GLP-1r modulating compounds

Abstract

To provide methods of 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. The present disclosure relates to compounds that bind to and act as agonists or modulators of the glucagon-like peptide-1 receptor (GLP-1R) and act as agonists or modulators of GLP-1R. The disclosure further relates to the use of the compounds for the treatment and / or prevention of diseases and / or conditions with the compounds.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 62 / 926,270, filed October 25, 2019, and U.S. Provisional Application No. 63 / 028,187, filed May 21, 2020, both of which are incorporated herein in their entirety for all purposes.

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

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

[0004] GLP-1R agonists are currently being investigated in relation to diabetes, obesity, and NASH. GLP-1R agonists include peptides such as exenatide, liraglutide, and dulaglutide, which are approved for the management of type 2 diabetes. Such peptides are primarily administered via 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, that have 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 [Means for solving the problem]

[0006] In one embodiment, the present disclosure provides a compound of formula (IA-1):

[0007] [ka] During the ceremony, R 1 But C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -SR 1b , -S(O)R 1b , -S(O)(NH)R 1b , -S(O)2R 1b , -S(O)2N(R 1b )(R 1c ), -S(O)(NR 1b )R 1c , -C(O)N(R 1b)(R 1c ), -C(O)R 1b , or -C(O)OR 1c and Alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl each optionally have 1 to 4 Z 1 is replaced by Ring A is C 6~10 aryl or heteroaryl, each of which optionally has 1 to 4 Z 1a is replaced by Ring B is C 6~10 aryl or heteroaryl, each of which optionally contains 1 to 4 R 4 is replaced by R 2 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -CN, -OR 2a , -SR 2a , -S(O)R 2a , -S(O)(NH)R 2a , -S(O)2R 2a , -S(O)2N(R 2a )(R 2b ), or -S(O)(NR 2a )R 2b and alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl each optionally having 1 to 4 Z 1 is replaced by X 1 , X 2 , and X 3 each independently represents -N=, -C(H)=, or -C(R 8 )=, R 3 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6Alkynyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -CN, -NO2, -OR 3a , -C(O)R 3a , -CH2C(O)OR 3a , -C(O)OR 3a , -C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)R 3b , -N(R 3a )C(O)OR 3b , -N(R 3a )C(O)N(R 3b )2, -C(O)NHS(O)2R 3a , -C(O)NR 3a S(O)2R 3b , -C(O)NR 3a S(O)NR 3b R 3c , -C(O)NR 3a -S(O)(=NR 3b )R 3c , -S(O)2R 3a , -S(O)2OR 3a , -S(O)2N(R 3a )(R 3b ), -N(R 3a )S(O)2R 3b , -S(O)2NHC(O)R 3a , -S(O)(=NR 3a )R 3b , -S(O)(=NR 3a )NR 3b , -S(=NR 3a )(=NR 3b )R 3c , -P(O)(OR 3a )(R 3b ), -P(O)(OR 3a )(OR 3b ), -B(OR 3a )(OR 3b ), or -OC 1~6 Alkyl-C(O)OR 3awherein alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl each optionally comprises 1 to 4 R 3d is replaced by Each R 3a , R 3b , and R 3c However, independently, H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~8 Alkoxyalkyl, -C 1~4 Alkyl-N(R 9a )(R 9b ), -C 1~4 Alkyl-N(R 9a )C(O)-OC 1~4 Alkyl-OP(O)(OR 9c )2, -C 1~4 Alkyl-C(O)N(R 9a )(R 9b ), -C 1~4 Alkyl-OC(O)-C 1~4 Alkyl, -C 1~4 Alkyl-OC(O)-OC 1~4 Alkyl, -C 1~4 Alkyl-OC(O)-C 1~4 Alkyl-N(R 9a )(R 9b ), -C 1~4 Alkyl-OC(O)-C 1~4 Alkyl-OP(O)(OR 9c )2, -C 1~4 Alkyl-C 3~8 Cycloalkyl, -C 1~4 Alkyl-heterocyclyl Lu, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -CHCH(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)(R 9c )(N(R 9d )2), -C(O)OCH2P(O)(R 9c )(N(R 9d )2) or C 1~6 alkyl-heterocyclyl, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl each optionally having 1 to 4 Z 1bis replaced by Each R 4 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 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 4a , -C(O)R 4a , -C(O)OR 4a , -C(O)N(R 4a )(R 4b ), -N(R 4a )(R 4b ), -N(R 4a )2(R 4b ) + , -N(R 4a )-C(O)R 4b , -N(R 4a )C(O)O(R 4b ), -N(R 4a )C(O)N(R 4b )(R 4c ), -N(R 4a )S(O)2(R 4b ), -N(R 4a )S(O)2-N(R 4b )(R 4c ), -N(R 4a )S(O)2O(R 4b ), -OC(O)R 4a , -OC(O)OR 4a , -OC(O)-N(R 4a )(R 4b ), -SR 4a , -S(O)R 4a , -S(O)(NH)R 4a , -S(O)2R 4a , -S(O)2N(R 4a )(R 4b ), -S(O)(NR 4a )R 4b , or -Si(R 4a )3, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally containing 1 to 4 Z 1b is replaced by Alternatively, two R attached to adjacent ring atoms 4 The groups, in combination with the atoms to which they are attached, form C 5~10 cycloalkyl or heterocyclyl, each of which optionally has 1 to 4 Z 1b is replaced by R 5a and R 5b However, independently, H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkoxyalkyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, -C 1~6 Alkyl-N(R 9a )(R 9b ), -CN, -OR 5a1 , or -N(R 5a1 )(R 5a2 ) or Alternatively, R 5a and R 5b combine with the atoms to which they are bonded to form C 3~10 cycloalkyl or heterocyclyl, each of which optionally has 1 to 4 R 5a3 is replaced by Each R 5a1 and R 5a2 However, independently, H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally containing 1 to 4 R 5a4 is replaced by V is -C(O)-, -O-, -N(R 6a )- or -C(R 6b )(R 6c )- and R 6a But H, C 1~6 Alkyl, C 3~10 Cycloalkyl, heterocyclyl, -S (O)2R 6a1 , or -S(O)N(R 6a1 )(NR 6a2 ) wherein cycloalkyl or heterocyclyl are each optionally selected from C 1~6 substituted with alkyl, F, or -CN; Each R 6b and R 6c However, independently, H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkoxyalkyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, -C 1~6 Alkyl-N(R 9a )(R 9b ), -CN, -OR 6c1 , or -N(R 6c2 )(R 6c3 ), wherein alkyl, cycloalkyl, or heterocyclyl each optionally contains 1 to 4 R 6b1 is replaced by Alternatively, R 6b and R 6c combine with the atoms to which they are bonded to form C 3~10 cycloalkyl or heterocyclyl, each of which optionally has 1 to 4 R 6b1 is replaced by Alternatively, R 6a or R 6c But one R 4 In combination with the groups and the atoms to which they are attached, C 5~10 cycloalkyl or heterocyclyl, each of which optionally has 1 to 4 R 10 is replaced by Y is -N(R 7 )-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NH)-, or -S(O)(=NR 7 )- and Each R 1a , R3d , R 5a3 , R 5a4 , R 6b1 , and R 10 But independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, COR 3e , -NO2, or -C(O)N(R 2a )(R 2b ) wherein the heterocyclyl or heteroaryl is optionally selected from C 1~6 Alkyl, C 1~6 Haloalkyl, or C 1~6 substituted with haloalkoxy; Each R 6a1 , R 6a2 , R 6c1 , R 6c2 , R 6c3 , and R 7 However, independently, H, C 1~6 Alkyl or C 3~10 is cycloalkyl, Each R 8 But independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, COR 3e , -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 6~10aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(heterocyclyl), -NH(C 6~10 aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 1~8 haloalkyl)2, -N(C 2~6 alkenyl)2, -N(C 2~6 alkynyl)2, -N(C 3~15 -N(cycloalkyl)2, -N(heterocyclyl)2, -N(C 6~10 aryl), -N(heteroaryl), -N(C 1~9 Alkyl)(C 1~8 haloalkyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 alkyl)(heterocyclyl), -N(C 1~9 Alkyl)(C 6~10 aryl), -N(C 1~9 alkyl)(heteroaryl), -C(O)(C 1~9 alkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 2~6 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 3~15cycloalkyl), -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 1~9 alkyl), -NHC(O)NH(C 1~8haloalkyl), -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, In each instance, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally contains 1 to 3 C1~9 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 alkyl)2, Each R 9a and R 9b However, independently, H, C 1~6 Alkyl or C 1~6 Haloalkyl or R 9a and R9b together form a six-membered heterocyclyl, each Z 1 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 12a , -C(O)-R 12a , -C(O)OR 12a , -C(O)-N(R 12a )(R 12b ), -N(R 12a )(R 12b ), -N(R 12a )2(R 12b ) + , -N(R 12a )C(O)-R 12b , -N(R 12a )C(O)OR 12b , -N(R 12a )C(O)N(R 12b )(R 12c ), -N(R 12a )S(O)2(R 12b ), -NR 12a S(O)2N(R 12b )(R 12c ), -NR 12a S(O)2O(R 12b ), -OC(O)R 12a , -OC(O)OR 12a , -OC(O)-N(R 12a )(R 12b ), -SR 12a , -S(O)R 12a , -S(O)(NH)R 12a , -S(O)2R 12a , -S(O)2N(R 12a )(R 12b ), -S(O)(NR 12a )R 12b , or -Si(R12a )3, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally containing 1 to 4 Z 1a is replaced by each Z 1a 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, -CN, -N3, -OR 12a , -C(O)R 12a , -C(O)OR 12a , -C(O)N(R 12a )(R 12b ), -N(R 12a )(R 12b ), -N(R 12a )2(R 12b ) + , -N(R 12a )-C(O)R 12b , -N(R 12a )C(O)O(R 12b ), -N(R 12a )C(O)N(R 12b )(R 12c ), -N(R 12a )S(O)2(R 12b ), -N(R 12a )S(O)2-N(R 12b )(R 12c ), -N(R 12a )S(O)2O(R 12b ), -OC(O)R 12a , -OC(O)OR 12a , -OC(O)-N(R 12a )(R 12b ), -SR 12a , -S(O)R 12a , -S(O)(NH)R 12a , -S(O)2R12a , -S(O)2N(R 12a )(R 12b ), -S(O)(NR 12a )R 12b , or -Si(R 12a )3, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally containing 1 to 4 Z 1b is replaced by each Z 1b But independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, COR 3e , -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)(C1~8 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 Haloal Kill), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 -C(O)(cycloalkyl), -C(O)(heterocyclyl), -C(O)(C 6~10 aryl), -C(O)(heteroaryl), -C(O)O(C 1~9 alkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(heterocyclyl), -C(O)O(C 6~10 aryl), -C(O)O(heteroaryl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 1~8 haloalkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -C(O)NH(C 3~15 cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(C 6~10 aryl), -C(O)NH(heteroaryl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6alkynyl)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, In each instance, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally contains 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 3~15cycloalkyl), -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 alkyl)2, Each R 1b , R 1c , R 2a , R 2b , R 4a , R 4b , R 4c , R 9c , R 9d , R 12a , R 12b , and R 12c However, independently, H, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally containing 1 to 4 Z 1b is replaced by Each R 3e However, independently, H, C 1~6 Alkyl, C 1~6 Haloalkyl, -C1~4 Alkyl-N(R 9a )(R 9b ), -C 1~4 Alkyl-C(O)N(R 9a )(R 9b ), -C 1~4 Alkyl-OC(O)-C 1~4 Alkyl, -C 1~4 Alkyl-OC(O)-OC 1~4 Alkyl, -C 1~4 Alkyl-OC(O)-C 1~4 Alkyl-N(R 9a )(R 9b ), -C 1~4 Alkyl-C 3~8 Cycloalkyl, -C 1~4 Alkyl-heterocyclyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -P(O)(OR 9c )2, -CH2P(O)(OR 9c )2, -OCH2P(O)(OR 9c )2, -C(O)OCH2P(O)(OR 9c )2, -P(O)(R 9c )(OR 9d ), -OP(O)(R 9c )(OR 9d ), -CH2P(O)(R 9c )(OR 9d ), -C(O)OCH2P(O)(R 9c )(OR 9d ), -P(O)(N(R 9c )2)2, -CH2P(O)(N(R 9c )2)2, -C(O)OCH2P(O)(N(R 9c )2)2, -P(O)(N(R 9c )2)(OR 9d ), -CH2P(O)(N(R 9c )2)(OR 9d ), -C(O)OCH2P(O)(N(R 9c )2)(OR 9d ), -P(O)(R 9c )(N(R 9d )2), -CH2P(O)(R 9c )(N(R 9d)2)、 or -C(O)OCH2P(O)(R 9c )(N(R 9d )2) wherein alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl each optionally contains 1 to 4 Z 1b each heteroaryl having 5 to 12 ring members and 1 to 4 heteroatoms which are each independently N, O, or S; Each heterocyclyl has 3 to 12 ring members and 1 to 4 heteroatoms, each independently N, O, or S, or a pharmaceutically acceptable salt thereof.

[0008] The present disclosure further provides pharmaceutical compositions, methods, and uses comprising compounds of formula (I), (IA-1), (IA-2), or pharmaceutically acceptable salts thereof. For example, the compounds of the present disclosure are generally useful in methods for treating GLP-1R-mediated diseases or conditions. DETAILED DESCRIPTION OF THE INVENTION

[0009] 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" means indicates that the alkyl group has 1 to 6 carbon atoms.

[0010] "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., C1~10 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(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2 -Methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH (-C(CH)(CHCH)), 2-methyl-3-pentyl (-CH(CHCH)CH(CH)), 2,3-dimethyl-2-butyl (-C(CH)CH(CH)), 3,3-dimethyl-2-butyl (-CH(CH)C(CH)), and octyl (-(CH)CH). Alkyl groups can be unsubstituted or substituted.

[0011] "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.

[0012] 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.

[0013] "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.

[0014] "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 alkynyl). Example groups include, but are not limited to, acetylenyl (-C≡CH), propargyl (-CH2C≡CH), and -CH2-C≡C-CH3. Alkynyl groups can be unsubstituted or substituted.

[0015] "Halogen" refers to fluoro (-F), chloro (-Cl), bromo (-Br) and iodo (-I).

[0016] "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.

[0017] "Haloalkoxy" is an alkoxy as defined herein, wherein one or more hydrogen atoms of the alkyl in the alkyloxy are independently replaced by a halogen, which may be the same or different, such that the alkyl is divalent. The alkoxy group and halogen may be any of those described above. In some embodiments, the haloalkoxy defines the number of carbon atoms in the alkyl portion, e.g., C 1~4 Haloalkoxy includes OCF3, OCH2F, OCH2CF3, OCH2CH2CF3, OCCl2CH2CH2CH3, and OC(CH3)2(CF2H). A haloalkoxy group can be unsubstituted or substituted.

[0018] "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.

[0019] "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.

[0020] As used herein, "aryl" refers to a monovalent or divalent single all-carbon aromatic ring or an 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 refers to fused polycyclic ring systems (e.g., aryls) having about 9 to 20 carbon atoms in which multiple rings are aromatic. (Ring systems containing 2, 3, or 4 rings). The rings of fused polycyclic systems can be connected to each other via fused bonds if permitted by valence requirements. When referring to a particular atom-range-membered aryl (e.g., a 6- to 10-membered aryl), the atom range is based on the total ring atoms of the aryl. For example, a 6-membered aryl would include phenyl, and a 10-membered aryl would include naphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like. Aryl groups can be unsubstituted or substituted.

[0021] "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.

[0022] As used herein, "heterocyclyl" or "heterocycle" or "heterocycloalkyl" refers to a single saturated or partially unsaturated non-aromatic ring or non-aromatic polycyclic ring system having at least one heteroatom within the ring (i.e., at least one cyclic (i.e., ring-shaped) heteroatom selected from oxygen, nitrogen, and sulfur). Unless otherwise specified, a heterocyclyl group has 3 to about 20 ring atoms, e.g., 3 to 12 ring atoms, e.g., 4 to 12 ring atoms, 4 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 3 to 5 ring atoms, or 4 to 6 ring atoms, or 4 to 5 ring atoms. Thus, the term includes a single saturated or partially unsaturated ring (e.g., a 3-, 4-, 5-, 6-, or 7-membered ring) having about 1 to 6 ring carbon atoms and about 1 to 3 ring heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. The rings of fused polycyclic (e.g., bicyclic heterocyclyl) systems can be connected to each other via fused, spiro, and bridged bonds, where 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.

[0023] "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., each independently). C with 1 to 3 heteroatoms, each of which is N, O, or S 1~6 Alkyl-3 to 12-membered heterocyclyl). The alkylheterocyclyl group can be unsubstituted or substituted.

[0024] "Heteroaryl" refers to a single aromatic ring having at least one atom other than carbon within the ring, the atom being selected from the group consisting of oxygen, nitrogen, and sulfur. "Heteroaryl" also includes fused polycyclic ring systems having at least one such aromatic ring, which are further described below. Thus, a "heteroaryl" contains a single aromatic 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 also 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 a fused bond if permitted by valence requirements. It is understood that the individual rings of a fused polycyclic ring system can be connected to each other in any order. It is understood that the point of attachment of a heteroaryl or heteroaryl fused polycyclic ring system can be at any suitable atom (e.g., nitrogen) of the heteroaryl or heteroaryl fused polycyclic ring system, including carbon atoms and heteroatoms. It is also understood that when referring to a particular atom range-membered heteroaryl (e.g., a 5- to 10-membered heteroaryl), the atom range is for the total ring atoms of the heteroaryl and includes carbon atoms and heteroatoms. It is also understood that fused polycyclic rings can include an aryl ring fused to a saturated or partially unsaturated heterocyclic ring (e.g., a 3-, 4-, 5-, 6-, or 7-membered ring) having about 1 to 6 ring carbon atoms and about 1 to 3 ring heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring.For example, a 5-membered heteroaryl includes thiazolyl, and a 10-membered heteroaryl includes quinolinyl. Exemplary heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, and tetrazolyl. Heteroaryl groups can be unsubstituted or substituted.

[0025] "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.

[0026] As used herein, "oxo" refers to =O.

[0027] 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.

[0028] "Compounds of the disclosure" include compounds disclosed herein, for example, compounds of the disclosure include compounds of formula (I), (Ia), (Ib), (Ic), and (Id), including compounds of the Examples. In some embodiments, "compounds of the disclosure" include compounds of formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and (Id).

[0029] A "pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, filler, lubricant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for use in humans or domestic animals.

[0030] As used herein, "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 compound sufficient to effect such treatment of the disease. The effective amount varies depending on the compound, the disease and its severity, and the age, weight, etc., of the subject being treated. An effective amount can include a range of amounts. As understood in the art, an effective amount can 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 can be considered in the context of administering one or more therapeutic agents; a single agent can be considered to be administered in an effective amount if 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 can optionally be reduced by the combined action (e.g., additive or synergistic effect) of the compounds.

[0031] 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., within seconds, minutes, or hours of administration of a compound disclosed herein. For example, in some embodiments, a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by administration of 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 administration of 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 administration of 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 administration of 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.

[0032] Pharmaceutically acceptable salts, hydrates, solvates, tautomers, 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 use in veterinary or human medicine.

[0033] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts or as free bases, where appropriate. Pharmaceutically acceptable salts are non-toxic salts of the free base form of a compound that possess the desired pharmacological activity of the free base. These salts can be derived from inorganic or organic acids or bases. For example, compounds containing a basic nitrogen can be prepared as pharmaceutically acceptable salts by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, disulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, etc. , 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, methylsulfonate, propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, and mandelate salts. Lists 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.

[0034] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein also include alkali metal (e.g., sodium, potassium), alkaline earth metal (e.g., magnesium), ammonium, and N(C1≡C4 alkyl)4 salts. + Also included are salts derived from appropriate bases such as , Also included are base addition salts such as sodium or potassium salts.

[0035] Also provided are compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, wherein 1 to n hydrogen atoms bonded to a carbon atom can 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 can enhance resistance to metabolism and thus can be useful for increasing the half-life of the compounds described herein, or their pharmaceutically acceptable salts, isomers, or mixtures, when administered to a mammal. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds can be synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0036] 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. Substitution with positron-emitting isotopes, e.g. 11 C. 18 F, 15 O and 13N may be useful in Positron Emission Topography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of formula (IA-1) and / or (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 the appropriate isotopically labeled reagent in place of the previously used non-labeled reagent.

[0037] 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, such as chromatography and fractional crystallization. Individual Conventional techniques for the preparation / isolation of enantiomers are chiral synthesis from suitable optically pure precursors or, for example, chiral high pressure liquid chromatography. This includes resolution of a racemate (or a racemate of a salt or derivative) using chiral chromatography (HPLC). When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, these compounds are intended to include both the E and Z geometric isomers. Likewise, all tautomeric forms are intended to be included. When 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.

[0038] 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 refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0039] 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.

[0040] 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.

[0041] As used herein, "hydrate" refers to a compound of the present disclosure that is chemically associated with one or more molecules of water.

[0042] "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.

[0043] As used herein, "prodrug" refers to a derivative of a drug that, upon administration to the human body, is converted into the parent drug through 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 through some chemical or enzymatic pathway.

[0044] As used herein, "treatment" or "treating" or "treating" refers to an approach for obtaining a beneficial or desired result. For purposes of this disclosure, beneficial or desired results include, but are 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" refers to 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, improving the disease state, slowing the progression of the disease, improving quality of life, etc. The present invention relates to a method for treating a disease or condition, and the method includes one or more of: increasing the risk of developing a disease or condition; and / or prolonging survival. As used herein, "at-risk individual" refers to an individual who is at risk of developing the condition being treated. An "at-risk" individual may or may not have a detectable disease or condition, and may or may not exhibit detectable disease prior to treatment with the methods described herein. "At-risk" means that an individual has one or more so-called risk factors, which are measurable parameters that correlate with the development of a disease or condition and are known in the art. Individuals who have one or more of these risk factors have a higher probability of developing the disease or condition than individuals without these risk factors.

[0045] II. Compounds In some embodiments, the compound of the present disclosure is a compound of formula (IA-1):

