8 (M+H + ).

[0563] Preparation of Intermediate I-96:

[0564] [ka]

[0565] 2-(4-Bromo-2,5-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (I-96). 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 in the manner described for intermediate I-2, substituting 2-(4-bromo-2,5-difluorophenyl)acetic acid for 2-(4-bromo-2-fluorophenyl)acetic acid. ES / MS: 439.8 (M+H + ).

[0566] Preparation of Intermediate I-97:

[0567] [ka]

[0568] (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 mixture was directly concentrated and purified by flash chromatography (eluent: EtOAc / hexanes) to give the desired product.

[0569] 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 mixture was heated to 0° C. The mixture was cooled to rt and carbon tetrabromide (1.49 g, 0.00450 mol) was added in a single 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 + ).

[0570] The following intermediates were prepared in the manner described for intermediate I-97.

[0571] [ka]

[0572] Preparation of Intermediate I-98:

[0573] [ka]

[0574] 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 mixture was then stirred for 30 minutes. Upon completion, the mixture was diluted with EtOAc (50 mL), washed with water (10 mL), washed with brine (10 mL), dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography (eluent: MeOH / EtOAc / hexanes) to give the desired product. ES / MS: 167.2 (M+H + ).

[0575] 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 mixture was stirred for 15 minutes. Upon completion, the mixture was filtered, concentrated, and purified by flash chromatography (eluent: EtOAc / hexanes) to give I-98. ES / MS: 229.0 (M+H + ).

[0576] The following intermediates were prepared in the manner described for intermediate I-98.

[0577] [ka]

[0578] Preparation of Intermediate I-99:

[0579] [ka]

[0580] (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 slowly added to the mixture via an addition funnel while stirring at −78° C. After the addition, the mixture was maintained at −78° C. for 30 minutes with stirring before removing the cooling bath. The mixture was maintained at room temperature with stirring 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, 1H), 4.13 (d, J = 9.5 Hz, 1H), 4.07 (d, J = 9.5 Hz, 1H), 1.28 (s, 3H), 1.18 (s, 3H).

[0581] (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.) prepared as above in toluene (50 mL) was added slowly via an addition funnel at 0 °C. The mixture was maintained at 0 °C for 30 min before removing the cooling bath, and the mixture was stirred at room temperature for 4 h. The 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 3-azido-4,4-dimethyldihydrofuran-2(3H)-one. The crude material was carried on immediately to the next step without purification.

[0582] 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., followed by the slow addition of diisobutylaluminum hydride (1.0 M in toluene) (32.2 mL, 32.2 mmol, 1.2 equiv.) at the same temperature. The mixture was stirred at −78° C. for 2 hours until no starting material remained. The reaction was diluted with a saturated solution of potassium sodium tartrate. The mixture was quenched by adding (100 mL). 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. 1H NMR (400 MHz, CDCl3) δ = 5.58-5.29 (m, 1H), 3.93-3.76 (m, 2H), 3.66-3.50 (m, 2H), 1.19-1.08 (m, 6H).

[0583] 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 then 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 no starting material remained. Water (100 mL) was then added to the 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=6.1,9.8Hz,1H),3.77(dd,J=3.9,9.8Hz,1H),3.65(dd,J=3.9,6.1Hz,1H),3.58-3.50(m,2H),1.13(d,J=6.1Hz,6H).

[0584] 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 before filtering through a plug of Celite. The solution was diluted with 4M tetrahydrofuran-3-amine in methanol (5.0 mL) before being concentrated in vacuo. Acidification with HCl gave 4,4-dimethyltetrahydrofuran-3-amine as the hydrochloride salt: 1H NMR (400 MHz, 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).

[0585] Preparation of intermediate I-100:

[0586] [ka]

[0587] Methyl 3-[[(S)-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 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 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 3-[[(3S)-4,4-dichloro-2-(2-methyl-1,2-dihydro- ... Methyl methyltetrahydrofuran-3-ylamino-4-nitrobenzoate was obtained, and its structure was confirmed by X-ray crystallography. 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), 4.02 (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+).

[0588] [ka]

[0589] Methyl 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]benzimidazole-5-carboxylate (Intermediate I-101): In a 200 mL flask, add 2-[(4-bromo-2,5-difluoro-phenyl)methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran in dioxane (24 mL). A suspension of methyl [3-yl]benzimidazole-5-carboxylate (Intermediate I-82, 2329 mg, 4.86 mmol), bis(pinacolato)diboron (1506 mg, 5.93 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (541 mg, 0.729 mmol), and potassium propionate (1635 mg, 14.6 mmol) was degassed with argon for 5 minutes and then heated at 110 °C for 50 minutes. The mixture was cooled to room temperature. To the mixture was added sodium carbonate (2000 mmol / L, 5.48 mL, 11.0 mmol). The mixture was stirred at room temperature for 5 minutes. To the mixture was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (358 mg, 0.483 mmol) and 4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluorobenzonitrile (Intermediate I-3, 2238 mg, 7.29 mmol). The mixture was degassed with argon for 5 minutes and then thermally heated at 90°C for 1 hour and 15 minutes. The mixture was diluted with EtOAc and filtered through Celite. The filtrate was washed with brine, dried over sodium sulfate, and purified by silica gel column chromatography (eluent: EtOAc / hexane) to give methyl 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]benzimidazole-5-carboxylate (Intermediate I-101), the structure of which was confirmed by X-ray crystallography. ES / MS: 626.6 (M+H+). 1H NMR(400MHz, クロロホルム-d)δ8.56(s,1H),8.02(dd,J=8.5,1.5Hz,1H),7.79(dd,J=9.7,5.6Hz,2H),7 .70(dt,J=14.3,7.6Hz,2H),7.53(dt,J=7.3,1.1Hz,1H),7.49(dd,J=7.9,1.5Hz,1H),7.43(dd,J =9.3,1.5Hz,1H),7.09(dd,J=11.3,6.0Hz,1H),6.86(d,J=8.1Hz,1H),5.61(s,2H),4.73-4.56(m ,2H),4.46-4.32(m,34H),3.96(d,J=6.8Hz,4H),3.81(d,J=8.7Hz,1H),1.36(s,3H),0.69(s,3H).

