GLP-1R Modulating Compounds

Abstract

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

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 967,289, filed on January 29, 2020. The entire content of that application is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure relates to compounds that bind to the glucagon - like peptide - 1 receptor (GLP - 1R) and act as agonists or modulators thereof, and to 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 disorders by means of the compounds. Background Art

[0004] Glucagon - like peptide - 1 (GLP - 1) is a peptide hormone secreted by enteroendocrine cells in the intestine in response to a meal. GLP - 1 is thought to play a role in the regulation of post - prandial blood glucose by directly increasing meal - induced pancreatic β - cell insulin secretion and by promoting satiety through delaying the transit of food through the intestine. GLP - 1 mediates intracellular signaling through the GLP - 1 receptor (GLP - 1R), which belongs to the family of G - protein - coupled receptors present on the cell membrane and can lead to the accumulation of the second messenger cyclic adenosine monophosphate (cAMP) upon activation. Non - alcoholic steatohepatitis (NASH) can be associated with features of the metabolic syndrome, including obesity, type 2 diabetes, insulin resistance, and cardiovascular disease.

[0005] GLP - 1R agonists are currently being studied in the context of diabetes, obesity, and NASH. GLP - 1R agonists include peptides that have been approved for the treatment of type 2 diabetes, such as exenatide, liraglutide, and dulaglutide. Such peptides are mainly 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 of the GLP - 1R agonist compared to that of endogenous GLP - 1.

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

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

[0008]

[0009] or a pharmaceutically acceptable salt thereof, wherein

[0010] R 1 is C 1-6 alkyl, C 1-6 haloalkyl, 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 ,

[0011] wherein said alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl or heterocyclic is each optionally substituted with one to four Z 1 substituents;

[0012] Ring A is an aromatic ring, wherein U 1 , U 2 , U 3 are each independently -C(H)=, -C(Z 1a )= or -N=;

[0013] Ring B is C 6-10 aryl or heteroaryl, said aryl or heteroaryl each optionally substituted with one to four R 4 substituents;

[0014] R 2 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, -S-R 2a , -S(O)R 2a , -S(O)(NH)R 2a , -S(O) 2 R 2a , -S(O) 2 N(R 2a )(R 2b ) or -S(O)(NR 2a )R 2b ,

[0015] wherein said alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is each optionally substituted with one to four Z 1 substituents;

[0016] X 1 、X 2 and X3 Each independently is ═N═, ═C(H)═ or ═C(R 8 )═;

[0017] Y 1 and Y 2 each is ═C(R y1 )(R y2 )-, ═N(R y1 )-, ═O-, ═S-, ═S(O) 2 - or ═C(O)-;

[0018] W is ═C(R 5 )- or ═N-,

[0019] wherein when W is ═N, one of Y 1 and Y 2 is ═C(R y1 )(R y2 )- or ═C(O)- and the other of Y 1 and Y 2 is ═C(R y1 )(R y2 )-, ═C(O)- or ═S(O) 2 -;

[0020] R 3 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-10 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, -CN, -NO 2 , -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) 2 R 3a , -C(O)NR 3a S(O) 2 R 3b , -C(O)NR 3a S(O) 2 NR3b R 3c 、 -C(O)NR 3a -S(O)(=NR 3b )R 3c -S(O) 2 R 3a 、 -S(O) 2 OR 3a 、 -S(O) 2 N(R 3a )(R 3b )、 -N(R 3a )S(O) 2 R 3b 、 -S(O) 2 NHC(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, heterocyclic group, aryl or heteroaryl is each optionally substituted by one to four R 3d substituents;

[0021] Each R 3a , R 3b and R 3c is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, -C 1-4 alkyl-N(R 9a )(R 9b ), -C 1-4 alkyl-C(O)N(R 9a )(R 9b ), -C 1-4 alkyl-O-C(O)-C 1-4 alkyl, -C 1-4 alkyl-O-C(O)-O-C 1-4 alkyl, -C 1-4 alkyl-O-C(O)-C 1-4 alkyl-N(R 9a )(R 9b)、-C 1-4 alkyl-C 3-8 cycloalkyl, -C 1-4 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 、-CH 2 P(O)(OR 9c ) 2 、-OCH 2 P(O)(OR 9c ) 2 、-C(O)OCH 2 P(O)(OR 9c ) 2 、-P(O)(R 9c )(OR 9d )、-OP(O)(R 9c )(OR 9d )、-CH 2 P(O)(R 9c )(OR 9d )、-OCH 2 P(O)(R 9c )(OR 9d )、-C(O)OCH 2 P(O)(R 9c )(OR 9d )、-P(O)(N(R 9c ) 2 ) 2 、-OP(O)(N(R 9c ) 2 ) 2 、-CH 2 P(O)(N(R 9c ) 2 ) 2 、-OCH 2 P(O)(N(R 9c ) 2 ) 2 、-C(O)OCH 2 P(O)(N(R 9c ) 2 ) 2 、-P(O)(N(R 9c ) 2 )(OR 9d )、-OP(O)(N(R 9c) 2 )(OR 9d )、-CH 2 P(O)(N(R 9c ) 2 )(OR 9d )、-OCH 2 P(O)(N(R 9c ) 2 )(OR 9d )、-C(O)OCH 2 P(O)(N(R 9c ) 2 )(OR 9d )、-P(O)(R 9c )(N(R 9d ) 2 )、-OP(O)(R 9c )(N(R 9d ) 2 )、-CH 2 P(O)(R 9c )(N(R 9d ) 2 )、-OCH 2 P(O)(R 9c )(N(R 9d ) 2 ) or -C(O)OCH 2 P(O)(R 9c )(N(R 9d ) 2 );

[0022] wherein said alkyl, alkenyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted with one to four Z 1b substituents,

[0023] each R 4 independently is C 1-9 alkyl, C 1-8 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-15 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, oxo group, -NO 2 , -CN, -N 3 , -O-R 4a , -C(O)R 4a , -C(O)O-R 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) 2 O(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) 2 R 4a 、-S(O) 2 N(R 4a )(R 4b )、-S(O)(NR 4a )R 4b or -Si(R 4a ) 3 ;

[0024] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace;

[0025] or two R attached to adjacent ring atoms 4 The groups combine with the atoms to which they are attached to form C 5-10 Cycloalkyl or heterocyclic group, each of which is optionally substituted by one to four Z 1b replace;

[0026] 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, -OCH 3 , -CN, oxo group and -N(R x1 )(R x2 );

[0027] Alternatively, R 5 and R y1 combine with the atom to which they are attached to form a cycloalkyl or heterocyclic group optionally substituted by an oxo group; 3-10

[0028] R x1 and R x2 are each independently H, C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, -S(O) 2 R 6a1 or -S(O) 2 N(R 6a1 )(NR 6a2 ), wherein the C 1-6 alkyl, cycloalkyl or heterocyclic group is each optionally substituted by F, -CN, oxo group or C 3-6 cycloalkyl;

[0029] Alternatively, R x1 and R x2 combine with the atom to which they are attached to form a heterocyclic group, which is optionally substituted by one to four R 6b1 ;

[0030] V is -C(O)-, -O-, -N(R 6a )- or -C(R 6b )(R 6c );

[0031] R 6a is H, C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, -S(O) 2 R 6a1 or -S(O) 2 N(R 6a1 )(NR 6a2 ), wherein the cycloalkyl or heterocyclic group is each optionally substituted by C 1-6 alkyl, F or -CN;

[0032] Each R 6b and R 6c is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkoxyalkyl, halogen, C 3-10 cycloalkyl, heterocyclic group, -C1-6 alkyl-N(R 9a )(R 9b ), -CN, -OR 6c1 or -N(R 6c2 )(R 6c3 ), where the alkyl, cycloalkyl or heterocyclic group is each optionally substituted by one to four R 6b1 substituents;

[0033] Or R 6b and R 6c combine with the atoms to which they are attached to form a C 3-10 cycloalkyl or heterocyclic group, and the cycloalkyl or heterocyclic group is each optionally substituted by one to four R 6b1 substituents;

[0034] Or R 6a or R 6c combines with an R 4 group and the atoms to which they are attached to form a C 5-10 cycloalkyl or heterocyclic group, and the cycloalkyl or heterocyclic group is each optionally substituted by one to four R 10 substituents;

[0035] Each R y1 and R y2 is independently H, a halogen group, C 1-6 alkyl, C 1-6 haloalkyl, where the alkyl and haloalkyl are each optionally substituted by an oxo group;

[0036] Each R 3d , R 6b1 and R 10 is independently C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, a halogen, C 3-10 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, oxo group, -OH, -CN, -NO 2 or -C(O)N(R 2a )(R 2b ), where the heterocyclic group or heteroaryl is optionally substituted by C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 haloalkoxy; and

[0037] Each R 6a1 , R 6a2 , R6c1 , R 6c2 and R 6c3 are independently H, C 1-6 alkyl or C 3-10 cycloalkyl;

[0038] Each R 9a and R 9b are independently H, C 1-6 alkyl or C 1-6 haloalkyl;

[0039] Each Z 1 is independently C 1-9 alkyl, C 1-8 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-15 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, oxo group, -NO 2 , -N 3 , -CN, -O-R 12a , -C(O)-R 12a , -C(O)O-R 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) 2 N(R 12b )(R 12c ), -NR 12a S(O) 2 O(R 12b ), -OC(O)R 12a , -OC(O)OR 12a , -OC(O)-N(R12a )(R 12b ),-SR 12a 、-S(O)R 12a 、-S(O)(NH)R 12a 、-S(O) 2 R 12a 、-S(O) 2 N(R 12a )(R 12b )、-S(O)(NR 12a )R 12b or -Si(R 12a ) 3 ;

[0040] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1a replace;

[0041] Each Z 1a Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, 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, -NO 2 、-CN、-N 3 、-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) 2 O(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) 2 R 12a 、-S(O) 2 N(R 12a )(R 12b )、-S(O)(NR 12a )R 12b or -Si(R 12a ) 3 ;

[0042] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace;

[0043] Each R 8 or Z 1b Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, -NO 2 、-NH 2 、-N 3 ,-SH,-O(C 1-9 Alkyl), -O(C 1-8 Haloalkyl), -O(C 2-6 -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 -NH(C 2-6 Alkynyl), -NH(C 3-15 Cycloalkyl), -NH(heterocyclyl), -NH(C6-10 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(heterocyclic group) 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 group)、-N(C 1-9 alkyl)(C 6-10 aryl)、-N(C 1-9 alkyl)(heteroaryl)、-C(O)(C 1-9 alkyl)、-C(O)(C 1-8 haloalkyl)、-C(O)(C 2-6 alkenyl)、-C(O)(C 2-6 alkynyl)、-C(O)(C 3-15 cycloalkyl)、-C(O)(heterocyclic group)、-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(heterocyclic group)、-C(O)O(C 6-10 aryl)、-C(O)O(heteroaryl)、-C(O)NH 2 、-C(O)NH(C 1-9 alkyl)、-C(O)NH(C 1-8 haloalkyl)、-C(O)NH(C 2-6 alkenyl)、-C(O)NH(C 2-6(alkynyl), -C(O)NH(C 3-15 cycloalkyl), -C(O)NH(heterocyclic group), -C(O)NH(C 6-10 aryl), -C(O)NH(heteroaryl), -C(O)N(C 1-9 alkyl) 2 , -C(O)N(C 1-8 haloalkyl) 2 , -C(O)N(C 2-6 alkenyl) 2 , -C(O)N(C 2-6 alkynyl) 2 , -C(O)N(C 3-15 cycloalkyl) 2 , -C(O)N(heterocyclic group) 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)(heterocyclic group), -NHC(O)(C 6-10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 1-8 haloalkyl), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C 2-6 alkynyl), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O(heterocyclic group), -NHC(O)O(C 6-10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -NHC(O)NH(C 1-8 haloalkyl), -NHC(O)NH(C 2-6 alkenyl), -NHC(O)NH(C 2-6 alkynyl), -NHC(O)NH(C 3-15 cycloalkyl), -NHC(O)NH(heterocyclic group), -NHC(O)NH(C 6-10 aryl), -NHC(O)NH(heteroaryl), -NHS(O)(C 1-9 alkyl), -N(C 1-9 alkyl)(S(O)(C1-9 alkyl), -S(C 1-9 alkyl), -S(C 1-8 haloalkyl), -S(C 2-6 alkenyl), -S(C 2-6 alkynyl), -S(C 3-15 cycloalkyl), -S(heterocyclic group), -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 haloalkyl), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 alkynyl), -S(O)(C 3-15 cycloalkyl), -S(O)(heterocyclic group), -S(O)(C 6-10 aryl), -S(O)(heteroaryl), -S(O) 2 (C 1-9 alkyl), -S(O) 2 (C 1-8 haloalkyl), -S(O) 2 (C 2-6 alkenyl), -S(O) 2 (C 2-6 alkynyl), -S(O) 2 (C 3-15 cycloalkyl), -S(O) 2 (heterocyclic group), -S(O) 2 (C 6-10 aryl), -S(O) 2 (heteroaryl), -S(O)(NH)(C 1-9 alkyl), -S(O) 2 NH(C 1-9 alkyl) or -S(O) 2 N(C 1-9 alkyl) 2 ;

[0044] wherein the alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted in each instance by one to three C 1-9 alkyl, C 1-8 haloalkyl, halogen, -OH, -NH 2 , -O(C 1-9 alkyl), -O(C 1-8 haloalkyl), -O(C 3-15 cycloalkyl), -O(heterocyclic group), -O(aryl), -O(heteroaryl), -NH(C 1-9 alkyl), -NH(C1-8 (haloalkyl), -NH(C 3-15 cycloalkyl), -NH(heterocyclic group), -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)(heterocyclic group), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 1-8 haloalkyl), -NHC(O)O(C 2-6 alkynyl), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O(heterocyclic group), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -S(O) 2 (C 1-9 alkyl), -S(O) 2 (C 1-8 haloalkyl), -S(O) 2 (C 3-15 cycloalkyl), -S(O) 2 (heterocyclic group), -S(O) 2 (aryl), -S(O) 2 (heteroaryl), -S(O)(NH)(C 1-9 alkyl), -S(O) 2 NH(C 1-9 alkyl) or -S(O) 2 N(C 1-9 alkyl) 2 is substituted; and

[0045] 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 is independently H, C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-15Cycloalkyl, heterocyclic group, C 6-10 aryl or heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted with one to four Z 1b substituents;

[0046] wherein each heteroaryl has 5 to 12 ring members and has one to four heteroatoms each independently being N, O or S; and

[0047] wherein each heterocyclic group has 3 to 12 ring members and has one to four heteroatoms each independently being N, O or S.

[0048] 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 for treating GLP-1R-mediated diseases or disorders. Detailed Description

[0049] I. Definitions

[0050] 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. Dashes at the front or end of a chemical group are for convenience in indicating the point of attachment to the parent moiety; a chemical group can be depicted without one or more dashes without loss of its ordinary meaning. Prefixes such as "C u-v " or "C u -C v " indicate that the following group has u to v carbon atoms, where u and v are integers. For example, "C 1-6 alkyl" or "C 1 -C 6 alkyl" indicate that the alkyl group has 1 to 6 carbon atoms.

[0051] "Alkyl" is a monovalent or divalent straight-chain 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 1-4 alkyl). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3) 2-propyl (i-Pr, isopropyl, -CH(CH 3 ) 2 ) 1-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ) 2-methyl-1-propyl (i-Bu, isobutyl, -CH 2 CH(CH 3 ) 2 ) 2-butyl (s-Bu, sec-butyl, -CH(CH 3 ) 2 CH 3 ) 2-methyl-2-propyl (t-Bu, tert-butyl, -C(CH 3 ) 3 ) 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH(CH 3 ) 2 CH 2 CH 3 ) 3-pentyl (-CH(CH 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH 2 CH(CH 3 ) 2 CH 3 ) 1-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-hexyl (-CH(CH 3 ) 2 CH 2 CH 2 CH 3)、3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 ))、2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 )、3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 ) 2 CH 3 )、4-methyl-2-pentyl (-CH(CH 3 ) 2 CH(CH 3 ) 2 )、3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 )、2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 )、2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 )、3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 ) and octyl (-(CH 2 ) 7 CH 3 ). The alkyl group can be unsubstituted or substituted.

[0052] "Alkoxy" refers to the group -O-alkyl, where alkyl is defined as above. For example, C 1-4 Alkoxy refers to an -O-alkyl group having from 1 to 4 carbons. The alkoxy group can be unsubstituted or substituted.

[0053] "Alkoxyalkyl" is an alkoxy group attached to an alkyl as defined above such that the alkyl is divalent. For example, C 2-6 Alkoxyalkyl includes -CH 2 -OMe, -CH 2 -O-iPr, -CH 2 -CH 2 -OMe, -CH 2 -CH2 -O-CH 2 -CH 3 and -CH 2 -CH 2 -O-tBu. The alkoxyalkyl group can be unsubstituted or substituted.

[0054] "Alkenyl" is a monovalent or divalent straight-chain or branched hydrocarbon radical having at least one carbon-carbon double bond. For example, the alkenyl group can have 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), or 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2-4 alkenyl). Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH 2 ), allyl (-CH 2 CH=CH 2 ), and -CH 2 -CH=CH-CH 3 . The alkenyl group can be unsubstituted or substituted.

[0055] "Alkynyl" is a monovalent or divalent straight-chain or branched hydrocarbon radical having at least one carbon-carbon triple bond. For example, the alkynyl group can have 2 to 8 carbon atoms (i.e., C 2-8 alkynyl), or 2 to 6 carbon atoms (i.e., C 2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2-4 alkynyl). Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH 2 C≡CH), and -CH 2 -C≡C-CH 3 . The alkynyl group can be unsubstituted or substituted.

[0056] "Halogen" refers to fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I).

[0057] "Haloalkyl" is an alkyl as defined herein, wherein one or more hydrogen atoms of the alkyl are independently replaced by halogen (which can be the same or different), such that the alkyl is divalent. The alkyl group and the halogen can be any of those described above. In some embodiments, the haloalkyl defines the number of carbon atoms in the alkyl portion. For example, C 1-4 haloalkyl includes CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CH 2 CH 2 CF 3 , CCl2 CH 2 CH 2 CH 3 and C(CH 3 ) 2 (CF 2 H). The haloalkyl group can be unsubstituted or substituted.

[0058] "Haloalkoxy" is an alkoxy group as defined herein, wherein one or more hydrogen atoms of the alkyl group in the alkoxy group are independently substituted by halogen (which can be the same or different), such that the alkyl group is divalent. The alkoxy group and the halogen can be any of those described above. In some embodiments, the haloalkoxy defines the number of carbon atoms in the alkyl portion, e.g., C 1-4 Haloalkoxy includes OCF 3 , OCH 2 F, OCH 2 CF 3 , OCH 2 CH 2 CF 3 , OCCl 2 CH 2 CH 2 CH 3 and OC(CH 3 ) 2 (CF 2 H). The haloalkoxy group can be unsubstituted or substituted.

[0059] "Cycloalkyl" is a monovalent or divalent single all-carbon ring or polyfused all-carbon ring system, wherein the ring is non-aromatic, saturated or unsaturated 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 polyfused ring systems having about 7 to 12 carbon atoms (e.g., a ring system containing 2 rings). When valence requirements permit, these rings of the polyfused ring system can be connected to each other by fusion, spiro, or bridge bonds. Exemplary polycyclic cycloalkyl groups include octahydroindene, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[2.2.2]oct-2-ene, and spiro[2.5]octane. The cycloalkyl group can be unsubstituted or substituted.

[0060] "Alkylcycloalkyl" means an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently replaced by cycloalkyl groups (which may be the same or different). The alkyl group and the cycloalkyl group can be any of those described above. In some embodiments, the number of carbon atoms in the alkyl and cycloalkyl moieties can be specified individually, e.g., C 1-6 alkyl-C 3-12 cycloalkyl. The alkylcycloalkyl group can be unsubstituted or substituted.

[0061] As used herein, "aryl" means a monovalent or divalent single fully carbon aromatic ring or polyfused fully 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 phenyl radicals. Aryl also includes polyfused ring systems having about 9 to 20 carbon atoms (e.g., ring systems containing 2, 3, or 4 rings), wherein multiple rings are aromatic. When valence requirements permit, these rings of the polyfused ring system can be interconnected by fused bonds. It should also be understood that when referring to a certain atomic range of aryl (e.g., 6-10 membered aryl), the atomic range is the total ring atoms of the aryl. For example, a 6-membered aryl will include phenyl, and a 10-membered aryl will include naphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, etc. The aryl group can be unsubstituted or substituted.

[0062] "Alkylaryl" means an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently replaced by aryl groups (which may be the same or different). The alkyl group and the aryl group can be any of those described above, such that the alkyl is divalent. In some embodiments, the alkylaryl group has 7 to 24 carbon atoms, 7 to 16 carbon atoms, 7 to 13 carbon atoms, or 7 to 11 carbon atoms. The alkylaryl group defined by the number of carbon atoms refers to the total number of carbon atoms present in the combined constitutive alkyl and aryl groups. For example, C 7 alkylaryl refers to benzyl, and 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 individually, e.g., C 1-6 alkyl-C 6-10 aryl. Non-limiting examples of alkylaryl groups include, but are not limited to, benzyl, 2,2-dimethylphenyl, n-pentylphenyl, 1-methylnaphthyl, 2-ethylnaphthyl, etc. The alkylaryl group can be unsubstituted or substituted.