[0046] [ka] During the ceremony, R 1 But C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -SR 1b , -S(O)R 1b , -S(O)(NH)R 1b , -S(O)2R 1b , -S(O)2N(R 1b )(R 1c ), -S(O)(NR 1b )R 1c , -C(O)N(R 1b )(R 1c ), -C(O)R 1b , or -C(O)OR 1c and Alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl each optionally have 1 to 4 Z1 is replaced by Ring A is C 6~10 aryl or heteroaryl, each of which optionally has 1 to 4 Z 1a is replaced by Ring B is C 6~10 aryl or heteroaryl, each of which optionally contains 1 to 4 R 4 is replaced by R 2 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -CN, -OR 2a , -SR 2a , -S(O)R 2a , -S(O)(NH)R 2a , -S(O)2R 2a , -S(O)2N(R 2a )(R 2b ), or -S(O)(NR 2a )R 2b and alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl each optionally having 1 to 4 Z 1 is replaced by X 1 , X 2 , and X 3 each independently represents -N=, -C(H)=, or -C(R 8 )=, R 3 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -CN, -NO2, -OR 3a , -C(O)R 3a , -CH2C(O)OR 3a , -C(O)OR3a , -C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)R 3b , -N(R 3a )C(O)OR 3b , -N(R 3a )C(O)N(R 3b )2, -C(O)NHS(O)2R 3a , -C(O)NR 3a S(O)2R 3b , -C(O)NR 3a S(O)NR 3b R 3c , -C(O)NR 3a -S(O)(=NR 3b )R 3c , -S(O)2R 3a , -S(O)2OR 3a , -S(O)2N(R 3a )(R 3b ), -N(R 3a )S(O)2R 3b , -S(O)2NHC(O)R 3a , -S(O)(=NR 3a )R 3b , -S(O)(=NR 3a )NR 3b , -S(=NR 3a )(=NR 3b )R 3c , -P(O)(OR 3a )(R 3b ), -P(O)(OR 3a )(O R 3b ), -B(OR 3a )(OR 3b ), or -OC 1~6 Alkyl-C(O)OR 3a wherein alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl each optionally comprises 1 to 4 R 3d is replaced by Each R 3a , R 3b , and R 3c However, independently, H, C 1~6 Alkyl, C 1~6Haloalkyl, C 2~8 Alkoxyalkyl, -C 1~4 Alkyl-N(R 9a )(R 9b ), -C 1~4 Alkyl-N(R 9a )C(O)-OC 1~4 Alkyl-OP(O)(OR 9c )2, -C 1~4 Alkyl-C(O)N(R 9a )(R 9b ), -C 1~4 Alkyl-OC(O)-C 1~4 Alkyl, -C 1~4 Alkyl-OC(O)-OC 1~4 Alkyl, -C 1~4 Alkyl-OC(O)-C 1~4 Alkyl-N(R 9a )(R 9b ), -C 1~4 Alkyl-OC(O)-C 1~4 Alkyl-OP(O)(OR 9c )2, -C 1~4 Alkyl-C 3~8 Cycloalkyl, -C 1~4 Alkyl-heterocyclyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -CHCH(N(R 9a )2)C(O)OR 9b , -P(O)(OR 9c )2, -OP(O)(OR 9c )2, -CH2P(O)(OR 9c )2, -CH2OP(O)(OR 9c )2, -OCH2P(O)(OR 9c )2, -C(O)OCH2P(O)(OR 9c )2, -P(O)(R 9c )(OR 9d ), -OP(O)(R 9c )(OR 9d ), -CH2P(O)(R 9c )(OR 9d ), -OCH2P(O)(R 9c )(OR9d ), -C(O)OCH2P(O)(R 9c )(OR 9d ), -P(O)(N(R 9c )2)2, -OP(O)(N(R 9c )2)2, -CH2P(O)(N(R 9c )2)2, -OCH2P(O)(N(R 9c )2)2, -C(O)OCH2P(O)(N(R 9c )2)2, -P(O)(N(R 9c )2)(OR 9d ), -OP(O)(N(R 9c )2)(OR 9d ), -CH2P(O)(N(R 9c )2)(OR 9d ), -OCH2P(O)(N(R 9c )2)(OR 9d ), -C(O)OCH2P(O)(N(R 9c )2)(OR 9d ), -P(O)(R 9c )(N(R 9d )2), -OP(O)(R 9c )(N(R 9d )2), -CH2P(O)(R 9c )(N(R 9d )2), -OCH2P(O)(R 9c )(N(R 9d )2), -C(O)OCH2P(O)(R 9c )(N(R 9d )2) or C 1~6 alkyl-heterocyclyl, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl each optionally having 1 to 4 Z 1b is replaced by Each R 4 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 3~15 Cycloalkyl, heterocyclyl, C6~10 Aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 4a , -C(O)R 4a , -C(O)OR 4a , -C(O)N(R 4a )(R 4b ), -N(R 4a )(R 4b ), -N(R 4a )2(R 4b ) + , -N(R 4a )-C(O)R 4b , -N(R 4a )C(O)O(R 4b ), -N(R 4a )C(O)N(R 4b )(R 4c ), -N(R 4a )S(O)2(R 4b ), -N(R 4a )S(O)2-N(R 4b )(R 4c ), -N(R 4a )S(O)2O(R 4b ), -OC(O)R 4a , -OC(O)OR 4a , -OC(O)-N(R 4a )(R 4b ), -SR 4a , -S(O)R 4a , -S(O)(NH)R 4a , -S(O)2R 4a , -S(O)2N(R 4a )(R 4b ), -S(O)(NR 4a )R 4b , or -Si(R 4a )3, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally containing 1 to 4 Z 1b is replaced by Alternatively, two R attached to adjacent ring atoms 4 The groups, in combination with the atoms to which they are attached, form C 5~10 cycloalkyl or heterocyclyl, each of which optionally has 1 to 4 Z1b is replaced by R 5a and R 5b However, independently, H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkoxyalkyl, halogen, C 3~10 cycloalkyl, heterocyclyl, -C 1~6 Alkyl-N(R 9a )(R 9b ), -CN, -OR 5a1 , or -N(R 5a1 )(R 5a2 ) or Alternatively, R 5a and R 5b combine with the atoms to which they are bonded to form C 3~10 cycloalkyl or heterocyclyl, each of which optionally has 1 to 4 R 5a3 is replaced by Each R 5a1 and R 5a2 However, independently, H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally containing 1 to 4 R 5a4 is replaced by V is -C(O)-, -O-, -N(R 6a )- or -C(R 6b )(R 6c )- and R 6a But H, C 1~6 Alkyl, C 3~10 Cycloalkyl, heterocyclyl, -S(O)2R 6a1 , or -S(O)N(R 6a1 )(NR 6a2 ) wherein cycloalkyl or heterocyclyl are each optionally selected from C 1~6 substituted with alkyl, F, or -CN; Each R 6b and R 6c However, independently, H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkoxyalkyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, -C 1~6 Alkyl-N(R 9a )(R 9b ), -CN, -OR 6c1 , or -N(R 6c2 )(R 6c3 ), wherein alkyl, cycloalkyl, or heterocyclyl each optionally contains 1 to 4 R 6b1 is replaced by Alternatively, R 6b and R 6c combine with the atoms to which they are bonded to form C 3~10 cycloalkyl or heterocyclyl, each of which optionally has 1 to 4 R 6b1 is replaced by Alternatively, R 6a or R 6c But one R 4 In combination with the groups and the atoms to which they are attached, C 5~10 cycloalkyl or heterocyclyl, each of which optionally has 1 to 4 R 10 is replaced by Y is -N(R 7 )-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NH)-, or -S(O)(=NR 7 )- and Each R 1a , R 3d , R 5a3 , R 5a4 , R 6b1 , and R 10 But independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6Alkynyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, COR 3e , -NO2, or -C(O)N(R 2a )(R 2b ) wherein the heterocyclyl or heteroaryl is optionally selected from C 1~6 Alkyl, C 1~6 Haloalkyl, or C 1~6 substituted with haloalkoxy; Each R 6a1 , R 6a2 , R 6c1 , R 6c2 , R 6c3 , and R 7 However, independently, H, C 1~6 Alkyl or C 3~10 is cycloalkyl, Each R 8 But independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, COR 3e , -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(C1~9 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 -N(aryl)2, -N(heteroaryl)2 , -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(C3~15 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 1~9 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)(C1~9 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, In each instance, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally contains 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) -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 alkyl)2, 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 Z 1 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 3~15Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -NO2, -N3, -CN, -OR 12a , -C(O)-R 12a , -C(O)OR 12a , -C(O)-N(R 12a )(R 12b ), -N(R 12a )(R 12b ), -N(R 12a )2(R 12b ) + , -N(R 12a )C(O)-R 12b , -N(R 12a )C(O)OR 12b , -N(R 12a )C(O)N(R 12b )(R 12c ), -N(R 12a )S(O)2(R 12b ), -NR 12a S(O)2N(R 12b )(R 12c ), -NR 12a S(O)2O(R 12b ), -OC(O)R 12a , -OC(O)OR 12a , -OC(O)-N(R 12a )(R 12b ), -SR 12a , -S(O)R 12a , -S(O)(NH)R 12a , -S(O)2R 12a , -S(O)2N(R 12a )(R 12b ), -S(O)(NR 12a )R 12b , or -Si(R 12a )3, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally containing 1 to 4 Z 1a is replaced by each Z 1a But independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Alkoxy, C 1~6Haloalkoxy, 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, -CN, -N3, -OR 12a , -C(O)R 12a , -C(O)OR 12a , -C(O)N(R 12a )(R 12b ), -N(R 12a )(R 12b ), -N(R 12a )2(R 12b ) + , -N(R 12a )-C(O)R 12b , -N(R 12a )C(O)O(R 12b ), -N(R 12a )C(O)N(R 12b )(R 12c ), -N(R 12a )S(O)2(R 12b ), -N(R 12a )S(O)2-N(R 12b )(R 12c ), -N(R 12a )S(O)2O(R 12b ), -OC(O)R 12a , -OC(O)OR 12a , -OC(O)-N(R 12a )(R 12b ), -SR 12a , -S(O)R 12a , -S(O)(NH)R 12a , -S(O)2R 12a , -S(O)2N(R 12a )(R 12b ), -S(O)(NR 12a )R 12b , or -Si(R 12a )3, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally containing 1 to 4 Z 1b is replaced by each Z1b But independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, COR 3e , -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 6~10aryl), -N(C 1~9 alkyl)(heteroaryl), -C(O)(C 1~9 alkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 -C(O)(cycloalkyl), -C(O)(heterocyclyl), -C(O)(C 6~10 aryl), -C(O)(heteroaryl), -C(O)O(C 1~9 alkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(heterocyclyl), -C(O)O(C 6~10 aryl), -C(O)O(heteroaryl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 1~8 haloalkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -C(O)NH(C 3~15 cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(C 6~10 aryl), -C(O)NH(heteroaryl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C 6~10 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 3~15cycloalkyl), -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 1~9alkyl), -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, In each instance, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally contains 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 1~9alkyl), S(O)2(C 1~9 alkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 3~15 -cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)(NH)(C 1~9 alkyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, Each R 1b , R 1c , R 2a , R 2b , R 4a , R 4b , R 4c , R 9c , R 9d , R 12a , R 12b , and R 12c However, independently, H, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally containing 1 to 4 Z 1b is replaced by Each R 3e However, independently, H, C 1~6 Alkyl, C 1~6 Haloalkyl, -C 1~4 Alkyl-N(R 9a )(R 9b ), -C 1~4 Alkyl-C(O)N(R 9a )(R 9b ), -C 1~4 Alkyl-OC(O)-C 1~4 Alkyl, -C 1~4 Alkyl-OC(O)-OC 1~4 Alkyl, -C 1~4 Alkyl-OC(O)-C 1~4 Alkyl-N(R 9a )(R9b ), -C 1~4 Alkyl-C 3~8 Cycloalkyl, -C 1~4 Alkyl-heterocyclyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -P(O)(OR 9c )2, -CH2P(O)(OR 9c )2, -OCH2P(O)(OR 9c )2, -C(O)OCH2P(O)(OR 9c )2, -P(O)(R 9c )(OR 9d ), -OP(O)(R 9c )(OR 9d ), -CH2P(O)(R 9c )(OR 9d ), -C(O)OCH2P(O)(R 9c )(OR 9d ), -P(O)(N(R 9c )2)2, -CH2P(O)(N(R 9c )2)2, -C(O)OCH2P(O)(N(R 9c )2)2, -P(O)(N(R 9c )2)(OR 9d ), -CH2P(O)(N(R 9c )2)(OR 9d ), -C(O)OCH2P(O)(N(R 9c )2)(OR 9d ), -P(O)(R 9c )(N(R 9d )2), -CH2P(O)(R 9c )(N(R 9d )2), or -C(O)OCH2P(O)(R 9c )(N(R 9d )2) wherein alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl each optionally contains 1 to 4 Z 1b each heteroaryl having 5 to 12 ring members and 1 to 4 heteroatoms which are each independently N, O, or S; Each heterocyclyl has from 3 to 12 ring members and from 1 to 4 heteroatoms, each independently N, O, or S, or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, the compound of the present disclosure is a compound of formula (IA-1):

[0048] [ka] During the ceremony, R 1 But C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -SR 1b , -S(O)R 1b , -S(O)(NH)R 1b , -S(O)2R 1b , -S(O)2N(R 1b )(R 1c ), -S(O)(NR 1b )R 1c , -C(O)N(R 1b )(R 1c ), -C(O)R 1b , or -C(O)OR 1c and Alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl each optionally have 1 to 4 Z 1 is replaced by Ring A is C 6~10 aryl or heteroaryl, each of which optionally has 1 to 4 Z 1a is replaced by Ring B is C 6~10 aryl or heteroaryl, each of which optionally contains 1 to 4 R 4 is replaced by R 2 But H, C 1~6 Alkyl, C1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -CN, -OR 2a , -SR 2a , -S(O)R 2a , -S(O)(NH)R 2a , -S(O)2R 2a , -S(O)2N(R 2a )(R 2b ), or -S(O)(NR 2a )R 2b and alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl each optionally having 1 to 4 Z 1 is replaced by X 1 , X 2 , and X 3 each independently represents -N=, -C(H)=, or -C(R 8 )=, R 3 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -CN, -NO2, -OR 3a , -C(O)R 3a , C(O)OR 3a , -C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)R 3b , -N(R 3a )C(O)OR 3b , -N(R 3a )C(O)N(R 3b )2, -C(O)NHS(O)2R 3a , -C(O)NR 3a S(O)2R 3b , -C(O)NR 3a S(O)NR 3b R3c , -C(O)NR 3a -S(O)(=NR 3b )R 3c , -S(O)2R 3a , -S(O)2OR 3a , -S(O)2N(R 3a )(R 3b ), -N(R 3a )S(O)2R 3b , -S(O)2NHC(O)R 3a , -S(O)(=NR 3a )R 3b , -S(O)(=NR 3a )NR 3b , -S(=NR 3a )(=NR 3b )R 3c , -P(O)(OR 3a )(R 3b ), -P(O)(OR 3a )(OR 3b ), or -B(OR 3a )(OR 3b wherein alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally selected from 1 to 4 R 3d is replaced by Each R 3a , R 3b , and R 3c However, independently, H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~8 Alkoxyalkyl, -C 1~4 Alkyl-N(R 9a )(R 9b ), -C 1~4 Alkyl-C(O)N(R 9a )(R 9b ), -C 1~4 Alkyl-OC(O)-C 1~4 Alkyl, -C 1~4 Alkyl-OC(O)-OC 1~4 Alkyl, -C 1~4 Alkyl-OC(O)-C 1~4 Alkyl-N(R 9a )(R 9b ), -C 1~4Alkyl-C 3~8 Cycloalkyl, -C 1~4 Alkyl-heterocyclyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -P(O)(OR 9c )2, -OP(O)(OR 9c )2, -CH2P(O)(OR 9c )2, -OCH2P(O)(OR 9c )2, -C( O)OCH2P(O)(OR 9c )2, -P(O)(R 9c )(OR 9d ), -OP(O)(R 9c )(OR 9d ), -CH2P(O)(R 9c )(OR 9d ), -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)(R 9c )(N(R 9d )2), or -C(O)OCH2P(O)(R 9c )(N(R 9d )2) and alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl each optionally having 1 to 4 Z 1b is replaced by Each R 4 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 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 4a , -C(O)R 4a , -C(O)OR 4a , -C(O)N(R 4a )(R 4b ), -N(R 4a )(R 4b ), -N(R 4a )2(R 4b ) + , -N(R 4a )-C(O)R 4b , -N(R 4a )C(O)O(R 4b ), -N(R 4a )C(O)N(R 4b )(R 4c ), -N(R 4a )S(O)2(R 4b ), -N(R 4a )S(O)2-N(R 4b )(R 4c ), -N(R 4a )S(O)2O(R 4b ), -OC(O)R 4a , -OC(O)OR 4a , -OC(O)-N(R 4a )(R 4b ), -SR4a , -S(O)R 4a , -S(O)(NH)R 4a , -S(O)2R 4a , -S(O)2N(R 4a )(R 4b ), -S(O)(NR 4a )R 4b , or -Si(R 4a )3, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally containing 1 to 4 Z 1b is replaced by Alternatively, two R attached to adjacent ring atoms 4 The groups, in combination with the atoms to which they are attached, form C 5~10 cycloalkyl or heterocyclyl, each of which optionally has 1 to 4 Z 1b is replaced by R 5a and R 5b However, independently, H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkoxyalkyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, -C 1~6 Alkyl-N(R 9a )(R 9b ), -CN, -OR 5a1 , or -N(R 5a1 )(R 5a2 ) or Alternatively, R 5a and R 5b combine with the atoms to which they are bonded to form C 3~10 cycloalkyl or heterocyclyl, each of which optionally has 1 to 4 R 5a3 is replaced by Each R 5a1 and R 5a2 However, independently, H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, heterocyclyl, C6~10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally containing 1 to 4 R 5a4 is replaced by V is -C(O)-, -O-, -N(R 6a )- or -C(R 6b )(R 6c )- and R 6a But H, C 1~6 Alkyl, C 3~10 Cycloalkyl, heterocyclyl, -S(O)2R 6a1 , or -S(O)N(R 6a1 )(NR 6a2 ) wherein cycloalkyl or heterocyclyl are each optionally selected from C 1~6 substituted with alkyl, F, or -CN; Each R 6b and R 6c However, independently, H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkoxyalkyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, -C 1~6 Alkyl-N(R 9a )(R 9b ), -CN, -OR 6c1 , or -N(R 6c2 )(R 6c3 ), wherein alkyl, cycloalkyl, or heterocyclyl each optionally contains 1 to 4 R 6b1 is replaced by Alternatively, R 6b and R 6c combine with the atoms to which they are bonded to form C 3~10 cycloalkyl or heterocyclyl, each of which optionally has 1 to 4 R 6b1 is replaced by Alternatively, R 6a or R 6c But one R 4 In combination with the groups and the atoms to which they are attached, C 5~10cycloalkyl or heterocyclyl, each of which optionally has 1 to 4 R 10 is replaced by Y is -N(R 7 )-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NH)-, or -S(O)(=NR 7 )- and Each R 1a , R 3d , R 5a3 , R 5a4 , R 6b1 , and R 10 But independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, COR 3e , -NO2, or -C(O)N(R 2a )(R 2b ) and The heterocyclyl or heteroaryl is optionally selected from C 1~6 Alkyl, C 1~6 Haloalkyl, or C 1~6 substituted with haloalkoxy; Each R 6a1 , R 6a2 , R 6c1 , R 6c2 , R 6c3 , and R 7 However, independently, H, C 1~6 Alkyl or C 3~10 is cycloalkyl, Each R 8 But independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10Aryl, heteroaryl, oxo, -OH, -CN, COR 3e , -NO2, -NH2, -N3, -SH, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 -Cycloalkyl), -O(heterocyclyl), -O(C 6~10 aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(heterocyclyl), -NH(C 6~10 aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 1~8 haloalkyl)2, -N(C 2~6 alkenyl)2, -N(C 2~6 alkynyl)2, -N(C 3~15 -N(cycloalkyl)2, -N(heterocyclyl)2, -N(C 6~10 aryl), -N(heteroaryl), -N(C 1~9 Alkyl)(C 1~8 haloalkyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 alkyl)(heterocyclyl), -N(C 1~9 Alkyl)(C 6~10 aryl), -N(C 1~9 alkyl)(heteroaryl), -C(O)(C 1~9 alkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 2~6 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 Haloal Kill)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 2~6alkenyl), -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(C6~10 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, In each instance, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally contains 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 1~9alkyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, Each R 9a and R 9b However, independently, H, C 1~6 Alkyl or C 1~6 is haloalkyl, each Z 1 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~ 6Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -NO2, -N3, -CN, -OR 12a , -C(O)-R 12a , -C(O)OR 12a , -C(O)-N(R 12a )(R 12b ), -N(R 12a )(R 12b ), -N(R 12a )2(R 12b ) + , -N(R 12a )C(O)-R 12b , -N(R 12a )C(O)OR 12b , -N(R 12a )C(O)N(R 12b )(R 12c ), -N(R 12a )S(O)2(R 12b ), -NR 12a S(O)2N(R 12b )(R 12c ), -NR 12a S(O)2O(R 12b ), -OC(O)R 12a , -OC(O)OR 12a , -OC(O)-N(R 12a )(R 12b ), -SR 12a, -S(O)R 12a , -S(O)(NH)R 12a , -S(O)2R 12a , -S(O)2N(R 12a )(R 12b ), -S(O)(NR 12a )R 12b , or -Si(R 12a )3, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally containing 1 to 4 Z 1a is replaced by each Z 1a 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, -CN, -N3, -OR 12a , -C(O)R 12a , -C(O)OR 12a , -C(O)N(R 12a )(R 12b ), -N(R 12a )(R 12b ), -N(R 12a )2(R 12b ) + , -N(R 12a )-C(O)R 12b , -N(R 12a )C(O)O(R 12b ), -N(R 12a )C(O)N(R 12b )(R 12c ), -N(R 12a )S(O)2(R 12b ), -N(R 12a )S(O)2-N(R 12b )(R 12c ), -N(R 12a )S(O)2O(R 12b ), -OC(O)R12a , -OC(O)OR 12a , -OC(O)-N(R 12a )(R 12b ), -SR 12a , -S(O)R 12a , -S(O)(NH)R 12a , -S(O)2R 12a , -S(O)2N(R 12a )(R 12b ), -S(O)(NR 12a )R 12b , or -Si(R 12a )3, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally containing 1 to 4 Z 1b is replaced by each Z 1b But independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, COR 3e , -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(C2~6 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 1~8 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(C6~10 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 1~9 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(C1~8 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, In each instance, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally contains 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 alkyl)2, Each R 1b , R 1c , R 2a , R 2b , R 4a , R 4b , R 4c , R 9c , R 9d , R 12a , R 12b , and R 12c However, independently, H, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, heterocyclyl, C 6~10alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally containing 1 to 4 Z 1b is replaced by Each R 3e However, independently, H, C 1~6 Alkyl, C 1~6 Haloalkyl, -C 1~4 Alkyl-N(R 9a )(R 9b ), -C 1~4 Alkyl-C(O)N(R 9a )(R 9b ), -C 1~4 Alkyl-OC(O)-C 1~4 Alkyl, -C 1~4 Alkyl-OC(O)-OC 1~4 Alkyl, -C 1~4 Alkyl-OC(O)-C 1~4 Alkyl-N(R 9a )(R 9b ), -C 1~4 Alkyl-C 3~8 Cycloalkyl, -C 1~4 Alkyl-heterocyclyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -P(O)(OR 9c )2, -CH2P(O)(OR 9c )2, -OCH2P(O)(OR 9c )2, -C(O)OCH2P(O)(OR 9c )2, -P(O)(R 9c )(OR 9d ), -OP(O)(R 9c )(OR 9d ), -CH2P(O)(R 9c )(OR 9d ), -C(O)OCH2P(O)(R 9c )(OR 9d ), -P(O)(N(R 9c )2)2, -CH2P(O)(N(R 9c )2)2, -C(O)OCH2P(O)(N(R 9c )2)2, -P(O)(N(R 9c )2)(OR9d ), -CH2P(O)(N(R 9c )2)(OR 9d ), -C(O)OCH2P(O)(N(R 9c )2)(OR 9d ), -P(O)(R 9c )(N(R 9d )2), -CH2P(O)(R 9c )(N(R 9d )2), or -C(O)OCH2P(O)(R 9c )(N(R 9d )2) wherein alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl each optionally contains 1 to 4 Z 1b each heteroaryl having 5 to 12 ring members and 1 to 4 heteroatoms which are each independently N, O, or S; Each heterocyclyl has from 3 to 12 ring members and from 1 to 4 heteroatoms, each independently N, O, or S, or a pharmaceutically acceptable salt thereof.

[0049] In some embodiments, the compound of the present disclosure is a compound of formula (I):

[0050] [ka] During the ceremony, R 1 But C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -SR 1b , -S(O)R 1b , -S(O)(NH)R 1b , -S(O)2R 1b , -S(O)2N(R 1b )(R 1c ), -S(O)(NR 1b )R 1c , -C(O)N(R 1b )(R1c ), -C(O)R 1b , or -C(O)OR 1c and Alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl each optionally have 1 to 4 Z 1 is replaced by Ring A is C 6~10 aryl or heteroaryl, each of which optionally has 1 to 4 Z 1a is replaced by Ring B is C 6~10 aryl or heteroaryl, each of which optionally contains 1 to 4 R 4 is replaced by R 2 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -CN, -OR 2a , -SR 2a , -S(O)R 2a , -S(O)(NH)R 2a , -S(O)2R 2a , -S(O)2N(R 2a )(R 2b ), or -S(O)(NR 2a )R 2b and alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl each optionally having 1 to 4 Z 1 is replaced by X 1 , X 2 , and X 3 each independently represents -N=, -C(H)=, or -C(R 8 )=, R 3 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -CN, -NO2, -OR 3a , -C(O)R 3a , C(O)OR 3a , -C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)R 3b , -N(R 3a )C(O)OR 3b , -N(R 3a )C(O)N(R 3b )2, -C(O)NHS(O)2R 3a , -C(O)NR 3a S(O)2R 3b , -C(O)NR 3a S(O)NR 3b R 3c , -C(O)NR 3a -S(O)(=NR 3b )R 3c , -S(O) 2 R 3a , -S(O)2OR 3a , -S(O)2N(R 3a )(R 3b ), -N(R 3a )S(O)2R 3b , -S(O)2NHC(O)R 3a , -S(O)(=NR 3a )R 3b , -S(O)(=NR 3a )NR 3b , -S(=NR 3a )(=NR 3b )R 3c , -P(O)(OR 3a )(R 3b ), -P(O)(OR 3a )(OR 3b ), or -B(OR 3a )(OR 3b wherein alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally selected from 1 to 4 R 3d is replaced by Each R 3a , R 3b, and R 3c However, independently, H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~8 Alkoxyalkyl, -C 1~4 Alkyl-N(R 9a )(R 9b ), -C 1~4 Alkyl-C(O)N(R 9a )(R 9b ), -C 1~4 Alkyl-OC(O)-C 1~4 Alkyl, -C 1~4 Alkyl-OC(O)-OC 1~4 Alkyl, -C 1~4 Alkyl-OC(O)-C 1~4 Alkyl-N(R 9a )(R 9b ), -C 1~4 Alkyl-C 3~8 Cycloalkyl, -C 1~4 Alkyl-heterocyclyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -P(O)(OR 9c )2, -OP(O)(OR 9c )2, -CH2P(O)(OR 9c )2, -OCH2P(O)(OR 9c )2, -C(O)OCH2P(O)(OR 9c )2, -P(O)(R 9c )(OR 9d ), -OP(O)(R 9c )(OR 9d ), -CH2P(O)(R 9c )(OR 9d ), -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)(R 9c )(N(R 9d )2), or -C(O)OCH2P(O)(R 9c )(N(R 9d )2) and alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl each optionally having 1 to 4 Z 1b is replaced by Each R 4 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 N, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 4a , -C(O)R 4a , -C(O)OR 4a , -C(O)N(R 4a )(R 4b ), -N(R 4a )(R 4b ), -N(R 4a)2(R 4b ) + , -N(R 4a )-C(O)R 4b , -N(R 4a )C(O)O(R 4b ), -N(R 4a )C(O)N(R 4b )(R 4c ), -N(R 4a )S(O)2(R 4b ), -N(R 4a )S(O)2-N(R 4b )(R 4c ), -N(R 4a )S(O)2O(R 4b ), -OC(O)R 4a , -OC(O)OR 4a , -OC(O)-N(R 4a )(R 4b ), -SR 4a , -S(O)R 4a , -S(O)(NH)R 4a , -S(O)2R 4a , -S(O)2N(R 4a )(R 4b ), -S(O)(NR 4a )R 4b , or -Si(R 4a )3, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally containing 1 to 4 Z 1b is replaced by Alternatively, two R attached to adjacent ring atoms 4 The groups, in combination with the atoms to which they are attached, form C 5~10 cycloalkyl or heterocyclyl, each of which optionally has 1 to 4 Z 1b is replaced by R 5a and R 5b However, independently, H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkoxyalkyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, -CN, -OR5a1 , or -N(R 5a1 )(R 5a2 ) or Alternatively, R 5a and R 5b combine with the atoms to which they are bonded to form C 3~10 cycloalkyl or heterocyclyl, each of which optionally has 1 to 4 R 5a3 is replaced by Each R 5a1 and R 5a2 However, independently, H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally containing 1 to 4 R 5a4 is replaced by V is -C(O)-, -O-, -N(R 6a )- or -C(R 6b )(R 6c )- and R 6a But H, C 1~6 Alkyl, C 3~10 Cycloalkyl, heterocyclyl, -S(O)2R 6a1 , or -S(O)N(R 6a1 )(NR 6a2 ) wherein cycloalkyl or heterocyclyl are each optionally selected from C 1~6 substituted with alkyl, F, or -CN; Each R 6b and R 6c However, independently, H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkoxyalkyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, -CN, -OR 6c1 , or -N(R 6c2 )(R 6c3 ), wherein alkyl, cycloalkyl, or heterocyclyl each optionally contains 1 to 4 R6b1 is replaced by Alternatively, R 6b and R 6c combine with the atoms to which they are bonded to form C 3~10 cycloalkyl or heterocyclyl, each of which optionally has 1 to 4 R 6b1 is replaced by Alternatively, R 6a or R 6c But one R 4 In combination with the groups and the atoms to which they are attached, C 5~10 cycloalkyl or heterocyclyl, each of which optionally has 1 to 4 R 10 is replaced by Y is -N(R 7 )-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NH)-, or -S(O)(=NR 7 )- and Each R 1a , R 3d , R 5a3 , R 5a4 , R 6b1 , and R 10 But independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, NO2, or -C(O)N(R 2a )(R 2b ) and heterocyclic aryl or heteroaryl is optionally C 1~6 Alkyl, C 1~6 Haloalkyl, or C 1~6 substituted with haloalkoxy; Each R 6a1 , R 6a2 , R 6c1 , R6c2 , R 6c3 , and R 7 However, independently, H, C 1~6 Alkyl or C 3~10 is cycloalkyl, Each R 9a and R 9b However, independently, H, C 1~6 Alkyl or C 1~6 is haloalkyl, each Z 1 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 12a , -C(O)-R 12a , -C(O)OR 12a , -C(O)-N(R 12a )(R 12b ), -N(R 12a )(R 12b ), -N(R 12a )2(R 12b ) + , -N(R 12a )C(O)-R 12b , -N(R 12a )C(O)OR 12b , -N(R 12a )C(O)N(R 12b )(R 12c ), -N(R 12a )S(O)2(R 12b ), -NR 12a S(O)2N(R 12b )(R 12c ), -NR 12a S(O)2O(R 12b ), -OC(O)R 12a , -OC(O)OR 12a , -OC(O)-N(R 12a )(R 12b ), -SR12a , -S(O)R 12a , -S(O)(NH)R 12a , -S(O)2R 12a , -S(O)2N(R 12a )(R 12b ), -S(O)(NR 12a )R 12b , or -Si(R 12a )3, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally containing 1 to 4 Z 1a is replaced by each Z 1a 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, -CN, -N3, -OR 12a , -C(O)R 12a , -C(O)OR 12a , -C(O)N(R 12a )(R 12b ), -N(R 12a )(R 12b ), -N(R 12a )2(R 12b ) + , -N(R 12a )-C(O)R 12b , -N(R 12a )C(O)O(R 12b ), -N(R 12a )C(O)N(R 12b )(R 12c ), -N(R 12a )S(O)2(R 12b ), -N(R 12a )S(O)2-N(R 12b )(R 12c ), -N(R 12a )S(O)2O(R 12b), -OC(O)R 12a , -OC(O)OR 12a , -OC(O)-N(R 12a )(R 12b ), -SR 12a , -S(O)R 12a , -S(O)(NH)R 12a , -S(O)2R 12a , -S(O)2N(R 12a )(R 12b ), -S(O)(NR 12a )R 12b , or -Si(R 12a )3, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally containing 1 to 4 Z 1b is replaced by Each R 8 or Z 1b But independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, NO2, -NH2, -N3, -SH, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 -Cycloalkyl), -O(heterocyclyl), -O(C 6~10 aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(heterocyclyl), -NH(C 6~10 aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 1~8haloalkyl)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)2, -N(heteroaryl)2, -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 3~15cycloalkyl), -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 1~9 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 1~9alkyl), -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, In each instance, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally contains 1 to 3 C 1~9 Alkyl, C 1~8 Haloalkyl, halogen, -OH, -NH2, -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 alkyl)2, and each R 1b , R 1c , R 2a , R 2b , R 4a , R 4b , R 4c , R 9c , R 9d , R 12a , R 12b , and R 12c However, independently, H, C 1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, heterocyclyl, C 6~10alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally containing 1 to 4 Z 1b is replaced by each heteroaryl has 5 to 12 ring members and 1 to 4 heteroatoms, each independently N, O, or S; Each heterocyclyl has from 3 to 12 ring members and from 1 to 4 heteroatoms, each independently N, O, or S, or a pharmaceutically acceptable salt thereof.

