GLP-1R modulating compounds

Abstract

The present disclosure provides GLP-1R agonists, and compositions, methods, and kits thereof. Such compounds are generally useful in the treatment of GLP-1R mediated diseases or disorders. # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese invention patent application (application date: January 27, 2021; application number: 202180009387.5 (international application number: PCT / US2021 / 015197); invention name: GLP-1R regulating compounds).

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 967,289, filed January 29, 2020. The entire contents of that application are incorporated herein by reference in their entirety. Technical Field

[0004] 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

[0005] 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.

[0006] GLP-1R agonists are currently being studied in conjunction with 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.

[0007] 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

[0008] In one embodiment, the present disclosure provides compounds of formula (I):

[0009]

[0010] or a pharmaceutically acceptable salt thereof, wherein

[0011] 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, -C(O)N(R 1b )(R 1c ),-C(O)R 1b or-C(O)OR 1c ,

[0012] wherein the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl groups are each optionally substituted by one to four Z 1 replace;

[0013] Ring A is an aromatic ring, wherein U 1 、U 2 、U 3 Each independently represents -C(H)=, -C(Z 1a )=or-N=;

[0014] Ring B is C 6-10 aryl or heteroaryl, each of which is optionally substituted by one to four R 4 replace;

[0015] 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, -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 ,

[0016] wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1 replace;

[0017] X 1 、X 2 and X 3 Each independently represents -N=, -C(H)= or -C(R 8 )=;

[0018] Y 1 and Y 2 Each is -C(R y1 )(R y2 )-、-N(R y1 )-, -O-, -S-, -S(O)2- or -C(O)-;

[0019] W is -C(R 5 )-or-N-,

[0020] When W is -N, Y 1 and Y 2 One of them is -C(R y1 )(R y2 )-or-C(O)-and Y 1 and Y 2 The other one is -C(R y1 )(R y2 )-, -C(O)- or -S(O)2-;

[0021] 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)NR3a 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 each of the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups is optionally substituted by one to four R 3d replace;

[0022] 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, -C1-4 alkyl - heterocyclic group, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, 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)、-OCH(2)P(O)(R 9c )(N(R 9d)2) or -C(O)OCH2P(O)(R 9c )(N(R 9d )2);

[0023] wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace,

[0024] 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 )(R4b )、-S(O)(NR 4a )R 4b or -Si(R 4a )3;

[0025] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace;

[0026] 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 heterocyclyl, each of which is optionally substituted by one to four Z 1b replace;

[0027] R 5 is H, cyclopropyl or C 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted by one, two or three groups selected from halogen, -OH, -OCH3, -CN, oxo and -N(R x1 )(R x2 ) group substitution;

[0028] or R 5 and R y1 Combined with the atoms to which they are attached to form a C optionally substituted with an oxo group 3-10 a cycloalkyl group or a heterocyclic group;

[0029] R x1 and R x2 Each independently is H, C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, -S(O)2R 6a1 or -S(O)2N(R 6a1 )(NR 6a2 ), wherein the C 1-6 Alkyl, cycloalkyl or heterocyclyl are each optionally replaced by F, -CN, oxo or C 3-6 cycloalkyl substitution;

[0030] or R x1 and R x2 Combined with the atoms to which they are attached to form a heterocyclic group, the heterocyclic group is optionally substituted by one to four R 6b1 replace;

[0031] V is -C(O)-, -O-, -N(R 6a )-or-C(R 6b )(R 6c )-;

[0032] R6a 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 groups are each optionally replaced by C 1-6 Alkyl, F or -CN substitution;

[0033] 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;

[0034] or R 6b and R 6c Combine with the atoms to which they are attached to form C 3-10 Cycloalkyl or heterocyclyl, each of which is optionally substituted by one to four R 6b1 replace;

[0035] 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 heterocyclyl, each of which is optionally substituted by one to four R 10 replace;

[0036] Each R y1 and R y2 are independently H, halo, C 1-6 Alkyl, C 1-6 haloalkyl, wherein the alkyl and haloalkyl are each optionally substituted with oxo;

[0037] Each R 3d 、R 6b1 and R 10 Independently C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6Halogenated 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 -C(O)N(R 2a )(R 2b ), 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

[0038] Each R 6a1 、R 6a2 、R 6c1 、R 6c2 and R 6c3 Independently H, C 1-6 Alkyl or C 3-10 Cycloalkyl;

[0039] Each R 9a and R 9b Independently H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0040] 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;

[0041] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1a replace;

[0042] 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;

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

[0044] 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(C2-6 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 3-15 Cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(C6-10 aryl), -C(O)NH(heteroaryl), -C(O)N(C 1-9 Alkyl)2, -C(O)N(C 1-8 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 3-15 Cycloalkyl), -S(heterocyclyl), -S(C 6-10aryl), -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;

[0045] wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group 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 3-15Cycloalkyl), -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; and

[0046] 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;

[0047] wherein each heteroaryl group has 5 to 12 ring members and has one to four heteroatoms each independently being N, O, or S; and

[0048] wherein each heterocyclyl has 3 to 12 ring members and has one to four heteroatoms each independently being N, O or S.

[0049] The present disclosure also provides pharmaceutical compositions, methods, and uses comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.For example, the compounds of the present disclosure can generally be used in methods of treating a GLP-1R-mediated disease or condition. DETAILED DESCRIPTION

[0050] I. Definition

[0051] 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.

[0052] "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.

[0053] "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.

[0054] "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.

[0055] "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.

[0056] "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 (ie, 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.

[0057] "Halogen" refers to fluorine (-F), chlorine (-Cl), bromine (-Br) and iodine (-I).

[0058] "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.

[0059] "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.

[0060] "Cycloalkyl" is a monovalent or divalent single all-carbon ring or a polycondensed all-carbon ring system, wherein the ring is a non-aromatic saturated or unsaturated ring in each instance. 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 system 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.

[0061] "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.

[0062] 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.

[0063] "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.

[0064] 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.

[0065] "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 having from 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.

[0066] "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 multiple fused ring systems are further described below. Thus, "heteroaryl" includes a single aromatic ring having from about 1 to 6 carbon atoms and from about 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur. The sulfur and nitrogen atoms may also be present in oxidized form, provided that the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridinyl, pyrimidinyl, oxazolyl or furyl. "Heteroaryl" also includes multiple fused ring systems (for example, ring systems comprising 2, 3 or 4 rings), wherein the heteroaryl group as defined above is fused to one or more rings selected from heteroaryl (to form, for example, 1,8-naphthyridinyl) and fused 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 multiple 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 multiple fused ring system may be interconnected by fused bonds. It should be understood that the individual rings of the multiple 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 polycondensed ring system may be located on any suitable atom of the heteroaryl or heteroaryl polycondensed ring system, including carbon atoms and heteroatoms (e.g., nitrogen). It should also be understood that when a certain atomic range unit heteroaryl (e.g., 5 to 10 member heteroaryl) is cited, the atomic range is the total ring atoms of the heteroaryl and includes carbon atoms and heteroatoms. It should also be understood that the ring of the polycondensed ring system may include an aryl ring fused to a heterocycle (e.g., 3, 4, 5, 6 or 7 membered ring) having a saturated or partially unsaturated bond, 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 heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, Azolyl, iso oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzo Azolyl, indazolyl, quinol quinazolinyl, benzofuranyl, benzimidazolyl, thienyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl and tetrazolyl. Heteroaryl groups can be unsubstituted or substituted.

[0067] "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 having 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.

[0068] As used herein, "oxo" refers to =0.

[0069] 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.

[0070] "Compounds of the present disclosure" include compounds disclosed herein, for example, compounds of the present disclosure include compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), including the compounds of the Examples.

[0071] "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 as acceptable for use in humans or veterinary animals.

[0072] 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 is sufficient to affect such treatment of a disease when administered to a subject to treat 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 a desired or beneficial result can be achieved or realized in combination with one or more other agents, 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).

[0073] 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 administration of 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 administration of 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 administration of a unit dose of one or more additional therapeutic agents a few hours (e.g., 1 hour to 12 hours) later. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound of the present disclosure a few hours (e.g., 1 hour to 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.

[0074] 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.

[0075] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts or, where appropriate, as free bases. A "pharmaceutically acceptable salt" is a non-toxic salt of the free base form of a compound that possesses the desired pharmacological activity of the free base. These salts can be derived from inorganic acids, organic acids, or bases. For example, a compound containing a basic nitrogen can be prepared as a pharmaceutically acceptable salt 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, succinate ... Pharmaceutically acceptable salts 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.

[0076] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein also include those 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.

[0077] 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 substituted with 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 a starting material in which one or more hydrogen atoms have been replaced with deuterium. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) comprises one or more deuterium atoms.

[0078] 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 N substitution can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the Examples listed below using an appropriate isotopically labeled reagent instead of the non-labeled reagent previously employed.

[0079] The compounds of the embodiments disclosed herein or their pharmaceutically acceptable salts may include one or more asymmetric centers and therefore may produce enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- or as (D)- or (L)- for amino acids based on absolute stereochemistry. The 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 / separating individual enantiomers include chiral synthesis from suitable optically pure precursors or using, for example, chiral high pressure liquid chromatography (HPLC) to resolve racemates (or racemates of salts or derivatives). When the compounds described herein contain olefinic double bonds or other geometric asymmetric centers, and unless otherwise indicated, it is intended that the compounds include E and Z geometric isomers. Likewise, it is also intended to include all tautomeric forms. Where a compound is represented in its chiral form, it is understood that the embodiment encompasses, but is not limited to, the specific diastereoisomer or enantiomerically enriched form. Where chirality is not specified but present, it is understood that the embodiment relates to the specific diastereoisomer or enantiomerically enriched form; or a racemic or non-racemic mixture of such a compound. As used herein, a "non-racemic mixture" is a mixture of stereoisomers that is not in a 1:1 ratio.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] As used herein, "hydrate" refers to a compound of the present disclosure chemically associated with one or more water molecules.

[0084] "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.

[0085] 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.

[0086] As used herein, "treatment" or "treat" or "treating" refers to an approach for obtaining beneficial or desired results. For the purposes of this disclosure, beneficial or desired results include, but are not limited to, alleviation of symptoms and / or reduction in the extent of symptoms and / or prevention of worsening of symptoms associated with a disease or condition. In one embodiment, "treatment" or "treating" 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 extent of the disease or condition); b) slowing or preventing the development of one or more symptoms associated with a disease or condition (e.g., stabilizing the disease or condition, delaying worsening or progression of the disease or condition); and c) alleviating a disease or condition, e.g., causing regression of clinical symptoms, improving the disease state, delaying progression of the disease, improving quality of life, and / or prolonging survival.

[0087] As used herein, "at-risk individual" refers to an individual who is at risk of developing a condition to be treated. An "at-risk" individual may or may not have a detectable disease or condition and may or may not have displayed detectable disease prior to treatment with the methods described herein. "At-risk" means that the individual has one or more so-called risk factors, which are 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.

[0088] II.Compounds

[0089] In some embodiments, the compounds of the present disclosure are compounds of formula (I): or a compound of any other formula as described herein, or a pharmaceutically acceptable salt thereof, wherein

[0090] 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, -C(O)N(R1b )(R 1c ),-C(O)R 1b or-C(O)OR 1c ,

[0091] wherein the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl groups are each optionally substituted by one to four Z 1 replace;

[0092] Ring A is an aromatic ring, wherein U 1 、U 2 、U 3 Each independently represents -C(H)=, -C(Z 1a )=or-N=;

[0093] Ring B is C 6-10 aryl or heteroaryl, each of which is optionally substituted by one to four R 4 replace;

[0094] 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, -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 ,

[0095] wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1 replace;

[0096] X 1 、X 2 and X 3 Each independently represents -N=, -C(H)= or -C(R 8 )=;

[0097] Y 1 and Y 2 Each is -C(R y1 )(R y2 )-、-N(R y1 )-, -O-, -S-, -S(O)2- or -C(O)-; W is -C(R5 )-or-N-,

[0098] When W is -N, Y 1 and Y 2 One of them is -C(R y1 )(R y2 )-or-C(O)-and Y 1 and Y 2 The other one is -C(R y1 )(R y2 )-, -C(O)- or -S(O)2-;

[0099] 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;

[0100] 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)(R9c )(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);

[0101] wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace,

[0102] 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 6-10Aryl, 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;

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

[0104] 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 heterocyclyl, each of which is optionally substituted by one to four Z 1b replace;

[0105] R 5is H, cyclopropyl or C 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted by one, two or three groups selected from halogen, -OH, -OCH3, -CN, oxo and -N(R x1 )(R x2 ) group substitution;

[0106] or R 5 and R y1 Combined with the atoms to which they are attached to form a C optionally substituted with an oxo group 3-10 a cycloalkyl group or a heterocyclic group;

[0107] R x1 and R x2 Each independently is H, C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, -S(O)2R 6a1 or -S(O)2N(R 6a1 )(NR 6a2 ), wherein the C 1-6 Alkyl, cycloalkyl or heterocyclyl are each optionally replaced by F, -CN, oxo or C 3-6 cycloalkyl substitution;

[0108] or R x1 and R x2 Combined with the atoms to which they are attached to form a heterocyclic group, the heterocyclic group is optionally substituted by one to four R 6b1 replace;

[0109] V is -C(O)-, -O-, -N(R 6a )-or-C(R 6b )(R 6c )-;

[0110] 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 groups are each optionally replaced by C 1-6 Alkyl, F or -CN substitution;

[0111] 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(R9a )(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;

[0112] or R 6b and R 6c Combine with the atoms to which they are attached to form C 3-10 Cycloalkyl or heterocyclyl, each of which is optionally substituted by one to four R 6b1 replace;

[0113] 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 heterocyclyl, each of which is optionally substituted by one to four R 10 replace;

[0114] Each R y1 and R y2 are independently H, halo, C 1-6 Alkyl, C 1-6 haloalkyl, wherein the alkyl and haloalkyl are each optionally substituted with oxo;

[0115] Each R 3d 、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 -C(O)N(R 2a )(R 2b ), 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

[0116] Each R 6a1 、R 6a2 、R 6c1 、R 6c2 and R6c3 Independently H, C 1-6 Alkyl or C 3-10 Cycloalkyl;

[0117] Each R 9a and R 9b Independently H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0118] 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)2R12a 、-S(O)2N(R 12a )(R 12b )、-S(O)(NR 12a )R 12b or -Si(R 12a )3;

[0119] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1a replace;

[0120] 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)R12a 、-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;

[0121] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace;

[0122] 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(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)(C2-6 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)(C 3-15Cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6-10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 1-8 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 Alkyl)2;

[0123] wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group 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 3-15 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; and

[0124] 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;

[0125] wherein each heteroaryl group has 5 to 12 ring members and has one to four heteroatoms each independently being N, O, or S; and

[0126] wherein each heterocyclyl has 3 to 12 ring members and has one to four heteroatoms each independently being N, O or S.

[0127] In some embodiments, the compound of the present disclosure is a compound of Formula (Ia):

[0128]

[0129] or a pharmaceutically acceptable salt thereof, wherein

[0130] Ring B is C 6-10 aryl or heteroaryl, each of which is optionally substituted by one to four R 4 replace;

[0131] 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, -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 ,

[0132] wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1 replace;

[0133] X 1 、X 2 and X 3 Each independently represents -N=, -C(H)= or -C(R 8 )=;

[0134] 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 )R3c 、-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;

[0135] 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)(R9c )(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);

[0136] wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace,

[0137] 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;

[0138] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace;

[0139] 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 heterocyclyl, each of which is optionally substituted by one to four Z 1b replace;

[0140] R 5 is H, cyclopropyl or C 1-3 Alkyl, wherein the C 1-3The alkyl group is optionally substituted by one, two or three groups selected from halogen, -OH, -OCH3, -CN, oxo and -N(R x1 )(R x2 ) group substitution;

[0141] or R 5 and R y1 Combined with the atoms to which they are attached to form a C optionally substituted with an oxo group 3-10 a cycloalkyl group or a heterocyclic group;

[0142] R x1 and R x2 Each independently is H, C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, -S(O)2R 6a1 or -S(O)2N(R 6a1 )(NR 6a2 ), wherein the C 1-6 Alkyl, cycloalkyl or heterocyclyl are each optionally replaced by F, -CN, oxo or C 3-6 cycloalkyl substitution;

[0143] or R x1 and R x2 Combined with the atoms to which they are attached to form a heterocyclic group, the heterocyclic group is optionally substituted by one to four R 6b1 replace;

[0144] V is -C(O)-, -O-, -N(R 6a )-or-C(R 6b )(R 6c )-;

[0145] 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 groups are each optionally replaced by C 1-6 Alkyl, F or -CN substitution;

[0146] 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,-OR6c1 or -N(R 6c2 )(R 6c3 ), wherein the alkyl, cycloalkyl or heterocyclyl groups are each optionally substituted by one to four R 6b1 replace;

[0147] or R 6b and R 6c Combine with the atoms to which they are attached to form C 3-10 Cycloalkyl or heterocyclyl, each of which is optionally substituted by one to four R 6b1 replace;

[0148] 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 heterocyclyl, each of which is optionally substituted by one to four R 10 replace;

[0149] Each R y1 and R y2 are independently H, halo, C 1-6 Alkyl, C 1-6 haloalkyl, wherein the alkyl and haloalkyl are each optionally substituted with oxo;

[0150] Each R 3d 、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 -C(O)N(R 2a )(R 2b ), 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

[0151] Each R 6a1 、R 6a2 、R 6c1 、R 6c2 and R 6c3 Independently H, C 1-6 Alkyl or C3-10 Cycloalkyl;

[0152] Each R 9a and R 9b Independently H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0153] 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 )(R12b )、-S(O)(NR 12a )R 12b or -Si(R 12a )3;

[0154] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1a replace;

[0155] 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; wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted by one to four Z 1b replace;

[0156] 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(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(C1-9 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)(C 6-10aryl), -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;

[0157] wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group 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 3-15 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; and

[0158] Each R 1b 、R 1c 、R 2a 、R 2b 、R4a 、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;

[0159] subscript p is 1, 2, or 3; and

[0160] Subscript q is 0, 1, or 2;

[0161] wherein each heteroaryl group has 5 to 12 ring members and has one to four heteroatoms each independently being N, O, or S; and

[0162] wherein each heterocyclyl has 3 to 12 ring members and has one to four heteroatoms each independently being N, O or S.

[0163] In some embodiments, the compound of the present disclosure is a compound of Formula (Ib):

[0164]

[0165] or a pharmaceutically acceptable salt thereof, wherein

[0166] Ring B is C 6-10 aryl or heteroaryl, each of which is optionally substituted by one to four R 4 replace;

[0167] 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, -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 ,

[0168] wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1 replace;

[0169] X 1 、X 2 and X 3 Each independently represents -N=, -C(H)= or -C(R 8 )=;

[0170] Y 1 and Y 2 Each is -C(R y1 )(R y2 )-、-N(R y1 )-, -O-, -S-, -S(O)2- or -C(O)-;

[0171] 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;

[0172] 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);

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

[0174] Each R 4 Independently C 1-9 Alkyl, C1-8 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;

[0175] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace;

[0176] or two R attached to adjacent ring atoms4 The groups combine with the atoms to which they are attached to form C 5-10 Cycloalkyl or heterocyclyl, each of which is optionally substituted by one to four Z 1b replace;

[0177] R 5 is H, cyclopropyl or C 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted by one, two or three groups selected from halogen, -OH, -OCH3, -CN, oxo and -N(R x1 )(R x2 ) group substitution;

[0178] or R 5 and R y1 Combined with the atoms to which they are attached to form a C optionally substituted with an oxo group 3-10 a cycloalkyl group or a heterocyclic group;

[0179] R x1 and R x2 Each independently is H, C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, -S(O)2R 6a1 or -S(O)2N(R 6a1 )(NR 6a2 ), wherein the C 1-6 Alkyl, cycloalkyl or heterocyclyl are each optionally replaced by F, -CN, oxo or C 3-6 cycloalkyl substitution;

[0180] or R x1 and R x2 Combined with the atoms to which they are attached to form a heterocyclic group, the heterocyclic group is optionally substituted by one to four R 6b1 replace;

[0181] V is -C(O)-, -O-, -N(R 6a )-or-C(R 6b )(R 6c )-;

[0182] R 6a H, C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, -S(O)2R 6a1 or

[0183] -S(O)2N(R 6a1 )(NR 6a2 ), wherein the cycloalkyl or heterocyclyl groups are each optionally replaced by C 1-6 alkyl

[0184] -, F or -CN substitution;

[0185] 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;

[0186] or R 6b and R 6c Combine with the atoms to which they are attached to form C 3-10 Cycloalkyl or heterocyclyl, each of which is optionally substituted by one to four R 6b1 replace;

[0187] 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 heterocyclyl, each of which is optionally substituted by one to four R 10 replace;

[0188] Each R y1 and R y2 are independently H, halo, C 1-6 Alkyl, C 1-6 haloalkyl, wherein the alkyl and haloalkyl are each optionally substituted with oxo;

[0189] Each R 3d 、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, -CN, -NO2 or

[0190] -C(O)N(R 2a )(R 2b ), 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

[0191] Each R 6a1 、R 6a2 、R 6c1 、R 6c2 and R 6c3 Independently H, C 1-6 Alkyl or C 3-10 Cycloalkyl;

[0192] Each R 9a and R 9b Independently H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0193] 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;

[0194] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1a replace;

[0195] 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; wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted by one to four Z 1b replace;

[0196] 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 2-6Alkenyl)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;

[0197] wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group 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(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; and

[0198] 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;

[0199] subscript p is 1, 2, or 3; and

[0200] Subscript q is 0, 1, or 2;

[0201] wherein each heteroaryl group has 5 to 12 ring members and has one to four heteroatoms each independently being N, O, or S; and

[0202] wherein each heterocyclyl has 3 to 12 ring members and has one to four heteroatoms each independently being N, O or S.