[0063] As used herein, "heterocyclic group" or "heterocycle" or "heterocycloalkyl" refers to a single saturated or partially unsaturated non-aromatic ring or non-aromatic polycyclic system having at least one heteroatom in the ring (i.e., at least one cyclic (i.e., ring-shaped) heteroatom selected from oxygen, nitrogen, and sulfur). Unless otherwise specified, a heterocyclic group has from 3 to about 20 ring atoms, such as from 3 to 12 ring atoms, such as from 4 to 12 ring atoms, from 4 to 10 ring atoms, or from 3 to 8 ring atoms, or from 3 to 6 ring atoms, or from 3 to 5 ring atoms, or from 4 to 6 ring atoms, or from 4 to 5 ring atoms. Thus, the term includes a single saturated or partially unsaturated ring (e.g., a 3-, 4-, 5-, 6-, or 7-membered ring) having from about 1 to 6 ring carbon atoms and from 1 to 3 cyclic heteroatoms selected from oxygen, nitrogen, and sulfur in the ring. When valence requirements permit, these rings of a polyfused ring system (e.g., a bicyclic heterocyclic group) can be connected to each other by fusion, spiro, and bridging bonds. Heterocycles include, but are not limited to, azetidine, aziridine, imidazolidine, morpholine, ethylene oxide (epoxide), oxetane, thietane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, 2-oxa-6-azaspiro[3.3]hept-6-yl, 6-oxa-1-azaspiro[3.3]hept-1-yl, 2-thia-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, and the like. A heterocyclic group can be unsubstituted or substituted.

[0064] "Alkylheterocyclic group" refers to an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently replaced by a heterocyclic group (which can be the same or different). The alkyl group and the heterocyclic group can be any of those described above such that the alkyl is divalent. In some embodiments, the number of atoms in the alkyl and heterocyclic moieties can be specified individually, e.g., C with one to three heteroatoms each independently being N, O, or S 1-6 alkyl-3 to 12-membered heterocyclic group. An alkylheterocyclic group can be unsubstituted or substituted.

[0065] "Heteroaryl" means a monocyclic aromatic ring having at least one atom other than carbon, where the atom is selected from oxygen, nitrogen, and sulfur; "heteroaryl" also includes a polyfused ring system having at least one such aromatic ring, which polyfused ring system will be further described below. Thus, "heteroaryl" includes monocyclic aromatic rings having from about 1 to 6 carbon atoms and from about 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur. Sulfur and nitrogen atoms can also be in oxidized forms, provided that the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, azolyl, or furyl. "Heteroaryl" also includes polyfused ring systems (e.g., ring systems containing 2, 3, or 4 rings), where a 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 polyfused ring system. Thus, a heteroaryl (monocyclic aromatic ring or polyfused ring system) can have from about 1 to 20 carbon atoms and from 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, these rings of the polyfused ring system can be connected to each other by fused bonds. It should be understood that the individual rings of the polyfused ring system can be connected to each other in any order. It should be understood that the point of attachment of a heteroaryl or heteroaryl polyfused ring system can be on any suitable atom of the heteroaryl or heteroaryl polyfused ring system, including carbon atoms and heteroatoms (e.g., nitrogen). It should also be understood that when referring to a heteroaryl having a certain atom range (e.g., 5- to 10-membered heteroaryl), the atom range is the total ring atoms of the heteroaryl and includes carbon atoms and heteroatoms. It should also be understood that the rings of the polycyclic ring system can include aryl rings fused to heterocyclic rings having saturated or partially unsaturated bonds (e.g., 3-, 4-, 5-, 6-, or 7-membered rings) having from about 1 to 6 ring carbon atoms and from about 1 to 3 ring heteroatoms selected from oxygen, nitrogen, and sulfur. For example, 5-membered heteroaryl includes thiazolyl, and 10-membered heteroaryl includes quinolinyl. Exemplary heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, azolyl, iso azolyl, thiazolyl, furyl, diazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzo azolyl, indazolyl, quin olinyl, quinazolinyl, benzofuryl, benzimidazolyl, thienyl, pyrrolo[2,3-b]pyridyl, quinazolin-4(3H)-one, triazolyl, and tetrazolyl. The heteroaryl group can be unsubstituted or substituted.

[0066] "Alkyl heteroaryl" means an alkyl group as defined herein, wherein 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 can be any of those described above. In some embodiments, the number of atoms in the alkyl and heteroaryl moieties is specified separately. For example, C with one to four heteroatoms each independently being N, O, or S 1-6 alkyl-5- to 10-membered heteroaryl. The alkyl heteroaryl group can be unsubstituted or substituted.

[0067] As used herein, "oxo group" means ═O.

[0068] As used herein, "substituted" means that one or more hydrogen atoms in the group are independently replaced by one or more substituents (e.g., 1, 2, 3, or 4 or more), as indicated.

[0069] "Compounds of the present disclosure" include the compounds disclosed herein. For example, the compounds of the present disclosure include compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If), including the compounds of the examples.

[0070] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifying agent that has been approved by the U.S. Food and Drug Administration as acceptable for use in humans or livestock.

[0071] As used herein, "therapeutically effective amount" or "effective amount" means an amount capable of effectively eliciting a desired biological or medical response, including the amount of a compound 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 to be treated, and the age, weight, etc. of the subject. The effective amount can include a range of amounts. As understood in the art, the effective amount can be one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired therapeutic endpoint. The effective amount can be considered in the context of administering one or more therapeutic agents, and a single agent can be considered to be administered in an effective amount if, in combination with one or more other agents, a desired or beneficial result can be achieved or realized. The appropriate dose of any co-administered compound can optionally be reduced due to the combined action of the compounds (e.g., additive or synergistic effects).

[0072] As used herein, "co-administer" means administering a unit dose of a compound disclosed herein before or after administering a unit dose of one or more additional therapeutic agents, e.g., administering a compound disclosed herein within seconds, minutes, or hours of administering one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound of the present disclosure is administered first, followed by a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of a compound of the present disclosure within seconds or minutes. In some embodiments, a unit dose of a compound of the present disclosure is administered first, and then a unit dose of one or more additional therapeutic agents is administered hours (e.g., 1 hour - 12 hours) later. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, and then a unit dose of a compound of the present disclosure is administered hours (e.g., 1 hour - 12 hours) later. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally means administering the 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.

[0073] 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 substances that can be used to prepare pharmaceutical compositions suitable for veterinary or human drug use.

[0074] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts, or, where appropriate, as the free base. "Pharmaceutically acceptable salts" are non-toxic salts of the free base form of the compound, which salts possess 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 sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, octanoate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, benzenesulfonate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmaceutically acceptable salts can be found in "Remington: The Science and Practice of Pharmacy", 21st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0075] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein also include salts derived from suitable bases such as alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium, and N(C 1 -C 4 alkyl) 4 + ). Also included are base addition salts such as sodium or potassium salts.

[0076] Also provided are the compounds described herein or pharmaceutically acceptable salts, isomers, or mixtures thereof, wherein 1 to n hydrogen atoms attached to carbon atoms may be replaced by deuterium atoms or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such compounds can increase resistance to metabolism and can thus be used to increase the half-life of the compounds described herein or pharmaceutically acceptable salts, isomers, or mixtures thereof when administered to a mammal. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci., Vol. 5, No. 12, pp. 524-527, 1984. Such compounds are synthesized by methods well known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium. In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) contain one or more deuterium atoms.

[0077] Examples of isotopes that can 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. Substitution with positron-emitting isotopes such as 11 C, 18 F, 15 O, and 13 N 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 similar to those described in the examples listed below using appropriate isotopically labeled reagents in place of the non-labeled reagents previously employed.

[0078] The compounds of the embodiments disclosed herein, or pharmaceutically acceptable salts thereof, may include one or more asymmetric centers and, thus, may give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R)- or (S)- or, for amino acids, as (D)- or (L)-. This disclosure is intended to embrace all such possible isomers, as well as their racemic and optically pure forms. The 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 the preparation / separation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC). When the compounds described herein contain an olefinic double bond or other geometrically asymmetric centers, and unless otherwise specified, the compounds are intended to include the E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. When the compounds are represented in their chiral forms, it is to be understood that the embodiments cover, but are not limited to, specific diastereomeric or enantiomerically enriched forms. When chirality is not specified but is present, it is to be understood that the embodiments relate to specific diastereomers or enantiomerically enriched forms; or racemic or non-racemic mixtures of such compounds. As used herein, a "non-racemic mixture" is a mixture of stereoisomers in a ratio other than 1:1.

[0079] As used herein, a "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. This disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers", which refers to two stereoisomers that are non-overlapping mirror images of each other.

[0080] As used herein, a "tautomer" involves the transfer of a proton from one atom of a molecule to another atom of the same molecule. In some embodiments, this disclosure includes tautomers of the compounds.

[0081] As used herein, a "solvate" refers to the result of the interaction of a solvent and a compound. Solvates of the salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0082] As used herein, a "hydrate" refers to a compound of this disclosure that is chemically associated with one or more water molecules.

[0083] "Prevention" ("prevention" or "preventing") means any treatment of a disease or disorder that results in the clinical symptoms of the disease or disorder not developing. In some embodiments, the compounds can be administered to a subject (including a human) at risk or having a family history of a disease or disorder.

[0084] As used herein, a "prodrug" is a derivative of a drug that is converted to the parent drug upon administration to a human subject according to some chemical or enzymatic pathway. In some embodiments, a "prodrug" is a biologically inactive derivative of a drug that is converted to a biologically active parent drug upon administration to a human subject according to some chemical or enzymatic pathway.

[0085] As used herein, "Treatment" or "treat" or "treating" refers to a method for obtaining a beneficial or desired result. For the purposes of this disclosure, beneficial or desired results include, but are not limited to, alleviation of symptoms and / or reduction in the degree of symptoms and / or prevention of worsening of symptoms associated with a disease or disorder. In one embodiment, "treatment" or "treating" includes one or more of the following: a) inhibiting a disease or disorder (e.g., reducing one or more symptoms caused by the disease or disorder, and / or reducing the degree of the disease or disorder); b) slowing or arresting the development of one or more symptoms associated with the disease or disorder (e.g., stabilizing the disease or disorder, delaying the worsening or progression of the disease or disorder); and c) alleviating the disease or disorder, e.g., causing the regression of clinical symptoms, improving the disease state, delaying the progression of the disease, enhancing the quality of life, and / or prolonging survival.

[0086] As used herein, an "individual at risk" is an individual at risk of developing a disorder to be treated. An individual "at risk" may or may not have a detectable disease or disorder and may or may not show a 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 disorder. An individual having one or more of these risk factors has a higher probability of developing the disease or disorder than an individual without these risk factors.

[0087] II. Compounds

[0088] In some embodiments, the compounds of the present disclosure are compounds of formula (I): or compounds of other formulas described herein, or pharmaceutically acceptable salts thereof, wherein

[0089] R 1 is C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, heteroaryl, -C(O)N(R1b )(R 1c )、 -C(O)R 1b or -C(O)OR 1c ,

[0090] wherein said alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl or heterocyclic group is each optionally substituted by one to four Z 1 substituents;

[0091] Ring A is an aromatic ring, wherein U 1 , U 2 , U 3 are each independently -C(H)=, -C(Z 1a )= or -N=;

[0092] Ring B is a C 6-10 aryl or heteroaryl, and said aryl or heteroaryl is each optionally substituted by one to four R 4 substituents;

[0093] R 2 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, -S-R 2a , -S(O)R 2a , -S(O)(NH)R 2a , -S(O) 2 R 2a , -S(O) 2 N(R 2a )(R 2b ) or -S(O)(NR 2a )R 2b ,

[0094] wherein said alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted by one to four Z 1 substituents;

[0095] X 1 , X 2 and X 3 are each independently -N=, -C(H)= or -C(R 8 )=;

[0096] Y 1 and Y 2 are each -C(R y1 )(R y2 )-, -N(R y1 )-, -O-, -S-, -S(O)2 -or -C(O)-;

[0097] W is -C(R 5 )- or -N-,

[0098] where when W is -N, Y 1 and Y 2 one of which is -C(R y1 )(R y2 )- or -C(O)- and Y 1 and Y 2 the other of which is -C(R y1 )(R y2 )-, -C(O)- or -S(O) 2 -;

[0099] R 3 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-10 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, -CN, -NO 2 , -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) 2 R 3a , -C(O)NR 3a S(O) 2 R 3b , -C(O)NR 3a S(O) 2 NR 3b R 3c , -C(O)NR 3a -S(O)(=NR 3b )R 3c -S(O) 2 R 3a , -S(O) 2 OR 3a , -S(O) 2 N(R3a )(R 3b )、 -N(R 3a )S(O) 2 R 3b 、 -S(O) 2 NHC(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, heterocyclic group, aryl or heteroaryl is each optionally substituted by one to four R 3d substituents;

[0100] Each R 3a , R 3b and R 3c is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, -C 1-4 alkyl-N(R 9a )(R 9b ), -C 1-4 alkyl-C(O)N(R 9a )(R 9b ), -C 1-4 alkyl-O-C(O)-C 1-4 alkyl, -C 1-4 alkyl-O-C(O)-O-C 1-4 alkyl, -C 1-4 alkyl-O-C(O)-C 1-4 alkyl-N(R 9a )(R 9b ), -C 1-4 alkyl-C 3-8 cycloalkyl, -C 1-4 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 , -CH 2 P(O)(OR 9c ) 2 , -OCH 2 P(O)(OR 9c ) 2 , -C(O)OCH 2 P(O)(OR 9c ) 2 , -P(O)(R 9c )(OR 9d ), -OP(O)(R 9c )(OR 9d ), -CH 2 P(O)(R 9c )(OR 9d ), -OCH 2 P(O)(R 9c )(OR 9d ), -C(O)OCH 2 P(O)(R 9c )(OR 9d ), -P(O)(N(R 9c ) 2 ) 2 , -OP(O)(N(R 9c ) 2 ) 2 , -CH 2 P(O)(N(R 9c ) 2 ) 2 , -OCH 2 P(O)(N(R 9c ) 2 ) 2 , -C(O)OCH 2 P(O)(N(R 9c ) 2 ) 2 , -P(O)(N(R 9c ) 2 )(OR 9d ), -OP(O)(N(R 9c ) 2 )(OR 9d ), -CH 2 P(O)(N(R 9c ) 2 )(OR 9d ), -OCH 2 P(O)(N(R 9c ) 2 )(OR 9d)、 -C(O)OCH 2 P(O)(N(R 9c ) 2 )(OR 9d )、 -P(O)(R 9c )(N(R 9d ) 2 )、 -OP(O)(R 9c )(N(R 9d ) 2 )、 -CH 2 P(O)(R 9c )(N(R 9d ) 2 )、 -OCH 2 P(O)(R 9c )(N(R 9d ) 2 ) or -C(O)OCH 2 P(O)(R 9c )(N(R 9d ) 2 );wherein the alkyl, alkenyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted by one to four Z 1b substituted,

[0101] each R 4 independently is C 1-9 alkyl, C 1-8 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-15 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, oxo group, -NO 2 、 -CN、 -N 3 、 -O-R 4a 、 -C(O)R 4a 、 -C(O)O-R 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(R4b )(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) 2 O(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) 2 R 4a 、-S(O) 2 N(R 4a )(R 4b )、-S(O)(NR 4a )R 4b or -Si(R 4a ) 3 ;

[0102] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace;

[0103] or two R attached to adjacent ring atoms 4 The groups combine with the atoms to which they are attached to form C 5-10 Cycloalkyl or heterocyclic group, each of which is optionally substituted by one to four Z 1b replace;

[0104] 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, -OCH 3 , -CN, oxo and -N(R x1 )(R x2 ) is substituted by a group;

[0105] 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 Cycloalkyl or heterocyclic group;

[0106] R x1 and R x2 each independently is H, C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, -S(O) 2 R 6a1 or -S(O) 2 N(R 6a1 )(NR 6a2 ), wherein the C 1-6 alkyl, cycloalkyl or heterocyclic group is each optionally substituted by F, -CN, oxo group or C 3-6 cycloalkyl;

[0107] Or R x1 and R x2 combine with the atoms to which they are attached to form a heterocyclic group, and the heterocyclic group is optionally substituted by one to four R 6b1 ;

[0108] V is -C(O)-, -O-, -N(R 6a ), - or -C(R 6b )(R 6c );

[0109] R 6a is H, C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, -S(O) 2 R 6a1 or -S(O) 2 N(R 6a1 )(NR 6a2 ), wherein the cycloalkyl or heterocyclic group is each optionally substituted by C 1-6 alkyl, F or -CN;

[0110] Each R 6b and R 6c independently is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkoxyalkyl, halogen, C 3-10 cycloalkyl, heterocyclic group, -C 1-6 alkyl-N(R 9a )(R 9b ), -CN, -OR 6c1 or -N(R 6c2 )(R 6c3 ), wherein the alkyl, cycloalkyl or heterocyclic group is each optionally substituted by one to four R 6b1 ;

[0111] Or R 6b and R6c combine with the atoms to which they are attached to form a C 3-10 cycloalkyl or heterocyclic group, each of which is optionally substituted by one to four R 6b1 substituents;

[0112] or R 6a or R 6c combines with an R 4 group and the atoms to which they are attached to form a C 5-10 cycloalkyl or heterocyclic group, each of which is optionally substituted by one to four R 10 substituents;

[0113] Each R y1 and R y2 is independently H, a halogen group, C 1-6 alkyl, C 1-6 haloalkyl, wherein the alkyl and haloalkyl are each optionally substituted by an oxo group;

[0114] Each R 3d , R 6b1 and R 10 is independently C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-10 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, oxo group, -OH, -CN, -NO 2 or -C(O)N(R 2a )(R 2b ), wherein the heterocyclic group or heteroaryl is optionally substituted by C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 haloalkoxy; and

[0115] Each R 6a1 , R 6a2 , R 6c1 , R 6c2 and R 6c3 is independently H, C 1-6 alkyl or C 3-10 cycloalkyl;

[0116] Each R 9a and R 9b is independently H, C 1-6 alkyl or C 1-6 haloalkyl;

[0117] Each Z 1 is independently C 1-9 alkyl, C 1-8 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-15 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, oxo group, -NO 2 , -N 3 , -CN, -O-R 12a , -C(O)-R 12a , -C(O)O-R 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) 2 N(R 12b )(R 12c ), -NR 12a S(O) 2 O(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) 2 R 12a , -S(O) 2 N(R 12a )(R 12b ), -S(O)(NR12a )R 12b or -Si(R 12a ) 3 ;

[0118] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted by one to four Z 1a substituents;

[0119] each Z 1a is independently C 1-9 alkyl, C 1-8 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-15 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, oxo group, -NO 2 , -CN, -N 3 , -O-R 12a , -C(O)R 12a , -C(O)O-R 12a , -C(O)N(R 12a )(R 12b ), -N(R 12a )(R 12b ), -N(R 12a )(R 2 )(R 12b ), -N(R + )(R 12a )-C(O)R 12b , -N(R 12a )(R 12b )C(O)O(R 12a ), -N(R 12b )(R 12c )C(O)N(R 12a )(R 2 ), -N(R 12b )(R 12a )S(O) 2 -N(R 12b )(R 12c ), -N(R 12a )S(O) 2 O(R 12b ), -OC(O)R 12a , -OC(O)OR 12a , -OC(O)-N(R 12a )(R 12b ), -S-R12a 、 -S(O)R 12a 、 -S(O)(NH)R 12a 、 -S(O) 2 R 12a 、 -S(O) 2 N(R 12a )(R 12b )、 -S(O)(NR 12a )R 12b or -Si(R 12a ) 3 ;

[0120] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted by one to four Z 1b ;

[0121] Each R 8 or Z 1b is independently C 1-9 alkyl, C 1-8 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-15 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, oxo group, -OH, -CN, -NO 2 、 -NH 2 、 -N 3 、 -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(heterocyclic group), -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(heterocyclic group), -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(heterocyclic group) 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 group), -N(C 1-9 alkyl)(C 6-10 aryl), -N(C 1-9 alkyl)(heteroaryl), -C(O)(C 1-9 alkyl), -C(O)(C 1-8 haloalkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 alkynyl), -C(O)(C 3-15 cycloalkyl), -C(O)(heterocyclic group), -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(heterocyclic group), -C(O)O(C 6-10 aryl), -C(O)O(heteroaryl), -C(O)NH 2 , -C(O)NH(C 1-9 alkyl), -C(O)NH(C 1-8 haloalkyl), -C(O)NH(C 2-6 alkenyl), -C(O)NH(C 2-6 alkynyl), -C(O)NH(C 3-15 cycloalkyl), -C(O)NH(heterocyclic group), -C(O)NH(C 6-10 aryl), -C(O)NH(heteroaryl), -C(O)N(C 1-9 alkyl) 2 , -C(O)N(C 1-8 haloalkyl) 2 , -C(O)N(C 2-6 alkenyl)2 ,-C(O)N(C 2-6 alkynyl) 2 ,-C(O)N(C 3-15 cycloalkyl) 2 ,-C(O)N(heterocyclic group) 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)(heterocyclic group),-NHC(O)(C 6-10 aryl),-NHC(O)(heteroaryl),-NHC(O)O(C 1-9 alkyl),-NHC(O)O(C 1-8 haloalkyl),-NHC(O)O(C 2-6 alkenyl),-NHC(O)O(C 2-6 alkynyl),-NHC(O)O(C 3-15 cycloalkyl),-NHC(O)O(heterocyclic group),-NHC(O)O(C 6-10 aryl),-NHC(O)O(heteroaryl),-NHC(O)NH(C 1-9 alkyl),-NHC(O)NH(C 1-8 haloalkyl),-NHC(O)NH(C 2-6 alkenyl),-NHC(O)NH(C 2-6 alkynyl),-NHC(O)NH(C 3-15 cycloalkyl),-NHC(O)NH(heterocyclic group),-NHC(O)NH(C 6-10 aryl),-NHC(O)NH(heteroaryl),-NHS(O)(C 1-9 alkyl),-N(C 1-9 alkyl)(S(O)(C 1-9 alkyl),-S(C 1-9 alkyl),-S(C 1-8 haloalkyl),-S(C 2-6 alkenyl),-S(C 2-6 alkynyl),-S(C 3-15 cycloalkyl),-S(heterocyclic group),-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 haloalkyl), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 alkynyl), -S(O)(C 3-15 cycloalkyl), -S(O)(heterocyclic group), -S(O)(C 6-10 aryl), -S(O)(heteroaryl), -S(O) 2 (C 1-9 alkyl), -S(O) 2 (C 1-8 haloalkyl), -S(O) 2 (C 2-6 alkenyl), -S(O) 2 (C 2-6 alkynyl), -S(O) 2 (C 3-15 cycloalkyl), -S(O) 2 (heterocyclic group), -S(O) 2 (C 6-10 aryl), -S(O) 2 (heteroaryl), -S(O)(NH)(C 1-9 alkyl), -S(O) 2 NH(C 1-9 alkyl) or -S(O) 2 N(C 1-9 alkyl) 2 ;