[0590] Preparation of intermediate I-101 (Method 2):

[0591]

change

[0592] (S)-4-(2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorophenyl)acetamido)-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)benzoate (I-101-1): HATU (12.2 g, 32.3 mmol) followed by N,N-diisopropylethylamine (19.6 mL, 112 mmol) was dissolved in DMF (36 mL) and M To a solution of 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorophenyl)acetic acid (Intermediate I-7, 10.1 g, 25.3 mmol) and (S)-4-amino-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)benzoate (Intermediate I-80, 6.07 g, 23.0 mmol) in eCN (36 mL) was added, and the resulting solution was stirred at room temperature overnight. The mixture was then diluted with EtOAc and washed sequentially with saturated NH4Cl, 10% LiCl, saturated NaHCO3 (x2), 1 N NaOH, and brine. The organic phase was dried over MgSO, filtered, and concentrated to give (S)-4-(2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorophenyl)acetamido)-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)methyl benzoate (Intermediate I-101-1), which was carried forward assuming 100% yield. ES / MS: 645.2 (M+1).

[0593] (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate I-101): Trifluoromethanesulfonic anhydride (5.79 mL, 34.4 mmol) was dissolved in DCM to give (S)-4-(2-(4 To a solution of methyl -(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorophenyl)acetamido)-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)benzoate (I-101-1, 14.8 g, 23.0 mmol) and triphenylphosphine oxide (9.59 g, 34.4 mmol) was added dropwise under argon at 0° C. for 10 minutes. The mixture was stirred for 15 minutes, brought to room temperature, and stirred for 25 minutes. The reaction was quenched with saturated NaHCO3 and the phases were separated. The aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4, filtered, concentrated and purified by silica gel flash column chromatography (EtOAc / Hex gradient) to give (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carbohydrate. Methyl benzoate (intermediate I-101) was obtained.

[0594] Preparation of Intermediate I-102:

[0595] [ka]

[0596] 2-Bromo-6-[(4-chloro-2-fluoro-phenyl)methoxy]pyridine (Intermediate I-102): A round-bottom flask was charged with (4-chloro-2-fluoro-phenyl)methanol (800 mg, 5.0 mmol, 1.1 equiv), 2-bromo-6-fluoropyridine (800 mg, 4.6 mol, 1.0 equiv), and cesium carbonate (2.3 g, 6.8 mmol, 1.5 equiv). Anhydrous acetonitrile (15 mL) was added, and the resulting mixture was heated to reflux and stirred for 12 hours. After cooling to room temperature, the mixture was filtered through a plug of Celite and then concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc / hexanes gradient) to give the title compound. ES / MS m / z: 317.8 (M+H). + .

[0597] Preparation of intermediate I-103:

[0598] [ka]

[0599] Methyl 2-[[4-[6-[(4-chloro-2-fluoro-phenyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]benzimidazole-5-carboxylate (intermediate I-103). A 25 mL microwave vial was charged with methyl 2-[(4-bromo-2,5-difluorophenyl)methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]benzimidazole-5-carboxylate (Intermediate I-82, 800 mg, 1.67 mmol, 1.0 equiv.), PdCl(dppf) (186 mg, 0.25 mmol, 0.15 equiv.), potassium propionate (560 mg, 5.01 mmol, 3.0 equiv.), and B2Pin (510 mg, 2.00 mol, 1.2 equiv.). Anhydrous 1,4-dioxane (10 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 oven, and stirred for 1 hour. After cooling to room temperature, 2-bromo-6-[(4-chloro-2-fluoro-phenyl)methoxy]pyridine (Intermediate I-102, 580 mg, 1.84 mmol, 1.1 equiv.), PdCl(dppf) (62 mg, 0.0834 mmol, 0.05 equiv.), and 2M aqueous NaCO (2.0 mL, 4.17 mmol, 2.5 equiv.) were added. The resulting mixture was heated to 100 °C under argon and stirred for 3 h before cooling to room temperature and filtering through a plug of Celite and MgSO. The filtrate was concentrated and purified by column chromatography (silica gel, EtOAc / hexanes gradient) to give the title compound. ES / MS m / z: 635.6 (M+H). + .

[0600] Preparation of intermediate I-104:

[0601] [ka]

[0602] Methyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate I-104). 2-[4-[6-[(4-cyano-2-fluorophenyl)methoxy]-2-pyridyl]-2,5-difluorophenyl]acetic acid (Intermediate I-7, 500 mg, 1.26 mmol), methyl 4-amino-3-[(4,4-dimethyltetrahydrofuran-3-yl)amino]benzoate (Intermediate I-25, 365 mg, 1.38 mmol), and o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (573 mg, 1.51 mmol) were combined in DMF (5.00 mL), and N,N-diisopropylethylamine (1.09 mL, 6.28 mmol) was added. The mixture was stirred at room temperature for 3 hours. The mixture was partitioned between EtOAc and saturated NH4Cl. The organic phase was dried, filtered, and concentrated in vacuo. The crude material was taken up in acetic acid (2 mL) and heated to 100° C. for 72 h. The resulting mixture was then concentrated in vacuo and partitioned between EtOAc and saturated NaHCO. The organic phase was dried, filtered, and concentrated in vacuo. Silica gel flash chromatography (EtOAc / hexanes) afforded the title compound. ES / MS: m / z 627.2 [M+H] + .

[0603] Preparation of intermediate I-105:

[0604] [ka]

[0605] 4-Bromo-2-[(4-chloro-2-fluoro-phenyl)methoxy]pyrimidine (Intermediate I-105): To a 50 mL RBF, (4-chloro-2-fluoro-phenyl)methanol (186 mg, 1.16 mmol) was added to THF (6 mL), the flask was placed under nitrogen, and cooled to 0 °C. Potassium tert-butoxide (1.05 mL, 0.362 mmol, 1 M THF) was added dropwise, and the solution was stirred at 0 °C for 15 min. To a separate 50 mL RBF, 4-bromo-2-methylsulfonyl-pyrimidine (250 mg, 1.05 mmol) in THF (6 mL) was added, and the mixture was cooled to -78 °C. The first solution (deprotonated alcohol) was taken up in a syringe and added dropwise to the second solution at -78 °C. The solution was stirred at -78°C for 1 hour, then 1 mL of water was added dropwise and the solution was allowed to warm to room temperature. The solution was diluted with EtOAc and water, and 2 mL of saturated aqueous NH4Cl was added to acidify the solution. The layers were then separated, and the aqueous layer was extracted once with EtOAc. The combined organic layers were dried over MgSO4, filtered, concentrated, and purified by silica gel flash column chromatography (EtOAc / Hex gradient) to give 4-bromo-2-[(4-chloro-2-fluoro-phenyl)methoxy]pyrimidine (Intermediate I-105). ES / MS m / z: 318.9 (M+H) + .