[0203] In some embodiments, the compound of the present disclosure is a compound of Formula (Ic):

[0204]

[0205] or a pharmaceutically acceptable salt thereof, wherein

[0206] 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 6-10Aryl, heteroaryl, -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 ,

[0207] wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1 replace;

[0208] X 1 、X 2 and X 3 Each independently represents -N=, -C(H)= or -C(R 8 )=;

[0209] 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(R3a )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;

[0210] 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)(OR9c )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); wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted by one to four Z 1b replace,

[0211] Each R 4 Independently C 1-9 Alkyl, C 1-8 Halogenated alkyl, C1-6 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;

[0212] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace;

[0213] or two R attached to adjacent ring atoms 4The groups combine with the atoms to which they are attached to form C 5-10 Cycloalkyl or heterocyclyl, each of which is optionally substituted by one to four Z 1b replace;

[0214] R 5 is H, cyclopropyl or C 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted by one, two or three groups selected from halogen, -OH, -OCH3, -CN, oxo and -N(R x1 )(R x2 ) group substitution;

[0215] or R 5 and R y1 Combined with the atoms to which they are attached to form a C optionally substituted with an oxo group 3-10 a cycloalkyl group or a heterocyclic group;

[0216] R x1 and R x2 Each independently is H, C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, -S(O)2R 6a1 or -S(O)2N(R 6a1 )(NR 6a2 ), wherein the C 1-6 Alkyl, cycloalkyl or heterocyclyl are each optionally replaced by F, -CN, oxo or C 3-6 cycloalkyl substitution;

[0217] or R x1 and R x2 Combined with the atoms to which they are attached to form a heterocyclic group, the heterocyclic group is optionally substituted by one to four R 6b1 replace;

[0218] V is -C(O)-, -O-, -N(R 6a )-or-C(R 6b )(R 6c )-;

[0219] 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 groups are each optionally replaced by C 1-6 alkyl

[0220] -, F or -CN substitution;

[0221] 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;

[0222] or R 6b and R 6c Combine with the atoms to which they are attached to form C 3-10 Cycloalkyl or heterocyclyl, each of which is optionally substituted by one to four R 6b1 replace;

[0223] 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 heterocyclyl, each of which is optionally substituted by one to four R 10 replace;

[0224] Each R y1 and R y2 are independently H, halo, C 1-6 Alkyl, C 1-6 haloalkyl, wherein the alkyl and haloalkyl are each optionally substituted with oxo;

[0225] Each R 3d 、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 -C(O)N(R 2a )(R 2b ), wherein the heterocyclic or heteroaryl group is optionally replaced by C1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 haloalkoxy substituted; and

[0226] Each R 6a1 、R 6a2 、R 6c1 、R 6c2 and R 6c3 Independently H, C 1-6 Alkyl or C 3-10 Cycloalkyl;

[0227] Each R 9a and R 9b Independently H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0228] 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)R12a 、-OC(O)OR 12a 、-OC(O)-N(R 12a )(R 12b ),-SR 12a 、-S(O)R 12a 、-S(O)(NH)R 12a 、-S(O)2R 12a 、-S(O)2N(R 12a )(R 12b )、-S(O)(NR 12a )R 12b or -Si(R 12a )3;

[0229] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1a replace;

[0230] 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(R12a )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;

[0231] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace;

[0232] 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(C 2-6 Alkynyl)2, -N(C 3-15Cycloalkyl)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 3-15 Cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C 6-10Aryl)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 3-15 Cycloalkyl), -S(O)(heterocyclyl), -S(O)(C 6-10aryl), -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;

[0233] wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group 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; and

[0234] 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;

[0235] The subscript p is 1, 2, or 3;

[0236] subscript q is 0, 1, or 2; and

[0237] subscript n is 0, 1, 2, or 3; and

[0238] wherein each heteroaryl group has 5 to 12 ring members and has one to four heteroatoms each independently being N, O, or S; and

[0239] wherein each heterocyclyl has 3 to 12 ring members and has one to four heteroatoms each independently being N, O or S.

[0240] In some embodiments, the compound of the present disclosure is a compound of Formula (Id):

[0241]

[0242] or a pharmaceutically acceptable salt thereof, wherein

[0243] R 2 H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, -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 ,

[0244] wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1 replace;

[0245] X 1 、X 2 and X 3 Each independently represents -N=, -C(H)= or -C(R 8 )=;

[0246] 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 )(R3b )、-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;

[0247] 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);

[0248] wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace,

[0249] Each R 4Independently 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;

[0250] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace;

[0251] 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 heterocyclyl, each of which is optionally substituted by one to four Z 1b replace;

[0252] R 5 is H, cyclopropyl or C 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted by one, two or three groups selected from halogen, -OH, -OCH3, -CN, oxo and -N(R x1 )(R x2 ) group substitution;

[0253] or R 5 and R y1 Combined with the atoms to which they are attached to form a C optionally substituted with an oxo group 3-10 a cycloalkyl group or a heterocyclic group;

[0254] R x1 and R x2 Each independently is H, C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, -S(O)2R 6a1 or -S(O)2N(R 6a1 )(NR 6a2 ), wherein the C 1-6 Alkyl, cycloalkyl or heterocyclyl are each optionally replaced by F, -CN, oxo or C 3-6 cycloalkyl substitution;

[0255] or R x1 and R x2 Combined with the atoms to which they are attached to form a heterocyclic group, the heterocyclic group is optionally substituted by one to four R 6b1 replace;

[0256] V is -C(O)-, -O-, -N(R 6a )-or-C(R 6b )(R 6c )-;

[0257] 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 groups are each optionally replaced by C 1-6 Alkyl, F or -CN substitution;

[0258] 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;

[0259] or R 6b and R 6c Combine with the atoms to which they are attached to form C 3-10 Cycloalkyl or heterocyclyl, each of which is optionally substituted by one to four R 6b1 replace;

[0260] 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 heterocyclyl, each of which is optionally substituted by one to four R 10 replace;

[0261] Each R y1 and R y2 are independently H, halo, C 1-6 Alkyl, C 1-6 haloalkyl, wherein the alkyl and haloalkyl are each optionally substituted with oxo;

[0262] Each R 3d 、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, -CN, -NO2 or

[0263] -C(O)N(R 2a)(R 2b ), 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

[0264] Each R 6a1 、R 6a2 、R 6c1 、R 6c2 and R 6c3 Independently H, C 1-6 Alkyl or C 3-10 Cycloalkyl;

[0265] Each R 9a and R 9b Independently H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0266] 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;

[0267] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1a replace;

[0268] 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;

[0269] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace;

[0270] 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;

[0271] wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group 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; and

[0272] 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;

[0273] The subscript p is 1, 2, or 3;

[0274] subscript q is 0, 1, or 2; and

[0275] subscript n is 0, 1, 2, or 3; and

[0276] wherein each heteroaryl group has 5 to 12 ring members and has one to four heteroatoms each independently being N, O, or S; and

[0277] wherein each heterocyclyl has 3 to 12 ring members and has one to four heteroatoms each independently being N, O or S.

[0278] In some embodiments, the compound of the present disclosure is a compound of Formula (Ie):

[0279]

[0280] or a pharmaceutically acceptable salt thereof, wherein

[0281] R 2 H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, -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 wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1 replace;

[0282] 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)(=NR3a )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;

[0283] 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 )(OR9d )、-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);

[0284] wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace,

[0285] 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, C3-15 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;

[0286] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace;

[0287] 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 heterocyclyl, each of which is optionally substituted by one to four Z 1b replace;

[0288] R 5 is H, cyclopropyl or C 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted by one, two or three groups selected from halogen, -OH, -OCH3, -CN, oxo and -N(R x1 )(R x2 ) group substitution;

[0289] or R 5 and R y1 Combined with the atoms to which they are attached to form a C optionally substituted with an oxo group 3-10 a cycloalkyl group or a heterocyclic group;

[0290] R x1 and R x2 Each independently is H, C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, -S(O)2R 6a1 or -S(O)2N(R 6a1 )(NR 6a2 ), wherein the C 1-6 Alkyl, cycloalkyl or heterocyclyl are each optionally replaced by F, -CN, oxo or C 3-6 cycloalkyl substitution;

[0291] or R x1 and R x2 Combined with the atoms to which they are attached to form a heterocyclic group, the heterocyclic group is optionally substituted by one to four R 6b1 replace;

[0292] 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 groups are each optionally replaced by C 1-6 alkyl

[0293] -, F or -CN substitution;

[0294] 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;

[0295] or R 6b and R 6c Combine with the atoms to which they are attached to form C 3-10 Cycloalkyl or heterocyclyl, each of which is optionally substituted by one to four R 6b1 replace;

[0296] 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 heterocyclyl, each of which is optionally substituted by one to four R 10 replace;

[0297] Each R y1 and R y2 are independently H, halo, C 1-6 Alkyl, C 1-6 haloalkyl, wherein the alkyl and haloalkyl are each optionally substituted with oxo;

[0298] Each R 3d 、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, -CN, -NO2 or

[0299] -C(O)N(R 2a )(R 2b ), 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

[0300] Each R 6a1 、R 6a2 、R 6c1 、R 6c2and R 6c3 Independently H, C 1-6 Alkyl or C 3-10 Cycloalkyl;

[0301] Each R 9a and R 9b Independently H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0302] 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)2R12a 、-S(O)2N(R 12a )(R 12b )、-S(O)(NR 12a )R 12b or -Si(R 12a )3;

[0303] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1a replace;

[0304] 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)R12a 、-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; wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted by one to four Z 1b replace;

[0305] 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(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(C1-9 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)(C 3-15Cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6-10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 1-8 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 Alkyl)2;

[0306] wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group 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 3-15 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; and

[0307] 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;

[0308] The subscript p is 1, 2, or 3;

[0309] subscript q is 0, 1, or 2; and

[0310] subscript n is 0, 1, 2, or 3; and

[0311] wherein each heteroaryl group has 5 to 12 ring members and has one to four independently

[0312] wherein each heterocyclyl group has 3 to 12 ring members and has one to four independently

[0313] The heteroatom is N, O or S.

[0314] In some embodiments, the compounds of the present disclosure are compounds of formula (If):

[0315]

[0316] or a pharmaceutically acceptable salt thereof, wherein

[0317] 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, -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 wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1 replace;

[0318] 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;

[0319] 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(R9c )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);

[0320] wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace,

[0321] 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(R4a )(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;

[0322] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace;

[0323] 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 heterocyclyl, each of which is optionally substituted by one to four Z 1b replace;

[0324] R 5 is H, cyclopropyl or C 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted by one, two or three groups selected from halogen, -OH, -OCH3, -CN, oxo and -N(R x1 )(R x2 ) group substitution;

[0325] or R 5 and R y1 Combined with the atoms to which they are attached to form a C optionally substituted with an oxo group 3-10 a cycloalkyl group or a heterocyclic group;

[0326] R x1 and R x2 Each independently is H, C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, -S(O)2R 6a1 or -S(O)2N(R 6a1 )(NR 6a2 ), wherein the C 1-6 Alkyl, cycloalkyl or heterocyclyl are each optionally replaced by F, -CN, oxo or C 3-6 cycloalkyl substitution;

[0327] or R x1 and R x2 Combined with the atoms to which they are attached to form a heterocyclic group, the heterocyclic group is optionally substituted by one to four R 6b1 replace;

[0328] 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 groups are each optionally replaced by C 1-6 Alkyl, F or -CN substitution;

[0329] 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;

[0330] or R 6b and R 6c Combine with the atoms to which they are attached to form C 3-10Cycloalkyl or heterocyclyl, each of which is optionally substituted by one to four R 6b1 replace;

[0331] 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 heterocyclyl, each of which is optionally substituted by one to four R 10 replace;

[0332] Each R y1 and R y2 are independently H, halo, C 1-6 Alkyl, C 1-6 haloalkyl, wherein the alkyl and haloalkyl are each optionally substituted with oxo;

[0333] Each R 3d 、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, -CN, -NO2 or

[0334] -C(O)N(R 2a )(R 2b ), 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

[0335] Each R 6a1 、R 6a2 、R 6c1 、R 6c2 and R 6c3 Independently H, C 1-6 Alkyl or C 3-10 Cycloalkyl;

[0336] Each R 9a and R 9b Independently H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0337] Each Z1 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;

[0338] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z1a replace;

[0339] 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; wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted by one to four Z 1b replace;

[0340] 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(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 1-9alkyl), -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 1-9 alkyl), -NHC(O)O(C 1-8 Halogenated alkyl), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C 2-6Alkynyl), -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(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2;

[0341] wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group 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 3-15 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; and

[0342] 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, C1-9 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;

[0343] The subscript p is 1, 2, or 3;

[0344] subscript q is 0, 1, or 2; and

[0345] subscript n is 0, 1, 2, or 3; and

[0346] wherein each heteroaryl group has 5 to 12 ring members and has one to four heteroatoms each independently being N, O, or S; and

[0347] wherein each heterocyclyl has 3 to 12 ring members and has one to four heteroatoms each independently being N, O or S.

[0348] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, R 1 C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclic, C 6-10 wherein the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl groups are each optionally substituted by one to four Z 1 replace.

[0349] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, R 1 C 6-10 aryl or heteroaryl, each of which is optionally substituted by one to three Z 1 replace.

[0350] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R1 is a 6-membered aryl or a 5- or 6-membered heteroaryl, wherein the aryl or heteroaryl is substituted by one, two or three selected from C 1-8 Haloalkyl, halogen, C 1-6 Alkoxy, -CN and -C(O)-N(R 12a )(R 12b ) group substituted.

[0351] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, R 1is a 6-membered aryl group or a 5- or 6-membered heteroaryl group, wherein the aryl group or heteroaryl group is substituted by one or two -Cl, -F or -CN.

[0352] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), or pharmaceutically acceptable salts thereof, R 5 In some embodiments, R 5 It is a methyl group.

[0353] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, Y 1 and Y 2 In some embodiments, at least one of Y is -O-. 1 and Y 2 All are -O-.

[0354] In some embodiments, the present disclosure provides compounds having the structure of Formula (Ia) or (Ib), or pharmaceutically acceptable salts thereof:

[0355]

[0356] in:

[0357] The subscript p is 1, 2, or 3;

[0358] subscript q is 0, 1, or 2; and

[0359] where R 2 、R 3 、R 5 , Ring B, V, X 1 、X 2 、X 3 , Z 1a and Z 1b As shown in this article.

[0360] In some embodiments, the present disclosure provides a compound having the structure of Formula (Ia) or a pharmaceutically acceptable salt thereof:

[0361]

[0362] where R 2 、R 3 、R 5 , Ring B, V, X 1 、X 2 、X 3 , Z 1a , Z 1b , p and q are as shown in this article.

[0363] In some embodiments, the present disclosure provides a compound having the structure of Formula (Ib) or a pharmaceutically acceptable salt thereof:

[0364]

[0365] where R 2 、R 3 、R 5 , Ring B, V, X 1 、X 2 、X 3 , Z 1a , Z 1b , p and q are as shown in this article.

[0366] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), or pharmaceutically acceptable salts thereof, each Z 1a 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 12a 、-C(O)N(R 12a )(R 12b ), each of which is optionally replaced by Z 1b replace.

[0367] In some embodiments of the compounds of Formula (I), (Ia) and / or (Ib), 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, Ring B is

[0368]

[0369] Each of which is optionally replaced by one to three R 4 replace.

[0370] In some embodiments of the compounds of Formula (I), (Ia) and / or (Ib), or pharmaceutically acceptable salts thereof, Ring B is

[0371]

[0372] Each of which is optionally replaced by one or two R4 replace.

[0373] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, have the structure of Formula (Ic) or (Id):

[0374]

[0375] in

[0376] Subscript n is 0, 1, 2, or 3;

[0377] subscript p is 1, 2, or 3; and

[0378] where R 2 、R 3 、R 4 、R 5 , V, X 1 、X 2 、X 3 and Z 1 As defined herein.

[0379] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, X 1 、X 2 and X 3 Each is independently -CH=, -C(F)=, -C(Cl)=, -C(Br)= or -C(CN)=.

[0380] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, V is -O-, -NH-, or -CH2-.

[0381] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, have the structure of Formula (Ie) or (If):

[0382]

[0383] in

[0384] Subscript n is 0, 1, 2, or 3;

[0385] subscript p is 1, 2, or 3; and

[0386] where R 2 、R 3 、R 4 、R 5 and Z 1 As defined herein.

[0387] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, have the structure of Formula (Ig):

[0388]

[0389] in

[0390] subscript n is 0, 1, 2, or 3; and

[0391] The subscript p is 1, 2, or 3.

[0392] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), 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, 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 ), wherein the heteroaryl or heterocyclyl is each optionally substituted by one to four halogen, C 1-6 Halogenated alkyl, C 3-6 The cycloalkyl group is substituted with a 4- to 6-membered heterocyclic group or -CN.

[0393] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), 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 Haloalkoxy, halogen, oxo, -OH, -CN, or -NO2, C 3-10 In some embodiments, each Z is cycloalkyl, 3 to 12 membered heterocyclyl having one to three heteroatoms, or 5 to 10 membered heteroaryl having one to three heteroatoms. 1 Independently C 1-6 Halogenated alkyl, C1-6 In some embodiments, each Z is substituted with halogen, halogen, -CN, or a 5- to 6-membered heteroaryl group having one to three heteroatoms. 1 are independently halogen, C 1-6 Halogenated alkyl, C 1-3 Alkoxy, C 3-10 Cycloalkyl or -CN.

[0394] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), 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, -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 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, C3-10 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 ).

[0395] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), or pharmaceutically acceptable salts thereof, R 2 C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, heteroaryl, C 1-6 Alkyl-C 3-10 Cycloalkyl, C 1-6 Alkyl-heterocyclyl, C 1-6 Alkyl-C 3-10 Cycloalkyl-C 1-6 Alkyl, C 1-6 Alkyl-heterocyclyl-C 1-6 Alkyl or C 1-6 Alkyl-heteroaryl, each of which is optionally substituted by one to four Z 1b In some embodiments, R 2 C 1-6 Alkyl-C 3-10 Cycloalkyl or C 1-6 Alkyl-C 3-10 Cycloalkyl-C 1-6 Alkyl, each of which is optionally substituted by one to four Z 1b replace.

[0396] In some embodiments, wherein R 2 for:

[0397]

[0398] In some embodiments, R 2 for:

[0399]

[0400] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), or pharmaceutically acceptable salts thereof, R 3 Heteroaryl, -C(O)OH, -C(O)OR 3a 、-C(O)N(R3a )S(O)2(R 3b )、-S(O)2NHC(O)R 3a or -C(O)N(R 3a )S(O)2N(R 3b )(R 3c ), wherein the heteroaryl group is optionally substituted by one to four R 3d In some embodiments, 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, R 3 It is -C(O)OH.

[0401] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), or pharmaceutically acceptable salts thereof, each R 4 Independently C 1-6 Alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkoxyalkyl, halogen, oxo, -CN or -OR 4a In some embodiments, each R 4 Independently C 1-6 Alkyl, halogen, oxo, -CN or -OR 4a In some embodiments, each R 4 Independently C 1-6 alkyl, halogen, oxo, -OH, or -CN. In some embodiments, each R 4 are independently F, oxo or -CN.

[0402] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), or pharmaceutically acceptable salts thereof, R 6a H, C 1-6 Alkyl, C 3-10 In some embodiments, each R 6b and R 6c Independently H, C 1-3 Alkyl, F, Cl or -CN.

[0403] In some embodiments of the compounds of Formula (I), (Ic), (Id), (Ie), (If), and / or (Ig), or pharmaceutically acceptable salts thereof, subscript n is 0, 1, or 2.

[0404] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), or pharmaceutically acceptable salts thereof, subscript p is 1 or 2.

[0405] In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), or a pharmaceutically acceptable salt thereof, has the following formula:

[0406]

[0407]

[0408]

[0409]

[0410]

[0411] Also disclosed herein are in vivo metabolic products of the compounds described herein, to the extent that such products are novel and unobvious relative 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 unobvious compounds are produced by methods comprising contacting the compound with a mammal for a period of time sufficient to produce its metabolic products. Such products are typically produced by preparing radiolabeled (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.

[0412] 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.

[0413] III. Methods for preparing compounds

[0414] 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.

[0415] Solution 1 :

[0416]

[0417] Compounds of formula 1.3 can be assembled by first reacting an amine with intermediate 1.1 in the presence of a suitable base (e.g., DIPEA, KOtBu, etc.) to give intermediate 1.2, which can then be converted to intermediate 1.3 using suitable reducing conditions (e.g., H2 and Pd / C, Fe and HCl, etc.).

[0418] Option 2 :

[0419]

[0420] Compounds of formula 2.7 can be assembled by reacting a substituted diol of general structure 2.1 with a ketone or aldehyde of general structure 2.2 and a catalytic amount of a weak acid catalyst such as p-toluenesulfonic acid in an aprotic solvent such as benzene, toluene, or xylene at reflux. During this reaction, water can be removed by passing through a Dean-Stark trap or azeotropically with molecular sieves. Catechols of formula 2.1 can also react with dihalides of formula 2.3 in the presence of an organic base such as pyridine to form compounds of general structure 2.7. Alternatively, acetals or ketals of acyclic (dashed line absent) or cyclic (dashed line present) structures 2.4 can react with catechols of formula 2.1 in the presence of an acid or base to provide compounds of structure 2.7. In a similar manner, acyclic (dashed line absent) or cyclic (dashed line present) thioacetals or thioketals of structure 2.5 can react with catechols of formula 2.1 in the presence of mercuric salts, mild oxidizing agents, or alkylating agents to give compounds of structure 2.7. Alternatively, alkynes of formula 2.6 (where R1 is aryl or heteroaryl) can be reacted with a catechol of formula 2.1 in the presence of triruthenium dodecacarbonyl in an aprotic solvent such as toluene to form a compound of formula 2.7. The reaction is degassed with an inert gas such as argon or nitrogen and stirred at 100°C.

[0421] Option 3 :

[0422]

[0423] Exemplary compounds of formula (I) (such as the compound of formula (1g) depicted above) can first be assembled by combining intermediate 3.1 with intermediate 1.3 under standard amide bond forming conditions (e.g., DIPEA with HATU, etc.). Treatment with a suitable acid catalyst (e.g., HCl, AcOH, etc.) can produce intermediate 3.3. Halogen metal exchange of -X to -M can then be achieved using a suitable reagent (e.g., iPrMgBr, etc.), or transition metal coupling can be achieved using a suitable palladium catalyst and metal source (e.g., B2Pin2, Bu6Sn2, etc.) to provide intermediate 3.4. This can then be coupled to intermediate 2.7 using a suitable palladium catalyst to provide intermediate 3.5. If R = methyl or ethyl, standard ester hydrolysis conditions (e.g., LiOH, LiI and pyridine, Me3SnOH, etc.) can be used to convert compound 3.5 to formula (Ig). If R = tert-butyl, compound 3.5 can be converted to formula (Ig) in the presence of a protic acid (e.g., trifluoroacetic acid, etc.).

[0424] Option 4 :

[0425]

[0426] Exemplary compounds of formula (I), including compounds of formula (Ig) above, can be formed by first converting intermediate 2.7 to the metallated variant intermediate 4.1 using a suitable palladium catalyst and a metal source (e.g., bis(neopentylethylene glycol)diboron, B2Pin2, Bu6Sn2, etc.). This can then be coupled to intermediate 3.3 using a suitable palladium catalyst to provide intermediate 3.5. If R is methyl or ethyl, standard ester hydrolysis conditions (e.g., LiOH, LiI and pyridine, Me3SnOH, etc.) can be used to convert compound 3.5 to formula (Ig). If R is tert-butyl, compound 3.5 can be converted to formula (Ig) in the presence of a protic acid (e.g., trifluoroacetic acid, etc.).