[0051] In some embodiments of the compounds of Formula (I), (IA-1), and / or other formulae described herein, or pharmaceutically acceptable salts thereof, R 1 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms each independently being N, O or S, or 3-12 membered heterocyclyl having 1-3 heteroatoms each independently being N, O or S, wherein the cycloalkyl, aryl, heteroaryl and heterocyclyl each optionally contain 1-3 Z 1 is replaced by Ring A is C 6~10 aryl, a 5- to 10-membered heteroaryl having 1 to 3 heteroatoms each independently being N, O, or S, or a 3- to 12-membered heterocyclyl having 1 to 3 heteroatoms each independently being N, O, or S, wherein the aryl, heteroaryl, and heterocyclyl each optionally contain 1 to 4 Z 1 is replaced by Ring B is C 6~10 aryl, or a 5- to 10-membered heteroaryl having 1 to 3 heteroatoms, each independently N, O, or S, wherein the aryl and heteroaryl each optionally contain 1 to 4 R 4 is replaced by R2 But H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 2~6 Alkoxyalkyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 1~6 Alkyl-heterocyclyl, C 1~6 Alkyl-C 6~10 Aryl, C 1~6 Alkyl-heteroaryl, C 1~6 Alkyl-C 3~10 Cycloalkyl-C 1~6 Alkyl, C 1~6 Alkyl-heterocyclyl-C 1~6 Alkyl, -CN, -C(O)R 2a , -C(O)OR 2a , -C(O)N(R 2a )(R 2b ), -C(O)NR 2c S(O)2R 2a , -S(O)2R 2a , -S(O)2N(R 2a )(R 2b ), or -S(O)NR 2c C(O)R 2a wherein each heterocyclyl contains 3 to 12 ring members and 1 to 3 heteroatoms, each independently N, O, or S; each heteroaryl contains 5 to 10 ring members and 1 to 3 heteroatoms, each independently N, O, or S; and the cycloalkyl, aryl, heteroaryl, and heterocyclyl each optionally contain 1 to 4 Z 1b is replaced by X 1 , X 2 , and X 3 each independently represents -N= or -C(R 8 )=, R 3 But H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6Alkynyl, C 1~6 Haloalkyl, halogen, C 3~10 Cycloalkyl, C 6~10 Aryl, 3- to 12-membered heterocyclyl having 1 to 3 heteroatoms, each independently N, O, or S; 5- to 10-membered heteroaryl having 1 to 4 heteroatoms, each independently N, O, or S; -CN, -NO2, -C(O)R 3a , -C(O)OR 3a , -C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)R 3b , -N(R 3a )C(O)OR 3b , -N(R 3a )C(O)N(R 3b )2, -C(O)NHS(O)2R 3a , -S(O)2R 3a , -S(O)2OR 3a , -S(O)2N(R 3a )(R 3b ), -N(R 3a )S(O)2R 3b , -S(O)2NHC(O)R 3a , -S(O)(=NR 3a )R 3b , -S(O)(=NR 3a )NR 3b , -S(=NR 3a )(=NR 3b )R 3c , -P(O)(OR 3a )(R 3b ), -P(O)(OR 3a )(OR 3b ), or -B(OR 3a )(OR 3b wherein alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl are each optionally selected from 1 to 4 R 3d is replaced by Each R 2a , R 2b , R 2c , R 3a , R 3b , and R 3c However, independently, H, C1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, C 6~10 aryl, a 3- to 12-membered heterocyclyl having 1 to 3 heteroatoms, each independently N, O, or S, or a 5- to 10-membered heteroaryl having 1 to 4 heteroatoms, each independently N, O, or S; Each R 4 However, independently, H, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, halogen, C 3~10 cycloalkyl, 3- to 12-membered heterocyclyl having 1-3 heteroatoms, each independently N, O, or S; oxo, OH, —CN, —NO2, —N3, C(O)OR 4a , or C(O)N(R 4a )(R 4b ) wherein cycloalkyl and heterocyclyl each optionally contain 1 to 4 R 4c is replaced by Each R 4a and R 4b However, independently, H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, C 6~10 aryl, a 3- to 12-membered heterocyclyl having 1 to 3 heteroatoms, each independently N, O, or S, or a 5- to 10-membered heteroaryl having 1 to 4 heteroatoms, each independently N, O, or S; Alternatively, two R attached to adjacent ring atoms 4 The groups, in combination with the atoms to which they are attached, form C 3~10 cycloalkyl or 3- to 12-membered heterocyclyl having 1-3 heteroatoms, each independently N, O, or S, and the cycloalkyl and heterocyclyl each optionally contain 1-4 R 4cis replaced by R 5a and R 5b However, independently, H, C 1~6 Alkyl, halogen, C 3~10 cycloalkyl, 3- to 12-membered heterocyclyl having 1 to 3 heteroatoms, each independently N, O, or S; -CN, -OR 5a1 , or -N(R 5a1 )(R 5a2 ) wherein cycloalkyl and heterocyclyl each optionally contain 1 to 4 R 5a3 is replaced by Each R 5a1 , R 5a1 , and R 5a2 However, independently, H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 aryl, 3- to 12-membered heterocyclyl having 1-3 heteroatoms each independently being N, O, or S, or 5- to 10-membered heteroaryl having 1-3 heteroatoms each independently being N, O, or S, and the cycloalkyl, aryl, heteroaryl, and heterocyclyl each optionally contain 1-4 R 5a4 is replaced by V is -C(O)-, -O-, -N(R 6a )-, -C(R 6b )(R 6c )- and R 6a But H, C 1~6 Alkyl, C 3~10 cycloalkyl, 3- to 12-membered heterocyclyl having 1 to 3 heteroatoms, each independently N, O, or S; -S(O)2 R 6a1 , or -S(O)N(R 6a1 )(NR 6a2 ) wherein cycloalkyl and heterocyclyl are each optionally selected from F, CN, or C 1~6 is substituted with alkyl, Each R 6b and R 6care independently H, halogen, -CN, C 1~6 Alkyl, C 3~10 cycloalkyl, 3- to 12-membered heterocyclyl having 1-3 heteroatoms, each independently N, O, or S; -OR 6c1 , or -N(R 6c2 )(R 6c3 wherein alkyl, cycloalkyl, and heterocyclyl are each optionally selected from 1 to 4 R 6b1 is replaced by Alternatively, R 6b and R 6c in combination with the atoms to which they are attached, optionally 1 to 4 R 6b1 C replaced with 3~10 Forming Alternatively, R 6c But one R 4 In combination with the groups and the atoms to which they are attached, C 3~10 cycloalkyl or 3- to 12-membered heterocyclyl having 1-3 heteroatoms, each independently N, O, or S, and the cycloalkyl and heterocyclyl each optionally contain 1-4 R 4c is replaced by Y is -N(R 7 )-, -O-, -S-, -S(O)-, -S(=NH)-, or -S(=NR 7 )- and Each R 8 But H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, halogen, C 3~10 Cycloalkyl, C 6~10 Aryl, 3- to 12-membered heterocyclyl having 1 to 3 heteroatoms, each independently N, O, or S; 5- to 10-membered heteroaryl having 1 to 4 heteroatoms, each independently N, O, or S; -CN, -NO2, -C(O)R 3a , -C(O)OR 3a , -C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)R3b , -N(R 3a )C(O)OR 3b , -N(R 3a )C(O)N(R 3b )2, -C(O)NHS(O)2R 3a , -S(O)2R 3a , -S(O)2OR 3a , -S(O)2N(R 3a )(R 3b ), -N(R 3a )S(O)2R 3b , -S(O)2NHC(O)R 3a , -S(O)(=NR 3a )R 3b , -S(O)(=NR 3a )NR 3b , -S(=NR 3a )(=NR 3b )R 3c , -P(O)(OR 3a )(R 3b ), -P(O)(OR 3a )(OR 3b ), or -B(OR 3a )(OR 3b ) and each Z 1b , R 3d , R 4c , R 5a3 , R 5a4 , and R 6b1 But independently, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, halogen, C 3~10 cycloalkyl, 3- to 12-membered heterocyclyl having 1-3 heteroatoms, each independently N, O, or S; 5- to 10-membered heteroaryl having 1-3 heteroatoms, each independently N, O, or S; oxo, —OH, —CN, or —NO2; Each R 6a1 , R 6a2 , R 6c1 , R 6c2 , R 6c3 , and R 7 But independently, C 1~6 Alkyl or C 3~10It is cycloalkyl.

[0052] In some embodiments of the compounds of Formula (I), (IA-1), and / or other formulae described herein, or pharmaceutically acceptable salts thereof, R 1 is C 6~10 aryl, heteroaryl, or heterocyclyl, wherein the aryl, heteroaryl, or heterocyclyl optionally has one to three Z 1 In some embodiments of the compounds of Formula (I), (IA-1), and / or other formulae described herein, or pharmaceutically acceptable salts thereof, R 1 is C 6~10 aryl, heteroaryl, or heterocyclyl, wherein the aryl, heteroaryl, or heterocyclyl optionally has 1 to 3 R 1a In some embodiments of the compounds of Formula (I), (IA-1), and / or other formulae described herein, or pharmaceutically acceptable salts thereof, R 1 is C 6~10 aryl, a 5- to 10-membered heteroaryl having 1 to 3 heteroatoms, each independently O, N, or S; or a 4- to 12-membered heterocyclyl having 1 to 3 heteroatoms, each independently O, N, or S; and the aryl, heteroaryl, or heterocyclyl optionally has 1 to 3 R 1a is replaced by In some embodiments of compounds of formula (I), (IA-1), and / or other formulas described herein, R 1 is heterocyclyl, C 6~10 aryl, or each optionally 1 to 3 Z 1 and Z is a 6-membered heteroaryl substituted with 1 independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, halogen, oxo, -OH, -CN, or -NO2, C 3~10It is a cycloalkyl, a 3- to 12-membered heterocyclyl having 1 to 3 heteroatoms, or a 5- to 10-membered heteroaryl having 1 to 3 heteroatoms.

[0053] In some embodiments of the compounds of Formula (I), (IA-1), and / or other formulae described herein, or pharmaceutically acceptable salts thereof, each R 5a and R 5b are independently H, C 1~6 Alkyl, F, Cl, -OR 5a1 , -CN, C 3~10 In some embodiments of the compounds of Formula (I), (IA-1), and / or (IA-2), or pharmaceutically acceptable salts thereof, R 5a is H and R 5b is H, C 1~6 Alkyl, F, Cl, -OR 5a1 , -CN, C 3~10 In some embodiments, each R 5a and R 5b is H.

[0054] In some embodiments of the compounds of Formula (I), (IA-1), and / or other formulae described herein, or pharmaceutically acceptable salts thereof, Y is —O—.

[0055] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof has the structure of Formula (Ia):

[0056] [ka] where the subscript p is 1, 2, or 3.

[0057] In some embodiments of the compounds of Formula (I), (IA-1), (Ia), and / or other formulae described herein, or pharmaceutically acceptable salts thereof, ring A is C 6~10aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with 1 to 3 Z 1a and each Z 1a independently, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 2~6 Alkoxyalkyl, C 3~10 Cycloalkyl, C 6~10 Aryl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -C(O)N(R 2a )(R 2b ), oxo, -OH, halogen, -CN, -NO2, -OR 12a , C 3~10 Cycloalkyl, heterocyclyl, heterocyclyl-C 1~6 Alkyl, heterocyclyl-C 1~6 Haloalkyl, Heteroaryl, Heteroaryl-C 1~6 Alkyl or heteroaryl-C 1~6 haloalkyl, each of which is optionally selected from Z 1b In some embodiments of the compounds of Formula (I), (IA-1), (Ia), and / or other formulas described herein, or pharmaceutically acceptable salts thereof, ring A is substituted with C 6~10 aryl or a 5-10 membered heteroaryl having 1-3 heteroatoms each independently being O, N, or S, and the aryl or heteroaryl optionally has 1-3 Z 1a In some embodiments of the compounds of Formula (I), (IA-1), (Ia), and / or other formulas described herein, or pharmaceutically acceptable salts thereof, ring A is phenyl or a 5-6 membered heteroaryl, and the phenyl or heteroaryl is optionally substituted with 1-3 Z 1a Formula (I), (IA-1), (IA-2), and / or ( In some embodiments of the compound of formula Ia), or a pharmaceutically acceptable salt thereof, ring A is phenyl or a 5-6 membered heteroaryl having 1-3 heteroatoms, each independently O, N, or S, and the phenyl or heteroaryl optionally has 1-3 Z 1a In some embodiments of the compounds of Formula (I), (IA-1), (Ia), and / or other formulas described herein, or pharmaceutically acceptable salts thereof, ring A is substituted with:

[0058] [ka] wherein each ring optionally contains one or two Z 1a is replaced by .

[0059] In some embodiments of the compounds of Formula (I), (IA-1), (Ia), and / or other formulas described herein, or pharmaceutically acceptable salts thereof, ring A is

[0060] [ka] wherein each ring optionally contains one or two Z 1a is replaced by .

[0061] In some embodiments of Formula (I), (IA-1), (IA-2), and / or (Ia), or a pharmaceutically acceptable salt thereof, ring A is

[0062] [ka] wherein each ring is optionally substituted with one or two halogens.

[0063] In some embodiments, the compound of Formula (I), (IA-1), and / or (Ia), or a pharmaceutically acceptable salt thereof, has the structure of Formula (Ib):

[0064] [ka] In the formula, Z 1a is a halogen, C 1~4 Alkyl, -OR 12a , or -CN, C 1~4 The alkyl is optionally selected from Z 1b is replaced by the subscript p is 1, 2, or 3; The subscript q is 0, 1, or 2.

[0065] In some embodiments, the compound of Formula (I), (IA-1), and / or (Ia), or a pharmaceutically acceptable salt thereof, has the structure of Formula (Ib-1):

[0066] [ka] During the ceremony, the subscript p is 1, 2, or 3; The subscript q is 0, 1, or 2.

[0067] In some embodiments of Formula (IA-1), (I), (Ia), (Ib) and / or (Ib-1), or a pharmaceutically acceptable salt thereof, Ring B is phenyl or a 5-6 membered heteroaryl, and the phenyl or heteroaryl optionally contains 1-4 R 4 In some embodiments of the compound of Formula (IA-1), (I), (Ia), (Ib) and / or (Ib-1), or a pharmaceutically acceptable salt thereof, Ring B is phenyl or a 5-6 membered heteroaryl having 1-3 heteroatoms, each independently O, N, or S, and the phenyl or heteroaryl is optionally substituted with 1-4 R 4 In some embodiments of the compounds of Formula (IA-1), (I), (Ia), (Ib) and / or (Ib-1), or a pharmaceutically acceptable salt thereof, Ring B is substituted with:

[0068] [ka] each of which optionally contains one or two R 4 is replaced by .

[0069] In some embodiments of the compounds of Formula (IA-1), (I), (Ia), (Ib) and / or (Ib-1), or pharmaceutically acceptable salts thereof, Ring B is

[0070] [ka] each of which optionally contains one or two R 4 is replaced by .

[0071] In some embodiments of the compounds of Formula (IA-1), (I), (Ia), (Ib) and / or (Ib-1), or pharmaceutically acceptable salts thereof, Ring B is

[0072] [ka] and optionally one or two R 4 is replaced by .

[0073] In some embodiments of the compounds of Formula (I), (IA-1), and / or other formulas described herein, or pharmaceutically acceptable salts thereof, ring B is substituted with 1, 2, or 3 halogen. In some embodiments of the compounds of Formula (I), (IA-1), and / or other formulas described herein, or pharmaceutically acceptable salts thereof, ring B is substituted with 1, 2, or 3 fluoro.

[0074] In some embodiments, the compound of Formula (I), (IA-1), and / or (Ia), and / or other formulas described herein, or a pharmaceutically acceptable salt thereof, has the formula:

[0075] [ka] During the ceremony, X A and X B are each independently -CH= or -N=, the subscript n is 0, 1, 2, or 3; The subscript p is 1, 2, or 3.

[0076] In embodiments of the compounds of Formula (I), (IA-1), (Ia), (Ib), (Ib-1) and / or (Ic), and / or other formulae described herein, or pharmaceutically acceptable salts thereof, X 1 , X 2 , and X 3 are each independently -N=, -CH=, -C(F)=, -C(Cl)=, -C(Br)=, or -C(CN)=. In embodiments of compounds of Formula (I), (IA-1), and / or other formulas described herein, or pharmaceutically acceptable salts thereof, X 1 , X 2 , and X 3 are each independently -CH=, -C(F)=, -C(Cl)=, -C(Br)=, or -C(CN)=. In embodiments of compounds of Formula (I), (IA-1), and / or other formulas described herein, or pharmaceutically acceptable salts thereof, X 1 , X 2 , and X 3 are each independently -N=, -CH=, or -C(F)=. In some embodiments, X 1 , X 2 , and X 3 Two of the groups are -CH= and one is -N=. For example, X 1 can be -N = X 2 and X 3 and each is -CH=. In some embodiments of the compounds of Formula (I), (IA-1), and / or other formulae described herein, or pharmaceutically acceptable salts thereof, X 1 , X 2 , and X 3 Two of X are -CH= and one is -C(F)=. In some embodiments, X 1 , X 2 , and X3 are -CH=, respectively.

[0077] In some embodiments of a compound of Formula (I), (IA-1), (IA-2), (Ia), (Ib), (Ib-1), and / or (Ic), or a pharmaceutically acceptable salt thereof, V is -O-, -NH-, or -CH-. In some embodiments of a compound of Formula (I), (IA-1), and / or other formulas described herein, or a pharmaceutically acceptable salt thereof, V is -O-. In some embodiments, V is -CH-. In some embodiments of Formula (I), (IAI), (IA-2), and / or other formulas described herein, V is -CH-, -CH(CH)-, or -C(CH)-. In some embodiments, V is -CH-.

[0078] In some embodiments, the compound of Formula (I), (IA-1), (Ia), and / or (Ic), and / or other formulae described herein, or a pharmaceutically acceptable salt thereof, has the formula:

[0079] [ka] During the ceremony, X A and X B are each independently -CH= or -N=, the subscript n is 0, 1, 2, or 3; The subscript p is 1, 2, or 3.

[0080] In some embodiments of a compound of Formula (Ic) and / or (Id), or a pharmaceutically acceptable salt thereof, the subscript n is 0, 1, or 2. In some embodiments, the subscript n is 0. In some embodiments of a compound of Formula (I) or other compounds described herein, the subscript n is 1. In some embodiments, the subscript n is 2.

[0081] In some embodiments of Formula (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or a pharmaceutically acceptable salt thereof, the subscript p is 1 or 2. In some embodiments, the subscript p is 1. In some embodiments of a compound of Formula (I) or other compounds described herein, the subscript p is 2.

[0082] In some embodiments of the compounds of Formula (Ib) and / or (Ib-1), or pharmaceutically acceptable salts thereof, the subscript q is 0 or 1. In some embodiments, the subscript q is 0. In some embodiments, the subscript q is 1.

[0083] In some embodiments of the compounds of Formula (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, X A and X B One of X is -CH= and the other is -N=. In some embodiments, X A is -N = X B is -CH=. In some embodiments, X A is -CH=, and X B is -N=.

[0084] In some embodiments of compounds of Formula (IA-1), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), and / or other formulae described herein, or pharmaceutically acceptable salts thereof, each Z 1 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, halogen, C 3~10In some embodiments of a compound of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or a pharmaceutically acceptable salt thereof, each Z is cycloalkyl, 3-12 membered heterocyclyl having 1-3 heteroatoms each independently being N, O, or S, 5-10 membered heteroaryl having 1-3 heteroatoms each independently being N, O, or S, oxo, -OH, -CN, or -NO2. 1 are independently halogen, C 1~6 Haloalkyl, C 1~6 In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, each Z 1 are independently halogen, C 1~6 Haloalkyl, C 1~6 haloalkoxy, —CN, or 5-6 membered heteroaryl having 1-3 heteroatoms, each independently being N, O, or S. In embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, each Z 1 is German Standing C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, heterocyclyl-C 1~6 Alkyl, heterocyclyl-C 1~6 Haloalkyl, Heteroaryl-C 1~6 Alkyl, Heteroaryl-C 1~6 Haloalkyl, oxo, -OH, -CN, -NO2, or -C(O)N(R 12a )(R 12b), wherein the heteroaryl or heterocyclyl each optionally contains 1 to 4 halogen atoms, —CN, C 1~6 Haloalkyl, C 3~6 cycloalkyl or 4- to 6-membered heterocyclyl. In some embodiments, each Z 1 are independently halogen, C 1~6 Haloalkyl, -CN, C 1~3 Alkoxy or C 3~10 In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, each Z 1 independently, C 1~6 Haloalkyl, C 1~6 haloalkoxy, halogen, 5-6 membered heteroaryl having 1-3 heteroatoms, each independently N, O, or S, or -CN. 1 are independently halogen, C 1~6 In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, each Z 1 are independently halogen, C 1~6 Haloalkyl, C 1~3 Alkoxy, C 3~10 In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, each Z 1 are independently halogen, C 1~3 Haloalkyl, C 1~3 In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, each R 2d are independently F, C 1~6 Haloalkyl, -CN, or C 3~10In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or a pharmaceutically acceptable salt thereof, each Z 1 is independently halogen or —CN. In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, Z 1 In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, Z 1 is a halogen.

[0085] In some embodiments, Formula (I), (IA-1) and / or other formulae described herein, or pharmaceutically acceptable salts thereof, has the formula (IA-2):

[0086] [ka] During the ceremony, U is -CH= or -N=; X B is -CH= or -N=, R B But C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 haloalkoxy, halogen, or -CN; X 1 and X 2 each independently represents -N=, -C(H)=, or -C(R 8 )=, X 3 where -C(H)= Each R 4 But independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 1~6 Haloalkoxy, C 2~6 Alkenyl, C2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, oxo, -NO2, -N3, -OR 4a , -C(O)R 4a , -C(O)OR 4a , -C(O)N(R 4a )(R 4b ), -N(R 4a )(R 4b ), -N(R 4a )2(R 4b ) + , -N(R 4a )C(O)O(R 4b ), -N(R 4a )C(O)N(R 4b )(R 4c ), -N(R 4a )S(O)2-N(R 4b )(R 4c ), -N(R 4a )S(O)2O(R 4b ), -OC(O)R 4a , -OC(O)OR 4a , -OC(O)-N(R 4a )(R 4b ), -SR 4a , -S(O)R 4a , -S(O)(NH)R 4a , -S(O)2R 4a , -S(O)2N(R 4a )(R 4b ), -S(O)(NR 4a )R 4b , or -Si(R 4a )3, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally containing 1 to 4 Z 1b is replaced by Alternatively, two R attached to adjacent ring atoms 4 The groups, in combination with the atoms to which they are attached, form C 5~10 cycloalkyl or heterocyclyl, each of which optionally has 1 to 4 Z 1b is replaced by V is -C(O)-, -O-, -N(R 6a )- or -C(R 6b )(R 6c )- and R 6a But H, C 1~6 Alkyl, C 3~10 Cycloalkyl, heterocyclyl, -S(O)2R 6a1 , or -S(O)N(R 6a1 )(NR 6a2 ) wherein cycloalkyl or heterocyclyl are each optionally selected from C 1~6 substituted with alkyl, F, or -CN; Each R 6b and R 6c are independently H or C 1~6 is alkyl, Each R 1a , R 3d , R 5a3 , R 5a4 , and R 10 But independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, COR 3e , -NO2, or -C(O)N(R 2a )(R 2b ) wherein the heterocyclyl or heteroaryl is optionally selected from C 1~6 Alkyl, C 1~6 Haloalkyl, or C 1~6 substituted with haloalkoxy; Each R 6a1 , R 6a2 , R 6c1 , R 6c2 , R 6c3 , and R 7 However, independently, H, C 1~6 Alkyl or C 3~10 is cycloalkyl, Each R 8 But independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, COR 3e , -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)(C6~10 aryl), -N(C 1~9 alkyl)(heteroaryl), -C(O)(C 1~9 alkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 2~6 alkenyl), -C(O)(C 2~6 alkynyl), -C(O)(C 3~15 -C(O)(cycloalkyl), -C(O)(heterocyclyl), -C(O)(C 6~10 aryl), -C(O)(heteroaryl), -C(O)O(C 1~9 alkyl), -C(O)O(C 1~8 haloalkyl), -C(O)O(C 2~6 alkenyl), -C(O)O(C 2~6 alkynyl), -C(O)O(C 3~15 cycloalkyl), -C(O)O(heterocyclyl), -C(O)O(C 6~10 aryl), -C(O)O(heteroaryl), -C(O)NH2, -C(O)NH(C 1~9 alkyl), -C(O)NH(C 1~8 haloalkyl), -C(O)NH(C 2~6 alkenyl), -C(O)NH(C 2~6 alkynyl), -C(O)NH(C 3~15 cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(C 6~10 aryl), -C(O)NH(heteroaryl), -C(O)N(C 1~9 alkyl)2, -C(O)N(C 1~8 haloalkyl)2, -C(O)N(C 2~6 alkenyl)2, -C(O)N(C 2~6 alkynyl)2, -C(O)N(C 3~15 cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C 6~10 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)(C3~15 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(C1~9 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, In each instance, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally contains 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(C1~9 alkyl), S(O)2(C 1~9 alkyl), -S(O)2(C 1~8 haloalkyl), -S(O)2(C 3~15 -cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)(NH)(C 1~9 alkyl), -S(O)2NH(C 1~9 alkyl), or -S(O)N(C 1~9 alkyl)2, Each R 9a and R 9b However, independently, H, C 1~6 Alkyl or C 1~6 is haloalkyl, each Z 1 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 12a , -C(O)-R 12a , -C(O)OR 12a , -C(O)-N(R 12a )(R 12b ), -N(R 12a )(R 12b ), -N(R 12a )2(R 12b ) + , -N(R 12a )C(O)-R 12b , -N(R 12a )C(O)OR 12b , -N(R 12a )C(O)N(R 12b )(R 12c ), -N(R 12a )S(O)2(R 12b ), -NR 12a S(O)2N(R 12b )(R12c ), -NR 12a S(O)2O(R 12b ), -OC(O)R 12a , -OC(O)OR 12a , -OC(O)-N(R 12a )(R 12b ), -SR 12a , -S (O)R 12a , -S(O)(NH)R 12a , -S(O)2R 12a , -S(O)2N(R 12a )(R 12b ), -S(O)(NR 12a )R 12b , or -Si(R 12a )3, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally containing 1 to 4 Z 1a is replaced by each Z 1a 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, -CN, -N3, -OR 12a , -C(O)R 12a , -C(O)OR 12a , -C(O)N(R 12a )(R 12b ), -N(R 12a )(R 12b ), -N(R 12a )2(R 12b ) + , -N(R 12a )-C(O)R 12b , -N(R 12a )C(O)O(R 12b ), -N(R 12a )C(O)N(R 12b)(R 12c ), -N(R 12a )S(O)2(R 12b ), -N(R 12a )S(O)2-N(R 12b )(R 12c ), -N(R 12a )S(O)2O(R 12b ), -OC(O)R 12a , -OC(O)OR 12a , -OC(O)-N(R 12a )(R 12b ), -SR 12a , -S(O)R 12a , -S(O)(NH)R 12a , -S(O)2R 12a , -S(O)2N(R 12a )(R 12b ), -S(O)(NR 12a )R 12b , or -Si(R 12a )3, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally containing 1 to 4 Z 1b is replaced by each Z 1b But independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, COR 3e , -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 Cyclo alkyl), -O(heterocyclyl), -O(C 6~10 aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(heterocyclyl), -NH(C 6~10 aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 1~8 haloalkyl)2, -N(C 2~6 alkenyl)2, -N(C 2~6 alkynyl)2, -N(C 3~15 -N(cycloalkyl)2, -N(heterocyclyl)2, -N(C 6~10 aryl), -N(heteroaryl), -N(C 1~9 Alkyl)(C 1~8 haloalkyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 alkyl)(heterocyclyl), -N(C 1~9 Alkyl)(C 6~10 aryl), -N(C 1~9 alkyl)(heteroaryl), -C(O)(C 1~9 alkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 2~6 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(C1~9 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 1~9 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 3~15cycloalkyl), -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(C1 ~9 alkyl), or -S(O)N(C 1~9 alkyl)2, In each instance, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally contains 1 to 3 C 1~9 Alkyl, C 1~8 Haloalkyl, halogen, -OH, -NH2, CO2H, -O(C 1~9alkyl), -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 alkyl)2, Each R 1b , R 1c , R 2a , R 2b , R 4a , R 4b , R 4c , R 9c , R 9d , R 12a , R 12b , and R 12c However, independently, H, C1~9 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally containing 1 to 4 Z 1b is replaced by Each R 3e However, independently, H, C 1~6 Alkyl, C 1~6 Haloalkyl, -C 1~4 Alkyl-N(R 9a )(R 9b ), -C 1~4 Alkyl-C(O)N(R 9a )(R 9b ), -C 1~4 Alkyl-OC(O)-C 1~4 Alkyl, -C 1~4 Alkyl-OC(O)-OC 1~4 Alkyl, -C 1~4 Alkyl-OC(O)-C 1~4 Alkyl-N(R 9a )(R 9b ), -C 1~4 Alkyl-C 3~8 Cycloalkyl, -C 1~4 Alkyl-heterocyclyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, -P(O)(OR 9c )2, -CH2P(O)(OR 9c )2, -OCH2P(O)(OR 9c )2, -C(O)OCH2P(O)(OR 9c )2, -P(O)(R 9c )(OR 9d ), -OP(O)(R 9c )(OR 9d ), -CH2P(O)(R 9c )(OR 9d ), -C(O)OCH2P(O)(R 9c )(OR 9d ), -P(O)(N(R 9c)2)2, -CH2P(O)(N(R 9c )2)2, -C(O)OCH2P(O)(N(R 9c )2)2, -P(O)(N(R 9c )2)(OR 9d ), -CH2P(O)(N(R 9c )2)(OR 9d ), -C(O)OCH2P(O)(N(R 9c )2)(OR 9d ), -P(O)(R 9c )(N(R 9d )2), -CH2P(O)(R 9c )(N(R 9d )2), or -C(O)OCH2P(O)(R 9c )(N(R 9d )2) wherein alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl each optionally contains 1 to 4 Z 1b each heteroaryl having 5 to 12 ring members and 1 to 4 heteroatoms which are each independently N, O, or S; each heterocyclyl, unless otherwise specified, has 3 to 12 ring members and 1 to 4 heteroatoms, each independently N, O, or S; m is 0, 1, or 2.