[0122] wherein the alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted in each instance by one to three C 1-9 alkyl, C 1-8 haloalkyl, halogen, -OH, -NH 2 , -O(C 1-9 alkyl), -O(C 1-8 haloalkyl), -O(C 3-15 cycloalkyl), -O(heterocyclic group), -O(aryl), -O(heteroaryl), -NH(C 1-9 alkyl), -NH(C 1-8 haloalkyl), -NH(C 3-15 cycloalkyl), -NH(heterocyclic group), -NH(aryl), -NH(heteroaryl), -N(C 1-9 alkyl) 2 , -N(C 3-15 cycloalkyl) 2 , -NHC(O)(C 1-8 haloalkyl), -NHC(O)(C 3-15cycloalkyl), -NHC(O)(heterocyclic group), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 1-8 haloalkyl), -NHC(O)O(C 2-6 alkynyl), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O(heterocyclic group), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -S(O) 2 (C 1-9 alkyl), -S(O) 2 (C 1-8 haloalkyl), -S(O) 2 (C 3-15 cycloalkyl), -S(O) 2 (heterocyclic group), -S(O) 2 (aryl), -S(O) 2 (heteroaryl), -S(O)(NH)(C 1-9 alkyl), -S(O) 2 NH(C 1-9 alkyl) or -S(O) 2 N(C 1-9 alkyl) 2 is substituted; and

[0123] 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 is independently H, C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-15 cycloalkyl, heterocyclic group, C 6-10 aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted by one to four Z 1b substituted;

[0124] wherein each heteroaryl has 5 to 12 ring members and has one to four heteroatoms each independently being N, O or S; and

[0125] Each heterocyclic group has from 3 to 12 ring members and has from one to four heteroatoms each independently being N, O or S.

[0126] In some embodiments, the compounds of the present disclosure are compounds of formula (Ia):

[0127]

[0128] or a pharmaceutically acceptable salt thereof, wherein

[0129] Ring B is C 6-10 aryl or heteroaryl, each of which is optionally substituted with one to four R 4 substituents;

[0130] R 2 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, -S-R 2a 、-S(O)R 2a 、-S(O)(NH)R 2a 、-S(O) 2 R 2a 、-S(O) 2 N(R 2a )(R 2b ) or -S(O)(NR 2a )R 2b ,

[0131] wherein the alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted with one to four Z 1 substituents;

[0132] X 1 、X 2 and X 3 are each independently -N=, -C(H)= or -C(R 8 )=;

[0133] R 3 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-10 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, -CN, -NO 2 、-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) 2 R 3a , -C(O)NR 3a S(O) 2 R 3b , -C(O)NR 3a S(O) 2 NR 3b R 3c , -C(O)NR 3a -S(O)(=NR 3b )R 3c , -S(O) 2 R 3a , -S(O) 2 OR 3a , -S(O) 2 N(R 3a )(R 3b ), -N(R 3a )S(O) 2 R 3b , -S(O) 2 NHC(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, heterocyclic group, aryl or heteroaryl is each optionally substituted by one to four R 3d substituents;

[0134] Each R 3a , R 3b and R 3c is independently H, C1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, -C 1-4 alkyl-N(R 9a )(R 9b )、-C 1-4 alkyl-C(O)N(R 9a )(R 9b )、-C 1-4 alkyl-O-C(O)-C 1-4 alkyl、-C 1-4 alkyl-O-C(O)-O-C 1-4 alkyl、-C 1-4 alkyl-O-C(O)-C 1-4 alkyl-N(R 9a )(R 9b )、-C 1-4 alkyl-C 3-8 cycloalkyl、-C 1-4 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 、-CH 2 P(O)(OR 9c ) 2 、-OCH 2 P(O)(OR 9c ) 2 、-C(O)OCH 2 P(O)(OR 9c ) 2 、-P(O)(R 9c )(OR 9d )、-OP(O)(R 9c )(OR 9d )、-CH 2 P(O)(R 9c )(OR 9d )、-OCH 2 P(O)(R 9c )(OR 9d )、-C(O)OCH 2 P(O)(R 9c )(OR 9d )、-P(O)(N(R 9c ) 2 ) 2 、-OP(O)(N(R9c ) 2 ) 2 ,-CH 2 P(O)(N(R 9c ) 2 ) 2 ,-OCH 2 P(O)(N(R 9c ) 2 ) 2 ,-C(O)OCH 2 P(O)(N(R 9c ) 2 ) 2 ,-P(O)(N(R 9c ) 2 )(OR 9d )、-OP(O)(N(R 9c ) 2 )(OR 9d )、-CH 2 P(O)(N(R 9c ) 2 )(OR 9d )、-OCH 2 P(O)(N(R 9c ) 2 )(OR 9d )、-C(O)OCH 2 P(O)(N(R 9c ) 2 )(OR 9d )、-P(O)(R 9c )(N(R 9d ) 2 )、-OP(O)(R 9c )(N(R 9d ) 2 )、-CH 2 P(O)(R 9c )(N(R 9d ) 2 )、-OCH 2 P(O)(R 9c )(N(R 9d ) 2 ) or -C(O)OCH 2 P(O)(R 9c )(N(R 9d ) 2 );

[0135] wherein said alkyl, alkenyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted by one to four Z 1b substituents,

[0136] each R4 Independently C 1-9 alkyl, C 1-8 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-15 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, oxo group, -NO 2 、 -CN, -N 3 、 -O-R 4a 、 -C(O)R 4a 、 -C(O)O-R 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) 2 O(R 4b )、 -OC(O)R 4a 、 -OC(O)OR 4a 、 -OC(O)-N(R 4a )(R 4b )、 -S-R 4a 、 -S(O)R 4a 、 -S(O)(NH)R 4a 、 -S(O) 2 R 4a 、 -S(O) 2 N(R 4a )(R 4b )、 -S(O)(NR 4a )R 4b or -Si(R 4a) 3 ;

[0137] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted with one to four Z 1b substituents;

[0138] or two R groups attached to adjacent ring atoms combine with the atoms to which they are attached to form a C 4 cycloalkyl or heterocyclic group, and the cycloalkyl or heterocyclic group is each optionally substituted with one to four Z 5-10 substituents; 1b substituents;

[0139] R 5 is H, cyclopropyl or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one, two or three groups selected from halogen, -OH, -OCH 3 , -CN, oxo and -N(R x1 )(R x2 );

[0140] or R 5 and R y1 combine with the atoms to which they are attached to form a C 3-10 cycloalkyl or heterocyclic group optionally substituted with an oxo group;

[0141] R x1 and R x2 are each independently H, C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, -S(O) 2 R 6a1 or -S(O) 2 N(R 6a1 )(NR 6a2 ), wherein the C 1-6 alkyl, cycloalkyl or heterocyclic group is each optionally substituted with F, -CN, oxo or C 3-6 cycloalkyl;

[0142] or R x1 and R x2 combine with the atoms to which they are attached to form a heterocyclic group, and the heterocyclic group is optionally substituted with one to four R 6b1 substituents;

[0143] V is -C(O)-, -O-, -N(R 6a )- or -C(R 6b )(R 6c )-;

[0144] R 6a is H, C1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, -S(O) 2 R 6a1 or -S(O) 2 N(R 6a1 )(NR 6a2 ), where the cycloalkyl or heterocyclic group is each optionally substituted by C 1-6 alkyl, F or -CN;

[0145] Each R 6b and R 6c is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkoxyalkyl, halogen, C 3-10 cycloalkyl, heterocyclic group, -C 1-6 alkyl-N(R 9a )(R 9b ), -CN, -OR 6c1 or -N(R 6c2 )(R 6c3 ), where the alkyl, cycloalkyl or heterocyclic group is each optionally substituted by one to four R 6b1 substituents;

[0146] Or R 6b and R 6c combine with the atoms to which they are attached to form a C 3-10 cycloalkyl or heterocyclic group, and the

[0147] cycloalkyl or heterocyclic group is each optionally substituted by one to four R 6b1 substituents;

[0148] Or R 6a or R 6c combines with an R 4 group and the atoms to which they are attached to form a C 5-10 cycloalkyl or heterocyclic group, and the cycloalkyl or heterocyclic group is each optionally substituted by one to four R 10 substituents;

[0149] Each R y1 and R y2 is independently H, halo group, C 1-6 alkyl, C 1-6 haloalkyl, where the alkyl and haloalkyl are each optionally substituted by an oxo group;

[0150] Each R 3d 、R 6b1 and R 10 is independently C 1-6 alkyl, C 1-6 haloalkyl, C1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-10 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, oxo group, -OH, -CN, -NO 2 or -C(O)N(R 2a )(R 2b ), wherein the heterocyclic group or heteroaryl is optionally substituted by C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 haloalkoxy; and

[0151] each R 6a1 , R 6a2 , R 6c1 , R 6c2 and R 6c3 is independently H, C 1-6 alkyl or C 3-10 cycloalkyl;

[0152] each R 9a and R 9b is independently H, C 1-6 alkyl or C 1-6 haloalkyl;

[0153] each Z 1 is independently C 1-9 alkyl, C 1-8 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-15 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, oxo group, -NO 2 , -N 3 , -CN, -O-R 12a , -C(O)-R 12a , -C(O)O-R 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) 2 N(R 12b )(R 12c ),-NR 12a S(O) 2 O(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) 2 R 12a 、-S(O) 2 N(R 12a )(R 12b )、-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 for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -NO 2 、-CN、-N 3 、-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) 2 O(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) 2 R 12a , -S(O) 2 N(R 12a )(R 12b ), -S(O)(NR 12a )R 12b or -Si(R 12a ) 3 ;

[0156] wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted by one to four Z 1b substituents;

[0157] each R 8 or Z 1b is independently C 1-9 alkyl, C 1-8 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-15 cycloalkyl, heterocyclic group, C 6-10Aryl, heteroaryl, oxo group, -OH, -CN, -NO 2 , -NH 2 , -N 3 , -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(heterocyclic group), -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(heterocyclic group), -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(heterocyclic group) 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 group), -N(C 1-9 alkyl)(C 6-10 aryl), -N(C 1-9 alkyl)(heteroaryl), -C(O)(C 1-9 alkyl), -C(O)(C 1-8 haloalkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 alkynyl), -C(O)(C 3-15(cycloalkyl), -C(O)(heterocyclic group), -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(heterocyclic group), -C(O)O(C 6-10 aryl), -C(O)O(heteroaryl), -C(O)NH 2 , -C(O)NH(C 1-9 alkyl), -C(O)NH(C 1-8 haloalkyl), -C(O)NH(C 2-6 alkenyl), -C(O)NH(C 2-6 alkynyl), -C(O)NH(C 3-15 cycloalkyl), -C(O)NH(heterocyclic group), -C(O)NH(C 6-10 aryl), -C(O)NH(heteroaryl), -C(O)N(C 1-9 alkyl) 2 , -C(O)N(C 1-8 haloalkyl) 2 , -C(O)N(C 2-6 alkenyl) 2 , -C(O)N(C 2-6 alkynyl) 2 , -C(O)N(C 3-15 cycloalkyl) 2 , -C(O)N(heterocyclic group) 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)(heterocyclic group), -NHC(O)(C 6-10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 1-8 haloalkyl), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O(heterocyclic group), -NHC(O)O(C 6-10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -NHC(O)NH(C 1-8 haloalkyl), -NHC(O)NH(C 2-6 alkenyl), -NHC(O)NH(C 2-6 alkynyl), -NHC(O)NH(C 3-15 cycloalkyl), -NHC(O)NH(heterocyclic group), -NHC(O)NH(C 6-10 aryl), -NHC(O)NH(heteroaryl), -NHS(O)(C 1-9 alkyl), -N(C 1-9 alkyl)(S(O)(C 1-9 alkyl), -S(C 1-9 alkyl), -S(C 1-8 haloalkyl), -S(C 2-6 alkenyl), -S(C 2-6 alkynyl), -S(C 3-15 cycloalkyl), -S(heterocyclic group), -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 haloalkyl), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 alkynyl), -S(O)(C 3-15 cycloalkyl), -S(O)(heterocyclic group), -S(O)(C 6-10 aryl), -S(O)(heteroaryl), -S(O) 2 (C 1-9 alkyl), -S(O) 2 (C 1-8 haloalkyl), -S(O) 2 (C 2-6 alkenyl), -S(O) 2 (C 2-6 alkynyl), -S(O) 2 (C 3-15 cycloalkyl), -S(O) 2 (heterocyclic group), -S(O) 2 (C 6-10 aryl), -S(O) 2(heteroaryl), -S(O)(NH)(C 1-9 alkyl), -S(O) 2 NH(C 1-9 alkyl) or -S(O) 2 N(C 1-9 alkyl) 2 ;

[0158] wherein the alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted in each instance by one to three C 1-9 alkyl, C 1-8 haloalkyl, halogen, -OH, -NH 2 , -O(C 1-9 alkyl), -O(C 1-8 haloalkyl), -O(C 3-15 cycloalkyl), -O(heterocyclic group), -O(aryl), -O(heteroaryl), -NH(C 1-9 alkyl), -NH(C 1-8 haloalkyl), -NH(C 3-15 cycloalkyl), -NH(heterocyclic group), -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)(heterocyclic group), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 1-8 haloalkyl), -NHC(O)O(C 2-6 alkynyl), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O(heterocyclic group), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -S(O) 2 (C 1-9 alkyl), -S(O) 2 (C 1-8 haloalkyl), -S(O) 2 (C 3-15 cycloalkyl), -S(O) 2 (heterocyclic group), -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) 2 N(C 1-9 alkyl) 2 is substituted; and

[0159] 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 is independently H, C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-15 cycloalkyl, heterocyclic group, C 6-10 aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted with one to four Z 1b substituents;

[0160] subscript p is 1, 2 or 3; and

[0161] subscript q is 0, 1 or 2;

[0162] wherein each heteroaryl has 5 to 12 ring members and has one to four heteroatoms each independently being N, O or S; and

[0163] wherein each heterocyclic group has 3 to 12 ring members and has one to four heteroatoms each independently being N, O or S.

[0164] In some embodiments, the compounds of the present disclosure are compounds of formula (Ib):

[0165]

[0166] or a pharmaceutically acceptable salt thereof, wherein

[0167] ring B is C 6-10 aryl or heteroaryl, the aryl or heteroaryl being each optionally substituted with one to four R 4 substituents;

[0168] R 2 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10Cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, -S-R 2a , -S(O)R 2a , -S(O)(NH)R 2a , -S(O) 2 R 2a , -S(O) 2 N(R 2a )(R 2b ) or -S(O)(NR 2a )R 2b ,

[0169] wherein the alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted by one to four Z 1 substituents;

[0170] X 1 , X 2 and X 3 are each independently -N=, -C(H)= or -C(R 8 )=;

[0171] Y 1 and Y 2 are each -C(R y1 )(R y2 )-, -N(R y1 )-, -O-, -S-, -S(O) 2 - or -C(O)-;

[0172] R 3 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-10 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, -CN, -NO 2 , -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) 2 R 3a , -C(O)NR3a S(O) 2 R 3b 、 -C(O)NR 3a S(O) 2 NR 3b R 3c 、 -C(O)NR 3a -S(O)(=NR 3b )R 3c -S(O) 2 R 3a 、 -S(O) 2 OR 3a 、 -S(O) 2 N(R 3a )(R 3b )、 -N(R 3a )S(O) 2 R 3b 、 -S(O) 2 NHC(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, heterocyclic group, aryl or heteroaryl is each optionally substituted with one to four R 3d substituents;

[0173] Each R 3a , R 3b and R 3c is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, -C 1-4 alkyl-N(R 9a )(R 9b ), -C 1-4 alkyl-C(O)N(R 9a )(R 9b ), -C 1-4 alkyl-O-C(O)-C 1-4 alkyl, -C 1-4 alkyl-O-C(O)-O-C1-4 alkyl, -C 1-4 alkyl - O - C(O) - C 1-4 alkyl - N(R 9a )(R 9b )、-C 1-4 alkyl - C 3-8 cycloalkyl, -C 1-4 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 、-CH 2 P(O)(OR 9c ) 2 、-OCH 2 P(O)(OR 9c ) 2 、-C(O)OCH 2 P(O)(OR 9c ) 2 、-P(O)(R 9c )(OR 9d )、-OP(O)(R 9c )(OR 9d )、-CH 2 P(O)(R 9c )(OR 9d )、-OCH 2 P(O)(R 9c )(OR 9d )、-C(O)OCH 2 P(O)(R 9c )(OR 9d )、-P(O)(N(R 9c ) 2 ) 2 、-OP(O)(N(R 9c ) 2 ) 2 、-CH 2 P(O)(N(R 9c ) 2 ) 2 、-OCH 2 P(O)(N(R 9c ) 2 ) 2 、-C(O)OCH 2 P(O)(N(R 9c ) 2 )2 , -P(O)(N(R 9c )) 2 )(OR 9d ), -OP(O)(N(R 9c )) 2 )(OR 9d ), -CH 2 P(O)(N(R 9c )) 2 )(OR 9d ), -OCH 2 P(O)(N(R 9c )) 2 )(OR 9d ), -C(O)OCH 2 P(O)(N(R 9c )) 2 )(OR 9d ), -P(O)(R 9c )(N(R 9d )) 2 ), -OP(O)(R 9c )(N(R 9d )) 2 ), -CH 2 P(O)(R 9c )(N(R 9d )) 2 ), -OCH 2 P(O)(R 9c )(N(R 9d )) 2 ) or -C(O)OCH 2 P(O)(R 9c )(N(R 9d )) 2 );

[0174] wherein the alkyl, alkenyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted by one to four Z 1b substituents,

[0175] each R 4 is independently C 1-9 alkyl, C 1-8 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-15 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, oxo group, -NO 2 , -CN, -N 3 , -O-R 4a, -C(O)R 4a , -C(O)O-R 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) 2 O(R 4b ), -OC(O)R 4a , -OC(O)OR 4a , -OC(O)-N(R 4a )(R 4b ), -S-R 4a , -S(O)R 4a , -S(O)(NH)R 4a , -S(O) 2 R 4a , -S(O) 2 N(R 4a )(R 4b ), -S(O)(NR 4a )R 4b or -Si(R 4a ), 3 ;

[0176] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted by one to four Z 1b substituents;

[0177] alternatively, two R 4 groups attached to adjacent ring atoms combine with the atoms to which they are attached to form a C 5-10 cycloalkyl or heterocyclic group, and the cycloalkyl or heterocyclic group is each optionally substituted by one to four Z 1b substituents;

[0178] R 5 is H, cyclopropyl or C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted by one, two or three groups selected from halogen, -OH, -OCH 3 , -CN, oxo and -N(R x1 )(R x2 );

[0179] Or R 5 and R y1 combine with the atoms to which they are attached to form a C 3-10 cycloalkyl or heterocyclic group optionally substituted by an oxo group;

[0180] R x1 and R x2 are each independently H, C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, -S(O) 2 R 6a1 or -S(O) 2 N(R 6a1 )(NR 6a2 ), wherein said C 1-6 alkyl, cycloalkyl or heterocyclic group is each optionally substituted by F, -CN, oxo or C 3-6 cycloalkyl;

[0181] Or R x1 and R x2 combine with the atoms to which they are attached to form a heterocyclic group, said heterocyclic group being optionally substituted by one to four R 6b1 ;

[0182] V is -C(O)-, -O-, -N(R 6a )- or -C(R 6b )(R 6c )-;

[0183] R 6a is H, C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, -S(O) 2 R 6a1 or -S(O) 2 N(R 6a1 )(NR 6a2 ), wherein said cycloalkyl or heterocyclic group is each optionally substituted by C 1-6 alkyl, F or -CN;

