GLP-1R Modulating Compounds

Abstract

The present disclosure provides GLP-1R agonists and compositions, methods and kits thereof. Such compounds can generally be used to treat GLP-1R-mediated diseases or conditions in humans.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] 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. Technical Field

[0003] The present disclosure relates to compounds that bind to the glucagon-like peptide-1 receptor (GLP-1R) and act as agonists or modulators thereof, and compounds that act as agonists or modulators of GLP-1R. The present disclosure also relates to the use of the compounds for treating and / or preventing diseases and / or conditions by the compounds. Background Art

[0004] 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 the regulation of postprandial blood glucose, both by directly increasing meal-induced insulin secretion from pancreatic beta cells and by promoting satiety by delaying the transit of food through the intestine. GLP-1 mediates intracellular signaling through the GLP-1 receptor (GLP-1R), which belongs to a family of G protein-coupled receptors present on cell membranes and, upon activation, leads to the accumulation of the second messenger cyclic adenosine monophosphate (cAMP). Non-alcoholic steatohepatitis (NASH) can be associated with features of the metabolic syndrome, including obesity, type 2 diabetes, insulin resistance, and cardiovascular disease.

[0005] GLP-1R agonists are currently being studied for the treatment of diabetes, obesity, and NASH. GLP-1R agonists include peptides approved for the treatment of type 2 diabetes, such as exenatide, liraglutide, and dulaglutide. These peptides are primarily administered by subcutaneous injection. Oral GLP-1 agonists are also being studied 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 for the GLP-1R agonists than that of endogenous GLP-1.

[0006] In the treatment of metabolic and related diseases, including but not limited to NASH, obesity, and type 2 diabetes, there remains a need for compounds that possess desirable therapeutic, metabolic properties, and / or ease of administration, such as agonists of the GLP-1R. Summary of the Invention

[0007] In one embodiment, the present disclosure provides a compound of formula (IA-1):

[0008]

[0009] or a pharmaceutically acceptable salt thereof, wherein

[0010] R 1 C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclic, 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 ,

[0011] wherein the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are each optionally substituted by one to four Z 1 replace;

[0012] Ring A is C 6-10 aryl or heteroaryl, each of which is optionally substituted by one to four Z 1a replace;

[0013] Ring B is C 6-10 aryl or heteroaryl, each of which is optionally substituted by one to four R 4 replace;

[0014] R 2 H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclic, 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)(NR2a )R 2b ,

[0015] wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1 replace;

[0016] X 1 、X 2 and X 3 Each independently represents -N=, -C(H)= or -C(R 8 )=;

[0017] R 3 H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-10 Cycloalkyl, heterocyclic, 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)2NR 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 3a , wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four R 3d replace;

[0018] Each R 3a 、R 3b and R 3c Independently H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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, heterocyclic, C 6-10 Aryl, heteroaryl, -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)(R 9c )(N(R 9d)2) or C 1-6 alkyl-heterocyclyl;

[0019] wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace,

[0020] Each R 4 Independently C 1-9 Alkyl, C 1-8 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, 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)(NR4a )R 4b or -Si(R 4a )3;

[0021] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace;

[0022] or two R attached to adjacent ring atoms 4 The groups combine with the atoms to which they are attached to form C 5-10 Cycloalkyl or heterocyclic group, the cycloalkyl or heterocyclic group is optionally substituted by one to four Z 1b replace;

[0023] R 5a and R 5b Each independently is H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkoxyalkyl, halogen, C 3-10 Cycloalkyl, heterocyclic, -C 1-6 Alkyl-N(R 9a )(R 9b ),-CN,-OR 5a1 or

[0024] -N(R 5a1 )(R 5a2 );

[0025] or R 5a and R 5b Combine with the atoms to which they are attached to form C 3-10 Cycloalkyl or heterocyclic group, the cycloalkyl or heterocyclic group is optionally substituted by one to four R 5a3 replace;

[0026] Each R 5a1 and R 5a2 Independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclic, C 6-10 aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four R 5a4 replace;

[0027] V is -C(O)-, -O-, -N(R 6a )-or-C(R 6b )(R 6c )-;

[0028] R 6aH, C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, -S(O)2R 6a1 or -S(O)2N(R 6a1 )(NR 6a2 ), wherein the cycloalkyl or heterocyclyl are each optionally replaced by C 1-6 Alkyl, F or -CN substitution;

[0029] Each R 6b and R 6c Independently H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkoxyalkyl, halogen, C 3-10 Cycloalkyl, heterocyclic, -C 1-6 Alkyl-N(R 9a )(R 9b ),-CN,-OR 6c1 or -N(R 6c2 )(R 6c3 ), wherein the alkyl, cycloalkyl or heterocyclyl groups are each optionally substituted by one to four R 6b1 replace;

[0030] or R 6b and R 6c Combine with the atoms to which they are attached to form C 3-10 Cycloalkyl or heterocyclic group, the cycloalkyl or heterocyclic group is optionally substituted by one to four R 6b1 replace;

[0031] or R 6a or R 6c With an R 4 The groups and the atoms to which they are attached combine to form C 5-10 Cycloalkyl or heterocyclic group, the cycloalkyl or heterocyclic group is optionally substituted by one to four R 10 replace;

[0032] Y is -N(R 7 )-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NH)- or -S(O)(=NR 7 )-;

[0033] Each R 1a 、R 3d 、R 5a3 、R 5a4 、R 6b1 and R 10 Independently C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C1-6 Halogenated alkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-10 Cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, CO2R 3e 、-NO2 or -C(O)N(R 2a )(R 2b ), wherein the heterocyclyl or heteroaryl is optionally replaced by C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 haloalkoxy substituted; and

[0034] Each R 6a1 、R 6a2 、R 6c1 、R 6c2 、R 6c3 and R 7 Independently H, C 1-6 Alkyl or C 3-10 Cycloalkyl;

[0035] Each R 8 Independently C 1-9 Alkyl, C 1-8 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, CO2R 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 2-6Alkenyl)2, -N(C 2-6 Alkynyl)2, -N(C 3-15 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)(heterocyclic), -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 Halogenated alkyl), -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 Halogenated alkyl), -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 Halogenated alkyl), -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 Halogenated alkyl)2, -C(O)N(C 2-6 Alkenyl)2, -C(O)N(C 2-6 Alkynyl)2, -C(O)N(C3-15 Cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C 6-10 Aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C 1-9 alkyl), -NHC(O)(C 1-8 Haloalkyl), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 Alkynyl), -NHC(O)(C 3-15 Cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6-10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 1-8 Halogenated alkyl), -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 Halogenated alkyl), -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 Halogenated alkyl), -S(C 2-6 alkenyl), -S(C 2-6 Alkynyl), -S(C 3-15 Cycloalkyl), -S(heterocyclyl), -S(C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2, -S(O)(C 1-9 alkyl), -S(O)(C 1-8 Halogenated alkyl), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 Alkynyl), -S(O)(C3-15 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 Halogenated alkyl), -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)2N(C 1-9 Alkyl)2;

[0036] wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl radical is optionally substituted by one to three 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 Halogenated alkyl), -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 Halogenated alkyl), -S(O)2(C3-15 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)2N(C 1-9 alkyl)2 substituted;

[0037] Each R 9a and R 9b Independently H, C 1-6 Alkyl or C 1-6 Haloalkyl, or R 9a and R 9b Together they form a 6-membered heterocyclic group;

[0038] Each Z 1 Independently C 1-9 Alkyl, C 1-8 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic group,

[0039] C 6-10 Aryl, heteroaryl, oxo, -NO2, -N3, -CN, -OR 12a 、-C(O)-R 12a 、-C(O)OR 12a 、

[0040] -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 、

[0041] -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 ),

[0042] -NR 12a S(O)2N(R12b )(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;

[0043] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1a replace;

[0044] Each Z 1a Independently C 1-9 Alkyl, C 1-8 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 12a 、-C(O)R 12a 、

[0045] -C(O)OR 12a 、-C(O)N(R 12a )(R 12b )、-N(R 12a )(R 12b )、-N(R 12a )2(R 12b ) + 、

[0046] -N(R 12a )-C(O)R 12b 、-N(R 12a )C(O)O(R 12b )、-N(R 12a )C(O)N(R12b )(R 12c ),

[0047] -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 ),

[0048] -OC(O)R 12a 、-OC(O)OR 12a 、-OC(O)-N(R 12a )(R 12b ),-SR 12a 、

[0049] -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;

[0050] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace;

[0051] Each Z 1b Independently C 1-9 Alkyl, C 1-8 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, CO2R 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(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 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)(heterocyclic), -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 Halogenated alkyl), -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 Halogenated alkyl), -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 Halogenated alkyl), -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 Halogenated alkyl)2, -C(O)N(C 2-6 Alkenyl)2, -C(O)N(C 2-6 Alkynyl)2, -C(O)N(C 3-15 Cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C 6-10 Aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C 1-9 alkyl), -NHC(O)(C 1-8 Haloalkyl), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 Alkynyl), -NHC(O)(C 3-15 Cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6-10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 1-8 Halogenated alkyl), -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 Halogenated alkyl), -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 Halogenated alkyl), -S(C 2-6 alkenyl), -S(C 2-6 Alkynyl), -S(C 3-15Cycloalkyl), -S(heterocyclyl), -S(C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2, -S(O)(C 1-9 alkyl), -S(O)(C 1-8 Halogenated alkyl), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 Alkynyl), -S(O)(C 3-15 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 Halogenated alkyl), -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)2N(C 1-9 Alkyl)2;

[0052] wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl radical is optionally substituted by one to three 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 Halogenated alkyl), -NHC(O)O(C2-6 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 Halogenated alkyl), -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)2N(C 1-9 alkyl)2 substituted;

[0053] 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 Independently H, C 1-9 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-15 Cycloalkyl, heterocyclic, C 6-10 aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace; and

[0054] Each R 3e 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(R9a )(R 9b ),-C 1-4 Alkyl-C 3-8 Cycloalkyl, -C 1-4 Alkyl-heterocyclyl, C 3-10 Cycloalkyl, heterocyclic, 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 the alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted by one to four Z 1b substituted; wherein each heteroaryl has 5 to 12 ring members and has one to four heteroatoms each independently being N, O or S; and

[0055] wherein each heterocyclyl has 3 to 12 ring members and has one to four heteroatoms each independently being N, O or S.

[0056] The present disclosure also 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 can generally be used in methods for treating GLP-1R-mediated diseases or conditions. DETAILED DESCRIPTION

[0057] I. Definition

[0058] 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 beginning or end of a chemical group is provided for convenience to indicate the point of attachment to the parent moiety; a chemical group may be depicted without one or more dashes without loss of its ordinary meaning. A prefix such as "C u-v ” or “C u -C v " indicates that the following group has u to v carbon atoms, where u and v are integers. For example, "C 1-6 "Alkyl" or "C1-C6 alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0059] "Alkyl" is a monovalent or divalent straight or branched chain saturated hydrocarbon radical. For example, an alkyl group can have 1 to 10 carbon atoms (i.e., C 1-10 alkyl) or 1 to 8 carbon atoms (i.e., C 1-8 alkyl) or 1 to 6 carbon atoms (i.e., C 1-6 alkyl) or 1 to 4 carbon atoms (i.e., C 1-4Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, isopropyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, -CH(C H3)2CH3), 2-methyl-2-propyl (t-Bu, tert-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)2CH2CH3), 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 (-CH 2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(C Alkyl groups can be unsubstituted or substituted.

[0060] "Alkoxy" refers to the group -O-alkyl, where alkyl is as defined above. For example, C 1-4 Alkoxy refers to an -O-alkyl group having 1 to 4 carbons. Alkoxy groups can be unsubstituted or substituted.

[0061] "Alkoxyalkyl" is an alkoxy group attached to an alkyl group as defined above, such that the alkyl group is divalent. For example, C 2-6 Alkoxyalkyl groups include -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.

[0062] "Alkenyl" is a monovalent or divalent straight or branched hydrocarbon radical having at least one carbon-carbon double bond. For example, an alkenyl group can have 2 to 8 carbon atoms (i.e., C 2-8 alkenyl) or 2 to 6 carbon atoms (ie, C 2-6 alkenyl) or 2 to 4 carbon atoms (ie, C 2-4 Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and -CH2-CH=CH-CH3. Alkenyl groups can be unsubstituted or substituted.

[0063] "Alkynyl" is a monovalent or divalent straight or branched chain hydrocarbon radical having at least one carbon-carbon triple bond. For example, an alkynyl group can have 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 (ie, C 2-4 Alkynyl). Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), and -CH2-C≡C-CH3. Alkynyl groups can be unsubstituted or substituted.

[0064] "Halogen" refers to fluorine (-F), chlorine (-Cl), bromine (-Br) and iodine (-I).

[0065] "Haloalkyl" is an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently substituted with halogen (which may be the same or different) such that the alkyl group is divalent. The alkyl group and the halogen may be any of those described above. In some embodiments, the haloalkyl group defines the number of carbon atoms in the alkyl portion, for example, C 1-4 Haloalkyl groups include CF3, CH2F, CHF2, CH2CF3, CH2CH2CF3, CCl2CH2CH2CH3, and C(CH3)2(CF2H). Haloalkyl groups can be unsubstituted or substituted.

[0066] "Haloalkoxy" is an alkoxy group as defined herein, wherein one or more hydrogen atoms of the alkyl group in the alkoxy group are independently replaced by halogen (which may be the same or different) such that the alkyl group is divalent. The alkoxy group and the halogen may be any of those described above. In some embodiments, the haloalkoxy group defines the number of carbon atoms in the alkyl portion, for example, C 1-4 Haloalkoxy groups include OCF3, OCH2F, OCH2CF3, OCH2CH2CF3, OCCl2CH2CH2CH3, and OC(CH3)2(CF2H).Haloalkoxy groups can be unsubstituted or substituted.

[0067] " cycloalkyl " is a monovalent or divalent single full carbon ring or a polycondensed full carbon ring system, wherein the ring is a non-aromatic saturated or unsaturated ring in each example. 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 monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl and cyclooctyl. Cycloalkyl also includes polycondensed ring systems (for example, ring systems comprising 2 rings) with about 7 to 12 carbon atoms. When valence requirements allow, these rings of the polycondensed ring systems can be interconnected by condensation, spirocycle or bridge bond. Exemplary polycyclic 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.

[0068] "Alkylcycloalkyl" refers to an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently replaced by a cycloalkyl group (which may be the same or different). The alkyl group and the cycloalkyl group may be any of those described above. In some embodiments, the number of carbon atoms in the alkyl and cycloalkyl moieties may be specified separately, for example, C 1-6 Alkyl-C 3-12 Cycloalkyl. Alkylcycloalkyl groups can be unsubstituted or substituted.

[0069] As used herein, "aryl" refers to a monovalent or divalent single all-carbon aromatic ring or a polycondensed all-carbon ring system, wherein the ring is aromatic. For example, in some embodiments, the 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 a phenyl radical. Aryl also includes a polycondensed ring system (for example, a ring system comprising 2, 3, or 4 rings) having about 9 to 20 carbon atoms, wherein multiple rings are aromatic. When valence requirements permit, these rings of the polycondensed ring system can be interconnected by fused bonds. It should also be understood that when citing a certain atomic range aryl (for example, a 6-10 yuan aryl), the atomic range is the total ring atoms of the aryl. For example, a 6-yuan aryl will include a phenyl, and a 10-yuan aryl will include a naphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, etc. Aryl groups can be unsubstituted or substituted.

[0070] "Alkylaryl" refers to an alkyl group as defined herein in which one or more hydrogen atoms of the alkyl group are independently replaced by an aryl group (which may be the same or different). The alkyl group and the aryl group may be any of those described above, such that the alkyl group 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 combined constituent alkyl and aryl groups. For example, C7 alkylaryl refers to benzyl, while C 11 Alkylaryl includes 1-methylnaphthyl and n-pentylphenyl. In some embodiments, the number of carbon atoms in the alkyl and aryl moieties can be specified separately, for example, C 1-6 Alkyl-C 6-10 Aryl. Non-limiting examples of alkylaryl groups include, but are not limited to, benzyl, 2,2-dimethylphenyl, n-pentylphenyl, 1-methylnaphthyl, 2-ethylnaphthyl, etc. The alkylaryl group can be unsubstituted or substituted.

[0071] 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 in the ring (i.e., at least one cyclic (i.e., annular) heteroatom selected from oxygen, nitrogen, and sulfur). Unless otherwise indicated, a heterocyclyl group has 3 to about 20 ring atoms, such as 3 to 12 ring atoms, such as 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 single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6, or 7-membered rings) having about 1 to 6 ring carbon atoms and about 1 to 3 ring heteroatoms selected from oxygen, nitrogen, and sulfur in the ring. When valence requirements allow, these rings of multiple fused rings (e.g., bicyclic heterocyclic radicals) can be interconnected by fusion, spirocycles, and bridge bonds. Heterocycles include, but are not limited to, azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, thiamidine, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, 2-oxa-6-azaspiro[3.3]hept-6-yl, 6-oxa-1-azaspiro[3.3]hept-1-yl, 2- Thiophene-6-azaspiro[3.3]hept-6-yl, 2,6-diazaspiro[3.3]hept-2-yl, 2-azabicyclo[3.1.0]hex-2-yl, 3-azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.1.1]hexyl, 2-azabicyclo[2.2.1]hept-2-yl, 4-azaspiro[2.4]heptyl, 5-azaspiro[2.4]heptyl, etc. The heterocyclyl group can be unsubstituted or substituted.

[0072] "Alkylheterocyclyl" refers to an alkyl group as defined herein in which one or more hydrogen atoms of the alkyl group are independently replaced by a heterocyclyl group (which may be the same or different). The alkyl group and the heterocyclyl group may be any of those described above, such that the alkyl group is divalent. In some embodiments, the number of atoms in the alkyl and heterocyclyl moieties may be specified separately, for example, a C alkyl group with one to three heteroatoms, each independently N, O, or S. 1-6 Alkyl-3 to 12 membered heterocyclyl. Alkylheterocyclyl groups can be unsubstituted or substituted.

[0073] "Heteroaryl" refers to a single aromatic ring having at least one atom other than carbon in the ring, wherein the atom is selected from oxygen, nitrogen and sulfur; "heteroaryl" also includes multiple fused ring systems having at least one such aromatic ring, which will be further described below. Thus, "heteroaryl" includes a single aromatic ring having about 1 to 6 carbon atoms and about 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur. The sulfur and nitrogen atoms may also exist in oxidized form, provided that the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl or furyl. "Heteroaryl" also includes multiple fused ring systems (e.g., ring systems comprising 2, 3 or 4 rings), wherein a heteroaryl group as defined above is fused to one or more rings selected from heteroaryl (to form, for example, 1,8-naphthyridinyl) and to an aryl group (to form, for example, benzimidazolyl or indazolyl), thereby forming a multiple fused ring system. Thus, the heteroaryl group (single aromatic ring or multi-fused ring system) may have about 1 to 20 carbon atoms and about 1 to 6 heteroatoms within the heteroaryl ring. For example, tetrazolyl has 1 carbon atom and 4 nitrogen heteroatoms within the ring. When valence requirements permit, the rings of the multi-fused ring system may be interconnected by fused bonds. It should be understood that the individual rings of the multi-fused ring system may be connected in any order relative to each other. It should be understood that the point of attachment of the heteroaryl or heteroaryl multi-fused ring system may be located on any suitable atom of the heteroaryl or heteroaryl multi-fused ring system, including carbon atoms and heteroatoms (e.g., nitrogen). It should also be understood that when a certain atomic range membered heteroaryl group (e.g., 5 to 10 membered heteroaryl group) is cited, the atomic range is the total ring atoms of the heteroaryl group and includes carbon atoms and heteroatoms. It is also understood that the rings of the polyfused ring system may include an aryl ring (e.g., a 3-, 4-, 5-, 6-, or 7-membered ring) fused to a heterocyclic ring having saturated or partially unsaturated bonds, having about 1 to 6 ring carbon atoms and about 1 to 3 ring heteroatoms selected from oxygen, nitrogen, and sulfur in the ring. For example, a 5-membered heteroaryl includes thiazolyl, and a 10-membered heteroaryl includes quinolinyl. Exemplary heteroaryl groups 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, quinoxalinyl, quinazolinyl, benzofuranyl, benzimidazolyl, thienyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, and tetrazolyl. The heteroaryl group can be unsubstituted or substituted.

[0074] "Alkylheteroaryl" refers to an alkyl group as defined herein in which one or more hydrogen atoms of the alkyl group are independently replaced by heteroaryl groups (which may be the same or different) such that the alkyl group is divalent. The alkyl group and the heteroaryl group may be any of those described above. In some embodiments, the number of atoms in the alkyl and heteroaryl moieties is specified separately, for example, a C alkyl group with one to four heteroatoms, each independently N, O, or S. 1-6 Alkyl-5 to 10 membered heteroaryl. Alkylheteroaryl groups can be unsubstituted or substituted.

[0075] As used herein, "oxo" refers to =0.

[0076] As used herein, "substituted" means that one or more hydrogen atoms in the group are independently replaced with one or more substituents (eg, 1, 2, 3, or 4 or more), as indicated.

[0077] "Compounds of the present disclosure" include compounds disclosed herein, for example, compounds of the present disclosure include compounds of Formula (I), (Ia), (Ib), (Ic), and (Id), including the compounds of the Examples. In some embodiments, "compounds of the present disclosure" include compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and (Id).

[0078] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, vehicle, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. Food and Drug Administration for use in humans or veterinary animals.

[0079] As used herein, "therapeutically effective amount" or "effective amount" refers to an amount that is effective to elicit a desired biological or medical response, including an amount of a compound that, when administered to a subject to treat a disease, is sufficient to affect such treatment of the disease. The effective amount will vary depending on the compound, the disease and its severity, and the age, weight, etc. of the subject to be treated. The effective amount may include a range of amounts. As understood in the art, an effective amount may be one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired therapeutic endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and if used in combination with one or more other agents, a desired or beneficial result can be achieved or realized, then a single agent may be considered to be administered in an effective amount. The appropriate dosage of any co-administered compound may optionally be reduced due to the combined action of the compounds (e.g., additive or synergistic effect).

[0080] As used herein, "co-administration" refers to administering a unit dose of a compound disclosed herein before or after administering a unit dose of one or more additional therapeutic agents, for example, administering a compound disclosed herein within seconds, minutes, or hours of administering one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound of the present disclosure is administered first, followed by a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of a compound of the present disclosure within seconds or minutes. In some embodiments, a unit dose of a compound of the present disclosure is administered first, followed by a unit dose of one or more additional therapeutic agents a few hours (e.g., 1 hour - 12 hours) later. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of a compound of the present disclosure a few hours (e.g., 1 hour - 12 hours) later. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to administering a compound disclosed herein and one or more additional therapeutic agents simultaneously or sequentially, such that a therapeutically effective amount of each agent is present in the subject.