[0087] Some embodiments of the compounds of formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, In the embodiment, R 2 is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 2~6 Alkoxyalkyl, -CN, -C(O)R 2a , -C(O)OR 2a , -C(O)N(R 2a )(R 2b ), -C(O)NR 2c S(O)2R 2a , -S(O)2R 2a, -S(O)2N(R 2a )(R 2b ), -S(O)NR 2c C(O)R 2a , C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl-C 1~6 Alkyl, C 1~6 Alkyl-heterocyclyl-C 1~6 Alkyl, C 6~10 Aryl, C 1~6 Alkyl-C 6~10 Aryl, heterocyclyl, C 1~6 Alkyl-heterocyclyl, heteroaryl or C 1~6 alkyl-heteroaryl, wherein alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl each optionally contain one or more Z 1b In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, R 2 is H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 1~6 Alkyl-heterocyclyl, C 1~6 Alkyl-C 6~10 Aryl, C 1~6 Alkyl-heteroaryl, C 1~6 Alkyl-C 3~10 Cycloalkyl-C 1~6 Alkyl, C 1~6 Alkyl-heterocyclyl-C 1~6 Alkyl, -CN, -C(O)R 2a , -C(O)OR 2a, -C(O)N(R 2a )(R 2b ), -C(O)NR 2c S(O)2R 2a , -S(O)2R 2a , -S(O)2N(R 2a )(R 2b ), or -S(O)NR 2c C(O)R 2a wherein alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl each optionally contain 1 to 4 Z 1b In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, R 2 is H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 1~6 Alkyl-heterocyclyl, C 1~6 Alkyl-C 6~10 Aryl, C 1~6 Alkyl-heteroaryl, C 1~6 Alkyl-C 3~10 Cycloalkyl-C 1~6 Alkyl, C 1~6 Alkyl-heterocyclyl-C 1~6 Alkyl, -CN, -C(O)R 2a , -C(O)OR 2a , -C(O)N(R 2a )(R 2b ), -C(O)NR 2c S(O)2R 2a , -S(O)2R 2a , -S(O)2N(R 2a )(R 2b ), or -S(O)NR 2c C(O)R 2awherein alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl each optionally contain 1 to 4 Z 1b and each Z 1b independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 2~6 Alkoxyalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, heterocyclyl-C 1~6 Alkyl, heterocyclyl-C 1~6 Haloalkyl, Heteroaryl-C 1~6 Alkyl, Heteroaryl-C 1~6 Haloalkyl, oxo, -OH, -CN, -NO2, or -C(O)N(R 12a )(R 12b In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, R 2 is H, C 1~6 Alkyl, C 2~6 Alkoxyalkyl, C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, heterocyclyl, C 1~6 Alkyl-heterocyclyl, heteroaryl or C 1~6 alkyl-heteroaryl, wherein each heterocyclyl contains 3 to 12 ring members and 1 to 3 heteroatoms, each independently N, O, or S; each heteroaryl contains 5 to 10 ring members and 1 to 3 heteroatoms, each independently N, O, or S; and each cycloalkyl, heterocyclyl, and heteroaryl optionally contain 1 to 4 Z 1b The compounds of formula (IA-1), (IA-2), (I In some embodiments of the compounds of formula (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, R 2 is C 1~6 Alkyl, C 2~6 Alkoxyalkyl, C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 1~6 Alkyl-heteroaryl, or C 1~6 alkyl-heterocyclyl, where each heterocyclyl contains 3 to 12 ring members and 1 to 3 heteroatoms, each independently N, O, or S; each heteroaryl contains 5 to 10 ring members and 1 to 3 heteroatoms, each independently N, O, or S; and cycloalkyl, heterocyclyl, and heteroaryl each optionally contain one or two Z 1b In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, R 2 is C 1~6 Alkyl, C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl, C 1~6 Alkyl-C 3~10 Cycloalkyl-C 1~6 Alkyl, C 1~6 Alkyl-heterocyclyl-C 1~6 Alkyl, heterocyclyl, C 1~6 Alkyl-heterocyclyl, heteroaryl or C 1~6 alkyl-heteroaryl, each of which optionally has 1 to 4 Z 1b In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, R 2 is C 1~6 Alkyl-C 3~10 Cycloalkyl or C 1~6 Alkyl-C 3~10 Cycloalkyl-C1~6 alkyl, and optionally 1 to 4 Z 1b is replaced by .

[0088] In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, R 2 is C 1~6 alkyl, and optionally 1 to 4 Z 1b In some embodiments of compounds of formula (IA-1), (IA-2), (I), and / or other formulas described herein, R 2 is C 3~10 cycloalkyl or heterocyclyl, each of which optionally has 1 to 4 Z 1b In some embodiments of formula (IA-1), (IA-2), (I), and / or other formulas described herein, R 2 is C 1~6 Alkyl-heterocyclyl-C 1~6 Alkyl or C 1~6 alkyl-heterocyclyl, each of which optionally has 1 to 4 Z 1b is replaced by .

[0089] In some embodiments of compounds of formula (IA-1), (IA-2), (I), and / or other formulas described herein, R 2 teeth,

[0090] [ka] is.

[0091] In some embodiments of the compounds of formula (IA-1), (IA-2), and / or other formulas described herein, or pharmaceutically acceptable salts thereof, R 1 but heterocyclyl, C 6~10aryl, or 6-membered heteroaryl, each of which optionally contains 1 to 3 C 1~6 substituted with haloalkyl, halogen, or -CN; R B is methyl, halogen, -CN, or -OCH3; R 2 but,

[0092] [ka] and R 3 But -C(O)R 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 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, or C 1~6 alkyl-heterocyclyl, wherein the alkyl or heterocyclyl is each optionally substituted with 1 to 4 halogens; Each R 4is independently F, oxo, or —CN; R 5a and R 5b are H, respectively, Y is -O-, and each R 8 are independently H or halogen; Each R 9a , R 9b , and R 9c are independently H or C 1~6 is alkyl, m is 0 or 1; n is 1 or 2.

[0093] In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, R 3 is -C(O)OR 3a , -C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)R 3b , -N(R 3a )C(O)OR 3b , -N(R 3a )C(O)N(R 3b )(R 3c ), -C(O)NHS(O)R 3a , -S(O)2R 3a , -S(O)2OR 3a , -S(O)2N(R 3a )(R 3b ), -N(R 3a )S(O)2R 3b , -S(O)2NHC(O)R 3a , -S(O)(=NR 3a )R 3b , -S(O)(=NR 3a )NR 3b , -S(=NR 3a )(=NR 3b )R 3c , -P(O)(OR 3a )(R 3b ), -P(O)(OR 3a )(OR 3b ), -B(OR3a )(OR 3b ), or a 5-10 membered heteroaryl having 1-4 heteroatoms, each independently N, O, or S. In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id), or a pharmaceutically acceptable salt thereof, R 3 is H, halogen, heteroaryl, -C(O)NH2, -C(O)OH, -CH2C(O)OR 3a , -C(O)OR 3a , -C(O)N(R 3a )S(O)2(R 3b ), -S(O)2NHC(O)R 3a , -P(O)(OR 3a )2, -C(O)N(R 3a )S(O)2N(R 3b )(R 3c ), or -OC 1~6 Alkyl-C(O)OR 3a and the heteroaryl optionally contains 1 to 4 R 3d In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, R 3 -C(O)OH, -C(O)OR 3a , -C(O)N(R 3a )S(O)2(R 3b ), -S(O)2NHC(O)R 3a , -C(O)NR 3a S(O)NR 3b R 3c or heteroaryl, which optionally contains 1 to 4 R 3d In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, R 3 optionally, 1 to 4 R 3d In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl substituted with So, R3 is -C(O)OR 3a In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, R 3 is —C(O)OH.

[0094] In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, R 3 teeth,

[0095] [ka] is.

[0096] In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, R 3a is H, C 1~4 Alkyl-N(R 9a )(R 9b ), -C 1~4 a Rukill-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(R 9c )2)2、-P(O)(N(R 9c )2)(OR 9d )、-OP(O)(N(R 9c )2)(OR 9d )、-CH2P(O)(N(R 9c )2)(OR 9d )、-OCH2P(O)(N(R 9c )2)(OR 9d )、-C(O)OCH2P(O)(N(R 9c )2)(OR 9d )、-P(O)(R 9c )(N(R 9d )2)、-OP(O)(R 9c )(N(R 9d )2)、-CH2P(O)(R 9c )(N(R 9d )2)、-OCH2P(O)(R 9c )(N(R 9d )2)、-C(O)OCH2P(O)(R9c )(N(R 9d )2) or C 1~6 alkyl-heterocyclyl, wherein the alkyl or heterocyclyl is each optionally substituted with 1 to 4 halogens.

[0097] In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, R 3 -H, -Br,

[0098] [ka] is.

[0099] In some embodiments of the compounds of Formula (I), (IA-1), (IA-2), (Ia), (Ib), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, each R 3a , R 3b , and R 3c are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, or C 3~10 It is cycloalkyl.

[0100] In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, each R 4 independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, halogen, oxo, -CN, or -OR 4a In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, each R 4 independently, C 1~6 Alkyl, C2~6 Alkoxyalkyl, C 1~6 Alkoxy, C 1~6 haloalkoxy, In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or a pharmaceutically acceptable salt thereof, two R attached to adjacent ring atoms are 4 The groups, in combination with the atoms to which they are attached, form C 3~10 In some embodiments of a compound of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or a pharmaceutically acceptable salt thereof, each R 4 independently, C 1~6 Alkyl, halogen, oxo, -CN, or -OR 4a In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, each R 4 is independently F, oxo, or —CN.

[0101] In some embodiments of the compounds of Formula (IA-1), (IA-2), and / or (I), or pharmaceutically acceptable salts thereof, each R 5a and R 5b are independently H, C 1~6 Alkyl, F, Cl, C 3~10 cycloalkyl, a 3- to 12-membered heterocyclyl having 1-3 heteroatoms, each independently O, N, or S, or -CN.

[0102] In some embodiments of the compounds of Formula (IA-1), (IA-2), and / or (I), or pharmaceutically acceptable salts thereof, R 6a is H, C 1~6 Alkyl, C 3~10 In some embodiments, R is cycloalkyl, or heterocyclyl. 6a is H, C 1~6Alkyl, C 3~10 cycloalkyl, or a 3- to 12-membered heterocyclyl having 1 to 3 heteroatoms, each independently O, N, or S.

[0103] In some embodiments of the compounds of Formula (IA-1), (IA-2), and / or (I), or pharmaceutically acceptable salts thereof, each R 6b and R 6c are independently H, F, Cl, C 1~3 In some embodiments, each R 6b and R 6c are independently H, F, Cl, or —CN.

[0104] In some embodiments of the compounds of Formula (IA-1), (IA-2), and / or (I), or pharmaceutically acceptable salts thereof, R 6c is one R 4 In combination with the groups and the atoms to which they are attached, C 3~10 cycloalkyl or 3- to 12-membered heterocyclyl having 1-3 heteroatoms, each independently N, O, or S, and the cycloalkyl and heterocyclyl each optionally contain 1-4 R 4c is replaced by .

[0105] In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, each R 8 independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 2~6 alkenyl), -O(C 2~6alkynyl), -O(C 3~15 -Cycloalkyl), -O(heterocyclyl), -O(C 6~10 aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(heterocyclyl), -NH(C 6~10 aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 1~8 haloalkyl)2, -N(C 2~6 alkenyl)2, -N(C 2~6 alkynyl)2, -N(C 3~15 -N(cycloalkyl)2, -N(heterocyclyl)2, -N(C 6~10 aryl), -N(heteroaryl), -N(C 1~9 Alkyl)(C 1~8 haloalkyl), -N(C 1~9 Alkyl)(C 2~ 6 alkenyl), -N(C 1~9 Alkyl)(C 2~6 alkynyl), -N(C 1~9 Alkyl)(C 3~15 cycloalkyl), -N(C 1~9 alkyl)(heterocyclyl), -N(C 1~9 Alkyl)(C 6~10 aryl), -N(C 1~9 alkyl)(heteroaryl), -C(O)(C 1~9 alkyl), -C(O)(C 1~8 haloalkyl), -C(O)(C 2~6 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(C2~6 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(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(C1~9 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 In some embodiments, each R 8independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 -Cycloalkyl), -O(heterocyclyl), -O(C 6~10 aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C 2~6 alkenyl) , -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(heterocyclyl), -NH(C 6~10 aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 1~8 haloalkyl)2, -N(C 2~6 alkenyl)2, -N(C 2~6 alkynyl)2, -N(C 3~15 -N(cycloalkyl)2, -N(heterocyclyl)2, -N(C 6~10 aryl), -N(heteroaryl), -N(C 1~9 Alkyl)(C 1~8 haloalkyl), -N(C 1~9 Alkyl)(C 2~6 alkenyl), -N(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 1~9alkyl)(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 In some embodiments, each R 8 independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 aryl, heteroaryl, oxo, —OH, —CN, —NO, or —NH. In some embodiments, each R 8 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~7 In some embodiments of the compounds of Formula (I), (IA-1), and / or (IA-2), or pharmaceutically acceptable salts thereof, each R is cycloalkyl, oxo, -OH, -CN, or -NH. 8 independently, C 1~3 Alkyl, C 1~3 Haloalkyl, halogen, C 3~7 In some embodiments, each R 8 independently, C 1~3Alkyl, C 1~3 Haloalkyl, halogen, C 3~7 The compounds of formula (I), (IA-1), and / or (IA-2), or pharmaceutically acceptable salts thereof, R 8 is C 1~9 Alkyl, halogen, or -O(C 1~9 In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, each Z 1b independently, C 1~9 Alkyl, C 1~8 Halo Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 -Cycloalkyl), -O(heterocyclyl), -O(C 6~10 aryl), -O(heteroaryl), -NH(C 1~9 alkyl), -NH(C 1~8 haloalkyl), -NH(C 2~6 alkenyl), -NH(C 2~6 alkynyl), -NH(C 3~15 cycloalkyl), -NH(heterocyclyl), -NH(C 6~10 aryl), -NH(heteroaryl), -N(C 1~9 alkyl)2, -N(C 1~8 haloalkyl)2, -N(C 2~6 alkenyl)2, -N(C 2~6 alkynyl)2, -N(C 3~15 -N(cycloalkyl)2, -N(heterocyclyl)2, -N(C 6~10 aryl), -N(heteroaryl), -N(C1~9 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 -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(C2~6 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 In some embodiments, in Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id), or a pharmaceutically acceptable salt thereof, each Z 1b independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 Aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C 1~9 alkyl), -O(C 1~8 haloalkyl), -O(C 2~6 alkenyl), -O(C 2~6 alkynyl), -O(C 3~15 -Cycloalkyl), -O(heterocyclyl), -O(C 6~10 aryl), -O(heteroaryl), -NH(C 1~9alkyl), -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(heterocycloalkyl) Krill)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(C6~10 In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, each Z 1b independently, C 1~9 Alkyl, C 1~8 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~15 Cycloalkyl, heterocyclyl, C 6~10 In some embodiments, in Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id), or a pharmaceutically acceptable salt thereof, each Z is aryl, heteroaryl, oxo, -OH, -CN, -NO, or -NH. 1b independently, C 1~3 Alkyl, C 1~3 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, halogen, C 3~7 In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, each Z 1b independently, C 1~3 Alkyl, C 1~3 Haloalkyl, halogen, C 3~7 In some embodiments of the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, each Z 1b independently, C 1~3 Alkyl, C 1~3 Haloalkoxy, halogen, C 3~7 It is cycloalkyl, oxo, or -CN.

[0106] In some embodiments, the compound of Formula (I), (IA-1), (IA-2), (Ia), (Ib), (Ic), and / or (Id), or a pharmaceutically acceptable salt thereof, has the formula:

[0107] [ka]

[0108] [ka]

[0109] [ka]

[0110] [ka]

[0111] In some embodiments, the compounds of the present disclosure have the following structure:

[0112] [ka]

[0113] [ka]

[0114] [ka]

[0115] [ka]

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[0170] Some embodiments of the compounds of formula (I), (IA-1), or other formulae described herein In this embodiment, the compound has the structure:

[0171] [ka]

[0172] The in vivo metabolic products of the compounds described herein are also disclosed to the extent that such products are novel and not apparent over the prior art. Such products may result from the oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, primarily through enzymatic processes. Thus, included are novel and not apparent 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.

[0173] 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. Simply because compounds are stable to the gastrointestinal tract does not mean that they cannot be hydrolyzed in vivo. Prodrugs are typically stable in the digestive system, but may not be substantially hydrolyzed to the parent drug in the gastrointestinal lumen, liver, lungs, or other metabolic organs, or generally within cells. As used herein, a prodrug is understood to be a compound that is chemically designed to efficiently liberate the parent drug after overcoming a biological barrier to oral delivery.

[0174] III. Methods for Preparing the 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.

[0175] [ka]

[0176] 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, which can be converted to intermediate 1.3 using suitable reduction conditions (e.g., H and Pd / C, Fe and HCl, etc.).

[0177] [ka]

[0178] Compounds of formula (IA-1), (IA-2), and / or formula (I), having the structure of compounds of formula 2.9, can be prepared by first reacting intermediate 2.1 (X21 and X 22 Intermediate 2.3 can be assembled by coupling intermediate 2.4 (M=Li, MgBr, MgCl, or MgI, commercially available or commercially available) with a heteroatom containing intermediate 2.2 (Y=O, NH, or S) via metal-mediated cross-coupling using a suitable base (e.g., DIPEA, KOtBu, etc.) or a suitable palladium catalyst to give intermediate 2.3 (Scheme 2). Intermediate 2.6, obtained by metallation of the corresponding halide, can be combined with intermediate 2.3 using a suitable palladium catalyst to deliver intermediate 2.5. After conversion of intermediate 2.6 to an acid using standard conditions (e.g., LiOH, LiI, and pyridine), intermediate 1.3 is added using standard amide bond forming conditions (e.g., DIPEA with HATU, etc.) to give 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.). This intermediate can be converted to compounds of formula (IA-1), (IA-2), and / or formula (I) using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine, etc.).

[0179] Although Scheme 2 above is exemplified using intermediate 2.1 as a dihalopyridine, any dihalogenated A-ring starting material can be used to provide analogous compounds of formula (IA-1), (IA-2), and / or formula (I).

[0180] [ka]

[0181] In some embodiments, compounds of Formula (IA-1), (IA-2), and / or Formula (I) having the structure of a compound of Formula 2.9 can be prepared by first reacting intermediate 3.1 (X 31Intermediate 3.3 can be assembled by combining intermediate 1.3 (R = alkyl, alkylaryl, or aryl) with intermediate 1.4 (R = alkyl, alkylaryl, or aryl) under standard amide bond forming conditions (e.g., DIPEA with HATU, etc.) (Scheme 3). Treatment with a suitable acid catalyst (e.g., HCl, AcOH, etc.) can deliver intermediate 3.3. -X 31 Halogen metal exchange from -M to -M can be achieved using a suitable reagent (e.g., iPrMgBr, etc.) or transition metal coupling using a suitable palladium catalyst and metal source (e.g., B2Pin2, Bu6Sn2, etc.) to provide intermediate 2.8, which can be converted to compounds of formula (IA-1), (IA-2), and / or formula (I) using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine, etc.).

[0182] [ka]

[0183] In some embodiments, compounds of formula 2.9 can be formed by first converting intermediate 2.3 to metalated variant intermediate 4.1 using a suitable palladium catalyst and metal source (e.g., 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 (IA-1), (IA-2), and / or formula (I) using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine, etc.).

[0184] [ka]

[0185] Compounds of formula (IA-1), (IA-2), and / or formula (I) having the structure of compounds of formula 5.3 can be assembled by first coupling intermediate 5.1 to a halogen-X (X is Cl, Br, or I) using a suitable coupling partner and a palladium catalyst to deliver intermediate 5.2, which can be converted to compounds of formula 5.3 using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine, etc.) (Scheme 5).

[0186] [ka]

[0187] Compounds of formula (IA-1), (IA-2), and / or formula (I), having the structure of compounds of formula 6.1, can be obtained by reacting intermediate 2.9 with a sulfonamide under suitable coupling conditions (e.g., EDC and DMAP) (Scheme 6).

[0188] [ka]

[0189] Compounds of formula (IA-1), (IA-2), and / or formula (I) having the structure of compounds of formula 7.3 can be assembled by first coupling intermediate 7.1 to halogen-X using a suitable coupling partner and a palladium catalyst to deliver intermediate 7.2, which can be converted to compounds of formula 7.3 using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine, etc.) (Scheme 7).

[0190] [ka]

[0191] Compounds of formula (IA-1), (IA-2), and / or (IA-3) having the structure of compounds of formula 2.9 Compounds of formula (I) can be assembled by first cross-coupling intermediate 3.4 to intermediate 2.1 using a suitable transition metal catalyst (e.g., palladium, etc.) (Scheme 8). This can then be coupled with heteroatom containing intermediate 2.2 (Y=O, NH, 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 compounds of formula (IA-1), (IA-2), and / or formula (I), having the structure of compounds of formula 2.9, using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine, etc.).

[0192] 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 (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0193] In some embodiments of the present disclosure, pharmaceutical compositions comprise compounds of formula (I), (IA-1), and / or (IA-2), or pharmaceutically acceptable salts thereof, and one or more additional therapeutic agents, as described more fully below.

[0194] 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 can 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 be generally 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.

[0195] The compositions include those suitable for various routes of administration, including oral administration. The compositions may be presented in unit dosage form or may be prepared by any of the methods well known in the art of pharmacy. Such methods include bringing the active ingredient (e.g., a compound of the present disclosure or a pharmaceutical salt thereof) into association with one or more pharmaceutically acceptable excipients. The compositions may be prepared by uniformly and intimately bringing the active ingredient into association with a liquid excipient, or a finely divided solid excipient, or both, and then, if necessary, shaping the product. Techniques and formulations are generally found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0196] 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.

[0197] 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. The pharmaceutical composition containing the active ingredient may be in any form suitable for the intended method of administration. For example, when used for oral administration, it may be in the form of a tablet, troche, lozenge, aqueous or other liquid. The active ingredient may be prepared as an oil suspension, dispersible powder or granule, emulsion, hard or soft capsule, syrup, or elixir. Compositions intended for oral use 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 they 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 alone or with a wax may be employed.

[0198] 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 approximately 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 are about 5 to about 95% (weight:weight) of the total composition.

[0199] 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. It is also understood that in one aspect, 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.

[0200] In some embodiments, the pharmaceutical compositions are for human or animal use.

[0201] 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.

[0202] 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.

[0203] 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.

[0204] V. Route of Administration The compounds of the present disclosure (also referred to herein as the active ingredients) can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (buccal), and topical. 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.

[0205] 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.

[0206] 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.

[0207] 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.

[0208] 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.

[0209] 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 from about 1 mg per dose to about 1000 mg per dose, such as from about 50 mg per dose to about 500 mg per dose, or from about 100 mg per dose to about 400 mg per dose, or from about 150 mg per dose to about 350 mg per dose, or from about 200 mg per dose to about 300 mg per dose. Other therapeutically effective amounts of the compounds of the present disclosure are about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or about 500 mg per dose. Other therapeutically effective amounts of the compounds of the present disclosure are about 100 mg per dose, or about 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, or about 500 mg per dose. A single dose can be administered hourly, daily, or weekly. For example, a single dose can be administered once every 1, 2, 3, 4, 6, 8, 12, 16 hours, or once every 24 hours. A single dose can also be administered once every 1, 2, 3, 4, 5, 6 days, or once every 7 days. A single dose can also be administered once every 1, 2, 3 weeks, or once every 4 weeks. In some embodiments, a single dose can be administered once weekly. A single dose can also be administered once monthly.

[0210] Also included in the disclosure are kits comprising a compound of the present disclosure, or an enantiomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing any of the above. In one embodiment, the kit further comprises instructions for use. In one aspect, the kit comprises a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and a label and / or instructions for use of the compound in treating an indication, such as a disease or condition described herein. In one embodiment, the kit comprises one or more (e.g., 1, 2, 3, 4, Kits containing the compound in combination with one or two, or one to three, or one to four) additional therapeutic agents are provided.

[0211] 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 may be a vial, bottle, ampoule, pre-filled syringe, or infusion bag.

[0212] VI. Combination Therapy In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be combined with a therapeutically effective amount of one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents. In some embodiments, the additional therapeutic agents include an apoptotic signal-regulating kinase (ASK-1) inhibitor, a farnesoid X receptor (FXR) agonist, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, fish oil, acetyl-coA carboxylase inhibitor, or a combination thereof. acetyl-coA carboxylase (ACC) inhibitors or TGFβ antagonists, or a combination thereof.