[0184] Each R 6b and R 6c is independently H, C1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkoxyalkyl, halogen, C 3-10 cycloalkyl, heterocyclic group, -C 1-6 alkyl-N(R 9a )(R 9b ), -CN, -OR 6c1 or -N(R 6c2 )(R 6c3 ), wherein the alkyl, cycloalkyl or heterocyclic group is each optionally substituted by one to four R 6b1 substituents;

[0185] Or R 6b and R 6c combine with the atoms to which they are attached to form a C 3-10 cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is each optionally substituted by one to four R 6b1 substituents;

[0186] Or R 6a or R 6c combines with an R 4 group and the atoms to which they are attached to form a C 5-10 cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is each optionally substituted by one to four R 10 substituents;

[0187] Each R y1 and R y2 is independently H, a halo group, C 1-6 alkyl, C 1-6 haloalkyl, wherein the alkyl and haloalkyl are each optionally substituted by an oxo group;

[0188] Each R 3d , R 6b1 and R 10 is independently C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-10 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, oxo group, -OH, -CN, -CN, -NO 2 or

[0189] -C(O)N(R 2a )(R 2b ), wherein the heterocyclic group or heteroaryl is optionally substituted by C1-6 alkyl, C 1-6 haloalkyl, or C 1-6 haloalkoxy substituted; and

[0190] each R 6a1 , R 6a2 , R 6c1 , R 6c2 and R 6c3 is independently H, C 1-6 alkyl, or C 3-10 cycloalkyl;

[0191] each R 9a and R 9b is independently H, C 1-6 alkyl, or C 1-6 haloalkyl;

[0192] each Z 1 is independently C 1-9 alkyl, C 1-8 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-15 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, oxo group, -NO 2 , -N 3 , -CN, -O-R 12a , -C(O)-R 12a , -C(O)O-R 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) 2 N(R 12b )(R12c ), -NR 12a S(O) 2 O(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) 2 R 12a , -S(O) 2 N(R 12a )(R 12b ), -S(O)(NR 12a )R 12b or -Si(R 12a ), 3 ;

[0193] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted by one to four Z 1a substituents;

[0194] Each Z 1a is independently C 1-9 alkyl, C 1-8 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-15 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, oxo group, -NO 2 , -CN, -N 3 , -O-R 12a , -C(O)R 12a , -C(O)O-R 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) 2 O(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) 2 R 12a 、-S(O) 2 N(R 12a )(R 12b )、-S(O)(NR 12a )R 12b or -Si(R 12a ) 3 ;

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

[0196] Each R 8 or Z 1b Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, -NO 2 、-NH 2 、-N 3 ,-SH,-O(C 1-9 Alkyl), -O(C 1-8 Haloalkyl), -O(C 2-6 -O(C 2-6 Alkynyl), -O(C 3-15 Cycloalkyl), -O(heterocyclyl), -O(C 6-10 aryl), -O(heteroaryl), -NH(C1-9 alkyl), -NH(C 1-8 haloalkyl), -NH(C 2-6 alkenyl), -NH(C 2-6 alkynyl), -NH(C 3-15 cycloalkyl), -NH(heterocyclic group), -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(heterocyclic group) 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 group), -N(C 1-9 alkyl)(C 6-10 aryl), -N(C 1-9 alkyl)(heteroaryl), -C(O)(C 1-9 alkyl), -C(O)(C 1-8 haloalkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 alkynyl), -C(O)(C 3-15 cycloalkyl), -C(O)(heterocyclic group), -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(heterocyclic group), -C(O)O(C 6-10 aryl), -C(O)O(heteroaryl), -C(O)NH2 , -C(O)NH(C 1-9 alkyl), -C(O)NH(C 1-8 haloalkyl), -C(O)NH(C 2-6 alkenyl), -C(O)NH(C 2-6 alkynyl), -C(O)NH(C 3-15 cycloalkyl), -C(O)NH(heterocyclic group), -C(O)NH(C 6-10 aryl), -C(O)NH(heteroaryl), -C(O)N(C 1-9 alkyl) 2 , -C(O)N(C 1-8 haloalkyl) 2 , -C(O)N(C 2-6 alkenyl) 2 , -C(O)N(C 2-6 alkynyl) 2 , -C(O)N(C 3-15 cycloalkyl) 2 , -C(O)N(heterocyclic group) 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)(heterocyclic group), -NHC(O)(C 6-10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 1-8 haloalkyl), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C 2-6 alkynyl), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O(heterocyclic group), -NHC(O)O(C 6-10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -NHC(O)NH(C 1-8 haloalkyl), -NHC(O)NH(C 2-6 alkenyl), -NHC(O)NH(C 2-6 alkynyl), -NHC(O)NH(C 3-15(cycloalkyl), -NHC(O)NH(heterocyclic group), -NHC(O)NH(C 6-10 aryl), -NHC(O)NH(heteroaryl), -NHS(O)(C 1-9 alkyl), -N(C 1-9 alkyl)(S(O)(C 1-9 alkyl), -S(C 1-9 alkyl), -S(C 1-8 haloalkyl), -S(C 2-6 alkenyl), -S(C 2-6 alkynyl), -S(C 3-15 cycloalkyl), -S(heterocyclic group), -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 haloalkyl), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 alkynyl), -S(O)(C 3-15 cycloalkyl), -S(O)(heterocyclic group), -S(O)(C 6-10 aryl), -S(O)(heteroaryl), -S(O) 2 (C 1-9 alkyl), -S(O) 2 (C 1-8 haloalkyl), -S(O) 2 (C 2-6 alkenyl), -S(O) 2 (C 2-6 alkynyl), -S(O) 2 (C 3-15 cycloalkyl), -S(O) 2 (heterocyclic group), -S(O) 2 (C 6-10 aryl), -S(O) 2 (heteroaryl), -S(O)(NH)(C 1-9 alkyl), -S(O) 2 NH(C 1-9 alkyl) or -S(O) 2 N(C 1-9 alkyl) 2 ;

[0197] wherein the alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted in each instance with one to three C 1-9 alkyl, C 1-8 haloalkyl, halogen, -OH, -NH 2 , -O(C1-9 alkyl), -O(C 1-8 haloalkyl), -O(C 3-15 cycloalkyl), -O(heterocyclic group), -O(aryl), -O(heteroaryl), -NH(C 1-9 alkyl), -NH(C 1-8 haloalkyl), -NH(C 3-15 cycloalkyl), -NH(heterocyclic group), -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)(heterocyclic group), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 1-8 haloalkyl), -NHC(O)O(C 2-6 alkynyl), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O(heterocyclic group), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -S(O) 2 (C 1-9 alkyl), -S(O) 2 (C 1-8 haloalkyl), -S(O) 2 (C 3-15 cycloalkyl), -S(O) 2 (heterocyclic group), -S(O) 2 (aryl), -S(O) 2 (heteroaryl), -S(O)(NH)(C 1-9 alkyl), -S(O) 2 NH(C 1-9 alkyl) or -S(O) 2 N(C 1-9 alkyl) 2 is substituted; and

[0198] each R 1b , R 1c , R 2a , R 2b , R 4a , R 4b , R 4c , R 9c , R 9d , R12a , R 12b and R 12c are 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 said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl is each optionally substituted with one to four Z 1b substituents;

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

[0200] The subscript q is 0, 1 or 2;

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

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

[0203] In some embodiments, the compounds of the present disclosure are compounds of formula (Ic):

[0204]

[0205] or a pharmaceutically acceptable salt thereof, wherein

[0206] R 2 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, -S-R 2a , -S(O)R 2a , -S(O)(NH)R 2a , -S(O) 2 R 2a , -S(O) 2 N(R 2a )(R 2b ) or -S(O)(NR 2a )R 2b ,

[0207] wherein said alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is each optionally substituted with one to four Z 1 substituents;

[0208] X 1 、X2 and X 3 each independently is ═N═, ═C(H)═ or ═C(R 8 )═;

[0209] R 3 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-10 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, -CN, -NO 2 , -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) 2 R 3a , -C(O)NR 3a S(O) 2 R 3b , -C(O)NR 3a S(O) 2 NR 3b R 3c , -C(O)NR 3a -S(O)(═NR 3b )R 3c -S(O) 2 R 3a , -S(O) 2 OR 3a , -S(O) 2 N(R 3a )(R 3b ), -N(R 3a )S(O) 2 R 3b , -S(O) 2 NHC(O)R 3a , -S(O)(═NR 3a )R 3b , -S(O)(═NR 3a )NR 3b , -S(═NR 3a )(═NR3b )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, heterocyclic group, aryl or heteroaryl is each optionally substituted with one to four R 3d substituents;

[0210] Each R 3a , R 3b and R 3c is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, -C 1-4 alkyl-N(R 9a )(R 9b ), -C 1-4 alkyl-C(O)N(R 9a )(R 9b ), -C 1-4 alkyl-O-C(O)-C 1-4 alkyl, -C 1-4 alkyl-O-C(O)-O-C 1-4 alkyl, -C 1-4 alkyl-O-C(O)-C 1-4 alkyl-N(R 9a )(R 9b ), -C 1-4 alkyl-C 3-8 cycloalkyl, -C 1-4 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 , -CH 2 P(O)(OR 9c ), 2 , -OCH 2 P(O)(OR 9c ), 2 , -C(O)OCH 2 P(O)(OR 9c ), 2 , -P(O)(R 9c )(OR9d )、 -OP(O)(R 9c )(OR 9d )、 -CH 2 P(O)(R 9c )(OR 9d )、 -OCH 2 P(O)(R 9c )(OR 9d )、 -C(O)OCH 2 P(O)(R 9c )(OR 9d )、 -P(O)(N(R 9c ) 2 ) 2 、 -OP(O)(N(R 9c ) 2 ) 2 、 -CH 2 P(O)(N(R 9c ) 2 ) 2 、 -OCH 2 P(O)(N(R 9c ) 2 ) 2 、 -C(O)OCH 2 P(O)(N(R 9c ) 2 ) 2 、 -P(O)(N(R 9c ) 2 )(OR 9d )、 -OP(O)(N(R 9c ) 2 )(OR 9d 、 -CH 2 P(O)(N(R 9c ) 2 )(OR 9d )、 -OCH 2 P(O)(N(R 9c ) 2 )(OR 9d )、 -C(O)OCH 2 P(O)(N(R 9c ) 2 )(OR 9d )、 -P(O)(R 9c )(N(R 9d ) 2 )、 -OP(O)(R 9c )(N(R 9d ) 2 )、 -CH 2 P(O)(R 9c)(N(R 9d ) 2 )、 -OCH 2 P(O)(R 9c )(N(R 9d ) 2 ) or -C(O)OCH 2 P(O)(R 9c )(N(R 9d ) 2 );

[0211] wherein said alkyl, alkenyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted with one to four Z 1b substituents,

[0212] each R 4 is independently C 1-9 alkyl, C 1-8 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-15 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, oxo group, -NO 2 , -CN, -N 3 , -O-R 4a , -C(O)R 4a , -C(O)O-R 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) 2 O(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) 2 R 4a 、-S(O) 2 N(R 4a )(R 4b )、-S(O)(NR 4a )R 4b or -Si(R 4a ) 3 ;

[0213] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace;

[0214] or two R attached to adjacent ring atoms 4 The groups combine with the atoms to which they are attached to form C 5-10 Cycloalkyl or heterocyclic group, each of which is optionally substituted by one to four Z 1b replace;

[0215] 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, -OCH 3 , -CN, oxo and -N(R x1 )(R x2 ) is substituted by a group;

[0216] 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 Cycloalkyl or heterocyclic group;

[0217] R x1 and R x2 Each independently is H, C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, -S(O) 2 R 6a1 or -S(O) 2 N(R 6a1 )(NR 6a2 ), wherein the C 1-6An alkyl group, a cycloalkyl group or a heterocyclic group is each optionally substituted with F, -CN, an oxo group or C 3-6 by a cycloalkyl group;

[0218] Or R x1 and R x2 combine with the atoms to which they are attached to form a heterocyclic group, which heterocyclic group is optionally substituted with one to four R 6b1 substituents;

[0219] V is -C(O)-, -O-, -N(R 6a ), or -C(R 6b )(R 6c );

[0220] R 6a is H, C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, -S(O) 2 R 6a1 or -S(O) 2 N(R 6a1 )(NR 6a2 ), where the cycloalkyl group or the heterocyclic group is each optionally substituted with C 1-6 alkyl, F or -CN;

[0221] Each R 6b and R 6c is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkoxyalkyl, halogen, C 3-10 cycloalkyl, heterocyclic group, -C 1-6 alkyl-N(R 9a )(R 9b ), -CN, -OR 6c1 or -N(R 6c2 )(R 6c3 ), where the alkyl group, the cycloalkyl group or the heterocyclic group is each optionally substituted with one to four R 6b1 substituents;

[0222] Or R 6b and R 6c combine with the atoms to which they are attached to form a C 3-10 cycloalkyl group or a heterocyclic group, which cycloalkyl group or heterocyclic group is each optionally substituted with one to four R 6b1 substituents;

[0223] Or R 6a or R 6c combines with an R 4 group and the atoms to which they are attached to form a C 5-10A cycloalkyl or heterocyclic group, each of which is optionally substituted by one to four Rs 10 substituted;

[0224] Each R y1 and R y2 is independently H, a halogen group, C 1-6 alkyl, C 1-6 haloalkyl, wherein the alkyl and haloalkyl are each optionally substituted by an oxo group;

[0225] Each R 3d 、R 6b1 and R 10 is independently C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, a halogen, C 3-10 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, oxo group, -OH, -CN, -NO 2 or -C(O)N(R 2a )(R 2b ), wherein the heterocyclic group or heteroaryl is optionally substituted by C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 haloalkoxy; and

[0226] Each R 6a1 、R 6a2 、R 6c1 、R 6c2 and R 6c3 is independently H, C 1-6 alkyl or C 3-10 cycloalkyl;

[0227] Each R 9a and R 9b is independently H, C 1-6 alkyl or C 1-6 haloalkyl;

[0228] Each Z 1 is independently C 1-9 alkyl, C 1-8 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, a halogen, C 3-15Cycloalkyl, heterocyclic group, C 6-10 Aryl, heteroaryl, oxo group, -NO 2 、-N 3 、-CN, -O-R 12a 、-C(O)-R 12a 、-C(O)O-R 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) 2 N(R 12b )(R 12c )、-NR 12a S(O) 2 O(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) 2 R 12a 、-S(O) 2 N(R 12a )(R 12b )、-S(O)(NR 12a )R 12b or -Si(R 12a ) 3 ;

[0229] Wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted by one to four Z 1a substituents;

[0230] Each Z 1aIndependently C 1-9 alkyl, C 1-8 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-15 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, oxo group, -NO 2 , -CN, -N 3 , -O-R 12a , -C(O)R 12a , -C(O)O-R 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) 2 O(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) 2 R 12a , -S(O) 2 N(R 12a )(R 12b ), -S(O)(NR 12a )R 12b or -Si(R12a ) 3 ;

[0231] Wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted by one to four Z 1b substituents;

[0232] Each R 8 or Z 1b is independently C 1-9 alkyl, C 1-8 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-15 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, oxo group, -OH, -CN, -NO 2 , -NH 2 , -N 3 , -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(heterocyclic group), -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(heterocyclic group), -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(heterocyclic group) 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 (haloalkyl), -C(O)(C 2-6 (alkenyl), -C(O)(C 2-6 (alkynyl), -C(O)(C 3-15 (cycloalkyl), -C(O)(heterocyclic), -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(heterocyclic), -C(O)O(C 6-10 (aryl), -C(O)O(heteroaryl), -C(O)NH 2 , -C(O)NH(C 1-9 (alkyl), -C(O)NH(C 1-8 (haloalkyl), -C(O)NH(C 2-6 (alkenyl), -C(O)NH(C 2-6 (alkynyl), -C(O)NH(C 3-15 (cycloalkyl), -C(O)NH(heterocyclic), -C(O)NH(C 6-10 (aryl), -C(O)NH(heteroaryl), -C(O)N(C 1-9 (alkyl) 2 , -C(O)N(C 1-8 (haloalkyl) 2 , -C(O)N(C 2-6 (alkenyl) 2 , -C(O)N(C 2-6 (alkynyl) 2 , -C(O)N(C 3-15 (cycloalkyl) 2 , -C(O)N(heterocyclic) 2 , -C(O)N(C 6-10 (aryl) 2 , -C(O)N(heteroaryl) 2 , -NHCO(C1-9 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)(heterocyclic group), -NHC(O)(C 6-10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 1-8 haloalkyl), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C 2-6 alkynyl), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O(heterocyclic group), -NHC(O)O(C 6-10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -NHC(O)NH(C 1-8 haloalkyl), -NHC(O)NH(C 2-6 alkenyl), -NHC(O)NH(C 2-6 alkynyl), -NHC(O)NH(C 3-15 cycloalkyl), -NHC(O)NH(heterocyclic group), -NHC(O)NH(C 6-10 aryl), -NHC(O)NH(heteroaryl), -NHS(O)(C 1-9 alkyl), -N(C 1-9 alkyl)(S(O)(C 1-9 alkyl), -S(C 1-9 alkyl), -S(C 1-8 haloalkyl), -S(C 2-6 alkenyl), -S(C 2-6 alkynyl), -S(C 3-15 cycloalkyl), -S(heterocyclic group), -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 haloalkyl), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 alkynyl), -S(O)(C 3-15 cycloalkyl), -S(O)(heterocyclic group), -S(O)(C 6-10 aryl), -S(O)(heteroaryl), -S(O)2 (C 1-9 alkyl), -S(O) 2 (C 1-8 haloalkyl), -S(O) 2 (C 2-6 alkenyl), -S(O) 2 (C 2-6 alkynyl), -S(O) 2 (C 3-15 cycloalkyl), -S(O) 2 (heterocyclic group), -S(O) 2 (C 6-10 aryl), -S(O) 2 (heteroaryl), -S(O)(NH)(C 1-9 alkyl), -S(O) 2 NH(C 1-9 alkyl) or -S(O) 2 N(C 1-9 alkyl) 2 ;

[0233] wherein the alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted in each instance by one to three C 1-9 alkyl, C 1-8 haloalkyl, halogen, -OH, -NH 2 , -O(C 1-9 alkyl), -O(C 1-8 haloalkyl), -O(C 3-15 cycloalkyl), -O(heterocyclic group), -O(aryl), -O(heteroaryl), -NH(C 1-9 alkyl), -NH(C 1-8 haloalkyl), -NH(C 3-15 cycloalkyl), -NH(heterocyclic group), -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)(heterocyclic group), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 1-8 haloalkyl), -NHC(O)O(C 2-6 alkynyl), -NHC(O)O(C 3-15cycloalkyl), -NHC(O)O(heterocyclic group), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -S(O) 2 (C 1-9 alkyl), -S(O) 2 (C 1-8 haloalkyl), -S(O) 2 (C 3-15 cycloalkyl), -S(O) 2 (heterocyclic group), -S(O) 2 (aryl), -S(O) 2 (heteroaryl), -S(O)(NH)(C 1-9 alkyl), -S(O) 2 NH(C 1-9 alkyl) or -S(O) 2 N(C 1-9 alkyl) 2 substituted; 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 is independently H, C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-15 cycloalkyl, heterocyclic group, C 6-10 aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted by one to four Z 1b substituted;

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

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

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

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

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

[0240] In some embodiments, the compounds of the present disclosure are compounds of formula (Id):

[0241]

[0242] or a pharmaceutically acceptable salt thereof, wherein

[0243] R 2 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, heteroaryl, -S-R 2a 、-S(O)R 2a 、-S(O)(NH)R 2a 、-S(O) 2 R 2a 、-S(O) 2 N(R 2a )(R 2b ) or -S(O)(NR 2a )R 2b ,

[0244] wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is each optionally substituted with one to four Z 1 substituents;

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

[0246] R 3 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, heteroaryl, -CN, -NO 2 、-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) 2 R 3a , -C(O)NR 3a S(O) 2 R 3b , -C(O)NR 3a S(O) 2 NR 3b R 3c , -C(O)NR 3a -S(O)(=NR 3b )R 3c -S(O) 2 R 3a , -S(O) 2 OR 3a , -S(O) 2 N(R 3a )(R 3b ), -N(R 3a )S(O) 2 R 3b , -S(O) 2 NHC(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, heterocyclic group, aryl or heteroaryl is each optionally substituted by one to four R 3d ;

[0247] Each R 3a , R 3b and R 3c is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, -C 1-4 alkyl-N(R 9a )(R 9b ), -C 1-4 alkyl-C(O)N(R9a )(R 9b )、-C 1-4 alkyl - O - C(O) - C 1-4 alkyl、-C 1-4 alkyl - O - C(O) - O - C 1-4 alkyl、-C 1-4 alkyl - O - C(O) - C 1-4 alkyl - N(R 9a )(R 9b )、-C 1-4 alkyl - C 3-8 cycloalkyl、-C 1-4 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 、-CH 2 P(O)(OR 9c ) 2 、-OCH 2 P(O)(OR 9c ) 2 、-C(O)OCH 2 P(O)(OR 9c ) 2 、-P(O)(R 9c )(OR 9d )、-OP(O)(R 9c )(OR 9d )、-CH 2 P(O)(R 9c )(OR 9d )、-OCH 2 P(O)(R 9c )(OR 9d )、-C(O)OCH 2 P(O)(R 9c )(OR 9d )、-P(O)(N(R 9c ) 2 ) 2 、-OP(O)(N(R 9c ) 2 ) 2 、-CH 2 P(O)(N(R 9c ) 2 ) 2 、-OCH 2 P(O)(N(R9c ) 2 ) 2 ,-C(O)OCH 2 P(O)(N(R 9c ) 2 ) 2 ,-P(O)(N(R 9c ) 2 )(OR 9d )、-OP(O)(N(R 9c ) 2 )(OR 9d )、-CH 2 P(O)(N(R 9c ) 2 )(OR 9d )、-OCH 2 P(O)(N(R 9c ) 2 )(OR 9d )、-C(O)OCH 2 P(O)(N(R 9c ) 2 )(OR 9d )、-P(O)(R 9c )(N(R 9d ) 2 )、-OP(O)(R 9c )(N(R 9d ) 2 )、-CH 2 P(O)(R 9c )(N(R 9d ) 2 )、-OCH 2 P(O)(R 9c )(N(R 9d ) 2 ) or -C(O)OCH 2 P(O)(R 9c )(N(R 9d ) 2 ); wherein the alkyl, alkenyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted by one to four Z 1b substituted,