[0081] Also provided are pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0082] 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 the compound that have the desired pharmacological activity of the free base. These salts can be derived from inorganic or organic acids or bases. For example, compounds containing basic nitrogen can be prepared as pharmaceutically acceptable salts by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyrates, succinates, octanedioates ... The pharmaceutically acceptable salts of the present invention include benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, benzenesulfonate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate and mandelate. A list of other suitable pharmaceutically acceptable salts can be found in "Remington: The Science and Practice of Pharmacy", 21st edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0083] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein also include salts derived from suitable bases such as alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium, and N(C1≡C4 alkyl)4 + Also included are base addition salts such as sodium or potassium salts.

[0084] Also provided are compounds described herein or pharmaceutically acceptable salts, isomers or mixtures thereof, wherein 1 to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom or D, where n is the number of hydrogen atoms in the molecule. As known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds can increase resistance to metabolism and are therefore useful for increasing the half-life of a compound described herein or a pharmaceutically acceptable salt, isomer or mixture thereof when administered to a mammal. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci., Vol. 5, No. 12, pp. 524-527, 1984. Such compounds are synthesized by methods well known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0085] Examples of isotopes that may be incorporated into the disclosed compounds also 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. Use of positron-emitting isotopes such as 11 C. 18 F. 15 O and 13 Substitution of N can be used in positron emission tomography (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 methods analogous to those described in the Examples listed below using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.

[0086] The compounds of the embodiments disclosed herein or their pharmaceutically acceptable salts may include one or more asymmetric centers and, thus, may produce enantiomers, diastereomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R)- or (S)- or as (D)- or (L)- for amino acids. The present disclosure is intended to include all such possible isomers and their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolving racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise indicated, it is intended that the compounds include E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. Where compounds are represented in their chiral form, it is understood that the embodiments encompass, but are not limited to, the specific diastereomer or enantiomerically enriched form. Where chirality is not specified but exists, it is understood that the embodiments relate to the specific diastereomer or enantiomerically enriched form; or a racemic or non-racemic mixture of such compounds. As used herein, a "non-racemic mixture" is a mixture of stereoisomers that is not in a 1:1 ratio.

[0087] As used herein, "stereoisomer" refers to a compound composed of the same atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. 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.

[0088] As used herein, "tautomers" involve 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.

[0089] As used herein, "solvate" refers to the result of the interaction of a solvent and a compound. Also provided are solvates of the salts of the compounds described herein. Also provided are hydrates of the compounds described herein.

[0090] As used herein, "hydrate" refers to a compound of the present disclosure chemically associated with one or more water molecules.

[0091] "Prevention" or "preventing" means any treatment of a disease or condition that results in the clinical symptoms of the disease or condition not developing. In some embodiments, the compound can be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.

[0092] As used herein, a "prodrug" is a derivative of a drug that is converted to the parent drug according to some chemical or enzymatic pathway when administered to the human body. In some embodiments, a "prodrug" is a biologically inactive derivative of a drug that is converted to the biologically active parent drug according to some chemical or enzymatic pathway when administered to the human body.

[0093] As used herein, "treatment" refers to a method for obtaining a beneficial or desired result. For the purposes of this disclosure, a beneficial or desired result includes, but is not limited to, alleviation of symptoms and / or reduction of the degree of symptoms and / or prevention of worsening of symptoms associated with a disease or condition. In one embodiment, "treatment" includes one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms caused by the disease or condition, and / or reducing the degree of the disease or condition); b) slowing down or preventing the development of one or more symptoms associated with a disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition); and c) alleviating the disease or condition, such as causing regression of clinical symptoms, improving the disease state, delaying the progression of the disease, improving the quality of life, and / or prolonging survival. As used herein, "individual at risk" refers to an individual at risk of developing a condition to be treated. An individual "at risk" may or may not have a detectable disease or condition, and may or may not show a detectable disease before treatment with the methods described herein. "At risk" means that an individual has one or more so-called risk factors, which are measurable parameters known in the art that are associated with the development of a disease or condition. An individual with one or more of these risk factors has a higher probability of developing the disease or condition than an individual without these risk factors.

[0094] II.Compounds

[0095] In some embodiments, the compound of the present disclosure is a compound of formula (IA-1):

[0096]

[0097] or a pharmaceutically acceptable salt thereof, wherein

[0098] R 1 C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, -SR1b 、-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 ,

[0099] wherein the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are each optionally substituted by one to four Z 1 replace;

[0100] Ring A is C 6-10 aryl or heteroaryl, each of which is optionally substituted by one to four Z 1a replace;

[0101] Ring B is C 6-10 aryl or heteroaryl, each of which is optionally substituted by one to four R 4 replace;

[0102] R 2 H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclic, 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 ,

[0103] wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1 replace;

[0104] X 1 、X 2 and X 3 Each independently represents -N=, -C(H)= or -C(R 8 )=;

[0105] R 3 H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-10 Cycloalkyl, heterocyclic, 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)2NR 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 1-6Alkyl-C(O)OR 3a , wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four R 3d replace;

[0106] Each R 3a 、R 3b and R 3c Independently H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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, heterocyclic, C 6-10 Aryl, heteroaryl, -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)(R 9c )(N(R 9d )2) or C 1-6 alkyl-heterocyclyl;

[0107] wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace,

[0108] Each R 4 Independently C 1-9 Alkyl, C 1-8 Halogenated alkyl, C 1-6 Halogenated alkoxy, C2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, 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;

[0109] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace;

[0110] or two R attached to adjacent ring atoms 4 The groups combine with the atoms to which they are attached to form C 5-10Cycloalkyl or heterocyclic group, the cycloalkyl or heterocyclic group is optionally substituted by one to four Z 1b replace;

[0111] R 5a and R 5b Each independently is H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkoxyalkyl, halogen, C 3-10 Cycloalkyl, heterocyclic, -C 1-6 Alkyl-N(R 9a )(R 9b ),-CN,-OR 5a1 or -N(R 5a1 )(R 5a2 );

[0112] or R 5a and R 5b Combine with the atoms to which they are attached to form C 3-10 Cycloalkyl or heterocyclic group, the cycloalkyl or heterocyclic group is optionally substituted by one to four R 5a3 replace;

[0113] Each R 5a1 and R 5a2 Independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclic, C 6-10 aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four R 5a4 replace;

[0114] V is -C(O)-, -O-, -N(R 6a )-or-C(R 6b )(R 6c )-;

[0115] R 6a H, C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, -S(O)2R 6a1 or -S(O)2N(R 6a1 )(NR 6a2 ), wherein the cycloalkyl or heterocyclyl are each optionally replaced by C 1-6 Alkyl, F or -CN substitution;

[0116] Each R 6b and R 6c Independently H, C 1-6 Alkyl, C 1-6Halogenated alkyl, C 2-6 Alkoxyalkyl, halogen, C 3-10 Cycloalkyl, heterocyclic, -C 1-6 Alkyl-N(R 9a )(R 9b ),-CN,-OR 6c1 or -N(R 6c2 )(R 6c3 ), wherein the alkyl, cycloalkyl or heterocyclyl groups are each optionally substituted by one to four R 6b1 replace;

[0117] or R 6b and R 6c Combine with the atoms to which they are attached to form C 3-10 Cycloalkyl or heterocyclic group, the cycloalkyl or heterocyclic group is optionally substituted by one to four R 6b1 replace;

[0118] or R 6a or R 6c With an R 4 The groups and the atoms to which they are attached combine to form C 5-10 Cycloalkyl or heterocyclic group, the cycloalkyl or heterocyclic group is optionally substituted by one to four R 10 replace;

[0119] Y is -N(R 7 )-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NH)- or -S(O)(=NR 7 )-;

[0120] Each R 1a 、R 3d 、R 5a3 、R 5a4 、R 6b1 and R 10 Independently C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-10 Cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, CO2R 3e , -NO2 or

[0121] -C(O)N(R 2a )(R 2b ), wherein the heterocyclyl or heteroaryl is optionally replaced by C 1-6Alkyl, C 1-6 Haloalkyl or C 1-6 haloalkoxy substituted; and

[0122] Each R 6a1 、R 6a2 、R 6c1 、R 6c2 、R 6c3 and R 7 Independently H, C 1-6 Alkyl or C 3-10 Cycloalkyl;

[0123] Each R 8 Independently C 1-9 Alkyl, C 1-8 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, CO2R 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 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 1-9Alkyl)(C 3-15 Cycloalkyl), -N(C 1-9 alkyl)(heterocyclic), -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 Halogenated alkyl), -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 Halogenated alkyl), -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 Halogenated alkyl), -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 Halogenated alkyl)2, -C(O)N(C 2-6 Alkenyl)2, -C(O)N(C 2-6 Alkynyl)2, -C(O)N(C 3-15 Cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C 6-10 Aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C 1-9 alkyl), -NHC(O)(C 1-8 Haloalkyl), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 Alkynyl), -NHC(O)(C 3-15 Cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C6-10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 1-8 Halogenated alkyl), -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 Halogenated alkyl), -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 Halogenated alkyl), -S(C 2-6 alkenyl), -S(C 2-6 Alkynyl), -S(C 3-15 Cycloalkyl), -S(heterocyclyl), -S(C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2, -S(O)(C 1-9 alkyl), -S(O)(C 1-8 Halogenated alkyl), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 Alkynyl), -S(O)(C 3-15 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 Halogenated alkyl), -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 6-10aryl), -S(O)2(heteroaryl), -S(O)(NH)(C 1-9 alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2;

[0124] wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl radical is optionally substituted by one to three 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 Halogenated alkyl), -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 Halogenated alkyl), -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)2N(C 1-9 alkyl)2 substituted;

[0125] Each R 9a and R 9b Independently H, C 1-6 Alkyl or C1-6 Haloalkyl, or R 9a and R 9b Together they form a 6-membered heterocyclic group;

[0126] Each Z 1 Independently C 1-9 Alkyl, C 1-8 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, 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;

[0127] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1a replace;

[0128] Each Z 1a Independently C 1-9 Alkyl, C 1-8 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, 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;

[0129] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace;

[0130] Each Z 1b Independently C 1-9 Alkyl, C 1-8 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, CO2R 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 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)(heterocyclic), -N(C1-9 Alkyl)(C 6-10 Aryl), -N(C 1-9 alkyl)(heteroaryl), -C(O)(C 1-9 alkyl), -C(O)(C 1-8 Halogenated alkyl), -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 Halogenated alkyl), -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 Halogenated alkyl), -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 Halogenated alkyl)2, -C(O)N(C 2-6 Alkenyl)2, -C(O)N(C 2-6 Alkynyl)2, -C(O)N(C 3-15 Cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C 6-10 Aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C 1-9 alkyl), -NHC(O)(C 1-8 Haloalkyl), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 Alkynyl), -NHC(O)(C 3-15 Cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6-10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1-9alkyl), -NHC(O)O(C 1-8 Halogenated alkyl), -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 Halogenated alkyl), -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 Halogenated alkyl), -S(C 2-6 alkenyl), -S(C 2-6 Alkynyl), -S(C 3-15 Cycloalkyl), -S(heterocyclyl), -S(C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2, -S(O)(C 1-9 alkyl), -S(O)(C 1-8 Halogenated alkyl), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 Alkynyl), -S(O)(C 3-15 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 Halogenated alkyl), -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)2N(C 1-9 Alkyl)2;

[0131] wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl radical is optionally substituted by one to three 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 Halogenated alkyl), -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 Halogenated alkyl), -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)2N(C 1-9 alkyl)2 substituted;

[0132] 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 Independently H, C 1-9 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-15 Cycloalkyl, heterocyclic, C 6-10 aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace; and

[0133] Each R 3e 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, heterocyclic, 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 the alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted by one to four Z 1b substituted; wherein each heteroaryl has 5 to 12 ring members and has one to four heteroatoms each independently being N, O or S; and

[0134] wherein each heterocyclyl has 3 to 12 ring members and has one to four heteroatoms each independently being N, O or S.

[0135] In some embodiments, the compound of the present disclosure is a compound of formula (IA-1):

[0136]

[0137] or a pharmaceutically acceptable salt thereof, wherein

[0138] R 1 C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclic, 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)OR1c ,

[0139] wherein the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are each optionally substituted by one to four Z 1 replace;

[0140] Ring A is C 6-10 aryl or heteroaryl, each of which is optionally substituted by one to four Z 1a replace;

[0141] Ring B is C 6-10 aryl or heteroaryl, each of which is optionally substituted by one to four R 4 replace;

[0142] R 2 H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclic, 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 ,

[0143] wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1 replace;

[0144] X 1 、X 2 and X 3 Each independently represents -N=, -C(H)= or -C(R 8 )=;

[0145] R 3 H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-10 Cycloalkyl, heterocyclic, 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)2NR 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 ) or -B(OR 3a )(OR 3b ), wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four R 3d replace;

[0146] Each R 3a 、R 3b and R 3c Independently H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-8 Alkoxyalkyl, -C 1-4 Alkyl-N(R 9a )(R 9b ),-C 1-4 Alkyl-C(O)N(R9a )(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, heterocyclic, 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);

[0147] wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace,

[0148] Each R 4 Independently C 1-9 Alkyl, C 1-8 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, 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(R4a )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;

[0149] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace;

[0150] or two R attached to adjacent ring atoms 4 The groups combine with the atoms to which they are attached to form C 5-10 Cycloalkyl or heterocyclic group, the cycloalkyl or heterocyclic group is optionally substituted by one to four Z 1b replace;

[0151] R 5a and R 5b Each independently is H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkoxyalkyl, halogen, C 3-10 Cycloalkyl, heterocyclic, -C 1-6 Alkyl-N(R 9a )(R 9b ),-CN,-OR 5a1 or

[0152] -N(R 5a1 )(R 5a2 );

[0153] or R 5a and R 5b Combine with the atoms to which they are attached to form C 3-10 Cycloalkyl or heterocyclic group, the cycloalkyl or heterocyclic group is optionally substituted by one to four R 5a3 replace;

[0154] Each R 5a1 and R 5a2 Independently H, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl,

[0155] C 3-10 Cycloalkyl, heterocyclic, C 6-10 aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four R 5a4 replace;

[0156] V is -C(O)-, -O-, -N(R 6a )-or-C(R 6b )(R 6c )-;

[0157] R 6a H, C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, -S(O)2R 6a1 or -S(O)2N(R 6a1 )(NR 6a2 ), wherein the cycloalkyl or heterocyclyl are each optionally replaced by C 1-6 Alkyl, F or -CN substitution;

[0158] Each R 6b and R 6c Independently H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkoxyalkyl, halogen, C 3-10 Cycloalkyl, heterocyclic, -C 1-6 Alkyl-N(R 9a )(R 9b ),-CN,-OR 6c1 or -N(R 6c2 )(R 6c3 ), wherein the alkyl, cycloalkyl or heterocyclyl groups are each optionally substituted by one to four R 6b1 replace;

[0159] or R 6b and R 6c Combine with the atoms to which they are attached to form C 3-10 Cycloalkyl or heterocyclic group, the cycloalkyl or heterocyclic group is optionally substituted by one to four R 6b1 replace;

[0160] or R 6a or R 6c With an R 4 The groups and the atoms to which they are attached combine to form C 5-10 Cycloalkyl or heterocyclic group, the cycloalkyl or heterocyclic group is optionally substituted by one to four R 10 replace;

[0161] Y is -N(R 7 )-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NH)- or -S(O)(=NR 7 )-;

[0162] Each R 1a 、R 3d 、R 5a3 、R 5a4 、R 6b1 and R 10 Independently C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen,

[0163] C 3-10 Cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, CO2R 3e 、

[0164] -NO2 or -C(O)N(R 2a )(R 2b ),

[0165] wherein the heterocyclic or heteroaryl group is optionally replaced by C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 haloalkoxy substituted; and

[0166] Each R 6a1 、R 6a2 、R 6c1 、R 6c2 、R 6c3 and R 7 Independently H, C 1-6 Alkyl or C 3-10 Cycloalkyl;

[0167] Each R 8 Independently C 1-9 Alkyl, C 1-8 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, CO2R 3e , -NO2, -NH2, -N3, -SH, -O(C 1-9alkyl), -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 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)(heterocyclic), -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 Halogenated alkyl), -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 Halogenated alkyl), -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 aryl), -C(O)O(heteroaryl), -C(O)NH2, -C(O)NH(C 1-9 alkyl), -C(O)NH(C 1-8 Halogenated alkyl), -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 Halogenated alkyl)2, -C(O)N(C 2-6 Alkenyl)2, -C(O)N(C 2-6 Alkynyl)2, -C(O)N(C 3-15 Cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C 6-10 Aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C 1-9 alkyl), -NHC(O)(C 1-8 Haloalkyl), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 Alkynyl), -NHC(O)(C 3-15 Cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6-10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 1-8 Halogenated alkyl), -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 Halogenated alkyl), -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)(C1-9 Alkyl), -N(C 1-9 Alkyl)(S(O)(C 1-9 Alkyl), -S(C 1-9 Alkyl), -S(C 1-8 Halogenated alkyl), -S(C 2-6 alkenyl), -S(C 2-6 Alkynyl), -S(C 3-15 Cycloalkyl), -S(heterocyclyl), -S(C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2, -S(O)(C 1-9 alkyl), -S(O)(C 1-8 Halogenated alkyl), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 Alkynyl), -S(O)(C 3-15 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 Halogenated alkyl), -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)2N(C 1-9 Alkyl)2;

[0168] wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl radical is optionally substituted by one to three 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 3-15Cycloalkyl)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 Halogenated alkyl), -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 Halogenated alkyl), -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)2N(C 1-9 alkyl)2 substituted;

[0169] Each R 9a and R 9b Independently H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0170] Each Z 1 Independently C 1-9 Alkyl, C 1-8 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, 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(R12a )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;

[0171] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1a replace;

[0172] Each Z 1a Independently C 1-9 Alkyl, C 1-8 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, 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;

[0173] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace;

[0174] Each Z 1b Independently C 1-9 Alkyl, C 1-8 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, CO2R 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 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)(heterocyclic), -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 Halogenated alkyl), -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 Halogenated alkyl), -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 Halogenated alkyl), -C(O)NH(C 2-6alkenyl), -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 Halogenated alkyl)2, -C(O)N(C 2-6 Alkenyl)2, -C(O)N(C 2-6 Alkynyl)2, -C(O)N(C 3-15 Cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C 6-10 Aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C 1-9 alkyl), -NHC(O)(C 1-8 Haloalkyl), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 Alkynyl), -NHC(O)(C 3-15 Cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6-10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 1-8 Halogenated alkyl), -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 Halogenated alkyl), -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 Halogenated alkyl), -S(C2-6 alkenyl), -S(C 2-6 Alkynyl), -S(C 3-15 Cycloalkyl), -S(heterocyclyl), -S(C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2, -S(O)(C 1-9 alkyl), -S(O)(C 1-8 Halogenated alkyl), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 Alkynyl), -S(O)(C 3-15 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 Halogenated alkyl), -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)2N(C 1-9 Alkyl)2;

[0175] wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl radical is optionally substituted by one to three 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(C1-9 alkyl), -NHC(O)O(C 1-8 Halogenated alkyl), -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 Halogenated alkyl), -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)2N(C 1-9 alkyl)2 substituted;

[0176] 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 Independently H, C 1-9 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-15 Cycloalkyl, heterocyclic, C 6-10 aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace; and

[0177] Each R 3e 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 1-4Alkyl, -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, heterocyclic, C 6-10 Aryl, heteroaryl, -P(O)(OR 9c )2、-CH2P(O)(OR 9c )2、-OCH2P(O)(OR 9c )2.

[0178] -C(O)OCH2P(O)(OR 9c )2、-P(O)(R 9c )(OR 9d ),-OP(O)(R 9c )(OR 9d ),

[0179] -CH2P(O)(R 9c )(OR 9d )、-C(O)OCH2P(O)(R 9c )(OR 9d ),

[0180] -P(O)(N(R 9c )2)2、-CH2P(O)(N(R 9c )2)2、-C(O)OCH2P(O)(N(R 9c )2)2、

[0181] -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)

[0182] -CH2P(O)(R 9c )(N(R 9d )2) or -C(O)OCH2P(O)(R 9c )(N(R 9d )2); wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted by one to four Z1b substituted; wherein each heteroaryl has 5 to 12 ring members and has one to four heteroatoms each independently being N, O or S; and

[0183] wherein each heterocyclyl has 3 to 12 ring members and has one to four heteroatoms each independently being N, O or S.