[0427] Option 5 :

[0428]

[0429] The compound of formula 5.1 can be obtained by reacting the compound of formula (I) with a sulfonamide under suitable coupling conditions (eg, EDC and DMAP, etc.).

[0430] Option 6 :

[0431]

[0432] Compounds of formula 6.3 can be assembled by first coupling to the halo-X of intermediate 6.1 using a suitable coupling partner and a palladium catalyst to provide intermediate 6.2, which can be converted to compound 6.3 using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine, etc.).

[0433] Option 7 :

[0434]

[0435] Compounds of formula (Ig) can also be assembled by protecting the alcohol group of intermediate 7.1 (protecting group Pg can be benzyl or trimethylsilylethoxymethyl) to provide intermediate 7.2. Cross-coupling of intermediate 3.4 with intermediate 7.2 using a suitable transition metal catalyst (e.g., palladium, etc.) can provide intermediate 7.3. This can then be deprotected (e.g., using a metal catalyst and H2 gas when Pg is benzyl, or by using HCl or TFA when Pg is trimethylsilylethoxymethyl) to provide intermediate 7.4. Intermediate 7.4 can be reacted with carbonyl-containing intermediate 2.2 or alkyne intermediate 2.6 in a manner similar to the procedure described in Scheme 2 to provide intermediate 3.5. This can then be converted to formula (Ig) using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine, etc.).

[0436] Option 8 :

[0437]

[0438] Compounds of formula (Ig) can also be assembled by first coupling intermediate 2.7 with intermediate 8.1 (commercially available or obtained by metalation of the corresponding halide) using a suitable palladium catalyst to provide intermediate 8.2. After conversion to acid 8.3 using standard conditions (e.g., LiOH, LiI, and pyridine, etc.), intermediate 1.3 can be coupled using standard amide bond forming conditions (e.g., DIPEA with HATU, etc.) to provide intermediate 8.4. This can then be converted to the corresponding benzimidazole 3.5 under the influence of an acid catalyst (e.g., HCl, AcOH, TFA, etc.), which can then be converted to formula (Ig) using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine, etc.).

[0439] Option 9 :

[0440]

[0441] Compounds of formula 9.3 can be assembled by first coupling to the halogen-X of intermediate 9.1 using a suitable coupling partner and a metal catalyst (e.g., palladium, etc.) to provide intermediate 9.2, which can be converted to compound 9.3 using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine, etc.).

[0442] IV. Pharmaceutical Preparations

[0443] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0444] In some embodiments, pharmaceutical compositions comprise a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, as more fully described below.

[0445] 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 conventional practice. Tablets can contain excipients, including glidants, fillers, binders, etc. Aqueous compositions can be prepared in sterile form and, when intended to be delivered by a method other than oral administration, can generally be isotonic. In some embodiments, the composition may 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, etc. In some embodiments, the composition is provided as a solid dosage form, including a solid oral dosage form.

[0446] 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 Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0447] 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.

[0448] The 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. The pharmaceutical compositions containing active ingredients can be in any form suitable for the intended method of administration. For example, when used for oral use, tablets, lozenges, lozenges, 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 making 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 making 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-delay material such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with a wax.

[0449] 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 about 1 mg to 1000 mg of active material, formulated together with an appropriate and convenient amount of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutically acceptable excipient comprises about 5% to about 95% (weight:weight) of the total composition.

[0450] 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.

[0451] In some embodiments, the pharmaceutical compositions described above are for use in humans or animals.

[0452] The present disclosure also includes compounds of the present disclosure administered as the sole active ingredient of a pharmaceutically acceptable composition, which active ingredient can be prepared by conventional methods known in the art, for example, by binding the active ingredient to a pharmaceutically acceptable, therapeutically inert organic and / or inorganic carrier or excipient, or by mixing the active ingredient therewith. In one aspect, provided herein are the uses of compounds of the present disclosure as second or additional active ingredients that have synergistic effects with other active ingredients in known drugs, or administering compounds of the present disclosure together with such drugs.

[0453] The compounds of the present disclosure may also be used in prodrug or other suitably modified forms that release the active ingredient in vivo.

[0454] V. Route of Administration

[0455] 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.

[0456] 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 on a daily or intermittent schedule during the life of the individual.

[0457] The dosage or frequency of administration of the disclosed compounds may be adjusted during the course of treatment according to the judgment of the administering physician.

[0458] The compound can be administered to an individual (eg, a human) in an effective amount. In some embodiments, the compound is administered once daily.

[0459] The compound can be used by any available approach and method, such as by oral or parenteral (e.g., intravenous) administration. The therapeutically effective amount of the 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.

[0460] 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.

[0461] 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 further 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.

[0462] 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.

[0463] VI. Combination Therapy

[0464] 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.

[0465] 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 Alstrom syndrome protein 1 (ALMS1) / PKCα protein interaction inhibitor, an Apelin receptor agonist, an acetyl-CoA carboxylase inhibitor, a diacylglycerol-O-acyltransferase 2 inhibitor, an adenosine A3 receptor agonist, 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 islet 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, CCL26 gene inhibitors, CCR2 chemokine antagonists, CCR2 chemokine antagonists, angiotensin II AT-1 receptor antagonists, CCR3 chemokine antagonists, CCR5 chemokine antagonists, CD3 antagonists, chloride channel stimulators, CNR1 inhibitors, connective tissue growth factor ligand inhibitors, cyclin D1 inhibitors, cytochrome P450 7A1 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, galectin-3 inhibitors, GDNF family receptor alpha-like agonists, glucagon receptor agonists, glucagon-like peptide 1 agonists, glucocorticoid receptor antagonists, glucose 6-phosphate 1-dehydrogenase inhibitors, G protein-coupled bile acid receptor 1 agonists, G protein-coupled receptor 84 antagonists, hedgehog (Hh) Regulators, hepatitis C virus NS3 protease inhibitors, hepatocyte nuclear factor 4 alpha regulator (HNF4A), hepatocyte growth factor regulators, histone deacetylase inhibitors, STAT-3 regulators, HMG coenzyme A reductase inhibitors, HSD17B13 gene inhibitors, hydrolase inhibitors, hypoxia-inducible factor-2alpha 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 regulators, 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, 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, myelin basic protein stimulators, NACHT LRRsPYD domain protein 3 (NLRP3) inhibitor, NAD-dependent deacetylase sirtuin stimulator, NADPH oxidase inhibitor (NOX), nicotinic acid receptor 1 agonist, P2Y13 purinergic receptor stimulator, erythroid 2-related factor 2 stimulator, nuclear receptor modulator, P2X7 purinergic receptor modulator, PACAP Type I receptor agonists, PDE3 inhibitors, PDE4 inhibitors, PDE5 inhibitors, PDGF receptor β modulators, phenylalanine hydroxylase stimulators, phospholipase C inhibitors, PPARα agonists, PPARδ agonists, PPARγ agonists, peptidylprolyl cis-trans isomerase A inhibitors, PPARγ modulators, protease-activated receptor-2 antagonists, protein kinase modulators, PTGS2 gene 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, SREBP transcription factor inhibitors, STAT-1 inhibitors agents, 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, TLR-9 antagonists, VDR agonists, transglutaminase inhibitors, tyrosine kinase receptor modulators, GPCR modulators, nuclear hormone receptor modulators, WNT modulators or YAP / TAZ modulators and zonulin inhibitors.

[0466] Non-limiting examples of the one or more additional therapeutic agents include:

[0467] -ACE inhibitors, such as enalapril;

[0468] - aldehyde dehydrogenase inhibitors, such as ADX-629;

[0469] - acetyl-CoA carboxylase (ACC) inhibitors, such as NDI-010976 (firsocostat), DRM-01, gemcabene, PF-05175157, QLT-091382, PF-05221304;

[0470] - acetyl-CoA carboxylase / diacylglycerol O-acyltransferase 2 inhibitors, such as PF-07055341;

[0471] - adenosine receptor agonists, such as CF-102 (namodenoson), CF-101, CF-502, CGS21680;

[0472] - adenosine A3 receptor antagonists, such as FM-101;

[0473] - adiponectin receptor agonists, such as ADP-355, ADP-399;

[0474] - Adrenergic receptor antagonists, such as bromocriptine, VI-0521;

[0475] - aldehyde dehydrogenase 2 stimulators, such as FP-045;

[0476] - alpha-glucosidase inhibitors (such as voglibose, acarbose, or miglitol);

[0477] - Amylin / calcitonin receptor agonists, such as KBP-042, KBP-089;

[0478] -AMP-activated protein kinase stimulators, such as PXL-770, O-304;

[0479] -AMP kinase activators / ATP citrate lyase inhibitors, such as bempedoic acid (ETC-1002, ESP-55016)

[0480] -AMP-activated protein kinase / endothelial nitric oxide synthase / NAD-dependent deacetylase sirtuin-1 stimulators, such as NS-0200 (leucine + metformin + sildenafil);

[0481] - Androgen receptor agonists, such as LPCN-1144 and LPCN-1148;

[0482] - angiotensin II AT-1 receptor antagonists, such as irbesartan;

[0483] - Angiopoietin-related protein-3 inhibitors, such as IONIS-ANGPTL3-LRx;

[0484] - apelin receptor agonists, such as CB-5064;

[0485] - anti-lysyl oxidase homolog 2 (LOXL2) monoclonal antibodies (e.g., simtuzumab);

[0486] - Autophagy protein regulators, such as A-2906;

[0487] - autotaxin inhibitors, such as PAT-505, PAT-048, GLPG-1690, X-165, PF-8380, TJC-0265, TJC-0316, AM-063, BBT-877;

[0488] - Axl tyrosine kinase receptor inhibitors, such as bemcentinib (BGB-324, R-428);

[0489] - Bax protein stimulators, such as CBL-514;

[0490] - Bioactive lipids, such as DS-102;

[0491] - Biguanides, such as metformin;

[0492] - Cannabinoid receptor modulators, such as namacizumab, GWP-42004, REV-200, CRB-4001, SCN-002;

[0493] Cysteine ​​protease inhibitors, such as emricasan;

[0494] -Pan cathepsin B inhibitors, such as VBY-376;

[0495] -Pan cathepsin inhibitors, such as VBY-825;

[0496] - CCL26 gene inhibitors, such as KDDF-201410-10;

[0497] - CCR2 / CCR5 chemokine antagonists such as cenicriviroc, maraviroc, CCX-872, WXSH-0213;

[0498] - CCR2 / CCR5 chemokine antagonists and FXR agonists, such as LJC-242 (tropifexor + cenivriviroc);

[0499] - CCR2 chemokine antagonists, such as propagermanium;

[0500] - CCR2 chemokine / angiotensin II AT-1 receptor antagonists, such as DMX-200, DMX-250;

[0501] - CCR3 chemokine antagonists, such as bertilimumab;

[0502] - CD3 antagonists, such as NI-0401 (foralumab);

[0503] - Chloride channel stimulants, such as coprostone and lubiprostone;

[0504] - casein kinase-1 (CK1) delta / epsilon inhibitors, such as PF-05006739;

[0505] - connective tissue growth factor ligand inhibitors, such as PBI-4050;

[0506] - CXCR4 chemokine antagonists, such as AD-214;

[0507] - diacylglycerol acyltransferase 2 (DGAT2) inhibitors, such as IONIS-DGAT2Rx, PF-06865571;

[0508] - diglyceride acyltransferase 1 (DGAT1) inhibitors, such as GSK-3008356;

[0509] - diacylglycerol O-acyltransferase 1 (DGAT1) / cytochrome P450 2E1 inhibitors (CYP2E1), such as SNP-610;

[0510] -Dihydroorotate dehydrogenase inhibitors, such as vedofluanimol;

[0511] - dipeptidyl peptidase IV inhibitors such as linagliptin, evogliptin, sitagliptin, vildagliptin, saxagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, dutogliptin, or omarigliptin;

[0512] - eotaxin ligand inhibitors, such as cefixime, CM-101;

[0513] - extracellular matrix protein modulators, such as CNX-024;

[0514] - farnesoid X receptor (FXR) agonists such as AGN-242266, AGN-242256, EP-024297, RDX-023, BWL-200, AKN-083, EDP-305, GNF-5120, GS-9674, HPG-1860, LMB-763, obeticholic acid, Px-102, Px-103, M790, M780, M450, M-480, MET-409, PX20606, EYP-001, TERN-101, TC-100, INT-2228, ZG-5266, or cilofexor;

[0515] - Farnesoid X receptor (FXR) / G protein-coupled bile acid receptor 1 (TGR5) agonists, such as INT-767;

[0516] - fatty acid synthase inhibitors, such as TVB-2640, FT-8225;

[0517] - fibroblast growth factor 19 (rhFGF19) / cytochrome P450 (CYP) 7A1 inhibitors, such as NGM-282;

[0518] - Fibroblast growth factor 21 (FGF-21) ligands, such as BMS-986171, BIO89-100, BMS-986036, B-1344;

[0519] - Fibroblast growth factor 21 (FGF-21) / glucagon-like peptide 1 (GLP-1) agonists, such as YH-25723 (YH-25724; YH-22241), AKR-001;

[0520] - FGF receptor agonists / Klothoβ stimulators, such as BFKB-8488A (RG-7992);

[0521] -Galectin-3 inhibitors, such as GR-MD-02, GB-1107 (Gal-300), GB1211 (Gal-400);

[0522] - GDNF family receptor α-like agonists, such as NGM-395;

[0523] - Glitazars, such as saroglitazar, aleglitazar, muraglitazar, or tesaglitazar;

[0524] - glitazones (e.g. pioglitazone, rosiglitazone, balaglitazone, rivoglitazone or lobeglitazone),

[0525] - Glucagon-like peptide 1 receptor (GLP-1R) agonists, such as ALT-801, AC-3174, liraglutide, cotyledonide (MEDI-0382), SAR-425899, LY-3305677, HM-15211, YH-25723, YH-GLP1, RPC-8844, PB-718, semaglutide;

[0526] - Gastric inhibitory peptide / glucagon-like peptide-1 (GIP / GLP-1) receptor co-agonists, such as tilportide (LY-3298176);

[0527] -PEGylated long-acting glucagon-like peptide-1 / glucagon (GLP-1R / GCGR) dual receptor agonists, such as DD-01;

[0528] - glucocorticoid receptor antagonists, such as CORT-118335 (miricorilant);

[0529] - Glucose 6-phosphate 1-dehydrogenase inhibitors, such as ST001;

[0530] - glucokinase stimulators, such as sinogliatin (RO-5305552);

[0531] - G-protein-coupled bile acid receptor 1 (TGR5) agonists, such as RDX-009, INT-777;

[0532] - GPR40 agonists (FFAR1 / FFA1 agonists, such as fasiglifam);

[0533] - Glucose-dependent insulinotropic peptide (GIP) and its analogs;

[0534] - heat shock protein 47 (HSP47) inhibitors, such as ND-L02-s0201;

[0535] - Hedgehog and / or TGFβ ligand inhibitors, such as Oxy-210;

[0536] - histone deacetylase inhibitors / STAT-3 modulators, such as SFX-01;

[0537] - HMG-CoA reductase inhibitors, such as atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin;

[0538] - HSD17B13 gene inhibitors, such as ARO-HSD;

[0539] - Hydrolase inhibitors, such as ABD-X;

[0540] - hypoxia-inducible factor-2α inhibitors, such as PT-2567;

[0541] - IL-10 agonists, such as pegylated iloleukin;

[0542] - ileal bile acid sodium cotransporter inhibitors, such as orvixibat (A-4250), voxibat potassium ethanolate hydrate (SHP-262), GSK2330672, CJ-14199, and eloxibat (A-3309);

[0543] - Insulin sensitizers such as KBP-042, MSDC-0602K, MSDC-5514, Px-102, RG-125 (AZD4076), tolimidone, VVP-100X, CB-4211, ETI-101;

[0544] - Insulin ligands / ds-insulin receptor agonists, such as ORMD-0801;

[0545] - Insulin or insulin analogs;

[0546] - integrin antagonists, such as IDL-2965;

[0547] - IL-6 receptor agonists, such as KM-2702;

[0548] - dual integrin α-V / β-6 and α-V / β-1 inhibitors, such as PLN-74809;

[0549] - Interleukin-17 ligand inhibitors, such as nitrazepam;

[0550] - Jak1 / 2 tyrosine kinase inhibitors, such as baricitinib;

[0551] -Jun N-terminal kinase-1 inhibitors, such as CC-90001;

[0552] - Ketohexokinase (KHK) inhibitors, such as PF-06835919;

[0553] -βKlotho (KLB)-FGF1c agonists, such as MK-3655 (NGM-313);

[0554] - 5-lipoxygenase inhibitors, such as tipelukast (MN-001), DS-102 (AF-102);

[0555] - lipoprotein lipase inhibitors, such as CAT-2003;

[0556] - LPL gene stimulators, such as alipogene tiparvovec;

[0557] - Liver X receptor (LXR) inhibitors, such as PX-L603, PX-L493, BMS-852927, T-0901317, GW-3965, SR-9238;

[0558] - Lysophosphatidic acid-1 receptor antagonists, such as BMT-053011, UD-009 (CP-2090), AR-479, ITMN-10534, BMS-986020, KI-16198;

[0559] - lysyl oxidase homolog 2 inhibitors, such as sintuzumab, PXS-5382A (PXS-5338);

[0560] - macrophage mannose receptor 1 modulators, such as temanoset-Cy3 (technetium Tc 99m temanoset);

[0561] - Meglitinides, such as nateglinide and repaglinide;

[0562] - membrane copper amine oxidase (VAP-1) inhibitors, such as TERN-201;

[0563] - MEKK-5 protein kinase (ASK-1) inhibitors, such as CJ-16871, sirolimus (GS-4997), SRT-015, GS-444217, GST-HG-151;

[0564] - MCH receptor-1 antagonists, such as CSTI-100 (ALB-127158);

[0565] - Semicarbazide-sensitive amine oxidase / vascular adhesion protein-1 (SSAO / VAP-1) inhibitors, such as PXS-4728A (BI-1467335);

[0566] - sulfonylureas, such as tolbutamide, glyburide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyrimide, glimepiride, or glipizide;

[0567] -Methionine aminopeptidase-2 inhibitors, such as ZGN-1061, ZGN-839, ZN-1345;

[0568] - methyl CpG binding protein 2 modulators, such as cysteamine;

[0569] - Mineralocorticoid receptor antagonists (MCRAs), such as MT-3995 (apalidone);

[0570] - Mitochondrial uncouplers, such as 2,4-dinitrophenol, Mito-99-0053, and HU6;

[0571] - mixed lineage kinase-3 inhibitors, such as URMC-099-C;

[0572] -Myelin basic protein stimulators, such as olesoxime;

[0573] - Chloroperoxidase inhibitors, such as PF-06667272, AZM-198;

[0574] - NADPH oxidase inhibitors such as GKT-831, GenKyoTex, APX-311, setanaxib - niacin receptor 1 agonists such as ARI-3037MO;

[0575] -NACHT LRR PYD domain protein 3 (NLRP3) inhibitors, such as KDDF-201406-03, NBC-6, IFM-514, JT-194 (JT-349);

[0576] - NFE2L2 gene inhibitors, such as GeRP-amiR-144;

[0577] - nuclear receptor modulators, such as DUR-928 (DV-928);

[0578] - P2X7 purinergic receptor modulators, such as SGM-1019;

[0579] - P2Y13 purinergic receptor stimulators, such as CER-209;

[0580] - PDE 3 / 4 inhibitors, such as talukast (MN-001);

[0581] - PDE 5 inhibitors, such as sildenafil, MSTM-102;

[0582] -PDGF receptor β modulators, such as BOT-191, BOT-509;

[0583] - peptidylprolyl cis-trans isomerase inhibitors, such as CRV-431 (CPI-432-32), NVP-018, NV-556 (NVP-025);

[0584] - phenylalanine hydroxylase stimulators, such as HepaStem;

[0585] - PPAR agonists such as chiglitazar, elafinranor (GFT-505), seladelparlysine (MBX-8025), deuterated pioglitazone R-enantiomer, pioglitazone, DRX-065, saroglitazar, lanileno (IVA-337), CHS-131, pemafibrate (K-877), ZSP-0678;

[0586] - protease-activated receptor-2 antagonists, such as PZ-235;

[0587] - Protein kinase modulators, such as CNX-014;

[0588] -PTGS2 gene inhibitors, such as STP-705 and STP-707;

[0589] - Resistin / CAP1 (adenylate cyclase-associated protein 1) interaction inhibitors, such as DWJ-211;

[0590] -Rev protein modulators, such as ABX-464;

[0591] - Rho-associated protein kinase (ROCK) inhibitors, such as REDX-10178 (REDX-10325), KD-025, TDI-01;

[0592] - S-nitrosoglutathione reductase (GSNOR) enzyme inhibitors, such as SL-891;

[0593] - sodium glucose transporter-2 (SGLT2) inhibitors, such as ipragliflozin, remogliflozin etabonate, ertugliflozin, dapagliflozin, tofogliflozin, sotagliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate;

[0594] - sodium glucose transporter-1 / 2 (SGLT 1 / 2) inhibitors, such as licogliflozin bis(prolinate) (LIK-066);

[0595] - SREBP transcription factor inhibitors, such as CAT-2003, MDV-4463;

[0596] - stearoyl-CoA desaturase-1 inhibitors, such as aramchol;

[0597] - thiazolidinediones, such as pioglitazone, rosiglitazone, or lobeglitazone;

[0598] - thyroid hormone receptor beta agonists, such as ALG-009, ASC-41, CNPT-101101, CNPT-101207, resmetirom (MGL-3196), MGL-3745, VK-2809;

[0599] -TLR-2 / TLR-4 antagonists, such as VB-201 (CI-201);

[0600] -TLR-4 antagonists, such as JKB-121, JKB-122;

[0601] - tyrosine kinase receptor modulators, such as CNX-025, GFE-2137 (repurposed nitazoxanide);

[0602] - TLR-9 antagonists, such as GNKS-356;

[0603] -TNF antagonists, such as ALF-421;

[0604] - GPCR modulators, such as CNX-023;

[0605] - nuclear hormone receptor modulators, such as Px-102;

[0606] - VDR agonists, such as CK-15;

[0607] - Xanthine oxidase / urate anion exchanger 1 (URAT1) inhibitors, such as RLBN-1001, RLBN-1127; and

[0608] - Zonulin inhibitors, such as lorazotide acetate (INN-202).