[0248] each R 4 is independently C 1-9 alkyl, C 1-8 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-15 cycloalkyl, heterocyclic group, C6-10 aryl, heteroaryl, oxo group, -NO 2 , -CN, -N 3 , -O-R 4a , -C(O)R 4a , -C(O)O-R 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) 2 O(R 4b ), -OC(O)R 4a , -OC(O)OR 4a , -OC(O)-N(R 4a )(R 4b ), -S-R 4a , -S(O)R 4a , -S(O)(NH)R 4a , -S(O) 2 R 4a , -S(O) 2 N(R 4a )(R 4b ), -S(O)(NR 4a )R 4b or -Si(R 4a ) 3 ;

[0249] wherein each of said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted with one to four Z 1b substituents;

[0250] or two R's attached to adjacent ring atoms 4The group combines with the atom to which it is attached to form a C 5-10 cycloalkyl or heterocyclic group, each of which is optionally substituted by one to four Z 1b substituents;

[0251] R 5 is H, cyclopropyl or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted by one, two or three groups selected from halogen, -OH, -OCH 3 , -CN, oxo group and -N(R x1 )(R x2 );

[0252] Or R 5 and R y1 combine with the atom to which they are attached to form a C 3-10 cycloalkyl or heterocyclic group optionally substituted by an oxo group;

[0253] R x1 and R x2 are each independently H, C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, -S(O) 2 R 6a1 or -S(O) 2 N(R 6a1 )(NR 6a2 ), wherein the C 1-6 alkyl, cycloalkyl or heterocyclic group is each optionally substituted by F, -CN, oxo group or C 3-6 cycloalkyl;

[0254] Or R x1 and R x2 combine with the atom to which they are attached to form a heterocyclic group, which is optionally substituted by one to four R 6b1 substituents;

[0255] V is -C(O)-, -O-, -N(R 6a )- or -C(R 6b )(R 6c );

[0256] R 6a is H, C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, -S(O) 2 R 6a1 or -S(O) 2 N(R 6a1 )(NR 6a2 ), wherein the cycloalkyl or heterocyclic group is each optionally substituted by C 1-6substituted with an alkyl group, F or -CN;

[0257] Each R 6b and R 6c are independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkoxyalkyl, halogen, C 3-10 cycloalkyl, heterocyclic group, -C 1-6 alkyl-N(R 9a )(R 9b ), -CN, -OR 6c1 or -N(R 6c2 )(R 6c3 ), where the alkyl, cycloalkyl or heterocyclic group is each optionally substituted with one to four R 6b1 substituents;

[0258] Or R 6b and R 6c combine with the atoms to which they are attached to form a C 3-10 cycloalkyl or heterocyclic group, where the cycloalkyl or heterocyclic group is each optionally substituted with one to four R 6b1 substituents;

[0259] Or R 6a or R 6c combines with an R 4 group and the atoms to which they are attached to form a C 5-10 cycloalkyl or heterocyclic group, where the cycloalkyl or heterocyclic group is each optionally substituted with one to four R 10 substituents;

[0260] Each R y1 and R y2 are independently H, halo group, C 1-6 alkyl, C 1-6 haloalkyl, where the alkyl and haloalkyl are each optionally substituted with an oxo group;

[0261] Each R 3d , R 6b1 and R 10 are independently C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-10 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, oxo group, -OH, -CN, -CN, -NO 2 or

[0262] -C(O)N(R 2a )(R 2b ),wherein the heterocyclic group or heteroaryl group is optionally substituted by C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 haloalkoxy; and

[0263] each R 6a1 , R 6a2 , R 6c1 , R 6c2 and R 6c3 is independently H, C 1-6 alkyl or C 3-10 cycloalkyl;

[0264] each R 9a and R 9b is independently H, C 1-6 alkyl or C 1-6 haloalkyl;

[0265] each Z 1 is independently C 1-9 alkyl, C 1-8 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-15 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, oxo group, -NO 2 , -N 3 , -CN, -O-R 12a , -C(O)-R 12a , -C(O)O-R 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) 2 N(R 12b )(R 12c ),-NR 12a S(O) 2 O(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) 2 R 12a 、-S(O) 2 N(R 12a )(R 12b )、-S(O)(NR 12a )R 12b or -Si(R 12a ) 3 ;

[0266] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1a replace;

[0267] Each Z 1a Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, 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, -NO 2 、-CN、-N 3 、-OR 12a 、-C(O)R 12a 、-C(O)OR 12a 、-C(O)N(R 12a )(R 12b )、-N(R 12a )(R 12b )、-N(R 12a ) 2 (R 12b ) + 、-N(R12a )-C(O)R 12b 、-N(R 12a )C(O)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) 2 O(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) 2 R 12a 、-S(O) 2 N(R 12a )(R 12b )、-S(O)(NR 12a )R 12b or -Si(R 12a ) 3 ;

[0268] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace;

[0269] Each R 8 or Z 1b Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, -NO 2 、-NH 2 、-N 3 ,-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(heterocyclic group), -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(heterocyclic group), -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(heterocyclic group) 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 group), -N(C 1-9 (alkyl)(C 6-10 (aryl), -N(C 1-9 (alkyl)(heteroaryl), -C(O)(C 1-9 (alkyl), -C(O)(C 1-8 (haloalkyl), -C(O)(C 2-6 (alkenyl), -C(O)(C 2-6 (alkynyl), -C(O)(C 3-15 (cycloalkyl), -C(O)(heterocyclic group), -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(heterocyclic group), -C(O)O(C 6-10 aryl), -C(O)O(heteroaryl), -C(O)NH 2 , -C(O)NH(C 1-9 alkyl), -C(O)NH(C 1-8 haloalkyl), -C(O)NH(C 2-6 alkenyl), -C(O)NH(C 2-6 alkynyl), -C(O)NH(C 3-15 cycloalkyl), -C(O)NH(heterocyclic group), -C(O)NH(C 6-10 aryl), -C(O)NH(heteroaryl), -C(O)N(C 1-9 alkyl) 2 , -C(O)N(C 1-8 haloalkyl) 2 , -C(O)N(C 2-6 alkenyl) 2 , -C(O)N(C 2-6 alkynyl) 2 , -C(O)N(C 3-15 cycloalkyl) 2 , -C(O)N(heterocyclic group) 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)(heterocyclic group), -NHC(O)(C 6-10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 1-8 haloalkyl), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C 2-6 alkynyl), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O(heterocyclic group), -NHC(O)O(C 6-10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -NHC(O)NH(C 1-8(haloalkyl), -NHC(O)NH(C 2-6 alkenyl), -NHC(O)NH(C 2-6 alkynyl), -NHC(O)NH(C 3-15 cycloalkyl), -NHC(O)NH(heterocyclic group), -NHC(O)NH(C 6-10 aryl), -NHC(O)NH(heteroaryl), -NHS(O)(C 1-9 alkyl), -N(C 1-9 alkyl)(S(O)(C 1-9 alkyl), -S(C 1-9 alkyl), -S(C 1-8 haloalkyl), -S(C 2-6 alkenyl), -S(C 2-6 alkynyl), -S(C 3-15 cycloalkyl), -S(heterocyclic group), -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 haloalkyl), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 alkynyl), -S(O)(C 3-15 cycloalkyl), -S(O)(heterocyclic group), -S(O)(C 6-10 aryl), -S(O)(heteroaryl), -S(O) 2 (C 1-9 alkyl), -S(O) 2 (C 1-8 haloalkyl), -S(O) 2 (C 2-6 alkenyl), -S(O) 2 (C 2-6 alkynyl), -S(O) 2 (C 3-15 cycloalkyl), -S(O) 2 (heterocyclic group), -S(O) 2 (C 6-10 aryl), -S(O) 2 (heteroaryl), -S(O)(NH)(C 1-9 alkyl), -S(O) 2 NH(C 1-9 alkyl) or -S(O) 2 N(C 1-9 alkyl) 2 ;

[0270] wherein the alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted in each instance with one to three C 1-9 alkyl, C 1-8 haloalkyl, halogen, -OH, -NH 2 -, -O(C 1-9 alkyl), -O(C 1-8 haloalkyl), -O(C 3-15 cycloalkyl), -O(heterocyclic group), -O(aryl), -O(heteroaryl), -NH(C 1-9 alkyl), -NH(C 1-8 haloalkyl), -NH(C 3-15 cycloalkyl), -NH(heterocyclic group), -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)(heterocyclic group), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 1-8 haloalkyl), -NHC(O)O(C 2-6 alkynyl), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O(heterocyclic group), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -S(O) 2 (C 1-9 alkyl), -S(O) 2 (C 1-8 haloalkyl), -S(O) 2 (C 3-15 cycloalkyl), -S(O) 2 (heterocyclic group), -S(O) 2 (aryl), -S(O) 2 (heteroaryl), -S(O)(NH)(C 1-9 alkyl), -S(O) 2 NH(C 1-9 alkyl) or -S(O) 2 N(C 1-9 alkyl) 2 substituted; and

[0271] 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 are independently H, C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-15 cycloalkyl, heterocyclic group, C 6-10 aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted by one to four Z 1b substituents;

[0272] The subscript p is 1, 2 or 3;

[0273] The subscript q is 0, 1 or 2; and

[0274] The subscript n is 0, 1, 2 or 3; and

[0275] wherein each heteroaryl has 5 to 12 ring members and has one to four heteroatoms each independently being N, O or S; and

[0276] wherein each heterocyclic group has 3 to 12 ring members and has one to four heteroatoms each independently being N, O or S.

[0277] In some embodiments, the compounds of the present disclosure are compounds of formula (Ie):

[0278]

[0279] or a pharmaceutically acceptable salt thereof, wherein

[0280] R 2 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, -S-R 2a , -S(O)R 2a , -S(O)(NH)R 2a , -S(O) 2 R 2a , -S(O) 2 N(R 2a )(R 2b ) or -S(O)(NR 2a )R2b ,

[0281] wherein the alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted with one to four Z 1 substituents;

[0282] R 3 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-10 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, -CN, -NO 2 , -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) 2 R 3a , -C(O)NR 3a S(O) 2 R 3b , -C(O)NR 3a S(O) 2 NR 3b R 3c , -C(O)NR 3a -S(O)(=NR 3b )R 3c -S(O) 2 R 3a , -S(O) 2 OR 3a , -S(O) 2 N(R 3a )(R 3b ), -N(R 3a )S(O) 2 R 3b , -S(O) 2 NHC(O)R 3a , -S(O)(=NR 3a )R 3b , -S(O)(=NR 3a )NR 3b , -S(=NR3a )(=NR 3b )R 3c 、-P(O)(OR 3a )(R 3b )、-P(O)(OR 3a )(OR 3b ) or -B(OR 3a )(OR 3b ), where the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted by one to four R 3d substituents;

[0283] Each R 3a , R 3b and R 3c is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, -C 1-4 alkyl-N(R 9a )(R 9b ), -C 1-4 alkyl-C(O)N(R 9a )(R 9b ), -C 1-4 alkyl-O-C(O)-C 1-4 alkyl, -C 1-4 alkyl-O-C(O)-O-C 1-4 alkyl, -C 1-4 alkyl-O-C(O)-C 1-4 alkyl-N(R 9a )(R 9b ), -C 1-4 alkyl-C 3-8 cycloalkyl, -C 1-4 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 -CH 2 P(O)(OR 9c ), 2 -OCH 2 P(O)(OR 9c ), 2 -C(O)OCH 2 P(O)(OR 9c ), 2 -P(O)(R9c )(OR 9d )、 -OP(O)(R 9c )(OR 9d )、 -CH 2 P(O)(R 9c )(OR 9d )、 -OCH 2 P(O)(R 9c )(OR 9d )、 -C(O)OCH 2 P(O)(R 9c )(OR 9d )、 -P(O)(N(R 9c ) 2 ) 2 、 -OP(O)(N(R 9c ) 2 ) 2 、 -CH 2 P(O)(N(R 9c ) 2 ) 2 、 -OCH 2 P(O)(N(R 9c ) 2 ) 2 、 -C(O)OCH 2 P(O)(N(R 9c ) 2 ) 2 、 -P(O)(N(R 9c ) 2 )(OR 9d )、 -OP(O)(N(R 9c ) 2 )(OR 9d )、 -CH 2 P(O)(N(R 9c ) 2 )(OR 9d )、 -OCH 2 P(O)(N(R 9c ) 2 )(OR 9d )、 -C(O)OCH 2 P(O)(N(R 9c ) 2 )(OR 9d )、 -P(O)(R 9c )(N(R 9d ) 2 )、 -OP(O)(R 9c )(N(R 9d ) 2 )、 -CH 2P(O)(R 9c )(N(R 9d ) 2 ),-OCH 2 P(O)(R 9c )(N(R 9d ) 2 ) or -C(O)OCH 2 P(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 for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -NO 2 、-CN、-N 3 、-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)2 O(R 4b )、 -OC(O)R 4a 、 -OC(O)OR 4a 、 -OC(O)-N(R 4a )(R 4b )、 -S-R 4a 、 -S(O)R 4a 、 -S(O)(NH)R 4a 、 -S(O) 2 R 4a 、 -S(O) 2 N(R 4a )(R 4b )、 -S(O)(NR 4a )R 4b or -Si(R 4a ) 3 ;

[0286] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted by one to four Z 1b substituents;

[0287] alternatively, two R 4 groups attached to adjacent ring atoms combine with the atoms to which they are attached to form a C 5-10 cycloalkyl or heterocyclic group, and the cycloalkyl or heterocyclic group is each optionally substituted by one to four Z 1b substituents;

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

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

[0290] R x1 and R x2 are each independently H, C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, -S(O) 2 R 6a1 or -S(O) 2 N(R 6a1 )(NR 6a2), wherein said C 1-6 The alkyl group, cycloalkyl group or heterocyclic group is each optionally substituted by F, -CN, an oxo group or C 3-6 substituted by a cycloalkyl group;

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

[0292] R 6a is H, C 1-6 alkyl group, C 3-10 cycloalkyl group, heterocyclic group, -S(O) 2 R 6a1 or -S(O) 2 N(R 6a1 )(NR 6a2 ), wherein the cycloalkyl group or heterocyclic group is each optionally substituted by C 1-6 alkyl group, F or -CN;

[0293] Each R 6b and R 6c is independently H, C 1-6 alkyl group, C 1-6 haloalkyl group, C 2-6 alkoxyalkyl group, halogen, C 3-10 cycloalkyl group, heterocyclic group, -C 1-6 alkyl group -N(R 9a )(R 9b ), -CN, -OR 6c1 or -N(R 6c2 )(R 6c3 ), wherein the alkyl group, cycloalkyl group or heterocyclic group is each optionally substituted by one to four R 6b1 substituted;

[0294] Or R 6b and R 6c combine with the atoms to which they are attached to form a C 3-10 cycloalkyl group or heterocyclic group, and the cycloalkyl group or heterocyclic group is each optionally substituted by one to four R 6b1 substituted;

[0295] Or R 6a or R 6c combine with an R 4 group and the atoms to which they are attached to form a C 5-10 cycloalkyl group or heterocyclic group, and the cycloalkyl group or heterocyclic group is each optionally substituted by one to four R 10 substituted;

[0296] Each R y1 and Ry2 Independently H, a halogen group, C 1-6 alkyl, C 1-6 haloalkyl, wherein the alkyl and haloalkyl are each optionally substituted with an oxo group;

[0297] Each R 3d , R 6b1 and R 10 is independently C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-10 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, oxo group, -OH, -CN, -CN, -NO 2 or

[0298] -C(O)N(R 2a )(R 2b ), wherein the heterocyclic group or heteroaryl is optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 haloalkoxy; and

[0299] Each R 6a1 , R 6a2 , R 6c1 , R 6c2 and R 6c3 is independently H, C 1-6 alkyl or C 3-10 cycloalkyl;

[0300] Each R 9a and R 9b is independently H, C 1-6 alkyl or C 1-6 haloalkyl;

[0301] Each Z 1 is independently C 1-9 alkyl, C 1-8 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-15 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, oxo group, -NO 2 , -N 3, -CN, -O-R 12a , -C(O)-R 12a , -C(O)O-R 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) 2 N(R 12b )(R 12c ), -NR 12a S(O) 2 O(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) 2 R 12a , -S(O) 2 N(R 12a )(R 12b ), -S(O)(NR 12a )R 12b or -Si(R 12a ) 3 ;

[0302] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted by one to four Z 1a substituents;

[0303] each Z 1a is independently C 1-9 alkyl, C 1-8 haloalkyl, C 1-6 alkoxy, C1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-15 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, oxo group, -NO 2 , -CN, -N 3 , -O-R 12a , -C(O)R 12a , -C(O)O-R 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) 2 O(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) 2 R 12a , -S(O) 2 N(R 12a )(R 12b ), -S(O)(NR 12a )R 12b or -Si(R 12a ) 3 ;

[0304] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted by one to four Z 1b substituted;

[0305] each R 8 or Z 1b is independently C 1-9 alkyl, C 1-8 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-15 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, oxo group, -OH, -CN, -NO 2 , -NH 2 , -N 3 , -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(heterocyclic group), -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(heterocyclic group), -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(heterocyclic group) 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)(C3-15 cycloalkyl), -N(C 1-9 alkyl)(heterocyclic group), -N(C 1-9 alkyl)(C 6-10 aryl), -N(C 1-9 alkyl)(heteroaryl), -C(O)(C 1-9 alkyl), -C(O)(C 1-8 haloalkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 alkynyl), -C(O)(C 3-15 cycloalkyl), -C(O)(heterocyclic group), -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(heterocyclic group), -C(O)O(C 6-10 aryl), -C(O)O(heteroaryl), -C(O)NH 2 、-C(O)NH(C 1-9 alkyl), -C(O)NH(C 1-8 haloalkyl), -C(O)NH(C 2-6 alkenyl), -C(O)NH(C 2-6 alkynyl), -C(O)NH(C 3-15 cycloalkyl), -C(O)NH(heterocyclic group), -C(O)NH(C 6-10 aryl), -C(O)NH(heteroaryl), -C(O)N(C 1-9 alkyl) 2 、-C(O)N(C 1-8 haloalkyl) 2 、-C(O)N(C 2-6 alkenyl) 2 、-C(O)N(C 2-6 alkynyl) 2 、-C(O)N(C 3-15 cycloalkyl) 2 、-C(O)N(heterocyclic group) 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)(heterocyclic group), -NHC(O)(C 6-10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 1-8 haloalkyl), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C 2-6 alkynyl), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O(heterocyclic group), -NHC(O)O(C 6-10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -NHC(O)NH(C 1-8 haloalkyl), -NHC(O)NH(C 2-6 alkenyl), -NHC(O)NH(C 2-6 alkynyl), -NHC(O)NH(C 3-15 cycloalkyl), -NHC(O)NH(heterocyclic group), -NHC(O)NH(C 6-10 aryl), -NHC(O)NH(heteroaryl), -NHS(O)(C 1-9 alkyl), -N(C 1-9 alkyl)(S(O)(C 1-9 alkyl), -S(C 1-9 alkyl), -S(C 1-8 haloalkyl), -S(C 2-6 alkenyl), -S(C 2-6 alkynyl), -S(C 3-15 cycloalkyl), -S(heterocyclic group), -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 haloalkyl), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 alkynyl), -S(O)(C 3-15 cycloalkyl), -S(O)(heterocyclic group), -S(O)(C 6-10 aryl), -S(O)(heteroaryl), -S(O) 2 (C 1-9 alkyl), -S(O)2 (C 1-8 (haloalkyl), -S(O) 2 (C 2-6 (alkenyl), -S(O) 2 (C 2-6 (alkynyl), -S(O) 2 (C 3-15 (cycloalkyl), -S(O) 2 (heterocyclic group), -S(O) 2 (C 6-10 (aryl), -S(O) 2 (heteroaryl), -S(O)(NH)(C 1-9 (alkyl), -S(O) 2 NH(C 1-9 (alkyl) or -S(O) 2 N(C 1-9 (alkyl) 2 ;

[0306] wherein the alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted, in each occurrence, with one to three C 1-9 alkyl, C 1-8 haloalkyl, halogen, -OH, -NH 2 , -O(C 1-9 alkyl), -O(C 1-8 haloalkyl), -O(C 3-15 cycloalkyl), -O(heterocyclic group), -O(aryl), -O(heteroaryl), -NH(C 1-9 alkyl), -NH(C 1-8 haloalkyl), -NH(C 3-15 cycloalkyl), -NH(heterocyclic group), -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)(heterocyclic group), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 1-8 haloalkyl), -NHC(O)O(C 2-6 alkynyl), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O(heterocyclic group), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 (alkyl), -S(O)2 (C 1-9 alkyl), -S(O) 2 (C 1-8 haloalkyl), -S(O) 2 (C 3-15 cycloalkyl), -S(O) 2 (heterocycloalkyl), -S(O) 2 (aryl), -S(O) 2 (heteroaryl), -S(O)(NH)(C 1-9 alkyl), -S(O) 2 NH(C 1-9 alkyl) or -S(O) 2 N(C 1-9 alkyl) 2 substituted; 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 is independently H, C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-15 cycloalkyl, heterocycloalkyl, C 6-10 aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is each optionally substituted with one to four Z 1b substituted;

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

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

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

[0311] wherein each heteroaryl has 5 to 12 ring members and has one to four heteroatoms each independently being N, O or S; and

[0312] wherein each heterocycloalkyl has 3 to 12 ring members and has one to four heteroatoms each independently being N, O or S.