[0213] In some embodiments, the therapeutic agent or combination of therapeutic agents is an ACE inhibitor, a 2-acylglycerol O-acyltransferase 2 ( ... 2, DGAT2 inhibitor, acetaldehyde dehydrogenase inhibitor, acetyl CoA Carboxylase inhibitor, adrenergic receptor agonist, Alstrom syndrome protein 1 (ALMS1) / PKC alpha protein Protein interaction inhibitors, apelin receptor agonists, diacylglycerol O-acyltransferase 2 inhibitors, adenosine A3 receptor agonists, adenosine A3 receptor antagonists, adiponectin receptor agonists, aldehyde dehydrogenase 2 stimulators, AKT protein kinase inhibitors, AMP-activated protein kinase (AMPK), AMP kinase activators, ATP citrate lyase inhibitors, AMP-activated protein kinase stimulators, endothelial nitric oxide synthase stimulators, NAD-dependent deacetylase sirtuin-1 stimulators, adrenergic receptor antagonists, androgen receptor agonists, amylin receptor agonists, angiotensin II AT-1 receptor antagonists, 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, CCR2 chemokine antagonists, angiotensin II AT-1 receptor antagonists, CCR3 chemokine antagonists, CCR5 chemokine antagonists, CD3 antagonists, CDGSH iron-sulfur domain protein modulators, chitinase inhibitors, chloride channel stimulators, chitotriosidase-1 inhibitors, CNR1 inhibitors, connective tissue growth factor ligand inhibitors, cyclin D1 inhibitors, cytochrome P450 7A1 inhibitor, DGAT1 / 2 inhibitor, diacylglycerol O acyltransferase 1 inhibitor (DGAT1), cytochrome P450 2E1 inhibitorinhibitor, CYP2E1), CXCR4 chemokine antagonist, dihydroceramide δ4 desaturase inhibitor, dihydroorotate dehydrogenase inhibitor, dipeptidyl peptidase IV inhibitor, endosialin modulator, eotaxin ligand inhibitor, extracellular matrix protein modulator, farnesoid X receptor agonist, fatty acid synthase inhibitor, FGF1 receptor agonist, fibroblast growth factor (FGF-15, F GF-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 (HNF4A), hepatocyte growth factor modulator, histone deacetylase inhibitor, STAT-3 modulator, HMG CoA reductase inhibitor, HSD17B13 gene inhibitor, 5-HT 2a receptor antagonist, hydrolase inhibitor, hypoxia-inducible factor-2α inhibitor, IL-10 agonist, IL-17 antagonist, IL-22 agonist, ileal sodium bile acid cotransporter inhibitor, insulin sensitizer, insulin ligand agonist, insulin receptor agonist, integrin modulator, integrin antagonist, integrin α-V / β-1 antagonist, integrin α-V / β-6 antagonist, interleukin-1 receptor-associated kinase 4 4, IRAK4 inhibitor, IL-6 receptor agonist, 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 anti-cancer drugs, 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-2 1) inhibitors, mitochondrial uncouplers, mixed lineage kinase-3 inhibitors, motile sperm domain protein 2 inhibitors, myelin basic protein stimulators, NACHT LRR PYD domain protein 3 (NLRP3) inhibitors, N AD-dependent deacetylase sirtuin stimulator, NADPH oxidase inhibitor (NADPH oxidase inhibitor, NOX), NFE2L2 gene inhibitor, nicotinic acid receptor 1 agonist, opioid receptor μ antagonist, P2Y13 purinergic receptor stimulator, nuclear erythroid 2-related factor 2 stimulator, nuclear receptor modulator, P2X7 purinergic receptor modulator, PACAP type I receptor agonist, PDE3 inhibitor, PDE4 inhibitor, PDE5 inhibitor, PDGF receptor β modulator, phenylalanine hydroxylase stimulator, phospholipase C inhibitor, phosphodiester hydrolase inhibitor, PPARα agonist, PPARδ agonist, PPARγ agonist, peptidyl-prolyl cis-trans isomerase A inhibitor, PNPLA3 gene inhibitor, PPARγ modulator, protease-activated receptor-2 antagonist, protein kinase modulator, protein NOV homolog modulator, PTGS2 gene inhibitor, renin inhibitor, resistin / CAP1 (adenylyl cyclase associated protein 1, adenylyl cyclase-related protein 1 interaction inhibitors, Rho-associated protein kinase inhibitors, S-nitrosoglutathione reductase (GSNOR) enzyme inhibitors, sodium glucose transporter-2 inhibitors, sphingolipid δ4 desaturase DES1 inhibitors, SREBP transcription factor inhibitors, STAT-1 inhibitors, stearoyl-CoA desaturase-1 inhibitors, STK25 inhibitors, inhibitors of cytokine signaling-1 stimulators, inhibitors of cytokine signaling-3 stimulators, telomerase stimulators, TERT gene modulators, TGFβ (TGFB1) ligand inhibitors, TN F antagonists, transforming growth factor β (TGF-β), transforming growth factor β activated kinase 1 (TAK1), thyroid hormone receptor β agonists, TLR-4 antagonists, transglutaminase inhibitors, tyrosine kinase receptor modulators, GPCR modulators, nuclear hormone receptor modulators, TLR-9 antagonists, VDR agonists, WNT modulators, or YAP / TAZ modulators and zonulin inhibitors.

[0214] 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 and ADP-399, -Adrenergic receptor antagonists such as bromocriptine, phentermine, and VI-0521 - aldehyde dehydrogenase 2 stimulators such as FP-045, alpha-glucosidase inhibitors (e.g., voglibose, acarbose, or miglitol), - amylin / calcitonin receptor agonists such as KBP-042, KBP-089, -AMP-activated protein kinase stimulators such as C-455, PXL-770, and O-304, -AMP kinase activators / ATP citrate lyase inhibitors such as bempedoic acid (ETC-1002, ESP-55016), -AMP-activated protein kinase / endothelial nitric oxide synthase / NAD-dependent deacetylase sirtuin-1 stimulators such as NS-0200 (leucine + metformin + sildenafil), - androgen receptor agonists such as LPCN-1144, LPCN-1148, and testosterone prodrugs, - Angiotensin II AT-1 receptor antagonists such as irbesartan, Angiopoietin-related protein-3 inhibitors (IONIS-ANGPTL3-LRx) such as bupanorsen, -Apelin receptor agonists such as CB-5064 and MBT-2, -autophagy protein modulators such as A-2906, - Autotaxin (ectonucleotide pyrophosphatase / phosphodiesterase 2 (NPP2 or ENPP2)) inhibitors such as FP10.47, PAT-505, PAT-048, GLPG-1690, X-165, PF-8380, TJC-0265, TJC-0316, AM-063, and BBT-877; -Axl tyrosine kinase receptor inhibitors such as bemcentinib (BGB-324, R-428), Bax protein stimulators, such as CBL-514, -bioactive lipids such as DS-102, -Cannabinoid receptor modulators such as nimacimab, GWP-42004, REV-200, CRB-4001, INV-101, and SCN-002 Tar, -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, -CXCR4 chemokine antagonists such as AD-214, -Diglyceride acyltransferase 2 (DGAT2) inhibitors such as IONIS-DGAT2Rx and PF-06865571; -Diglyceride acyltransferase 1 (DGAT1) inhibitors, such as GSK-3008356; -Diacylglycerol O-acyltransferase 1 (DGAT1) / cytochrome P450 2E1 inhibitors, such as SNP-610 YP2E1), -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- Farnesoid X receptor (FXR) agonists such as 102, Px-103, M790, M780, M450, M-480, MET-409, MET-642, PX20606, SYHA-1805, bonafexor (EYP-001), TERN-101, TC-100, INT-2228, TQA-3526, and ZG-5266; -farnesoid X receptor (FXR) / G protein-coupled bile acid receptor 1 (TGR5) agonists, such as INT-767; -fatty acid synthase inhibitors such as TVB-2640 and FT8225, -Fibroblast growth factor 19 (rhFGF19) / cytochrome P450 (CYP) 7A1 inhibitors, such as aldafermin (NGM-282); -Fibroblast growth factor 21 (FGF-2) such as AP-025, BMS-986171, B-1654, BIO89-100, and BOS-580 1) ligand, -Pegbelfermin (BMS-986036), B-1344, - fibroblast growth factor 21 (FGF-21) / glucagon-like peptide 1 (GLP-1) agonists such as YH-25723 (YH-25724, YH-22241) and effluxifermin (AKR-001), -FGF receptor agonists / Klotho β stimulators such as BFKB-8488A (RG-7992), -Free fatty acid receptor 1 agonists, such as SCO-267, Galectin-3 inhibitors such as Bellapectin (GR-MD-02), GB-1107 (Gal-300), and GB-1211 (Gal-400); - GDNF family receptor alpha-like agonists, such as NGM-395, Glucagon-like peptide 1 (GLP1R) agents 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 efinogdutide; Gastric inhibitory polypeptide / glucagon-like peptide-1 (GIP / Glucagon-like peptide-1), such as tirzepatide (LY-3298176) GLP-1 receptor co-agonist, -PEGylated long-acting glucagon-like peptide-1 / glucagon, such as DD-01 (GLP-1R / GCGR ) Receptor dual agonist, -glucagon / GLP1 receptor agonists, such as BI-456906, - glucocorticoid receptor antagonists, such as CORT-118335 (milicorilant); -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 and / or 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); Insulins such as KBP-042, azemiglitazone potassium (MSDC-0602K), ION-224, MSDC-5514, Px-102, RG-125 (AZD4076), trimidone, VVP-100X, CB-4211, ETI-101, and pioglitazone sensitizers, -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 and LY-3478045; - β Klotho (KLB)-FGF1c agonists such as MK-3655 (NGM-313), - leukotriene A4 hydrolase inhibitors, such as LYS-006; - 5-lipoxygenase inhibitors such as tipelukast (MN-001), epereuton (DS-102, (AF-102), etc. - Lipoprotein lipase inhibitors, such as CAT-2003, -LPL gene stimulators such as alipogene tiparvovec, Liver X receptor (LXR) inhibitors such as PX-665, PX-L603, PX-L493, BMS-852927, T-0901317, GW-3965, and SR-9238; lysophosphatidic acid-1 receptor antagonists such as BMT-053011, UD-009 (CP-2090), AR-479, ITMN-10534, BMS-986020, and KI-16198; -Lysyl oxidase homolog 2 inhibitors, such as simtuzumab and PXS-5382A (PXS-5338), - macrophage mannose receptor 1 modulators such as tilmanocept-Cy3 (technetium Tc 99m tilmanocept); -matrix metalloproteinase inhibitors, such as ALS-L1023, - membrane copper amine oxidase (VAP-1) inhibitors, such as TERN-201 and TT-01025; - MEKK-5 protein kinase (ASK-1) inhibitors such as CJ-16871, CS-17919, selonsertib (GS-4997), SRT-015, GS-444217, GST-HG-151, and TERN-301; - MCH receptor-1 antagonists, such as CSTI-100 (ALB-127158), Semicarbazide-Sensitive Amine Oxidase / Vascular Adhesion Protein-1 (SSAO / VAP-1) inhibitors, such as PXS-4728A (BI-1467335), - methionine aminopeptidase-2 inhibitors such as ZGN-1061, ZGN-839, and ZN-1345; -methyl-CpG binding protein 2 modulators, such as mercaptamines, -Mineralocorticoid receptor antagonists (MCRA), such as MT-3995 (aparalenone), -mitochondrial uncouplers such as 2,4-dinitrophenol, HU6, and Mito-99-0053, - mixed lineage kinase-3 inhibitors, such as URMC-099-C, -Motile sperm domain protein 2 inhibitors, such as VB-601; -Myelin basic protein stimulators such as olesoxime, -myeloperoxidase inhibitors such as PF-06667272, AZM-198, - NADPH oxidase inhibitors such as GKT-831, GenKyoTex, APX-311, and setanaxib, - Nicotinic acid receptor 1 agonists, such as ARI-3037MO, NACHT LRR PYD domain protein 3 (NACHT LRR PYD) domain protein 3 (NLRP3) inhibitor, -NFE2L2 gene inhibitors such as GeRP-amiR-144 - 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 and 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; -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, -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, and VK-2809 , -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 -TNF antagonists such as ALF-421 -GPCR modulators such as CNX-023, -nuclear hormone receptor modulators such as Px-102, -VDR agonists such as CK-15, -xanthine oxidase inhibitors, such as ACQT-1127, -xanthine oxidase / urate anion exchanger 1 (URAT1) inhibitors such as RLBN-1001 and RLBN-1127, and -Zonulin inhibitors such as lorazotide acetate (INN-202).

[0215] In some embodiments, the one or more additional therapeutic agents are A-4250, AC-3174, acetylsalicylic acid, AK-20, alipogen tiparvovec, AMX-342, AN-3015, anti-TAGE antibody, aramchol, ARI-3037MO, ASP-8232, AZD-2693, bertilimumab, betaine anhydrous, BI-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, cobiprostone, colesevelam, dabigatran etexilate methanesulfonate, dapagliflozin, DCR-LIV1, deuterated pioglitazone R-enantiomer, 2,4-Dinitrophenol, DRX-065, DS-102, DUR-928, EDP-305, elafibranor (GFT-505), emricasan, enalapril, ertugliflozin, evogliptin, F-351, fluasterone (ST-002), FT-4101, GDD-3898, GH-509, GKT-831, GNF-5120, GRI-0621, GR-MD-02, GS-300, GS-4997, GS-9674 , 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, IONIS-DGAT2Rx, ipragliflozin, irbesarta, propagermanium, IVA-337, J2H-1702, JKB-121, KB -GE-001, KBLP-004, KBLP-009, KBP-042, KD-025, M790, M780, M450, metformin, sildenafil, LB-700, LC-280126, linagliptin, liraglutide, (LJN-452) (Tropifexor), LM-011, LM-002 (CVI-LM-002), LMB-763, LYN-100, MB-N-008, MBX-8025, MDV-4463, mercapta Min, 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 (obeticholic, acid, OCA), 25HC3S, olesoxime, PAT-505, PAT-048, PBI-4547, 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), RPI-500, S-72 3595, saroglitazar, SBP-301, semaglutide, SH-2442, SHC-028, SHC-023, simtuzumab, solithromycin, sotagliflozin, statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), synbiotics, TCM-606F, TEV-45478, TQA-3526, TQA-3563, tipelukast (MN-001), TLY-012, TRX-318, TVB-2640, TXR-612 , TS-20004, UD-009, UN-03, ursodeoxycholic acid, VBY-376, VBY-825, VK-2809, vismodegib, vorixib potassium ethanolate hydrate (SHP-626), VVP-100X, WAV-301, WNT-974, WXSH-0038, WXSH-0078, XEN-103, XRx-117, XTYW-003, XW-003, XW-004, ZGN-839, ZG-5216, ZSYM-008, ZYSM-007.

[0216] In some embodiments, the compounds of the present disclosure are selected from the group consisting of peptide YY or analogs thereof, neuropeptide Y receptor type 2 (NPYR2) agonists, NPYR1 agonists, NPYR5 antagonists, cannabinoid receptor type 1 (CB1R) antagonists, lipase inhibitors (e.g., orlistat), human proislet peptide (HIP), melanocortin receptor 4 agonists (melanocortin-4 receptor, MC4R) (e.g., setomelanotide), melanin-concentrating hormone receptor 1 antagonists, farnesoid X receptor (FXR) agonists (e.g., obeticholic acid), apoptosis signal-regulating kinase (ASK-1) inhibitors, zonisamide, phentermine (alone or in combination with topiramate), norepinephrine / dopamine reuptake inhibitors (e.g., buproprion), opioid receptor antagonists (e.g., naltophenone), lexon), combinations of norepinephrine / dopamine reuptake inhibitors and opioid receptor antagonists (e.g., combinations of buproprion and naltrexone), GDF-15 analogs, sibutramine, cholecystokinin agonists, amylin and its analogs (e.g., pramlintide), leptin and its analogs (e.g., metroleptin), serotonergic agents (e.g., lorcaserin), methionine aminopeptidase 2 (MMA), 2, MetAP2 inhibitors (e.g., beloranib or ZGN-1061), phen dimetrazine, diethylpropion, benzphetamine, SGLT2 inhibitors (e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, or ertugliflozin), SGLTL1 inhibitors, dual SGLT2 / SGLT1 inhibitors, fibroblast growth factor receptor (FGFR) modulators, AMP-activated protein kinase (AMPK) activators, biotin, MAS receptor modulators, or glucagon receptor agonists (alone or in combination with another GLP-1 R agonist, e.g., liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, or semaglutide), insulin sensitizers such as thiazolidinedione (TZD), peroxisome proliferator-activated Receptor α (peroxisome proliferator-activated receptor alpha, PPARα) Nist, fish oil, acetyl-coA carboxylase (ACC) ) inhibitors, transforming growth factor beta (TGFβ) antagonists, GDNF family receptor alpha like (GFRAL) agonists, and melanocortin-4 receptor (MC4R) agonists (the pharmacology of specific named drugs). The compounds are combined with one or more therapeutic agents selected from anti-obesity agents (including pharmaceutically acceptable salts and pharmaceutically acceptable salts of such agents and salts).

[0217] In some embodiments, the methods and compositions comprise administering a therapeutically effective amount of a compound of formula (IA-1), (I- A-2), and / or a compound of Formula (I), and a therapeutically effective amount of a farnesoid X receptor (FXR) agonist. In some embodiments, the FXR agonist is a compound of Formula (II) or (III):

[0218] [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.

[0219] In some embodiments, the methods and compositions comprise a therapeutically effective amount of a compound of Formula (IA-1), (IA-2), and / or Formula (I) and a therapeutically effective amount of an ASK1 inhibitor. In some embodiments, the ASK-1 inhibitor is a compound of Formula (IV):

[0220] [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.

[0221] In some embodiments, the methods and compositions comprise a therapeutically effective amount of a compound of Formula (IA-1), (IA-2), and / or Formula (I) and a therapeutically effective amount of an acetyl-CoA carboxylase (ACC) inhibitor. In certain embodiments, the ACC inhibitor is a compound of Formula (V):

[0222] [ka] or a pharmaceutically acceptable salt thereof.

[0223] In some embodiments, the methods and compositions comprise a therapeutically effective amount of a compound of Formula (IA-1), (IA-2), and / or Formula (I) and a therapeutically effective amount of a thyroid hormone receptor (THR) beta agonist. In certain embodiments, the THR beta agonist is a compound of Formula (VI):

[0224] [ka] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.

[0225] VII. Treatment method In some embodiments, compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, are useful in methods for treating and / or preventing a GLP-1R-mediated disease or condition. In some embodiments, the method for treating and / or preventing a GLP-1R-mediated disease or condition comprises administering to a subject in need thereof a pharmaceutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0226] In some embodiments, the disease or condition is a liver disease or related disease or condition, such as liver fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cirrhosis, compensated liver fibrosis, degenerative liver fibrosis, hepatocellular carcinoma, primary biliary cirrhosis, or 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.

[0227] GLP-1R agonists are currently being investigated in relation to certain disorders and conditions, including diabetes. GLP-1 analogs that are DPP4 resistant and have a longer half-life than endogenous GLP-1 have been reported to be associated with weight loss and improved insulin action. Liraglutide, a peptide GLP-1R agonist approved for the treatment of diabetes, has been reported to show favorable improvement in outcomes in NASH subjects.

[0228] In some embodiments, the present disclosure relates to the use of a compound of Formula (I), (IA-1), (IA-2), 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 (IA-1), (IA-2), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prevention and / or treatment of a disease or condition mediated by GLP-1R, such as a liver disease or a metabolic disease.For example, some embodiments are directed to the treatment of chronic intrahepatic or certain forms of extrahepatic cholestatic conditions, liver fibrosis, acute intrahepatic cholestatic conditions, obstructive or chronic inflammatory diseases resulting from inadequate bile composition, gastrointestinal conditions associated with reduced intake of dietary fat and fat-soluble dietary vitamins, inflammatory bowel disease, lipid and lipoprotein disorders, type II diabetes and clinical complications of types I and II diabetes, conditions resulting from chronic fatty and fibrotic degeneration of organs due to forced lipid and particularly triglyceride accumulation and subsequent activation of pro-fibrotic pathways, and disease, 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 virally mediated forms of hepatitis. Associated cholestatic and fibrotic effects, 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 infarction, stroke, hemorrhagic stroke, ischemic stroke The present invention provides a compound of formula (I), (IA-1), and / or (IA-2), or a pharmaceutically acceptable salt thereof, or use thereof for the treatment and / or prevention of chronic obstructive pulmonary disease, 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.

[0229] 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.

[0230] The present disclosure also relates to compounds according to Formula (IA-1), (IA-2), and / or Formula (I), or pharmaceutical compositions comprising such compounds, 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, methods for treating and / or preventing cardiovascular disorders comprise administering to a subject in need thereof a compound of Formula (IA-1), (IA-2), and / or Formula (I).

[0231] The present disclosure further relates to compounds or pharmaceutical compositions for the treatment and / or prevention of obesity and related disorders such as metabolic syndrome (a combined condition of dyslipidemia, diabetes, and abnormally high body mass index), which can overcome GLP1R-mediated lowering of serum triglycerides, blood glucose, and increased insulin sensitivity and GLP1R-mediated weight loss. In some embodiments, a method for treating and / or preventing a metabolic disease comprises administering to a subject in need thereof a compound of Formula (I). In some embodiments, a method for treating and / or preventing a metabolic disease comprises administering to a subject in need thereof a compound of Formula (IA-1) and / or (IA-2).

[0232] In further embodiments, the compounds or pharmaceutical compositions of the present disclosure are useful for 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 (IA-1) and / or (IA-2) to a subject in need of such treatment and / or prevention.

[0233] 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 to a subject in need thereof a compound of Formula (IA-1) and / or (IA-2). In some embodiments, methods for treating and / or preventing NASH comprise administering to a subject in need thereof a compound of Formula (I). In some embodiments, methods for treating and / or preventing NASH comprise administering to a subject in need thereof a compound of Formula (IA-1) and / or (IA-2).

[0234] 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.

[0235] 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.

[0236] 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.

[0237] VIII. Working Examples Many general references are available that provide generally known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds (see, for example, Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th edition, Wiley-Interscience, 2013).

[0238] 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.R.Snyder and J.J.Kirkland, John Wiley and Sons, 1979, and "Thin Layer Chromatography," E.Stahl (ed.), Springer-Verlag, New York, 1989. See York, 1969.

[0239] 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.

[0240] 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 appropriately selected to obtain 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.

[0241] The examples provided herein describe the synthesis of the compounds disclosed herein, as well as the intermediates used to prepare the compounds.It should be understood that the individual steps described herein can be combined.It should also be understood that separate batches of compounds can be combined and then proceed to the next synthetic step.

[0242] 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 modifications 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.

[0243] In some embodiments, the present disclosure generally provides a particular enantiomer or diastereomer as the desired product, but the stereochemistry of the enantiomer or diastereomer has not been determined in all cases. When the stereochemistry of a particular stereocenter in an enantiomer or diastereomer is not determined, the compound is derived without indicating the stereochemistry at that particular stereocenter, even though the compound may be substantially enantiomerically or diastereomerically pure.

[0244] Representative syntheses of compounds of the present disclosure are described in the following schemes and examples below. [Example]

[0245] 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.

[0246] 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.

[0247] [Table 1-1]

[0248] [Table 1-2]

[0249] A. Synthesis of intermediates

[0250] [ka]

[0251] 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-methoxyethylamine (34.9 mL, 402 mmol). The resulting solution was heated to 55 °C for 6 h. Upon completion, the solvent was removed and the resulting residue was taken up in EtOAc (150 mL), washed with brine (30 mL), concentrated, and carried forward without further purification. Methyl 3-(2-methoxyethylamino)-4-nitrobenzoate (20.0 g, 78.7 mmol) was then dissolved in 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 under a hydrogen balloon at room temperature for 16 hours. The reaction mixture was filtered through Celite, washed with EtOAc (100 mL), and concentrated to give the desired compound without further purification. ES / MS: 225.2 (M+H + ).

[0252] [ka]

[0253] 4-(((6-bromo-5-methylpyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (I-2) and 4-(((6-chloro-3-methylpyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (I-3) (( ... + ).

[0254] [ka]

[0255] 4-(((2-chloropyrimidin-4-yl)oxy)methyl)-3-fluorobenzonitrile (I-4): To a solution of 3-fluoro-4-(hydroxymethyl)benzonitrile (609 mg, 4.03 mmol) in tetrahydrofuran (1.00 mL) was added potassium tert-butoxide (237 mg, 2.11 mmol) and stirred at room temperature for 5 minutes. This solution was then added to a frozen solution of 2,4-dichloropyrimidine (300 mg, 2.01 mmol) in N,N-dimethylformamide (1.50 mL), cooled to -78 °C, and the reaction mixture was allowed to slowly warm to room temperature and stirred for 1 hour. The mixture was poured into 50 mL of water and stirred for 5 minutes. The precipitate was isolated to give the title compound, which was used directly without further purification. ES / MS m / z: 264.1 (M+H + ); 1H NMR(400MHz,CDCl3)δ8.39(d,J=5.7Hz,1H),7.66(t,J=7.4Hz,1H),7.53(dd,J=8 .0,1.5Hz,1H),7.44(dd,J=9.2,1.5Hz,1H),6.78(d,J=5.7Hz,1H),5.57(s,2H).

[0256] [ka]

[0257] Methyl 4-{[2-(4-bromo-2-fluorophenyl)acetyl]amino}-3-(2-methoxyethylamino)benzoate: To a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (1.00 g, 4.29 mmol) in DMF (20.0 mL), methyl 4-amino-3-(2-methoxyethylamino)benzoate (1.18 g, 5.28 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.96 g, 5.15 mmol) were added, followed by N,N-diisopropylethylamine (3.74 mL, 21.5 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The reaction was concentrated in vacuo, and the residue was taken up in EtOAc and washed with water (1×) and brine (1×). 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: 583.5 (M+H + ).

[0258] Methyl 2-[(4-bromo-2-fluoro-phenyl)methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate: The crude product from the previous step, methyl 4-{[2-(4-bromo-2-fluoro-phenyl)acetyl]amino}-3-(2-methoxyethylamino)benzoate (1.89 g, 4.29 mmol), was dissolved in AcOH (40.0 mL) and the reaction mixture was heated to 60 °C for 2 h. The reaction mixture was concentrated in vacuo, and the crude residue was taken up in DCM and washed with saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with DCM (2 times). The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by column chromatography (0-100% EtOAc in hexanes) to give the title compound. ES / MS m / z: 421.9 (M+H + ).

[0259] 2-{[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-3-(2-methoxyethyl)benzimidazole-5-carboxylate: To a vial, add 2-[(4-bromo-2-fluoro-phenyl)methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (200 mg, 0.475 mmol). To the resulting 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). Xanthene (4.80 mL) was added and the reaction was heated to 100° C. for 24 h. The reaction mixture was filtered through Celite, eluting with DCM, and the filtrate was concentrated in vacuo. The crude residue was purified by column chromatography (0-100% EtOAc in hexanes) to give the title compound. ES / MS m / z: 469.4 (M+H + ).

[0260] [ka]

[0261] 4-[(6-Bromo-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile (I-6): To a dried 100 mL RBF was added 3-fluoro-4-(hydroxymethyl)benzonitrile (2 g, 13.2 mmol). The material was dissolved in dry THF (20 mL) at 0 °C under a nitrogen atmosphere. Sodium hydride (60% dispersion in mineral oil, 0.507 g, 13.2 mmol) was added in one portion, and the mixture was stirred at 0 °C under N for 30 minutes. 2,6-Dibromopyridine (3.13 g, 13.2 mmol) was then added, and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc (100 mL) and 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).

[0262] [ka]

[0263] 3-Fluoro-4-[(6-tributylstannyl-2-pyridyl)oxymethyl]benzonitrile (I-7): To a 40 mL vial was added 4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile (I-6) (400 mg, 1.3 mmol), tetrakis(triphenylphosphine)palladium(0) (151 mg, 0.13 mmol), and tributyl(tributylstannyl)stannane (907 mg, 1.56 mmol). Toluene (8 mL) was added, and the mixture was degassed with argon for 2 minutes. The vial was sealed and stirred at 100 °C overnight. LCMS indicated apparent formation of the product, and the vial was cooled to room temperature. The mixture was dry-loaded onto silica gel and purified by silica gel chromatography (eluent: hexane, then EtOAc / hexane) to give intermediate I-7. ES / MS: 517.402 (M+H + ).