[0606] Preparation of intermediate I-106:

[0607] [ka]

[0608] (S)-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)-5-fluoro-4-benzoate methyl ester (Intermediate I-106): 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 before cooling 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 subsequent step without further purification.

[0609] Preparation of intermediate I-107:

[0610] [ka]

[0611] Methyl (S)-4-amino-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)-5-fluorobenzoate (Intermediate I-107): Methyl (S)-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)-5-fluoro-4-nitrobenzoate (Intermediate I-106, 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) afforded methyl (S)-4-amino-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)-5-fluorobenzoate (Intermediate I-107). ES / MS m / z: 283.2 (M+H) + .

[0612] Preparation of intermediate I-108:

[0613] [ka]

[0614] (S)-4-(2-(4-bromo-2,5-difluorophenyl)acetamido)-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)-5-fluorobenzoate methyl ester (I-108-1): (S)-4-amino-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)-5-fluorobenzoate methyl ester (Intermediate) in MeCN (10.0 mL) cooled to 0 °C. To a solution of I-107 (2000 mg, 7.08 mmol) and 2-(4-bromo-2,5-difluorophenyl)acetic acid (1867 mg, 7.44 mmol), 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 mixture was warmed to room temperature and stirred for 30 minutes. The mixture was concentrated in vacuo to give (S)-4-(2-(4-bromo-2,5-difluorophenyl)acetamido)-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)-5-fluorobenzoate methyl ester (I-108-1), which was carried on to the next step without further purification.

[0615] Methyl 2-[(4-bromo-2,5-difluorophenyl)methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]-7-fluorobenzimidazole-5-carboxylate (Intermediate I-108): To methyl (S)-4-(2-(4-bromo-2,5-difluorophenyl)acetamido)-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)-5-fluorobenzoate (I-108-1, 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 hours and then cooled to room temperature. A 20 mL aliquot of water was added, stirred for 1 hour, and then 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-108). ES / MS m / z: 497.0 (M+H). + .

[0616] Preparation of intermediate I-109:

[0617] [ka]

[0618] 4-[(6-Bromo-3-fluoro-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile (Intermediate I-109): 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 before cooling 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 (gradient of EtOAc in hexanes) afforded 4-[(6-bromo-3-fluoro-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile (Intermediate I-109). ES / MS m / z: 326.1 (M+H). + .

[0619] Preparation of intermediate I-110:

[0620] [ka]

[0621] Methyl 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-5-fluoro-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]-7-fluoro-benzimidazole-5-carboxylate (Intermediate I-110): In a 2 mL microwave vial, add 2-[(4-bromo-2,5-difluorophenyl)methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]-7-fluoro-benzimidazo[pi]ate. Methyl 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (400 mg, 0.69 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (184 mg, 0.73 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (77.7 mg, 0.1 mmol), potassium propionate (233 mg, 2.08 mmol), and 2.5 mL of 1,4-dioxane were charged. Argon was bubbled through the mixture for 5 minutes before heating in a microwave at 120° C. for 1 hour. Sodium carbonate (0.72 mL, 1.44 mmol, 2 M) was then added, followed by 4-[(6-bromo-3-fluoro-2-pyridyl)oxymethyl]-3-fluorobenzonitrile (Intermediate I-109, 247 mg, 0.76 mmol). The mixture was heated to 110° C. for 1 h, then filtered, concentrated, and purified by silica gel chromatography (EtOAc / hexanes gradient) to give 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-5-fluoro-2-pyridyl]-2,5-difluorophenyl]methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]-7-fluorobenzimide. Methyl 5-isothiazolidin-1-carboxylate (Intermediate I-110) was obtained. ES / MS m / z: 663.6 (M+H) + .

[0622] Preparation of intermediate I-111:

[0623] [ka]

[0624] (S)-2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2,5-difluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-4-fluoro-1H-benzo[d]imidazole-6-carboxylate (Intermediate I-111): In a 2 mL microwave vial, add 2-[(4-bromo-2,5-difluorophenyl)methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]-7-fluorobenzimidazole-5 Methyl 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (24 mg, 0.09 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10.2 mg, 0.01 mmol), potassium propionate (30.4 mg, 0.27 mmol), and 2.5 mL of 1,4-dioxane were charged. Argon was bubbled through the mixture for 5 minutes before heating in a microwave at 120 °C for 1 hour. Sodium carbonate (0.09 mL, 0.188 mmol, 2 M) was then added, followed by 4-bromo-2-[(4-chloro-2-fluoro-phenyl)methoxy]pyrimidine (Intermediate I-105, 46.0 mg, 0.14 mmol). The mixture was heated to 110° C. for 1 hour, then filtered, concentrated, and purified by silica gel chromatography (EtOAc / hexane gradient) to give (S)-2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2,5-difluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-4-fluoro-1H-benzo[d]imidazole-6-carboxylate (Intermediate I-111). ES / MS m / z: 656.1 (M+H). + .

[0625] Preparation of intermediate I-112:

[0626] [ka]

[0627] (4-chloro-6-fluoropyridin-3-yl)methanol (I-112-1):N aBH4 (117 mg, 3.09 mmol) was added to a solution of 4-chloro-6-fluoronicotinaldehyde (470 mg, 2.95 mmol) in MeOH (12 mL) at 0 °C, and the solution was stirred for 5 minutes. The reaction was quenched with saturated NH4Cl and concentrated. This was dissolved in EtOAc, washed with water, then brine, dried over MgSO4, filtered, and concentrated to give (4-chloro-6-fluoropyridin-3-yl)methanol (I-112-1). ES / MS: 161.9 (M+H) + .

[0628] 4-Chloro-5-(chloromethyl)-2-fluoropyridine (I-112-2): Thionyl chloride (0.53 mL, 7.4 mmol) was added to a solution of (4-chloro-6-fluoropyridin-3-yl)methanol (I-112-1, 476 mg, 2.95 mmol) in DCM (25 mL), and the resulting solution was stirred for 1 h. Additional thionyl chloride (0.53 mL, 7.4 mmol) was added, and the resulting solution was stirred for 1 h. Additional thionyl chloride (0.21 mL, 2.9 mmol) was added, and the resulting solution was stirred for 30 min. The mixture was concentrated, redissolved in DCM, and saturated NaHCO was added dropwise slowly. The phases were separated, and the organic phase was dried over MgSO, filtered, and concentrated to give 4-chloro-5-(chloromethyl)-2-fluoropyridine (I-112-2). 1H NMR (400 MHz, chloroform-d) δ 8.30 (s, 1H), 7.05 (d, J = 2.7 Hz, 1H), 4.67 (s, 2H).