[0184] In some embodiments, the compounds of the present disclosure are compounds of formula (I):

[0185]

[0186] or a pharmaceutically acceptable salt thereof, wherein

[0187] R 1 C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclic, 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 ,

[0188] wherein the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are each optionally substituted by one to four Z 1 replace;

[0189] Ring A is C 6-10 aryl or heteroaryl, each of which is optionally substituted by one to four Z 1a replace;

[0190] Ring B is C 6-10 aryl or heteroaryl, each of which is optionally substituted by one to four R 4 replace;

[0191] R 2 H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclic, 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 ,

[0192] wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1 replace;

[0193] X 1 、X 2 and X 3 Each independently represents -N=, -C(H)= or -C(R 8 )=;

[0194] R 3 H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-10 Cycloalkyl, heterocyclic, 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)2NR 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 ) or -B(OR 3a )(OR 3b ), wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four R 3d replace;

[0195] Each R 3a 、R 3b and R 3c Independently H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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, heterocyclic, 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);

[0196] wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z1b replace;

[0197] Each R 4 Independently C 1-9 Alkyl, C 1-8 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, 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;

[0198] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace;

[0199] or two R attached to adjacent ring atoms 4 The groups combine with the atoms to which they are attached to form C 5-10 Cycloalkyl or heterocyclic group, the cycloalkyl or heterocyclic group is optionally substituted by one to four Z 1b replace;

[0200] R 5a and R 5b Each independently is H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkoxyalkyl, halogen, C 3-10 Cycloalkyl, heterocyclyl, -CN, -OR 5a1 or -N(R 5a1 )(R 5a2 );

[0201] or R 5a and R 5b Combine with the atoms to which they are attached to form C 3-10 Cycloalkyl or heterocyclic group, the cycloalkyl or heterocyclic group is optionally substituted by one to four R 5a3 replace;

[0202] Each R 5a1 and R 5a2 Independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclic, C 6-10 aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four R 5a4 replace;

[0203] V is -C(O)-, -O-, -N(R 6a )-or-C(R 6b )(R 6c )-;

[0204] R 6a H, C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, -S(O)2R 6a1 or -S(O)2N(R 6a1 )(NR 6a2 ), wherein the cycloalkyl or heterocyclyl are each optionally replaced by C 1-6 Alkyl, F or -CN substitution;

[0205] Each R 6b and R 6c Independently H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkoxyalkyl, halogen, C 3-10 Cycloalkyl, heterocyclyl, -CN, -OR 6c1 or -N(R 6c2 )(R 6c3 ), wherein the alkyl, cycloalkyl or heterocyclyl groups are each optionally substituted by one to four R 6b1 replace;

[0206] or R 6b and R 6c Combine with the atoms to which they are attached to form C 3-10 Cycloalkyl or heterocyclic group, the cycloalkyl or heterocyclic group is optionally substituted by one to four R 6b1 replace;

[0207] or R 6a or R 6c With an R 4 The groups and the atoms to which they are attached combine to form C 5-10 Cycloalkyl or heterocyclic group, the cycloalkyl or heterocyclic group is optionally substituted by one to four R 10 replace;

[0208] Y is -N(R 7 )-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NH)- or -S(O)(=NR 7 )-;

[0209] Each R 1a 、R 3d 、R 5a3 、R 5a4 、R 6b1 and R 10 Independently C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-10 Cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, -NO2 or

[0210] -C(O)N(R 2a )(R 2b), wherein the heterocyclyl or heteroaryl is optionally replaced by C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 haloalkoxy substituted; and

[0211] Each R 6a1 、R 6a2 、R 6c1 、R 6c2 、R 6c3 and R 7 Independently H, C 1-6 Alkyl or C 3-10 Cycloalkyl;

[0212] Each R 9a and R 9b Independently H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0213] Each Z 1 Independently C 1-9 Alkyl, C 1-8 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, 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 12aS(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;

[0214] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1a replace;

[0215] Each Z 1a Independently C 1-9 Alkyl, C 1-8 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, 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(R12b )(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;

[0216] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace;

[0217] Each R 8 or Z 1b Independently C 1-9 Alkyl, C 1-8 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, 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(C2-6 Alkynyl)2, -N(C 3-15 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)(heterocyclic), -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 Halogenated alkyl), -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 Halogenated alkyl), -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 Halogenated alkyl), -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 Halogenated alkyl)2, -C(O)N(C 2-6 Alkenyl)2, -C(O)N(C 2-6 Alkynyl)2, -C(O)N(C 3-15Cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C 6-10 Aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C 1-9 alkyl), -NHC(O)(C 1-8 Haloalkyl), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 Alkynyl), -NHC(O)(C 3-15 Cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6-10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 1-8 Halogenated alkyl), -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 Halogenated alkyl), -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 Halogenated alkyl), -S(C 2-6 alkenyl), -S(C 2-6 Alkynyl), -S(C 3-15 Cycloalkyl), -S(heterocyclyl), -S(C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2, -S(O)(C 1-9 alkyl), -S(O)(C 1-8 Halogenated alkyl), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 Alkynyl), -S(O)(C 3-15Cycloalkyl), -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 Halogenated alkyl), -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)2N(C 1-9 Alkyl)2;

[0218] wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl radical is optionally substituted by one to three 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 Halogenated alkyl), -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 Halogenated alkyl), -S(O)2(C 3-15Cycloalkyl), -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)2N(C 1-9 alkyl)2 substituted;

[0219] and

[0220] 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 Independently H, C 1-9 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-15 Cycloalkyl, heterocyclic, C 6-10 aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace;

[0221] wherein each heteroaryl group has 5 to 12 ring members and has one to four heteroatoms each independently being N, O or S; and

[0222] wherein each heterocyclyl has 3 to 12 ring members and has one to four heteroatoms each independently being N, O or S.

[0223] In some embodiments of the compound of Formula (I), (IA-1), and / or other formulae described herein, or a pharmaceutically acceptable salt thereof,

[0224] R 1 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl having one to three heteroatoms each independently being N, O or S, or 3- to 12-membered heterocyclyl having one to three heteroatoms each independently being N, O or S, wherein the cycloalkyl, aryl, heteroaryl and heterocyclyl are each optionally substituted by one to three Z 1 replace;

[0225] Ring A is C 6-10aryl, 5- to 10-membered heteroaryl having one to three heteroatoms each independently being N, O or S, or 3- to 12-membered heterocyclyl having one to three heteroatoms each independently being N, O or S, wherein the aryl, heteroaryl and heterocyclyl are each optionally substituted by one to four Z 1 replace;

[0226] Ring B is C 6-10 aryl or 5- to 10-membered heteroaryl having one to three heteroatoms each independently being N, O or S, wherein the aryl and heteroaryl are each optionally substituted by one to four R 4 replace;

[0227] R 2 H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 2-6 Alkoxyalkyl, C 3-10 Cycloalkyl, heterocyclic, 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)2NR 2c C(O)R 2a , wherein each heterocyclyl comprises 3 to 12 ring members and 1 to 3 heteroatoms each independently being N, O or S, wherein each heteroaryl comprises 5 to 10 ring members and 1 to 3 heteroatoms each independently being N, O or S, and wherein the cycloalkyl, aryl, heteroaryl and heterocyclyl are each optionally substituted by one to four Z 1b replace;

[0228] X 1 、X 2 and X3 Each independently is -N= or -C(R 8 )=;

[0229] R 3 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 one to three heteroatoms each independently being N, O or S, 5- to 10-membered heteroaryl having one to four heteroatoms each independently being 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 the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is each optionally substituted by one to four R 3d replace;

[0230] Each R 2a 、R 2b 、R2c 、R 3a 、R 3b and R 3c Independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, C 6-10 aryl, 3- to 12-membered heterocyclyl having one to three heteroatoms each independently being N, O or S, or 5- to 10-membered heteroaryl having one to four heteroatoms each independently being N, O or S;

[0231] Each R 4 Independently H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, halogen, C 3-10 Cycloalkyl, 3- to 12-membered heterocyclyl having one to three heteroatoms each independently being N, O or S, oxo, -OH, -CN, -NO2, -N3, C(O)OR 4a or C(O)N(R 4a )(R 4b ), wherein the cycloalkyl and heterocyclyl groups are each optionally substituted by one to four R 4c replace;

[0232] Each R 4a and R 4b Independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, C 6-10 aryl, 3- to 12-membered heterocyclyl having one to three heteroatoms each independently being N, O or S, or 5- to 10-membered heteroaryl having one to four heteroatoms each independently being N, O or S;

[0233] Alternatively, two R attached to adjacent ring atoms 4 The groups combine with the atoms to which they are attached to form C 3-10 Cycloalkyl or 3 to 12 membered heterocyclyl having one to three heteroatoms each independently being N, O or S, wherein the cycloalkyl and heterocyclyl are each optionally substituted by one to four R 4c replace;

[0234] R 5a and R 5b Each independently is H, C 1-6 Alkyl, halogen, C 3-10Cycloalkyl, 3- to 12-membered heterocyclyl having one to three heteroatoms each independently being N, O or S, -CN,

[0235] -OR 5a1 or -N(R 5a1 )(R 5a2 ), wherein the cycloalkyl and heterocyclyl groups are each optionally substituted by one to four R 5a3 replace;

[0236] Each R 5a1 、R 5a1 and R 5a2 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 one to three heteroatoms each independently being N, O or S, or 5 to 10 membered heteroaryl having one to three heteroatoms each independently being N, O or S, wherein the cycloalkyl, aryl, heteroaryl and heterocyclyl are each optionally substituted by one to four R 5a4 replace;

[0237] V is -C(O)-, -O-, -N(R 6a )-、-C(R 6b )(R 6c )-;

[0238] R 6a H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3- to 12-membered heterocyclic group having one to three heteroatoms each independently being N, O or S, -S(O)2R 6a1 or -S(O)2N(R 6a1 )(NR 6a2 ), wherein the cycloalkyl and heterocyclyl are each optionally replaced by F, CN or C 1-6 Alkyl substitution;

[0239] Each R 6b and R 6c are independently H, halogen, -CN, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3- to 12-membered heterocyclyl having one to three heteroatoms each independently being N, O or S, -OR 6c1 or -N(R 6c2 )(R 6c3 ), wherein the alkyl, cycloalkyl and heterocyclyl groups are each optionally substituted by one to four R 6b1 replace;

[0240] Alternatively, R 6band R 6c Combine with the atoms to which they are attached to form C 3-10 Cycloalkyl, the cycloalkyl group is optionally substituted by one to four R 6b1 replace;

[0241] Alternatively, R 6c With an R 4 The groups and the atoms to which they are attached combine to form C 3-10 Cycloalkyl or 3 to 12 membered heterocyclyl having one to three heteroatoms each independently being N, O or S, wherein the cycloalkyl and heterocyclyl are each optionally substituted by one to four R 4c replace;

[0242] Y is -N(R 7 )-, -O-, -S-, -S(O)-, -S(=NH)- or -S(=NR 7 )-;

[0243] Each R 8 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 one to three heteroatoms each independently being N, O or S, or 5- to 10-membered heteroaryl having one to four heteroatoms each independently being 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 )NR3b 、-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 );

[0244] Each Z 1b 、R 3d 、R 4c 、R 5a3 、R 5a4 and R 6b1 Independently C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, halogen, C 3-10 Cycloalkyl, 3- to 12-membered heterocyclyl having one to three heteroatoms each independently being N, O, or S, 5- to 10-membered heteroaryl having one to three heteroatoms each independently being N, O, or S, oxo, -OH, -CN, or -NO2; and

[0245] Each R 6a1 、R 6a2 、R 6c1 、R 6c2 、R 6c3 and R 7 Independently C 1-6 Alkyl or C 3-10 Cycloalkyl.

[0246] In some embodiments of compounds of Formula (I), (IA-1), and / or other formulae described herein, or pharmaceutically acceptable salts thereof, R 1 C 6-10 aryl, heteroaryl or heterocyclic group, wherein the aryl, heteroaryl or heterocyclic group is optionally substituted by one to three Z 1 In some embodiments of the compound of Formula (I), (IA-1), and / or other formulae described herein, or a pharmaceutically acceptable salt thereof, R 1 C 6-10 aryl, heteroaryl or heterocyclic group, wherein the aryl, heteroaryl or heterocyclic group is optionally substituted by one to three R 1a In some embodiments of the compound of Formula (I), (IA-1), and / or other formulae described herein, or a pharmaceutically acceptable salt thereof, R 1 C 6-10aryl, 5- to 10-membered heteroaryl having one to three heteroatoms each independently being O, N or S, or 4- to 12-membered heterocyclyl having one to three heteroatoms each independently being O, N or S, wherein the aryl, heteroaryl or heterocyclyl is optionally substituted by one to three R 1a In some embodiments of compounds of Formula (I), (IA-1), and / or other formulae described herein, R 1 is a heterocyclic group, C 6-10 aryl or 6-membered heteroaryl, the heterocyclic group, aryl or heteroaryl each optionally substituted by one to three Z 1 Substituted, where Z 1 Independently C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, oxo, -OH, -CN, or -NO2, C 3-10 cycloalkyl, 3- to 12-membered heterocyclyl having one to three heteroatoms, or 5- to 10-membered heteroaryl having one to three heteroatoms.

[0247] In some embodiments of compounds of Formula (I), (IA-1), and / or other formulae described herein, or pharmaceutically acceptable salts thereof, each R 5a and R 5b 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 H, C 1-6 Alkyl, F, Cl, -OR 5a1 、-CN、C 3-10 In some embodiments, each R 5a and R 5b For H.

[0248] In some embodiments of the compound of Formula (I), (IA-1), and / or other formulae described herein, or a pharmaceutically acceptable salt thereof, Y is -O-.

[0249] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof has the structure of Formula (Ia):

[0250]

[0251] where the subscript p is 1, 2, or 3.

[0252] 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 6-10 aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one to three Z 1a Substitute, where 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 Halogenated alkyl, 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 substituted by Z 1b 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 6-10 aryl or 5- to 10-membered heteroaryl having one to three heteroatoms each independently being O, N or S, wherein the aryl or heteroaryl is optionally substituted by one to three Z 1a In some embodiments of the compound of Formula (I), (IA-1), (Ia), and / or other formulae described herein, or a pharmaceutically acceptable salt thereof, Ring A is phenyl or a 5- to 6-membered heteroaryl group, wherein the phenyl or heteroaryl group is optionally substituted with one to three Z 1a In some embodiments of the compounds of Formula (I), (IA-1), (IA-2) and / or (Ia), or pharmaceutically acceptable salts thereof, Ring A is phenyl or a 5- to 6-membered heteroaryl group having one to three heteroatoms each independently being O, N, or S, wherein the phenyl or heteroaryl group is optionally substituted with one to three Z 1a 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

[0253]

[0254] wherein each ring is optionally substituted by one or two Z 1a replace.

[0255] 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

[0256]

[0257] wherein each ring is optionally substituted by one or two Z 1a replace.

[0258] In some embodiments of the compounds of Formula (I), (IA-1), (IA-2) and / or (Ia), or pharmaceutically acceptable salts thereof, Ring A is

[0259]

[0260] wherein each ring is optionally substituted with one or two halogens.

[0261] 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):

[0262]

[0263] where Z 1a Halogen, C 1-4 Alkyl, -OR 12a or -CN, where the C 1-4 The alkyl group is optionally replaced by Z 1b replace.

[0264] subscript p is 1, 2, or 3; and

[0265] The subscript q is 0, 1, or 2.

[0266] 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):

[0267]

[0268] in

[0269] subscript p is 1, 2, or 3; and

[0270] The subscript q is 0, 1, or 2.

[0271] 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 phenyl or a 5- to 6-membered heteroaryl group, wherein the phenyl or heteroaryl group is optionally substituted by one to four R 4 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 phenyl or a 5- to 6-membered heteroaryl group having one to three heteroatoms each independently being O, N, or S, wherein the phenyl or heteroaryl group is optionally substituted by one to four R 4 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

[0272]

[0273] These groups are each optionally replaced by one or two R 4 replace.

[0274] 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

[0275]

[0276] These groups are each optionally replaced by one or two R 4 replace.

[0277] 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

[0278]

[0279] The group is optionally replaced by one or two R 4 replace.

[0280] In some embodiments of compounds of Formula (I), (IA-1), and / or other formulae described herein, or pharmaceutically acceptable salts thereof, Ring B is substituted with one, two, or three halogens. In some embodiments of compounds of Formula (I), (IA-1), and / or other formulae described herein, or pharmaceutically acceptable salts thereof, Ring B is substituted with one, two, or three fluorines.

[0281] In some embodiments, the compound of Formula (I), (IA-1) and / or (Ia) and / or other formulae described herein, or a pharmaceutically acceptable salt thereof, has the formula:

[0282]

[0283] in

[0284] X A and X B Each independently represents -CH= or -N=;

[0285] subscript n is 0, 1, 2, or 3; and

[0286] The subscript p is 1, 2, or 3.

[0287] In some embodiments of 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 Each is independently -N=, -CH=, -C(F)=, -C(Cl)=, -C(Br)=, or -C(CN)=. In some embodiments of the compound of Formula (I), (IA-1), and / or other formulae described herein, or a pharmaceutically acceptable salt thereof, X 1 、X 2 and X 3 Each is independently -CH=, -C(F)=, -C(Cl)=, -C(Br)=, or -C(CN)=. In some embodiments of the compound of Formula (I), (IA-1), and / or other formulae described herein, or a pharmaceutically acceptable salt thereof, X 1 、X 2 and X 3 Each is independently -N=, -CH= or -C(F)=. In some embodiments, X 1 、X 2 and X 3 Two of them are -CH= and one is -N=. For example, X 1 Can be -N=, and X 2 and X 3 Each is -CH=. In some embodiments of the compound of Formula (I), (IA-1) and / or other formulae described herein, or a pharmaceutically acceptable salt thereof, X 1 、X 2 and X 3 In some embodiments, X 1 、X 2 and X 3 Each is -CH=.

[0288] In some embodiments of the compounds of Formula (I), (IA-1), (IA-2), (Ia), (Ib), (Ib-1) and / or (Ic), or pharmaceutically acceptable salts thereof, V is -O-, -NH-, or -CH2-.

[0289] In some embodiments of compounds of Formula (I), (IA-1), and / or other formulae described herein, or pharmaceutically acceptable salts thereof, V is -O-. In some embodiments, V is -CH2. In some embodiments of compounds of Formula (I), (IAI), (IA-2), and / or other formulae described herein, V is -CH2-, -CH(CH3)-, or -C(CH3)2-. In some embodiments, V is -CH2.

[0290] 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:

[0291]

[0292] in

[0293] X A and X B Each independently represents -CH= or -N=;

[0294] subscript n is 0, 1, 2, or 3; and

[0295] The subscript p is 1, 2, or 3.

[0296] In some embodiments of compounds of Formula (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, subscript n is 0, 1, or 2. In some embodiments, subscript n is 0. In some embodiments of compounds of Formula (I) or other compounds described herein, subscript n is 1. In some embodiments, subscript n is 2.

[0297] In some embodiments of compounds of Formula (Ia), (Ib), (Ib-1), (Ic), and / or (Id), or pharmaceutically acceptable salts thereof, subscript p is 1 or 2. In some embodiments, subscript p is 1. In some embodiments of compounds of Formula (I) or other compounds described herein, subscript p is 2.

[0298] In some embodiments of the compound of Formula (Ib) and / or (Ib-1), or a pharmaceutically acceptable salt thereof, subscript q is 0 or 1. In some embodiments, subscript q is 0. In some embodiments, subscript q is 1.

[0299] In some embodiments of the compound of Formula (Ic) and / or (Id) or a pharmaceutically acceptable salt thereof, X A and X B One of them is -CH= and the other is -N=. In some embodiments, X A =-N, X B In some embodiments, X A -CH=, X B is -N=.

[0300] 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 C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, C 3-10 cycloalkyl, 3- to 12-membered heterocyclyl having one to three heteroatoms each independently being N, O, or S, 5- to 10-membered heteroaryl having one to three heteroatoms each independently being N, O, or S, oxo, -OH, -CN, or -NO. 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 Halogenated alkyl, 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 Halogenated alkyl, C 1-6 haloalkoxy, -CN, or a 5- to 6-membered heteroaryl group having one to three heteroatoms each independently being 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 pharmaceutically acceptable salts thereof, each Z 1 Independently C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C2-6 Alkynyl, halogen, C 3-10 Cycloalkyl, heterocyclic, 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 is each optionally substituted by one to four halogen, -CN, C 1-6 Halogenated alkyl, C 3-6 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 Halogenated alkyl, C 1-6 haloalkoxy, halogen, 5- to 6-membered heteroaryl having one to three heteroatoms each independently being N, O, or S, or -CN. In some embodiments, each Z 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 Halogenated alkyl, 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 Halogenated alkyl, 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 Independently F, C 1-6Haloalkyl, -CN 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 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 such as F.

[0301] In some embodiments, the compound of Formula (I), (IA-1), and / or other formulae described herein, or a pharmaceutically acceptable salt thereof, has Formula (IA-2):

[0302]

[0303] in

[0304] U is -CH= or -N=;

[0305] X B is -CH= or -N=;

[0306] R B C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, halogen or -CN;

[0307] X 1 and X 2 Each independently represents -N=, -C(H)= or -C(R 8 )=;

[0308] X 3 is -C(H)=;

[0309] Each R 4 Independently C 1-9 Alkyl, C 1-8 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, C 6-10Aryl, 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;

[0310] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace;

[0311] or two R attached to adjacent ring atoms 4 The groups combine with the atoms to which they are attached to form C 5-10 Cycloalkyl or heterocyclic group, the cycloalkyl or heterocyclic group is optionally substituted by one to four Z 1b replace;

[0312] V is -C(O)-, -O-, -N(R 6a )-or-C(R 6b )(R 6c )-;

[0313] R 6aH, C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, -S(O)2R 6a1 or -S(O)2N(R 6a1 )(NR 6a2 ), wherein the cycloalkyl or heterocyclyl are each optionally replaced by C 1-6 Alkyl, F or -CN substitution;

[0314] Each R 6b and R 6c are independently H or C 1-6 alkyl;

[0315] Each R 1a 、R 3d 、R 5a3 、R 5a4 and R 10 Independently C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-10 Cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, CO2R 3e 、-NO2 or -C(O)N(R 2a )(R 2b ), wherein the heterocyclyl or heteroaryl is optionally replaced by C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 haloalkoxy substituted; and

[0316] Each R 6a1 、R 6a2 、R 6c1 、R 6c2 、R 6c3 and R 7 Independently H, C 1-6 Alkyl or C 3-10 Cycloalkyl;

[0317] Each R 8 Independently C 1-9 Alkyl, C 1-8 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, CO2R 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 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)(heterocyclic), -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 Halogenated alkyl), -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 Halogenated alkyl), -C(O)O(C 2-6 alkenyl), -C(O)O(C 2-6 Alkynyl), -C(O)O(C3-15 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 Halogenated alkyl), -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 Halogenated alkyl)2, -C(O)N(C 2-6 Alkenyl)2, -C(O)N(C 2-6 Alkynyl)2, -C(O)N(C 3-15 Cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C 6-10 Aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C 1-9 alkyl), -NHC(O)(C 1-8 Haloalkyl), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 Alkynyl), -NHC(O)(C 3-15 Cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6-10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 1-8 Halogenated alkyl), -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 Halogenated alkyl), -NHC(O)NH(C 2-6 alkenyl), -NHC(O)NH(C 2-6 Alkynyl), -NHC(O)NH(C 3-15 Cycloalkyl), -NHC(O)NH(heterocyclyl), -NHC(O)NH(C6-10 aryl), -NHC(O)NH(heteroaryl), -NHS(O)(C 1-9 Alkyl), -N(C 1-9 Alkyl)(S(O)(C 1-9 Alkyl), -S(C 1-9 Alkyl), -S(C 1-8 Halogenated alkyl), -S(C 2-6 alkenyl), -S(C 2-6 Alkynyl), -S(C 3-15 Cycloalkyl), -S(heterocyclyl), -S(C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2, -S(O)(C 1-9 alkyl), -S(O)(C 1-8 Halogenated alkyl), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 Alkynyl), -S(O)(C 3-15 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 Halogenated alkyl), -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)2N(C 1-9 Alkyl)2;

[0318] wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl radical is optionally substituted by one to three 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(C1-9 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 Halogenated alkyl), -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 Halogenated alkyl), -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)2N(C 1-9 alkyl)2 substituted;

[0319] Each R 9a and R 9b Independently H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0320] Each Z 1 Independently C 1-9 Alkyl, C 1-8 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, 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;

[0321] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1a replace;

[0322] Each Z 1a Independently C 1-9 Alkyl, C 1-8 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, 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;

[0323] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace;

[0324] Each Z 1b Independently C 1-9 Alkyl, C 1-8 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, CO2R 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 3-15Cycloalkyl), -O(heterocyclyl), -O(C 6-10 aryl), -O(heteroaryl), -NH(C 1-9 Alkyl), -NH(C 1-8 Haloalkyl), -NH(C 2-6 alkenyl), -NH(C 2-6 Alkynyl), -NH(C 3-15 Cycloalkyl), -NH(heterocyclyl), -NH(C 6-10 aryl), -NH(heteroaryl), -N(C 1-9 Alkyl)2, -N(C 1-8 Haloalkyl)2, -N(C 2-6 Alkenyl)2, -N(C 2-6 Alkynyl)2, -N(C 3-15 Cycloalkyl)2, -N(heterocyclyl)2, -N(C 6-10 aryl)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)(heterocyclic), -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 Halogenated alkyl), -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 Halogenated alkyl), -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 1-8Halogenated alkyl), -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 Halogenated alkyl)2, -C(O)N(C 2-6 Alkenyl)2, -C(O)N(C 2-6 Alkynyl)2, -C(O)N(C 3-15 Cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C 6-10 Aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C 1-9 alkyl), -NHC(O)(C 1-8 Haloalkyl), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 Alkynyl), -NHC(O)(C 3-15 Cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6-10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 1-8 Halogenated alkyl), -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 Halogenated alkyl), -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 Halogenated alkyl), -S(C 2-6 alkenyl), -S(C 2-6 Alkynyl), -S(C 3-15 Cycloalkyl), -S(heterocyclyl), -S(C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2, -S(O)(C 1-9 alkyl), -S(O)(C 1-8 Halogenated alkyl), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 Alkynyl), -S(O)(C 3-15 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 Halogenated alkyl), -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)2N(C 1-9 Alkyl)2;

[0325] wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl radical is optionally substituted by one to three 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 Halogenated alkyl), -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 Halogenated alkyl), -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)2N(C 1-9 alkyl)2 substituted;

[0326] 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 Independently H, C 1-9 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-15 Cycloalkyl, heterocyclic, C 6-10 aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace; and

[0327] Each R 3e 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)-C1-4 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, heterocyclic, 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 the alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted by one to four Z 1b substituted; wherein each heteroaryl has 5 to 12 ring members and has one to four heteroatoms each independently being N, O or S; and

[0328] wherein, unless otherwise specified, each heterocyclyl has 3 to 12 ring members and has one to four heteroatoms each independently being N, O, or S; and

[0329] m is 0, 1 or 2.