[0313] In some embodiments, the compounds of the present disclosure are compounds of formula (If):

[0314]

[0315] or a pharmaceutically acceptable salt thereof, wherein

[0316] R 2 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, -S-R 2a , -S(O)R 2a , -S(O)(NH)R 2a , -S(O) 2 R 2a , -S(O) 2 N(R 2a )(R 2b ) or -S(O)(NR 2a )R 2b ,

[0317] wherein said alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is each optionally substituted by one to four Z 1 substituents;

[0318] R 3 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, -CN, -NO 2 , -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) 2 R 3a , -C(O)NR 3a S(O) 2 R 3b , -C(O)NR 3a S(O) 2 NR3b R 3c 、 -C(O)NR 3a -S(O)(=NR 3b )R 3c -S(O) 2 R 3a 、 -S(O) 2 OR 3a 、 -S(O) 2 N(R 3a )(R 3b )、 -N(R 3a )S(O) 2 R 3b 、 -S(O) 2 NHC(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, heterocyclic group, aryl or heteroaryl is each optionally substituted with one to four R 3d substituents;

[0319] Each R 3a 、 R 3b and R 3c is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, -C 1-4 alkyl-N(R 9a )(R 9b ), -C 1-4 alkyl-C(O)N(R 9a )(R 9b ), -C 1-4 alkyl-O-C(O)-C 1-4 alkyl, -C 1-4 alkyl-O-C(O)-O-C 1-4 alkyl, -C 1-4 alkyl-O-C(O)-C 1-4 alkyl-N(R 9a )(R 9b)、-C 1-4 alkyl-C 3-8 cycloalkyl, -C 1-4 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 、-CH 2 P(O)(OR 9c ) 2 、-OCH 2 P(O)(OR 9c ) 2 、-C(O)OCH 2 P(O)(OR 9c ) 2 、-P(O)(R 9c )(OR 9d )、-OP(O)(R 9c )(OR 9d )、-CH 2 P(O)(R 9c )(OR 9d )、-OCH 2 P(O)(R 9c )(OR 9d )、-C(O)OCH 2 P(O)(R 9c )(OR 9d )、-P(O)(N(R 9c ) 2 ) 2 、-OP(O)(N(R 9c ) 2 ) 2 、-CH 2 P(O)(N(R 9c ) 2 ) 2 、-OCH 2 P(O)(N(R 9c ) 2 ) 2 、-C(O)OCH 2 P(O)(N(R 9c ) 2 ) 2 、-P(O)(N(R 9c ) 2 )(OR 9d )、-OP(O)(N(R 9c) 2 )(OR 9d )、-CH 2 P(O)(N(R 9c ) 2 )(OR 9d )、-OCH 2 P(O)(N(R 9c ) 2 )(OR 9d )、-C(O)OCH 2 P(O)(N(R 9c ) 2 )(OR 9d )、-P(O)(R 9c )(N(R 9d ) 2 )、-OP(O)(R 9c )(N(R 9d ) 2 )、-CH 2 P(O)(R 9c )(N(R 9d ) 2 )、-OCH 2 P(O)(R 9c )(N(R 9d ) 2 ) or -C(O)OCH 2 P(O)(R 9c )(N(R 9d ) 2 );

[0320] wherein the alkyl, alkenyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted with one to four Z 1b substituents,

[0321] each R 4 is independently C 1-9 alkyl, C 1-8 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-15 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, oxo group, -NO 2 , -CN, -N 3 , -O-R 4a , -C(O)R 4a , -C(O)O-R 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) 2 O(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) 2 R 4a 、-S(O) 2 N(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 heterocyclic group, 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 1-3The alkyl group is optionally substituted by one, two or three groups selected from halogen, -OH, -OCH 3 , -CN, oxo group and -N(R x1 )(R x2 );

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

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

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

[0328] R 6a is H, C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, -S(O) 2 R 6a1 or -S(O) 2 N(R 6a1 )(NR 6a2 ), wherein the cycloalkyl or heterocyclic group is each optionally substituted by C 1-6 alkyl, F or -CN;

[0329] Each R 6b and R 6c is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkoxyalkyl, halogen, C 3-10 cycloalkyl, heterocyclic group, -C 1-6 alkyl-N(R 9a )(R 9b ), -CN, -OR 6c1 or -N(R 6c2 )(R​6c3 ), wherein each of the alkyl, cycloalkyl or heterocyclic group is optionally substituted by one to four R 6b1 substituents;

[0330] or R 6b and R 6c combine with the atoms to which they are attached to form a C 3-10 cycloalkyl or heterocyclic group, each of the cycloalkyl or heterocyclic group being optionally substituted by one to four R 6b1 substituents;

[0331] or R 6a or R 6c combines with an R 4 group and the atoms to which they are attached to form a C 5-10 cycloalkyl or heterocyclic group, each of the cycloalkyl or heterocyclic group being optionally substituted by one to four R 10 substituents;

[0332] Each R y1 and R y2 is independently H, a halogen group, C 1-6 alkyl, C 1-6 haloalkyl, wherein each of the alkyl and haloalkyl is optionally substituted by an oxo group;

[0333] Each R 3d , R 6b1 and R 10 is independently C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-10 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, oxo group, -OH, -CN, -CN, -NO 2 or

[0334] -C(O)N(R 2a )(R 2b ), wherein the heterocyclic group or heteroaryl is optionally substituted by C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 haloalkoxy; and

[0335] Each R 6a1 , R 6a2 , R 6c1 , R 6c2 and R 6c3 is independently H, C 1-6alkyl or C 3-10 cycloalkyl;

[0336] Each R 9a and R 9b is independently H, C 1-6 alkyl or C 1-6 haloalkyl;

[0337] Each Z 1 is independently C 1-9 alkyl, C 1-8 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-15 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, oxo group, -NO 2 , -N 3 , -CN, -O-R 12a , -C(O)-R 12a , -C(O)O-R 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) 2 N(R 12b )(R 12c ), -NR 12a S(O) 2 O(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) 2 R 12a 、-S(O) 2 N(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 Z 1a replace;

[0339] Each Z 1a Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, 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, -NO 2 、-CN、-N 3 、-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)2 O(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) 2 R 12a 、 - S(O) 2 N(R 12a )(R 12b )、 - S(O)(NR 12a )R 12b or - Si(R 12a ) 3 ;

[0340] wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted with one to four Z 1b substituents;

[0341] Each R 8 or Z 1b is independently C 1-9 alkyl, C 1-8 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-15 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, oxo group, - OH, - CN, - NO 2 2, - NH 2 2, - N 3 3, - 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(heterocyclic group), - 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(heterocyclic group), - NH(C 6-10 aryl), - NH(heteroaryl), - N(C 1-9 alkyl) 2 2, - N(C1-8 haloalkyl 2 、 -N(C 2-6 alkenyl) 2 、 -N(C 2-6 alkynyl) 2 、 -N(C 3-15 cycloalkyl) 2 、 -N(heterocyclic group) 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 group)、 -N(C 1-9 alkyl)(C 6-10 aryl)、 -N(C 1-9 alkyl)(heteroaryl)、 -C(O)(C 1-9 alkyl)、 -C(O)(C 1-8 haloalkyl)、 -C(O)(C 2-6 alkenyl)、 -C(O)(C 2-6 alkynyl)、 -C(O)(C 3-15 cycloalkyl)、 -C(O)(heterocyclic group)、 -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(heterocyclic group)、 -C(O)O(C 6-10 aryl)、 -C(O)O(heteroaryl)、 -C(O)NH 2 、 -C(O)NH(C 1-9 alkyl)、 -C(O)NH(C 1-8 haloalkyl)、 -C(O)NH(C 2-6 alkenyl)、 -C(O)NH(C 2-6 alkynyl)、 -C(O)NH(C 3-15 cycloalkyl)、 -C(O)NH(heterocyclic group)、 -C(O)NH(C 6-10(aryl), -C(O)NH(heteroaryl), -C(O)N(C 1-9 alkyl) 2 、-C(O)N(C 1-8 haloalkyl) 2 、-C(O)N(C 2-6 alkenyl) 2 、-C(O)N(C 2-6 alkynyl) 2 、-C(O)N(C 3-15 cycloalkyl) 2 、-C(O)N(heterocyclic group) 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)(heterocyclic group)、-NHC(O)(C 6-10 aryl)、-NHC(O)(heteroaryl)、-NHC(O)O(C 1-9 alkyl)、-NHC(O)O(C 1-8 haloalkyl)、-NHC(O)O(C 2-6 alkenyl)、-NHC(O)O(C 2-6 alkynyl)、-NHC(O)O(C 3-15 cycloalkyl)、-NHC(O)O(heterocyclic group)、-NHC(O)O(C 6-10 aryl)、-NHC(O)O(heteroaryl)、-NHC(O)NH(C 1-9 alkyl)、-NHC(O)NH(C 1-8 haloalkyl)、-NHC(O)NH(C 2-6 alkenyl)、-NHC(O)NH(C 2-6 alkynyl)、-NHC(O)NH(C 3-15 cycloalkyl)、-NHC(O)NH(heterocyclic group)、-NHC(O)NH(C 6-10 aryl)、-NHC(O)NH(heteroaryl)、-NHS(O)(C 1-9 alkyl)、-N(C 1-9 alkyl)(S(O)(C 1-9 alkyl)、-S(C 1-9 alkyl)、-S(C 1-8 haloalkyl)、-S(C2-6 alkenyl), -S(C 2-6 alkynyl), -S(C 3-15 cycloalkyl), -S(heterocyclic group), -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 haloalkyl), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 alkynyl), -S(O)(C 3-15 cycloalkyl), -S(O)(heterocyclic group), -S(O)(C 6-10 aryl), -S(O)(heteroaryl), -S(O) 2 (C 1-9 alkyl), -S(O) 2 (C 1-8 haloalkyl), -S(O) 2 (C 2-6 alkenyl), -S(O) 2 (C 2-6 alkynyl), -S(O) 2 (C 3-15 cycloalkyl), -S(O) 2 (heterocyclic group), -S(O) 2 (C 6-10 aryl), -S(O) 2 (heteroaryl), -S(O)(NH)(C 1-9 alkyl), -S(O) 2 NH(C 1-9 alkyl) or -S(O) 2 N(C 1-9 alkyl) 2 ;

[0342] wherein the alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted in each instance by one to three C 1-9 alkyl, C 1-8 haloalkyl, halogen, -OH, -NH 2 , -O(C 1-9 alkyl), -O(C 1-8 haloalkyl), -O(C 3-15 cycloalkyl), -O(heterocyclic group), -O(aryl), -O(heteroaryl), -NH(C 1-9 alkyl), -NH(C 1-8 haloalkyl), -NH(C 3-15(cycloalkyl), -NH(heterocyclic group), -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)(heterocyclic group), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)O(C( 1-9 (alkyl), -NHC(O)O(C( 1-8 (haloalkyl), -NHC(O)O(C( 2-6 (alkynyl), -NHC(O)O(C( 3-15 (cycloalkyl), -NHC(O)O(heterocyclic group), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C( 1-9 (alkyl), -S(O)( 2 (C( 1-9 (alkyl), -S(O)( 2 (C( 1-8 (haloalkyl), -S(O)( 2 (C( 3-15 (cycloalkyl), -S(O)( 2 (heterocyclic group), -S(O)( 2 (aryl), -S(O)( 2 (heteroaryl), -S(O)(NH)(C( 1-9 (alkyl), -S(O)( 2 (NH(C( 1-9 (alkyl) or -S(O)( 2 (N(C( 1-9 (alkyl)( 2 is substituted; and( (

[0343] (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 (is independently H, C( 1-9 (alkyl), C( 2-6 (alkenyl), C( 2-6 (alkynyl), C( 3-15 (cycloalkyl), heterocyclic group, C( 6-10An aryl or heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one to four Z 1b substituted;

[0344] The subscript p is 1, 2 or 3;

[0345] The subscript q is 0, 1 or 2; and

[0346] The subscript n is 0, 1, 2 or 3; and

[0347] wherein each heteroaryl has 5 to 12 ring members and has one to four heteroatoms each independently being N, O or S; and

[0348] wherein each heterocycloalkyl has 3 to 12 ring members and has one to four heteroatoms each independently being N, O or S.

[0349] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 1 is C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl or heteroaryl; wherein each of said alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl is optionally substituted with one to four Z 1 substituted.

[0350] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 1 is C 6-10 aryl or heteroaryl, and said aryl or heteroaryl is optionally substituted with one to three Z 1 substituted.

[0351] 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, and said aryl or heteroaryl is substituted with 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 ).

[0352] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 1 is a 6-membered aryl or a 5- or 6-membered heteroaryl, and said aryl or heteroaryl is substituted with one or two -Cl, -F or -CN.

[0353] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If) and / or (Ig) or their pharmaceutically acceptable salts, R 5 is hydrogen or methyl. In some embodiments, R 5 is methyl.

[0354] In some embodiments of the compounds of formula (I) or their pharmaceutically acceptable salts, at least one of Y 1 and Y 2 is -O-. In some embodiments, both Y 1 and Y 2 are -O-.

[0355] In some embodiments, the present disclosure provides compounds having the structure of formula (Ia) or (Ib) or their pharmaceutically acceptable salts:

[0356]

[0357] wherein:

[0358] the subscript p is 1, 2 or 3;

[0359] the subscript q is 0, 1 or 2; and

[0360] wherein R 2 、R 3 、R 5 、ring B, V, X 1 、X 2 、X 3 、Z 1a and Z 1b are as shown herein.

[0361] In some embodiments, the present disclosure provides compounds having the structure of formula (Ia) or their pharmaceutically acceptable salts:

[0362]

[0363] wherein 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 herein.

[0364] In some embodiments, the present disclosure provides compounds having the structure of formula (Ib) or their pharmaceutically acceptable salts:

[0365]

[0366] wherein 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 herein.

[0367] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and / or (Ig) or their pharmaceutically acceptable salts, each Z 1a is independently C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, heteroaryl, oxo, -OH, -CN, -NO 2 , -OR 12a , -C(O)N(R 12a )(R 12b ), wherein each is optionally substituted with Z 1b .

[0368] In some embodiments of the compounds of formula (I), (Ia), and / or (Ib) or their pharmaceutically acceptable salts, ring B is phenyl or a 5- to 6-membered heteroaryl, wherein the phenyl or heteroaryl is optionally substituted with one to four R 4 . In some embodiments, ring B is

[0369]

[0370] each of which is optionally substituted with one to three R 4 .

[0371] In some embodiments of the compounds of formula (I), (Ia), and / or (Ib) or their pharmaceutically acceptable salts, ring B is

[0372]

[0373] each of which is optionally substituted with one or two R 4 .

[0374] In some embodiments, the compounds of the present disclosure or their pharmaceutically acceptable salts have the structure of formula (Ic) or (Id):

[0375]

[0376] wherein

[0377] the subscript n is 0, 1, 2, or 3;

[0378] the subscript p is 1, 2, or 3; and

[0379] wherein R 2 , R 3 , R 4 , R 5 , V, X 1 , X 2 , X 3 , and Z 1 are as defined herein.

[0380] 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 are each independently –CH═, –C(F)═, -C(Cl)═, -C(Br)═, or -C(CN)═.

[0381] 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 -CH 2 -.

[0382] In some embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof have the structure of formula (Ie) or (If):

[0383]

[0384] wherein

[0385] the subscript n is 0, 1, 2, or 3;

[0386] the subscript p is 1, 2, or 3; and

[0387] wherein R 2 , R 3 , R 4 , R 5 , and Z 1 are as defined herein.

[0388] In some embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof have the structure of formula (Ig):

[0389]

[0390] wherein

[0391] the subscript n is 0, 1, 2 or 3; and

[0392] the subscript p is 1, 2 or 3.

[0393] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If) and / or (Ig) or their pharmaceutically acceptable salts, each Z 1 is independently C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-10 cycloalkyl, heterocycloalkyl, C 6-10 aryl, heteroaryl, heterocycloalkyl-C 1-6 alkyl, heterocycloalkyl-C 1-6 haloalkyl, heteroaryl-C 1-6 alkyl, heteroaryl-C 1-6 haloalkyl, oxo, -OH, -CN, -NO 2 or -C(O)N(R 12a )(R 12b ), wherein the heteroaryl or heterocycloalkyl is each optionally substituted with one to four halogens, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl or -CN.

[0394] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If) and / or (Ig) or their pharmaceutically acceptable salts, each Z 1 is independently C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, oxo, -OH, -CN, or -NO 2 , C 3-10 cycloalkyl, 3 to 12 membered heterocycloalkyl having one to three heteroatoms, or 5 to 10 membered heteroaryl having one to three heteroatoms. In some embodiments, each Z 1 is independently C 1-6 haloalkyl, C 1-6 haloalkoxy, halogen, -CN, or 5 to 6 membered heteroaryl having one to three heteroatoms. In some embodiments, each Z 1Independently being halogen, C 1-6 haloalkyl, C 1-3 alkoxy, C 3-10 cycloalkyl or -CN.

[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 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, C 1-6 alkyl-C 3-10 cycloalkyl, C 1-6 alkyl-heterocyclic group, 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-heterocyclic group-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) 2 R 2a , -S(O) 2 R 2a , -S(O) 2 N(R 2a )(R 2b ), or -S(O) 2 NR 2c C(O)R 2a , wherein the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic group are each optionally substituted by one to four Z 1b , wherein each Z 1b is independently C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-10Cycloalkyl, heterocyclic group, C 6-10 Aryl, heteroaryl, heterocyclic group-C 1-6 Alkyl, heterocyclic group-C 1-6 Halogenated alkyl, heteroaryl-C 1-6 Alkyl, heteroaryl-C 1-6 Halogenated alkyl, oxo group, -OH, -CN, -NO 2 Or -C(O)N(R 12a )(R 12b ).

[0396] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If) and / or (Ig) or their pharmaceutically acceptable salts, R 2 Is C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic group, heteroaryl, C 1-6 Alkyl-C 3-10 Cycloalkyl, C 1-6 Alkyl-heterocyclic group, C 1-6 Alkyl-C 3-10 Cycloalkyl-C 1-6 Alkyl, C 1-6 Alkyl-heterocyclic group-C 1-6 Alkyl or C 1-6 Alkyl-heteroaryl, each of which is optionally substituted by one to four Z 1b Substituted. In some embodiments, R 2 Is 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 Substituted.

[0397] In some embodiments, wherein R 2 Is:

[0398]

[0399] In some embodiments, R 2 Is:

[0400]

[0401] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If) and / or (Ig) or their pharmaceutically acceptable salts, R 3 Is heteroaryl, -C(O)OH, -C(O)OR 3a , -C(O)N(R3a )S(O) 2 (R 3b )、-S(O) 2 NHC(O)R 3a or -C(O)N(R 3a )S(O) 2 N(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.

[0402] 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 for C 1-6 Alkyl, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, halogen, oxo, -CN or -OR 4a In some embodiments, each R 4 Independently for C 1-6 Alkyl, halogen, oxo, -CN or -OR 4a In some embodiments, each R 4 Independently for C 1-6 alkyl, halogen, oxo, -OH or -CN. In some embodiments, each R 4 is independently F, oxo or -CN.

[0403] 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.

[0404] In some embodiments of the compounds of formula (I), (Ic), (Id), (Ie), (If) and / or (Ig) or pharmaceutically acceptable salts thereof, the subscript n is 0, 1 or 2.

[0405] In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If) and / or (Ig) or pharmaceutically acceptable salts thereof, the subscript p is 1 or 2.

[0406] In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If) and / or (Ig) or pharmaceutically acceptable salts thereof have the following formula:

[0407]

[0408]

[0409]

[0410]

[0411]

[0412] Also disclosed herein are the in vivo metabolites of the compounds described herein, to the extent that such products are novel and non-obvious relative to the prior art. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, mainly due to enzymatic processes. Thus, novel and non-obvious compounds are produced by a method that includes exposing a compound to a mammal for a period of time sufficient to produce its metabolites. Such products are typically identified by preparing a radiolabeled (e.g., 14 C or 3 H) compound, parenterally administering the radiolabeled compound to an animal, such as a rat, mouse, guinea pig, monkey or human, 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 isolated because they are labeled (other products are isolated using antibodies capable of binding to epitopes surviving in the metabolite). The metabolite structure is determined in a conventional manner, e.g., by MS or NMR analysis. Generally, the analysis of metabolites can be carried out in the same manner as conventional drug metabolism studies well known to those skilled in the art. The conversion products can be used for diagnostic assays of the therapeutic dose of the compound as long as they are not otherwise found in vivo, even if they do not have GLP-1R activity themselves.