[0629] 5-(((6-Bromopyridin-2-yl)oxy)methyl)-4-chloro-2-fluoropyridine (I-112-3): A slurry of 6-bromopyridin-2-ol (557 mg, 3.2 mmol), 4-chloro-5-(chloromethyl)-2-fluoropyridine (I-112-2, 480 mg, 2.7 mmol), and CsCO (2.17 g, 6.7 mmol) in CAN (9 mL) was heated at 70 °C for 30 min. The mixture was filtered through Celite, concentrated, and purified by silica gel flash column chromatography (EtOAc gradient in Hex) to give 5-(((6-bromopyridin-2-yl)oxy)methyl)-4-chloro-2-fluoropyridine (I-112-3). ES / MS: 317.0 (M+H). + .

[0630] 5-(((6-Bromopyridin-2-yl)oxy)methyl)-4-chloro-2-(1H-1,2,3-triazol-1-yl)pyridine (Intermediate I-112): A slurry of 5-(((6-bromopyridin-2-yl)oxy)methyl)-4-chloro-2-fluoropyridine (I-112-3, 110 mg, 0.31 mmol), 1H-1,2,3-triazole (0.018 mL, 0.31 mmol), and KCO (87 mg, 0.63 mmol) in DMSO (1.4 mL) was heated at 70 °C for 4 h. The mixture was diluted with brine and extracted twice with EtOAc. The combined organic phases were dried over MgSO, filtered, concentrated, and purified by silica gel flash column chromatography (EtOAc gradient in Hex) to give 5-(((6-bromopyridin-2-yl)oxy)methyl)-4-chloro-2-(1H-1,2,3-triazol-1-yl)pyridine (Intermediate I-112) as the earlier eluting of two isomeric compounds. H NMR (400 MHz, chloroform-d) δ 8.66 (s, 1H), 8.58 (s, 1H), 8.31 (s, 1H), 7.84 (d, J = 1.2 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H), 5.54 (s, 2H).

[0631] Preparation of intermediate I-113:

[0632]

change

[0633] (S)-2-(4-(6-((4-chloro-6-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate I-113): (S)-2-(4-bromo-2,5-difluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl) in dioxane (1 mL). A slurry of methyl 1H-benzo[d]imidazole-6-carboxylate (Intermediate I-82, 20 mg, 0.04 mmol), bis(pinacolato)diboron (13.8 mg, 0.05 mmol), potassium propionate (14 mg, 0.125 mmol), and bis(diphenylphosphino)ferrocene]dichloropalladium(II) (4.6 mg, 0.006 mmol) was sparged with argon for 5 minutes, sealed, and heated at 110 °C for 1 hour. The mixture was cooled to room temperature, sodium carbonate (2 M, 0.05 mL, 0.1 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. A solution of bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.1 mg, 0.004 mmol) and 5-(((6-bromopyridin-2-yl)oxy)methyl)-4-chloro-2-(1H-1,2,3-triazol-1-yl)pyridine (Intermediate I-112) in dioxane (1 mL) was added, and the mixture was degassed with Ar for 5 min and then heated at 90° C. for 2 h. The mixture was diluted with EtOAc, washed with brine (2x), dried over MgSO4, filtered, concentrated, and purified by silica gel flash chromatography (EtOAc gradient in hexanes) to give (S)-2-(4-(6-((4-chloro-6-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate I-113). ES / MS m / z: 686.1 (M+H). + .

[0634] Preparation of intermediate I-114:

[0635] [ka]

[0636] 4-[(6-Bromo-2-pyridyl)oxymethyl]benzonitrile (Intermediate I-114): A mixture of 4-(bromomethyl)benzonitrile (200 mg, 1.0 mmol), 6-bromopyridin-2-ol (180 mg, 1.0 mmol), and cesium carbonate (400 mg, 1.2 mmol) was stirred in acetonitrile (5 mL) at room temperature for 3 hours. The mixture was filtered through Celite and concentrated in vacuo to give 4-[(6-bromo-2-pyridyl)oxymethyl]benzonitrile (Intermediate I-114). ES / MS m / z: 289.2 (M+H). + .

[0637] Preparation of intermediate I-115:

[0638] [ka]

[0639] 2-[[4-[6-[(4-cyanophenyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]benzimidazole-5-carboxylate (Intermediate I-115): 2-[(4-bromo-3-fluoro-phenyl)methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5 To the methyl 1-carboxylate (Intermediate I-82, 30 mg, 0.0626 mmol) was added bis(pinacolato)diboron (23 mg, 0.090 mmol), potassium propionate (23 mg, 0.208 mmol), Pd(dppf)Cl (7.7 mg, 0.0104 mmol), and dioxane (1.5 mL). The mixture was degassed under argon for 30 seconds and heated at 100 °C for 16 hours. Then, Sodium carbonate (2 M in water, 0.070 mL, 0.14 mmol) was added, and the mixture was stirred at room temperature for 1 minute. Additional Pd(dppf)Cl (3.9 mg, 0.0052 mmol) was then added, followed by 4-[(6-bromo-2-pyridyl)oxymethyl]benzonitrile (Intermediate I-114, 20 mg, 0.0692 mmol). The mixture was sealed under argon and heated at 90 °C for 3 hours. The organic layer was directly purified by silica gel flash chromatography (EtOAc gradient in Hex) to give methyl 2-[[4-[6-[(4-cyanophenyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-3-[(3S)-4,4-dimethyltetrahydrofuran-3-yl]benzimidazole-5-carboxylate (Intermediate I-115). ES / MS m / z: 609.5 [M+H] + .