[0264] [ka]

[0265] 2-(2-Bromopyrimidin-5-yl)acetic acid (I-8): To a 40 mL vial was added ethyl 2-(2-bromopyrimidin-5-yl)acetate (250 mg, 1.02 mmol), acetonitrile (3 mL), and THF (3 mL). Lithium hydroxide (49 mg, 2.04 mmol) dissolved in water (0.75 mL) was added, and the mixture was stirred at 65 °C for 1 h. LCMS showed apparent formation of the product, so the mixture was diluted with EtOAc (60 mL) and acidified with 1 M HCl. The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 30 mL). The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure to give the product, which was used without further purification. ES / MS: 217.006 (M+H). + ).

[0266] [ka]

[0267] 6-Bromoisochroman-1-carboxylic acid (I-9): To a 40 mL vial was added 2-(3-bromophenyl)ethanol (500 mg, 2.49 mmol) and glyoxylic acid monohydrate (458 mg, 4.97 mmol). Trifluoroacetic acid (2 mL) was added, and the mixture was stirred at 70 °C overnight. The mixture was concentrated under reduced pressure, and the crude residue was partitioned between EtOAc (75 mL) and water (50 mL) and basified with 1 M NaOH. The layers were separated, and the aqueous layer was washed once more with EtOAc (50 mL). The aqueous layer was acidified with 1 M HCl (pH < 4) and extracted with EtOAc (3 × 75 mL). These combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. Intermediate I-9 was used without further purification.

[0268] [ka]

[0269] 7-Bromochroman-4-carboxylic acid (I-10): To a suspension of 7-bromochroman-4-one (1 g, 4.4 mmol) in THF (5 mL) was added zinc(II) iodide (85 mg, 0.264 mmol), followed by the dropwise addition of trimethylsilylformonitrile (1.65 mL, 13.2 mmol) via syringe. The reaction was stirred overnight at room temperature and then diluted with EtOAc (50 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The crude material was then dissolved in acetic acid (15 mL) and concentrated hydrochloric acid (15 mL) and stannous chloride (3.32 g, 17.5 mmol) was added. ) was added. The reaction was heated to reflux for 24 hours. The mixture was cooled, diluted with dichloromethane (50 mL), and washed with water (50 mL) and brine (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The material was determined to be sufficiently pure to carry forward without further purification. 1H NMR (400MHz, CDCl3) δ7.21-7.15(m,1H),7.09-7.00(m,2H),4.33-4.23(m,2H),3.79(dd,J=6.1,3.8Hz,1H),2.46-2.30(m,1H),2.21-2.13(m,1H).

[0270] [ka]

[0271] Methyl 2-(4-bromo-2-hydroxyphenyl)acetate: To a solution of 2-(4-bromo-2-hydroxyphenyl)acetic acid (250 mg, 1.08 mmol) in methanol (10 mL) was added concentrated sulfuric acid (0.1 mL). The mixture was heated at 60° C. for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (10 mL) and the mixture was extracted with EtOAc (2×30 mL). The combined organic phases were dried over MgSO4. Concentration under reduced pressure gave the product, which was carried forward without further purification. 1 H NMR (400MHz, CDCl3) δ7.14(d,J=2.0Hz,1H),7.04(dd,J=8.1,2.0Hz,1H),6.97(d,J=8.1Hz,1H),3.79(s,3H),3.66(s,2H).

[0272] Methyl 2-(4-bromo-2-(difluoromethoxy)phenyl)acetate: To a mixture of methyl 2-(4-bromo-2-hydroxy-phenyl)acetate (250 mg, 1.02 mmol), aqueous KOH (30 wt%, 4 mL), and acetonitrile (5 mL) at −78° C. was added chlorodifluoroacetophenone (972 mg, 5.1 mmol). The reaction mixture was warmed to room temperature and then heated to 80° C. overnight. The mixture was diluted with water (10 mL) and extracted with EtO (3×50 mL). The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: EtOAc / hexanes) to give the product. 1H NMR (400MHz, CDCl3) δ7.40-7.33(m,2H),7.19(d,J=8.1Hz,1H),6.50(t,J=73.4Hz,1H),3.73(s,3H),3.67(s,2H).

[0273] 2-[4-Bromo-2-(difluoromethoxy)phenyl]acetic acid (I-11): To a 25 mL RBF was added methyl 2-(4-bromo-2-(difluoromethoxy)phenyl)acetate (154 mg, 0.522 mmol), THF (4 mL), and acetonitrile (4 mL). Lithium hydroxide (1 M in water, 2.61 mL, 2.61 mmol) was added, and the mixture was stirred at 70 °C overnight. The mixture was acidified with 1 M HCl and diluted with water (20 mL) and Et The mixture was partitioned between HCl (50 mL) and HCl (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was carried forward without further purification.

[0274] [ka]

[0275] Methyl 4-amino-3-(((1-methylcyclopropyl)methyl)amino)benzoate (I-12): Methyl 4-amino-3-(((1-methylcyclopropyl)methyl)amino)benzoate was prepared exactly as described for intermediate I-1, substituting (1-methylcyclopropyl)methanamine hydrochloride for methoxyethylamine. ES / MS: 235.1 (M+H + ).

[0276] [ka]

[0277] Methyl 4-amino-3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)benzoate (I-13): Methyl 4-amino-3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)benzoate was prepared exactly as described for intermediate I-1, substituting (1-(fluoromethyl)cyclopropyl)methanamine; 2,2,2-trifluoroacetic acid for methoxyethylamine. ES / MS: 253.3 (M+H + ).

[0278] [ka]

[0279] Methyl 4-amino-3-((3-fluoro-2,2-dimethylpropyl)amino)benzoate (I-14): Methyl 4-amino-3-((3-fluoro-2,2-dimethylpropyl)amino)benzoate was prepared exactly as described for intermediate I-1, substituting 3-fluoro-2,2-dimethyl-propan-1-amine hydrochloride for methoxyethylamine. ES / MS: 255.4 (M+H + ).

[0280] [ka]

[0281] Methyl 4-amino-3-((3,3-difluoro-2,2-dimethylpropyl)amino)benzoate (I-15): Methyl 4-amino-3-((3,3-difluoro-2,2-dimethylpropyl)amino)benzoate was prepared exactly as described for intermediate I-1, substituting 3,3-difluoro-2,2-dimethyl-propan-1-amine for methoxyethylamine; hydrogen chloride. ES / MS: 273.2 (M+H + ).

[0282] [ka]

[0283] Methyl 4-amino-3-(((1-cyanocyclopropyl)methyl)amino)benzoate (I-16): Methyl 4-amino-3-(((1-cyanocyclopropyl)methyl)amino)benzoate was prepared exactly as described for intermediate I-1, substituting 1-(aminomethyl)cyclopropanecarbonitrile hydrochloride for methoxyethylamine. ES / MS: 246.3 (M+H + ).

[0284] [ka]

[0285] Methyl 4-amino-3-((2-cyano-2-methylpropyl)amino)benzoate (I-17): Methyl 4-amino-3-(((1-cyanocyclopropyl)methyl)amino)benzoate was prepared exactly as described for intermediate I-1, substituting 3-amino-2,2-dimethyl-propanenitrile for methoxyethylamine. ES / MS: 248.4 (M+H + ).

[0286] [ka]

[0287] Methyl 4-amino-3-((3-cyano-2,2-dimethylpropyl)amino)benzoate (I-18): Methyl 4-amino-3-((3-cyano-2,2-dimethylpropyl)amino)benzoate was prepared exactly as described for intermediate I-1, substituting 4-amino-3,3-dimethyl-butanenitrile for methoxyethylamine. ES / MS: 262.5 (M+H + ).

[0288] [ka]

[0289] Methyl 4-amino-3-((oxetan-2-ylmethyl)amino)benzoate (I-19): Methyl 4-amino-3-((oxetan-2-ylmethyl)amino)benzoate was prepared exactly as described for intermediate I-1, substituting oxetan-2-ylmethanamine for methoxyethylamine. ES / MS: 237.0 (M+H + ).

[0290] [ka]

[0291] 4-(((6-Chloropyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile: To a suspension of potassium tert-butoxide, reagent grade, 95% (6.3 g, 56.14 mmol) in THF (80 mL) was added 3-fluoro-4-(hydroxymethyl)benzonitrile (5.64 g, 37.3 mmol) at 10–15 °C. The black solution was stirred for 45 min, after which 2,6-dichloropyridine (4.6 g, 31.08 mmol) was added and stirred for 18 h. The mixture was poured into saturated NH4Cl (20 mL). EtOAc (20 mL) was added and the mixture was stirred for 15 min. The resulting mixture was filtered through Celite, the organic layer was separated, and the aqueous layer was extracted with EtOAc (2 × 120 mL). The combined organic extracts were washed with brine (100 mL) and dried over sodium sulfate to give the crude product, which was purified by silica gel chromatography (eluent: EtOAc / hexanes). ES / MS: 263.2 (M+H + ); 1 H NMR(400MHz,CDCl3)δ7.68(t,J=7.5Hz,1H),7.60(dd,J=8.2,7.5Hz,1H),7.50(dd,J=7.9,1.6Hz,1H),7.4 2(dd,J=9.2,1.6Hz,1H),6.99(dd,J=7.5,0.7Hz,1H),6.77(dd,J=8.2,0.7Hz,1H),5.51(t,J=0.9Hz,2H).

[0292] [ka]

[0293] 1-(tert-Butyl) 3-methyl 2-(5-bromo-3-fluoropyridin-2-yl)malonate: To a 40 mL vial was added tert-butylmethyl malonate (898 mg, 5.16 mmol) and DMF (10 mL). The solution was cooled to 0 °C, and NaH (60% in mineral oil, 237 mg, 6.19 mmol) was added. The reaction mixture was stirred at room temperature for 20 minutes, and gas evolution was observed. The reaction was then cooled to 0 °C, and 5-bromo-2,3-difluoropyridine (1.0 g, 5.16 mmol) was added, and the reaction was stirred overnight. LCMS showed product formation. The mixture was partitioned between EtOAc (50 mL) and water (20 mL), and the organic layer was separated, dried over MgSO and concentrated under reduced pressure to give 1-(tert-butyl) 3-methyl 2-(5-bromo-3-fluoropyridin-2-yl)malonate, which was carried on directly to the next step. ES / MS: 348.470 (M+H + ).

[0294] Methyl 2-(5-bromo-3-fluoropyridin-2-yl)acetate: To a 100 mL RBF was added 1-(tert-butyl) 3-methyl 2-(5-bromo-3-fluoropyridin-2-yl)malonate (1.4 g, 4.02 mmol), trifluoroacetic acid (10 mL), and CHCl (10 mL). The mixture was stirred at room temperature overnight. LC / MS indicated the formation of the product. The solvent was evaporated under reduced pressure to give the product as the trifluoroacetic acid salt. ES / MS: 248.347 (M+H). + ).

[0295] 2-(5-Bromo-3-fluoro-2-pyridyl)acetic acid (I-21): To 40 mL of RBF was added methyl 2-(5-bromo-3-fluoropyridin-2-yl)acetate (trifluoroacetate salt) (1.2 g, 3.31 mmol). Methanol (10 mL) and THF (5 mL) were added, followed by 1 M NaOH (6.63 mL, 6.63 mmol). The reaction mixture was stirred at 70 °C overnight. The mixture was concentrated under reduced pressure, and the residue was dissolved in water and acidified with 1 N HCl. The resulting mixture was extracted three times with a mixture of DCM and methanol. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was carried forward without further purification. ES / MS: 234.159 (M+H) + ).

[0296] [ka]

[0297] Methyl 4-amino-3-(((1,1-dioxidothietan-2-yl)methyl)amino)benzoate (I-22): Methyl 4-amino-3-(((1,1-dioxidothietan-2-yl)methyl)amino)benzoate was prepared as described for intermediate I-1, substituting (1,1-dioxothietan-2-yl)methanamine; hydrochloride for methoxyethylamine. Prepared exactly as described above. ES / MS: 285.2 (M+H + ).

[0298] [ka]

[0299] Methyl 4-amino-3-(((1-(cyanomethyl)cyclopropyl)methyl)amino)benzoate (I-23): Methyl 4-amino-3-(((1-(cyanomethyl)cyclopropyl)methyl)amino)benzoate was prepared exactly as described for intermediate I-1, substituting 2-[1-(aminomethyl)cyclopropyl)acetonitrile hydrochloride for methoxyethylamine. ES / MS: 260.2 (M+H + ).

[0300] [ka]

[0301] Methyl 5-amino-6-(((1-methylcyclopropyl)methyl)amino)picolinate (I-24): Methyl 4-amino-3-((oxetan-2-ylmethyl)amino)benzoate was prepared exactly as described for intermediate I-1, substituting (1-methylcyclopropyl)methanamine hydrochloride for methoxyethylamine and methyl 3-fluoro-4-nitro-benzoate with methyl 6-chloro-5-nitro-pyridine-2-carboxylate. ES / MS: 236.3 (M+H + ).

[0302] [ka]

[0303] 4-(((4-bromothiazol-2-yl)oxy)methyl)-3-fluorobenzonitrile (I-25): To a vial were added 4-bromo-2-chloro-thiazole (250 mg, 1.26 mmol), 3-fluoro-4-(hydroxymethyl)benzonitrile (0.209 g, 1.39 mmol), cesium carbonate (0.821 g, 2.52 mmol), and acetonitrile (4 mL), and the reaction mixture was heated to 60° C. for 16 hours. The reaction mixture was poured into water, and the precipitate was filtered off, washed with water, and dried under vacuum to give the title compound. ES / MS m / z: 314.3 (M+H + );1 H NMR(400MHz,CDCl3)δ7.66(t,J=7.5Hz,1H),7.56-7.50(m,1H),7.44(dd,J=9 .1,1.6Hz,1H),6.68(s,1H),5.60(s,2H).

[0304] [ka]

[0305] 4-((3-bromo-5-fluorophenoxy)methyl)-3-fluorobenzonitrile (I-26): To a vial were added 3-bromo-5-fluoro-phenol (300 mg, 1.57 mmol), 4-(bromomethyl)-3-fluoro-benzonitrile (370 mg, 1.73 mmol) and cesium carbonate (930 mg, 2.86 mmol), followed by acetonitrile (5.00 mL), and the reaction mixture was stirred for 16 hours at 60° C. The reaction mixture was poured into water, and the precipitate was filtered off, washed with water, and dried under vacuum to give the title compound. 1 H NMR (400MHz, CDCl3) δ7.67(t,J=7.5Hz,1H),7.56-7.52(m,1H),7.44(dd,J=9.3,1.6Hz,1H),6.99-6.92(m,2H),6.70-6.64(m,1H),5.17(s,2H).

[0306] [ka]

[0307] 4-((3-Bromo-4-fluorophenoxy)methyl)-3-fluorobenzonitrile (1-27): The title compound was prepared according to the procedure described for intermediate 1-26, substituting 3-bromo-4-fluoro-phenol for 3-bromo-5-fluoro-phenol. 1H NMR(400MHz,CDCl3)δ7.68(t,J=7.5Hz,1H),7.54(dd,J=8.0,1.6Hz,1H),7.43(dd,J=9.3,1 .5Hz,1H),7.21-7.17(m,1H),7.09(dd,J=9.0,8.0Hz,1H),6.93-6.87(m,1H),5.15(s,2H).

[0308] [ka]

[0309] 4-((3-bromo-5-cyanophenoxy)methyl)-3-fluorobenzonitrile (1-28): The title compound was prepared according to the procedure described for intermediate 1-26, substituting 3-bromo-5-fluoro-phenol with 3-bromo-5-hydroxy-benzonitrile. 1 H NMR (400MHz, CDCl3) δ7.66(t,J=7.5Hz,1H),7.58-7.53(m,1H),7.49±7.44(m,2H),7.42-7.39(m,1H),7.22-7.18(m,1H),5.21(s,2H).

[0310] [ka]

[0311] 4-((3-Bromo-5-methoxyphenoxy)methyl)-3-fluorobenzonitrile (1-29): The title compound was prepared according to the procedure described for intermediate 1-26, substituting 3-bromo-5-methoxy-phenol for 3-bromo-5-fluoro-phenol. 1 H NMR (400MHz, CDCl3) δ7.71-7.64(m,1H),7.56-7.51(m,1H),7.45-7.40(m,1H),6.79-6.72(m,2H),6.47(t,J=2.3Hz,1H),5.16(s,2H),3.80(s,3H).

[0312] [ka]

[0313] 4-(((6-Bromo-4-methylpyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (I-30): To a solution of 3-fluoro-4-(hydroxymethyl)benzonitrile (0.878 g, 5.81 mmol) in THF cooled to 0 °C, potassium tert-butoxide (0.982 g, 8.75 mmol) was added and the reaction mixture was stirred for 10 min. 2-Bromo-6-chloro-4-methyl-pyridine (1.00 g, 4.84 mmol) was then added and the reaction mixture was stirred at 0 °C for 1 h and then heated to 50 °C for 3 h. The reaction mixture was cooled to room temperature, poured into water, and the precipitate was filtered off and dried under vacuum to give the title compound as a mixture of Br / Cl isomers. ES / MS m / z: 321.1 (M+H + ), 277.1(M+H + ).

[0314] [ka]

[0315] Tert-butyl 4-nitro-3-((2,3-dimethoxy-3-oxopropyl)amino)benzoate: 3-Amino-2-methoxy-propanoic acid hydrochloride (355 mg, 2.3 mmol) was suspended in DCM / methanol (5 mL, 3:1) and TMS diazomethane (2.0 M, 1.1 mL, 2.3 mmol) was added until a pale yellow color persisted. The reaction was quenched by the addition of AcOH (approximately 1 drop), concentrated to dryness, dissolved in MeTHF (3 mL), and concentrated to dryness again. To the resulting crude amino ester dissolved in MeTHF (3 mL) was added tert-butyl 3-fluoro-4-nitro-benzoate (500 mg, 2.1 mmol) and DIPEA (1.1 mL, 6.2 mmol). The mixture was stirred at 80 °C overnight. The reaction was then cooled, diluted with EtOAc, rinsed with aqueous NH4Cl, dried over Na2SO4, filtered, and concentrated. ES / MS: 355.1 (M+H + )

[0316] Tert-butyl 4-amino-3-[(2,3-dimethoxy-3-oxopropyl)amino]benzoate (I-31): The crude tert-butyl 4-nitro-3-((2,3-dimethoxy-3-oxopropyl)amino)benzoate (approximately 2.1 mmol) from the above reaction was combined with saturated aqueous NH4Cl (2.5 mL) and iron powder (579 mg, 10.4 mmol) in ethanol (5 mL). The mixture was stirred at 60 °C for 45 min, then cooled, diluted with EtOAc (10 mL), filtered through MgSO4 and Celite, concentrated to dryness, and purified by column chromatography (40-85% EtOAc in hexanes) to give the title compound. ES / MS: 325.1 (M+H + ); 1 H NMR (400 MHz, chloroform-d) δ 7.47 (dd, J = 8.1, 1.8 Hz, 1H), 7.37 (d, J = 1.9 Hz, 1H), 7.28 (s, 1H), 6.68 (d, J = 8.1 Hz, 1H), 4.11 (dd, J = 6.3, 3.6 Hz, 1H), 3.80 (s, 3H), 3.56 (dd, J = 12.7, 3.8 Hz, 1H), 3.52 (s, 3H), 3.44 (dd, J = 12.7, 6.4 Hz, 1H), 1.59 (s, 9H).

[0317] Tert-butyl 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenyl]methyl]-3-(2,3-dimethoxy-3-oxo-propyl)benzimidazole-5-carboxylate (I-32): 2-[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenyl]acetic acid The acid (I-128, 240 mg, 0.63 mmol), tert-butyl 4-amino-3-[(2,3-dimethoxy-3-oxo-propyl)amino]benzoate (I-31, 235 mg, 0.73 mmol), HATU (360 mg, 0.95 mmol), and DIPEA (0.55 mL, 3.2 mmol) were combined in DCE / DMF (2:1, 3 mL) and stirred at 50 °C for 15 min. The reaction was cooled and eluted with Et The reaction mixture was diluted with HCl and rinsed with aqueous NH4Cl, aqueous NaHCO3, and brine. The organic fraction was dried over Na2SO4, filtered, and concentrated. The crude solid was dissolved in AcOH (2 mL) and stirred at 70 °C for 20 min, followed by stirring at 85 °C for 35 min and at 90 °C for 40 min. The reaction was then cooled to room temperature, concentrated to dryness, and purified by column chromatography (40-85% EtOAc in hexanes) to give the title compound. ES / MS: 669.4 (M+H + ); 1 H NMR(400MHz,chloroform-d)δ8.22-8.06(m,1H),7.97(d,J=8.5Hz,1H),7.78(d,J=8.4Hz,1H),7.76-7.63(m,4H),7.47(dd,J=7.9,1.5Hz,1H),7.42(dd,J=9 .3,1.6Hz,1H),7.36(d,J=7.4Hz,1H),6.82(d,J=8.2Hz,1H),5.62(s,2H),4 .64-4.36(m,4H),4.13-4.09(m,1H),3.83(s,3H),3.32(s,3H),1.66(s,9H). 19 F NMR (376 MHz, chloroform-d) δ -115.30--115.58 (m), -117.61.

[0318] I-33 and I-34: Tert-butyl 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenyl]methyl]-3-(2,3-dimethoxy-3-oxo-propyl)benzimidazole-5-carboxylate Isomer 1 and Isomer 2. tert-Butyl 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenyl]methyl]-3-(2,3-dimethoxy-3-oxo-propyl)benzimidazole-5-carboxylate, obtained as a mixture of two stereoisomers, was separated by chiral SFC (IG column with 45% EtOH co-solvent) to give two different stereoisomers (I-33 and I-34).

[0319] [ka]

[0320] 3-(6-(tert-Butoxycarbonyl)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-1H-benzo[d]imidazol-1-yl)-2-methoxypropanoic acid enantiomer 1 (I-35): Tert-butyl 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenyl]methyl]-3-(2,3-dimethoxy-3-oxo-propyl)benzimidazole-5-carboxylate (I-33 peak 1) (151 mg, 0.23 mmol) was combined with lithium hydroxide monohydrate (28 mg, 0.67 mmol) in THF (2 mL) and water (0.3 mL) and stirred at 30° C. After 45 min, the reaction was diluted with EtOAc (5 mL) and aqueous HCl (1 M, 2 mL). The organic layer was separated, rinsed with brine, dried over MgSO4, filtered, and concentrated to give the title compound. ES / MS: 655.2 (M+H + ).

[0321] 3-(6-(tert-Butoxycarbonyl)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-1H-benzo[d]imidazol-1-yl)-2-methoxypropanoic acid enantiomer 2 (I-36): Using a similar procedure, tert-butyl 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenyl]methyl]-3-(2,3-dimethoxy-3-oxo-propyl)benzimidazole-5-carboxylate was hydrolyzed. Peak 2: ES / MS: 655.2 (M+H + ).

[0322] [ka]

[0323] Methyl 3-[[3-(tert-butoxycarbonylamino)-2-methoxy-propyl]amino]-4-nitro-benzoate (I-37): Methyl 3-fluoro-4-nitro-benzoate (1300 mg, 6.53 mmol), 2-methoxypropane-1,3-diamine (1020 mg, 9.79 mmol), and DIPEA (4.4 mL, 26 mmol) were combined in MeTHF (10 mL) and stirred at 75 °C for 3 h. The reaction was cooled to room temperature, diluted with DCM (10 mL), and di-tert-butyl dicarbonate (4.3 g, 20 mmol) was added. After 30 min, the reaction was diluted with EtOAc (50 mL) and rinsed twice with aqueous NH4Cl and once with brine. The organic fraction was dried over Na2SO4, filtered, concentrated, and purified by column chromatography to provide the title compound. ES / MS: 384.0 (M+H + ).

[0324] Methyl 4-amino-3-[[3-(tert-butoxycarbonylamino)-2-methoxy-propyl]amino]benzoate (I-38): Methyl 3-[[3-(tert-butoxycarbonylamino)-2-methoxy-propyl]amino]-4-nitro-benzoate (I-37, 1.8 g, 4.7 mmol) was combined with iron powder (1.05 g, 18.8 mmol) and saturated aqueous NH4Cl (4.7 mL) in ethanol (20 mL). The mixture was stirred at 60 °C for 10 min, then cooled to room temperature, diluted with EtOAc (100 mL), filtered through Celite, and rinsed twice with brine. The organic fraction was dried over Na2SO4, filtered, and concentrated to give the title compound. ES / MS: 354.1 (M+H) + ).

[0325] Methyl 3-[3-(tert-butoxycarbonylamino)-2-methoxy-propyl]-2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenyl]methyl]benzimidazole-5-carboxylate (I-39): 4-amino-3-[[3-(tert-butoxycarbonylamino)-2-methyl Methyl [4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenyl]benzoate (I-38, 500 mg, 1.4 mmol), 2-[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenyl]acetic acid (I-128, 460 mg, 1.2 mmol), HATU (689 mg, 1.81 mmol), and DIPEA (1.05 mL, 6.05 mmol) were mixed with DCE / DMF (2:1, 6 mL) and stirred at 50 °C for 45 min. The reaction was cooled, diluted with EtOAc, and rinsed with aqueous NH Cl, aqueous NaHCO, and brine. The organic fraction was dried over Na SO , filtered, and concentrated. The crude solid was dissolved in DCE / AcOH (1:2, 5 mL) and stirred at 80 °C for 30 min, then cooled to room temperature, concentrated to dryness, and purified by column chromatography (40-85% EtOAc in hexanes) to give the title compound. ES / MS: 698.3 (M+H + ); 1 H NMR (400 MHz, chloroform-d) δ 8.13 (s, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.85 (s, 1H), 7.78-7.63 (m, 4H), 7.48 (dd, J = 7.9, 1.6 Hz, 1H), 7.42 (dd, J = 9.2, 1.5 Hz, 1H), 7.37 (d, J = 7.5 Hz, 1H) ),6.83(d,J=8.2Hz,1H),5.62(s,2H),4.89(t,J=6.0Hz,1H),4.56(s,1H),4.30(s,2H) ,3.98(s,3H),3.67-3.56(m,1H),3.42(s,2H),3.12(s,3H),2.12(s,1H),1.49(s,9H).

[0326] Methyl 1-(3-amino-2-methoxypropyl)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-1H-benzo[d]imidazole-6-carboxylate enantiomers 1 and 2 (I-40 and I-41): Methyl 3-[3-(tert-butoxycarbonylamino)-2-methoxypropyl]-2-[[4-[6-[(4-cyano-2-fluorophenyl)methoxy]-2-pyridyl]-2-fluorophenyl]methyl]benzimidazole-5-carboxylate, obtained as a mixture of two stereoisomers, was separated by chiral SFC (IG column with 40% EtOH co-solvent) to give two different stereoisomers. The separated enantiomers were separately subjected to TFA (65 equivalents) at room temperature for 5 min. The reaction was diluted with water, quenched with 1M NaOH to pH 7, and extracted three times with DCM. The combined organic fractions were rinsed with aqueous NaHCO and brine, then dried over NaSO, filtered, and concentrated to give the title compound. ES / MS: 598.5 (M+H + ).

[0327] [ka]

[0328] 4-[[2-(4-bromo-2,6-difluoro-phenyl)acetyl]amino]-3 Methyl-(2-methoxyethylamino)benzoate: To a solution of 2-(4-bromo-2,6-difluorophenyl)acetic acid (3.67 g, 0.0146 mol), methyl 4-amino-3-(2-methoxyethylamino)benzoate (3.00 g, 0.0134 mol), and 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 99% (3.78 g, 0.00993 mol) in DMF (35 mL) was added N,N-diisopropylethylamine (11.7 mL, 0.0669 mol). The mixture was stirred overnight at room temperature. The reaction was diluted with EtOAc and washed with 5% LiCl, saturated NaHCO3, and brine. The organic extract was dried over sodium sulfate and concentrated. The crude residue was carried forward without further purification. ES / MS m / z: 457.0, 459.0 (M+H + )

[0329] Methyl 2-[(4-bromo-2,6-difluoro-phenyl)methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (I-42): A solution of methyl 4-[[2-(4-bromo-2,6-difluoro-phenyl)acetyl]amino]-3-(2-methoxyethylamino)benzoate (6.12 g, 0.0134 mol) in AcOH (24 mL) and DCE (24 mL) was heated at 60° C. for 7 h. The mixture was concentrated and chromatographed (eluent: EtOAc / hexane) to give the title compound. ES / MS m / z: 439.0, 441.0 (M+H + ); 1 H NMR(400MHz,CDCl3)δ8.09(dd,J=1.5,0.7Hz,1H),7.96(dd,J=8.5,1.6Hz,1H),7.74(d,J=8.5Hz,1H),7. 16(d,J=6.8Hz,2H),4.46(t,J=5.2Hz,2H),4.36(s,2H),3.97(s,3H),3.74(t,J=5.1Hz,2H),3.31(s,3H).