[0609] 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, eicosanylaminocholanic acid, ARI-3037MO, ASP-8232, AZD-2693, bacitrazumab, anhydrous betaine, BI-1467335, BMS-986036, BMS-986171, BMT-053011, BOT-191, BTT-1023, budenoside, BX-003, CAT-2003, cinevir, CBW-511, CER-209, CF-102, CGS21680, CNX- 014, CNX-023, CNX-024, CNX-025, cobiprostone, colesevelam, dapagliflozin, DCR-LIV1, deuterated pioglitazone R-enantiomer, 2,4-dinitrophenol, DRX-065, DS-102, DUR-928, EDP-305, elabenolide (GFT-505), enlicasin, enalapril, erpagliflozin, emragliflozin, F-351, fluasterone (ST-002), FT-4101, GDD-3898, GH-509, GKT-831, GNF-5120, GRI-0621, GR-MD-02, GS-300, GS-4997, GS- 9674, HEC-96719, HTD-1801, HSG-4112, HST-202, HST-201, hydrochlorothiazide, icosabutate (PRC-4016), eicosapent ethyl, IMM-124-E, INT-767, INV-240, IONIS-DGAT2Rx, empagliflozin, irbesartan, propagermanium, IVA-337, JKB-121, KB-GE-001, KBP-042, KD-025, M790, M780, M450, metformin, sildenafil, LB-700, LC-280126, linagliptin, liraglutide, LJN-452 (zopivotal ), LM-011, LM-002 (CVI-LM-002), LMB-763, LYN-100, MBX-8025, MDV-4463, cysteamine, MGL-3196, MGL-3745, MP-301, MSDC-0602K, namasizumab, NC-101, NDI-010976, ND-L02-s0201 (BMS-986263), NGM-282, NGM-313, NGM-386, NGM-395, NP-011, NP-135, NP-160, demethylursodeoxycholic acid, NVP-022, O-304, obeticholic acid (OCA), 25HC3S, olesoxime,PAT-505, PAT-048, PBI-4547, PEGylated iloleukin, PF-05221304, pioglitazone, pirfenidone, PRI-724, PX20606, Px-102, PX-L603, PX-L493, PXS-4728A, PZ-235, RCYM-001, RDX-009, repagliflozin etabonate, RG-125 (AZD4076), RPI-500, sarogliflozin, semaglutide, SH-2442, cintuzumab, solithromycin, sotagliflozin, statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin) statin, simvastatin), symbiotic, TCM-606F, TEV-45478, TQA-3526, TQA-3563, talukast (MN-001), TLY-012, TRX-318, TVB-2640, UD-009, ursodeoxycholic acid, VBY-376, VBY-825, VK-2809, vismodegib, voxibater potassium ethanolate hydrate (SHP-626), VVP-100X, WAV-301, WNT-974, XEN-103, XRx-117, ZGN-839, ZG-5216, ZSYM-008, ZYSM-007.

[0610] In some embodiments, the compounds of the present disclosure are combined with anti-obesity agents including, but not limited to, peptide YY or its analogs, neuropeptide Y receptor type 2 (NPYR2) agonists, NPYR1 or 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), zonisamide, phentermine (alone or in combination with topiramate), norepinephrine / dopamine reuptake inhibitors (e.g., bupropion), opioid receptor antagonists (e.g., naltrexone), combinations of norepinephrine / dopamine reuptake inhibitors and opioid receptor antagonists (e.g., a combination of bupropion and naltrexone), GDF-15 analogs, 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), phendimetrazine, diethylpropion, benzphetamine, SGLT2 inhibitors (e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, 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, dulaglutide, albiglutide, lixisenatide, or semaglutide), including pharmaceutically acceptable salts of the specifically named agents and pharmaceutically acceptable solvates of the agents and salts.

[0611] In some embodiments, the methods and compositions comprise a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), or a pharmaceutically acceptable salt thereof, 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):

[0612]

[0613]

[0614] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof.

[0615] In some embodiments, the methods and compositions comprise a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an ASK1 inhibitor. In some embodiments, the ASK1 inhibitor is a compound of Formula (IV):

[0616]

[0617] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof.

[0618] In some embodiments, the methods and compositions comprise a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an acetyl-CoA carboxylase (ACC) inhibitor. In certain embodiments, the ACC inhibitor is a compound of Formula (V):

[0619]

[0620] or a pharmaceutically acceptable salt thereof.

[0621] In some embodiments, the methods and compositions comprise a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig), or a pharmaceutically acceptable salt thereof, 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):

[0622]

[0623] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof.

[0624] VII. Treatment Methods

[0625] In some embodiments, the compounds of the present disclosure are useful in methods of treating and / or preventing a GLP-1R mediated disease or condition. In some embodiments, the methods of treating and / or preventing a GLP-1R mediated disease or condition comprise administering to a subject in need thereof a pharmaceutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0626] 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.

[0627] 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.

[0628] In some embodiments, the present disclosure relates to the use of a compound of formula (I) or other formulae described herein, 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) or other formulae described herein, or a pharmaceutically acceptable salt thereof, or use thereof, for treating and / or preventing chronic intrahepatic or some forms of extrahepatic cholestatic conditions, liver fibrosis, acute intradigestive cholestatic conditions, obstructive or chronic inflammatory conditions caused by inappropriate bile composition, gastrointestinal conditions with reduced dietary fat intake and fat-soluble dietary vitamins, inflammatory bowel disease, lipid and lipid protein diseases, type II diabetes and clinical complications of type I and type II diabetes, accumulation and subsequent development of lipids and, in particular, triglycerides due to forced Conditions and diseases caused by the activation of pro-fibrotic 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 caused by 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 or liver dysfunction as a result of chronic liver disease or surgical liver resection liver disease, 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 young, early-onset diabetes, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, obesity 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.

[0629] 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.

[0630] The present disclosure also relates to a compound according to formula (I) or other formulae as described herein, or a pharmaceutical composition comprising said compound, for use in the prophylactic and post-traumatic treatment of cardiovascular disease, such as acute myocardial infarction, acute stroke, or thrombosis occurring as an end point of chronic obstructive atherosclerosis. In some embodiments, a method for treating and / or preventing cardiovascular disease comprises administering a compound of formula (I) or other formulae as described herein to a subject in need thereof.

[0631] 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 comprise administering a compound of formula (I) or other formulae described herein to a subject in need thereof.

[0632] 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) or other formulas as described herein to a subject in need thereof.

[0633] In addition, the compounds or pharmaceutical compositions of the present invention can be used to prevent and / or treat the conditions and diseases caused by the accumulation of forced lipids and / or triglycerides and the activation of subsequent profibrotic pathways, which result in chronic fatty and fibrotic degeneration of organs. 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 Alzheimer's disease in the brain or diabetic neuropathy in the peripheral nervous system. 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 profibrotic pathways includes administering a compound of formula (I) to a subject in need thereof. In some embodiments, the method for treating and / or preventing NASH includes administering a compound of formula (I) or other formulas as described herein to a subject in need thereof.

[0634] 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.

[0635] 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.

[0636] 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.

[0637] VIII. Examples

[0638] 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).

[0639] 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.

[0640] 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.

[0641] 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.

[0642] 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 individual batches of compounds can be combined and then continued in the next synthesis step.

[0643] In 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.

[0644] 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.

[0645] Representative syntheses of compounds of the present disclosure are described in the following schemes and in the following examples.

[0646] The compounds detailed in the examples were synthesized according to the general synthetic methods described below. Unless otherwise indicated, compound nomenclature was assigned using ChemDraw version 18.1.0.535 (PerkinElmer Informatics, Inc.).

[0647] abbreviation

[0648] 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.

[0649] Table 1. List of abbreviations and acronyms .

[0650]

[0651]

[0652] A. Synthesis of Intermediates

[0653] Preparation of intermediate I-1 :

[0654]

[0655] 4-(Dibromomethyl)-3-fluorobenzonitrile: To a 40 mL vial was added 3-fluoro-4-formylbenzonitrile (500 mg, 3.35 mmol), triphenylphosphine (1.76 g, 6.71 mmol), tetrabutylammonium iodide (1.24 g, 3.35 mmol), and 1,2-dibromoethane (7 mL). The solution was heated at 60 ° C overnight. LCMS showed the formation of the product by UV. The mixture was concentrated under reduced pressure and purified by silica gel chromatography (eluent: EtOAc / hexanes) to give the desired product, 4-(dibromomethyl)-3-fluorobenzonitrile, which was carried on to the next step. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.00 (dd, J = 8.1, 7.4 Hz, 1H), 7.58 (ddd, J = 8.2, 1.5, 0.8 Hz, 1H), 7.38 (dd, J = 9.4, 1.6 Hz, 1H), 6.91 (s, 1H).

[0656] 4-(4-Bromobenzo[d][1,3]dioxol-2-yl)-3-fluorobenzonitrile: To a 40 mL vial was added 4-(dibromomethyl)-3-fluorobenzonitrile (744 mg, 2.54 mmol) and 3-bromobenzene-1,2-diol (400 mg, 2.12 mmol). The mixture was dissolved in pyridine (2 mL) and the vial was sealed with a Teflon cap. The solution was heated at 90 °C overnight. LCMS indicated the formation of the product by UV. The mixture was concentrated under reduced pressure and purified by silica gel chromatography (eluent: EtOAc / hexane) to give the desired product I-1. 1H NMR (400 MHz, CHLOROFORM-d) δ7.76 (dd, J=8.0, 6.8 Hz, 1H), 7.56 (dd, J=8.1, 1.5 Hz, 1H), 7.50 (dd, J=9.3, 1.5 Hz, 1H), 7.33 (s, 1H), 7.06 (dd, J=7.7, 1.6 Hz, 1H), 6.87-6.75 (m, 2H).

[0657] Preparation of intermediate I-2 :

[0658]

[0659] 2-(4-Bromo-2-methylbenzo[d][1,3]dioxol-2-yl)-5-chloropyridine: To a 40 mL vial were added 5-chloro-2-ethynylpyridine (1 g, 7.27 mmol), 3-bromobenzene-1,2-diol (1.37 g, 7.27 mmol) and triruthenium dodecacarbonyl (139 mg, 0.218 mmol). The mixture was dissolved in anhydrous toluene (15 mL) and the mixture was degassed with argon for 2 minutes. The vial was sealed with a Teflon cap. The solution was heated at 100 °C overnight. LCMS showed the formation of the product by UV. The mixture was cooled and then diluted with EtOAc (30 mL). The mixture was filtered through celite (rinsing with EtOAc) and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel chromatography (eluent: EtOAc / hexanes) to give the desired product I-2. ES / MS: 328.1 (M+H + ). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.66 (dd, J = 2.4, 0.7 Hz, 1H), 7.73 (dd, J = 8.4, 2.4 Hz, 1H), 7.63 (dd, J = 8.4, 0.8 Hz, 1H), 6.99 (dd, J = 7.9, 1.4 Hz, 1H), 6.82-6.69 (m, 2H), 2.13 (s, 3H).

[0660] Preparation of intermediate I-3 :

[0661]

[0662] 4-Bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxole: To a 250 mL RBF was added 1-(4-chloro-2-fluoro-phenyl)ethanone (9.59 g, 55.6 mmol), 3-bromobenzene-1,2-diol (10 g, 52.9 mmol), and p-toluenesulfonic acid monohydrate (500 mg, 2.65 mmol). The mixture was dissolved in anhydrous toluene (50 mL). The solution was refluxed under Dean-Stark conditions for 48 hours. The mixture was then cooled and dry loaded onto silica. The crude material was purified by silica gel chromatography (eluent: EtOAc / hexane) to give the desired product I-3. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.57 (t, J = 8.4 Hz, 1H), 7.20-7.09 (m, 2H), 6.98 (dd, J = 8.0, 1.4 Hz, 1H), 6.80-6.68 (m, 2H), 2.13 (s, 3H).

[0663] Preparation of intermediate I-4 :

[0664]

[0665] 5-Bromo-3a-(4-chlorophenyl)-1,2,3,3a-tetrahydrobenzo[d]pyrrolo[2,1-b] 4-Chloro-1-(4-chlorophenyl)butan-1-one (462 mg, 2.13 mmol) and 2-amino-6-bromophenol (400 mg, 2.13 mmol) were added to a 40 mL vial. The mixture was dissolved in pyridine (5 mL). The vial was sealed and stirred at 50 ° C for 4 h, followed by stirring at 90 ° C for 16 h. The mixture was concentrated under reduced pressure and the crude material was purified by silica gel chromatography (eluent: EtOAc / hexane) to give the desired product I-4. ES / MS: 350.2 (M + )。 1H NMR (400 MHz, CHLOROFORM-d) δ 7.65-7.56 (m, 2H), 7.38-7.31 (m, 2H), 6.98 (dd, J = 8.1, 1.2 Hz, 1H), 6.78 (dd, J = 7.6, 1.2 Hz, 1H), 6.75-6.65 (m, 1H), 3.62 (ddd, J = 10.7, 8.6, 6.1 Hz, 1H), 3.33 (ddd, J = 10.9, 7.1, 4.3 Hz, 1H), 2.76-2.59 (m, 1H), 2.29 (ddd, J = 13.7, 9.0, 6.7 Hz, 1H), 2.07-1.88 (m, 2H).

[0666] Preparation of intermediate I-5 :

[0667]

[0668] 5-Bromo-3a-(4-chlorophenyl)-3,3a-dihydrobenzo[d]pyrrolo[2,1-b] Oxazol-1(2H)-one: 4-(4-chlorophenyl)-4-oxobutanoic acid (1.13 g, 5.32 mmol) and 2-amino-6-bromophenol (1 g, 5.32 mmol) were added to a 100 mL RBF. The mixture was dissolved in anhydrous toluene (15 mL). The solution was refluxed under Dean-Stark conditions for 48 hours. The mixture was then cooled and dry loaded onto silica. The crude material was purified by silica gel chromatography (eluent: EtOAc / hexane) to give the desired product I-5. ES / MS: 364.2 (M + ). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.03-7.96 (m, 2H), 7.60 (dd, J = 8.0, 1.0 Hz, 1H), 7.54-7.45 (m, 3H), 7.21 (t, J = 8.0 Hz, 1H), 3.66 (dd, J = 7.7, 6.6 Hz, 2H), 3.45 (t, J = 7.0 Hz, 2H).

[0669] Preparation of intermediate I-6 :

[0670]

[0671]

[0266] Methyl 4-amino-3-(((1-(cyanomethyl)cyclopropyl)methyl)amino)benzoate: To a solution of methyl 3-fluoro-4-nitrobenzoate (700 mg, 3.52 mmol) in THF (10 mL) and DMF (5 mL) was added diisopropylethylamine (3.1 mL, 17.6 mmol) and 2-(1-(aminomethyl)cyclopropyl)acetonitrile hydrochloride (567 mg, 3.87 mmol). The resulting solution was heated to 70 °C for 24 hours. Upon completion, the solvent was removed and the resulting residue was dissolved in EtOAc (50 mL), washed with brine (10 mL), concentrated, and continued without further purification. Then methyl 3-(((1-(cyanomethyl)cyclopropyl)methyl)amino)-4-nitrobenzoate (1.0 g, 3.46 mmol) was dissolved in EtOAc:THF (2:1, 15 mL) and 10% palladium on carbon (368 mg, 0.346 mmol) was added. The resulting suspension was stirred at room temperature for 16 hours under a hydrogen balloon. The mixture was filtered through celite, washed with EtOAc (50 mL), and concentrated to give the desired product I-6 without further purification. ES / MS: 260.2 (M+H + ).

[0672] Preparation of intermediate I-7

[0673]

[0674] 4-amino-3-(2-methoxyethylamino) methyl benzoate:To a solution of 3-fluoro-4-nitro-methyl benzoate (50.0g, 251mmol) in THF (400mL), diisopropylethylamine (70.0mL, 402mmol) and 2-methoxyethylamine (34.9mL, 402mmol) are added. 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 salt water (30mL), concentrated, and can proceed without further purification. Then 3-(2-methoxyethylamino)-4-nitro-methyl benzoate (20.0g, 78.7mmol) is dissolved in EtOAc:EtOH (1:1, 140mL), followed by addition of 10% palladium on carbon (5.02g, 4.72mmol). The resulting suspension is stirred at room temperature for 16 hours under a hydrogen balloon. The reaction mixture was filtered through celite, washed with EtOAc (100 mL), and concentrated to give the desired product I-7 without further purification. ES / MS: 225.2 (M+H + ).

[0675] Preparation of intermediate I-8

[0676]

[0677] Methyl 4-amino-3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)benzoate (I-8): Methyl 4-amino-3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)benzoate was prepared as described for I-7 using (1-(fluoromethyl)cyclopropyl)methanamine; 2,2,2-trifluoroacetic acid instead of methoxyethylamine. ES / MS: 253.3 (M+H + ).

[0678] Preparation of intermediate I-9

[0679]

[0680] Methyl 4-amino-3-((oxetan-2-ylmethyl)amino)benzoate (I-9): Methyl 4-amino-3-((oxetan-2-ylmethyl)amino)benzoate was prepared as described for I-7 using (S)-oxetan-2-ylmethylamine in place of methoxyethylamine. ES / MS: 237.0 (M+H + ).

[0681] Preparation of intermediate I-10 :

[0682]

[0683] 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). Sulfuric acid (12.1 M, 2.05 mL, 24.9 mmol) and hydrogen peroxide (30% aqueous solution, 46.7 mL, 74.6 mmol) were added sequentially and the reaction was heated to 100 ° C for 1 hour. After that, the reaction was cooled to room temperature and then slowly poured into 300 mL of ice water while vortexing. 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 2×100 mL of EtOAc, and the combined organics were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (EtOAc / hexane gradient) to give the product.

[0684] (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 reaction was heated to 50 ° C for 16 hours. Afterwards, the reaction was concentrated in vacuo, and the residue was purified by column chromatography (0-25% EtOAc / hexanes) to give the product. ES / MS: 299.2 (M+H + ).

[0685] (S)-4-amino-3-fluoro-5-((oxetan-2-ylmethyl)amino)ethyl benzoate (I-10): (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 reaction 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-10). ES / MS: 269.2 (M+H + )。 1H 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).

[0686] Preparation of intermediate I-11 :

[0687]

[0688] 5-Amino-6-(((1-(fluoromethyl)cyclopropyl)methyl)amino)picolinic acid methyl ester: To a solution of 6-chloro-5-nitro-pyridine-2-carboxylic acid methyl ester (1.5 g, 6.93 mmol) in 10 mL of THF was added N-ethyldiisopropylamine (5.87 mL, 34.6 mmol). Then [1-(fluoromethyl)cyclopropyl]methylamine; 2,2,2-trifluoroacetic acid (1.5 g, 6.93 mmol) were added at RT. The mixture was stirred overnight, diluted with 50 mL of EtOAc, and washed with 20 mL of brine and water. The organic layer was dried and concentrated. The mixture was dissolved in 10 mL of ethanol and 5 mL of water. Iron (2.4 g, 43.2 mmol) and ammonium chloride (3.3 g, 61.8 mmol) were added to the solution. The mixture was heated to 80 ° C for 1 hour. The mixture was cooled and filtered through celite. The filtrate was diluted with 50 mL of EtOAc and washed with 20 mL of brine. The organic layer was dried and concentrated to give 1-11, which was used without further purification. ES / MS: 254.2 (M+H + ).

[0689] Preparation of intermediate I-12 :

[0690]

[0691] tert-Butyl 2,3-difluoro-4-nitrobenzoate: To a solution of 2,3-difluoro-4-nitrobenzoic acid (1.00 g, 4.92 mmol) in THF (15 mL) was added di-tert-butyl dicarbonate (2.15 g, 9.85 mmol) and 4-dimethylaminopyridine (180 mg, 1.48 mmol), and the resulting solution was stirred at 40 ° C for 3 hours. After completion, the solvent was removed by rotary evaporation, and the resulting residue was diluted with EtOAc (100 mL), washed with water (25 mL), brine (25 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by column chromatography (0-50% EtOAc / hexane) to give the title compound.

[0692] (S)-tert-butyl 2-fluoro-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoate: To a solution of tert-butyl 2,3-difluoro-4-nitrobenzoate (300 mg, 1.16 mmol) in THF (4 mL) was added diisopropylethylamine (0.61 mL, 3.47 mmol) and (S)-oxetan-2-ylmethylamine (0.12 mL, 1.2 mmol). The resulting solution was heated to 60 °C for 4 hours. Upon completion, the solvent was removed and the resulting residue was dissolved in EtOAc (50 mL), washed with water (10 mL), then with brine (10 mL), concentrated, and continued without further purification. ES / MS: 327.9 (M+H + ).

[0693] Tert-butyl (S)-4-amino-2-fluoro-3-((oxetan-2-ylmethyl)amino)benzoate: Tert-butyl (S)-2-fluoro-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoate (378 mg, 1.16 mmol) was dissolved in ethanol (5 mL) and saturated aqueous ammonium chloride (1.5 mL) was added. Iron powder (323 mg, 5.79 mmol) was then added to the reaction mixture and the reaction was heated to 60 °C. After 3 hours, the mixture was cooled to room temperature, filtered through Celite, washed with water (10 mL), MeOH (10 mL) and EtOAc (25 mL), and concentrated in vacuo. EtOAc (50 mL) was added to the resulting mixture. The organic solution was washed with water (25 mL), brine (25 mL), dried over MgSO4, filtered, and concentrated. The product I-12 was used without further purification. ES / MS: 298.0 (M+H + )

[0694] Preparation of intermediate I-13 :

[0695]

[0696] 1-(tert-Butyl)3-Methyl 2-(5-bromo-3-fluoropyridin-2-yl)malonate: To a 40 mL vial were 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 RT 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 directly continued in the next step. ES / MS: 348.5 (M+H + ).

[0697] Methyl 2-(5-bromo-3-fluoropyridin-2-yl)acetate: 1-(tert-butyl) 3-methyl 2-(5-bromo-3-fluoropyridin-2-yl)malonate (1.4 g, 4.02 mmol) was added to a 100 mL RBF, and trifluoroacetic acid (10 mL) and CHCl (10 mL) were added. The mixture was stirred at RT overnight. LCMS showed the formation of the product. The solvent was evaporated under reduced pressure to give the product as a TFA salt. ES / MS: 248.3 (M+H + )

[0698] 2-(5-bromo-3-fluoro-2-pyridyl)acetic acid (I-13): 2-(5-bromo-3-fluoropyridin-2-yl) methyl acetate (trifluoroacetate) (1.2 g, 3.31 mmol) was added to a 40 mL RBF. 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 overnight at 70 degrees. The mixture was concentrated under reduced pressure, and the residue was dissolved in water and acidified with 1 N HCl. The resulting mixture was extracted 3 times with a mixture of DCM and methanol. The combined organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material I-13 can proceed without further purification.

[0699] ES / MS: 234.159 (M+H + )

[0700] Preparation of intermediate I-14 :

[0701]

[0702] 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 (I-7) (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 h. The reaction was concentrated in vacuo, and the residue was 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 carried forward without further purification. ES / MS m / z: 583.5 (M+H + )

[0703] 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 h. The reaction mixture was then 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 (2X). The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by column chromatography (0-100% EtOAc / hexanes) to give the title compound. ES / MS m / z: 421.9 (M+H + ).