[0640] Preparation of intermediate I-116:

[0641] [ka]

[0642] Methyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3,6-trifluorophenyl)acetate (I-116-1): A mixture of methyl (4-bromo-2,3,6-trifluorophenyl)acetate (26.0 g, 91.9 mmol, 1.0 equiv), bis(pinacolato)diboron (30.3 g, 119.4 mmol, 1.3 equiv), Pd(dppf)Cl (3.36 g, 4.6 mmol, 0.05 equiv), and potassium propionate (36.1 g, 321.7 mmol, 3.5 equiv) in dioxane (400 mL) was degassed with argon. The mixture was stirred at 100 °C overnight. The mixture was cooled to room temperature, followed by the addition of aqueous Na2CO3 (2.0 M, 92 mL, 183.8 mmol, 2.0 equiv), Pd(dppf)Cl2 (3.36 g, 4.6 mmol, 0.05 equiv), and 4-(((6-bromopyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (Intermediate I-3, 28.2 g, 91.9 mmol, 1.0 equiv). The mixture was degassed with argon gas, and then the mixture was stirred at 100 °C for 2 h. The mixture was diluted with EtOAc (1000 mL) and washed with brine (500 mL × 2). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography (petroleum ether / EtOAc gradient) to give methyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3,6-trifluorophenyl)acetate (I-116-1). 1H NMR (400MHz, DMSO-d6): δ 7.93-7.90 (m, 2H), 7.78-7.72 (m, 2H), 7.65-7.60 (m, 1H), 7.56-7.54 (m, 1H), 7.04 (d, J=8.4Hz, 1H), 5.59 (s, 2H), 3.88 (s, 2H), 3.68 (s, 3H). ES / MS m / z: 431.0 [M+H] + .

[0643] 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3,6-trifluorophenyl)acetic acid (Intermediate I-116): A solution of methyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3,6-trifluorophenyl)acetate (I-116-1, 12.0 g, 27.9 mmol, 1.0 equiv) and aqueous LiOH (2 M, 16.8 mL, 33.5 mmol, 1.3 equiv) in CHCN (130 mL) was stirred at room temperature for 5 h. The mixture was diluted with 1N H The mixture was acidified with Cl to pH=6. The precipitated solid was collected by filtration, washed with water (10 mL×2), and then dried to give 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3,6-trifluorophenyl)acetic acid (Intermediate I-116). 1H NMR (400 MHz, DMSO-d6): δ 7.93-7.90 (m, 2H), 7.89-7.86 (m, 2H), 7.50-7.42 (m, 2H), 6.98 (d, J=8.4 Hz, 1H), 5.58 (s, 2H), 3.28 (s, 2H). ES / MS m / z: 417.0 [M+H] + .

[0644] Preparation of intermediate I-117:

[0645] [ka]

[0646] (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3,6-trifluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate 117): 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3,6-trifluorophenyl)acetic acid (Intermediate) in DMF (20 mL) To a solution of I-116 (320 mg, 0.77 mmol), methyl 4-amino-3-[[(3S)-4,4-dimethyltetrahydrofuran-3-yl]amino]benzoate (Intermediate I-80, 203 mg, 0.77 mmol), o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (292 mg, 0.77 mmol), and DIPEA (0.4 mL, 2.31 mmol) were added. The resulting solution was stirred at room temperature for 2 hours, after which the mixture was poured into 100 mL of saturated sodium bicarbonate solution and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with 20 mL of brine and dried over MgSO4. The organic layer was filtered and concentrated. The resulting residue was dissolved in 5.0 mL of acetic acid and stirred at 100 °C for 16 hours. The mixture was cooled and the solvent was removed in vacuo. The mixture was diluted with 50 mL of EtOAc and washed with 50 mL of saturated aqueous NaHCO3. The organic layer was dried over sodium sulfate. The organic layer was filtered and concentrated. This was purified by silica gel chromatography (eluent: EtOAc / hexane) to give (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3,6-trifluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate 117). ES / MS: 645.7 (M+H) + .

[0647] Preparation of intermediate I-118:

[0648] [ka]

[0649] (S)-2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2,5-difluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate I-118): A vial was charged with (S)-2-(4-bromo-2,5-difluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-1H Methyl-benzo[d]imidazole-6-carboxylate (Intermediate I-82, 100 mg, 0.21 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15.5 mg, 0.021 mmol), bis(pinacolato)diboron (80 mg, 0.3 mmol), and potassium propionate (70 mg, 0.63 mmol) were added, followed by 1,4-dioxane (1.0 mL). Argon was bubbled through the solution for 3 minutes, and then the mixture was heated to 110 °C for 70 minutes. To the mixture was added aqueous sodium carbonate (2.00 M, 0.21 mL, 0.42 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6.6 mg, 0.009 mmol), and 4-bromo-2-[(4-chloro-2-fluoro-phenyl)methoxy]pyrimidine (Intermediate I-105, 99.3 mg, 0.3 mmol). Argon was bubbled through the solution for 3 minutes, and then the mixture was heated to 100°C for 45 minutes. The mixture was filtered through Celite, washed with DCM, and concentrated in vacuo. The crude residue was purified by silica gel flash column chromatography (0-100% EtOAc in hexanes) to give (S)-methyl 2-(4-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2,5-difluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate I-118). ES / MS m / z: 637.8 (M+H). + ).

[0650] Preparation of intermediate I-119:

[0651] [ka]

[0652] Methyl 2-(4-bromo-2,3,6-trifluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-4-fluoro-1H-benzo[d]imidazole-6-carboxylate (Intermediate I-119): To a solution of 2-(4-bromo-2,3,6-trifluorophenyl)acetic acid (1.2 g, 4.46 mmol) in ACN (50 mL) was added methyl 4-amino-3-((4,4-dimethyltetrahydrofuran-3-yl)amino)-5-fluorobenzoate (Intermediate I-25, 1.26 g, 4.46 mmol), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (1.5 g, 5.35 mmol), and 1-methylimidazole (1.83 mL, 22.3 mmol). The resulting solution was stirred at room temperature for 16 hours, after which the mixture was added to 100 mL of The mixture was poured into saturated sodium bicarbonate solution and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with 50 mL of brine and dried over MgSO. The organic layer was filtered and concentrated. The mixture was purified by silica gel chromatography (eluent: EtOAc / hexane) to give intermediate I-119-1, which was dissolved in 50.0 mL of acetic acid. It was stirred at 120° C. for 40 hours. The mixture was cooled and the solvent was removed. The mixture was diluted with 100 mL of EtOAc and washed with 100 mL of saturated aqueous NaHCO. The organic layer was dried over sodium sulfate. The organic layer was filtered and concentrated. This was purified by silica gel flash column chromatography (eluent: EtOAc / hexane) to give methyl 2-(4-bromo-2,3,6-trifluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-4-fluoro-1H-benzo[d]imidazole-6-carboxylate (intermediate I-119). ES / MS: 515.6 (M+H) + .