[0330] Methyl 2-[[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (I-43): In a 200 mL round-bottom flask, add 1000 mg of methyl 2-[(4-bromo-2,6-difluoro-phenyl)methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (2.28 mmHg). A mixture of (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (695 mg, 2.74 mmol), (1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (81.5 mg, 0.115 mmol), and potassium acetate (671 mg, 6.84 mmol) was purged with Ar / vac three times. To this was added dioxane (24 mL), and the mixture was degassed with Ar for 5 minutes. The mixture was heated at 100 °C for 3.5 hours. The mixture was filtered through a plug of Celite, diluted with EtOAc, and washed with brine. The organic extract was dried over sodium sulfate and chromatographed (eluent: EtOAc / hexane). The resulting compound was diluted with EtOAc, washed twice with saturated NaHCO3, and dried over magnesium sulfate. The organic extract was filtered and concentrated, then diluted with EtO (2 mL) and sonicated to give a precipitate. To this was added hexane, and the mixture was filtered and rinsed with hexane to give the title compound. ES / MS m / z: 487.2 (M+H + ); 1 H NMR(400MHz, CDCl 3)δ8.17-8.07(m,1H),7.97(d,J=8.5Hz,1H),7.75(d,J=8.4Hz,1H),7.37(d,J=7.3Hz,2H ),4.45(t,J=5.2Hz,4H),3.97(s,3H),3.71(t,J=5.2Hz,2H),3.30(s,3H),1.35(s,12H).

[0331] [ka]

[0332] 3-(2-Methoxyethylamino)-4-nitro-benzonitrile: A solution of 3-fluoro-4-nitro-benzonitrile (2 g, 12.04 mmol), 2-methoxyethanamine (1.25 ml, 14.79 mmol), and N,N-diisopropylethylamine (3.2 ml, 18.37 mmol) in DMF was stirred at room temperature for 2 days. The mixture was diluted with EtOAc and washed twice with 5% LiCl and with brine. The organic extract was dried over sodium sulfate to give the title compound. ES / MS m / z: 222 (M+H + ); 1 H NMR(400MHz, CDCl 3) δ8.26(dd,J=8.7,1.7Hz,1H),8.23(s,1H),7.21(d,J=1.7Hz,1H),6.89(dt,J=8.8, 1.5Hz, 1H), 3.71 (dd, J=5.6, 4.8Hz, 2H), 3.51 (q, J=5.2Hz, 2H), 3.45 (d, J=1.0Hz, 3H).

[0333] N-(2-Methoxyethyl)-2-nitro-5-(2H-tetrazol-5-yl)aniline: In a 200 mL round-bottom flask, a suspension of 3-(2-methoxyethylamino)-4-nitro-benzonitrile (2.563 g, 11.6 mmol), sodium azide (1.51 g, 23.2 mmol), and ammonium chloride (1.24 g, 23.2 mmol) in DMF (50 mL) was heated at 110° C. overnight. The mixture was diluted with EtOAc and washed with 5% LiCl (3×50 mL). The aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were dried over sodium sulfate to give the title compound. ES / MS m / z: 265.2 (M+H). + ); 1 H NMR(400MHz,MeOD)δ8.32(d,J=8.8Hz,1H),7.77(d,J=1.8Hz,1H),7.35(dd,J=8.9,1.8 Hz,1H),3.82-3.69(m,2H),3.66(t,J=5.2Hz,2H),3.46(s,3H),3.01(d,J=0.5Hz,4H).

[0334] N-2-(2-Methoxyethyl)-4-(2H-tetrazol-5-yl)benzene-1,2-diamine (I-44): A solution of N-(2-methoxyethyl)-2-nitro-5-(2H-tetrazol-5-yl)aniline (93 mg, 352 μmol) in EtOH (25 mL) was degassed under vacuum with Ar three times. Pd / C (10%, 37.7 mg, 0.0354 mmol) was added, and the mixture was stirred under a balloon of hydrogen at room temperature overnight. The mixture was filtered through a plug of Celite, rinsed with EtOAc, and concentrated to give the title product, which was used in the subsequent step without further purification. ES / MS m / z: 235.2 (M+H). + )

[0335] [ka]

[0336] 4-(Hydroxymethyl)-3-methoxy-benzonitrile: In a 500 mL round-bottom flask, 4-formyl-3-methoxy-benzonitrile (3.46 g, 0.0215 mol) was dissolved in MeOH (115 mL) and THF (115 mL). The mixture was cooled to 0 °C, and then sodium borohydride (0.813 g, 0.0215 mol) was added in portions. The mixture was stirred under a N atmosphere at 0 °C for 2 h. EtOAc (175 mL) was added, followed by water (50 mL), and NH Cl was added slowly (50 mL, gas evolution). Brine was added, and the mixture was partitioned. The organic extract was dried over MgSO and concentrated, then rediluted with EtOAc and dried over sodium sulfate to give a crude residue, which was diluted with EtOAc (200 mL) and stirred with saturated aqueous Rochelle's salt for 2 h. The layers were separated and the organic extract was dried over sodium sulfate and concentrated to give the title compound, which was carried forward without further purification. 1 H NMR (400MHz, MeOD) δ7.59(dd,J=7.7,1.0Hz,1H),7.35(dd,J=7.8,1.5Hz,1H),7.29(d,J=1.4Hz,1H),4.68(s,2H),3.90(s,3H).

[0337] 4-[(4-Bromopyrimidin-2-yl)oxymethyl]-3-methoxy-benzonitrile (I-45): In a 100 mL RBF, a solution of 4-(hydroxymethyl)-3-methoxy-benzonitrile (0.918 g, 0.00563 mol) in THF (15 mL) was cooled to 0° C. Potassium tert-butoxide (1.00 M in THF, 5.10 mL, 0.00510 mol) was added and the mixture was stirred at 0° C. for 15 min.

[0338] In a separate 100 mL RBF, a solution of 4-bromo-2-methylsulfonyl-pyrimidine (1.20 g, 0.00506 mol) in THF (15 mL) was cooled to -78 °C. A solution of benzyl alcohol and KOtBu mixture was added via syringe over 5 min and stirred at -78 °C for 1 h. The mixture was diluted with 60 mL of EtOAc and 30 mL of water. The organic extract was dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent: EtOAc / hexane) to give the title compound. ES / MS m / z: 321.91 (M+H + ); 1 H NMR(400MHz,CDCl3)δ8.32(d,J=5.1Hz,1H),7.62(d,J=7.8Hz,1H),7.31(dd,J=7.8, 1.4Hz,1H), 7.21(d,J=5.2Hz,1H),7.14(d,J=1.4Hz,1H),5.52(s,2H),3.92(s,3H).

[0339] [ka]

[0340] 3-Fluoro-4-[(3-iodo-2-pyridyl)oxymethyl]benzonitrile (I-46): A suspension of 3-fluoro-4-(hydroxymethyl)benzonitrile (0.757 g, 5.01 mmol), 2-chloro-3-iodo-pyridine (1.00 g, 4.18 mmol), and cesium carbonate (2.45 g, 7.52 mmol) in THF (15 mL) was heated at 80 °C until the starting material was consumed. The reaction mixture was diluted with EtOAc and washed with brine. The organic extract was dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent: EtOAc / hexane) to give the title compound.

[0341] 1 H NMR(400MHz, CDCl 3) δ8.16-8.07(m,2H),7.79(dd,J=8.0,7.1Hz,1H),7.52(dd,J=7.9,1.5Hz,1H), 7.41(dd,J=9.3,1.5Hz,1H),6.74(dd,J=7.6,4.9Hz,1H),5.57(d,J=1.1Hz,2H).

[0342] [ka]

[0343] N-(6-Bromo-2-pyridyl)-4-cyano-2-fluoro-benzamide (I-47): To a suspension of 6-bromopyridin-2-amine (1050 mg, 0.578 mmol) and 4-cyano-2-fluoro-benzoyl chloride (138 mg, 0.751 mmol) in DCM (5 mL) was added pyridine (0.1 mL, 1.24 mmol). The mixture was stirred overnight at room temperature. The mixture was diluted with EtOAc and washed with NH4Cl and brine. The organic extract was dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent: EtOAc / hexane) to give the title compound. ES / MS m / z: 320.0, 322.0 (M+H). + ); 1H NMR(400MHz, CDCl 3) δ8.95(d,J=11.9Hz,1H),8.35(dd,J=8.2,0.7Hz,1H),8.27(t,J=7.8Hz,1H),7.66(d dd,J=8.0,4.7,3.2Hz,2H),7.57(dd,J=10.9,1.5Hz,1H),7.34(dd,J=7.7,0.7Hz,1H).

[0344] [ka]

[0345] N-(6-Bromo-2-pyridyl)benzamide (I-48): The title compound was prepared as described for I-47, substituting benzoyl chloride for 4-cyano-2-fluoro-benzoyl chloride. ES / MS m / z: 277.0, 279.0 (M+H + ); 1 H NMR (400MHz, CDCl3) δ8.59(s,1H),8.39(dd,J=8.2,0.7Hz,1H),8.07-7.87(m,2H),7.70-7.57(m,2H),7.57-7.47(m,2H),7.41-7.19(m,1H).

[0346] [ka]

[0347] 4-[(3-Iodo-2-pyridyl)oxymethyl]-3-methoxy-benzonitrile (I-49): A suspension of 3-fluoro-4-(hydroxymethyl)benzonitrile (0.128 g, 0.784 mmol), 2-fluoro-3-iodo-pyridine (0.150 g, 0.673 mmol), and cesium carbonate (0.400 g, 1.23 mmol) in THF (3 mL) was heated at 80 °C overnight. The reaction mixture was diluted with EtOAc and washed with brine. The organic extract was dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent: EtOAc / hexane) to give the title compound. ES / MS: 366.9 (M+H +); 1 H NMR(400MHz,CDCl3)δ8.15(dd,J=4.9,1.7Hz,1H),8.11(dd,J=7.5,1.7Hz,1H),7.73(d,J=7.8Hz,1H),7.35(d d,J=7.8,1.4Hz,1H),7.13(d,J=1.4Hz,1H),6.73(dd,J=7.6,4.9Hz,1H),5.51(d,J=1.1Hz,2H),3.93(s,3H).

[0348] [ka]

[0349] 4-[(6-Bromo-3-chloro-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile (I-50): A suspension of 3-fluoro-4-(hydroxymethyl)benzonitrile (0.237 g, 1.57 mmol), 6-bromo-3-chloro-2-fluoro-pyridine (0.300 g, 1.43 mmol), and potassium carbonate (0.591 g, 4.28 mmol) in NMP (5 mL) was heated at 100 °C overnight. The mixture was diluted with EtOAc and washed with 5% LiCl solution (3 times). The organic extract was dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent: EtOAc / hexane) to give the title compound. 1 H NMR (400MHz, CDCl3) δ7.74(t,J=7.5Hz,1H),7.59-7.47(m,2H),7.43(dd,J=9.3,1.5Hz,1H),7.11(d,J=7.9Hz,1H),5.57(s,2H). 19 F NMR (376MHz, CDCl3) δ-112.14--116.85(m).

[0350] [ka]

[0351] 3-Fluoro-4-[(6-fluoro-2-pyridyl)oxymethyl]benzonitrile (I-51): A suspension of 2,6-difluoropyridine (0.39 mL, 4.34 mmol), 3-fluoro-4-(hydroxymethyl)benzonitrile (0.72 g, 4.78 mmol), and potassium carbonate (1.8 g, 13.03 mmol) in NMP (10 mL) was heated at 100 °C overnight. The mixture was diluted with EtOAc and washed with 5% aqueous LiCl (3 times). The organic extract was dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent: EtOAc / hexane) to give the title product. ES / MS: 247.0 (M+H + ); 1 H NMR (400 MHz, chloroform-d) δ 7.73 (q, J = 8.0 Hz, 1H), 7.67 (t, J = 7.5 Hz, 1H), 7.50 (dd, J = 7.9, 1.6 Hz, 1H), 7.41 (dd, J = 9.3, 1.6 Hz, 1H), 6.73 (dd, J = 8.0, 1.6 Hz, 1H), 6.56 (dd, J = 7.8, 2.4 Hz, 1H), 5.48 (d, J = 1.2 Hz, 2H). 19 F NMR (376 MHz, chloroform-d) δ −70.47 (d, J = 8.7 Hz), −112.50-−117.78 (m).

[0352] [ka]

[0353] 2-Bromo-6-((4-(trifluoromethyl)benzyl)oxy)pyridine (I-52): 1-(Bromomethyl)-4-(trifluoromethyl)benzene (239 mg, 1 mmol) was added to 6-bromopyridin-2-ol (190 mg, 1.1 mmol) and cesium carbonate (360 mg, 1.1 mmol) in acetonitrile (4 mL). The mixture was stirred at ambient temperature overnight. The mixture was filtered through Celite and concentrated by rotary evaporation. The product was used without further purification to give the title compound. 1H NMR (400 MHz, chloroform-d) δ 7.66 (d, J = 8.2 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.48 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 7.4 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 5.45 (s, 2H).

[0354] [ka]

[0355] Methyl 4-amino-3-(((1-ethyl-2-methyl-1H-imidazol-5-yl)methyl)amino)benzoate (I-53): Methyl 4-amino-3-(((1-ethyl-2-methyl-1H-imidazol-5-yl)methyl)amino)benzoate was prepared as described in I-1, substituting chloro-[(3-ethyl-2-methyl-imidazol-4-yl)methyl]-imino-λ5-chlorane for methoxyethylamine. ES / MS: 289.3 (M+H + ).

[0356] [ka]

[0357] tert-Butyl 4-amino-3-(((1-ethyl-1H-pyrazol-5-yl)methyl)amino)benzoate (I-54): tert-Butyl 4-amino-3-(((1-ethyl-1H-pyrazol-5-yl)methyl)amino)benzoate was prepared exactly as described for I-1, except for replacing methoxyethylamine with (1-ethyl-1H-pyrazol-5-yl)methanamine. ES / MS: 317.4 (M+H + ).

[0358] [ka]

[0359] Methyl 4-amino-3-(((1-(2-methoxyethyl)-1H-imidazol-5-yl)methyl)amino)benzoate (I-55): Methyl 4-amino-3-(((1-(2-methoxyethyl)-1H-imidazol-5-yl)methyl)amino)benzoate was prepared exactly as described for I-1, substituting (1-(2-methoxyethyl)-1H-imidazol-5-yl)methanamine for methoxyethylamine. ES / MS: 305.4 (M+H + ).

[0360] [ka]

[0361] Methyl 4-amino-3-((pyrimidin-5-ylmethyl)amino)benzoate (I-56): Methyl 4-amino-3-((pyrimidin-5-ylmethyl)amino)benzoate was prepared exactly as described for I-1, substituting pyrimidin-5-ylmethanamine for methoxyethylamine. ES / MS: 259.3 (M+H + ).

[0362] [ka]

[0363] Methyl 4-amino-3-(((3-ethylpyridin-4-yl)methyl)amino)benzoate (I-57): Methyl 4-amino-3-(((3-ethylpyridin-4-yl)methyl)amino)benzoate was prepared exactly as described for I-1, substituting 3-ethyl-4-pyridyl)methanamine for methoxyethylamine. ES / MS: 286.3 (M+H + ).

[0364] [ka]

[0365] Methyl 4-amino-3-(benzylamino)benzoate (I-58): Methyl 4-amino-3-(benzylamino)benzoate is prepared by the reaction of methoxyethylamine with phenylmethanamine. Prepared exactly as described for I-1, with the following substitutions: ES / MS: 257.3 (M+H + ).

[0366] [ka]

[0367] 4-(((6-Bromopyridin-2-yl)oxy)methyl)benzonitrile (I-59): 4-(((6-Bromopyridin-2-yl)oxy)methyl)benzonitrile was prepared exactly as described for I-51, substituting 4-(bromomethyl)benzonitrile for 1-(bromomethyl)-4-(trifluoromethyl)benzene. 1 H NMR (400 MHz, chloroform-d) δ 7.79-7.64 (m, 2H), 7.59 (d, J = 8.1 Hz, 2H), 7.49 (dd, J = 8.1, 7.5 Hz, 1H), 7.19-7.05 (m, 1H), 6.80 (dd, J = 8.1, 0.6 Hz, 1H), 5.45 (s, 2H).

[0368] [ka]

[0369] Tert-butyl 2-(4-bromo-2-cyano-6-fluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (I-60): tert-Butyl 2-(4-bromo-2-cyano-6-fluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate was prepared exactly as described for intermediate I-5, substituting 2-(4-bromo-2-cyano-6-fluorophenyl)acetic acid for 2-(4-bromo-2-cyano-6-fluorophenyl)acetic acid. ES / MS: 488.7 (M+H + ).

[0370] [ka]

[0371] 2-(1-(4-Chloro-2-fluorophenyl)ethoxy)-3-iodopyridine (I-61): 3-Fluoro-4-(hydroxymethyl)benzonitrile (0.875 g, 5.01 mmol) and 2-chloro-3-iodo-pyridine (1.00 g, 4.18 mmol) were taken up in 1,4-dioxane (8.0 mL) and potassium tert-butoxide (0.703 g, 6.26 mmol) was added portionwise. After the addition, the mixture was sealed and heated to 110 °C for 8 h. Upon completion, the mixture was cooled to room temperature and diluted with EtOAc (100 mL) and water (100 mL). The organic phase was collected and the aqueous phase was extracted with EtOAc (2 × 50 mL). The combined organics were dried over MgSO, filtered, and concentrated in vacuo. The residue was then purified by normal phase column chromatography (eluent: EtOAc / hexane gradient) to provide the title compound.

[0372] [ka]

[0373] Ethyl 3,5-difluoro-4-nitrobenzoate: Ethyl 4-amino-3,5-difluorobenzoate (5.00 g, 24.9 mmol) was taken up in acetic acid (50.0 mL), and sulfuric acid (12.1 M, 2.05 mL, 24.9 mmol) and hydrogen peroxide (30% aqueous solution, 46.7 mL, 74.6 mmol) were added sequentially. The mixture was heated to 100 °C for 1 min. The mixture was then cooled to room temperature and then slowly poured into 300 mL of ice water with swirling. The mixture was then diluted with EtOAc (200 mL), transferred to a separatory funnel, and the organic phase was collected. The aqueous phase was extracted with EtOAc (2 × 100 mL), and the combined organics were dried over MgSO and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc / hexane gradient) to give the product.

[0374] (S)-3-Fluoro-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoate: Ethyl 3,5-difluoro-4-nitro-benzoate (2.50 g, 10.8 mmol) and (S)-oxetan-2-ylmethanamine (989 mg, 11.4 mol) were taken up in tetrahydrofuran (12.0 mL) and N,N-dimethylformamide (6.0 mL), and N,N-diisopropylethylamine (9.42 mL, 54.1 mmol) was added. The mixture was heated to 50 °C for 16 min. 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 + ).

[0375] (S)-4-amino-3-fluoro-5-(((oxetan-2-ylmethyl)amino Ethyl (S)-3-fluoro-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoate (I-62): Ethyl (S)-3-fluoro-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoate (2.20 g, 7.38 mmol) was taken up in ethanol (10 mL) and tetrahydrofuran (5 mL), and the mixture was sparged with nitrogen for 5 minutes. Palladium on carbon (10 wt. % loading, 785 mg, 0.74 mmol) was added, and sparging continued for 5 minutes. 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-62). ES / MS: 269.2 (M+H + ); 1H 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).

[0376] [ka]

[0377] Methyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-1H-benzo[d]imidazole-6-carboxylate (I-63): Methyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-1H-benzo[d]imidazole-6-carboxylate was prepared exactly as described for procedure 29, substituting 2-(3'-((4-cyano-2-fluorobenzyl)oxy)-3,4'-difluoro-(1,1'-biphenyl)-4-yl)acetic acid with 2-(4-(6-((4-cyano-2-fluoro-phenyl)methoxy)-2-pyridyl)-2-fluoro-phenyl)acetic acid. ES / MS: 511.2 (M+H + ).

[0378] [ka]

[0379] Methyl 2-(4-bromo-3-nitrobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate: 2-(4-bromo-3-nitrophenyl)acetic acid (1000 mg, 3.85 mmol), methyl 4-amino-3-(2-methoxyethylamino)benzoate (I-1), 862 mg, 3.85 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2485 mg, 5.77 mmol) were taken up in DMF (8 mL) and N,N-diisopropylethylamine (3.35 mL, 19.2 mmol) was added. The mixture was stirred at room temperature for 30 minutes. Following this time, the mixture was diluted with EtOAc (200 mL) and water (200 mL). The organic phase was collected and the aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The resulting residue was taken up in acetic acid (20 mL) and heated to 75 °C. After 7 h, the mixture was concentrated in vacuo and the mixture was diluted with EtOAc (50 mL). The organic phase was washed with saturated aqueous NaHCO3 (20 mL) and the aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (eluent: 20-100% hexane / EtOAc). ES / MS: 448.1 (M+H + ).

[0380] Methyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3-nitrobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate: To a vial was added methyl 2-(4-bromo-3-nitrobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (0.350 g, 0.781 mmol), bis(pinacolato)diboron (300 mg, 1.17 mmol), Pd(dppf)Cl (54 mg, 0.078 mmol), and potassium propionate (263 mg, 2.34 mmol). DMF (10 mL) was added, and the mixture was degassed with argon for 2 minutes. The vial was sealed, and the mixture was heated at 100 °C for 1 hour. Following this time, LC / MS indicated conversion of the aryl bromide to the intermediate boronic acid, and the mixture was cooled to room temperature. At this point, aqueous sodium carbonate (1.5 M, 1.56 mL, 2.34 mmol) was added, followed by Pd(dppf)Cl (54 mg, 0.078 mmol) and 4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile (I-6, 360 mg, 1.17 mmol). The vial was resealed and heated to 90 °C for 3 h. Following this time, the mixture was cooled to room temperature and diluted with EtOAc (50 mL) and water (50 mL). The organic phase was collected, and the aqueous phase was eluted with HCl. Extraction with tOAc (2 x 50 mL) was performed. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel chromatography (eluent: 20-80 EtOAc / hexanes) to give the desired product. ES / MS: 596.2 (M+H + ).

[0381] Methyl 2-(3-amino-4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (I-64): Methyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3-nitrobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (40 mg, 0.0675 mmol) was taken up in ethanol (0.50 mL), and water (0.15 mL) and acetic acid (0.15 mL) were added. Iron powder (38 mg, 0.675 mmol) was then added to the mixture, and the mixture was heated to 70 °C. After 2 h, the mixture was cooled to room temperature and filtered through Celite. The residue was diluted with EtOAc (10 mL) and water (10 mL). The organic phase was collected and the aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel chromatography (eluent: 20-80 EtOAc / hexanes) to give the desired product. ES / MS: 566.3 (M+H + ).

[0382] [ka]

[0383] Methyl 2-(2-amino-4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (I-65): Methyl 2-(2-amino-4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate was prepared exactly as described for I-64, substituting 2-(4-bromo-3-nitrophenyl)acetic acid with 2-(4-bromo-2-nitrophenyl)acetic acid. ES / MS: 566.2 (M+H). + ).

[0384] [ka]

[0385] 2-(3-bromo-4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (I-66): 2-(3-amino-4-(6-((4-cyano) Methyl 2-(2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (I-64, 26 mg, 0.0460 mmol) and copper(I) bromide (20 mg, 0.140 mmol) were suspended in 1.0 mL of EtOAc and 1.0 mL of MeCN. After stirring for 5 min, tBuONO was added, and the mixture was stirred at room temperature for 3 h. The residue was then diluted with 20 mL of EtOAc and washed with saturated aqueous NH4Cl (5 × 5 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel chromatography (eluent: EtOAc in hexane) to give the desired product. ES / MS: 631.0 (M+H + ).

[0386] [ka]

[0387] 2-(2-Bromo-4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (I-67): 2-(2-Bromo-4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate is prepared from 2-(3-amino-4-(6-(( Prepared exactly as described for I-66, substituting methyl 2-(2-amino-4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate I-65 for methyl 4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate I-64. ES / MS: 631.1 (M+H). + ).

[0388] [ka]

[0389] Tert-butyl 3-((2-methoxyethyl)amino)-4-nitrobenzoate: To a 500 mL RBF was added tert-butyl 3-fluoro-4-nitrobenzoate (10 g, 41.5 mmol). The material was dissolved in THF (150 mL) and 2-methoxyethanamine (7.2 mL, 82.9 mmol) and N,N-diisopropylethylamine (21.7 mL, 124 mmol) were added. The mixture was stirred at 50° C. overnight. The mixture was then concentrated to remove most of the THF and the crude material was dissolved in EtOAc (400 mL). The organics were washed with 50% NH4Cl (2 x 100 mL) and brine (1 x 50 mL). The organics were then dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was carried forward without further purification. ES / MS: 297.1 (M+H) + ); 1 H NMR (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).

[0390] Tert-butyl 4-amino-3-((2-methoxyethyl)amino)benzoate (I-68): To a 1 L RBF was added tert-butyl 3-((2-methoxyethyl)amino)-4-nitrobenzoate (13 g, 43.9 mmol), ethanol (100 mL), and EtOAc (50 mL). The mixture was stirred and sonicated until all material was dissolved. Nitrogen was bubbled through the mixture for 5 minutes, and then palladium on carbon (10 wt%, 2.33 g, 2.19 mmol) was added. Hydrogen was bubbled through the mixture for 5 minutes, and the mixture was stirred under a hydrogen balloon overnight. Nitrogen was then bubbled through the flask for 10 minutes, and then the mixture was filtered through Celite to remove the catalyst. The filtrate was concentrated under reduced pressure and used without further purification. ES / MS: 267.2 (M+H + ).

[0391] [ka]

[0392] 5-Bromo-2-((6-(methoxycarbonyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)methyl)benzoic acid: To 100 mL of RBF was added 7-bromoisochroman-1,3-dione (1.18 g, 4.91 mmol), methyl 4-amino-3-(2-methoxyethylamino)benzoate (I-1, 1 g, 4.46 mmol), and THF (20 mL). The mixture was stirred at 55 °C for 16 h. Then, AcOH (6 mL) was added and the mixture was stirred at 60 °C for 24 h. Analysis by LCMS showed conversion to the desired product. The volatiles were evaporated and the crude mixture was triturated with EtO (20 mL). The resulting solid was dried under vacuum and carried forward. ES / MS 447.6 (M+)

[0393] Methyl 2-(4-bromo-2-(hydroxymethyl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (I-69): In a 100 mL RBF, 5-bromo-2-((6-(methoxycarbonyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)methyl)benzoic acid (300 mg, 0.67 mmol) was dissolved in dry THF (20 mL) under a nitrogen atmosphere, and the solution was cooled to 0 °C. Borane dimethyl sulfide (0.083 mL, 0.87 mmol) was added dropwise via syringe, and the mixture was stirred at 0 °C and then slowly warmed to room temperature. Methanol (2 mL) was added slowly, followed by the addition of water (10 mL) and EtOAc (50 mL) to quench the reaction. The layers were separated, and the aqueous layer was extracted once with EtOAc (20 mL). The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (eluent: EtOAc in hexane) to give I-69. ES / MS: 433.1 (M+).