[0330] 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 H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, 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)2NR 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, heterocyclic, C 1-6 Alkyl-heterocyclyl, heteroaryl or C 1-6 Alkyl-heteroaryl, wherein the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are each optionally substituted by 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 H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, heterocyclic, 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)2NR 2c C(O)R 2a , wherein the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are each optionally substituted by one to four 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 H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclic, 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 )(R2b ),-C(O)NR 2c S(O)2R 2a 、-S(O)2R 2a 、-S(O)2N(R 2a )(R 2b ) or -S(O)2NR 2c C(O)R 2a , wherein the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are each optionally substituted by one to four Z 1b Substitute, where each Z 1b Independently C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-10 Cycloalkyl, heterocyclic, 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 H, C 1-6 Alkyl, C 2-6 Alkoxyalkyl, C 3-10 Cycloalkyl, C 1-6 Alkyl-C 3-10 Cycloalkyl, heterocyclic, C 1-6 Alkyl-heterocyclyl, heteroaryl or C 1-6 Alkyl-heteroaryl, wherein each heterocyclyl comprises 3 to 12 ring members and 1 to 3 heteroatoms each independently being N, O or S, wherein each heteroaryl comprises 5 to 10 ring members and 1 to 3 heteroatoms each independently being N, O or S, wherein the cycloalkyl, heterocyclyl and heteroaryl are each optionally substituted by one to four 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 C 1-6 Alkyl, C2-6 Alkoxyalkyl, C 3-10 Cycloalkyl, C 1-6 Alkyl-C 3-10 Cycloalkyl, C 1-6 Alkyl-heteroaryl or C 1-6 Alkyl-heterocyclyl, wherein each heterocyclyl comprises 3 to 12 ring members and 1 to 3 heteroatoms each independently being N, O or S, wherein each heteroaryl comprises 5 to 10 ring members and 1 to 3 heteroatoms each independently being N, O or S, and wherein the cycloalkyl, heterocyclyl and heteroaryl are each optionally substituted by 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 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, heterocyclic, C 1-6 Alkyl-heterocyclyl, heteroaryl or C 1-6 Alkyl-heteroaryl, each of which is optionally substituted by one to four 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 C 1-6 Alkyl-C 3-10 Cycloalkyl or C 1-6 Alkyl-C 3-10 Cycloalkyl-C 1-6 Alkyl, these groups are optionally replaced by one to four Z 1b replace.

[0331] 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 C 1-6 Alkyl, which is optionally substituted by one to four Z 1b In some embodiments of compounds of Formula (IA-1), (IA-2), (I), and / or other formulae described herein, R 2 C 3-10Cycloalkyl or heterocyclyl, each of which is optionally substituted by one to four Z 1b In some embodiments of compounds of Formula (IA-1), (IA-2), (I), and / or other formulae described herein, R 2 C 1-6 Alkyl-heterocyclyl-C 1-6 Alkyl or C 1-6 Alkyl-heterocyclyl, each of which is optionally substituted by one to four Z 1b replace.

[0332] In some embodiments of compounds of Formula (IA-1), (IA-2), (I), and / or other formulae described herein,

[0333] R 2 for

[0334]

[0335] In some embodiments of compounds of Formula (IA-1), (IA-2), and / or other formulae described herein, or pharmaceutically acceptable salts thereof,

[0336] R 1 is a heterocyclic group, C 6-10 aryl or 6-membered heteroaryl, each of which is optionally substituted by one to three C 1-6 Haloalkyl, halogen or -CN substitution;

[0337] R B is methyl, halogen, -CN or -OCH3;

[0338] R 2 for

[0339] R 3 -C(O)R 3a ;

[0340] R 3a 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 1-4Alkyl-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 one to four halogens;

[0341] Each R 4 are independently F, oxo or -CN;

[0342] R 5a and R 5b Each is H; and

[0343] Y is -O-; and

[0344] Each R 8 are independently H or halogen;

[0345] Each R 9a 、R 9b and R 9c are independently H or C 1-6 alkyl;

[0346] m is 0 or 1; and

[0347] n is 1 or 2.

[0348] 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)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)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 )、-B(OR 3a )(OR 3b ) or a 5- to 10-membered heteroaryl group having one to four heteroatoms each independently being 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 pharmaceutically acceptable salts thereof, R 3 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 , wherein the heteroaryl group is optionally substituted by one to four 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)2NR 3b R 3c or heteroaryl, wherein the heteroaryl is optionally substituted by one to four 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 is a 5- to 6-membered heteroaryl group, which is optionally substituted by one to four R 3d In some embodiments, R 3 -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 It is -C(O)OH.

[0349] In some embodiments of the compound of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id), or a pharmaceutically acceptable salt thereof,

[0350] R 3 for

[0351]

[0352]

[0353] 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 H, C 1-4 Alkyl-N(R 9a )(R 9b ),-C 1-4 Alkyl-N(R 9a )C(O)-OC 1-4 Alkyl-OP(O)(OR 9c )2、C 1-4 Alkyl-C(O)N(R 9a )(R 9b ),-C 1-4 Alkyl-OC(O)-C 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-OC 1-4 Alkyl, -C1-4 alkyl - O - C(O) - C 1-4 alkyl - N(R 9a )(R 9b )、 - C 1-4 alkyl - O - C(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)(R9c )(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, wherein the alkyl or heterocyclyl are each optionally substituted with one to four halogens.

[0354] 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 For H, -Br,

[0355]

[0356] 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 Independently H, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-10 Cycloalkyl.

[0357] 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 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclic, 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, C 2-6 Alkoxyalkyl, C 1-6 Alkoxy, C 1-6In 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, two R attached to adjacent ring atoms are 4 The groups combine with the atoms to which they are attached to form 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 R 4 Independently C 1-6 Alkyl, halogen, oxo, -CN or -OR 4 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 are independently F, oxo or -CN.

[0358] 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 Independently H, C 1-6 Alkyl, F, Cl, C 3-10 Cycloalkyl, 3- to 12-membered heterocyclyl having one to three heteroatoms each independently being O, N or S, or -CN.

[0359] In some embodiments of the compounds of Formula (IA-1), (IA-2) and / or (I), or pharmaceutically acceptable salts thereof, R 6a H, C 1-6 Alkyl, C 3-10 In some embodiments, R 6a H, C 1-6 Alkyl, C 3-10 Cycloalkyl or a 3- to 12-membered heterocyclyl having one to three heteroatoms each independently being O, N or S.

[0360] 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.

[0361] In some embodiments of the compounds of Formula (IA-1), (IA-2) and / or (I), or pharmaceutically acceptable salts thereof, R 6c With an R 4 The groups and the atoms to which they are attached combine to form C 3-10 Cycloalkyl or 3 to 12 membered heterocyclyl having one to three heteroatoms each independently being N, O or S, wherein the cycloalkyl and heterocyclyl are each optionally substituted by one to four R 4c replace.

[0362] 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 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, 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 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 1-9Alkyl)(C 2-6 Alkynyl), -N(C 1-9 Alkyl)(C 3-15 Cycloalkyl), -N(C 1-9 alkyl)(heterocyclic), -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 Halogenated alkyl), -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 Halogenated alkyl), -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 Halogenated alkyl), -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 Halogenated alkyl)2, -C(O)N(C 2-6 Alkenyl)2, -C(O)N(C 2-6 Alkynyl)2, -C(O)N(C 3-15 Cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C 6-10 Aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C 1-9 alkyl), -NHC(O)(C 1-8 Haloalkyl), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 Alkynyl), -NHC(O)(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 Halogenated alkyl), -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 Halogenated alkyl), -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 Halogenated alkyl), -S(C 2-6 alkenyl), -S(C 2-6 Alkynyl), -S(C 3-15 Cycloalkyl), -S(heterocyclyl), -S(C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2, -S(O)(C 1-9 alkyl), -S(O)(C 1-8 Halogenated alkyl), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 Alkynyl), -S(O)(C 3-15 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 Halogenated alkyl), -S(O)2(C 2-6 alkenyl), -S(O)2(C 2-6 Alkynyl), -S(O)2(C 3-15Cycloalkyl), -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)2N(C 1-9 In some embodiments, each R 8 Independently C 1-9 Alkyl, C 1-8 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, 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 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)(heterocyclic), -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 Halogenated alkyl), -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 Halogenated alkyl), -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 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, C 6-10 In some embodiments, each R 8 Independently C 1-3 Alkyl, C 1-3 Halogenated alkyl, 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 8 Independently C 1-3 Alkyl, C 1-3 Haloalkyl, halogen, C 3-7 In some embodiments, each R 8 Independently C 1-3 Alkyl, C 1-3 Haloalkyl, halogen, C 3-7 In the compounds of formula (I), (IA-1) and / or (IA-2) or pharmaceutically acceptable salts thereof, R 8 C 1-9 Alkyl, halogen or -O(C 1-9In 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 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, 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 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)(heterocyclic), -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 Halogenated alkyl), -C(O)(C2-6 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 Halogenated alkyl), -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 Halogenated alkyl), -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 Halogenated alkyl)2, -C(O)N(C 2-6 Alkenyl)2, -C(O)N(C 2-6 Alkynyl)2, -C(O)N(C 3-15 Cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C 6-10 Aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C 1-9 alkyl), -NHC(O)(C 1-8 Haloalkyl), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 Alkynyl), -NHC(O)(C 3-15 Cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6-10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 1-8 Halogenated alkyl), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C 2-6 Alkynyl), -NHC(O)O(C 3-15Cycloalkyl), -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 Halogenated alkyl), -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 Halogenated alkyl), -S(C 2-6 alkenyl), -S(C 2-6 Alkynyl), -S(C 3-15 Cycloalkyl), -S(heterocyclyl), -S(C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2, -S(O)(C 1-9 alkyl), -S(O)(C 1-8 Halogenated alkyl), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 Alkynyl), -S(O)(C 3-15 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 Halogenated alkyl), -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)2N(C 1-9In 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 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, 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 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)(heterocyclic), -N(C 1-9 Alkyl)(C 6-10 Aryl), -N(C 1-9 alkyl)(heteroaryl), -C(O)(C 1-9 alkyl), -C(O)(C 1-8Halogenated alkyl), -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 Halogenated alkyl), -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 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 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, C 6-10 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 1-3 Alkyl, C 1-3 Halogenated alkyl, 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 C1-3 Alkyl, C 1-3 Haloalkyl, halogen, C 3-7 Cycloalkyl, oxo or -CN.

[0363] 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:

[0364]

[0365]

[0366]

[0367]

[0368]

[0369] In some embodiments, the compounds of the present disclosure have the following structure:

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432] In some embodiments of a compound of Formula (I), (IA-1), or other formulae described herein, the compound has the following structure:

[0433]

[0434] Also disclosed herein are in vivo metabolic products of the compounds described herein, to the extent such products are novel and not significantly superior to the prior art. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, primarily due to enzymatic processes. Thus, novel and nonobvious compounds are produced by a method comprising contacting the compound with a mammal for a period of time sufficient to produce its metabolic products. Such products are typically prepared by radiolabeling (e.g., 14 C or 3 H) is identified by administering a radiolabeled compound to an animal, such as a rat, mouse, guinea pig, monkey or human, parenterally at a detectable dose (e.g., greater than about 0.5 mg / kg), allowing sufficient time for metabolism (usually about 30 seconds to 30 hours), and isolating its conversion products from urine, blood or other biological samples. These products can be easily separated due to being labeled (other products are separated by using antibodies that can bind to epitopes that survive in metabolites). The structure of the metabolite is determined in a conventional manner, for example, by MS or NMR analysis. In general, the analysis of metabolites can be performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. As long as the conversion products are not found in the body in another way, even if they do not have GLP-1R activity themselves, they can be used for diagnostic determination of therapeutic doses of the compound.

[0435] Formulas and methods for determining the stability of compounds in alternative gastrointestinal secretions are known. Compounds are defined herein as being stable in the gastrointestinal tract, wherein less than about 50 mol % of the protecting groups are deprotected in alternative intestinal or gastric fluids after incubation at 37°C for 1 hour. Just because a compound is stable to the gastrointestinal tract does not mean that they cannot be hydrolyzed in vivo. Prodrugs are generally stable in the digestive system, but can be substantially hydrolyzed to the parent drug in the digestive cavity, liver, lungs or other metabolic organs or generally speaking in cells. As used herein, prodrugs are understood to be compounds that are chemically designed to effectively release the parent drug after overcoming the oral delivery biological barrier.

[0436] III. Methods for preparing compounds

[0437] 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.

[0438] Solution 1

[0439]

[0440] Intermediate 1.3 can be assembled by reacting an amine with intermediate 1.1 (wherein X is a halogen and R is an alkyl, alkylaryl, or aryl) in the presence of a suitable base (e.g., DIPEA, KOtBu, etc.) to provide intermediate 1.2; intermediate 1.2 can be converted to intermediate 1.3 using suitable reducing conditions (e.g., H2 and Pd / C, Fe and HCl, etc.).

[0441] Option 2

[0442]

[0443] Compounds of formula (IA-1), (IA-2) and / or formula (I) having the structure of a compound of formula 2.9 can be combined as follows: first, intermediate 2.1 (wherein X is 2.1) is reacted with a suitable base (e.g., DIPEA, KOtBu, etc.) or with a suitable palladium catalyst by metal-mediated cross-coupling. 21 and X 22 Each is a leaving group, for example, a halogen, such as Cl or Br) coupled with a heteroatom-containing intermediate 2.2 (where Y = O, NH or S) to provide intermediate 2.3 (Scheme 2); intermediate 2.4 (where M = Li, MgBr, MgCl or MgI, commercially available or obtained by metalation of the corresponding halide) can be combined with intermediate 2.3 using a suitable palladium catalyst to provide intermediate 2.5; after conversion to acidic intermediate 2.6 using standard conditions (e.g., LiOH, LiI and pyridine, etc.), intermediate 1.3 can be added using standard amide bond forming conditions (e.g., DIPEA and HATU, etc.) to provide intermediate 2.7, which can 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.).

[0444] While Scheme 2 above is illustrated using intermediate 2.1 as the dihalopyridine, any dihalogenated A-ring starting material can be used to obtain analogous compounds of formula (IA-1), (IA-2), and / or formula (I).

[0445] Option 3

[0446]

[0447] 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 combined by first reacting intermediate 3.1 (wherein X 31 is Cl, Br or I) combined with intermediate 1.3 (wherein R = alkyl, alkylaryl or aryl) (Scheme 3); treatment with a suitable acid catalyst (e.g., HCl, AcOH, etc.) can provide intermediate 3.3; -X 31 Halogen metal exchange to -M can be achieved using a suitable reagent (e.g., iPrMgBr, etc.) or by transition metal coupling using a suitable palladium catalyst and metal source (e.g., B2Pin2, Bu6Sn2, etc.) to give 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.).

[0448] Option 4

[0449]

[0450] In some embodiments, compounds of formula 2.9 can be formed by first converting intermediate 2.3 to the metallated variant intermediate 4.1 (Scheme 4) using a suitable palladium catalyst and a metal source (e.g., B2Pin2, Bu6Sn2, etc.); intermediate 4.1 can be coupled with intermediate 3.3 using a suitable palladium catalyst to provide 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.).

[0451] Option 5

[0452]

[0453] Compounds of formula (IA-1), (IA-2) and / or formula (I) having the structure of a compound of formula 5.3 can be combined by first coupling the halogen -X (wherein X is Cl, Br or I) of intermediate 5.1 using a suitable coupling partner and a palladium catalyst to provide intermediate 5.2, which can be converted to the compound of formula 5.3 using standard ester hydrolysis conditions (e.g., LiOH, LiI and pyridine, etc.) (Scheme 5).

[0454] Option 6

[0455]

[0456] Compounds of formula (IA-1), (IA-2) and / or formula (I) having the structure of a compound of formula 6.1 can be obtained by reacting intermediate 2.9 with a sulfonamide under appropriate coupling conditions (e.g., EDC and DMAP, etc.) (Scheme 6).

[0457] Option 7

[0458]

[0459] Compounds of formula (IA-1), (IA-2) and / or formula (I) having the structure of a compound of formula 7.3 can be combined by first coupling the halogen-X of intermediate 7.1 using a suitable coupling partner and a palladium catalyst to provide intermediate 7.2, which can be converted to the compound of formula 7.3 using standard ester hydrolysis conditions (e.g., LiOH, LiI and pyridine, etc.) (Scheme 7).

[0460] Option 8

[0461]

[0462] Compounds of formula (IA-1), (IA-2) and / or formula (I) having the structure of a compound of formula 2.9 can be combined as follows: first, intermediate 3.4 is cross-coupled with intermediate 2.1 using a suitable transition metal catalyst (e.g., palladium, etc.) (Scheme 8); intermediate 8.1 can then be coupled with heteroatom-containing intermediate 2.2 (wherein Y = O, N or S) using a suitable base (e.g., DIPEA, KOtBu, etc.) or using a suitable palladium catalyst through a metal-mediated cross-coupling to obtain 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 a compound of formula 2.9 using standard ester hydrolysis conditions (e.g., LiOH, LiI and pyridine, etc.).

[0463] IV. Pharmaceutical Preparations

[0464] 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.

[0465] In some embodiments of the present disclosure, pharmaceutical compositions comprise a compound of Formula (I), (IA-1) and / or (IA-2), or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, as described more fully below.

[0466] Pharmaceutical compositions comprising 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 routine procedures. Tablets can contain excipients, including glidants, fillers, binders, and the like. Aqueous compositions can be prepared in a sterile form and, when intended for delivery by non-oral administration, can generally be isotonic. In some embodiments, the composition can include 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, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, and the like. In some embodiments, the composition is provided as a solid dosage form, including a solid oral dosage form.

[0467] The composition includes those suitable for various routes of administration (including oral administration). The composition can be present in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical field. Such methods include the following steps: the active ingredient (e.g., a compound of the present disclosure or a pharmaceutically acceptable salt thereof) is associated with one or more pharmaceutically acceptable excipients. The composition can be prepared by uniformly and tightly associating the active ingredient with a liquid excipient or a finely divided solid excipient or both, and then, if necessary, forming the product. Technology and formulations are generally found in "Remington: The Science and Practice of Pharmacy", 21st edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0468] Compositions suitable for oral administration described herein 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.

[0469] Pharmaceutical compositions disclosed herein comprise one or more compounds disclosed herein or pharmaceutically acceptable salts thereof, as well as pharmaceutically acceptable excipients and optional other therapeutic agents. Pharmaceutical compositions containing active ingredients can be in any form suitable for the intended method of administration. When used for oral use, for example, tablets, lozenges, pastilles, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs can be prepared. Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions can include one or more excipients, including sweeteners, flavorings, coloring agents and preservatives, so as to provide a palatable preparation. Tablets containing active ingredients mixed 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 carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, polyvinylpyrrolidone, calcium phosphate or sodium phosphate; granulating and disintegrants such as corn starch or alginic acid; binders such as cellulose, microcrystalline cellulose, starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, a time-delaying substance such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with a wax.

[0470] The amount of active ingredient that can be combined with the inactive ingredient to produce a dosage form can vary depending on the intended treatment subject and the mode of administration. For example, in some embodiments, a dosage form for oral administration to humans can contain approximately 1 mg to 1000 mg of the active substance, formulated together with an appropriate and convenient amount of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutically acceptable excipient comprises from about 5% to about 95% (weight:weight) of the total composition.

[0471] In some embodiments, in one variation, the composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof does not include an agent that affects the metabolic rate of the active ingredient. Thus, it will be understood that, in one aspect, the composition comprising a compound of the present disclosure does not include an agent that will affect (e.g., slow down, hinder, or delay) the metabolism of the compound of the present disclosure or any other active ingredient administered separately, sequentially, or simultaneously with the compound of the present disclosure. It will also be understood that, in one aspect, any of the methods, kits, articles, etc. described in detail herein does not include an agent that will affect (e.g., slow down, hinder, or delay) the metabolism of the compound of the present disclosure or any other active ingredient administered separately, sequentially, or simultaneously with the compound of the present disclosure.

[0472] In some embodiments, the pharmaceutical compositions described above are for use in humans or animals.

[0473] The present disclosure also includes compounds of the present disclosure administered as the sole active ingredient of a pharmaceutically acceptable composition, which can be prepared by conventional methods known in the art, for example, by combining the active ingredient with pharmaceutically acceptable, therapeutically inert organic and / or inorganic carriers or excipients, or by mixing the active ingredient with them.

[0474] In one aspect, provided herein are the use of a compound of the present disclosure as a second or additional active ingredient that acts synergistically with other active ingredients in known drugs, or the administration of a compound of the present disclosure with such drugs.

[0475] The compounds of the present disclosure may also be used in prodrug or other suitably modified forms that release the active ingredient in vivo.

[0476] V. Route of Administration

[0477] The compounds of the present disclosure (also referred to herein as active ingredients) can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intratumoral, intrathecal, and epidural) and the like. It should be understood that the preferred route may vary with, for example, the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0478] The compounds of the present disclosure can be administered to an individual for a desired period of time or duration according to an effective dosing regimen, 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 longer. In one variation, the compounds are administered daily or intermittently on a schedule for the duration of an individual's life.

[0479] The dosage or frequency of administration of the compounds of the present disclosure may be adjusted during the course of treatment based on the judgment of the administering physician.

[0480] The compound can be administered to an individual (eg, a human) in an effective amount. In some embodiments, the compound is administered once daily.