[0704] 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-Dichloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ... 1-Hexane (4.80 mL) was added and the reaction was heated to 100 ° C for 24 h. 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 / hexane) to give compound I-14. ES / MS m / z: 469.4 (M+H + ).

[0705] Preparation of intermediate I-15 :

[0706]

[0707] 5-(4-Bromo-2-methylbenzo[d][1,3]dioxol-2-yl)thiophene-2-carbonitrile (I-15): 5-(4-Bromo-2-methylbenzo[d][1,3]dioxol-2-yl)thiophene-2-carbonitrile was prepared according to the procedure described for intermediate I-2, substituting 5-ethynylthiophene-2-carbonitrile for 5-chloro-2-ethynylpyridine. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.54 (d, J = 3.9 Hz, 1H), 7.26 (d, J = 3.9 Hz, 1H), 7.02 (dd, J = 7.2, 2.2 Hz, 1H), 6.84-6.74 (m, 2H), 2.16 (s, 3H).

[0708] Preparation of intermediate I-16 :

[0709]

[0710] 2-(4-Bromo-2-methylbenzo[d][1,3]dioxol-2-yl)-1-methyl-1H-benzo[d]imidazole (I-16): 2-(4-Bromo-2-methylbenzo[d][1,3]dioxol-2-yl)-1-methyl-1H-benzo[d]imidazole was prepared according to the procedure described for intermediate I-2, substituting 2-ethynyl-1-methyl-1H-benzo[d]imidazole for 5-chloro-2-ethynylpyridine. ES / MS: 346.2 (M+H + ).

[0711] Preparation of intermediate I-17 :

[0712] Methyl 2-(4-bromo-2,6-difluorophenyl)acetate: To 2-(4-bromo-2,6-difluoro-phenyl)acetic acid (5.00 g, 1.99 mmol) was added 31.9 mL of HCl in methanol (1.25 M, 2 equivalents). The mixture was heated to 70°C overnight. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with 0-10% EtOAc / hexanes to give methyl 2-(4-bromo-2,6-difluoro-phenyl)acetate. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.16-7.08 (m, 2H), 3.74 (s, 3H), 3.69 (s, 2H).

[0713] Methyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorophenyl)acetate: 2-(4-bromo-2,6-difluoro-phenyl)acetic acid (2.83 g, 0.0107 mol) was dissolved in 1,4-difluorobenzene with potassium propionate (3.59 g, 0.0320 mol), bis(diphenylphosphino)ferrocene)palladium(II) chloride (1.19 g, 0.00160 mol) and bis(pinacolato)diboron (3.52 g, 0.0139 mol). 1-Hydroxy-2-nitro-1-oxadiazole (5-nitro-1-oxadiazole) (5.5g, 0.0160mol) was added to the 4-bromo-2-(4-chloro-2-fluoro-phenyl)-2-methyl-1,3-benzodioxole (5.5g, 0.0160mol) column. The mixture was capped and bubbled with nitrogen for five minutes. The mixture was then heated at 110°C for 1 hour. Thereafter, the reaction lid was opened and bis(diphenylphosphino)ferrocene)palladium dichloride (II) (0.594g, 0.0008mol) and 2M sodium bicarbonate aqueous solution (10.7mL, 0.0214mol) were added. The mixture was stirred at room temperature for two minutes, and then 4-bromo-2-(4-chloro-2-fluoro-phenyl)-2-methyl-1,3-benzodioxole (5.5g, 0.0160mol) was added. The mixture was then capped and heated at 95°C for 3 hours. LCMS showed that the borate was completely converted. The mixture was then cooled to room temperature, filtered through diatomaceous earth, and concentrated in vacuo. The mixture was directly loaded onto the column and eluted with a slow gradient of 0-30% EtOAc / hexane to obtain an oil. LC-MS (ESI) m / z 449.0 (M+H).

[0714] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorophenyl)acetic acid (I-17): Methyl 2-[4-[2-(4-chloro-2-fluoro-phenyl)-2-methyl-1,3-benzodioxol-4-yl]-2,6-difluoro-phenyl]acetate (1.50 g, 0.00334 mol) was dissolved in 15 mL of acetonitrile. 0.3 M lithium hydroxide solution (0.0167 mol, 16.7 mL) was then added and the mixture was heated at 100 ° C for 1 hour. LCMS showed quantitative conversion to the desired starting material. The reaction mixture was acidified to pH 6 by adding 1.0 M citric acid solution followed by water and EtOAc. The mixture was extracted three times with EtOAc, dried over magnesium sulfate, and concentrated under reduced pressure to give 2-[4-[2-(4-chloro-2-fluoro-phenyl)-2-methyl-1,3-benzodioxol-4-yl]-2,6-difluoro-phenyl]acetic acid. 1H NMR (400 MHz, CHLOROFORM-d) δ 11.53 (s, 1H), 7.56 (t, J = 8.2 Hz, 1H), 7.48-7.37 (m, 2H), 7.25-7.11 (m, 2H), 7.06 (dd, J = 7.9, 1.5 Hz, 1H), 6.99-6.86 (m, 2H), 3.86 (s, 2H), 2.16 (s, 3H). ES / MS: 436.0 (M+H).

[0715] Preparation of intermediate I-18 :

[0716] Methyl 4-amino-3-((2-(methylsulfonyl)ethyl)amino)benzoate: I-18 was prepared in the same manner as described for I-7 using 2-(methylsulfonyl)ethan-1-amine instead of methoxyethylamine. ES / MS: 273.2 (M+H+).

[0717] Preparation of intermediate I-19 :

[0718] Methyl 4-amino-3-((2-(difluoromethoxy)ethyl)amino)benzoate: I-19 was prepared in the same manner as described for I-7 using 2-(difluoromethoxy)ethan-1-amine instead of methoxyethylamine. ES / MS: 261.2 (M+H+).

[0719] Preparation of intermediates I-20 and I-21 :

[0720] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorophenyl)acetic acid 1-17 was separated as a mixture of two stereoisomers by chiral SFC (OJ-H column with 5% MeOH cosolvent) to afford two different stereoisomers.

[0721] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorophenyl)acetic acid: ES / MS: 436.1.

[0722] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorophenyl)acetic acid: ES / MS: 436.1.

[0723] Preparation of intermediate I-22 :

[0724] 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 room temperature for 3 days. The mixture was diluted with EtOAc, washed with 5% LiCl 2× and brine. The organic extract was dried over sodium sulfate to give the title product. ES / MSm / z:222(M+H+); 1H 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).

[0725] N-(2-Methoxyethyl)-2-nitro-5-(2H-tetrazol-5-yl)aniline: In a 200 ml round-bottom flask, a suspension of 3-(2-methoxyethylamino)-4-nitro-benzonitrile (2.563 g, 11.6 mmol), sodium azide (1.51 g, 23.2 mmol) and ammonium chloride (1.24 g, 23.2 mmol) in DMF (50 mL) was heated at 110° C. overnight. The mixture was diluted with EtOAc and washed with 5% LiCl 3×50 mL. The aqueous layer was extracted twice with EtOAc (100 mL). The combined organic extracts were dried over sodium sulfate to give the title product as an oil. ES / MSm / 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=8.9,1.8 Hz, 1H), 3.82-3.69 (m, 2H), 3.66 (t, J = 5.2Hz, 2H), 3.46 (s, 3H), 3.01 (d, J = 0.5Hz, 4H).

[0726] N2-(2-methoxyethyl)-4-(2H-tetrazol-5-yl)benzene-1,2-diamine (I-22): 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 / Vac. Pd / C (10%, 37.7 mg, 0.0354 mmol) was added to the mixture, and the mixture was stirred at room temperature under a hydrogen balloon overnight. The mixture was filtered through a plug of celite and rinsed with EtOAc. The mixture was concentrated to give the title product, which was used in the subsequent step without further purification. ES / MS m / z: 235.2 (M+H+).

[0727] Preparation of intermediate I-23 :

[0728] Tert-Butyl 2-(6-chloro-2-methoxypyridin-3-yl)acetate: In a 40 mL reaction vial, a mixture of 3-bromo-6-chloro-2-methoxy-pyridine (1000 mg, 4.50 mmol), Pd2(dba)3 (103 mg, 0.112 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (130 mg, 0.225 mmol) was degassed three times with Ar / vac. THF (10 mL) was added and degassed three times with Ar / vac. Bromo-(2-tert-butoxy-2-oxo-ethyl)zinc (0.500 M, 13.5 mL, 6.74 mmol) was added and the mixture was heated at 65 ° C for 3 hours. The reaction was diluted with EtOAc and brine. The organic extract was dried over sodium sulfate and purified by flash chromatography (eluent: EtOAc / hexane) to give the title compound. ES / MSm / z: 258.2 (M+H+); 1H NMR (400MHz, CDCl3) δ7.43 (dt, J = 7.6, 0.7Hz, 1H), 6.89 (d, J = 7.6Hz, 1H), 3.97 (s, 3H), 3.48 (s, 2H), 1.46 (s, 9H).

[0729] 2-(6-chloro-2-methoxypyridin-3-yl)acetic acid: To a solution of tert-butyl 2-(6-chloro-2-methoxy-3-pyridinyl)acetate (250 mg, 0.970 mmol) in DCM (5 mL) was added TFA (0.750 mL). The reaction was stirred at room temperature overnight, concentrated to dryness, and used in the next step without further purification. ES / MS m / z: 202.2 (M+H+).

[0730] Methyl 4-(2-(6-chloro-2-methoxypyridin-3-yl)acetamido)-3-((2-methoxyethyl)amino)benzoate: To a solution of 2-(6-chloro-2-methoxy-3-pyridinyl)acetic acid (196 mg, 0.972 mmol), methyl 4-amino-3-(2-methoxyethylamino)benzoate (262 mg, 1.17 mmol), methyl 4-amino-3-(2-methoxyethylamino)benzoate (262 mg, 1.17 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (626 mg, 1.65 mmol) in DMF (4 mL) was added N,N-diisopropylethylamine (0.800 mL, 4.59 mmol). The mixture was stirred at room temperature overnight. The reaction was diluted with EtOAc and washed with 5% LiCl, saturated NaHCO 3 , and brine. The organic extracts were dried over sodium sulfate and concentrated. Assuming complete conversion, the crude residue was carried forward without further purification. ES / MS m / z: 408.2 (M+H ).

[0731] Methyl 2-[(4-bromo-2,6-difluoro-phenyl)methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (I-23): A solution of methyl 4-[[2-(6-chloro-2-methoxy-3-pyridyl)acetyl]amino]-3-(2-methoxyethylamino)benzoate (397 mg, 0.973 mmol) and glacial acetic acid (3.5 mL, 61.2 mmol) in DCE (4 mL) was heated at 60° C. for 7 hours. The mixture was concentrated and chromatographed (eluent: EtOAc / hexanes) to provide the title compound. ES / MSm / z:390.2(M+H+); 1H NMR (400MHz, CDCl3) δ8.11(dd,J=1.6,0.7Hz,1H),7.99(dd,J=8.5,1.6Hz,1H),7.73(dd,J=8.5,0.6Hz,1H),7.46-7.38(m,1H), 6.87(d,J=7.7Hz,1H),4.39(t,J=5.4Hz,2H),4.30-4.25(m,2H),4.00(s,3H),3.97(s,3H),3.65(t,J=5.4Hz,2H),3.26(s,3H).

[0732] Preparation of intermediate I-24 :

[0733] 2-Chloro-5,5-dimethoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulene: To a 100 mL vial was added 3-2-chloro-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-one (1 g, 5.14 mmol), methanol (10 mL), HCl (2.5 M in methanol, 2.05 mL, 1.03 mmol) and trimethyl orthoformate (1.69 mL, 12.5 mmol). The solution was heated at 70 °C for 24 hours. The mixture was then cooled to room temperature and concentrated under reduced pressure. The crude material was diluted with ether (50 mL) and washed with 50% aqueous NaHCO3 (1 x 20 mL). The aqueous layer was back extracted with ether (1×50 mL), and the combined organic layers were dried over MgSO 4 , filtered, and concentrated under reduced pressure to give the desired product, 2-chloro-5,5-dimethoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulene, which was carried forward to the next step.

[0734] 4-Bromo-2'-chloro-6',7',8',9'-tetrahydrospiro[benzo[d][1,3]dioxole-2,5'-benzo[7]annulene]: To a 100 mL vial was added 2-chloro-5,5-dimethoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulene (800 mg, 3.32 mmol), 3-bromobenzene-1,2-diol (691 mg, 3.66 mmol), and p-toluenesulfonic acid monohydrate (63 mg, 0.33 mmol). The mixture was dissolved in toluene (10 mL) and the solution was heated at reflux under Dean-Stark conditions overnight. The mixture was then cooled, dry loaded onto silica, and purified by silica chromatography (eluent: EtOAc / hexanes) to give the desired product 1-24. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.62-7.54 (m, 1H), 7.28 (s, 1H), 7.17 (d, J = 7.7 Hz, 1H), 6.96 (dd, J = 8.1, 1.3 Hz, 1H), 6.77 (dd, J = 7.8, 1.2 Hz, 1H), 6.71 (t, J = 7.9 Hz, 1H), 3.06 (dt, J = 7.1, 2.3 Hz, 2H), 2.41-2.26 (m, 2H), 2.18-2.05 (m, 2H), 1.87-1.65 (m, 2H).

[0735] Preparation of intermediate I-25 :

[0736] 4'-Bromo-8-chloro-3,4-dihydro-2H-spiro[benzo[b] Hepta-5,2'-benzo[d][1,3]dioxole](I-25): 4'-bromo-8-chloro-3,4-dihydro-2H-spiro[benzo[b] Heptaquinone-5,2'-benzo[d][1,3]dioxole] was treated in the same manner as described for I-24 with 8-chloro-3,4-dihydrobenzo[b] Prepared using heptaquinone (2H)-one instead of 3-2-chloro-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-one. ES / MS: 367.0 (M+H+). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.54 (d, J = 8.4 Hz, 1H), 7.16-6.99 (m, 3H), 6.87-6.63 (m, 2H), 4.33 (ddd, J = 12.2, 6.2, 3.9 Hz, 1H), 4.24-4.09 (m, 1H), 2.58-2.36 (m, 2H), 2.31 (ddp, J = 17.8, 9.0, 4.5 Hz, 1H), 2.15 (tq, J = 11.4, 4.2 Hz, 1H).

[0737] Preparation of intermediate I-26 :

[0738] 4'-Bromo-8-chloro-3,4-dihydro-2H-spiro[benzo[b] Spiro[benzo[d][1,3]dioxole-5,2'-benzo[d][1,3]dioxole] (I-26): 4-Bromo-6'-chloro-3',4'-dihydro-2'H-spiro[benzo[d][1,3]dioxole-2,1'-naphthalene] was prepared in the same manner as described for I-24, substituting 6-chloro-3,4-dihydronaphthalen-1(2H)-one for 3-2-chloro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one. ES / MS: 353.1 (M+H+). 1H NMR (400 MHz, chloroform-d) δ 7.51 (d, J = 8.4 Hz, 1H), 7.26-7.19 (m, 2H), 7.04-6.96 (m, 1H), 6.79-6.75 (m, 2H), 2.89 (t, J = 6.3 Hz, 2H), 2.43-2.22 (m, 2H), 2.19-2.06 (m, 2H).

[0739] Preparation of intermediate I-27 :

[0740] 4-Bromo-2-(4-chloro-2-fluorophenyl)-2-ethylbenzo[d][1,3]dioxole (I-27): 4-Bromo-2-(4-chloro-2-fluorophenyl)-2-ethylbenzo[d][1,3]dioxole was prepared in the same manner as described for I-24, substituting 1-(4-chloro-2-fluorophenyl)propan-1-one for 3-2-chloro-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-one.

[0741] Preparation of intermediate I-28 :

[0742] 4-Bromo-2-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxole (I-28): 4-Bromo-2-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxole was prepared in the same manner as described for I-3, substituting 1-(4-chloro-2-fluorophenyl)ethan-1-one for 1-(2-fluoro-4-(trifluoromethyl)phenyl)ethan-1-one. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.83-7.73 (m, 1H), 7.49-7.36 (m, 2H), 7.05-6.84 (m, 2H), 6.83-6.67 (m, 1H), 2.25-2.09 (m, 3H).

[0743] Preparation of intermediate I-29 :

[0744] 4-Chloro-1-(diethoxyphosphorylmethyl)-2-fluoro-benzene: To a 40 mL vial (vented to atmosphere) was added 1-(bromomethyl)-4-chloro-2-fluoro-benzene (3.3 g, 14.8 mmol) and triethyl phosphite (2.53 mL, 14.8 mmol) (gas evolution). The mixture was heated at 100° C. for 3 hours. The mixture was cooled and used directly in the next step.

[0745] (E)-1-Bromo-3-(4-chloro-2-fluorostyryl)-2-fluorobenzene: To a 250 mL vial containing 4-chloro-1-(diethoxyphosphorylmethyl)-2-fluoro-benzene (4 g, 14.3 mmol) was added THF (100 mL) and the mixture was cooled to 0°C. Solid potassium tert-butoxide (2.4 g, 21.4 mmol) was added and the mixture was stirred at 0°C for 30 minutes. 3-Bromo-2-fluoro-benzaldehyde (2.89 g, 14.3 mmol) was added and the mixture was stirred at room temperature for 48 hours. The mixture was diluted with EtOAc (100 mL) and washed with saturated aqueous NH4Cl solution (1×50 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (eluent: EtOAc / hexanes) to give the desired product. 1H NMR (400 MHz, chloroform-d) δ 7.61-7.55 (m, 2H), 7.49 (ddd, J = 8.1, 6.5, 1.6 Hz, 1H), 7.29 (d, J = 6.2 Hz, 2H), 7.17 (ddd, J = 12.3, 10.4, 2.1 Hz, 2H), 7.06 (td, J = 7.9, 1.0 Hz, 1H).

[0746] 1-(3-Bromo-2-fluorophenyl)-2-(4-chloro-2-fluorophenyl)ethane-1,2-diol: To a 100 mL vial containing (E)-1-bromo-3-(4-chloro-2-fluorostyryl)-2-fluorobenzene (1 g, 3.03 mmol) was added tert-butanol (12 mL), water (10 mL), acetone (10 mL), citric acid (50% in water, 2.3 mL), potassium osmium(IV)ate dihydrate (5.6 mg, 0.015 mmol), and 4-methylmorpholine N-oxide (390 mg, 3.3 mmol). The solution was stirred at 40 °C overnight. LCMS indicated consumption of the starting material. The mixture was diluted with EtOAc (50 mL) and 2 mL of saturated aqueous NH4Cl was added. The layers were separated and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (eluent: EtOAc / hexanes) to give the desired product. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.57-7.38 (m, 3H), 7.24-6.89 (m, 3H), 5.16 (s, 2H).

[0747] 1-Bromo-7-chloro-4b,9b-dihydrobenzofuro[3,2-b]benzofuran (I-29): To a 40 mL vial containing 1-(3-bromo-2-fluorophenyl)-2-(4-chloro-2-fluorophenyl)ethane-1,2-diol (100 mg, 0.275 mmol) was added THF (5 mL) and the mixture was cooled to 0 ° C under a nitrogen atmosphere. Potassium tert-butoxide (1M THF, 0.825 mL, 0.825 mmol) was added and the mixture was stirred for 1 hour and warmed to room temperature. The mixture was quenched with water (2 mL) and diluted with EtOAc (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were dried over MgSO 4 , filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (eluent: EtOAc / hexanes) to give the desired product.

[0748] Preparation of intermediate I-30 :

[0749] Methyl 5-amino-6-(((1-(cyanomethyl)cyclopropyl)methyl)amino)picolinate (I-30): Methyl 5-amino-6-(((1-(cyanomethyl)cyclopropyl)methyl)amino)picolinate was prepared in a manner analogous to I-11 using 2-(1-(aminomethyl)cyclopropyl)acetonitrile hydrochloride in place of [1-(fluoromethyl)cyclopropyl]methanamine; 2,2,2-trifluoroacetic acid. ES / MS: 261.2 (M+H+).

[0750] Preparation of intermediates I-31 and I-32 :

[0751] 2-(4-Bromo-2-methyl-1,3-benzodioxol-2-yl)-5-chloropyridine (I-31 and I-32): 2-(4-Bromo-2-methyl-1,3-benzodioxol-2-yl)-5-chloro-pyridine (I-2) was separated by chiral SFC (AD-H column with 5% IPA-NH3 cosolvent) to give two different stereoisomers.

[0752] Peak 1: 2-(4-bromo-2-methyl-1,3-benzodioxol-2-yl)-5-chloropyridine (I-31): ES / MS: 328.1 (M+H+). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.66 (d, J = 2.4 Hz, 1H), 7.74 (dd, J = 8.4, 2.4 Hz, 1H), 7.63 (dd, J = 8.4, 0.7 Hz, 1H), 6.99 (dd, J = 8.0, 1.4 Hz, 1H), 6.81-6.70 (m, 2H), 2.13 (s, 3H).

[0753] Peak 2: 2-(4-bromo-2-methyl-1,3-benzodioxol-2-yl)-5-chloropyridine (I-32): ES / MS: 328.1 (M+H+). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.66 (d, J = 2.4 Hz, 1H), 7.74 (dd, J = 8.4, 2.4 Hz, 1H), 7.63 (dd, J = 8.4, 0.7 Hz, 1H), 6.99 (dd, J = 8.0, 1.4 Hz, 1H), 6.81-6.70 (m, 2H), 2.13 (s, 3H).

[0754] Preparation of intermediate I-33 :

[0755] Methyl 4-amino-3-(((4-ethyl-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate: Methyl 4-amino-3-(((4-ethyl-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate was prepared as described for I-6 in the same manner using (4-ethyl-4H-1,2,4-triazol-3-yl)methanamine instead of 2-(1-(aminomethyl)cyclopropyl)acetonitrile hydrochloride. ES / MS: 276.2 (M+H+).

[0756] Preparation of intermediate I-34 :

[0757] 4-amino-3-(( Methyl 4-amino-3-(((4-ethyl-4H-1,2,4-triazol-3-yl)methyl)amino)benzoate was used in the same manner as described for I-6. Prepared using oxazol-2-ylmethanamine hydrochloride instead of 2-(1-(aminomethyl)cyclopropyl)acetonitrile hydrochloride. ES / MS: 248.2 (M+H+).

[0758] Preparation of intermediates I-35 and I-36 :

[0759] 4-Bromo-2-(4-chloro-2-fluorophenyl)isoindolin-1-one: To a solution of 4-chloro-2-fluoroaniline (100 g, 0.69 mmol) in acetic acid (1.37 mL) was added methyl 3-bromo-2-(bromomethyl)benzoate (216 mg, 0.70 mmol). The resulting mixture was heated to 100° C. for 18 h, then cooled to room temperature and concentrated to dryness. The crude material was then purified by SiO column chromatography (eluent: EtOAc / hexanes) to afford 4-bromo-2-(4-chloro-2-fluorophenyl)isoindolin-1-one (I-35). ES / MS m / z: 341.954 (M+H+).