[0653] Preparation of intermediate I-120:

[0654] [ka]

[0655] Methyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3,6-trifluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-4-fluoro-1H-benzo[d]imidazole-6-carboxylate (Intermediate I-120): 2-(4-bromo-2,3,6-trifluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-4-fluoro-1H To methyl-benzo[d]imidazole-6-carboxylate (Intermediate I-119, 300 mg, 0.58 mmol) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (43.2 mg, 0.058 mmol), bis(pinacolato)diboron (222 mg, 0.87 mmol), and potassium propionate (196 mg, 1.75 mmol), followed by 1,4-dioxane (3.0 mL). Argon was bubbled through the solution for 3 minutes, and then the mixture was heated to 110 °C for 90 minutes. To the mixture was added aqueous sodium carbonate (2.00 M, 0.58 mL, 1.16 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (18.1 mg, 0.024 mmol), and 4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile (Intermediate I-3, 268 mg, 0.87 mmol). Argon was bubbled through the solution for 3 minutes, and then the mixture was heated to 100 °C for 60 minutes. The 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-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,3,6-trifluorobenzyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-4-fluoro-1H-benzo[d]imidazole-6-carboxylate (Intermediate I-120). ES / MS m / z: 663.5 (M+H+ ).

[0656] Preparation of intermediate I-121:

[0657] [ka]

[0658] tert-Butyl 2,3-difluoro-4-nitrobenzoate: 2,3-Difluoro-4-nitrobenzoic acid (1.00 g, 4.92 mmol) in THF (15 mL) at ambient temperature was treated with di-tert-butyl dicarbonate (2.15 g, 9.9 mmol) followed by 4-dimethylaminopyridine (180 mg, 1.5 mmol), and the resulting mixture was heated to 40 °C for 3 h. Upon completion, the mixture was poured into water (20 mL) and extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with brine (15 mL), dried over MgSO4, and purified by silica gel chromatography (eluent: EtOAc / hexanes) to afford tert-butyl 2,3-difluoro-4-nitrobenzoate.

[0659] tert-Butyl 4-amino-2-fluoro-3-((2-methoxyethyl)amino)benzoate (Intermediate I-121): tert-Butyl 2,3-difluoro-4-nitrobenzoate (200 mg, 0.77 mmol) was dissolved in THF (2 mL), then 2-methoxyethanamine (0.080 mL, 0.93 mmol) and diisopropylethylamine (0.40 mL, 2.3 mmol) were added, and the resulting mixture was heated to 60 °C for 16 h. Upon completion, the mixture was concentrated directly, and the crude residue was then taken up in EtOAc (25 mL) and washed with saturated aqueous NH4Cl (2 x 5 mL). The combined organic extracts were washed with brine (5 mL), dried over MgSO4, concentrated, and carried forward without purification. Crude tert-butyl 2-fluoro-3-((2-methoxyethyl)amino)-4-nitrobenzoate was dissolved in EtOH (5 mL), followed by the addition of iron (216 mg, 3.9 mmol) and saturated aqueous NH4Cl (2 mL). The resulting mixture was heated to 60 °C for 3 h. Upon completion, the solids were removed by filtration and washed with EtOAc (20 mL) and MeOH (20 mL). The filtrate was then concentrated, taken up in EtOAc (25 mL), and washed with water (5 mL) and brine (5 mL). The organic layer was then dried over MgSO4 and purified by silica gel chromatography (eluent: EtOAc / hexanes) to afford tert-butyl 4-amino-2-fluoro-3-((2-methoxyethyl)amino)benzoate (Intermediate I-121). ES / MS: 284.9 (M+H + ).

[0660] Preparation of intermediate I-122:

[0661] [ka]

[0662] tert-Butyl 2-(4-bromo-2,5-difluorobenzyl)-7-fluoro-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate I-122): To a solution of 2-(4-bromo-2,5-difluorophenyl)acetic acid (318 mg, 1.27 mmol) and tert-butyl 4-amino-2-fluoro-3-(2-methoxyethylamino)benzoate (Intermediate I-121, 250 mg, 0.9 mmol) in MeCN (8 mL) was added 1-methylimidazole (0.35 mL, 4.4 mmol) and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH, 300 mg, 1.1 mmol). The solution was stirred at room temperature for 2 h, diluted with EtOAc, and washed with HCl (1 M, aq.). The organic layer was concentrated to provide tert-butyl 4-[[2-(4-bromo-2,5-difluoro-phenyl)acetyl]amino]-2-fluoro-3-(2-methoxyethylamino)benzoate (I-122-1), which was dissolved in 5 mL of DCE and 0.38 mL of acetic acid. The mixture was stirred at 60 °C for 4 hours. The reaction was quenched with NaHCO and extracted twice with DCM. The organic phase was washed with brine, dried, filtered, concentrated, and purified by silica gel flash chromatography (EtOAc gradient in hexanes) to give tert-butyl 2-(4-bromo-2,5-difluorobenzyl)-7-fluoro-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate I-122). H NMR (400 MHz, chloroform-d) δ 7.86 (dd, J = 8.6, 6.7 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.35 (dd, J = 8.7, 5.6 Hz, 1H), 7.13 (dd, J = 8.3, 6.4 Hz, 1H), 4.62-4.40 (m, 4H), 3.78 (t, J = 5.1 Hz, 2H), 3.29 (s, 3H), 1.64 (s, 9H).

[0663] Preparation of intermediate I-123:

[0664] [ka]

[0665] tert-Butyl 2-(4-(6-((4-cyanobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-7-fluoro-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate I-123). A suspension of tert-butyl 2-(4-bromo-2,5-difluorobenzyl)-7-fluoro-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate I-122, 50 mg, 0.1 mmol), bis(pinacolato)diboron (34 mg, 0.135 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11.5 mg, 0.016 mmol), and potassium propionate (35 mg, 0.3 mmol) in dioxane (2 mL) was degassed with Ar for 20 min. The mixture was sealed and heated at 100 °C for 2 h. Sodium carbonate (2.0 M, 0.1 mL, 0.2 mmol) was added, and the mixture was stirred at room temperature for 10 min. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6 mg, 0.008 mmol) and 4-[(6-bromo-3-fluoro-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile (Intermediate I-109, 34 mg, 0.1 mmol) were added, and the mixture was degassed with Ar for 10 minutes, then sealed and heated at 90 °C for 3 hours. The mixture was diluted with EtOAc and washed with brine. The organic extract was dried over sodium sulfate and chromatographed (eluent: EtOAc / hexane) to give tert-butyl 2-(4-(6-((4-cyanobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-7-fluoro-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate I-123). ES / MS m / z: 665.2 (M+H + ).