[0481] Compound can be used by any available approach and method, such as by oral or parenteral (for example intravenous) administration.The therapeutically effective amount of compound can include about 0.00001mg / kg body weight / day to about 10mg / kg body weight / day, such as about 0.0001mg / kg body weight / day to about 10mg / kg body weight / day, or such as about 0.001mg / kg body weight / day to about 1mg / kg body weight / day, or such as about 0.01mg / kg body weight / day to about 1mg / kg body weight / day, or such as about 0.05mg / kg body weight / day to about 0.5mg / kg body weight / day, or such as about 0.3mg / day to about 30mg / day, or such as about 30mg / day to about 300mg / day.

[0482] The compounds of the present disclosure can be combined with one or more additional therapeutic agents at any dose of the compounds of the present disclosure (e.g., 1 mg to 1000 mg of compound). A therapeutically effective amount can include from about 1 mg / dose to about 1000 mg / dose, such as from about 50 mg / dose to about 500 mg / dose, or such as from about 100 mg / dose to about 400 mg / dose, or such as from about 150 mg / dose to about 350 mg / dose, or such as from about 200 mg / dose to about 300 mg / dose. Other therapeutically effective amounts of a compound of the present disclosure are about 100 mg / dose, about 125 mg / dose, about 150 mg / dose, about 175 mg / dose, about 200 mg / dose, about 225 mg / dose, about 250 mg / dose, about 275 mg / dose, about 300 mg / dose, about 325 mg / dose, about 350 mg / dose, about 375 mg / dose, about 400 mg / dose, about 425 mg / dose, about 450 mg / dose, about 475 mg / dose, or about 500 mg / dose. Other therapeutically effective amounts of compounds of the present disclosure are about 100 mg / dose, or about 125 mg / dose, about 150 mg / dose, about 175 mg / dose, about 200 mg / dose, about 225 mg / dose, about 250 mg / dose, about 275 mg / dose, about 300 mg / dose, about 350 mg / dose, about 400 mg / dose, about 450 mg / dose, or about 500 mg / 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 a week. A single dose can also be administered once a month.

[0483] The present disclosure also includes kits, which include compounds of the present disclosure, or enantiomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing any of the foregoing. In one embodiment, the kit also includes instructions for use. In one aspect, the kit includes compounds of the present disclosure, or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs thereof, and labels and / or instructions for use of compounds described herein for treatment indications (such as diseases or conditions described herein). In one embodiment, kits are provided, which include compounds of the present disclosure or pharmaceutically acceptable salts thereof in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.

[0484] Also provided herein are articles of manufacture in suitable containers comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof. The container can be a vial, jar, ampoule, preloaded syringe, and intravenous bag.

[0485] VI. Combination Therapy

[0486] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, may be combined with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents. In some embodiments, the additional therapeutic agent comprises an apoptosis signal-regulating kinase (ASK-1) inhibitor, a farnesoid X receptor (FXR) agonist, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, fish oil, an acetyl-CoA carboxylase (ACC) inhibitor, or a TGFβ antagonist, or a combination thereof.

[0487] In some embodiments, the therapeutic agent or combination of therapeutic agents is an ACE inhibitor, 2-acylglycerol O-acyltransferase 2 (DGAT2), an aldehyde dehydrogenase inhibitor, an acetyl-CoA carboxylase inhibitor, an adrenergic receptor agonist, an Alström syndrome protein 1 (ALMS1) / PKCα protein interaction inhibitor, an apelin receptor agonist, a diacylglycerol O-acyltransferase 2 inhibitor, an adenosine A3 receptor agonist, an adenosine A3 receptor antagonist, an adiponectin receptor agonist, an aldehyde dehydrogenase 2 stimulator, an AKT protein kinase inhibitor, an AMP-activated protein kinase (AMPK), an AMP kinase activator, an ATP citrate lyase inhibitor, an AMP-activated protein kinase stimulator, an endothelial nitric oxide synthase stimulator, an NAD-dependent deacetylase Sirtuin-1 stimulator, an adrenergic receptor antagonist, an androgen receptor agonist, an amylin receptor agonist, an angiotensin II AT-1 receptor antagonists, autophagy protein regulators, autotaxin inhibitors, Axl tyrosine kinase receptor inhibitors, Bax protein stimulators, β-catenin inhibitors, bioactive lipids, calcitonin agonists, cannabinoid receptor modulators, caspase inhibitors, caspase-3 stimulators, cathepsin inhibitors, caveolin-1 inhibitors, CCK receptor antagonists, CCL26 gene inhibitors, CCR2 chemokine antagonists, CCR2 chemokine antagonists, angiotensin II AT-1 receptor antagonists, CCR3 chemokine antagonists, CCR5 chemokine antagonists, CD3 antagonists, CDGSH iron-sulfur domain protein modulators, chitinase inhibitors, chloride channel stimulators, chitotriosidase 1 inhibitors, CNR1 inhibitors, connective tissue growth factor ligand inhibitors, cyclin D1 inhibitors, cytochrome P4507A1 inhibitors, DGAT1 / 2 inhibitors, diacylglycerol O-acyltransferase 1 inhibitors (DGAT1), cytochrome P4502E1 inhibitors (CYP2E1), CXCR4 chemokine antagonists, dihydroceramide δ4 desaturase inhibitors, dihydroorotate dehydrogenase inhibitors, dipeptidyl peptidase IV inhibitors, endosialin modulators, eotaxin ligand inhibitors, extracellular matrix protein modulators, farnesoid X receptor agonists, fatty acid synthase inhibitors, FGF1 receptor agonists, fibroblast growth factor (FGF-15, FGF-19, FGF-21) ligands, fibroblast activation protein inhibitors, free fatty acid receptor 1 agonists, galectin-3 inhibitors, GDNF family Glucagon receptor alpha-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 regulator (HNF4A), hepatocyte growth factor regulator, histone deacetylase inhibitor, STAT-3 modulator, HMG coenzyme A reductase inhibitor, HSD17B13 gene inhibitor, 5-HT 2a receptor antagonists, hydrolase inhibitors, hypoxia-inducible factor-2α inhibitors, IL-10 agonists, IL-17 antagonists, IL-22 agonists, ileal bile acid sodium cotransporter inhibitors, insulin sensitizers, insulin ligand agonists, insulin receptor agonists, integrin modulators, integrin antagonists, integrin α-V / β-1 antagonists, integrin α-V / β-6 antagonists, interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors, IL-6 receptor agonists, interleukin-17 ligand inhibitors, Jak2 tyrosine kinase inhibitors, Jun N-terminal kinase-1 inhibitors, Kelch-like ECH-associated protein 1 modulators, ketohexokinase (KHK) inhibitors, Klothoβ stimulators, leukotriene A4 hydrolase inhibitors, 5-lipoxygenase inhibitors, lipoprotein lipase inhibitors, liver X receptor, LPL gene stimulators, lysophosphatidic acid-1 receptor antagonists, lysyl oxidase homolog 2 inhibitors, LXR inverse agonists, macrophage mannose receptor 1 modulators, matrix metalloproteinase (MMP) inhibitors, MEKK-5 protein kinase inhibitors, MCH receptor-1 antagonists, membrane copper amine oxidase (VAP-1) inhibitors, methionine aminopeptidase-2 inhibitors, methyl CpG binding protein 2 modulators, microRNA-132 (miR-132) antagonists, microRNA-21 (miR-21) inhibitors, mitochondrial uncouplers, mixed lineage kinase 3 inhibitors, motile sperm domain-containing protein 2 inhibitors, myelin basic protein stimulators, NACHT LRRPYD domain protein 3 (NLRP3) inhibitors, NAD-dependent deacetylase sirtuin stimulators, NADPH oxidase inhibitors (NOX), NFE2L2 gene inhibitors, nicotinic acid receptor 1 agonists, opioid receptor μ antagonists, P2Y13 purinergic receptor stimulators, erythroid 2-related factor 2 stimulators, nuclear receptor modulators, P2X7 purinergic receptor modulators, PACAP Type I receptor agonists, PDE3 inhibitors, PDE4 inhibitors, PDE5 inhibitors, PDGF receptor beta modulators, phenylalanine hydroxylase stimulators, phospholipase C inhibitors, phosphodiester hydrolase inhibitors, PPARα agonists, PPARδ agonists, PPARγ agonists, peptidylprolyl cis-trans isomerase A inhibitors, PNPLA3 gene inhibitors, PPARγ modulators, protease-activated receptor-2 antagonists, protein kinase modulators, protein NOV homolog modulators, PTGS2 gene inhibitors, renin inhibitors, resistin / CAP1 (adenylate cyclase-associated protein 1) interaction inhibitors, Rho-associated protein kinase inhibitors, S-nitrosoglutathione reductase (GSNOR) enzyme inhibitors, sodium glucose transporter-2 inhibitors, sphingolipid delta 4 Desaturase DES1 inhibitors, SREBP transcription factor inhibitors, STAT-1 inhibitors, stearoyl-CoA desaturase-1 inhibitors, STK25 inhibitors, cytokine signaling inhibitor-1 stimulators, cytokine signaling inhibitor-3 stimulators, telomerase stimulators, TERT gene regulators, TGFβ (TGFB1) ligand inhibitors, TNF antagonists, transforming growth factor β (TGF-β), transforming growth factor β-activated kinase 1 (TAK1), thyroid hormone receptor β agonists, TLR-4 antagonists, transglutaminase inhibitors, tyrosine kinase receptor modulators, GPCR modulators, nuclear hormone receptor modulators, TLR-9 antagonists, VDR agonists, WNT modulators or YAP / TAZ modulators and zonulin inhibitors.

[0488] Non-limiting examples of one or more additional therapeutic agents include:

[0489] -ACE inhibitors, such as enalapril;

[0490] - aldehyde dehydrogenase inhibitors, such as ADX-629;

[0491] - acetyl-CoA carboxylase (ACC) inhibitors, such as NDI-010976 (firsocostat), DRM-01, gemcabene, GS-834356, PF-05175157, QLT-091382, PF-05221304;

[0492] - acetyl-CoA carboxylase / diacylglycerol O-acyltransferase 2 inhibitors, such as PF-07055341;

[0493] - adenosine receptor agonists, such as CF-102 (namodenoson), CF-101, CF-502, CGS21680;

[0494] - adenosine A3 receptor antagonists, such as FM-101;

[0495] - adiponectin receptor agonists, such as ADP-355, ADP-399;

[0496] - Adrenergic receptor antagonists, such as bromocriptine, phentermine, VI-0521;

[0497] - aldehyde dehydrogenase 2 stimulators, such as FP-045;

[0498] - alpha-glucosidase inhibitors (such as voglibose, acarbose, or miglitol);

[0499] - Amylin / calcitonin receptor agonists, such as KBP-042, KBP-089;

[0500] -AMP-activated protein kinase stimulators, such as C-455, PXL-770, O-304;

[0501] -AMP kinase activators / ATP citrate lyase inhibitors, such as bepedic acid (ETC-1002, ESP-55016);

[0502] -AMP-activated protein kinase / endothelial nitric oxide synthase / NAD-dependent deacetylase sirtuin-1 stimulators, such as NS-0200 (leucine + metformin + sildenafil);

[0503] - Androgen receptor agonists, such as LPCN-1144, LPCN-1148, testosterone prodrugs;

[0504] - angiotensin II AT-1 receptor antagonists, such as irbesartan;

[0505] -Angiopoietin-related protein-3 inhibitors, such as vupanorsen (IONIS-ANGPTL3-LRx);

[0506] - Apelin receptor agonists, such as CB-5064 and MBT-2;

[0507] - Autophagy protein regulators, such as A-2906;

[0508] - 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, BBT-877;

[0509] -Axl tyrosine kinase receptor inhibitors, such as besentinib (BGB-324, R-428);

[0510] - Bax protein stimulators, such as CBL-514;

[0511] - Bioactive lipids, such as DS-102;

[0512] - Cannabinoid receptor modulators, such as namacizumab, GWP-42004, REV-200, CRB-4001, INV-101, SCN-002;

[0513] - Cysteine ​​protease inhibitors, such as enlicasin;

[0514] -Pan cathepsin B inhibitors, such as VBY-376;

[0515] -Pan cathepsin inhibitors, such as VBY-825;

[0516] -CCK receptor antagonists, such as proglumide;

[0517] - CCL26 gene inhibitors, such as mosedipimod and KDDF-201410-10;

[0518] - CCR2 / CCR5 chemokine antagonists, such as BMS-687681, cinevir, maraviroc, CCX-872, leronlimab, WXSH-0213;

[0519] - CCR2 / CCR5 chemokine antagonists and FXR agonists, such as LJC-242 (zopivoxol + lipagliflozin);

[0520] - CCR2 chemokine antagonists, such as propagermanium;

[0521] - CCR2 chemokine / angiotensin II AT-1 receptor antagonists, such as DMX-200, DMX-250;

[0522] - CCR3 chemokine antagonists, such as bacitrazumab;

[0523] -CD3 antagonists, such as NI-0401 (foraminab);

[0524] - CDGSH iron-sulfur domain protein modulators, such as EYP-002;

[0525] - chitinase inhibitors, such as OATD-01;

[0526] - Chitotriosidase 1 inhibitors, such as OAT-2068;

[0527] - Chloride channel stimulants, such as coprostone and lubiprostone;

[0528] - casein kinase-1 (CK1) delta / epsilon inhibitors, such as PF-05006739;

[0529] - connective tissue growth factor ligand inhibitors, such as PBI-4050;

[0530] - CXCR4 chemokine antagonists, such as AD-214;

[0531] - diacylglycerol acyltransferase 2 (DGAT2) inhibitors, such as IONIS-DGAT2Rx, PF-06865571;

[0532] - diglyceride acyltransferase 1 (DGAT1) inhibitors, such as GSK-3008356;

[0533] - diacylglycerol O-acyltransferase 1 (DGAT1) / cytochrome P450 2E1 inhibitors (CYP2E1), such as SNP-610;

[0534] -Dihydroorotate dehydrogenase inhibitors, such as vedofluanimol;

[0535] -Dipeptidyl peptidase IV inhibitors, such as linagliptin and emligliptin;

[0536] - eotaxin ligand inhibitors, such as cefixime, CM-101;

[0537] - extracellular matrix protein modulators, such as CNX-024;

[0538] Farnesoid X receptor (FXR) agonists, such as AGN-242266, AGN-242256, ASC-42, EDP-297 (EP-024297), RDX-023, BWL-200, AKN-083, EDP-305, GNF-5120, cilofexor tromethamine (GS-9674), HPG-1860, IOT-022, LMB-763, obeticholic acid, Px-102, Px-103, M790, M780, M450, M-480, MET-409, MET-642, PX20606, SYHA-1805, velolimab (EYP-001), TERN-101, TC-100, INT-2228, TQA-3526, ZG-5266;

[0539] Farnesoid X receptor (FXR) / G protein-coupled bile acid receptor 1 (TGR5) agonists, such as INT-767;

[0540] - fatty acid synthase inhibitors, such as TVB-2640, FT-8225;

[0541] - fibroblast growth factor 19 (rhFGF19) / cytochrome P450 (CYP) 7A1 inhibitors, such as odafmin (NGM-282);

[0542] - fibroblast growth factor 21 (FGF-21) ligand modulators, such as AP-025, BMS-986171, B-1654, BIO89-100, BOS-580;

[0543] -Pegbelfermin(BMS-986036), B-1344;

[0544] - Fibroblast growth factor 21 (FGF-21) / glucagon-like peptide 1 (GLP-1) agonists, such as YH-25723 (YH-25724, YH-22241), efruxifermin (AKR-001);

[0545] - FGF receptor agonists / Klothoβ stimulators, such as BFKB-8488A (RG-7992);

[0546] - free fatty acid receptor 1 agonists, such as SCO-267;

[0547] -Galectin-3 inhibitors, such as belapectin (GR-MD-02), GB-1107 (Gal-300), GB-1211 (Gal-400);

[0548] - GDNF family receptor α-like agonists, such as NGM-395;

[0549] - Glucagon-like peptide 1 receptor (GLP1R) agonists, such as ALT-801, AC-3174, liraglutide, cotylurea (MEDI-0382), SAR-425899, LY-3305677, HM-15211, YH-25723, YH-GLP1, RPC-8844, PB-718, PF-06882961, semaglutide;

[0550] - Glucagon-like peptide 1 receptor agonists; oxyntomodulin ligands; glucagon receptor agonists such as inopedopeptide;

[0551] - Gastric inhibitory peptide / glucagon-like peptide-1 (GIP / GLP-1) receptor co-agonists, such as tilportide (LY-3298176);

[0552] -PEGylated long-acting glucagon-like peptide-1 / glucagon (GLP-1R / GCGR) receptor dual agonists, such as DD-01;

[0553] - Glucagon / GLP1 receptor agonists, such as BI-456906;

[0554] - glucocorticoid receptor antagonists, such as CORT-118335 (milkolan);

[0555] - Glucose 6-phosphate 1-dehydrogenase inhibitors, such as ST001;

[0556] - Glucokinase stimulators, such as dogliflozin, sinogliatin (RO-5305552);

[0557] - G protein-coupled bile acid receptor 1 (TGR5) agonists, such as RDX-009, INT-777, HY-209;

[0558] - G protein-coupled receptor 84 antagonists, such as PBI-4547;

[0559] - G protein-coupled receptor-119 agonists, such as DA-1241;

[0560] - Heat shock protein 47 (HSP47) inhibitors, such as ND-L02-s0201;

[0561] - Hedgehog and / or TGFβ ligand inhibitors, such as Oxy-210;

[0562] - histone deacetylase inhibitors / STAT-3 modulators, such as SFX-01;

[0563] - HMG-CoA reductase inhibitors, such as atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin;

[0564] -HSD17B13 gene inhibitors, such as ALN-HSD and ARO-HSD;

[0565] - hydrolase inhibitors, such as ABD-X;

[0566] - hypoxia-inducible factor-2α inhibitors, such as PT-2567;

[0567] - IL-10 agonists, such as pegylated iloleukin;

[0568] - ileal bile acid sodium cotransporter inhibitors, such as orvixibat (A-4250), voxibat potassium ethanolate hydrate (SHP-262), GSK2330672, CJ-14199, and eloxibat (A-3309);

[0569] - Insulin sensitizers such as KBP-042, azemiglitazone potassium (MSDC-0602K), ION-224, MSDC-5514, Px-102, RG-125 (AZD4076), tolimidone, VVP-100X, CB-4211, ETI-101, pioglitazone;

[0570] - Insulin ligands / ds-insulin receptor agonists, such as ORMD-0801;

[0571] - integrin antagonists, such as IDL-2965;

[0572] - IL-6 receptor agonists, such as KM-2702;

[0573] - dual integrin α-V / β-6 and α-V / β-1 inhibitors, such as PLN-74809;

[0574] - Interleukin-17 ligand inhibitors, such as nitrazepam;

[0575] - Jak1 / 2 tyrosine kinase inhibitors, such as baricitinib;

[0576] -Jun N-terminal kinase-1 inhibitors, such as CC-90001;

[0577] - Kelch-like ECH-related protein 1 modulators, such as α-cyclodextrin-stabilized sulforaphane;

[0578] - Ketohexokinase (KHK) inhibitors, such as PF-06835919, LY-3478045;

[0579] -βKlotho (KLB)-FGF1c agonists, such as MK-3655 (NGM-313);

[0580] - leukotriene A4 hydrolase inhibitors, such as LYS-006;

[0581] -5-lipoxygenase inhibitors, such as talukast (MN-001) and ipiliton (DS-102, AF-102);

[0582] - lipoprotein lipase inhibitors, such as CAT-2003;

[0583] - LPL gene stimulators, such as aripiprazole;

[0584] - Liver X receptor (LXR) inhibitors, such as PX-665, PX-L603, PX-L493, BMS-852927, T-0901317, GW-3965, SR-9238;

[0585] - Lysophosphatidic acid-1 receptor antagonists, such as BMT-053011, UD-009 (CP-2090), AR-479, ITMN-10534, BMS-986020, KI-16198;

[0586] - lysyl oxidase homolog 2 inhibitors, such as sintuzumab, PXS-5382A (PXS-5338);

[0587] - macrophage mannose receptor 1 modulators, such as temanose-Cy3 (technetium Tc 99m temanose);

[0588] - matrix metalloproteinase inhibitors, such as ALS-L1023;

[0589] - membrane copper amine oxidase (VAP-1) inhibitors, such as TERN-201, TT-01025;

[0590] - MEKK-5 protein kinase (ASK-1) inhibitors, such as CJ-16871, CS-17919, sirolimus (GS-4997), SRT-015, GS-444217, GST-HG-151, TERN-301;

[0591] - MCH receptor-1 antagonists, such as CSTI-100 (ALB-127158);

[0592] - Semicarbazide-sensitive amine oxidase / vascular adhesion protein-1 (SSAO / VAP-1) inhibitors, such as PXS-4728A (BI-1467335);

[0593] -Methionine aminopeptidase-2 inhibitors, such as ZGN-1061, ZGN-839, ZN-1345;

[0594] - methyl CpG binding protein 2 modulators, such as cysteamine;

[0595] - Mineralocorticoid receptor antagonists (MCRAs), such as MT-3995 (apalidone);

[0596] - Mitochondrial uncouplers, such as 2,4-dinitrophenol, HU6, Mito-99-0053;

[0597] - mixed lineage kinase-3 inhibitors, such as URMC-099-C;

[0598] - motile sperm domain protein 2 inhibitors, such as VB-601;

[0599] -Myelin basic protein stimulators, such as olesoxime;

[0600] - Chloroperoxidase inhibitors, such as PF-06667272, AZM-198;

[0601] - NADPH oxidase inhibitors such as GKT-831, GenKyoTex, APX-311, cetanacil;

[0602] - Nicotinic acid receptor 1 agonists, such as ARI-3037MO;

[0603] -NACHT LRR PYD domain protein 3 (NLRP3) inhibitors, such as KDDF-201406-03, NBC-6, IFM-514, JT-194 (JT-349);

[0604] - NFE2L2 gene inhibitors, such as GeRP-amiR-144;

[0605] - nuclear receptor modulators, such as DUR-928 (DV-928);

[0606] - Opioid receptor μ antagonists, such as methylnaltrexone;

[0607] - P2X7 purinergic receptor modulators, such as SGM-1019;

[0608] - P2Y13 purinergic receptor stimulators, such as CER-209;

[0609] - PDE 3 / 4 inhibitors, such as talukast (MN-001);

[0610] - PDE 5 inhibitors, such as sildenafil, MSTM-102;

[0611] -PDGF receptor β modulators, such as BOT-191, BOT-509;

[0612] - peptidylprolyl cis-trans isomerase inhibitors, such as CRV-431 (CPI-432-32), NVP-018, NV-556 (NVP-025);

[0613] - phenylalanine hydroxylase stimulators, such as HepaStem;

[0614] - phosphodiester hydrolase inhibitors, such as ZSP-1601;

[0615] - PNPLA3 gene inhibitors, such as AZD-2693;

[0616] - PPAR agonists, such as ciglitazone, elafinranor (GFT-505), seladelpar lysine (MBX-8025), deuterated pioglitazone R-enantiomer, pioglitazone, PXL-065 (DRX-065), saroglitazar, lanileno (IVA-337), CHS-131, pemafibrate (K-877), ZG-0588, ZSP-0678, ZSYM-008;

[0617] - protease-activated receptor-2 antagonists, such as PZ-235;

[0618] - Protein kinase modulators, such as CNX-014;

[0619] - NOV homolog modulators, such as BLR-200;

[0620] -PTGS2 gene inhibitors, such as STP-705 and STP-707;

[0621] -renin inhibitors, such as PRO-20;

[0622] - Resistin / CAP1 (adenylate cyclase-associated protein 1) interaction inhibitors, such as DWJ-211;

[0623] -Rev protein modulators, such as ABX-464;

[0624] - Rho-associated protein kinase (ROCK) inhibitors, such as REDX-10178 (REDX-10325), KD-025, RXC-007, TDI-01;

[0625] - S-nitrosoglutathione reductase (GSNOR) enzyme inhibitors, such as SL-891;

[0626] - sodium glucose transporter-2 (SGLT2) inhibitors, such as empagliflozin, repagliflozin etabonate, erpagliflozin, dapagliflozin, togliflozin, and sogliflozin;

[0627] - sodium glucose transporter-1 / 2 (SGLT1 / 2) inhibitors, such as licogliflozin bis(prolinate) (LIK-066);

[0628] - SREBP transcription factor inhibitors, such as CAT-2003, HPN-01, MDV-4463;

[0629] - stearoyl-CoA desaturase-1 inhibitors, such as eicosanoylaminocholanic acid;

[0630] - thyroid hormone receptor beta agonists, such as ALG-009, ASC-41, CNPT-101101, CNPT-101207, CS-27186, KY-41111, resmetirole (MGL-3196), MGL-3745, TERN-501, VK-2809;

[0631] -TLR-2 / TLR-4 antagonists, such as VB-201 (CI-201);

[0632] - TLR-4 antagonists, such as JKB-121, JKB-122, naltrexone;

[0633] - tyrosine kinase receptor modulators, such as CNX-025, GFE-2137 (repurposed nitazoxanide);

[0634] - TLR-9 antagonists, such as GNKS-356;

[0635] -TNF antagonists, such as ALF-421;

[0636] - GPCR modulators, such as CNX-023;

[0637] - nuclear hormone receptor modulators, such as Px-102;

[0638] - VDR agonists, such as CK-15;

[0639] - xanthine oxidase inhibitors, such as ACQT-1127;

[0640] - Xanthine oxidase / uric acid anion exchanger 1 (URAT1) inhibitors, such as RLBN-1001, RLBN-1127; and

[0641] - Zonulin inhibitors, such as larizolide acetate (INN-202).