[0413] Formulations and methods for determining the stability of compounds in surrogate gastrointestinal secretions are known. Compounds are defined herein as being stable in the gastrointestinal tract, where less than about 50 mole % of the protecting groups are deprotected in surrogate intestinal or gastric fluid after incubation at 37 °C for 1 hour. Just because a compound is stable to the gastrointestinal tract does not mean that it cannot be hydrolyzed in vivo. Prodrugs are generally stable in the digestive system, but can be substantially hydrolyzed to the parent drug in the digestive lumen, liver, lung, or other metabolic organs or generally intracellularly. As used herein, a prodrug is understood to be a compound that is chemically designed to effectively release the parent drug after overcoming the oral delivery biological barriers.

[0414] III. Methods for Preparing Compounds

[0415] The compounds of the present disclosure can be prepared by any method known in the art. The following exemplary general methods illustrate the routes that can be used to obtain the compounds of the present disclosure.

[0416] Scheme 1 :

[0417]

[0418] The compound of formula 1.3 can be assembled as follows: First, the amine is reacted with intermediate 1.1 in the presence of a suitable base (such as DIPEA, KOtBu, etc.) to give intermediate 1.2. Then it can be converted to intermediate 1.3 using suitable reducing conditions (such as H 2 and Pd / C, Fe and HCl, etc.).

[0419] Scheme 2 :

[0420]

[0421] The compound of Formula 2.7 can be assembled as follows: reacting a substituted diol having the general formula structure 2.1 with a ketone or aldehyde having the general formula 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) under reflux. During this reaction, water can be removed by a Dean-Stark trap or by azeotroping with molecular sieves. Catechol of Formula 2.1 can also react with a dihalide of Formula 2.3 in the presence of an organic base such as pyridine to form a compound having the general formula structure 2.7. Additionally, an acetal or ketal of an acyclic (dashed line absent) or cyclic (dashed line present) structure 2.4 can react with catechol of Formula 2.1 in the presence of an acid or base to obtain a compound of structure 2.7. In a similar manner, a thioacetal or thioketal of an acyclic (dashed line absent) or cyclic (dashed line present) structure 2.5 can react with catechol of Formula 2.1 in the presence of a mercury salt, a mild oxidant or an alkylating agent to obtain a compound of structure 2.7. Additionally, an alkyne of Formula 2.6 (where R 1 is an aryl or heteroaryl) can react with catechol of Formula 2.1 in the presence of dodecacarbonyltriruthenium 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.

[0422] Scheme 3 :

[0423]

[0424] Exemplary compounds of Formula (I) (such as the compound of Formula (1g) depicted above) can be first assembled by combining intermediate 3.1 with intermediate 1.3 under standard amide bond formation conditions (such as DIPEA and HATU, etc.). Treatment with a suitable acid catalyst (such as HCl, AcOH, etc.) can produce intermediate 3.3. Then, a halogen-metal exchange of -X to -M can be achieved using a suitable reagent (such as iPrMgBr, etc.), or a transition metal coupling can be achieved using a suitable palladium catalyst and a metal source (such as B 2 Pin 2 , Bu 6 Sn 2 etc.) to obtain intermediate 3.4. Then it can be coupled to intermediate 2.7 using a suitable palladium catalyst to obtain intermediate 3.5. If R = methyl or ethyl, the compound 3.5 can be converted to Formula (Ig) using standard ester hydrolysis conditions (such as LiOH, LiI and pyridine, Me 3 SnOH, etc.). If R = tert-butyl, the compound 3.5 can be converted to Formula (Ig) in the presence of a protic acid (such as trifluoroacetic acid, etc.).

[0425] Scheme 4 :

[0426]

[0427] Exemplary compounds of formula (I) (including compounds of formula (Ig) above) can be formed by using a suitable palladium catalyst and a metal source (such as bis(neopentyl glycol) diboron, B 2 Pin 2 、Bu 6 Sn 2 etc.) to first convert intermediate 2.7 into a metallated variant intermediate 4.1. It can then be coupled to intermediate 3.3 using a suitable palladium catalyst to obtain intermediate 3.5. If R is methyl or ethyl, compound 3.5 can be converted to formula (Ig) using standard ester hydrolysis conditions (such as LiOH, LiI, and pyridine, Me 3 SnOH, etc.). If R is tert-butyl, compound 3.5 can be converted to formula (Ig) in the presence of a protonic acid (such as trifluoroacetic acid, etc.).

[0428] Scheme 5 :

[0429]

[0430] The compound of formula 5.1 can be obtained by the reaction of formula (I) with a sulfonamide under suitable coupling conditions (such as EDC and DMAP, etc.).

[0431] Scheme 6 :

[0432]

[0433] The compound of formula 6.3 can be assembled by first coupling to the halogen - X of intermediate 6.1 using a suitable coupling partner and a palladium catalyst to obtain intermediate 6.2, which can be converted to compound 6.3 using standard ester hydrolysis conditions (such as LiOH, LiI, and pyridine, etc.).

[0434] Scheme 7 :

[0435]

[0436] Compounds of formula (Ig) can also be assembled by protecting the alcohol group of intermediate 7.1 (the protecting group Pg can be benzyl or trimethylsilylethoxymethyl) to obtain intermediate 7.2. Cross - coupling of an intermediate of type 3.4 with intermediate 7.2 using a suitable transition metal catalyst (such as palladium, etc.) gives intermediate 7.3. It can then be deprotected (such as using a metal catalyst and H 2The gas, or when Pg is trimethylsilylethoxymethyl, by using HCl or TFA) to obtain intermediate 7.4. Intermediate 7.4 can react with carbonyl-containing intermediate 2.2 or alkyne intermediate 2.6 in a manner similar to the procedure described in Scheme 2 to obtain intermediate 3.5. Then it can be converted to formula (Ig) using standard ester hydrolysis conditions (such as LiOH, LiI, and pyridine, etc.).

[0437] Scheme 8 :

[0438]

[0439] The compounds of formula (Ig) can also be assembled as follows: First, couple intermediate 2.7 with intermediate 8.1 (commercially available or obtained by metallation of the corresponding halide) using a suitable palladium catalyst to obtain intermediate 8.2. After converting to acid 8.3 using standard conditions (such as LiOH, LiI, and pyridine, etc.), couple intermediate 1.3 using standard amide bond formation conditions (such as DIPEA and HATU, etc.) to obtain intermediate 8.4. Then it can be converted to the corresponding benzimidazole 3.5 under the influence of an acid catalyst (such as HCl, AcOH, TFA, etc.), and then it can be converted to formula (Ig) using standard ester hydrolysis conditions (such as LiOH, LiI, and pyridine, etc.).

[0440] Scheme 9 :

[0441]

[0442] The compounds of formula 9.3 can be assembled as follows: First, couple to the halogen - X of intermediate 9.1 using a suitable coupling partner and a metal catalyst (such as palladium, etc.) to obtain intermediate 9.2, which can be converted to compound 9.3 using standard ester hydrolysis conditions (such as LiOH, LiI, and pyridine, etc.).

[0443] IV. Pharmaceutical Preparations

[0444] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure (such as 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.

[0445] In some embodiments, the pharmaceutical composition comprises 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, which are more fully described below.

[0446] A pharmaceutical composition comprising the compounds disclosed herein or a pharmaceutically acceptable salt 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 a sterile form and are generally isotonic when intended to be delivered by a route other than oral administration. In some embodiments, the composition can contain excipients such as those described in Rowe et al., “Handbook of Pharmaceutical Excipients”, 6th Edition, American Pharmacists Association, 2009. Excipients can include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, etc. In some embodiments, the composition is provided as a solid dosage form, including solid oral dosage forms.

[0447] The compositions include those suitable for various routes of administration, including oral administration. The compositions can be in unit dosage forms and can be prepared by any of the methods well known in the pharmaceutical art. Such methods include the step of associating the active ingredient (e.g., the compounds of the present disclosure or their medicinal salts) with one or more pharmaceutically acceptable excipients. The compositions can be prepared by uniformly and intimately associating the active ingredient with a liquid excipient or a subdivided solid excipient or both, and then, if necessary, shaping the product. Techniques and formulations are generally described in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0448] The compositions described herein suitable for oral administration can be in 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.

[0449] The pharmaceutical compositions disclosed herein comprise one or more of the compounds disclosed herein or pharmaceutically acceptable salts thereof, as well as pharmaceutically acceptable excipients and optionally other therapeutic agents. The pharmaceutical composition containing the active ingredient can be in any form suitable for the intended method of administration. For example, when used for oral administration, tablets, lozenges, troches, 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 by any method known in the art for manufacturing pharmaceutical compositions, and such compositions can contain one or more excipients, including sweetening agents, flavoring agents, coloring agents and preservatives, in order to provide a palatable preparation. Tablets containing the active ingredient admixed with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients can 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 disintegrating agents such as corn starch or alginic acid; binding agents such as cellulose, microcrystalline cellulose, starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. The tablets can be uncoated or can be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thus provide a sustained action over a longer period. For example, a delaying material such as glyceryl monostearate or glyceryl distearate can be used alone or in combination with wax.

[0450] The amount of the active ingredient that can be combined with the inactive ingredients to produce the dosage form can vary depending on the intended subject to be treated and the mode of administration. For example, in some embodiments, a dosage form for oral administration to a human can contain from about 1 mg to 1000 mg of the active material, formulated with a suitable and convenient amount of pharmaceutically acceptable excipients. In some embodiments, the pharmaceutically acceptable excipients comprise from about 5% to about 95% (weight: weight) of the total composition.

[0451] In some embodiments, in one variant, the composition comprising the compound disclosed herein or a pharmaceutically acceptable salt thereof does not contain an agent that affects the metabolic rate of the active ingredient. Thus, it should be understood that, in one aspect, the composition comprising the compound disclosed herein does not contain an agent that will affect (e.g., slow down, impede or delay) the metabolism of the compound disclosed herein or any other active ingredient administered separately, sequentially or simultaneously with the compound disclosed herein. It should also be understood that, in one aspect, any of the methods, kits, articles, etc. detailed herein do not contain an agent that will affect (e.g., slow down, impede or delay) the metabolism of the compound disclosed herein or any other active ingredient administered separately, sequentially or simultaneously with the compound disclosed herein.

[0452] In some embodiments, the above pharmaceutical compositions are for use in humans or animals.

[0453] The present disclosure also includes the compounds of the present disclosure administered as a single active ingredient in a pharmaceutically acceptable composition, which can be prepared by conventional methods known in the art, for example, by combining the active ingredient with a pharmaceutically acceptable, therapeutically inert organic and / or inorganic carrier or excipient, or by mixing the active ingredient with them. In one aspect, the present disclosure provides the use of the compounds of the present disclosure as a second or other active ingredient having a synergistic effect with other active ingredients in known drugs, or administering the compounds of the present disclosure together with such drugs.

[0454] The compounds of the present disclosure can also be used in the form of prodrugs or other suitable modified forms that release the active ingredient in vivo.

[0455] V. Routes of Administration

[0456] The compounds of the present disclosure (also referred to herein as active ingredients) can be administered by any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intratumoral, intrathecal, and epidural), etc. It should be understood that the preferred route may vary depending on, for example, the condition of the recipient. An advantage of some of the compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0457] The compounds of the present disclosure can be administered to an individual for the desired period 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 variant, the compound is administered on a daily or intermittent schedule throughout the life of the individual.

[0458] The dose or frequency of administration of the compounds of the present disclosure can be adjusted during the course of treatment according to the judgment of the administering physician.

[0459] The compound can be administered to an individual (such as a human) in an effective amount. In some embodiments, the compound is administered once a day.

[0460] The compounds can be administered by any available route and method, such as orally or parenterally (e.g., intravenously). The therapeutically effective amount of the compounds can include from about 0.00001 mg / kg body weight / day to about 10 mg / kg body weight / day, such as from about 0.0001 mg / kg body weight / day to about 10 mg / kg body weight / day, or such as from about 0.001 mg / kg body weight / day to about 1 mg / kg body weight / day, or such as from about 0.01 mg / kg body weight / day to about 1 mg / kg body weight / day, or such as from about 0.05 mg / kg body weight / day to about 0.5 mg / kg body weight / day, or such as from about 0.3 mg / day to about 30 mg / day, or such as from about 30 mg / day to about 300 mg / day.

[0461] 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 the compound). The 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 the compounds 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 the 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. The single dose can be administered hourly, daily or weekly. For example, the single dose can be administered once every 1, 2, 3, 4, 6, 8, 12, 16 hours, or once every 24 hours. The single dose can also be administered once every 1, 2, 3, 4, 5, 6 days, or once every 7 days. The single dose can also be administered once every 1, 2, 3 weeks, or once every 4 weeks. In some embodiments, the single dose can be administered once a week. The single dose can also be administered once a month.

[0462] The present disclosure also includes kits that include the 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 a compound of the present disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogue thereof, and a label and / or instructions for use of the compound in a therapeutic indication (such as a disease or disorder described herein). In one embodiment, kits are provided that include a compound of the present disclosure or a pharmaceutically acceptable salt 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.

[0463] Articles in suitable containers are also provided herein, which include the compounds of the present disclosure, or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogues thereof. The containers can be vials, jars, ampoules, pre-loaded syringes, and intravenous bags.

[0464] VI. Combination Therapies

[0465] In some embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof can 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 agents include apoptosis signal-regulating kinase (ASK-1) inhibitors, farnesoid X receptor (FXR) agonists, peroxisome proliferator-activated receptor α (PPARα) agonists, fish oil, acetyl-CoA carboxylase (ACC) inhibitors, or TGFβ antagonists, or combinations thereof.

[0466] 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, 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 amyloid polypeptide receptor agonist, an angiotensin II AT-1 receptor antagonist, an autophagy protein regulator, an autotaxin inhibitor, an Axl tyrosine kinase receptor inhibitor, a Bax protein stimulator, a β-catenin inhibitor, a bioactive lipid, a calcitonin agonist, a cannabinoid receptor modulator, a caspase inhibitor, a caspase-3 stimulator, a cathepsin inhibitor, a caveolin-1 inhibitor, a CCL26 gene inhibitor, a CCR2 chemokine antagonist, a CCR2 chemokine antagonist, an angiotensin II AT-1 receptor antagonist, a CCR3 chemokine antagonist, a CCR5 chemokine antagonist, a CD3 antagonist, a chloride channel stimulator, a CNR1 inhibitor, a connective tissue growth factor ligand inhibitor, a cyclin D1 inhibitor, a cytochrome P450 7A1 inhibitor, a DGAT1 / 2 inhibitor, a diacylglycerol O-acyltransferase 1 inhibitor (DGAT1), a cytochrome P4502E1 inhibitors (CYP2E1), CXCR4 chemokine antagonists, dihydroceramide δ4 desaturase inhibitors, dihydroorotate dehydrogenase inhibitors, dipeptidyl peptidase IV inhibitors, endosialin regulators, eotaxin ligand inhibitors, extracellular matrix protein regulators, 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 α-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 4α regulators (HNF4A), hepatocyte growth factor regulators, histone deacetylase inhibitors, STAT-3 regulators, HMG coenzyme A reductase inhibitors, HSD17B13 gene inhibitors, hydrolase inhibitors, hypoxia-inducible factor-2α inhibitors, IL-10 agonists, IL-17 antagonists, IL-22 agonists, ileal bile acid sodium cotransporter inhibitors, insulin sensitizers, insulin ligand agonists, insulin receptor agonists, integrin 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 regulators, ketohexokinase (KHK) inhibitors, Klothoβ stimulants, 5-lipoxygenase inhibitors, lipoprotein lipase inhibitors, liver X receptors, LPL gene stimulants, lysophosphatidic acid-1 receptor antagonists, lysyl oxidase homolog 2 inhibitors, LXR inverse agonists, macrophage mannose receptor 1 regulators, 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 regulators, microRNA-132 (miR-132) antagonists, microRNA-21 (miR-21) inhibitors, mitochondrial uncouplers, mixed lineage kinase 3 inhibitors, myelin basic protein stimulants, NACHT LRRPYD domain-containing protein 3 (NLRP3) inhibitor, NAD-dependent deacetylase Sirtuin stimulator, NADPH oxidase inhibitor (NOX), nicotinic acid receptor 1 agonist, P2Y13 purinergic receptor stimulator, nuclear erythroid 2-related factor 2 stimulator, nuclear receptor modulator, P2X7 purinergic receptor modulator, PACAP type I receptor agonist, PDE3 inhibitor, PDE4 inhibitor, PDE5 inhibitor, PDGF receptor β modulator, phenylalanine hydroxylase stimulator, phospholipase C inhibitor, PPARα agonist, PPARδ agonist, PPARγ agonist, peptidyl-prolyl cis-trans isomerase A inhibitor, PPARγ modulator, protease-activated receptor-2 antagonist, protein kinase modulator, PTGS2 gene inhibitor, resistin / CAP1 (adenylyl cyclase-associated protein 1) interaction inhibitor, Rho-associated protein kinase inhibitor, S-nitrosoglutathione reductase (GSNOR) enzyme inhibitor, sodium glucose transporter-2 inhibitor, SREBP transcription factor inhibitor, STAT-1 inhibitor, stearoyl-CoA desaturase-1 inhibitor, STK25 inhibitor, suppressor of cytokine signaling-1 stimulator, suppressor of cytokine signaling-3 stimulator, telomerase stimulator, TERT gene modulator, TGFβ (TGFB1) ligand inhibitor, TNF antagonist, transforming growth factor β (TGF-β), transforming growth factor β-activated kinase 1 (TAK1), thyroid hormone receptor β agonist, TLR-4 antagonist, TLR-9 antagonist, VDR agonist, transglutaminase inhibitor, tyrosine kinase receptor modulator, GPCR modulator, nuclear hormone receptor modulator, WNT modulator or YAP / TAZ modulator, and zonulin inhibitor.

[0467] Non-limiting examples of such one or more additional therapeutic agents include:

[0468] - ACE inhibitors such as enalapril;

[0469] - Aldehyde dehydrogenase inhibitors such as ADX-629;

[0470] - Acetyl-CoA carboxylase (ACC) inhibitors such as NDI-010976 (firsocostat), DRM-01, gemcabene, PF-05175157, QLT-091382, PF-05221304;

[0471] - Acetyl-CoA carboxylase / diacylglycerol O-acyltransferase 2 inhibitors such as PF-07055341;

[0472] -Adenosine receptor agonists, such as CF-102 (namodenoson), CF-101, CF-502, CGS21680;

[0473] -Adenosine A3 receptor antagonists, such as FM-101;

[0474] -Adiponectin receptor agonists, such as ADP-355, ADP-399;

[0475] -Adrenergic receptor antagonists, such as bromocriptine, VI-0521;

[0476] -Aldehyde dehydrogenase 2 stimulators, such as FP-045;

[0477] -α-Glucosidase inhibitors (e.g., voglibose, acarbose or miglitol);

[0478] -Amylin / calcitonin receptor agonists, such as KBP-042, KBP-089;

[0479] -AMP-activated protein kinase stimulators, such as PXL-770, O-304;

[0480] -AMP kinase activator / ATP citrate lyase inhibitor, such as bempedoic acid (ETC-1002, ESP-55016)

[0481] -AMP-activated protein kinase / endothelial nitric oxide synthase / NAD-dependent deacetylase sirtuin-1 stimulators, such as NS-0200 (leucine + metformin + sildenafil);

[0482] -Androgen receptor agonists, such as LPCN-1144, LPCN-1148;

[0483] -Angiotensin II AT-1 receptor antagonists, such as irbesartan;

[0484] -Angiopoietin-related protein-3 inhibitors, such as IONIS-ANGPTL3-LRx;

[0485] -Apelin receptor agonists, such as CB-5064;

[0486] -Anti-lysyl oxidase homolog 2 (LOXL2) monoclonal antibody (e.g., simtuzumab);

[0487] -Autophagy protein regulators, such as A-2906;

[0488] - Autocrine motility factor inhibitors, such as PAT-505, PAT-048, GLPG-1690, X-165, PF-8380, TJC-0265, TJC-0316, AM-063, BBT-877;

[0489] - Axl tyrosine kinase receptor inhibitors, such as bemcentinib (BGB-324, R-428);

[0490] - Bax protein stimulators, such as CBL-514;

[0491] - Bioactive lipids, such as DS-102;

[0492] - Biguanides, such as metformin;

[0493] - Cannabinoid receptor modulators, such as namacizumab, GWP-42004, REV-200, CRB-4001, SCN-002;

[0494] Cysteine protease inhibitors, such as emricasan;

[0495] - Pan-cathepsin B inhibitors, such as VBY-376;

[0496] - Pan-cathepsin inhibitors, such as VBY-825;

[0497] - CCL26 gene inhibitors, such as KDDF-201410-10;

[0498] - CCR2 / CCR5 chemokine antagonists, such as cenicriviroc, maraviroc, CCX-872, WXSH-0213;

[0499] - CCR2 / CCR5 chemokine antagonists and FXR agonists, such as LJC-242 (tropifexor + cenivriviroc);

[0500] - CCR2 chemokine antagonists, such as propizide;

[0501] - CCR2 chemokine / angiotensin II AT-1 receptor antagonists, such as DMX-200, DMX-250;

[0502] - CCR3 chemokine antagonists, such as bertilimumab;