[0666] Preparation of intermediate I-1001:

[0667] [ka]

[0668] (1R,3R,5R)-tert-Butyl 3-[(2-amino-5-methoxycarbonyl-anilino)methyl]-2-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate I-1001): (1R,3R,5R)-3-[(2-amino-5-methoxycarbonyl-anilino)methyl]-2-azabicyclo[3.1.0]hexane-2-carboxylate tert-Butyl (1R,3R,5R)-3-[(2-amino-5-methoxycarbonyl-anilino)methyl]-2-azabicyclo[3.1.0]hexane-2-carboxylate was reacted with (1R,3R,5R)-3-(aminomethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate. Prepared in the manner described for intermediate I-1, substituting tert-butyl 2-[3.1.0]hexane-2-carboxylate for 2-methoxyethylamine. ES / MS: 362.2 (M+H+). H NMR (400 MHz, chloroform-d) δ 7.39 (d, J = 8.1 Hz, 1H), 7.15 (s, 1H), 6.63 (d, J = 8.1 Hz, 1H), 4.58 (t, J = 11.0 Hz, 1H), 3.87 (s, 3H), 3.64 (d, J = 7.3 Hz, 1H), 3.27-3.09 (m, 1H), 3.00 (t, J = 11.0 Hz, 1H), 2.56 (q, J = 11.7 Hz, 1H), 1.95-1.70 (m, 1H), 1.53 (s, 10H), 0.81 (q, J = 7.1 Hz, 1H), 0.57 (d, J = 5.7 Hz, 1H).

[0669] Preparation of intermediate I-1002:

[0670] [ka]

[0671] 2-Bromo-4-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]pyrimidine (I-1002): To a solution of [2-fluoro-4-(trifluoromethyl)phenyl]methanol (1.1 g, 5.65 mmol) in tetrahydrofuran (3 mL) was added potassium tert-butoxide (0.333 g, 2.97 mmol). The solution was then stirred at room temperature for 5 minutes. Next, 2-bromo-4-fluoro-pyrimidine (0.500 g, 2.83 mmol) in N,N-dimethylformamide (5 mL) was added, and the mixture was cooled to −78° C. The mixture was then removed from the dry ice bath and stirred at room temperature over the weekend. Following this, the mixture was diluted with EtOAc and washed with 5% LiCl (2×) and brine. The organic extract was dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by flash chromatography (eluent: EtOAc / hexanes) to give the desired product. ES / MS: 351.0, 353.0 (M+H + ). 1H NMR (400 MHz, chloroform-d) δ 8.31 (d, J = 5.7 Hz, 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.48 (dd, J = 8.0, 1.5 Hz, 1H), 7.41 (dd, J = 9.7, 1.7 Hz, 1H), 6.79 (d, J = 5.7 Hz, 1H), 5.56 (s, 2H). 19F NMR (376 MHz, chloroform-d) δ -63.43, -115.50 (d, J = 7.5 Hz).

[0672] Preparation of intermediate I-1003:

[0673] [ka]

[0674] [2-Fluoro-4-[1-(trifluoromethyl)pyrazol-4-yl]phenyl]methanol (I-1003): (4-Bromo-2-fluoro-phenyl)methanol (100 mg, 0.01%) in 99.8% anhydrous 1,4-dioxane (2 mL) and water (1 mL). A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)pyrazole (153 mg, 0.59 mmol), 1,1'-bis(di-isopropylphosphino)ferrocenepalladium dichloride (29 mg, 0.049 mmol), and potassium carbonate (200 mg, 1.4 mmol) was degassed with argon for 5 minutes and then thermally heated at 100°C for 1 hour. Upon completion, the mixture was diluted with EtOAc and washed with brine. The organic extract was dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by flash chromatography (eluent: EtOAc / hexanes) to give the desired product. ES / MS: 261.2 (M+H + ). 1H NMR (400 MHz, chloroform-d) δ 8.06 (s, 1H), 8.04 (t, J = 0.9 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.33 (dd, J = 7.8, 1.7 Hz, 1H), 7.22 (dd, J = 10.8, 1.7 Hz, 1H), 4.82 (s, 2H). 19F NMR (376 MHz, chloroform-d) δ -61.00, -119.32.

[0675] Preparation of intermediate I-1004:

[0676] [ka]

[0677] Methyl 6-(1,2,4-triazol-1yl)pyridine-3-carboxylate: A suspension of methyl 6-chloropyridine-3-carboxylate (500 mg, 2.91 mmol), 1H-1,2,4-triazole (282 mg, 4.08 mmol), and potassium carbonate (564 mg, 4.08 mmol) in NMP (10 mL) was heated at 80° C. overnight. Upon completion, the mixture was extracted with EtOAc and washed with 5% LiCl (2×) and brine. The organic extract was dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by flash chromatography (eluent: EtOAc / hexanes) to give the desired product. ES / MS: 205.2 (M+H+ ). 1H NMR (400 MHz, chloroform-d) δ 9.27 (s, 1H), 9.10 (dd, J = 2.2, 0.8 Hz, 1H), 8.51 (dd, J = 8.6, 2.2 Hz, 1H), 8.15 (s, 1H), 8.01 (dd, J = 8.5, 0.8 Hz, 1H), 4.01 (s, 3H).

[0678] 6-(1,2,4-Triazol-1-yl)pyridine-3-carboxylic acid: A solution of methyl 6-(1,2,4-triazol-1-yl)pyridine-3-carboxylate (200 mg, 0.980 mmol) and lithium hydroxide monohydrate (215 mg, 5.12 mmol) in CHCN (9 mL) and water (3 mL) was stirred overnight at room temperature. The mixture was then extracted with EtOAc. The pH was adjusted to about 6 with 1N HCl (2.8 mL), followed by filtration and air-drying to give the desired product, which was used in the next step without further purification. ES / MS: 191.2 (M+H) + ). 1H NMR (400MHz, DMSO-d6) δ9.48 (s, 1H), 9.01 (d, J = 2.2 Hz, 1 H), 8.52 (dd, J = 8.5, 2.2 Hz, 1 H), 8.38 (s, 1 H), 7.99 (d, J = 8.6 Hz, 1 H).