[0642] In some embodiments, the one or more additional therapeutic agents are selected from A-4250, AC-3174, acetylsalicylic acid, AK-20, aliperkin, AMX-342, AN-3015, anti-TAGE antibodies, eicosanylaminocholanic acid, ARI-3037MO, ASP-8232, AZD-2693, betilimumab, anhydrous betaine, BI-1467335, BMS-986036, BMS-986171, BMT-053011, BOT-191, BTT-1023, budesonide, BX-003, CAT-2003, cinevir, CBW-511, CER-209, CF-102, CGS21680, C NX-014, CNX-023, CNX-024, CNX-025, cobiprostone, colesevelam, dabigatran mesylate, dapagliflozin, DCR-LIV1, deuterated pioglitazone R-enantiomer, 2,4-dinitrophenol, DRX-065, DS-102, DUR-928, EDP-305, elafibranor (GFT-505), enlicasin, enalapril, erpagliflozin, emdiagliptin, F-351, fluasterone (ST-002), FT-4101, GDD-3898, GH-509, GKT-831, GNF-5120, GRI-0621, GR-MD-02, GS-30 0, GS-4997, GS-9674, HEC-96719, HTD-1801, HS-10356, HSG-4112, HST-202, HST-201, HU-6, hydrochlorothiazide, icobutamol (PRC-4016), icosapent ethyl, IMM-124-E, INT-767, INV-240, IONIS-DGAT2Rx, empagliflozin, irbesartan, propagermanium, IVA-337, J2H-1702, JKB-121, KB-GE-001, KBLP-004, KBLP-009, KBP-042, KD-025, M790, M780, M450, metformin, cediramine Nafil, LB-700, LC-280126, linagliptin, liraglutide, (LJN-452)(zopifenoxol), LM-011, LM-002(CVI-LM-002), LMB-763, LYN-100, MB-N-008, MBX-8025, MDV-4463, cysteamine, MGL-3196, MGL-3745, MP-301, MSDC-0602K, namacizumab, NC-101, NDI-010976, ND-L02-s0201(BMS-986263), NGM-282, NGM-313, NGM-386, NGM-395, NP-011,NP-135, NP-160, norursodeoxycholic acid, NV-422, NVP-022, O-304, obeticholic acid (OCA), 25HC3S, olesoxime, PAT-505, PAT-048, PBI-4547, pegylated iloleukin, pioglitazone, pirfenidone, PRI-724, PX20606, Px-102, PX-L603, PX-L493, PXS- 4728A, PZ-235, PZH-2109, RCYM-001, RDX-009, repagliflozin ectocate, RG-125 (AZD4076), RPI-500, S-723595, sarogliflozin, SBP-301, semaglutide, SH-2442, SHC-028, SHC-023, cintuzumab, solithromycin, sogliflozin, statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), Symbiotic, 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, Vimodegib, Voxibater 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.

[0643] In some embodiments, the compounds of the present disclosure are combined with one or more therapeutic agents selected from anti-obesity agents, including but not limited to peptide YY or an analog thereof, neuropeptide Y receptor type 2 (NPYR2) agonists, NPYR1 agonists, NPYR5 antagonists, cannabinoid receptor type 1 (CB1 R) antagonists, lipase inhibitors (e.g., orlistat), human islet peptide (HIP), melanocortin receptor 4 agonists (e.g., semelatide), 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., bupropion), opioid receptor antagonists (e.g., naltrexone), norepinephrine / Combinations of dopamine reuptake inhibitors and opioid receptor antagonists (e.g., a combination of bupropion 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 (MetAP2) inhibitors (e.g., beloranib or ZGN-1061), benzphetamine, SGPT, diethylpropion, pheniramine, phenobarbital, phenobarbital, sedatives ... LT2 inhibitors (e.g., empagliflozin, canagliflozin, dapagliflozin, ispagliflozin, togliflozin, sergliflozin etabonate, repagliflozin etabonate, or empagliflozin), 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-1R agonist, e.g., liraglutide, exenatide, doxepin, or dapoxetine). The invention also includes pharmaceutically acceptable salts of the specifically named agents and pharmaceutically acceptable solvates of the agents and salts, including pharmaceutically acceptable salts of the specifically named agents and pharmaceutically acceptable solvates of the agents and salts.

[0644] 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 farnesoid X receptor (FXR) agonist. In some embodiments, the FXR agonist is a compound of Formula (II) or (III):

[0645]

[0646] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof.

[0647] 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 ASK1 inhibitor is a compound of Formula (IV):

[0648]

[0649] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof.

[0650] 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):

[0651]

[0652] or a pharmaceutically acceptable salt thereof.

[0653] 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) β agonist. In certain embodiments, the THR β agonist is a compound of Formula (VI):

[0654]

[0655] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof.

[0656] VII. Treatment Methods

[0657] In some embodiments, the compounds of Formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id), or pharmaceutically acceptable salts thereof, may be used 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.

[0658] In some embodiments, the disease or condition includes liver disease or related diseases or conditions, such as liver fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cirrhosis, compensated liver fibrosis, decompensated liver fibrosis, hepatocellular carcinoma, primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC). In some embodiments, the disease or condition includes metabolic disease or related diseases or conditions, such as diabetes, obesity or cardiovascular metabolic disease.

[0659] GLP-1R agonists are currently being studied in conjunction with certain diseases and conditions, including, for example, diabetes. GLP-1 analogs that are DPP4-resistant and have a longer half-life than endogenous GLP-1 have been reported to be associated with weight loss and improved insulin action. Liraglutide, a peptide GLP-1R agonist approved for use in conjunction with the treatment of diabetes, has been reported to show favorable improvements in outcomes in NASH subjects.

[0660] 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 preventing and / or treating 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 preventing and / or treating a disease or condition mediated by GLP-1R, such as a liver disease or a metabolic disease. For example, some embodiments provide a compound of formula (I), (IA-1) and / or (IA-2) or a pharmaceutically acceptable salt thereof or use thereof for treating and / or preventing chronic intrahepatic or some forms of extrahepatic cholestatic disorders, liver fibrosis, acute intradigestive cholestatic disorders, obstructive or chronic inflammatory disorders caused by inappropriate bile composition, gastrointestinal disorders associated with reduced dietary fat intake and fat-soluble dietary vitamins, inflammatory bowel disease, lipid and lipid protein disorders, type II diabetes and clinical complications of type I and type II diabetes, due to forced lipid and especially glycerol Conditions and diseases caused by the accumulation of triesters and the subsequent activation of profibrotic pathways leading to chronic fatty and fibrotic degeneration of organs, obesity and metabolic syndrome (a combination of dyslipidemia, diabetes, and an abnormally high body mass index), acute myocardial infarction, acute stroke, thrombosis as an end point of chronic obstructive atherosclerosis, persistent infection with intracellular bacteria or parasitic protozoa, non-malignant hyperproliferative diseases, malignant hyperproliferative diseases (e.g., colon adenocarcinoma and hepatocellular carcinoma), hepatic steatosis and related syndromes, liver failure as a result of chronic liver disease or surgical liver resection liver failure or dysfunction, hepatitis B infection, hepatitis C infection and / or cholestasis and fibrosis associated with alcohol-induced cirrhosis or virally transmitted forms of hepatitis, type 1 diabetes, prediabetes, idiopathic type 1 diabetes, latent autoimmune diabetes, maturity-onset diabetes of the juvenile, early-onset diabetes, diabetes associated with malnutrition, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral fat deposition accumulation, obesity, eating disorders, sleep apnea, weight gain, sugar cravings, dyslipidemia, hyperinsulinemia, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, 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, impaired glucose metabolism, or restenosis.

[0661] In some embodiments, a method for treating and / or preventing non-alcoholic fatty liver disease (NAFLD) comprises administering a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0662] The present disclosure also relates to compounds according to Formula (IA-1), (IA-2) and / or Formula (I), or pharmaceutical compositions comprising the same, for use in the prophylactic and post-traumatic treatment of cardiovascular disease, such as acute myocardial infarction, acute stroke, or thrombosis that occurs as an end point in chronic obstructive atherosclerosis. In some embodiments, a method for treating and / or preventing cardiovascular disease comprises administering a compound of Formula (IA-1), (IA-2) and / or Formula (I) to a subject in need thereof.

[0663] The present disclosure also relates to compounds or pharmaceutical compositions for treating and / or preventing obesity and related diseases, such as metabolic syndrome (a complex of dyslipidemia, diabetes, and abnormally high body mass index), which can be overcome by GLP1R-mediated reductions in serum triglycerides, blood sugar, and increased insulin sensitivity, as well as GLP1R-mediated weight loss. In some embodiments, methods for treating and / or preventing metabolic diseases include administering a compound of formula (I) to a subject in need thereof. In some embodiments, methods for treating and / or preventing metabolic diseases include administering a compound of formula (IA-1) and / or (IA-2) to a subject in need thereof.

[0664] In another embodiment, the compound or pharmaceutical composition of the present disclosure can be used to prevent and / or treat the clinical complications of type I and type II diabetes.The example of such complications includes diabetic nephropathy, diabetic retinopathy, diabetic neuropathy or peripheral arterial occlusive disease (PAOD). The disclosure also encompasses other clinical complications of diabetes. In some embodiments, the method for treating and / or preventing the complications of type I and type II diabetes includes administering a compound of formula (I) to a subject in need. In some embodiments, the method for treating and / or preventing the complications of type I and type II diabetes includes administering a compound of formula (IA-1) and / or (IA-2) to a subject in need.

[0665] In addition, it is also possible to prevent and / or treat the conditions and diseases caused by the accumulation of forced lipids and / or triglycerides and the activation of subsequent pro-fibrotic pathways by administering a compound or pharmaceutical composition of the present invention. Such conditions and diseases may include NASH and chronic cholestatic conditions in the liver, glomerulosclerosis and diabetic nephropathy in the kidneys, macular degeneration and diabetic retinopathy in the eyes, and neurodegenerative diseases, such as diabetic neuropathy in the Alzheimer's disease or peripheral nervous system in the brain. In some embodiments, the method for treating and / or preventing the conditions and diseases caused by the accumulation of forced lipids and / or triglycerides and the activation of subsequent pro-fibrotic pathways includes administering a compound of formula (I) to a subject in need. In some embodiments, methods for treating and / or preventing conditions and diseases caused by chronic fatty and fibrotic degeneration of organs due to forced accumulation of lipids and / or triglycerides and subsequent activation of pro-fibrotic pathways comprise administering a compound of formula (IA-1) and / or (IA-2) to a subject in need thereof. In some embodiments, methods for treating and / or preventing NASH comprise administering a compound of formula (I) to a subject in need thereof. In some embodiments, methods for treating and / or preventing NASH comprise administering a compound of formula (IA-1) and / or (IA-2) to a subject in need thereof.

[0666] Also provided herein is a pharmaceutical composition for treating a GLP-1R mediated disease or condition described herein, the pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0667] The present disclosure also describes the use of a medicament for treating a GLP-1R-mediated disease or condition, the medicament comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof. The medicaments mentioned herein can be prepared by conventional methods, comprising a combination of a compound of the present disclosure and a pharmaceutically acceptable carrier.

[0668] Also disclosed are compounds of the present disclosure, or pharmaceutically acceptable salts thereof, for use in treating a GLP-1R-mediated disease or condition. Also disclosed are compounds of the present disclosure, or pharmaceutically acceptable salts thereof, for use in preventing a GLP-1R-mediated disease or condition.

[0669] VIII. Examples

[0670] Numerous general references are available that provide generally well-known chemical synthesis schemes and conditions that can be used to synthesize the disclosed compounds (see, e.g., Smith, “March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure,” 7th ed., Wiley-Interscience, 2013).

[0671] Compounds as described herein can be purified by any method known in the art, including chromatographic methods 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 compounds disclosed herein can be purified by silica gel and / or alumina chromatography. See, for example, "Introduction to Modern Liquid Chromatography", 2nd edition, LRSnyder and JJKirkland, John Wiley and Sons, 1979; and "Thin Layer Chromatography", edited by E.Stahl, Springer-Verlag, New York, 1969.

[0672] In any of the processes for preparing the subject compounds, it may be necessary to protect sensitive or reactive groups on any of the molecules involved. This can be achieved with the aid of conventional protecting groups as described in standard texts, such as TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis," 4th edition, Wiley, New York, 2006. The protecting groups can be removed at a convenient subsequent stage using methods known in the art.

[0673] The exemplary chemical entities that can be used for the method of the embodiment will now be described by reference to the general preparation of this article and the illustrative synthesis schemes of the specific examples below. It will be appreciated by those skilled in the art that in order to obtain the various compounds herein, the starting material can be appropriately selected so that the final desired substituent will be carried through a reaction scheme that is optionally protected or unprotected to produce the desired product. Alternatively, it may be necessary to use a suitable group in the position of the final desired substituent, which can be carried through the reaction scheme and optionally replaced with the desired substituent. In addition, it will be appreciated by those skilled in the art that the conversions shown in the following schemes can be performed in any order that is compatible with the functionality of the side groups. Each reaction depicted in the general scheme can be run at a temperature of about 0°C to the reflux temperature of the organic solvent used.

[0674] The examples provided herein describe the synthesis of the compounds disclosed herein and the intermediates used to prepare these compounds. It should be understood that the various steps described herein can be combined. It should also be understood that separate batches of compounds can be combined and then carried out in the next synthesis step.

[0675] In the description of the following examples, specific embodiments are described. These embodiments are described in sufficient detail to enable those skilled in the art to practice certain embodiments of the present disclosure. Other embodiments may be utilized, and logical and other changes may be made without departing from the scope of the present disclosure. The embodiments also relate to methods and intermediates for preparing subject compounds or their pharmaceutically acceptable salts. Therefore, the following description is not intended to limit the scope of the present disclosure.

[0676] In some embodiments, the present disclosure generally provides a specific enantiomer or diastereomer as the desired product, although the stereochemistry of the enantiomer or diastereomer has not been determined in all cases. When the stereochemistry of a specific stereocenter in an enantiomer or diastereomer has not been determined, the compound is drawn without any stereochemistry shown for that specific stereocenter, even though the compound may be substantially enantiomerically or diastereomerically pure.

[0677] Representative syntheses of compounds of the present disclosure are described in the following schemes and in the following examples.

[0678] The compounds detailed in the examples were synthesized according to the general synthetic methods described below. Unless otherwise indicated, compounds were named using ChemDraw version 18.1.0.535 (PerkinElmer Informatics, Inc.).

[0679] abbreviation

[0680] Certain abbreviations and acronyms are used to describe the experimental details. Although most of these will be understood by those skilled in the art, Table 1 contains a list of many of these abbreviations and acronyms.

[0681] Table 1. List of abbreviations and acronyms

[0682]

[0683]

[0684]

[0685] A. Synthesis of intermediates

[0686] Intermediate I-1

[0687]

[0688] 4-amino 3-(2-methoxyethylamino) benzoic acid methyl ester (I-1): diisopropylethylamine (70.0mL, 402mmol) and 2-methoxyethylamine (34.9mL, 402mmol) are added to a solution of 3-fluoro-4-nitro-benzoic acid methyl ester (50.0g, 251mmol) in THF (400mL). The resulting solution is heated to 55°C for 6 hours. After completion, the solvent is removed and the resulting residue is dissolved in EtOAc (150mL), washed with brine (30mL), concentrated, and can be continued without further purification. Then 3-(2-methoxyethylamino)-4-nitro-benzoic acid methyl ester (20.0g, 78.7mmol) is dissolved in EtOAc:EtOH (1:1, 140mL), followed by the addition of 10% palladium on carbon (5.02g, 4.72mmol). The resulting suspension was stirred at room temperature under a hydrogen balloon 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 + ).

[0689] Intermediates I-2 and I-3

[0690]

[0691]

[0266] 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): To a mixture of 3-fluoro-4-(hydroxymethyl)benzonitrile (0.659 g, 4.36 mmol) and 2-bromo-6-chloro-3-methyl-pyridine (750 mg, 3.63 mmol) in THF (36.0 mL) was added potassium tert-butoxide (0.736 g, 6.56 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution, and the mixture was extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by column chromatography (0%-10% EtOAc / hexanes, then 1% MeOH / DCM) to give the title compound (inseparable mixture, approximately 2:1 ratio): ES / MS m / z: 321.2, 208.0 (M+H + ).

[0692] Intermediate I-4

[0693]

[0694] 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 slowly warmed 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 + ); 1 H 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).

[0695] Intermediate I-5

[0696]

[0697] 4-{[2-(4-bromo-2-fluoro-phenyl)acetyl]amino}-3-(2-methoxyethylamino)benzoic acid methyl ester: To a solution of 2-(4-bromo-2-fluoro-phenyl)acetic acid (1.00 g, 4.29 mmol) in DMF (20.0 mL) was added 4-amino-3-(2-methoxyethylamino)benzoic acid methyl ester (1.18 g, 5.28 mmol) and O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.96 g, 5.15 mmol), followed by addition of N,N-diisopropylethylamine (3.74 mL, 21.5 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The reactants were concentrated in vacuo, the residue was dissolved in EtOAc, and washed with water (1 x) and brine (1 x). 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 + ).

[0698] 2-[(4-Bromo-2-fluoro-phenyl)methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylic acid methyl ester: The crude product from the previous step, 4-{[2-(4-bromo-2-fluoro-phenyl)acetyl]amino}-3-(2-methoxyethylamino)benzoic acid methyl ester (1.89 g, 4.29 mmol) was dissolved in AcOH (40.0 mL) and the reaction mixture was heated to 60 ° C for 2 hours. The reaction mixture was concentrated in vacuo, and the crude residue was dissolved in DCM and washed with saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with DCM (2×). 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 / hexanes) to give the title compound: ES / MS m / z: 421.9 (M+H + ).

[0699] 2-{[2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-3-(2-methoxyethyl)benzimidazole-5-carboxylic acid methyl ester: To a vial was added 2-[(4-bromo-2-fluoro-phenyl)methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylic acid methyl ester (200 mg, 0.475 mmol), 4,4, 5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (145 mg, 0.570 mmol), (1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (33.6 mg, 0.0475 mmol) and potassium acetate (0.140 g, 1.42 mmol). 1,4-Dioxane (4.80 mL) was added and the reaction was heated to 100 ° C for 24 hours. The reaction mixture was filtered through Celite, eluted with DCM, and the filtrate was concentrated in vacuo. The crude residue was purified by column chromatography (0%-100% EtOAc / hexanes) to give the title compound: ES / MS m / z: 469.4 (M+H + ).

[0700] Intermediate I-6

[0701]

[0702] 4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile (I-6): 3-fluoro-4-(hydroxymethyl)benzonitrile (2 g, 13.2 mmol) was added to a dry 100 mL RBF. Under a nitrogen atmosphere, the material was dissolved in anhydrous THF (20 mL) at 0 ° C. 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 for 30 minutes under N2. 2,6-dibromopyridine (3.13 g, 13.2 mmol) was then added, and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc (100 mL) and water (20 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: EtOAc / hexanes) 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).

[0703] Intermediate I-7

[0704]

[0705] 3-Fluoro-4-[(6-tributyltin-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(tributyltin-2-pyridyl)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 showed clear product formation and the vial was cooled to room temperature. The mixture was dry loaded onto silica gel and purified by silica gel chromatography (eluent: hexanes, then EtOAc / hexanes) to give intermediate I-7: ES / MS: 517.402 (M+H + ).

[0706] Intermediate I-8

[0707]

[0708] 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) was dissolved in water (0.75 mL) and the mixture was stirred at 65 ° C for 1 hour. LCMS showed that the product was clearly formed, and the mixture was diluted with EtOAc (60 mL) and acidified with 1M HCl. The layers were separated and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layers were dried over MgSO 4 , filtered and concentrated under reduced pressure to give the product, which was used without further purification: ES / MS: 217.006 (M+H + ).

[0709] Intermediate I-9

[0710]

[0711] 6-Bromoisochroman-1-carboxylic acid (I-9): 2-(3-bromophenyl)ethanol (500 mg, 2.49 mmol) and glyoxylic acid monohydrate (458 mg, 4.97 mmol) were added to a 40 mL vial. 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 distributed between EtOAc (75 mL) and water (50 mL) and basified with 1 M NaOH. The layers were separated and the aqueous layer was washed again with EtOAc (50 mL). The aqueous layer was acidified with 1 M HCl (pH < 4) and extracted with EtOAc (3 × 75 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Intermediate I-9 was used without further purification.