[0394] [ka]

[0395] Methyl 2-(4-bromo-2-(methoxymethyl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (I-70): To a 40 mL vial was added methyl 2-[[4-bromo-2-(hydroxymethyl)phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (I-69) (100 mg, 0.23 mmol) and THF (2 mL). The solution was cooled to 0 °C, and NaH (60% mineral dispersion, 18 mg, 0.46 mmol) was added under a nitrogen atmosphere. The mixture was stirred at 0 °C for 15 min, iodomethane (0.073 mL, 1.15 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was quenched with 3 drops of water, and the crude mixture was loaded directly onto a silica-packed column. The crude material was purified by silica column chromatography (eluent: EtOAc in hexane) to give I-70. ES / MS: 447.1 (M+).

[0396] [ka]

[0397] Methyl 2-(4-bromo-2-(fluoromethyl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (I-71): To a 40 mL vial was added methyl 2-[[4-bromo-2-(hydroxymethyl)phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (I-69) (100 mg, 0.23 mmol) and THF (5 mL). The solution was placed under a nitrogen atmosphere and cooled to 0 °C. Diethylaminosulfur trifluoride (0.03 mL, 0.23 mmol) was added via syringe, and the mixture was stirred at 0 °C for 30 min. The mixture was diluted with CHCl (10 mL) and washed once with water (5 mL). The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The crude material was purified by silica column chromatography (eluent: EtOAc in hexanes) to give I-71. ES / MS: 435.1 (M+).

[0398] [ka]

[0399] Methyl 2-((4-bromo-5-fluoro-2-oxopyridin-1(2H)-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (I-72): To a 20 mL vial was added methyl 2-(chloromethyl)-3-(2-methoxyethyl)benzimidazole-5-carboxylate hydrochloride (416 mg, 1.3 mmol), 4-bromo-5-fluoro-1H-pyridin-2-one (250 mg, 1.3 mmol), potassium carbonate (900 mg, 6.51 mmol), and DMF (4 mL). N,N-Diisopropylethylamine (0.45 mL, 2.6 mmol) was added, and the mixture was stirred at 60 °C for 1 h. LCMS showed a mixture of two products (O-alkylated and N-alkylated), with the more polar product (N-alkylated) being favored. The mixture was diluted with EtOAc (50 mL) and washed with water (15 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica chromatography (eluent: EtOAc in hexane) to give I-72. ES / MS: 438.1 (M+).

[0400] [ka]

[0401] 2-Bromo-6-((4-chloro-2-fluorobenzyl)oxy)pyridine (I-73): 2-Bromo-6-((4-chloro-2-fluorobenzyl)oxy)pyridine was prepared exactly as described for I-6, substituting (4-chloro-2-fluorophenyl)methanol for 3-fluoro-4-(hydroxymethyl)benzonitrile. ES / MS: 317.8 (M+H + ); 1 H NMR (400 MHz, chloroform-d) δ 7.52-7.45 (m, 2H), 7.19-7.02 (m, 3H), 6.75 (d, J = 8.2 Hz, 1H), 5.43-5.38 (m, 2H).

[0402] [ka]

[0403] 2-Bromo-6-((4-chloro-2-methoxybenzyl)oxy)pyridine (I-74): 2-Bromo-6-((4-chloro-2-methoxybenzyl)oxy)pyridine is Prepared exactly as described for I-6, substituting (4-chloro-2-methoxyphenyl)methanol for 3-fluoro-4-(hydroxymethyl)benzonitrile. ES / MS: 329.9 (M+H + ); 1 H NMR(400MHz,chloroform-d)δ7.49-7.39(m,2H),7.09(d,J=7.4Hz,1H),6.97(dd,J=8.1, 2.0Hz, 1H), 6.91 (d, J=1.9Hz, 1H), 6.75 (d, J=8.2Hz, 1H), 5.37 (s, 2H), 3.88 (s, 3H).

[0404] [ka]

[0405] 4-(((6-Bromopyridin-2-yl)oxy)methyl)-3-methoxybenzonitrile (I-75): To a 20 mL vial was added 6-bromopyridin-2-ol (231 mg, 1.33 mmol), 4-(bromomethyl)-3-methoxy-benzonitrile (300 mg, 1.33 mmol), silver(II) carbonate (1.1 g, 3.98 mmol), and toluene (10 mL). The mixture was heated at 100 °C for 1 h. After that, the mixture was cooled and filtered through Celite to remove the solid precipitate and rinsed with EtOAc. The filtrate was concentrated, and the crude residue was purified by silica chromatography (eluent: EtOAc in hexanes) to give I-75. ES / MS: 319.1 (M+).

[0406] [ka]

[0407] 4-(((4-Bromopyrimidin-2-yl)oxy)methyl)-3-fluorobenzonitrile (I-76): 4-(((4-Bromopyrimidin-2-yl)oxy)methyl)-3-fluorobenzonitrile was prepared exactly as described for I-45, substituting 3-fluoro-4-(hydroxymethyl)benzonitrile for 4-(hydroxymethyl)-3-methoxy-benzonitrile. ES / MS: 319.9 (M+); 1 H NMR (400 MHz, chloroform-d) δ 8.32 (d, J = 5.2 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.31 (dd, J = 7.8, 1.4 Hz, 1H), 7.21 (d, J = 5.1 Hz, 1H), 7.14 (d, J = 1.4 Hz, 1H), 5.55-5.48 (m, 2H), 3.93 (s, 3H).

[0408] [ka]

[0409] 4-Bromo-2-((4-chloro-2-fluorobenzyl)oxy)pyrimidine (I-77): 4-Bromo-2-((4-chloro-2-fluorobenzyl)oxy)pyrimidine was prepared exactly as described for I-45, substituting (4-chloro-2-fluorophenyl)methanol for 4-(hydroxymethyl)-3-methoxy-benzonitrile. ES / MS: 318.9 (M+H + ); 1 H NMR (400 MHz, chloroform-d) δ 8.31 (d, J = 5.1 Hz, 1H), 7.51 (t, J = 8.1 Hz, 1H), 7.21 (d, J = 5.2 Hz, 1H), 7.19-7.13 (m, 2H), 5.51-5.46 (m, 2H).

[0410] [ka]

[0411] 4-Bromo-2-((4-chloro-2-methoxybenzyl)oxy)pyrimidine (I-78): 4-Bromo-2-((4-chloro-2-methoxybenzyl)oxy)pyrimidine was prepared exactly as described for I-45, substituting (4-chloro-2-methoxyphenyl)methanol for 4-(hydroxymethyl)-3-methoxy-benzonitrile. ES / MS: 318.9 (M+H + ); 1 H NMR (400 MHz, chloroform-d) δ 8.31 (d, J = 5.1 Hz, 1H), 7.51 (t, J = 8.1 Hz, 1H), 7.21 (d, J = 5.2 Hz, 1H), 7.19-7.13 (m, 2H), 5.51-5.46 (m, 2H).

[0412] [ka]

[0413] 2-((5-Chloro-2-fluorobenzyl)oxy)-3-iodopyridine (I-79): To a vial was added 2-chloro-3-iodo-pyridine (300 mg, 1.25 mmol), (5-chloro-2-fluoro-phenyl)methanol (302 mg, 1.88 mmol), CsCO (816 mg, 2.51 mmol), N,N-diisopropylethylamine (0.44 mL, 2.51 mmol), and NMP (1.5 mL). The mixture was heated at 120 °C overnight. The mixture was then cooled and dissolved in EtOAc (30 mL). The organics were washed with water (2 × 10 mL), and the organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The crude residue was purified by silica chromatography (eluent: EtOAc in hexanes) to give I-79. ES / MS: 318.9 (M+H) + ); 1 H NMR (400 MHz, chloroform-d) δ 8.31 (d, J = 5.1 Hz, 1H), 7.51 (t, J = 8.1 Hz, 1H), 7.21 (d, J = 5.2 Hz, 1H), 7.19-7.13 (m, 2H), 5.51-5.46 (m, 2H).

[0414] [ka]

[0415] Methyl 2-((4-bromo-6-methyl-2-oxopyridin-1(2H)-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (1-80): Methyl 2-((4-bromo-6-methyl-2-oxopyridin-1(2H)-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate was prepared exactly as described for 1-72, substituting 4-bromo-6-methylpyridin-2(1H)-one for 4-bromo-5-fluoro-1H-pyridin-2-one. ES / MS: 434.3 (M+); 1 H NMR(400MHz,chloroform-d)δ8.08(d,J=1.5Hz,1H),7.94(dd,J=8.5,1.6Hz,1H),7.69(d,J=8.5Hz,1H),6.70(d,J=2.1Hz,1H),6. 33(dd,J=2.2,0.9Hz,1H),5.46(s,2H),4.66(t,J=5.0Hz,2H),3.95(s,3H),3.72(t,J=5.0Hz,2H),3.28(s,3H),2.62(s,3H).

[0416] [ka]

[0417] 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 for 2 hours. 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-6 (14 g, 45.6 mmol) were added, and the mixture was degassed with Ar for 10 minutes, then sealed and heated at 100 °C for 1 hour. The reaction mixture was diluted with EtOAc and washed with brine. The organic extract was dried over sodium sulfate and chromatographed (eluent: EtOAc / hexane) to give the title product. ES / MS: 413.2 (M+H + ).

[0418] 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorophenyl)acetic acid (I-81). A solution of methyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorophenyl)acetate (12.5 g, 30.3 mmol) and lithium hydroxide (0.2 M, 19.7 mL, 39.4 mmol) in CH3CN (50 mL) was heated at 50 °C for 2 h. The mixture was acidified with 1 N hydrochloride to pH = 6-7. The material was crushed and filtered through a filter funnel. The solid was washed with water and dried overnight to give the product. ES / MS: 399.2 (M+H). + ); 1H NMR (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).

[0419] [ka]

[0420] 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorophenyl)acetic acid (I-82). 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorophenyl)acetic acid (I-82) was prepared in the same manner as I-81, substituting 2-(4-bromo-3-fluorophenyl)methyl acetate for 2-(4-bromo-2,5-difluorophenyl)methyl acetate. ES / MS: 381.2 (M+H + ); 1 H NMR (400MHz, methanol-d4) δ7.92(t,J=8.2Hz,1H),7.76(dt,J=14.4,7.6Hz,2H),7.66-7.55(m,2H), 7.49(dd,J=7.3,1.8Hz,1H),7.27-7.12(m,2H),6.88(d,J=8.1Hz,1H),5.63(s,2H),3.70(s,2H).

[0421] [ka]

[0422] 2-(4-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3-fluorophenyl)acetic acid (I-83): 2-(4-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3-fluorophenyl)acetic acid (I-83) was prepared in the same manner as I-82, replacing 4-(((6-bromopyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (I-6) with 4-(((4-bromopyrimidin-2-yl)oxy)methyl)-3-fluorobenzonitrile (I-76). ES / MS: 382.2 (M+H + ); 1 H NMR (400 MHz, methanol-d₄) δ 8.65 (d, J = 5.3 Hz, 1H), 8.11 (t, J = 8.1 Hz, 1H), 7.81 (t, J = 7.5 Hz, 1H), 7.69-7.59 (m, 3H), 7.36-7.22 (m, 2H), 5.70 (s, 2H), 3.74 (s, 2H).

[0423] [ka]

[0424] 4-(((2-Chloro-5-fluoropyrimidin-4-yl)oxy)methyl)-3-fluorobenzonitrile (1-84): 4-(((2-Chloro-5-fluoropyrimidin-4-yl)oxy)methyl)-3-fluorobenzonitrile was prepared as described for 1-25, using 2,4-dichloro-5-fluoropyrimidine instead of 4-bromo-2-chloro-thiazole. ES / MS: 282.2 [M+H] + ).

[0425] [ka]

[0426] 2-(4-(2-chloro-5-fluoropyrimidin-4-yl)-2,5-difluorobenzyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (I-85): To a vial containing 2-(4-bromo-2,5-difluorobenzyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (30.0 mg, 0.063 mmol) (synthesized in a manner similar to I-96), bis(pinacolato)diboron (20.8 mg, 0.082 mmol), Pd(dppf)Cl (7.0 mg, 0.0095 mmol), and potassium propionate (21.2 mg, 0.19 mmol) was added 1,4-dioxane (1.0 mL). The suspension was degassed by bubbling argon through it for 60 s, then the vial was sealed and thermally heated at 115 °C for 45 min. To the cooled mixture were added 2,4-dichloro-5-fluoropyrimidine (10.5 mg, 0.063 mmol), Pd(dppf)Cl (3.5 mg, 0.0047 mmol), and aqueous sodium carbonate (2 M, 63 μL, 0.13 mmol). The mixture was degassed by bubbling argon through for 60 seconds, then the vial was sealed and heated at 90 °C for 4 hours. The cooled mixture was filtered through a pad of Celite (eluent: EtOAc), concentrated, and purified by silica gel chromatography. Purification by column chromatography (eluent: EtOAc / hexane) gave the desired product. ES / MS: 527.0 [M+H] + .

[0427] [ka]

[0428] 4-[[(6-Chloro-2-pyridyl)amino]methyl]-3-fluoro-benzonitrile (I-86): To a microwave vial was added 4-(aminomethyl)-3-fluoro-benzonitrile hydrochloride (277 mg, 1.49 mmol), 2,6-dichloropyridine (200 mg, 1.35 mmol), N,N-diisopropylethylamine (0.942 mL, 5.41 mmol), and DMF. The solution was heated at 120 °C for 12 h. The crude solution was concentrated under reduced pressure and purified by silica column chromatography (50-100%) EtOAc in hexanes to give the title compound. ES / MS: 262.2 (M+H + ).

[0429] [ka]

[0430] 4-(((6-chloropyridin-2-yl)amino)methyl)-3-methoxybenzonitrile (1-87): 4-(((6-chloropyridin-2-yl)amino)methyl)-3-methoxybenzonitrile was prepared according to the procedure of 1-86 using 4-(aminomethyl)-3-fluoro-benzonitrile hydrochloride instead of 4-(aminomethyl)-3-methoxybenzonitrile. ES / MS: 274.1 (M+H + ).

[0431] [ka]

[0432] 3-Fluoro-4-[(3-iodo-2-pyridyl)oxymethyl]benzonitrile (I-88): To a microwave vial was added 3-fluoro-4-(hydroxymethyl)benzonitrile (114 mg, 0.75 mmol), 2-chloro-3-iodo-pyridine (150 mg, 0.63 mmol), cesium carbonate (367 mg, 1.13 mmol), and 5 mL of THF. The vial was sealed, and the mixture was heated to 80° C. for 16 h. The mixture The residue was cooled to room temperature, concentrated, and purified on a silica column (35-100% EtOAc in hexanes) to give the title compound. ES / MS: 354.9 (M+H + ).

[0433] [ka]

[0434] 2-[(2-Fluorophenyl)methoxy]-3-iodo-pyridine (I-89): To a microwave vial was added (4-chloro-2-fluoro-phenyl)methanol (121 mg, 0.75 mmol), 2-chloro-3-iodo-pyridine (120 mg, 0.50 mmol), cesium carbonate (294 mg, 0.90 mmol), and 5 mL of THF. The vial was sealed and the mixture was heated to 80 °C for 16 h. The mixture was cooled to room temperature, concentrated, and purified on a silica column (35-100% EtOAc in hexanes) to give the title compound. ES / MS: 363.8 (M+H + ).

[0435] [ka]

[0436] 4-[(3-Bromopyrazin-2-yl)oxymethyl]-3-fluoro-benzonitrile (I-90): To a microwave vial was added 3-fluoro-4-(hydroxymethyl)benzonitrile (335 mg, 2.22 mmol), 2,3-dibromopyrazine (440 mg, 1.85 mmol), cesium carbonate (1.08 g, 3.33 mmol), and THF (10 mL). The vial was sealed and the mixture was heated to 80 °C for 16 h. The mixture was cooled to room temperature, concentrated, and purified on a silica column (35-100%) with EtOAc in hexanes to give the title compound. ES / MS: 308.1 (M+).

[0437] [ka]

[0438] 2-[(2-Fluorophenyl)methoxy]-3-iodo-pyridine (I-91): In a microwave vial, add 3-fluoro-4-(hydroxymethyl)benzonitrile (94.8 mg, 0.75 mmol), 2-chloro-3-iodo-pyridine (120 mg, 0.50 mmol), cesium carbonate (294 mg, 0.90 mmol), and 5 mL of THF. The vial was sealed and the mixture was heated to 80° C. for 16 hours. The mixture was cooled to room temperature, concentrated, and purified on a silica column (35-100% EtOAc in hexanes) to give the title compound. ES / MS: 329.9 (M+H + ).

[0439] [ka]

[0440] 3-Fluoro-4-[(5-iodopyrimidin-4-yl)oxymethyl]benzonitrile (I-92): 3-Fluoro-4-[(5-iodopyrimidin-4-yl)oxymethyl]benzonitrile was prepared according to the procedure of I-88, except that 2-chloro-3-iodo-pyridine was used instead of 4-chloro-5-iodo-pyrimidine. ES / MS: 356.0 (M+H + ).

[0441] [ka]

[0442] 3-Fluoro-4-[(3-iodo-4-pyridyl)oxymethyl]benzonitrile (I-93): 3-Fluoro-4-[(3-iodo-4-pyridyl)oxymethyl]benzonitrile was prepared according to the procedure of I-88, except that 2-chloro-3-iodo-pyridine was used instead of 4-chloro-3-iodo-pyridine. ES / MS: 354.9 (M+H + ).

[0443] [ka]

[0444] 4-[(2-Bromophenoxy)methyl]-3-fluoro-benzonitrile (1-94): 4-[(2-Bromophenoxy)methyl]-3-fluoro-benzonitrile was made according to the procedure of 1-88, except that 2-chloro-3-iodo-pyridine was used instead of 2-bromophenol and 4-cyano-2-fluorobenzyl bromide was used instead of 3-fluoro-4-(hydroxymethyl)benzonitrile. 1 H NMR (400 MHz, methanol-d4) δ 7.92-7.85 (m, 1H), 7.68-7.56 (m, 3H), 7.35 (ddd, J = 8.2, 7.4, 1.6 Hz, 1H), 7. 16(dd,J=8.3,1.4Hz,1H),6.94(td,J=7.7,1.4Hz,1H),5.33(s,2H).

[0445] [ka]

[0446] 4-Bromo-3-((4-chloro-2-fluorobenzyl)oxy)isothiazole (I-95): To a vial was added 4-bromoisothiazol-3-ol (50.0 mg, 0.278 mmol) and cesium carbonate (181 mg, 0.555 mmol), followed by acetonitrile (1.00 mL), and the mixture was stirred at 80° C. for 3 hours. The mixture was poured into water, and the precipitate was filtered off, washed with water, and dried under vacuum to give the title compound. 1 H NMR (400 MHz, chloroform-d) δ 8.43 (s, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.22-7.13 (m, 2H), 5.50 (d, J = 1.1 Hz, 2H).

[0447] [ka]

[0448] Methyl 2-(4-bromo-3-fluorobenzyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (I-96): To a solution of 2-(4-bromo-3-fluoro-phenyl)acetic acid (300 mg, 1.29 mmol) in DMF (6.00 mL), methyl 4-amino-3-(((1-(cyanomethyl)cyclopropyl)methyl)amino)benzoate (334 mg, 1.29 mmol) and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (588 mg, 1.55 mmol) were added, followed by N,N-diisopropylethylamine 99.5% (1.12 mL, 6.44 mmol) purified by redistillation, and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo, taken up in EtOAc, and washed with water (1x) and brine (1x). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was dissolved in AcOH (12 mL), and the mixture was heated to 60°C for 3 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: 458.1 (M+H + ).

[0449] [ka]

[0450] 2-(4-Bromo-3-fluorobenzyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (I-97): 2-(4-Bromo-3-fluorobenzyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate was prepared exactly as described for I-96, substituting 4-amino-3-(((1-(cyanomethyl)cyclopropyl)methyl)amino)benzoate with 4-amino-3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)benzoate. ES / MS: 469.0 (M+H + ).

[0451] [ka]

[0452] 4-(((4-Bromoisothiazol-3-yl)oxy)methyl)-3-fluorobenzonitrile (I-98): 4-(((4-Bromoisothiazol-3-yl)oxy)methyl)-3-fluorobenzonitrile was prepared exactly as described for I-95, substituting 4-(bromomethyl)-3-fluoro-benzonitrile for 1-(bromomethyl)-4-chloro-2-fluoro-benzene. 1 H NMR (400 MHz, chloroform-d) δ 8.46 (s, 1H), 7.72 (t, J = 7.5 Hz, 1H), 7.53 (dd, J = 8.0, 1.5 Hz, 1H), 7.42 (dd, J = 9.2, 1.5 Hz, 1H), 5.60 (s, 2H).

[0453] [ka]

[0454] 2-Chloro-6-((4-cyano-2-fluorobenzyl)oxy)isonicotinonitrile (I-99): 2-Chloro-6-((4-cyano-2-fluorobenzyl)oxy)isonicotinonitrile is a 4-bromo-2-chloro-thiazole derivative converted to 2,6-dichloropyridine. Prepared exactly as described for I-25, substituting azine-4-carbonitrile. 1 H NMR (400 MHz, chloroform-d) δ 7.65 (t, J = 7.5 Hz, 1H), 7.54-7.50 (m, 1H), 7.46-7.41 (m, 1H), 7.20 (d, J = 1.0 Hz, 1H), 7.02 (d, J = 1.0 Hz, 1H), 5.53 (s, 2H).

[0455] [ka]

[0456] 4-(((4-Bromothiazol-2-yl)oxy)methyl)-3-fluorobenzonitrile (I-100): 4-(((4-Bromothiazol-2-yl)oxy)methyl)-3-fluorobenzonitrile was prepared exactly as described for I-25, substituting 2,6-dichloropyridine-4-carbonitrile for 4-bromo-2-chloro-thiazole. ES / MS: 469.0 (M+H + ); 1 H NMR (400 MHz, chloroform-d) δ 7.66 (t, J = 7.5 Hz, 1H), 7.56-7.50 (m, 1H), 7.44 (dd, J = 9.1, 1.6 Hz, 1H), 6.68 (s, 1H), 5.60 (s, 2H).

[0457] [ka]

[0458] 4-((3-Bromo-4-fluorophenoxy)methyl)-3-fluorobenzonitrile (I-101): 4-((3-Bromo-4-fluorophenoxy)methyl)-3-fluorobenzonitrile was prepared exactly as described for I-26, substituting 3-bromo-4-fluoro-phenol for 3-bromo-5-fluoro-phenol. 1 H NMR (400 MHz, chloroform-d) δ 7.68 (t, J = 7.5 Hz, 1H), 7.54 (dd, J = 8.0, 1.6 Hz, 1H), 7.43 (dd, J = 9.3, 1.5 Hz, 1H), 7.21-7.17 (m, 1H), 7.09 (dd, J = 9.0, 8.0 Hz, 1H), 6.93-6.87 (m, 1H), 5.15 (s, 2H).

[0459] [ka]

[0460] 2-Chloro-6-((4-cyano-2-fluorobenzyl)oxy)nicotinonitrile (I-102) and 6-chloro-2-((4-cyano-2-fluorobenzyl)oxy)nicotinonitrile (I-103): 2-Chloro-6-((4-cyano-2-fluorobenzyl)oxy)nicotinonitrile (I-102) and 6-chloro-2-((4-cyano-2-fluorobenzyl)oxy)nicotinonitrile (I-103) were prepared exactly as described for I-2 and I-3, substituting 2,6-dichloropyridine-3-carbonitrile for 2-bromo-6-chloro-3-methyl-pyridine (mixture of regioisomers). 1 H NMR (400 MHz, chloroform-d) δ 7.93-7.85 (m, 2H), 7.74 (t, J = 7.5 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.57-7.49 (m, 2H), 7.47-7.41 (m, 2H), 7.12 (d, J = 7.9 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 5.62 (s, 2H), 5.56 (s, 1H).

[0461] [ka]

[0462] 4-(((6-Chloro-5-fluoropyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (I-104) and 4-(((6-chloro-3-fluoropyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (I-105): 4-(((6-chloro-5-fluoropyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (I-104) and 4-(((6-chloro-3-fluoropyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (I-105) were prepared exactly as described for I-2 and I-3, replacing 2-bromo-6-chloro-3-methyl-pyridine with 2,6-dichloro-3-fluoro-pyridine (mixture of regioisomers). 1 H NMR (400MHz, chloroform-d) δ7.79(t,J=7.5Hz,1H),7.71(t,J=7.5Hz,1H),7.58(dd,J=7.9,1.5Hz,1H),7.52(dd,J=7.9 ,1.5Hz,1H),7.47-7.41(m,2H),7.41-7.35(m,1H),7.28-7.28(m,2H),6.97-6.93(m,1H),5.57(s,2H),5.27(s,2H).

[0463] [ka]

[0464] 4-(((4-Bromoisoxazol-3-yl)oxy)methyl)-3-fluorobenzonitrile (I-106): 4-(((4-Bromoisoxazol-3-yl)oxy)methyl)-3-fluorobenzonitrile (I-106) was prepared exactly as described for I-95, substituting 4-bromoisothiazol-3-ol for 4-bromoisoxazol-3-ol. 1 H NMR (400 MHz, chloroform) Mu-d) δ8.21(s,1H),7.69(t,J=7.5Hz,1H),7.55-7.50(m,1H),7.42(dd,J=9.1,1.5Hz,1H),5.45(s,2H),5.30(s,1H).

[0465] [ka]

[0466] 4-(((6-Chloro-4-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (I-107): 4-(((6-Chloro-4-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (I-107) was prepared exactly as described for I-25, substituting 2,6-dichloro-4-(trifluoromethyl)pyridine for 4-bromo-2-chloro-thiazole. 1 H NMR (400 MHz, chloroform-d) δ 7.67 (t, J = 7.5 Hz, 1H), 7.52 (dd, J = 7.9, 1.5 Hz, 1H), 7.43 (dd, J = 9.1, 1.5 Hz, 1H), 7.20 (s, 1H), 7.00 (s, 1H), 5.55 (s, 2H).

[0467] [ka]

[0468] 4-(((6-Chloro-4-iodopyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (I-108): 4-(((6-Chloro-4-iodopyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile was prepared exactly as described for I-25, substituting 2,6-dichloro-4-iodo-pyridine for 4-bromo-2-chloro-thiazole. ES / MS: 297.0 (M+H + ).

[0469] [ka]

[0470] Step 1. Methyl 2-(4-(6-(benzyloxy)pyridin-2-yl)-2-fluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate. To a solution of 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (I-5, 10 g, 21.4 mmol) and 2-benzyloxy-6-bromo-pyridine (6.50 g, 24.6 mmol) in dioxane (200 mL) was added Pd(dppf)Cl (1.60 g, 2.19 mmol) and potassium carbonate (2.00 M in water, 22.0 mL, 44.0 mmol). The solution was degassed with nitrogen and heated to 90°C (internal temperature) for 5.5 hours. Additional 2-benzyloxy-6-bromo-pyridine (0.850 g, 3.22 mmol) was added and heating continued for 1 hour. The mixture was then cooled to room temperature and diluted with EtOAc. The solution was decanted from the remaining solids and washed with brine (twice). The aqueous layer was back-extracted with EtOAc, and the combined organic layers were dried over magnesium sulfate and concentrated to dryness. The crude material was purified by SiO2 chromatography (eluent: 10-40% EtOAc / hexanes) to give methyl 2-(4-(6-(benzyloxy)pyridin-2-yl)-2-fluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate. ES / MS: 526.402 (M+H + ).

[0471] Step 2. Methyl 2-(2-fluoro-4-(6-hydroxypyridin-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (I-109). To a solution of methyl 2-(4-(6-(benzyloxy)pyridin-2-yl)-2-fluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (10.2 g, 19.4 mmol) in MeOH (200 mL) was added hydrogen chloride (4.00 M in 1,4-dioxane, 100 mL, 400 mmol). The solution was heated to 70 °C (external temperature) for 12 h. The mixture was then concentrated, dissolved in 10% MeOH / CHCl, and washed with aqueous bicarbonate. The aqueous layer was back-extracted with 10% MeOH / CHCl. The combined organic layers were washed with brine and dried over magnesium sulfate. After concentration to dryness, the resulting material was triturated with EtO by sonication, diluted with hexanes, and filtered to give methyl 2-(2-fluoro-4-(6...

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【Request Item 1】 Metabolic disorders.

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