[0760] 4-Bromo-2-(4-chloro-2-fluorophenyl)isoindoline: Borane-tetrahydrofuran complex (1M in THF, 1 mL, 1 mmol) was added to 4-bromo-2-(4-chloro-2-fluorophenyl)isoindoline-1-one (36 mg, 0.10 mmol). The resulting mixture was stirred at room temperature for 3 days and then diluted with methanol. The mixture was then concentrated to dryness, and the crude material was purified by SiO column chromatography (eluent: EtOAc / hexanes) to give 4-bromo-2-(4-chloro-2-fluorophenyl)isoindoline (I-36). ES / MS m / z: 326.019 (M+H+).

[0761] Preparation of intermediate I-37 :

[0762] 7-Bromo-2-(4-chloro-2-fluorophenyl)isoindolin-1-one: To a solution of 4-chloro-2-fluoroaniline (106 g, 0.73 mmol) in acetic acid (1.5 mL) was added methyl 2-bromo-6-(bromomethyl)benzoate (270 mg, 0.88 mmol). The resulting mixture was heated to 100° C. for 6 h, then cooled to room temperature and concentrated to dryness. The crude material was then purified by SiO column chromatography (eluent: EtOAc / hexanes) to afford 7-bromo-2-(4-chloro-2-fluorophenyl)isoindolin-1-one (I-37). ES / MS m / z: 342.074 (M+H+).

[0763] Preparation of intermediate I-38 :

[0764] 2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-ol: To a solution of benzene-1,2,3-triol (2.5 g, 19.8 mmol) and 1-(4-chloro-2-fluorophenyl)ethan-1-one (3.5 g, 20.3 mmol) in toluene (19.8 mL) was added p-toluenesulfonic acid (190 mg, 1.0 mmol). The resulting mixture was heated to reflux with a Dean-Stark trap for 2.5 days. The resulting mixture was concentrated to dryness, and the crude material was purified by SiO column chromatography (eluent: EtOAc / hexanes) to afford 2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-ol. 1H NMR (400MHz, CDCl3) δ7.61-7.52 (m, 1H), 7.20-7.10 (m, 2H), 6.73 (t, J = 8.1Hz, 1H), 6.54-6.47 (m, 2H), 5.09 (s, 1H), 2.10 (d, J = 1.2Hz, 3H).

[0765] 2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl trifluoromethanesulfonate: To a solution of 2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-ol (60 mg, 0.21 mmol) in dichloromethane (2 mL) was added trifluoromethanesulfonic anhydride (1 M in CHCl, 0.24 mL, 0.24 mmol) and triethylamine (0.06 mL, 0.43 mmol) at -78°C (external temperature, acetone / CO bath). The resulting mixture was stirred at -78°C for 20 minutes and slowly warmed to room temperature for 40 minutes. The resulting mixture was diluted with CHCl and washed with aqueous bicarbonate. The aqueous layer was back extracted with CHCl and concentrated to dryness. The crude material was then purified by SiO2 column chromatography (eluent: EtOAc / hexanes) to give 2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl trifluoromethanesulfonate (I-38). 1H NMR (400 MHz, CDCl3) δ 7.59 (t, J = 8.4 Hz, 1H), 7.18 (ddd, J = 9.6, 6.2, 2.1 Hz, 2H), 6.89-6.84 (m, 2H), 6.81 (dd, J = 6.9, 2.9 Hz, 1H), 2.13 (d, J = 1.1 Hz, 3H).

[0766] Preparation of intermediate I-39 :

[0767] 4-(1,1-Dimethoxyethyl)-3-fluorobenzonitrile: To a solution of 4-acetyl-3-fluorobenzonitrile (110 mg, 0.67 mmol) and p-toluenesulfonic acid (6 mg, 0.05 mmol) in methanol (0.79 mL) was added trimethyl orthoformate (0.1 mL, 0.91 mmol). The resulting mixture was heated to 50°C for 24 hours and then cooled to room temperature. The resulting mixture was diluted with diethyl ether and washed with dilute aqueous bicarbonate solution. The aqueous layer was stripped, dried over magnesium sulfate, and concentrated to dryness to yield 4-(1,1-dimethoxyethyl)-3-fluorobenzonitrile. 1H NMR (400MHz, CDCl3) δ7.82 (t, J = 7.9 Hz, 1H), 7.47 (dd, J = 8.2, 1.6 Hz, 1H), 7.37 (dd, J = 10.6, 1.6 Hz, 1H), 3.22 (s, 6H), 1.66 (d, J = 0.7 Hz, 3H).

[0768] 4-(4-bromo-2-methylbenzo[d][1,3]dioxol-2-yl)-3-fluorobenzonitrile: To a solution of 4-(1,1-dimethoxyethyl)-3-fluorobenzonitrile (141 mg, 0.67 mmol) and 3-bromobenzene-1,2-diol (133 mg, 0.70 mmol) in toluene (1.5 mL) was added p-toluenesulfonic acid (12 mg, 0.06 mmol). The resulting mixture was heated to 75 ° C for 4 days and concentrated to dryness. The crude material was then purified by SiO2 column chromatography (eluent: EtOAc / hexanes) to give 4-(4-bromo-2-methylbenzo[d][1,3]dioxol-2-yl)-3-fluorobenzonitrile (I-39). 1H NMR(400MHz,MeOD)δ7.81(t,J=7.7Hz,1H),7.69(dd,J=10.6,1.5Hz,1H),7.63(dd,J=8.0,1.6Hz,1H), 7.02(dd,J=8.2,1.2Hz,1H), 6.87(dd,J=7.8,1.2Hz,1H), 6.80(t,J=8.0Hz,1H), 2.13(d,J=1.1Hz,3H).

[0769] Preparation of intermediate I-40 :

[0770] Methyl 2-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate: Methyl 2-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate was prepared according to the preparation of Intermediate I-14 using 2-(4-bromo-2,5-difluorophenyl)acetic acid instead of 2-(4-bromo-2-fluorophenyl)acetic acid. ES / MS m / z: 487.257 (M+H+). 1H NMR (400MHz, CDCl3) δ8.10(d,J=1.6Hz,1H),8.00(dt,J=8.5,1.4Hz,1H),7.77(d,J=8.4Hz,1H),7.45(dd,J=9.4,4.6Hz,1H),6.98-6.88 (m,1H),4.40(d,J=3.2Hz,2H),4.32(t,J=5.2Hz,2H),3.97(d,J=1.1Hz,3H),3.64(t,J=5.2Hz,2H),3.25(d,J=1.8Hz,3H),1.36(s,12H).

[0771] Preparation of intermediate I-41 :

[0772] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2-fluorophenyl)acetic acid: 4-Bromo-2-(4-chloro-2-fluoro-phenyl)-2-methyl-1,3-benzodioxole (500 mg, 1.46 mmol) and ethyl 2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (538 mg, 1.75 mmol) were dissolved in 1,4-dioxolane. The mixture was stirred for 10 minutes at 4 ℃ for 2 hours.Then the mixture was added to 40 DEG C of 40 DEG C of 80 DEG C of 1% dextrose (1.0mL) and 4.5-dextrose (1.0mL) in ... in 2% dextrose (1.0mL) and 4.5-dextrose (1.0mL) in 2% dextrose (1.0mL) in 2% dextrose (1.0mL) and 4.5-dextrose (1.0mL) in 2% dextrose (1.0mL) in 2% dextrose (1.0mL) and 4.5-dextrose (1.0mL) in 2% dextrose (1.0mL) in 2% dextrose (1.0mL) in 2% dextrose (1.0mL)

[0773] The residue was dissolved in ACN (5.0 mL) and a LiOH aqueous solution (1.0 M, 2 mL) was added. The reaction was heated to 80 ° C for 2 hours. The reaction was cooled to ambient temperature and quenched with an HCl aqueous solution (1 M) until it was only slightly acidic as measured using pH test paper. The reaction was diluted with EtOAc (3 mL) and the organic layer was separated. The aqueous layer was extracted with EtOAc (2 × 5 mL) and the organic layers were combined, washed with brine (3 mL), dried over sodium sulfate, filtered and concentrated in vacuo and used without further purification. The title product was obtained. ES / MS: 439.0 (M + Na +).

[0774] Preparation of intermediate I-42 :

[0775] (S)-Methyl 4-amino-3-(((tetrahydrofuran-2-yl)methyl)amino)benzoate: Methyl (S)-4-amino-3-(((tetrahydrofuran-2-yl)methyl)amino)benzoate (I-42) was prepared as described for I-7 using [(2S)-tetrahydrofuran-2-yl]methanamine in place of methoxyethylamine. ES / MS m / z: 251.2 (M+H+).

[0776] B. Compound Examples

[0777] Procedure 1: Example 1 :

[0778]

[0779]

[0266] Methyl 2-(4-bromo-2,6-difluorobenzyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate: To a solution of methyl 2-(4-bromo-2,6-difluorophenyl)acetic acid (150 mg, 0.58 mmol), methyl 4-amino-3-(((1-(cyanomethyl)cyclopropyl)methyl)amino)benzoate (I-6) (174 mg, 0.69 mmol) and HATU (177 mg, 0.75 mmol) in DCM (3.0 mL) and DMF (1.5 mL) was added DIPEA (0.50 mL, 2.90 mmol). The reaction mixture was stirred at RT for 16 hours, then diluted with saturated aqueous ammonium chloride solution and EtOAc. The aqueous layer was extracted with two additional portions of EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, isolated by vacuum filtration, and concentrated in vacuo. The crude material was dissolved in dichloroethane (1.0 mL) and acetic acid (3.0 mL) and stirred at 60° C. for 4 hours. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (eluent: EtOAc / Hex) to give the desired product. ES / MS: 474.0, 476.0 (M+H +).

[0780] Methyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate: Methyl 2-(4-bromo-2,6-difluorobenzyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (40.0 mg, 0.084 mmol), bis(pinacolato)diboron (27.8 mg, 0.11 mmol), potassium propionate (28.4 mg, 0.25 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (9.4 mg, 0.013 mmol) were stirred in 1,4-difluorobenzyl HCl. The solution in 2-nitro-1-oxane (1.0 mL) was degassed by bubbling argon for 60 seconds and then heated at 110 ° C in a sealed tube for 45 minutes. The reaction mixture was cooled and then 2M aqueous sodium carbonate solution (84 μL, 0.17 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (4.7 mg, 0.0063 mmol) and 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxole (I-3) (29.0 mg, 0.084 mmol) were added. The solution was degassed by bubbling argon for 60 seconds and then heated at 80 ° C in a sealed tube for 2 hours. The reaction mixture was cooled, filtered through diatomaceous earth (eluent: EtOAc), and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: EtOAc / hexane) to give the desired product. ES / MS: 658.2 (M+H + ).

[0781]

[0266] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 1): To a solution of methyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (48.5 mg, 0.074 mmol) in MeCN (0.75 mL) was added 0.3 M aqueous lithium hydroxide (0.49 mL, 0.15 mmol). The reaction mixture was heated in a sealed tube at 100 °C for 2 minutes. The cooled reaction mixture was purified by RP-HPLC (eluent: water / MeCN*0.1% TFA) to give the product Example 1 as trifluoroacetate salt. ES / MS: 644.2 (M+H + ). 1H NMR (400MHz, MeOD) δ8.56 (dd, J=1.4, 0.7Hz, 1H), 8.14 (dd, J=8.6, 1.4Hz, 1H), 7.71 ( dd,J=8.5,0.6Hz,1H),7.64-7.53(m,3H),7.31(dd,J=10.9,2.0Hz,1H),7.23(ddd,J= 8.4, 2.0, 0.8Hz, 1H), 7.20 (dd, J=7.8, 1.5Hz, 1H), 7.03-6.93 (m, 2H), 4.76 (s, 2H), 4. 73(s,2H),2.64(s,2H),2.12(d,J=1.0Hz,3H),1.03-0.96(m,2H),0.96-0.88(m,2H).

[0782] Procedure 2, Example 2

[0783] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-7-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 2):

[0784]

[0785] To a solution of 2-(4-bromo-2,6-difluorophenyl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoic acid tert-butyl ester: To a solution of 2-(4-bromo-2,6-difluoro-phenyl)acetic acid (100 mg, 0.40 mmol) in DMF (2 mL) was added (S)-tert-butyl 4-amino-2-fluoro-3-((oxetan-2-ylmethyl)amino)benzoate (I-12) (106 mg, 0.36 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (227 mg, 0.60 mmol), followed by N,N-diisopropylethylamine (0.35 mL, 1.99 mmol), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was dissolved in EtOAc (40 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was dried over MgSO 4 , filtered and concentrated in vacuo. The crude residue was carried forward without further purification. ES / MS: 529.5 (M+H + ).

[0786] (S)-2-(4-bromo-2,6-difluorobenzyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid: The crude product (S)-tert-butyl 4-(2-(4-bromo-2,6-difluorophenyl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate (211 mg, 0.40 mmol) from the previous step was dissolved in AcOH (2 mL) and the reaction mixture was heated to 100° C. for 30 minutes. The reaction mixture was concentrated in vacuo and the crude residue was dissolved in EtOAc (40 mL) and washed with saturated aqueous sodium bicarbonate solution (4×10 mL), followed by water (10 mL) and brine (10 mL). The organic layer was dried over MgSO 4 , filtered and concentrated in vacuo. The crude residue was purified by column chromatography (0-100% EtOAc / hexanes) to give the title compound. ES / MS: 511.9 (M+H + ).

[0787] tert-Butyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-7-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate: To a vial was added (S)-2-(4-bromo-2,6-difluorobenzyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (67 mg, 0.13 mmol), potassium propionate (44 mg, 0.39 mmol), bis(pinacolato)diboron (43 mg, 0.17 mmol), 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (15 mg, 0.020 mmol), and dichlorobenzyl alcohol (100 mg, 0.003 mmol). alkane (1.5 mL). The resulting mixture was degassed by bubbling argon under the liquid surface for 1 minute, then the vial was sealed and placed in a 110°C heating block for 30 minutes. After cooling, the vial was opened and 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxole (54 mg, 0.16 mmol) (I-3), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.3 mg, 0.010 mmol) and potassium carbonate (2M aqueous solution, 0.13 mL, 0.26 mmol) were added to the reaction mixture. The resulting mixture was degassed by bubbling argon under the liquid surface for 1 minute, then the vial was sealed and placed in a 0°C heating block for 2 hours. Upon completion, the reaction mixture was cooled to room temperature, poured into water (15 mL) and extracted with EtOAc (2×25 mL). The organic layer was washed with brine (10 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by column chromatography (20-100% EtOAc / hexanes) to afford the title compound. ES / MS: 695.3 (M+H + ).

[0788]

[0266] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-7-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 2): To a solution of tert-butyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-7-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (40 mg, 0.057 mmol) in DCM (2 mL) was added 0.25 mL of TFA and the resulting solution was stirred at 40 °C for 1 hour. The reaction mixture was diluted with EtOAc (30 mL), washed with water (3×5 mL), concentrated and purified by RP-HPLC (eluent: water / MeCN 0.1% TFA). The combined fractions were then diluted with EtOAc (50 mL), washed with water (3×20 mL), brine (1×15 mL) and dried over MgSO 4 . The EtOAc was removed by rotary evaporation and the crude residue was dissolved in acetonitrile (20 mL) and concentrated to dryness twice. The residue was then dissolved in acetonitrile:water (2:1, 20 mL), frozen and placed on a lyophilizer to give the final compound Example 2. ES / MS: 639.6 (M+H + ). 1H NMR(400MHz,DMSO-d6)d 7.67-7.53(m,5H),7.44-7.35(m,2H),7.31(dd,J=8.0,1.3Hz,1H),7.07(dd,7.8,1.3Hz,1H),7.01(t,J=7.9Hz,1H),5.18-5.10(m,1Hz),4.85( dd,J=15.6,7.1Hz,1H),4.69(dd,J=15.7,2.8Hz,1H),4.62-4.51(m,2H) ,4.49-4.35(m,2H),2.90-2.70(m,1H),2.47-2.37(m,1H),2.12(s,3H).

[0789] Procedure 3: Example 3

[0790]

[0791] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-N-(cyclopropylsulfonyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxamide (Example 3): 2-[[4-[2-(4-chloro-2-fluoro-phenyl)-2-methyl-1,3-benzodioxol-4-yl]-2,6-difluoro-phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylic acid (Example 19) To a mixture of 4-(dimethylamino)-pyridine (20.0 mg, 0.0328 mmol), cyclopropanesulfonamide (11.9 mg, 0.0985 mmol), 4-(dimethylamino)-pyridine (16.9 mg, 0.138 mmol), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (26.4 mg, 0.138 mmol) in DMF (1.00 mL) was added N,N-diisopropylethylamine (0.0515 mL, 0.296 mmol) and the reaction mixture was stirred at room temperature for 16 h. The reaction was quenched by the addition of 50 μL of TFA and the crude reaction mixture was directly purified by RP-HPLC (15-76.84% 0.1% TFA-ACN in 0.1% TFA in water, 15 min gradient, column: Gemini 5 μM, NX-C18 110 Angstroms, 250×21.2 mm) to give the title compound Example 3 as a racemic mixture of trifluoroacetate salts. ES / MS m / z:712.3(M+H + ). 1 H NMR (400MHz, methanol-d4) δ8.41-8.37(m,1H),8.01(dd,J=8.6,1.6Hz,1H),7.76(dd,J=8.6,0. 7Hz,1H),7.65-7.54(m,3H),7.34(dd,J=11.0,2.0Hz,1H),7.29-7.24(m,1H),7.21(dd,J= 7.8,1.5Hz,1H),7.05-6.95(m,2H),4.85(s,3H),4.78(t,J=5.0Hz,2H),4.73(s,2H),3.8 7(t,J=4.9Hz,2H),3.25-3.17(m,1H),2.14(s,3H),1.41-1.28(m,2H),1.23-1.10(m,2H).

[0792] Procedure 4: Example 4

[0793]

[0794] Methyl 2-(4-(2-(4-cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2-fluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate: To a vial was added methyl 2-(4-bromo-2-fluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (prepared in a similar manner to the first step of Procedure 1) (60 mg, 0.142 mmol), bis(neopentylethylene glycol)diboron (64.3 mg, 0.285 mmol), Pd(dppf)Cl2 (16 mg, 0.0214 mmol), and potassium propionate (48 mg, 0.43 mmol). 1,4-Dioxol was added. To the flask was added 2-nitro-1-oxane (1.0 mL), and the mixture was degassed with argon for 30 seconds. The vial was sealed, and the mixture was heated at 120 ° C for 1 hour. The vial was cooled, and LCMS showed that the starting aryl bromide was converted to an intermediate boronic acid. Pd (dppf) Cl2 (8 mg, 0.012 mmol) and 4- (4-bromobenzo [d] [1,3] dioxol-2-yl) -3-fluorobenzonitrile (I-1) (41 mg, 0.128 mmol) were added, and sodium carbonate (2M aqueous solution, 0.18 mL, 0.356 mmol) was added. The flask was sealed and stirred at 90 ° C for 1 hour. LCMS showed conversion to the desired product, and the flask was cooled to RT. The organic layer was directly transferred to the loading column, and the crude material was purified by silica gel chromatography (eluent: EtOAc / hexane) to give the desired product. ES / MS: 582.4 (M + H + ).

[0795] 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2-fluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid: To a 40 mL vial was added methyl 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2-fluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (32.5 mg, 0.0559 mmol) and acetonitrile (1 mL). To the mixture was added LiOH HO (3.3 mg, 0.06 mmol) dissolved in water (0.2 mL), and the mixture was stirred at 55 °C for 3 hours. LCMS showed conversion of the starting material to the product. The mixture was acidified with 50% citric acid (0.2 mL) and 2 drops of trifluoroacetic acid were added. The material was purified by RP-HPLC (eluent: water / MeCN*0.1% TFA) to give the product Example 4 as a trifluoroacetate salt. ES / MS: 568.5 (M+H +). 1HNMR (400MHz, methanol-d4) δ8.53 (d, J=1.4Hz, 1H), 8.20 (dd, J=8.6, 1.5Hz, 1H) ,7.85-7.78(m,1H),7.78-7.63(m,4H),7.49(t,J=8.0Hz,1H),7.46(s,1H) ,7.23(dd,J=8.0,1.3Hz,1H),7.06(t,J=7.9Hz,1H),6.99(dd,J=7.8,1.2H z, 1H), 4.78 (t, J = 5.0Hz, 2H), 4.73 (s, 2H), 3.85-3.73 (m, 2H), 3.30 (s, 3H).

[0796] Procedure 5: Example 5

[0797]

[0798] Methyl 2-(4-(2-(4-cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate: To a vial was added bromobenzo[d][1,3]dioxol-2-yl)-3-fluorobenzonitrile (I-1) (65 mg, 0.203 mmol), bis(neopentylethylene glycol)diboron (60 mg, 0.264 mmol), Pd(dppf)Cl2 (22.6 mg, 0.03 mmol) and potassium propionate (68 mg, 0.609 mmol). 1,4-difluorobenzyl was added. To the flask was added 4- bromo-2- methylbenzyl alcohol (1.0 mL), and the mixture was degassed with argon for 30 seconds. The vial was sealed and the mixture was heated at 120 ° C for 30 minutes. The vial was cooled and LCMS showed that the starting aryl bromide was converted into an intermediate boronic acid. Pd (dppf) Cl2 (12 mg, 0.018 mmol) and 2- (4- bromo-2,6-difluorobenzyl) -1- (2-methoxyethyl) -1H- benzo [d] imidazole -6- carboxylic acid methyl ester (prepared in a similar manner to the first step of program 1) (93 mg, 0.212 mmol) were added, and sodium carbonate (2M aqueous solution, 0.2 mL, 0.406 mmol) was added. The flask was sealed and stirred at 90 ° C for 1 hour. LCMS showed that it was converted into the desired product, and the flask was cooled to room temperature. The organic layer was directly transferred to the loading column, and the crude material was purified by silica gel chromatography (eluent: EtOAc / hexane) to give the desired product. ES / MS: 600.3 (M+H + ).