[0712] Intermediate I-10

[0713]

[0714] 7-Bromochroman-4-carboxylic acid (I-10): Zinc (II) iodide (85 mg, 0.264 mmol) was added to a suspension of 7-bromochroman-4-one (1 g, 4.4 mmol) in THF (5 mL), followed by the dropwise addition of trimethylsilylcarbonitrile (1.65 mL, 13.2 mmol) via a syringe. The reaction was stirred at room temperature overnight, then diluted with EtOAc (50 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried over MgSO 4 , 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. The reaction was heated at 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 MgSO 4 , filtered, and concentrated. The material was determined to be of sufficient purity to proceed without further purification: 1 H 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).

[0715] Intermediate I-11

[0716]

[0717] Methyl 2-(4-bromo-2-hydroxyphenyl)acetate: To a solution of 2-(4-bromo-2-hydroxy-phenyl)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 MgSO . Concentration under reduced pressure gave the product, which was carried on without further purification: 1 H NMR (400MHz, CDCl3) δ7.14 (d, J = 2.0 Hz, 1H), 7.04 (dd, J = 8.1, 2.0 Hz, 1H), 6.97 (d, J = 8.1 Hz, 1H), 3.79 (s, 3H), 3.66 (s, 2H).

[0718] 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 solution (30 wt%, 4 mL) and acetonitrile (5 mL) was added chlorodifluoroacetophenone (972 mg, 5.1 mmol) at -78°C. 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 Et2O (3 x 50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: EtOAc / hexane) to give the product: 1 H 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).

[0719]

[0266] 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 partitioned between water (20 mL) and EtOAc (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 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.

[0720] Intermediate I-12

[0721]

[0722] Methyl 4-amino-3-(((1-methylcyclopropyl)methyl)amino)benzoate (I-12): Prepare methyl 4-amino-3-(((1-methylcyclopropyl)methyl)amino)benzoate as described for intermediate I-1, using (1-methylcyclopropyl)methanamine hydrochloride instead of methoxyethylamine: ES / MS: 235.1 (M+H + ).

[0723] Intermediate I-13

[0724]

[0725] Methyl 4-amino-3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)benzoate (I-13): Prepared as described for intermediate I-1, using (1-(fluoromethyl)cyclopropyl)methanamine 2,2,2-trifluoroacetic acid instead of methoxyethylamine: ES / MS: 253.3 (M+H + ).

[0726] Intermediate I-14

[0727]

[0728] Methyl 4-amino-3-((3-fluoro-2,2-dimethylpropyl)amino)benzoate (I-14): Prepare methyl 4-amino-3-((3-fluoro-2,2-dimethylpropyl)amino)benzoate as described for intermediate I-1, using 3-fluoro-2,2-dimethyl-propane-1-amine hydrochloride instead of methoxyethylamine: ES / MS: 255.4 (M+H + ).

[0729] Intermediate I-15

[0730]

[0731] Methyl 4-amino-3-((3,3-difluoro-2,2-dimethylpropyl)amino)benzoate (I-15): Prepare methyl 4-amino-3-((3,3-difluoro-2,2-dimethylpropyl)amino)benzoate as described for intermediate I-1, using 3,3-difluoro-2,2-dimethyl-propane-1-amine hydrochloride instead of methoxyethylamine: ES / MS: 273.2 (M+H + ).

[0732] Intermediate I-16

[0733]

[0734] Methyl 4-amino-3-(((1-cyanocyclopropyl)methyl)amino)benzoate (I-16): Prepare methyl 4-amino-3-(((1-cyanocyclopropyl)methyl)amino)benzoate as described for intermediate I-1, using 1-(aminomethyl)cyclopropanecarbonitrile hydrochloride instead of methoxyethylamine: ES / MS: 246.3 (M+H + ).

[0735] Intermediate I-17

[0736]

[0737] Methyl 4-amino-3-((2-cyano-methylpropyl)amino)benzoate (I-17): Prepare methyl 4-amino-3-(((1-cyanocyclopropyl)methyl)amino)benzoate as described for intermediate I-1, using 3-amino-2,2-dimethyl-propionitrile instead of methoxyethylamine: ES / MS: 248.4 (M+H + ).

[0738] Intermediate I-18

[0739]

[0740] Methyl 4-amino-3-((3-cyano-2,2-dimethylpropyl)amino)benzoate (I-18): Prepare methyl 4-amino-3-((3-cyano-2,2-dimethylpropyl)amino)benzoate as described for intermediate I-1, using 4-amino-3,3-dimethyl-butyronitrile instead of methoxyethylamine: ES / MS: 262.5 (M+H + ).

[0741] Intermediate I-19

[0742]

[0743] Methyl 4-amino-3-((oxetan-2-ylmethyl)amino)benzoate (I-19): Prepare methyl 4-amino-3-((oxetan-2-ylmethyl)amino)benzoate as described for intermediate I-1, substituting oxetan-2-ylmethylamine for methoxyethylamine: ES / MS: 237.0 (M+H + ).

[0744] Intermediate I-20

[0745]

[0746] 4-(((6-Chloropyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile: To a suspension of reagent grade 95% potassium tert-butoxide (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 minutes, then 2,6-dichloropyridine (4.6 g, 31.08 mmol) was added and stirred for 18 hours. The mixture was poured into saturated NH4Cl (20 mL) solution. EtOAc (20 mL) was added, and the mixture was stirred for 15 minutes. The resulting mixture was filtered through Celite, the organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x 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).

[0747] Intermediate I-21

[0748]

[0749] 1-(tert-Butyl) 3-methyl 2-(5-bromo-3-fluoropyridin-2-yl) malonate: To a 40 mL vial was added tert-butyl methyl 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 that the product was formed. The mixture was partitioned between EtOAc (50 mL) and water (20 mL), and the organic layer was separated, dried over MgSO4 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 in the next step: ES / MS: 348.470 (M+H + ).

[0750] 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 CH2Cl2 (10 mL). The mixture was stirred at room temperature overnight. LC / MS showed the formation of the product. The solvent was evaporated under reduced pressure to give the product as a trifluoroacetate salt: ES / MS: 248.347 (M+H + ).

[0751] 2-(5-Bromo-3-fluoro-2-pyridinyl)acetic acid (I-21): To a 40 mL RBF was added methyl 2-(5-bromo-3-fluoropyridin-2-yl)acetate (trifluoroacetate) (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 1N HCl. The resulting mixture was extracted 3 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 on without further purification: ES / MS: 234.159 (M+H + ).

[0752] Intermediate I-22

[0753]

[0754] Methyl 4-amino-3-(((1,1-dioxythiophen-2-yl)methyl)amino)benzoate (I-22): Prepare methyl 4-amino-3-(((1,1-dioxythiophen-2-yl)methyl)amino)benzoate as described for intermediate I-1, using (1,1-dioxythiophen-2-yl)methylamine hydrochloride instead of methoxyethylamine: ES / MS: 285.2 (M+H + ).

[0755] Intermediate I-23

[0756]

[0757] Methyl 4-amino-3-(((1-(cyanomethyl)cyclopropyl)methyl)amino)benzoate (I-23): Prepared as described for intermediate I-1, using 2-[1-(aminomethyl)cyclopropyl]acetonitrile hydrochloride instead of methoxyethylamine: ES / MS: 260.2 (M+H +).

[0758] Intermediate I-24

[0759]

[0760] 5-Amino-6-(((1-methylcyclopropyl)methyl)amino)picolinic acid methyl ester (I-24): 4-Amino-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester was prepared as described for intermediate I-1, using (1-methylcyclopropyl)methanamine hydrochloride instead of methoxyethylamine and 6-chloro-5-nitro-pyridine-2-carboxylic acid methyl ester instead of 3-fluoro-4-nitro-benzoic acid methyl ester: ES / MS: 236.3 (M+H + ).

[0761] Intermediate I-25

[0762]

[0763] 4-(((4-Bromothiazol-2-yl)oxy)methyl)-3-fluorobenzonitrile (I-25):

[0764] To a vial was 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 in vacuo 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).

[0765] Intermediate I-26

[0766]

[0767] 4-((3-Bromo-5-fluorophenoxy)methyl)-3-fluorobenzonitrile (I-26):

[0768] To a vial was 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 at 60° C. for 16 hours. The reaction mixture was poured into water and the precipitate was filtered off, washed with water and dried in vacuo 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).

[0769] Intermediate I-27

[0770]

[0771] 4-((3-Bromo-4-fluorophenoxy)methyl)-3-fluorobenzonitrile (1-27): The title compound was prepared according to the procedure as described for intermediate 1-26, substituting 3-bromo-4-fluoro-phenol for 3-bromo-5-fluoro-phenol: 1 H 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).

[0772] Intermediate I-28

[0773]

[0774] 4-((3-Bromo-5-cyanophenoxy)methyl)-3-fluorobenzonitrile (1-28): The title compound was prepared according to the procedure as described for intermediate 1-26, substituting 3-bromo-5-hydroxy-benzonitrile for 3-bromo-5-fluoro-phenol: 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).

[0775] Intermediate I-29

[0776]

[0777] 4-((3-Bromo-5-methoxyphenoxy)methyl)-3-fluorobenzonitrile (1-29): The title compound was prepared according to the procedure as 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).

[0778] Intermediate I-30

[0779]

[0780] 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. was added potassium tert-butoxide (0.982 g, 8.75 mmol) and the reaction mixture was stirred for 10 minutes. 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 hour and then heated to 50° C. for 3 hours. The reaction mixture was cooled to room temperature, poured into water, and the precipitate was filtered off and dried in vacuo to give the title compound as a mixture of Br / Cl isomers: ES / MS m / z: 321.1 (M+H + ),277.1(M+H + ).

[0781] Intermediates I-31, I-32, I-33 and I-34

[0782]

[0783] 4-nitro-3-((2,3-dimethoxy-3-oxopropyl) amino) tert-butyl benzoate: 3-amino-2-methoxy-propionic acid hydrochloride (355mg, 2.3mmol) is suspended in DCM / methanol (5mL, 3:1), and TMS diazomethane (2.0M, 1.1mL, 2.3mmol) is added until light yellow persists. The reactant is quenched by adding AcOH (about 1 drop), the reactant is concentrated to dryness, dissolved in MeTHF (3mL), and again concentrated to dryness. 3-fluoro-4-nitro-tert-butyl benzoate (500mg, 2.1mmol) and DIPEA (1.1mL, 6.2mmol) are added to the obtained crude amino ester dissolved in MeTHF (3mL). The mixture is stirred at 80°C overnight. The reaction was then cooled, diluted with EtOAc, washed with aqueous NH4Cl, dried over Na2SO4, filtered and concentrated: ES / MS: 355.1 (M+H + ).

[0784] Tert-Butyl 4-amino-3-[(2,3-dimethoxy-3-oxopropyl)amino]benzoate (I-31): Crude tert-butyl 4-nitro-3-((2,3-dimethoxy-3-oxopropyl)amino)benzoate (approximately 2.1 mmol) from the above reaction was mixed in ethanol (5 mL) with saturated aqueous NH4Cl (2.5 mL) and iron powder (579 mg, 10.4 mmol). The mixture was stirred at 60°C for 45 minutes, then cooled, diluted with EtOAc (10 mL), filtered through MgSO4 and Celite, concentrated to dryness, and purified by column chromatography (40%-85% EtOAc / hexanes) to give the title compound. ES / MS: 325.1 (M+H + ); 1 H NMR (400MHz, chloroform-d) δ7.47(dd,J=8.1,1.8Hz,1H),7.37(d,J=1.9Hz,1H),7.28(s,1H),6.68(d,J=8.1Hz,1H),4.11(dd, J=6.3,3.6Hz,1H),3.80(s,3H),3.56(dd,J=12.7,3.8Hz,1H),3.52(s,3H),3.44(dd,J=12.7,6.4Hz,1H),1.59(s,9H).

[0785]

[0146] Tert-Butyl 2-[[4-[6-[(4-Cyano-2-fluoro-phenyl)methoxy]-2-pyridinyl]-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-pyridinyl]-2-fluoro-phenyl]acetic 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, diluted with EtOAc and rinsed with NH4Cl aqueous solution, NaHCO3 aqueous solution 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 minutes, then at 85°C for 35 minutes, and at 90°C for 40 minutes. The reaction was then cooled to room temperature, concentrated to dryness, and purified by column chromatography (40%-85% EtOAc / hexane) 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.

[0786] I-33 and I-34: tert-Butyl 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridinyl]-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-pyridinyl]-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 cosolvent) to give two different stereoisomers (I-33 and I-34).

[0787] Intermediates I-35 and I-36 :

[0788]

[0789] 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-pyridinyl]-2-fluoro-phenyl]methyl]-3-(2,3-dimethoxy-3-oxopropyl)benzimidazole-5-carboxylate (I-33, peak 1) (151 mg, 0.23 mmol) was mixed 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 minutes, the reaction was diluted with EtOAc (5 mL) and aqueous HCl (1 M, 2 mL). The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated to give the title compound: ES / MS: 655.2 (M+H + ).

[0790] 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): A similar procedure was used to hydrolyze tert-butyl 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridinyl]-2-fluoro-phenyl]methyl]-3-(2,3-dimethoxy-3-oxo-propyl)benzimidazole-5-carboxylate. Peak 2: ES / MS: 655.2 (M+H + ).

[0791] Intermediates I-37, I-38, I-39, I-40, I-41 :

[0792]

[0793] 3-[[3-(tert-Butoxycarbonylamino)-2-methoxy-propyl]amino]-4-nitro-benzoic acid methyl ester (I-37): 3-Fluoro-4-nitro-benzoic acid methyl ester (1300 mg, 6.53 mmol), 2-methoxypropane-1,3-diamine (1020 mg, 9.79 mmol) and DIPEA (4.4 mL, 26 mmol) were mixed in MeTHF (10 mL) and stirred at 75 ° C for 3 hours. The reaction was cooled to RT, diluted with DCM (10 mL), and di-tert-butyl dicarbonate (4.3 g, 20 mmol) was added. After 30 minutes, the reaction was diluted with EtOAc (50 mL) and washed twice with aqueous NH4Cl solution and once with brine. The organic fraction was dried over Na2SO4, filtered, concentrated and purified by column chromatography to give the title compound: ES / MS: 384.0 (M+H + ).

[0794] 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 mixed with iron powder (1.05 g, 18.8 mmol) and saturated aqueous NH4Cl solution (4.7 mL) in ethanol (20 mL). The mixture was stirred at 60°C for 10 minutes, then cooled to RT, 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 + ).

[0795]

[0266] Methyl 3-[3-(tert-Butoxycarbonylamino)-2-methoxy-propyl]-2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridinyl]-2-fluoro-phenyl]methyl]benzimidazole-5-carboxylate (I-39): Methyl 4-amino-3-[[3-(tert-butoxycarbonylamino)-2-methoxy-propyl]amino]benzoate (I-38, 500 mg, 1.4 mmol), 2-[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridinyl]-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 minutes. The reaction was cooled, diluted with EtOAc and rinsed with NH4Cl aqueous solution, NaHCO3 aqueous solution and brine. The organic fraction was dried over Na2SO4, filtered and concentrated. The crude solid was dissolved in DCE / AcOH (1:2, 5 mL) and stirred at 80°C for 30 minutes, then cooled to room temperature, concentrated to dryness, and purified by column chromatography (40%-85% EtOAc / hexane) to give the title compound: ES / MS: 698.3 (M+H + ); 1 H NMR(400MHz, chloroform-d)δ8.13(s,1H),8.05(d,J=8.5Hz,1H),7.85(s,1H),7.78–7.63(m, 4H),7.48(dd,J=7.9,1.6Hz,1H),7.42(dd,J=9.2,1.5Hz,1H),7.37(d,J=7.5Hz,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).

[0796] 1-(3-Amino-2-methoxypropyl)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester Enantiomers 1 and 2 (I-40 and I-41): 3-[3-(tert-Butoxycarbonylamino)-2-methoxy-propyl]-2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridinyl]-2-fluoro-phenyl]methyl]benzimidazole-5-carboxylic acid methyl ester, obtained as a mixture of 2 stereoisomers, was separated by chiral SFC (IG column with 40% EtOH cosolvent) to give two different stereoisomers. The separated enantiomers were treated with TFA (65 equiv.) separately at RT for 5 min. The reaction was diluted with water, quenched with 1 M NaOH to pH 7 and extracted three times with DCM. The combined organic fractions were washed with aqueous NaHCO 3 and brine, then dried over Na 2 SO 4 , filtered and concentrated to give the title compound. ES / MS: 598.5 (M+H + ).

[0797] Intermediates I-42 and I-43 :

[0798]

[0799] 4-[[2-(4-bromo-2,6-difluoro-phenyl)acetyl]amino]-3-(2-methoxyethylamino)benzoic acid methyl ester: To a solution of 2-(4-bromo-2,6-difluoro-phenyl)acetic acid (3.67 g, 0.0146 mol), 4-amino-3-(2-methoxyethylamino)benzoic acid methyl ester (3.00 g, 0.0134 mol) and 2-(7-aza-1H-benzotriazole-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 RT. The reaction was diluted with EtOAc and washed with 5% LiCl, saturated NaHCO 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 + )

[0800] 2-[(4-Bromo-2,6-difluoro-phenyl)methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylic acid methyl ester (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 hours. The mixture was concentrated and chromatographed (eluent: EtOAc / hexanes) 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).

[0801] 2-[[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylic acid methyl ester (I-43): In a 200 mL round-bottom flask, 2-[(4-bromo-2,6-difluoro-phenyl)methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylic acid methyl ester (1000 mg, 2.28 mmol), A mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (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 / vacuum 3 times. Dioxane (24 mL) was added thereto 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 Celite plug, 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 treated with Et2O (2 mL) and sonicated to give a precipitate. Hexane was added thereto, 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, CDCl3) 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).

[0802] Intermediate I-44 :

[0803]

[0804] 3-(2-Methoxyethylamino)-4-nitro-benzonitrile: A solution of 3-fluoro-4-nitro-benzonitrile (2 g, 12.04 mmol), 2-methoxyethylamine (1.25 mL, 14.79 mmol) and N,N-diisopropylethylamine (3.2 mL, 18.37 mmol) in DMF was stirred at RT for two days. The mixture was diluted with EtOAc and washed twice with 5% LiCl and 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, CDCl3)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).

[0805] 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 x 50 mL). The aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate to give the title compound. ES / MS m / z: 265.2 (M+H + ); 1H NMR (400MHz, MeOD) δ8.32(d,J=8.8Hz,1H),7.77(d,J=1.8Hz,1H),7.35(dd,J=8.9,1. 8Hz, 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.

[0806] 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 three times with Ar vacuum. Pd / C (10%, 37.7 mg, 0.0354 mmol) was added and the mixture was stirred under a hydrogen balloon at RT overnight. The mixture was filtered through a Celite plug, 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 + )

[0807] Intermediate I-45 :

[0808]

[0809] 4-(Hydroxymethyl)-3-methoxy-benzonitrile: 4-Formyl-3-methoxy-benzonitrile (3.46 g, 0.0215 mol) was dissolved in MeOH (115 mL) and THF (115 mL) in a 500 mL round-bottom flask. The mixture was cooled to 0°C, and sodium borohydride (0.813 g, 0.0215 mol) was added portionwise. The mixture was stirred at 0°C under an N atmosphere for 2 hours. EtOAc (175 mL) was added, followed by the slow addition of water (50 mL) and NH4Cl (50 mL, gas evolution). Brine was added and the mixture was partitioned. The organic extract was dried over MgSO4 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 Rochelle's salt solution for 2 hours. 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).

[0810] 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.

[0811] 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 a mixture of benzyl alcohol and KOtBu was added via syringe over 5 minutes and stirred at -78 ° C for 1 hour. 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).

[0812] Intermediate I-46 :

[0813]

[0814] 3-Fluoro-4-[(3-iodo-2-pyridinyl)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 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 / hexanes) to give the title compound.

[0815] 1H NMR (400MHz, CDCl3) 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).

[0816] Intermediate I-47 :

[0817]

[0818] 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 RT. 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 + ); 1 H NMR (400MHz, CDCl3) 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 (ddd, 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).

[0819] Intermediate I-48 :

[0820]

[0821] N-(6-Bromo-2-pyridyl)benzamide (I-48): The title compound was prepared in the manner described for I-47, substituting benzoyl chloride for 4-cyano-2-fluoro-benzoyl chloride: ES / MS m / z: 277.0, 279.0 (M+H + ); 1H 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).

[0822] Intermediate I-49 :

[0823]

[0824] 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 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 / hexanes) to give the title compound. ES / MS: 366.9 (M+H + );

[0825] 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).

[0826] Intermediate I-50 :

[0827]

[0828] 4-[(6-Bromo-3-chloro-2-pyridinyl)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×). The organic extract was dried over sodium sulfate, concentrated and purified by silica gel column chromatography (eluent: EtOAc / hexanes) 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).

[0829] Intermediate I-51 :

[0830]

[0831] 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 (3x). The organic extract was dried over sodium sulfate, concentrated and purified by silica gel column chromatography (eluent: EtOAc / hexanes) to give the title product. ES / MS: 247.0 (M+H + ); 1 H NMR (400MHz, chloroform-d) δ7.73(q,J=8.0Hz,1H),7.67(t,J=7.5Hz,1H),7.50(dd,J=7.9,1.6Hz,1H),7.41(d d,J=9.3,1.6Hz,1H),6.73(dd,J=8.0,1.6Hz,1H),6.56(dd,J=7.8,2.4Hz,1H),5.48(d,J=1.2Hz,2H); 19 F NMR (376 MHz, chloroform-d) δ -70.47 (d, J = 8.7 Hz), -112.50–-117.78 (m).

[0832] Intermediate I-52

[0833]

[0834] 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. 1 H 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).

[0835] Intermediate I-53

[0836]

[0837] 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 in the manner described for I-1 using chloro-[(3-ethyl-2-methyl-imidazol-4-yl)methyl]-imino-λ5-chloroethane instead of methoxyethylamine. ES / MS: 289.3 (M+H + ).

[0838] Intermediate I-54

[0839]

[0840] tert-Butyl 4-amino-3-(((1-ethyl-1H-pyrazol-5-yl)methyl)amino)benzoate (I-54): Prepare tert-Butyl 4-amino-3-(((1-ethyl-1H-pyrazol-5-yl)methyl)amino)benzoate as described for I-1, but using (1-ethyl-1H-pyrazol-5-yl)methanamine instead of methoxyethylamine. ES / MS: 317.4 (M+H + ).

[0841] Intermediate I-55

[0842]

[0843] Methyl 4-amino-3-(((1-(2-methoxyethyl)-1H-imidazol-5-yl)methyl)amino)benzoate (I-55): Prepare methyl 4-amino-3-(((1-(2-methoxyethyl)-1H-imidazol-5-yl)methyl)amino)benzoate as described for I-1, using (1-(2-methoxyethyl)-1H-imidazol-5-yl)methanamine instead of methoxyethylamine: ES / MS: 305.4 (M+H + ).