[0679] [6-(1,2,4-Triazol-1-yl)-3-pyridyl]methanol (I-1004): 1,1'-Carbonyldiimidazole (261 mg, 1.61 mmol) was added to a solution of 6-(1,2,4-triazol-1-yl)pyridine-3-carboxylic acid (153 mg, 0.805 mmol) in THF (6 mL). The solution was stirred for 2 hours. Upon completion, the mixture was cooled to 0 °C, and then a solution of NaBH (152 mg, 4.02 mmol) in 1 mL of water was added. The mixture was then stirred at room temperature for 30 minutes. Upon completion, 1 mL of concentrated HCl was slowly added, and then the mixture was concentrated to remove THF. Upon removal of THF, the mixture was neutralized with saturated NaHCO and extracted three times with EtOAc. The organic extract was washed with brine and dried over sodium sulfate. The crude residue was purified by chromatography (eluent: EtOAc / hexanes) to give the desired product. ES / MS: 177.2 (M+H + ). 1H NMR (400 MHz, chloroform-d) δ 9.21 (s, 1H), 8.48 (s, 1H), 8.13 (s, 1H), 7.94 (t, J = 1.6 Hz, 2H), 4.83 (s, 2H).

[0680] Preparation of intermediate I-1005:

[0681] [ka]

[0682] [6-(Triazol-1-yl)-3-pyridyl]methanol (I-1005): [6-(triazol-1-yl)-3-pyridyl]methanol was prepared in the manner described for intermediate I-1004, substituting 1H-1,2,4-triazole for 1H-triazole. ES / MS: 177.2 (M+H). 1H NMR (400 MHz, chloroform-d) δ 8.62 (d, J = 1.2 Hz, 1H), 8.56-8.45 (m, 1H), 8.23 ​​(d, J = 8.2 Hz, 1H), 7.98 (dd, J = 8.4, 2.3 Hz, 1H), 7.86 (d, J = 1.2 Hz, 1H), 4.85 (s, 2H).

[0683] Preparation of intermediate I-1006:

[0684] [ka]

[0685] Methyl 6-oxazol-5-ylpyridine-3-carboxylate: Methyl 6-chloropyridine-3-carboxylate (200 mg, 1.2 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboro)-2-methyl-1,3,2-dioxaboro in 1,4-dioxane (4 mL) and water (2 mL). A suspension of 1,1'-bis(diisopropylphosphino)ferrocene palladium dichloride (69 mg, 0.12 mmol), and potassium carbonate (477 mg, 3.5 mmol) was degassed with argon for 5 minutes. The mixture was then thermally heated at 100°C for 1 hour. Upon completion, the mixture was diluted with EtOAc and washed with brine. The organic extract was dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by flash chromatography (eluent: EtOAc / hexanes) to give the desired product. ES / MS: 205.2 (M+H + ). 1H NMR (400 MHz, chloroform-d) δ 9.25 (dd, J = 2.1, 0.9 Hz, 1H), 8.40 (dd, J = 8.3, 2.1 Hz, 1H), 8.05 (s, 1H), 7.86 (s, 1H), 7.77 (dd, J = 8.3, 0.9 Hz, 1H), 4.00 (s, 3H).

[0686] 6-Oxazol-5-ylpyridine-3-carboxylic acid: A solution of methyl 6-oxazol-5-ylpyridine-3-carboxylate (117 mg, 0.573 mmol) and lithium hydroxide monohydrate (68.0 mg, 1.62 mmol) in CHCN (3 mL) and water (1 mL) was stirred overnight at room temperature. The mixture was diluted with EtOAc. The mixture was then adjusted to pH 6 with 1 N HCl (1.6 mL), then filtered and air-dried to give the desired product, which was used in the next step without further purification. ES / MS: 191.2 (M+H)+ ). 1H NMR (400 MHz, chloroform-d) δ 8.31 (d, J = 5.7 Hz, 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.48 (dd, J = 8.0, 1.5 Hz, 1H), 7.41 (dd, J = 9.7, 1.7 Hz, 1H), 6.79 (d, J = 5.7 Hz, 1H), 5.56 (s, 2H). 19F NMR (376 MHz, chloroform-d) δ -63.43, -115.50 (d, J = 7.5 Hz).

[0687] 6-Oxazol-5-yl-3-pyridyl)methanol (I-1006): 1,1'-Carbonyldiimidazole (141 mg, 0.872 mmol) was added to a suspension of 6-oxazol-5-ylpyridine-3-carboxylic acid (82.9 mg, 0.436 mmol) in THF (6 mL). The mixture was stirred for 2 h. Upon completion, the mixture was cooled to 0 °C, and then a solution of NaBH4 (152 mg, 4.02 mmol) in 1 mL of water was added. The mixture was stirred at room temperature for 30 min. Upon completion, 1 mL of concentrated HCl was slowly added and then concentrated to remove THF. The mixture was then neutralized with saturated NaHCO3 and extracted three times with EtOAc. The organic extracts were washed with brine and dried over sodium sulfate. The crude residue was purified by chromatography (eluent: EtOAc / hexanes) to give the desired product. ES / MS: 177.2 (M+H+). 1H NMR (400 MHz, chloroform-d) δ 8.65 (dd, J = 2.0, 0.9 Hz, 1H), 8.00 (s, 1H), 7.85 (dd, J = 8.1, 2.2 Hz, 1H), 7.75-7.67 (m, 2H), 4.81 (s, 2H).

[0688] Preparation of intermediate I-1007:

[0689] [ka]

[0690] 2-Imidazol-1-ylpyrimidine-5-carbaldehyde: 2-chloropyrimidine-5-carbaldehyde (250 mg, 1.75 mmol), imidazole (150 mg, 2.21 mmol), and potassium carbonate (339 mg, 2.46 mmol) in DMF (10 mL). A suspension of (2 mmol) was heated at 50° C. overnight. The next day, the mixture was diluted with EtOAc and washed with 5% LiCl (2×) and brine. The organic extract was dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by flash chromatography (eluent: EtOAc / hexanes) to give the desired product. ES / MS: 175.2 (M+H + ). 1H NMR (400 MHz, methanol-d4) δ 8.86 (s, 2H), 8.70 (t, J = 1.1 Hz, 1H), 8.03 (t, J = 1.4 Hz, 1H), 7.16 (t, J = 1.3 Hz, 1H).

[0691] 2-Imidazol-1-ylpyrimidin-5-yl)methanol (I-1007): Sodium borohydride (23.3 mg, 0.616 mmol) was added to a solution of 2-imidazol-1-ylpyrimidine-5-carbaldehyde (107 mg, 0.616 mmol) in MeOH (5 mL) at 0° C. The mixture was gradually warmed to room temperature and stirred for 4 h. At the completion of the time, the mixture was quenched with 1 mL ...

Claims

[Claim 1] The invention described in the specification.

Images