[0799] 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid: To a 40 mL vial was added methyl 2-(4-(2-(4-cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (70 mg, 0.117 mmol) and acetonitrile (1 mL). To the mixture was added LiOH HO (4.2 mg, 0.18 mmol) dissolved in water (0.2 mL), and the mixture was stirred at 55 °C for 5 hours. LCMS showed conversion of the starting material to the product. The mixture was acidified with 50% citric acid (0.2 mL) and 2 drops of trifluoroacetic acid were added. The material was purified by RP-HPLC (eluent: water / MeCN*0.1% TFA) to give the product Example 5 as a trifluoroacetate salt. ES / MS: 586.291 (M+H + ). 1H NMR (400MHz, methanol-d4) δ8.54(d,J=1.5Hz,1H),8.21(dd,J=8.5,1.6Hz,1H),7.86-7.62(m,4H),7.51-7.40(m,2H),7.35 (dd,J=10.0,6.2Hz,1H),7.12-6.98(m,3H),4.80(t,J=5.0Hz,2H),4.74(s,2H),3.83(t,J=4.9Hz,2H),3.30(s,3H).

[0800] Procedure 6: Example 32

[0801]

[0802] Methyl 2-(2-fluoro-4-(2-phenylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate: To a vial were added 4-bromo-2-phenylbenzo[d][1,3]dioxole (synthesized in the same manner as I-1 starting from dibromotoluene) (59 mg, 0.214 mmol), Pd(dppf)Cl2 (2 To the reaction mixture was added 2-[ ... + ).

[0803]

[0266] 2-(2-Fluoro-4-(2-phenylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid: To a 40 mL vial was added methyl 2-(2-fluoro-4-(2-phenylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.186 mmol) and acetonitrile (2 mL). To the mixture was added LiOH (11.1 mg, 0.464 mmol) dissolved in water (0.5 mL), and the mixture was stirred at 55 °C for 24 hours. LCMS showed conversion of the starting material to the product. The mixture was acidified with 50% citric acid (0.2 mL) and 2 drops of trifluoroacetic acid were added. Purification by RP-HPLC (eluent: water / MeCN*0.1% TFA) gave the product Example 32 as trifluoroacetate salt. ES / MS: 525.581 (M+H +). 1H NMR (400MHz, methanol-d4) δ8.55 (s, 1H), 8.23 ​​(dd, J = 8.6, 1.4Hz, 1H), 7.76 (d, J = 8. 6Hz,1H),7.74-7.64(m,2H),7.60(dd,J=7.4,2.4Hz,2H),7.56-7.42(m,4H), 7.19(d,J=8.1Hz,1H),7.13(s,1H),7.01(t,J=7.9Hz,1H),6.94(d,J=7.7Hz, 1H), 4.81 (t, J = 5.0Hz, 2H), 4.76 (s, 2H), 3.80 (t, J = 4.9Hz, 2H), 3.30 (s, 3H).

[0804] Procedure 7: Example 7

[0805]

[0806] Methyl 2-(3-bromo-2-hydroxyphenyl)acetate: Bromine (1.08 g, 6.74 mmol) was added dropwise to a solution of tert-butylamine (940 mg, 12.9 mmol) in PhMe (10 mL) at -30 ° C. The solution was stirred at -30 ° C for 1 h and then cooled to -78 ° C. A solution of methyl 2-(2-hydroxyphenyl)acetate (1.40 g, 8.42 mmol) in DCM (6 mL) was slowly added. The resulting mixture was slowly warmed to RT over 16 h under rapid stirring. H2O (50 mL) and EtOAc (50 mL) were added and the resulting mixture was poured into a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: EtOAc / hexane). ES / MS: 245.2 (M+H + ).

[0807] Methyl 2-(3-bromo-2-((tert-butyldimethylsilyl)oxy)phenyl)acetate: To a solution of methyl 2-(3-bromo-2-hydroxyphenyl)acetate (1.29 g, 5.26 mmol) in DCM (10 mL) was added imidazole (720 mg, 10.5 mmol) and tert-butylchlorodimethylsilane (1.20 g, 7.90 mmol) at RT. The mixture was stirred at room temperature for 1.5 h, then diluted with H O (50 mL) and DCM (50 mL) and poured into a separatory funnel. The layers were separated and the aqueous phase was extracted with DCM (2 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO , filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: EtOAc / hexane). 1HNMR (400 MHz, CHLOROFORM-d) δ 7.51-7.40 (m, 1H), 7.21-7.14 (m, 1H), 6.85 (t, J = 7.8 Hz, 1H), 3.72 (s, 3H), 3.69 (s, 2H), 1.06 (s, 9H), 0.30 (s, 6H).

[0808] 2-(3-Bromo-2-((tert-butyldimethylsilyl)oxy)phenyl)acetaldehyde: To a solution of methyl 2-(3-bromo-2-((tert-butyldimethylsilyl)oxy)phenyl)acetate (150 mg, 0.417 mmol) in DCM (10 mL) at 0°C was added diisobutylaluminum hydride (1 M in hexanes) (1.04 mL, 1.04 mmol) dropwise. The solution was warmed to RT over 1 hour with rapid stirring, then quenched with saturated aqueous potassium sodium tartrate (50 mL) and diluted with EtOAc (50 mL). The resulting slurry was filtered through a plug of celite, and the filter cake was washed with EtOAc (50 mL). The filtrate was poured into a separatory funnel and the layers were separated. The aqueous phase was extracted with EtOAc (2×50 mL), and the combined organic extracts were washed with brine (50 mL), dried over MgSO , filtered, and concentrated in vacuo.

[0809] The crude mixture was dissolved in DCM (10 mL). NaHCO (76 mg, 1.25 mmol) and Dess-Martin periodinane (270 mg) were added at RT. The mixture was stirred at RT for 1 h, then filtered through celite, and the filter cake was washed with DCM (20 mL). The filtrate was concentrated in vacuo and purified by silica gel chromatography (eluent: EtOAc / hexane). 1H NMR (400 MHz, chloroform-d) δ 9.68 (t, J = 2.1 Hz, 1H), 7.51 (dd, J = 8.0, 1.7 Hz, 1H), 7.09 (dd, J = 7.5, 1.7 Hz, 1H), 6.88 (t, J = 7.8 Hz, 1H), 3.71 (d, J = 2.1 Hz, 2H), 1.06 (s, 9H), 0.30 (s, 6H).

[0810] 2-Bromo-6-(2-hydroxy-2-phenylethyl)phenol: To a solution of 2-(3-bromo-2-((tert-butyldimethylsilyl)oxy)phenyl)acetaldehyde (100 mg, 0.30 mmol) in THF (5 mL) was added phenylmagnesium bromide (1 M in THF) (0.46 mL, 0.46 mmol) dropwise at 0°C. The resulting mixture was stirred at 0°C for 1 h, then quenched with saturated aqueous NH4Cl (10 mL) with rapid stirring and warmed to RT. The mixture was poured into a separatory funnel and the layers were separated. The aqueous phase was extracted with EtOAc (2 x 20 mL), and the combined organic extracts were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo.

[0811] The crude mixture is redissolved in THF (5mL). Tetrabutylammonium fluoride (1M in THF) (0.46mL, 0.46mmol) is added dropwise at RT, and the resulting mixture is stirred for 1h, then diluted with EtOAc (20mL) and saturated NaHCO3 aqueous solution (20mL). The mixture is poured into a separatory funnel and the layers are separated. The aqueous phase is extracted with EtOAc (2×20mL), and the combined organic extracts are washed with brine (50mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified by silica gel chromatography (eluent: EtOAc / hexane). 1H NMR (400MHz, chloroform-d) δ9.29(s,1H),7.37-7.26(m,5H),7.25-7.19(m,1H),6.82(dd,J=7.5,1.6Hz,1H),6.62(t,J=7 .7Hz, 1H), 5.49 (s, 1H), 5.10 (dd, J = 8.2, 3.1Hz, 1H), 3.14 (dd, J = 14.4, 8.2Hz, 1H), 3.02 (dd, J = 14.4, 3.1Hz, 1H).

[0812] 7-Bromo-2-phenyl-2,3-dihydrobenzofuran: To a solution of 2-bromo-6-(2-hydroxy-2-phenylethyl)phenol (48 mg, 0.164 mmol) in THF (6 mL) was added triphenylphosphine (52 mg, 0.20 mmol) and diisopropyl azodicarboxylate (50 mg, 0.25 mmol) at RT. The mixture was stirred at room temperature for 15 minutes and then concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: EtOAc / hexane). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.51-7.37 (m, 4H), 7.37-7.32 (m, 2H), 7.13 (dt, J = 7.2, 1.1 Hz, 1H), 6.79 (t, J = 7.6 Hz, 1H), 3.96-3.67 (m, 1H), 3.33 (ddt, J = 15.8, 7.9, 1.0 Hz, 1H).

[0813] Methyl 2-(2-fluoro-4-(2-phenyl-2,3-dihydrobenzofuran-7-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate: A 5 mL microwave vial was charged with methyl 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (I-14) (61 mg, 0.13 mmol), 7-bromo-2-phenyl-2,3-dihydrobenzofuran (30 mg, 0.11 mmol) and Pd(dppf)Cl2 (10 mg, 0.0135 mmol). Dihydrobenzofuran was added. The mixture was stirred for 2 h at 85 ° C. and then cooled to RT. After dilution with H2O (20 mL) and EtOAc (20 mL), the mixture was poured into a separatory funnel. The layers were separated and the aqueous phase was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: EtOAc / hexane). ES / MS: 537.20 (M+H + ).

[0814] 2-(2-Fluoro-4-(2-phenyl-2,3-dihydrobenzofuran-7-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid: Methyl 2-(2-fluoro-4-(2-phenyl-2,3-dihydrobenzofuran-7-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (43 mg, 0.080 mmol) was dissolved in acetonitrile (0.9 mL), after which LiOH (2 M in H2O) (0.2 mL, 0.40 mmol) was added and the resulting mixture was stirred at 50° C. for 3 h. The reaction mixture was adjusted to pH 2 using citric acid (1 M in H2O) (1 mL) and extracted with EtOAc (2×10 mL). The combined organics were concentrated and purified by RP-HPLC (eluent: H2O / MeCN 0.1% TFA) to give the product (Example 7) as a trifluoroacetate salt. ES / MS: 523.2 (M+H + ). 1H NMR (400MHz, DMSO-d6) δ8.31(d,J=1.5Hz,1H),7.89(dd,J=8.5,1.5Hz,1H),7.67(d,J =8.5Hz,1H),7.65-7.58(m,2H),7.49-7.37(m,6H),7.37-7.31(m,1H),7.28(dd,J=7.3 ,1.3Hz,1H),7.01(t,J=7.6Hz,1H),5.92(dd,J=9.4,8.1Hz,1H),4.64(t,J=5.2Hz,2H) ,4.51(s,2H),3.75(dd,J=15.9,9.4Hz,1H),3.66(t,J=5.0Hz,2H),3.25-3.14(m,4H).

[0815] Procedure 8: Example 8

[0816]

[0817] Methyl 2-(5-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)thiophen-2-yl)acetate: In an 8 ml reaction vial, methyl 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophen-2-yl]acetate (150 mg, 0.532 mmol), 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxole I-3 (198 mg, 0.575 mmol), (1,1'-bis(diphenylphosphino)ferrocene)-palladium(II) dichloride (30.1 mg, 0.0425 mmol) and sodium carbonate (2.00 M, 0.550 mL, 1.10 mmol) were added in distilled water. The suspension in 2 mL of ethanol was degassed with Ar for 5 minutes. The reaction was heated at 100° C. for 6 hours. The reaction was diluted with EtOAc and washed with brine. The organic extract was dried over sodium sulfate and purified by silica gel chromatography (eluent: EtOAc / hexane). 1H NMR (400MHz, CDCl3) δ7.58(t,J=8.3Hz,1H),7.48(d,J=3.7Hz,1H),7.18(dd,J=10.5,2.0Hz,1H),7.13(ddd,J=8.4,2.0,0.8Hz,1H),7.09(dd,J=8.1,1 .2Hz,1H),6.98(dd,J=3.7,1.0Hz,1H),6.84(t,J=7.9Hz,1H),6.75(dd,J= 7.7,1.1Hz,1H),3.89(d,J=0.9Hz,2H),3.78(s,3H),2.15(d,J=1.1Hz,3H).

[0818] 2-(5-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)thiophen-2-yl)acetic acid: A solution of methyl 2-[5-[2-(4-chloro-2-fluoro-phenyl)-2-methyl-1,3-benzodioxol-4-yl]-2-thiophen-2-yl]acetate (69.0 mg, 0.165 mmol) and lithium hydroxide monohydrate (19.3 mg, 0.461 mmol) in CH3CN (3 mL) and water (1 mL) was stirred at RT overnight. The reaction was diluted with EtOAc and adjusted to pH ~6 with 1N HCl (500 uL). The organic extract was dried over sodium sulfate to give the desired product. ES / MS: 405.0 (M + ).

[0819] 2-((5-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)thiophen-2-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester: 2-[5-[2-(4-chloro-2-fluoro-phenyl)-2-methyl-1,3-benzodioxol-4-yl]-2-thiophen-6-acetic acid (66.7 mg, 0.1 To the product of 4-nitro-1-pyrrolidone (50mg, 0.65mmol), 4-amino-3-(2-methoxyethylamino) methyl benzoate I-7 (44.3mg, 0.198mmol) and O-(7-azabenzotriazole-1-yl)-N, N, N ', N '-tetramethyluronium hexafluorophosphate (106mg, 0.279mmol) in DMF (3mL) is added N, N-diisopropylethylamine (0.135mL, 0.776mmol). The mixture is stirred overnight at RT. The mixture is diluted with EtOAc and washed with 5%LiCl, saturated NaHCO and salt water. The organic extract is dried over sodium sulfate to obtain a crude product, which is subsequently used in the following step.

[0820] A solution of methyl 4-[[2-[5-[2-(4-chloro-2-fluoro-phenyl)-2-methyl-1,3-benzodioxol-4-yl]-2-thienyl]acetyl]amino]-3-(2-methoxyethylamino)benzoate (101 mg, 0.165 mmol) in AcOH (0.650 mL) and DCE (4 mL) was heated at 60° C. for 18 hours. The reaction mixture was concentrated and purified by silica gel chromatography (eluent: EtOAc / hexane). ES / MS: 593.2 (M + )。 。 Multiple peak report 1H NMR (400 MHz, CDCl3) δ8.11 (t, J = 1.0 Hz, 1H), 8.07-7.96 (m, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.55 (t, J = 8.2 Hz, 1H), 7.46 (d, J = 3.7 Hz, 1H), 7.15 (dd, J = 10.6, 2.0 Hz, 1H), 7.11 (ddd, J = 8.3, 2.0, 0.7 Hz, 1H), 7.03 (d d,J=8.1,1.1Hz,1H),6.96(d,J=3.6Hz,1H),6.82(t,J=7.9Hz,1H),6.74(dd,J=7.8,1.2Hz,1H),4.67( s, 2H), 4.40 (t, J = 5.3Hz, 2H), 3.98 (s, 3H), 3.66 (t, J = 5.3Hz, 2H), 3.29 (s, 3H), 2.13 (d, J = 1.0Hz, 3H).

[0821] 2-((5-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)thiophen-2-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid: A mixture of methyl 2-[[5-[2-(4-chloro-2-fluoro-phenyl)-2-methyl-1,3-benzodioxol-4-yl]-2-thiophen-2-yl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (32.3 mg, 0.0545 mmol) and lithium hydroxide monohydrate (0.300 M, 0.545 mL, 0.163 mmol) in CH3CN (1 mL) was heated at 90°C for 15 min in a 40 ml reaction vial. The mixture was diluted with EtOAc and water and neutralized with 0.160 mL of 1 M citric acid. The organic extract was dried over sodium sulfate and purified by RP-HPLC (eluent: H2O / MeCN 0.1% TFA) to give the product (Example 8) as a trifluoroacetate salt. ES / MS: 593.2 (M + Multiplet report 1H NMR (400 MHz, DMSO) δ 12.83 (s, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.60-7.54 (m, 2H), 7.51 (d, J = 3.7 Hz, 1H), 7.35 (dd, J = 8.4, 2.1 Hz, 1H), 7.18-7.12 (m, 1H), 7.11 (d, J = 3.7 Hz, 1H), 6.94-6.79 (m, 2H), 4.64 (s, 2H), 4.56 (t, J = 5.0 Hz, 2H), 3.61 (t, J = 5.1 Hz, 2H), 3.19 (s, 3H), 2.10 (s, 3H).

[0822] Procedure 9: Example 9 and Example 13

[0823]

[0824] 1-((1-(2-amino-2-oxoethyl)cyclopropyl)methyl)-2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-4-fluoro-1H-benzo[d]imidazole-6-carboxylic acid (Example 9) and 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-4-fluoro -1H-Benzo[d]imidazole-6-carboxylic acid (Example 13): To a solution of ethyl 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (synthesized as in Procedure 1) (70 mg, 0.1 mmol) in MeCN (1 mL) was added 0.3 M aqueous lithium hydroxide solution (0.49 mL, 0.15 mmol). The reaction mixture was heated at 70 °C in a sealed tube for 2 h. The cooled reaction mixture was purified by RP-HPLC (eluent: water / MeCN*0.1% TFA) to give the products Example 9 and Example 13 as trifluoroacetate salts.

[0825] Example 9: ES / MS: 680.0 (M+H + ). 1H NMR (400MHz, methanol-d4) δ8.24(d,J=1.2Hz,1H),7.70-7.55(m,2H),7.51(d,J=9.0Hz,2H),7.33(dd,J=10.9,2.0Hz,1H),7 .27-7.14(m,2H),7.07-6.87(m,2H),4.69(s,2H),4.57(s,2H),2.26(s,2H),2.13(d,J=1.0Hz,3H),0.96-0.80(m,1H).

[0826] Example 13: ES / MS: 662.2 (M+H + ). 1H NMR (400MHz, methanol-d4) δ8.24(d,J=1.2Hz,1H),7.73-7.57(m,2H),7.57-7.46(m,2H),7.32(dd,J=10.9,2.0Hz,1H),7.2 8-7.15(m,2H),7.06-6.81(m,2H),4.66(s,2H),4.55(s,2H),2.61(s,2H),2.13(d,J=1.0Hz,3H),0.98-0.79(m,4H).

[0827] Procedure 10: Example 10 and Example 17

[0828]

[0829] 2-(4-(2-(2-carboxyethyl)-2-(4-chlorophenyl)-2,3-dihydrobenzo[d] oxazol-7-yl)-2,6-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 10) and 2-(4-(3a-(4-chlorophenyl)-1-oxo-1,2,3,3a-tetrahydrobenzo[d]pyrrolo[2,1-b] oxazol-5-yl)-2,6-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 17): to 2-(4-(3a-(4-chlorophenyl)-1-oxo-1,2,3,3a-tetrahydrobenzo[d]pyrrolo[2,1-b] To a solution of methyl (2-(2-(2-oxazol-5-yl)-2,6-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (synthesized as in Procedure 1) (112 mg, 0.174 mmol) in MeCN (1 mL) was added lithium hydroxide monohydrate (11 mg, 0.26 mmol) dissolved in water (0.5 mL). The reaction mixture was heated at 100° C. for 3 minutes in a sealed tube. The cooled reaction mixture was purified by RP-HPLC (eluent: water / MeCN*0.1% TFA) to give the products Example 10 and Example 17 as trifluoroacetate salts.

[0830] Example 10: ES / MS: 648.2 (M + ). 1H NMR (400MHz, methanol-d4) δ8.54(t,J=1.0Hz,1H),8.21(dd,J=8.6,1.4Hz,1H),8. 08-8.00(m,2H),7.76(d,J=8.6Hz,1H),7.57-7.50(m,2H),7.41-7.33(m,2H) ,7.33-7.21(m,2H),7.00(t,J=7.8Hz,1H),4.85-4.81(m,2H),4.78(s,2H),3 .88-3.81(m,2H),3.47(t,J=6.4Hz,2H),3.32(s,3H),2.94(t,J=6.4Hz,2H).

[0831] Example 17: ES / MS: 630.2 (M +). 1H NMR (400MHz, methanol-d4) δ8.58(s,1H),8.28-8.22(m,1H),8.12-8.01(m,2H),7.78(d,J=8.6Hz,1H),7.71(t,J=8.6Hz,4H), 7.59-7.44(m,3H),4.86-4.83(m,4H),3.87(t,J=4.9Hz,2H),3.74(t,J=6.6Hz,2H),3.46(t,J=6.5Hz,2H),3.32(s,3H).

[0832] Procedure 11: 2-(4-(2-(4-cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2-fluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 33 and Example 34):

[0833]

[0834] 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2-fluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid: 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2-fluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 4 obtained as described in Procedure 4) was separated as a mixture of two stereoisomers by chiral SFC (CELL-2 column with 30% EtOH-TFA cosolvent) to give two different stereoisomers.

[0835] 2-(4-(2-(4-cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2-fluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 33): ES / MS: 568.4 (M+H + ). 1H NMR (400MHz, methanol-d4) δ8.41(s,1H),8.13-8.06(m,1H),7.84-7.77(m,1H),7.77-7.59(m,5H),7.43(d,J=14.0Hz,2H),7.25-7.17(m ,1H),7.04(t,J=7.9Hz,1H),6.97(dd,J=7.6,1.1Hz,1H),4.67(t,J=5.0Hz,2H),4.62(s,2H),3.75(t,J=4.9Hz,2H),3.28(s,3H).

[0836] 2-(4-(2-(4-cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2-fluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 34). ES / MS: 568.4 (M+H + ). 1H NMR (400MHz, methanol-d4) δ8.41(s,1H),8.11(dd,J=8.6,1.5Hz,1H),7.80(t,J=7.5Hz,1H),7.77-7.57(m,5H),7.43(d,J=12.3Hz,2H),7.22(dd,J =8.0,1.2Hz,1H),7.04(t,J=7.9Hz,1H),6.97(dd,J=7.8,1.2Hz,1H),4.67(t,J=5.0Hz,2H),4.63(s,2H),3.75(t,J=5.0Hz,2H),3.28(s,3H).

[0837] Procedure 12: 2-(2-Fluoro-4-(2-phenylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 35 and Example 36):

[0838]

[0839] 2-(2-Fluoro-4-(2-phenylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid: 2-(2-Fluoro-4-(2-phenylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 32 obtained as described in Procedure 6) was separated as a mixture of two stereoisomers by chiral SFC (AD-H column with 30% MeOH co-solvent) to give two different stereoisomers.

[0840] 2-(2-Fluoro-4-(2-phenylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 35): ES / MS: 525.3 (M+H +). 1H NMR (400MHz, methanol-d4) δ8.52-8.48(m,1H),8.19(dd,J=8.6,1.4Hz,1H),7.75(d, J=8.6Hz,1H),7.72-7.64(m,2H),7.64-7.56(m,2H),7.52-7.42(m,4H),7.19(d d,J=8.1,1.2Hz,1H),7.13(s,1H),7.01(t,J=7.9Hz,1H),6.93(dd,J=7.7,1.2H z, 1H), 4.76 (t, J = 5.0Hz, 2H), 4.71 (s, 2H), 3.79 (t, J = 4.9Hz, 2H), 3.29 (s, 3H).