[0844] Intermediate I-56

[0845]

[0846] Methyl 4-amino-3-((pyrimidin-5-ylmethyl)amino)benzoate (I-56): Prepare methyl 4-amino-3-((pyrimidin-5-ylmethyl)amino)benzoate as described for I-1, using pyrimidin-5-ylmethylamine instead of methoxyethylamine. ES / MS: 259.3 (M+H + ).

[0847] Intermediate I-57

[0848]

[0849] Methyl 4-amino-3-(((3-ethylpyridin-4-yl)methyl)amino)benzoate (I-57): Prepare methyl 4-amino-3-(((3-ethylpyridin-4-yl)methyl)amino)benzoate as described for I-1, using (3-ethyl-4-pyridinyl)methanamine instead of methoxyethylamine: ES / MS: 286.3 (M+H + ).

[0850] Intermediate I-58

[0851]

[0852] Methyl 4-amino-3-(benzylamino)benzoate (I-58): Prepare methyl 4-amino-3-(benzylamino)benzoate as described for I-1, using phenylmethylamine instead of methoxyethylamine. ES / MS: 257.3 (M+H + ).

[0853] Intermediate I-59

[0854]

[0855] 4-(((6-Bromopyridin-2-yl)oxy)methyl)benzonitrile (I-59): 4-(((6-Bromopyridin-2-yl)oxy)methyl)benzonitrile was prepared 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).

[0856] Intermediate I-60

[0857]

[0858] 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 as described for intermediate I-5, using 2-(4-bromo-2-cyano-6-fluorophenyl)acetic acid instead of 2-(4-bromo-2-fluoro-phenyl)acetic acid. ES / MS: 488.7 (M+H + ).

[0859] Intermediate I-61

[0860]

[0861] 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 dissolved 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 hours. After completion, the mixture was cooled to RT 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 4 , filtered and concentrated in vacuo. The residue was then purified by normal phase column chromatography (eluent: EtOAc / hexane gradient) to give the title compound.

[0862] Intermediate I-62

[0863]

[0864] Ethyl 3,5-difluoro-4-nitrobenzoate: Ethyl 4-amino-3,5-difluorobenzoate (5.00 g, 24.9 mmol) was dissolved in acetic acid (50.0 mL), and sulfuric acid (12.1 M, 2.05 mL, 24.9 mmol) and hydrogen peroxide (30% in water, 46.7 mL, 74.6 mmol) were added sequentially. The mixture was heated to 100°C for 1 hour. The mixture was then cooled to room temperature and then slowly poured into 300 mL of ice water while rotating. The mixture was then diluted with EtOAc (200 mL), transferred to a separatory funnel, and the organic phase was collected. The aqueous phase was extracted with EtOAc (2×100 mL), and the combined organics were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc / hexane gradient) to give the product.

[0865] (S)-3-Fluoro-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoic acid ethyl ester: 3,5-Difluoro-4-nitro-benzoic acid ethyl ester (2.50 g, 10.8 mmol) and (S)-oxetan-2-ylmethylamine (989 mg, 11.4 mol) were dissolved 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 hours. Thereafter, 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 + ).

[0866] (S)-4-amino-3-fluoro-5-((oxetan-2-ylmethyl)amino)ethyl benzoate (I-62): (S)-3-fluoro-4-nitro-5-((oxetan-2-ylmethyl)amino)ethyl benzoate (2.20 g, 7.38 mmol) was dissolved in ethanol (10 mL) and tetrahydrofuran (5 mL), and the mixture was bubbled with nitrogen for 5 minutes. Palladium on carbon (10 wt % loading, 785 mg, 0.74 mmol) was then added and bubbling continued for 5 minutes. The solution was then bubbled with hydrogen for one minute, and the mixture was then placed under a hydrogen atmosphere balloon for 21 hours. After this, 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 afford (S)-ethyl 4-amino-3-fluoro-5-((oxetan-2-ylmethyl)amino)benzoate (I-62). ES / MS: 269.2 (M+H + );1 H NMR (400 MHz, chloroform) δ 7.44–7.30 (m, 2H), 5.13 (qd, J = 7.1, 3.4 Hz, 1H), 4.72 (ddd, J = 8.7, 7.4, 6.0 Hz, 1H), 4.62 (dt, J = 9.1, 6.1 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.58–3.30 (m, 2H), 2.76 (dtd, J = 11.4, 8.0, 6.1 Hz, 1H), 2.56 (ddt, J = 11.3, 9.0, 7.1 Hz, 1H), 1.37 (t, J = 7.1 Hz, 3H).

[0867] Intermediate I-63

[0868]

[0869] Methyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-1H-benzo[d]imidazole-6-carboxylate (I-63): 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-1H-benzo[d]imidazole-6-carboxylate was prepared identically to that 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-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-1H-benzo[d]imidazole-6-carboxylate: ES / MS: 511.2 (M+H + ).

[0870] Intermediate I-64

[0871]

[0872] 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 dissolved 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. Thereafter, 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 dissolved in acetic acid (20 mL) and heated to 75°C. After 7 hours, the mixture was concentrated in vacuo and diluted with EtOAc (50 mL). The organic phase was washed with saturated NaHCO3 aqueous solution (20 mL) and the aqueous phase was extracted with EtOAc (2×50 mL). The combined organic phases 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 + ).

[0873]

[0266] 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. After this, LC / MS showed that the aryl bromide was converted into the intermediate boronic acid, and the mixture was cooled to room temperature. At this time, aqueous sodium carbonate solution (1.5M, 1.56mL, 2.34mmol) was added, followed by Pd(dppf)Cl2 (54mg, 0.078mmol) and 4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluoro-benzonitrile (I-6, 360mg, 1.17mmol). The bottle was resealed and heated to 90°C for 3 hours. After this, the mixture was cooled to room temperature and diluted with EtOAc (50mL) and water (50mL). The organic phase was collected and the aqueous phase was extracted with EtOAc (2×50mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel chromatography (eluent: 20%-80% EtOAc / hexane) to obtain the desired product: ES / MS: 596.2 (M+H + ).

[0874] 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 dissolved 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 hours, 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 (2×10 mL). The combined organic phases were dried over Na 2 SO 4 and concentrated in vacuo. The crude material was purified by silica gel chromatography (eluent: 20%-80% EtOAc / hexane) to give the desired product. ES / MS: 566.3 (M+H + ).

[0875] Intermediate I-65

[0876]

[0877] 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 as described for I-64, substituting 2-(4-bromo-2-nitrophenyl)acetic acid for 2-(4-bromo-3-nitrophenyl)acetic acid. ES / MS: 566.2 (M+H + ).

[0878] Intermediate I-66

[0879]

[0880] Methyl 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): 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, 26 mg, 0.0460 mmol) and copper(I) bromide (20 mg, 0.140 mmol) were suspended in EtOAc (1.0 mL) and MeCN (1.0 mL). After stirring for 5 minutes, tBuONO was added and the mixture was stirred at RT for 3 hours. The residue was then diluted with EtOAc (20 mL) and washed with saturated aqueous NH4Cl solution (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 / hexanes) to give the desired product. ES / MS: 631.0 (M+H + ).

[0881] Intermediate I-67

[0882]

[0883] 2-(2-bromo-4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (I-67): As described for I-66, using 2-(2-amino-4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester 2-(2-bromo-4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester was prepared by replacing 2-(3-amino-4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (I-64) with ester (I-65). ES / MS: 631.1 (M+H + ).

[0884] Intermediate I-68

[0885]

[0886] 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-methoxyethylamine (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. Afterwards, the mixture was concentrated to remove most of the THF and the crude material was dissolved in EtOAc (400 mL). The organics were washed with 50% NH4Cl (2×100 mL) and brine (1×50 mL). The organics were then dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was carried forward without further purification: ES / MS: 297.1 (M+H + ); 1 H NMR (400 MHz, chloroform-d) δ 8.21 (d, J = 8.9 Hz, 1H), 7.55 (d, J = 1.7 Hz, 1H), 7.20 (dd, J = 8.9, 1.7 Hz, 1H), 3.72 (dd, J = 5.8, 4.8 Hz, 2H), 3.57 (q, J = 5.2 Hz, 2H), 3.46 (s, 3H), 1.62 (s, 9H).

[0887] 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 ultrasonicated until all the material 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 overnight under a hydrogen balloon. Subsequently, nitrogen was bubbled through the flask for 10 minutes, and the mixture was then filtered through Celite to remove the catalyst. The filtrate was concentrated under reduced pressure, and it was used without further purification: ES / MS: 267.2 (M+H + ).

[0888] Intermediate I-69

[0889]

[0890]

[0266] 5-Bromo-2-((6-(methoxycarbonyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)methyl)benzoic acid: To a 100 mL 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). After the mixture was stirred at 55 °C for 16 hours, AcOH (6 mL) was added and the mixture was stirred at 60 °C for 24 hours. Analysis by LCMS showed conversion to the desired product. The volatiles were evaporated and the crude mixture was triturated with Et2O (20 mL). The resulting solid was dried under vacuum and carried forward: ES / MS: 447.6 (M+).

[0891]

[0266] Methyl 2-(4-bromo-2-(hydroxymethyl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (I-69): In a 100 mL RBF, under nitrogen atmosphere, 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 anhydrous THF (20 mL), 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 slowly added to quench the residue, followed by water (10 mL) and EtOAc (50 mL). The layers were separated, and the aqueous layer was extracted once with EtOAc (20 mL). The combined organic layers were dried over MgSO 4 , filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (eluent: EtOAc / hexanes) to afford I-69. ES / MS: 433.1 (M+).

[0892] Intermediate I-70

[0893]

[0894]

[0266] 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 minutes, 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 directly added to a silica loading column. The crude material was purified by silica column chromatography (eluent: EtOAc / hexanes) to afford I-70. ES / MS:447.1(M+).

[0895] Intermediate I-71

[0896]

[0897]

[0266] 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 dichloromethane (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 minutes. 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 / hexanes) to afford I-71. ES / MS:435.1(M+).

[0898] Intermediate I-72

[0899]

[0900] 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 hour. LCMS showed a mixture of two products (O-alkylated and N-alkylated) favoring the more polar product (N-alkylated). 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 / hexane) to afford I-72. ES / MS: 438.1 (M+).

[0901] Intermediate I-73

[0902]

[0903] 2-Bromo-6-((4-chloro-2-fluorobenzyl)oxy)pyridine (I-73): Prepare 2-bromo-6-((4-chloro-2-fluorobenzyl)oxy)pyridine as described for I-6, using (4-chloro-2-fluorophenyl)methanol instead of 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).

[0904] Intermediate I-74

[0905]

[0906] 2-Bromo-6-((4-chloro-2-methoxybenzyl)oxy)pyridine (I-74): Prepare 2-bromo-6-((4-chloro-2-methoxybenzyl)oxy)pyridine as described for I-6, using (4-chloro-2-methoxyphenyl)methanol instead of 3-fluoro-4-(hydroxymethyl)benzonitrile. ES / MS: 329.9 (M+H + ); 1H NMR (400 MHz, chloroform-d) δ 7.49–7.39 (m, 2H), 7.09 (d, J = 7.4 Hz, 1H), 6.97 (dd, J = 8.1, 2.0 Hz, 1H), 6.91 (d, J = 1.9 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 5.37 (s, 2H), 3.88 (s, 3H).

[0907] Intermediate I-75

[0908]

[0909]

[0114] 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 hour. The mixture was then cooled and filtered through Celite to remove the solid precipitate, rinsing with EtOAc. The filtrate was concentrated, and the crude residue was purified by silica chromatography (eluent: EtOAc / hexanes) to afford I-75. ES / MS: 319.1 (M+).

[0910] Intermediate I-76

[0911]

[0912] 4-(((4-Bromopyrimidin-2-yl)oxy)methyl)-3-fluorobenzonitrile (I-76): Prepare 4-(((4-Bromopyrimidin-2-yl)oxy)methyl)-3-fluorobenzonitrile by using 3-fluoro-4-(hydroxymethyl)benzonitrile instead of 4-(hydroxymethyl)-3-methoxy-benzonitrile as described for I-45. 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).

[0913] Intermediate I-77

[0914]

[0915] 4-Bromo-2-((4-chloro-2-fluorobenzyl)oxy)pyrimidine (I-77): Prepare 4-bromo-2-((4-chloro-2-fluorobenzyl)oxy)pyrimidine as described for I-45, using (4-chloro-2-fluorophenyl)methanol instead of 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).

[0916] Intermediate I-78

[0917]

[0918] 4-Bromo-2-((4-chloro-2-methoxybenzyl)oxy)pyrimidine (I-78): Prepare 4-bromo-2-((4-chloro-2-methoxybenzyl)oxy)pyrimidine as described for I-45, using (4-chloro-2-methoxyphenyl)methanol instead of 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).

[0919] Intermediate I-79

[0920]

[0921] 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), Cs2CO3 (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 x 10 mL) and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica chromatography (eluent: EtOAc / hexanes) to afford 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).

[0922] Intermediate I-80

[0923]

[0924] Methyl 2-((4-bromo-6-methyl-2-oxopyridin-1(2H)-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (I-80): Prepare methyl 2-((4-bromo-6-methyl-2-oxopyridin-1(2H)-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate as described for I-72, substituting 4-bromo-5-fluoro-1H-pyridin-2-one with 4-bromo-6-methylpyridin-2(1H)-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).

[0925] Intermediate I-81

[0926]

[0927] 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(neopentylethylene glycol)diboron (17.9 g, 79.2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, PdCl(dppf) (2.94 g, 3.96 mmol), and potassium propionate (15.6 g, 139 mmol) in dioxane (50 mL) was degassed with Ar for 20 minutes. The mixture was sealed and heated at 100°C for 2 hours. Sodium carbonate (2.0 M, 39.6 mL, 79.2 mmol) was added, and the mixture was stirred at RT for 10 minutes. [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, 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 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 + ).

[0928] 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 hours. The mixture was acidified with 1N hydrochloric acid to pH = 6-7. The material precipitated and was filtered through a filter funnel. The solid was washed with water and dried overnight to give the product: ES / MS: 399.2 (M+H + ); 1 H NMR (400 MHz, methanol-d4) δ 7.83–7.77 (m, 1H), 7.78–7.65 (m, 2H), 7.64–7.59 (m, 2H), 7.58–7.51 (m, 1H), 7.26–7.14 (m, 1H), 6.91 (d, J = 8.2 Hz, 1H), 5.63 (s, 2H), 3.73 (d, J = 1.2 Hz, 2H).

[0929] Intermediate I-82

[0930]

[0931] 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 for I-81, using methyl 2-(4-bromo-3-fluorophenyl)acetate instead of methyl 2-(4-bromo-2,5-difluorophenyl)acetate. ES / MS: 381.2 (M + H + ); 1 H NMR (400 MHz, methanol-d4) δ 7.92 (t, J = 8.2 Hz, 1H), 7.76 (dt, J = 14.4, 7.6 Hz, 2H), 7.66–7.55 (m, 2H), 7.49 (dd, J = 7.3, 1.8 Hz, 1H), 7.27–7.12 (m, 2H), 6.88 (d, J = 8.1 Hz, 1H), 5.63 (s, 2H), 3.70 (s, 2H).

[0932] Intermediate I-83

[0933]

[0934] 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 for I-82, using 4-(((4-bromopyrimidin-2-yl)oxy)methyl)-3-fluorobenzonitrile (I-76) instead of 4-(((6-bromopyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (I-6). 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).

[0935] Intermediate I-84

[0936]

[0937] 4-(((2-Chloro-5-fluoropyrimidin-4-yl)oxy)methyl)-3-fluorobenzonitrile (I-84): 4-(((2-Chloro-5-fluoropyrimidin-4-yl)oxy)methyl)-3-fluorobenzonitrile was prepared as described for I-25, substituting 2,4-dichloro-5-fluoropyrimidine for 4-bromo-2-chloro-thiazole. ES / MS: 282.2 [M+H] + .

[0938] Intermediate I-85

[0939]

[0940] 2-(4-(2-chloro-5-fluoropyrimidin-4-yl)-2,5-difluorobenzyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (I-85):

[0941] To a vial containing methyl 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 for 60 seconds, then the vial was sealed and thermally heated at 115° C. for 45 minutes. To the cooled mixture was added 2,4-dichloro-5-fluoropyrimidine (10.5 mg, 0.063 mmol), Pd(dppf)Cl2 (3.5 mg, 0.0047 mmol) and aqueous sodium carbonate (2 M, 63 μL, 0.13 mmol). The mixture was degassed by bubbling argon for 60 seconds, then the vial was sealed and heated at 90 ° C for 4 hours. The cooled mixture was filtered through a Celite pad (eluent: EtOAc), concentrated, and purified by silica gel chromatography (eluent: EtOAc / hexane) to give the desired product. ES / MS: 527.0 [M + H] + .

[0942] Intermediate I-86

[0943]

[0944] 4-[[(6-Chloro-2-pyridinyl)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 to 120 °C for 12 hours. The crude solution was concentrated under reduced pressure and purified by silica column chromatography (50%-100% EtOAc / hexanes) to give the title compound. ES / MS: 262.2 (M+H + ).

[0945] Intermediate I-87

[0946]

[0947] 4-(((6-Chloropyridin-2-yl)amino)methyl)-3-methoxybenzonitrile (I-87): 4-(((6-Chloropyridin-2-yl)amino)methyl)-3-methoxybenzonitrile was prepared according to the procedure of I-86 using 4-(aminomethyl)-3-fluoro-benzonitrile hydrochloride instead of 4-(aminomethyl)-3-methoxybenzonitrile. ES / MS: 274.1 (M+H + ).

[0948] Intermediate I-88

[0949]

[0950] 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 THF. The vial was sealed and the mixture was heated to 80 ° C for 16 hours. The mixture was cooled to RT, concentrated, and purified on a silica gel column (35%-100% EtOAc / hexanes) to give the title compound: ES / MS: 354.9 (M+H + ).

[0951] Intermediate I-89 :

[0952]

[0953] 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 THF. The vial was sealed and the mixture was heated to 80 ° C for 16 hours. The mixture was cooled to RT, concentrated, and purified on a silica gel column (35%-100% EtOAc / hexanes) to give the title compound. ES / MS: 363.8 (M+H + ).

[0954] Intermediate I-90

[0955]

[0956] 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 hours. The mixture was cooled to RT, concentrated, and purified on a silica gel column (35%-100% EtOAc / hexanes) to give the title compound: ES / MS: 308.1 (M+).

[0957] Intermediate I-91

[0958]

[0959] 2-[(2-Fluorophenyl)methoxy]-3-iodo-pyridine (I-91): To a microwave vial was added 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 THF. The vial was sealed and the mixture was heated to 80° C. for 16 hours. The mixture was cooled to RT, concentrated, and purified on a silica gel column (35%-100% EtOAc / hexanes) to give the title compound: ES / MS: 329.9 (M+H + ).

[0960] Intermediate I-92

[0961]

[0962] 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, but using 2-chloro-3-iodo-pyridine instead of 4-chloro-5-iodo-pyrimidine. ES / MS: 356.0 (M+H + ).

[0963] Intermediate I-93

[0964]

[0965] 3-Fluoro-4-[(3-iodo-4-pyridinyl)oxymethyl]benzonitrile (I-93): 3-Fluoro-4-[(3-iodo-4-pyridinyl)oxymethyl]benzonitrile was prepared according to the procedure of I-88, but using 2-chloro-3-iodo-pyridine instead of 4-chloro-3-iodo-pyridine. ES / MS: 354.9 (M+H + ).

[0966] Intermediate I-94

[0967]

[0968] 4-[(2-Bromophenoxy)methyl]-3-fluoro-benzonitrile (I-94): 4-[(2-Bromophenoxy)methyl]-3-fluoro-benzonitrile was prepared following procedure I-88, but substituting 2-chloro-3-iodo-pyridine for 2-bromophenol and 4-cyano-2-fluorobenzyl bromide for 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, 1.4 Hz, 1H), 6.94 (td, J = 7.7, 1.4 Hz, 1H), 5.33 (s, 2H).

[0969] Intermediate I-95

[0970]

[0971] 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, washed with water, and dried under vacuum to give the title compound: 1H 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).

[0972] Intermediate I-96

[0973]

[0974] 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) was added 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), followed by 99.5% purification of N,N-diisopropylethylamine (1.12 mL, 6.44 mmol) by redistillation, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo, dissolved in EtOAc, and washed with water (1×) and brine (1×). 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 hours. The mixture was concentrated in vacuo, the crude residue was dissolved in DCM and washed with saturated aqueous sodium bicarbonate solution. The layers were separated, and the aqueous layer was extracted with DCM (2×). 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 / hexane) to give the title compound. ES / MS m / z:458.1 (M+H + ).

[0975] Intermediate I-97

[0976]

[0977] Methyl 2-(4-bromo-3-fluorobenzyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (I-97): Methyl 2-(4-bromo-3-fluorobenzyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate was prepared as described for I-96, substituting methyl 4-amino-3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)benzoate for methyl 4-amino-3-(((1-(cyanomethyl)cyclopropyl)methyl)amino)benzoate. ES / MS: 469.0 (M+H + ).

[0978] Intermediate I-98

[0979]

[0980] 4-(((4-Bromoisothiazol-3-yl)oxy)methyl)-3-fluorobenzonitrile (I-98): 4-(((4-Bromoisothiazol-3-yl)oxy)methyl)-3-fluorobenzonitrile was prepared as described for I-95, substituting 4-(bromomethyl)-3-fluoro-benzonitrile for 1-(bromomethyl)-4-chloro-2-fluoro-benzene. 1 H NMR (400 M...

Claims

1. A compound of formula (Ib-1) or a pharmaceutically acceptable salt thereof: in Ring B is C 6-10 Aryl, the C 6-10 The aryl group is optionally substituted by one to four R 4 replace; R 2 for X 1 , X 2 and X 3 Each is -C(H)=; R 3 is -C(O)OH; Each R 4 Independently for C 1-6 Alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkoxyalkyl, halogen, oxo, -CN or -OR 4a ; V is -CH2-; Each Z 1 are independently halogen, C 1-6 Haloalkyl, C 1-3 Alkoxy, C 3-10 Cycloalkyl or -CN; R 4a H, C 1-9 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-15 Cycloalkyl, heterocyclic, C 6-10 aryl or heteroaryl; wherein each heteroaryl has 5 to 12 ring members and has 1 to 4 heteroatoms each independently being N, O or S; wherein each heterocyclyl has 3 to 12 ring members and has 1 to 4 heteroatoms each independently being N, O or S; subscript p is 1, 2, or 3; and The subscript q is 0.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring B is The groups are each optionally substituted by one or two R 4 replace.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring B is The groups are each optionally substituted by one or two R 4 replace. 4 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring B is substituted with one or two halogens.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Each R 4 Independently for C 1-6 Alkyl, halogen, oxo, -CN or -OR 4a .

6. The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein Each R 4 Independently for C 1-6 Alkyl, halogen, oxo, -OH or -CN.

7. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein Each R 4 are independently F, oxo or -CN.

8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein The subscript p is 1 or 2.

9. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is:

10. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

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