[0841] 2-(2-Fluoro-4-(2-phenylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 36): ES / MS: 525.3 (M+H + ). 1H NMR (400MHz, methanol-d4) δ8.50(t,J=1.0Hz,1H),8.18(dd,J=8.6,1.4Hz,1H),7.75( d,J=8.6Hz,1H),7.71-7.64(m,2H),7.63-7.57(m,2H),7.51-7.40(m,4H),7.19( dd,J=8.1,1.2Hz,1H),7.13(s,1H),7.01(t,J=7.9Hz,1H),6.93(dd,J=7.7,1.2 Hz, 1H), 4.76 (t, J = 5.0 Hz, 2H), 4.71 (s, 2H), 3.78 (t, J = 4.9 Hz, 2H), 3.29 (s, 3H).

[0842] Procedure 13: 2-(4-(2-(4-cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 37 and Example 38):

[0843]

[0844] 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid: 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 5 obtained as described in Procedure 5) was separated as a mixture of two stereoisomers by chiral SFC (AD-H column with 40% MeOH co-solvent) to give two different stereoisomers.

[0845] 2-(4-(2-(4-cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 37): ES / MS: 586.2 (M+H + )。 1H NMR (400 MHz, methanol-d4) δ 8.59-8.34 (m, 1H), 8.21-8.02 (m, 1H), 7.93-7.53 (m, 4H), 7.41 (d, J = 8.8 Hz, 2H), 7.37-7.21 (m, 1H), 7.15-6.89 (m, 3H), 4.79-4.71 (m, 2H), 4.67 (s, 2H), 3.86-3.73 (m, 2H), 3.28 (s, 3H).

[0846] 2-(4-(2-(4-cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 38): ES / MS: 586.2 (M+H + ). 1H NMR (400MHz, methanol-d4) δ8.45(s,1H),8.14(dd,J=8.4,1.5Hz,1H),7.81(t,J=7.5Hz,1H),7.76-7.70(m,2H),7.67(dd,J=8.0,1.6Hz,1H),7. 48-7.37(m,2H),7.28(dd,J=10.1,6.2Hz,1H),7.12-6.97(m,3H),4.73(t,J=5.0Hz,2H),4.66(s,2H),3.79(t,J=4.9Hz,2H),3.29(s,3H).

[0847] Procedure 14: 2-(4-(2-(4-cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 39 and Example 40):

[0848]

[0849] 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid: 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 31 obtained as described in Procedure 1) was separated as a mixture of two stereoisomers by chiral SFC (CELL-2 column with 45% MeOH co-solvent) to give two different stereoisomers.

[0850] 2-(4-(2-(4-cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 39): ES / MS: 586.2 (M+H + ). 1H NMR (400MHz, methanol-d4) δ8.50(s,1H),8.18(dd,J=8.6,1.6Hz,1H),7.82(t,J=7.5Hz,1H),7.78-7.64(m,3H),7.49-7.40(m,2H ),7.31(dd,J=10.1,6.2Hz,1H),7.10-6.98(m,3H),4.77(t,J=5.0Hz,2H),4.70(s,2H),3.81(t,J=5.0Hz,2H),3.30(s,3H).

[0851] 2-(4-(2-(4-cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 40): ES / MS: 586.2 (M+H +)。 1H NMR (400 MHz, methanol-d4) δ 8.47 (s, 1H), 8.16 (dd, J = 8.5, 1.5 Hz, 1H), 7.82 (t, J = 7.4 Hz, 1H), 7.77-7.64 (m, 3H), 7.48-7.39 (m, 2H), 7.30 (dd, J = 10.0, 6.0 Hz, 1H), 7.10-6.98 (m, 3H), 4.75 (t, J = 5.1 Hz, 2H), 4.68 (s, 2H), 3.81 (t, J = 5.1 Hz, 2H), 3.29 (s, 3H).

[0852] Procedure 15: 2-(4-(2-(4-cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 41 and Example 42):

[0853]

[0854] 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid: 2-(4-(2-(4-Cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 30 obtained as described in Procedure 1) was separated as a mixture of two stereoisomers by chiral SFC (IG column with 50% MeOH co-solvent) to give two different stereoisomers.

[0855] 2-(4-(2-(4-cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 41): ES / MS: 598.1 (M+H +). 1H NMR (400MHz, methanol-d4) δ8.44(s,1H),8.09(d,J=8.5Hz,1H),7.82(t,J=7.4Hz,1H),7.72(dd,J=24.1,9.1Hz,3H),7.55(d,J=8.9Hz,2H),7.49(s,1H ),7.26(d,J=7.8Hz,1H),7.12-6.98(m,2H),5.31-5.21(m,1H),4.93-4. 61(m,5H),4.54-4.44(m,1H),2.84(t,J=9.4Hz,1H),2.61-2.47(m,1H).

[0856] 2-(4-(2-(4-cyano-2-fluorophenyl)benzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 42): ES / MS: 598.2 (M+H + ). 1H NMR (400MHz, methanol-d4) δ8.47(s,1H),8.11(d,J=8.5Hz,1H),7.82(t,J=7.5Hz, 1H),7.77-7.67(m,3H),7.55(d,J=8.9Hz,2H),7.48(s,1H),7.26(d,J=7.9H z,1H),7.11-6.98(m,2H),5.26(qd,J=7.3,2.4Hz,1H),4.84-4.62(m,5H),4 .50(dt,J=9.1,6.0Hz,1H),2.85(dq,J=14.6,7.7Hz,1H),2.64-2.50(m,1H).

[0857] Procedure 16: 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 43 and Example 44):

[0858]

[0859] 2-(4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid: 2-(4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 28 obtained as described in Procedure 1) was separated as a mixture of two stereoisomers by chiral SFC (AZ-H column with 25% IPA-NH3 cosolvent) to give two different stereoisomers.

[0860] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 43): ES / MS: 621.3 (M + )。 1H NMR (400 MHz, methanol-d4) δ8.32 (s, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.62 (t, J = 8.3 Hz, 1H), 7.32 (ddd, J = 19.8, 10.5, 4.0 Hz, 2H), 7.26-7.10 (m, 2H), 7.03-6 .86(m,3H),5.24-5.12(m,1H),4.74(dd,J=15.7,6.9Hz,1H),4.69-4.56(m,3H),4. 55-4.40(m,2H),2.79(dq,J=16.7,7.8,5.9Hz,1H),2.58-2.41(m,1H),2.06(s,3H).

[0861] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 44): ES / MS: 621.4 (M +). 1H NMR (400MHz, methanol-d4) δ8.31(dd,J=1.5,0.7Hz,1H),7.99(dd,J=8.5,1.5Hz,1H),7.6 7(dd,J=8.5,0.6Hz,1H),7.61(t,J=8.3Hz,1H),7.40-7.26(m,2H),7.26-7.15(m,2 H),7.02-6.87(m,3H),5.19(qd,J=7.0,2.6Hz,1H),4.78-4.39(m,7H),2.80(dtd,J =11.4, 8.2, 6.1Hz, 1H), 2.49 (ddt, J = 11.4, 9.2, 7.2Hz, 1H), 2.06 (d, J = 1.1Hz, 3H).

[0862] Procedure 17: 2-(4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 45 and Example 46):

[0863]

[0864] 2-(4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid: 2-(4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 29 obtained as described in Procedure 1) was separated as a mixture of two stereoisomers by chiral SFC (AD-H column with 35% MeOH-DEA cosolvent) to give two different stereoisomers.

[0865] 2-(4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 45): ES / MS: 604.2 (M +). 1H NMR (400MHz, methanol-d4) δ8.63(dd,J=2.4,0.7Hz,1H),8.52(t,J=1.0Hz,1H),8.17(dd,J=8.6,1.4Hz,1 H),7.92(dd,J=8.5,2.4Hz,1H),7.76(dd,J=8.6,0.7Hz,1H),7.71(dd,J=8.5,0.7Hz,1H),7.44(dd, J=10.0,6.0Hz,1H),7.33(dd,J=10.0,6.2Hz,1H),7.04-6.92(m,3H),5.25(qd,J=7.4,2.4Hz,1H), 4.99-4.64(m,5H),4.52(dt,J=9.1,5.9Hz,1H),2.95-2.77(m,1H),2.63-2.44(m,1H),2.07(s,3H).

[0866] 2-(4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 46): ES / MS: 604.2 (M + ). 1H NMR (400MHz, methanol-d4) δ8.63(dd,J=2.5,0.7Hz,1H),8.54-8.46(m,1H),8.15(dd,J=8.5,1.4Hz,1H ),7.92(dd,J=8.5,2.4Hz,1H),7.75(d,J=8.5Hz,1H),7.71(dd,J=8.5,0.7Hz,1H),7.43(dd,J=10 .0,6.0Hz,1H),7.31(dd,J=10.0,6.1Hz,1H),7.04-6.93(m,3H),5.23(dd,J=8.1,5.8Hz,1H),4. 86-4.64(m,5H),4.51(dt,J=9.2,6.0Hz,1H),2.93-2.76(m,1H),2.64-2.44(m,1H),2.07(s,3H).

[0867] Procedure 18: 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 47 and Example 48):

[0868]

[0869] 2-(4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid: 2-(4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 22 obtained as described in Procedure 1) was separated as a mixture of two stereoisomers by chiral SFC (AD-H column with 25% IPA-NH3 cosolvent) to give two different stereoisomers.

[0870] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 47): ES / MS: 621.2 (M + ). 1H NMR (400MHz, DMSO) δ12.79(s,1H),8.26(d,J=1.6Hz,1H),7.78(dd,J=8.4,1.6Hz,1H),7.67- 7.47(m,5H),7.39(dd,J=8.4,2.1Hz,1H),7.31(dd,J=7.9,1.4Hz,1H),7.10-6.95(m,2H),5. 12(qd,J=6.9,2.7Hz,1H),4.81(dd,J=15.6,6.8Hz,1H),4.68(dd,J=15.6,2.7Hz,1H),4.61- 4.39(m,3H),4.35(dt,J=9.1,5.9Hz,1H),2.82-2.71(m,1H),2.44-2.36(m,1H),2.12(s,3H).

[0871] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 48): ES / MS: 621.2 (M +). 1H NMR (400MHz, DMSO) δ12.77(s,1H),8.25(d,J=1.6Hz,1H),7.77(dd,J=8.4,1.6Hz,1H),7.69- 7.50(m,5H),7.39(dd,J=8.4,2.1Hz,1H),7.31(dd,J=7.9,1.4Hz,1H),7.16-6.93(m,2H),5. 12(tt,J=6.9,3.3Hz,1H),4.80(dd,J=15.7,6.8Hz,1H),4.67(dd,J=15.6,2.7Hz,1H),4.60- 4.39(m,3H),4.35(dt,J=9.0,5.9Hz,1H),2.78-2.71(m,1H),2.45-2.35(m,1H),2.12(s,3H).

[0872] Procedure 19: 2-(4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 49 and Example 50):

[0873]

[0874] 2-(4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid: 2-(4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 27 obtained as described in Procedure 1) was separated as a mixture of two stereoisomers by chiral SFC (AD-H column with 35% EtOH cosolvent) to give two different stereoisomers.

[0875] 2-(4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 49): ES / MS: 604.2 (M +). 1H NMR (400MHz, DMSO) δ12.81(s,1H),8.75(d,J=2.4Hz,1H),8.27(d,J=1.5Hz,1H),8.04(dd,J=8.5,2.5Hz,1H), 7.78(dd,J=8.5,1.6Hz,1H),7.71(d,J=8.5Hz,1H),7.57(dd,J=10.5,8.5Hz,4H),7.29(dd,J=7.4,1.9Hz,1H) ,7.22-6.91(m,3H),5.11(tt,J=7.1,3.7Hz,1H),4.81(dd,J=15.6,6.8Hz,1H),4.68(dd,J=15.5,2.7Hz,1H), 4.60-4.38(m,4H),4.35(dt,J=9.1,5.9Hz,1H),2.74(dq,J=11.1,7.6Hz,1H),2.45-2.35(m,1H),2.12(s,4H).

[0876] 2-(4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorobenzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 50): ES / MS: 604.2 (M + ). 1H NMR (400MHz, DMSO) δ12.79(s,1H),8.75(d,J=2.4Hz,1H),8.26(d,J=1.5Hz,1H),8.04(dd,J=8.5,2.5Hz,1H), 7.78(dd,J=8.5,1.6Hz,1H),7.71(d,J=8.6Hz,1H),7.56(t,J=8.9Hz,4H),7.29(dd,J=7.4,2.0Hz,1H),7.16- 6.92(m,2H),5.12(qd,J=6.9,2.7Hz,1H),4.81(dd,J=15.6,6.8Hz,1H),4.67(dd,J=15.6,2.7Hz,1H),4.61-4 .40(m,4H),4.35(dt,J=9.0,5.9Hz,1H),2.97-2.62(m,1H),2.39(ddt,J=11.3,9.1,6.9Hz,1H),2.12(s,4H).

[0877] Procedure 20: Example 82

[0878] 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridinyl]-2-fluoro-phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylic acid methyl ester: 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorophenyl)acetic acid I-17 (113 mg, 0.144 mmol), To a solution of methyl 4-amino-3-((2-(methylsulfonyl)ethyl)amino)benzoate I-18 (46.5 mg, 0.154 mmol) and O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (49 mg, 0.116 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine (0.085 mL, 0.776 mmol). The mixture was stirred at RT overnight. The mixture was diluted with EtOAc and washed with 5% LiCl, saturated NaHCO 3 and brine. The organic extract was dried over sodium sulfate to obtain a crude product. Then, acetic acid was added to the intermediate and the mixture was heated at 80° C. for 4 hours. After the reaction was complete, the compound was purified by silica gel chromatography and proceeded to the next step. ES / MS: 672.2 (M+H ).

[0879] 2-[[4-[2-(4-Chloro-2-fluoro-phenyl)-2-methyl-1,3-benzodioxol-4-yl]-2,6-difluoro-phenyl]methyl]-3-(2-methylsulfonylethyl)benzimidazole-5-carboxylic acid (Example 82): A solution of methyl 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridinyl]-2-fluoro-phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (40.0 mg, 0.0.05 mmol) and aqueous lithium hydroxide monohydrate (0.3 M, 4.2 mg, 0.17 mmol) in CH3CN (1 mL) was stirred at 100°C for 5 minutes. Upon completion, the reaction was diluted with EtOAc and adjusted to pH ~6 with 1N HCl. The organic extract was dried over sodium sulfate, filtered, concentrated and purified by RP-HPLC (eluent: water / MeCN*0.1% TFA) to give the desired product. ES / MS:658.2.1H NMR (400MHz, DMSO-d6) δ8.25(d,J=1.5Hz,1H),7.95-7.86(m,2H),7.83-7.71(m,4H),7.61(d,J=8.4Hz,1H),7.53(dd,J=7.6,1.7Hz,1H),7.38( dd,J=11.6,6.1Hz,1H),6.99(d,J=8.2Hz,1H),6.65(t,J=75.3Hz,1H),5.61(s,2H),4.72(t,J=5.1Hz,2H),4.44(s,2H),4.21(t,J=5.1Hz,2H).

[0880] Procedure 21: Example 84

[0881] 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorophenyl)-N-(2-((2-methoxyethyl)amino)-4-(2H-tetrazol-5-yl)phenyl)acetamide: To 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorophenyl)acetic acid (I-17, 61.0 mg, 0 To a solution of 4-(2-methoxyethyl)-4-(2H-tetrazol-5-yl)benzene-1,2-diamine (I-22, 35.7 mg, 0.152 mmol), N-(2-methoxyethyl)-4-(2H-tetrazol-5-yl)benzene-1,2-diamine (I-22, 35.7 mg, 0.152 mmol), and O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (79.2 mg, 0.208 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine (0.133 mL, 0.766 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with 5% LiCl solution and brine. The aqueous phase was extracted twice with EtOAc, and the combined organic extracts were dried over sodium sulfate. The crude residue was used in the next step without purification. ES / MS m / z: 651.2 (M+).

[0882]

[0266] 2-(4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-difluorobenzyl)-1-(2-methoxyethyl)-6-(2H-tetrazol-5-yl)-1H-benzo[d]imidazole (Example 84): A solution of 2-(4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorophenyl)-N-(2-((2-methoxyethyl)amino)-4-(2H-tetrazol-5-yl)phenyl)acetamide (91.3 mg, 0.140 mmol) and glacial acetic acid (0.521 mL, 9.12 mmol) in DCE (3 mL) was heated at 60°C overnight. The reaction was concentrated to dryness and purified by RP-HPLC (eluent: MeCN / H2O) to give the product as a trifluoroacetic acid salt. ES / MS: 633.2 (M+H+); 1HNMR (400MHz, DMSO) δ8.32 (d, J = 1.6Hz, 1H), 7.84 (dd, J=8.4,1.6Hz,1H),7.73(d,J=8.4Hz,1H),7.67-7.53(m,4H),7.39(dd,J=8.4, 2.1Hz,1H),7.32(dd,J=8.0,1.4Hz,1H),7.10-6.98(m,2H),4.65(d,J=5.3Hz ,2H),4.47(d,J=6.9Hz,2H),3.77(t,J=5.1Hz,2H),3.26(s,3H),2.13(s,3H).

[0883] Procedure 22: Exam...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein 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, -C(O)N(R 1b )(R 1c ),-C(O)R 1b or-C(O)OR 1c , wherein the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl groups are each optionally substituted by one to four Z 1 replace; Ring A is an aromatic ring, wherein U 1 、U 2 、U 3 Each independently represents -C(H)=, -C(Z 1a )=or-N=; Ring B is C 6-10 aryl or heteroaryl, each of which is optionally substituted by one to four R 4 replace; 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, -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 , wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1 replace; X 1 、X 2 and X 3 Each independently represents -N=, -C(H)= or -C(R 8 )=; Y 1 and Y 2 Each is -C(R y1 )(R y2 )-、-N(R y1 )-, -O-, -S-, -S(O)2- or -C(O)-; W is -C(R 5 )-or-N-, When W is -N, Y 1 and Y 2 One of them is -C(R y1 )(R y2 )-or-C(O)-and Y 1 and Y 2 The other one is -C(R y1 )(R y2 )-、-C(O)- or -S(O)2-;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 )(=NO 3b )R 3c 、- P(O)(OR 3a )(R 3b )、-P(O)(OR 3a )(OR 3b ) or -B(OR 3a )(OR 3b ), wherein each of the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups is optionally substituted by one to four R 3d replace; 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 ), -OP(O)(R 9c )(N(R 9d ), -CH2P(O)(R 9c )(N(R 9d ), -OCH2P(O)(R 9c )(N(R 9d ), or -C(O)OCH2P(O)(R 9c )(N(R 9d ); wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace, 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; wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace; 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 heterocyclyl, each of which is optionally substituted by one to four Z 1b replace; R 5 is H, cyclopropyl or C 1-3 Alkyl, wherein the C 1-3 The alkyl group is optionally substituted by one, two or three groups selected from halogen, -OH, -OCH3, -CN, oxo and -N(R x1 )(R x2 ) group substitution; or R 5 and R y1 Combined with the atoms to which they are attached to form a C optionally substituted with an oxo group 3-10 a cycloalkyl group or a heterocyclic group; R x1 and R x2 Each independently is H, C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, -S(O)2R 6a1 or -S(O)2N(R 6a1 )(NR 6a2 ), wherein the C 1-6 Alkyl, cycloalkyl or heterocyclyl are each optionally replaced by F, -CN, oxo or C 3-6 cycloalkyl substitution; or R x1 and R x2 Combined with the atoms to which they are attached to form a heterocyclic group, the heterocyclic group is optionally substituted by one to four R 6b1 replace; V is -C(O)-, -O-, -N(R 6a )-or-C(R 6b )(R 6c )-; 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 groups are each optionally replaced by C 1-6 Alkyl, F or -CN substitution; 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; or R 6b and R 6c Combine with the atoms to which they are attached to form C 3-10 Cycloalkyl or heterocyclyl, each of which is optionally substituted by one to four R 6b1 replace; 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 heterocyclyl, each of which is optionally substituted by one to four R 10 replace; Each R y1 and R y2 are independently H, halo, C 1-6 Alkyl, C 1-6 haloalkyl, wherein the alkyl and haloalkyl are each optionally substituted with oxo; Each R 3d 、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 -C(O)N(R 2a )(R 2b ), 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 Each R 6a1 、R 6a2 、R 6c1 、R 6c2 and R 6c3 Independently H, C 1-6 Alkyl or C 3-10 Cycloalkyl; Each R 9a and R 9b Independently H, C 1-6 Alkyl or C1-6 haloalkyl; 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)O-R 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 ),-S-R 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; wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1a replace; 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 )、-S-R 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; wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace; 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(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 haloalkyl), -C(O)O(C 2-6 alkenyl), -C(O)O(C 2-6 Alkynyl), -C(O)O(C 3-15 Cycloalkyl), -C(O)O(heterocyclyl), -C(O)O(C 6-10 aryl), -C(O)O(heteroaryl), -C(O)NH2, -C(O)NH(C 1-9 alkyl), -C(O)NH(C 1-8 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)(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; wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl radicals are optionally substituted in each instance with 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 3-15 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; and Each R 1b 、R 1c 、R 2a 、R 2b 、R 4a 、R 4b 、R 4c 、R 9c 、R 9d 、R 12a 、R 12b and R 12c 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; wherein each heteroaryl group has 5 to 12 ring members and has one to four heteroatoms each independently being N, O, or S; and wherein each heterocyclyl has 3 to 12 ring members and has one to four heteroatoms each independently being N, O or S.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclic, C 6-10 aryl or heteroaryl; wherein the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl groups are each optionally substituted by one to four Z 1 replace.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 1 C 6-10 aryl or heteroaryl, each of which is optionally substituted by one to three Z 1 replace.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 1 is a 6-membered aryl or a 5- or 6-membered heteroaryl, wherein the aryl or heteroaryl is substituted by one, two or three groups selected from C 1-8 Haloalkyl, halogen, C 1-6 Alkoxy, -CN and -C(O)-N(R 12a )(R 12b ) group substituted.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 1 is a 6-membered aryl group or a 5- or 6-membered heteroaryl group, wherein the aryl group or heteroaryl group is substituted by one or two -Cl, -F or -CN.

6. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen or methyl.

7. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Y 1 and Y 2 All are -O-.

8. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, The compound or a pharmaceutically acceptable salt thereof has the structure of formula (Ia) or (Ib): in: The subscript p is 1, 2, or 3; and The subscript q is 0, 1, or 2.

9. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Each Z 1a 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 12a or -C(O)N(R 12a )(R 12b ), each of which is optionally replaced by Z 1b replace.

10. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring B is phenyl or 5- to 6-membered heteroaryl, wherein the phenyl or heteroaryl is optionally substituted by one to four R 4 replace.

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