[0503] - CD3 antagonists, such as NI-0401 (foralumab);

[0504] - Chloride channel stimulants, such as colprostone and lubiprostone;

[0505] - Casein kinase-1 (CK1) δ / ε inhibitors, such as PF-05006739;

[0506] - Connective tissue growth factor ligand inhibitors, such as PBI-4050;

[0507] - CXCR4 chemokine antagonists, such as AD-214;

[0508] - Diacylglycerol acyltransferase 2 (DGAT2) inhibitors, such as IONIS-DGAT2Rx, PF-06865571;

[0509] - Diacylglycerol acyltransferase 1 (DGAT1) inhibitors, such as GSK-3008356;

[0510] - Diacylglycerol O-acyltransferase 1 (DGAT1) / Cytochrome P450 2E1 inhibitor (CYP2E1), such as SNP-610;

[0511] - Dihydroorotate dehydrogenase inhibitors, such as vedolizumab;

[0512] - Dipeptidyl peptidase IV inhibitors, such as linagliptin, evogliptin, sitagliptin, vildagliptin, saxagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, dutogliptin or omarigliptin;

[0513] - Eosinophil activating chemokine ligand inhibitors, such as bertilimumab, CM-101;

[0514] - Extracellular matrix protein regulators, such as CNX-024;

[0515] - 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;

[0516] - Farnesoid X receptor (FXR) / G protein-coupled bile acid receptor 1 (TGR5) agonists, such as INT-767;

[0517] - Fatty acid synthase inhibitors, such as TVB-2640, FT-8225;

[0518] - Fibroblast growth factor 19 (rhFGF19) / cytochrome P450 (CYP) 7A1 inhibitors, such as NGM-282;

[0519] - Fibroblast growth factor 21 (FGF-21) ligands, such as BMS-986171, BIO89-100, BMS-986036, B-1344;

[0520] - Fibroblast growth factor 21 (FGF-21) / glucagon-like peptide 1 (GLP-1) agonists, such as YH-25723 (YH-25724; YH-22241), AKR-001;

[0521] - FGF receptor agonists / Klothoβ stimulants, such as BFKB-8488A (RG-7992);

[0522] - Galectin-3 inhibitors, such as GR-MD-02, GB-1107 (Gal-300), GB1211 (Gal-400);

[0523] - GDNF family receptor α-like agonists, such as NGM-395;

[0524] - Glitazars, such as saroglitazar, aleglitazar, muraglitazar or tesaglitazar;

[0525] - Glitazones (such as pioglitazone, rosiglitazone, balaglitazone, rivoglitazone, or lobeglitazone),

[0526] - Glucagon-like peptide 1 receptor (GLP-1R) agonists, such as ALT-801, AC-3174, liraglutide, cotadutide (MEDI-0382), SAR-425899, LY-3305677, HM-15211, YH-25723, YH-GLP1, RPC-8844, PB-718, semaglutide;

[0527] - Gastric inhibitory polypeptide / glucagon-like peptide-1 (GIP / GLP-1) receptor co-agonists, such as tirzepatide (LY-3298176);

[0528] - PEGylated long-acting glucagon-like peptide-1 / glucagon (GLP-1R / GCGR) receptor dual agonists, such as DD-01;

[0529] - Glucocorticoid receptor antagonists, such as CORT-118335 (miricorilant);

[0530] - Glucose-6-phosphate 1-dehydrogenase inhibitors, such as ST001;

[0531] - Glucokinase stimulants, such as sinogliatin (RO-5305552);

[0532] - G-protein-coupled bile acid receptor 1 (TGR5) agonists, such as RDX-009, INT-777;

[0533] - GPR40 agonists (FFAR1 / FFA1 agonists, e.g., fasiglifam);

[0534] - Glucose-dependent insulinotropic polypeptide (GIP) and its analogs;

[0535] - Heat shock protein 47 (HSP47) inhibitors, such as ND-L02-s0201;

[0536] - Hedgehog protein and / or TGFβ ligand inhibitors, such as Oxy-210;

[0537] - Histone deacetylase inhibitors / STAT-3 modulators, such as SFX-01;

[0538] -HMG-CoA reductase inhibitors, such as atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin;

[0539] -HSD17B13 gene inhibitors, such as ARO-HSD;

[0540] -Hydrolase inhibitors, such as ABD-X;

[0541] -Hypoxia-inducible factor-2α inhibitors, such as PT-2567;

[0542] -IL-10 agonists, such as pegylated iloprost;

[0543] -Ileal bile acid co-transporter inhibitors, such as obeticholic acid (A-4250), volixibat ethanol potassium hydrate (SHP-262), GSK2330672, CJ-14199, elobixibat (A-3309);

[0544] -Insulin sensitizers, such as KBP-042, MSDC-0602K, MSDC-5514, Px-102, RG-125 (AZD4076), tolimidone, VVP-100X, CB-4211, ETI-101;

[0545] -Insulin ligand / ds insulin receptor agonists, such as ORMD-0801;

[0546] -Insulin or insulin analogs;

[0547] -Integrin antagonists, such as IDL-2965;

[0548] -IL-6 receptor agonists, such as KM-2702;

[0549] -Integrin α-V / β-6 and α-V / β-1 dual inhibitors, such as PLN-74809;

[0550] -Interleukin 17 ligand inhibitors, such as netakimab;

[0551] -Jak1 / 2 tyrosine kinase inhibitors, such as baricitinib;

[0552] -Jun N-terminal kinase-1 inhibitors, such as CC-90001;

[0553] -Ketose hexokinase (KHK) inhibitors, such as PF-06835919;

[0554] -βKlotho (KLB)-FGF1c agonists, such as MK-3655 (NGM-313);

[0555] -5-lipoxygenase inhibitors, such as tipelukast (MN-001), DS-102 (AF-102);

[0556] -lipoprotein lipase inhibitors, such as CAT-2003;

[0557] -LPL gene stimulants, such as alipogene tiparvovec;

[0558] -liver X receptor (LXR) inhibitors, such as PX-L603, PX-L493, BMS-852927, T-0901317, GW-3965, SR-9238;

[0559] -lysophosphatidic acid-1 receptor antagonists, such as BMT-053011, UD-009 (CP-2090), AR-479, ITMN-10534, BMS-986020, KI-16198;

[0560] -lysyl oxidase homolog 2 inhibitors, such as sintilimab, PXS-5382A (PXS-5338);

[0561] -macrophage mannose receptor 1 modulators, such as technetium Tc 99m temocapril (temanose-Cy3);

[0562] -glinides, such as nateglinide, repaglinide;

[0563] -membrane-bound copper amine oxidase (VAP-1) inhibitors, such as TERN-201;

[0564] -MEKK-5 protein kinase (ASK-1) inhibitors, such as CJ-16871, silonestat (GS-4997), SRT-015, GS-444217, GST-HG-151;

[0565] -MCH receptor-1 antagonists, such as CSTI-100 (ALB-127158);

[0566] -semicarbazide-sensitive amine oxidase / vascular adhesion protein-1 (SSAO / VAP-1) inhibitors, such as PXS-4728A (BI-1467335);

[0567] -sulfonylureas, such as tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glipizide, glimepiride or glipizine;

[0568] - Methionine aminopeptidase-2 inhibitors, such as ZGN-1061, ZGN-839, ZN-1345;

[0569] - Methyl CpG binding protein 2 regulators, such as mercaptoethylamine;

[0570] - Mineralocorticoid receptor antagonists (MCRA), such as MT-3995 (apalutamide);

[0571]

[0572] - Mitochondrial uncouplers, such as 2,4-dinitrophenol, Mito-99-0053 and HU6;

[0573] - Mixed lineage kinase-3 inhibitors, such as URMC-099-C;

[0574] - Myelin basic protein stimulants, such as olesoxime;

[0575] - Green peroxidase inhibitors, such as PF-06667272, AZM-198;

[0576] - NADPH oxidase inhibitors, such as GKT-831, GenKyoTex, APX-311, setanaxib - Nicotinic acid receptor 1 agonists, such as ARI-3037MO;

[0577] - NACHT LRR PYD domain-containing protein 3 (NLRP3) inhibitors, such as KDDF-201406-03, NBC-6, IFM-514, JT-194 (JT-349);

[0578] - NFE2L2 gene inhibitors, such as GeRP-amiR-144;

[0579] - Nuclear receptor regulators, such as DUR-928 (DV-928);

[0580] - P2X7 purinergic receptor regulators, such as SGM-1019;

[0581] - P2Y13 purinergic receptor stimulants, such as CER-209;

[0582] - PDE 3 / 4 inhibitors, such as terbutaline (MN-001);

[0583] - PDE 5 inhibitors, such as sildenafil, MSTM-102;

[0584] - PDGF receptor β regulators, such as BOT-191, BOT-509;

[0585] - Peptidyl - prolyl cis - trans isomerase inhibitors, such as CRV - 431 (CPI - 432 - 32), NVP - 018, NV - 556 (NVP - 025);

[0586] - Phenylalanine hydroxylase stimulants, such as HepaStem;

[0587] - PPAR agonists, such as chiglitazar, elafinranor (GFT - 505), seladelparlysine (MBX - 8025), deuterated pioglitazone R - enantiomer, pioglitazone, DRX - 065, saroglitazar, lanifibranor (IVA - 337), CHS - 131, pemafibrate (K - 877), ZSP - 0678;

[0588] - Protease - activated receptor - 2 antagonists, such as PZ - 235;

[0589] - Protein kinase regulators, such as CNX - 014;

[0590] - PTGS2 gene inhibitors, such as STP - 705, STP - 707;

[0591] - Resistin / CAP1 (adenylate cyclase - associated protein 1) interaction inhibitors, such as DWJ - 211;

[0592] - Rev protein regulators, such as ABX - 464;

[0593] - Rho - associated protein kinase (ROCK) inhibitors, such as REDX - 10178 (REDX - 10325), KD - 025, TDI - 01;

[0594] - S - nitrosoglutathione reductase (GSNOR) enzyme inhibitors, such as SL - 891;

[0595] - Sodium-glucose cotransporter-2 (SGLT2) inhibitors, such as ipragliflozin, remogliflozin etabonate, ertugliflozin, dapagliflozin, tofogliflozin, sotagliflozin, empagliflozin, canagliflozin, Ipraglrflozin, tofogliflozin, sergliflozin etabonate;

[0596] - Sodium-glucose cotransporter-1 / 2 (SGLT 1 / 2) inhibitors, such as licogliflozinbis(prolinate) (LIK-066);

[0597] - SREBP transcription factor inhibitors, such as CAT-2003, MDV-4463;

[0598] - Stearoyl-CoA desaturase-1 inhibitors, such as aramchol;

[0599] - Thiazolidinediones, such as pioglitazone, rosiglitazone or lobeglitazone;

[0600] - Thyroid hormone receptor beta agonists, such as ALG-009, ASC-41, CNPT-101101, CNPT-101207, resmetirom (MGL-3196), MGL-3745, VK-2809;

[0601] - TLR-2 / TLR-4 antagonists, such as VB-201 (CI-201);

[0602] - TLR-4 antagonists, such as JKB-121, JKB-122;

[0603] - Tyrosine kinase receptor modulators, such as CNX-025, GFE-2137 (repurposed nitazoxanide);

[0604] - TLR-9 antagonists, such as GNKS-356;

[0605] - TNF antagonists, such as ALF-421;

[0606] - GPCR modulators, such as CNX-023;

[0607] - Nuclear hormone receptor modulators, such as Px-102;

[0608] - VDR agonists, such as CK-15;

[0609] - Xanthine oxidase / urate anion exchanger 1 (URAT1) inhibitors, such as RLBN-1001, RLBN-1127; and

[0610] - Catenin inhibitors, such as lorazotide acetate (INN-202).

[0611] In some embodiments, one or more additional therapeutic agents are selected from A-4250, AC-3174, acetylsalicylic acid, AK-20, aliproclate, AMX-342, AN-3015, eicosanoylaminocholanic acid, ARI-3037MO, ASP-8232, AZD-2693, pertuzumab, anhydrous betaine, BI-1467335, BMS-986036, BMS-986171, BMT-053011, BOT-191, BTT-1023, budenoside, BX-003, CAT-2003, cenicriviroc, CBW-511, CER-209, CF-102, CGS21680, CNX-014, CNX-023, CNX-024, CNX-025, carboprost, colesevelam, dapagliflozin, DCR-LIV1, deuterated pioglitazone R-enantiomer, 2,4-dinitrophenol, DRX-065, DS-102, DUR-928, EDP-305, elafibranor (GFT-505), enilcanide, enalapril, empagliflozin, egregliptin, 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), eicosapentaenoic acid ethyl ester, IMM-124-E, INT-767, INV-240, IONIS-DGAT2Rx, empagliflozin, irbesartan, propyzamide, IVA-337, JKB-121, KB-GE-001, KBP-042, KD-025, M790, M780, M450, metformin, sildenafil, LB-700, LC-280126, linagliptin, liraglutide, LJN-452 (zopiclone), LM-011, LM-002 (CVI-LM-002), LMB-763, LYN-100, MBX-8025, MDV-4463, mercaptoethylamine, MGL-3196, MGL-3745, MP-301, MSDC-0602K, namilumab, NC-101, NDI-010976, ND-L02-s0201 (BMS-986263), NGM-282, NGM-313, NGM-386, NGM-395, NP-011, NP-135, NP-160, norursodeoxycholic acid, NVP-022, O-304, obeticholic acid (OCA), 25HC3S, olisoscil,PAT-505, PAT-048, PBI-4547, pegylated iloprost, PF-05221304, pioglitazone, pirfenidone, PRI-724, PX20606, Px-102, PX-L603, PX-L493, PXS-4728A, PZ-235, RCYM-001, RDX-009, empagliflozin, RG-125 (AZD4076), RPI-500, saroglitazar, semaglutide, SH-2442, sintilimab, solithromycin, sotagliflozin, statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), symbiosis, TCM-606F, TEV-45478, TQA-3526, TQA-3563, terbutaline (MN-001), TLY-012, TRX-318, TVB-2640, UD-009, ursodeoxycholic acid, VBY-376, VBY-825, VK-2809, vismodegib, fosfomycin trometamol hydrate (SHP-626), VVP-100X, WAV-301, WNT-974, XEN-103, XRx-117, ZGN-839, ZG-5216, ZSYM-008, ZYSM-007.

[0612] In some embodiments, the compounds of the present disclosure are combined with an anti-obesity agent, which includes but is not limited to peptide YY or its analogs, neuropeptide Y receptor type 2 (NPYR2) agonists, NPYR1 or NPYR5 antagonists, cannabinoid receptor type 1 (CB1R) antagonists, lipase inhibitors (e.g., orlistat), human islet peptide (HIP), melanocortin receptor 4 agonists (e.g., semaglutide), 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), a combination of norepinephrine / dopamine reuptake inhibitors and opioid receptor antagonists (e.g., a combination of bupropion and naltrexone), GDF-15 analogs, sibutramine, cholecystokinin agonists, amylin and its analogs (e.g., pramlintide), leptin and its analogs (e.g., metroleptin), serotonergic agents (e.g., lorcaserin), methionine aminopeptidase 2 (MetAP2) inhibitors (e.g., beloranib or ZGN-1061), benzphetamine, diethylpropion, benzphetamine, SGLT2 inhibitors (e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, togliflozin, sergliflozin etabonate, repagliflozin etabonate or ertugliflozin), SGLTL1 inhibitors, dual SGLT2 / SGLT1 inhibitors, fibroblast growth factor receptor (FGFR) modulators, AMP-activated protein kinase (AMPK) activators, biotin, MAS receptor modulators or glucagon receptor agonists (alone or in combination with another GLP-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.

[0613] 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):

[0614]

[0615]

[0616] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or tautomer thereof.

[0617] 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):

[0618]

[0619] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.

[0620] 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):

[0621]

[0622] or a pharmaceutically acceptable salt thereof.

[0623] 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 THRβ agonist is a compound of formula (VI):

[0624]

[0625] or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof.

[0626] VII. Methods of Treatment

[0627] In some embodiments, the compounds of the present disclosure can be used in methods for treating and / or preventing GLP-1R-mediated diseases or disorders. In some embodiments, the methods for treating and / or preventing GLP-1R-mediated diseases or disorders include administering to a subject in need thereof a pharmaceutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0628] In some embodiments, the disease or disorder includes liver disease or related diseases or disorders, 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 disorder includes metabolic diseases or related diseases or disorders, such as diabetes, obesity or cardiometabolic diseases.

[0629] GLP-1R agonists are currently being studied in the context of certain diseases and disorders, 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 combination with the treatment of diabetes, has been reported to show favorable improvements in the outcomes of NASH subjects.

[0630] In some embodiments, the present disclosure relates to the use of a compound of formula (I) or other formulas described herein or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating a GLP-1R-mediated disease or disorder, such as a liver disease or a metabolic disease. For example, some embodiments provide a compound of formula (I) or other formulas described herein or a pharmaceutically acceptable salt thereof or its use for treating and / or preventing chronic intrahepatic or some forms of extrahepatic cholestatic disorders, liver fibrosis, acute digestive intrahepatic cholestatic disorders, obstructive or chronic inflammatory disorders caused by improper bile components, gastrointestinal disorders associated with reduced dietary fat intake and fat-soluble dietary vitamins, inflammatory bowel disease, lipid and lipoprotein diseases, type II diabetes, and clinical complications of type I and type II diabetes, disorders and diseases caused by chronic steatosis and fibrotic degeneration of organs due to forced accumulation of lipids and especially triglycerides and subsequent activation of profibrotic pathways, obesity and metabolic syndrome (a syndrome combining dyslipidemia, diabetes, and an abnormally high body mass index), acute myocardial infarction, acute stroke, thrombi occurring as an endpoint of chronic obstructive atherosclerosis, persistent infections caused by intracellular bacteria or parasitic protozoa, non-malignant hyperproliferative diseases, malignant hyperproliferative diseases (such as colorectal adenocarcinoma and hepatocellular carcinoma), hepatic steatosis and related syndromes, liver failure or liver dysfunction as a result of chronic liver disease or surgical hepatectomy, hepatitis B infection, hepatitis C infection, and / or cholestatic and fibrotic effects associated with alcohol-induced cirrhosis or viral forms of hepatitis, type I 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, eating disorders, sleep apnea, weight gain, sugar craving, dyslipidemia, hyperinsulinemia, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, left ventricular hypertrophy, Parkinson's disease, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, angina, premenstrual syndrome, thrombosis, atherosclerosis, impaired glucose metabolism, or restenosis.

[0631] In some embodiments, a method for treating and / or preventing non-alcoholic fatty liver disease (NAFLD) comprises administering to a subject in need thereof a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0632] The present disclosure also relates to a compound according to formula (I) or other formulas described herein, or a pharmaceutical composition comprising said compound, for the prophylactic and post-traumatic treatment of cardiovascular diseases 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 a cardiovascular disease comprises administering to a subject in need thereof a compound according to formula (I) or other formulas described herein.

[0633] The present disclosure also relates to a compound or a pharmaceutical composition for treating and / or preventing obesity and related diseases such as metabolic syndrome (a syndrome combining dyslipidemia, diabetes and an abnormally high body mass index), which metabolic syndrome can be overcome by GLP1R-mediated reduction of serum triglycerides, blood glucose and increased insulin sensitivity, and GLP1R-mediated weight loss. In some embodiments, a method for treating and / or preventing a metabolic disease comprises administering to a subject in need thereof a compound according to formula (I) or other formulas described herein.

[0634] In another embodiment, the compounds or pharmaceutical compositions of the present disclosure can be used for preventing and / or treating clinical complications of type I and type II diabetes. Examples of such complications include diabetic nephropathy, diabetic retinopathy, diabetic neuropathy or peripheral arterial occlusive disease (PAOD). The present disclosure also encompasses other clinical complications of diabetes. In some embodiments, a method for treating and / or preventing complications of type I and type II diabetes comprises administering to a subject in need thereof a compound according to formula (I) or other formulas described herein.

[0635] Furthermore, the disorders and diseases caused by the forced accumulation of lipids and / or triglycerides and the subsequent activation of pro-fibrotic pathways leading to chronic steatosis and fibrotic degeneration of organs can also be prevented and / or treated by administering the compounds or pharmaceutical compositions of the present disclosure. Such disorders and diseases can include NASH and chronic cholestatic disorders in the liver, glomerulosclerosis and diabetic nephropathy in the kidney, macular degeneration and diabetic retinopathy in the eye, and neurodegenerative diseases such as Alzheimer's disease in the brain or diabetic neuropathy in the peripheral nervous system. In some embodiments, a method for treating and / or preventing disorders and diseases caused by the forced accumulation of lipids and / or triglycerides and the subsequent activation of pro-fibrotic pathways leading to chronic steatosis and fibrotic degeneration of organs comprises administering to a subject in need thereof a compound according to formula (I). In some embodiments, a method for treating and / or preventing NASH comprises administering to a subject in need thereof a compound according to formula (I) or other formulas described herein.

[0636] The present disclosure also provides a pharmaceutical composition for treating a GLP-1R-mediated disease or disorder as described herein, the pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0637] The present disclosure also describes the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof for preparing a medicament for treating a GLP-1R-mediated disease or disorder. The medicament mentioned herein can be prepared by conventional methods, including in combination with a compound of the present disclosure and a pharmaceutically acceptable carrier.

[0638] Also disclosed is a compound of the present disclosure or a pharmaceutically acceptable salt thereof for treating a GLP-1R-mediated disease or disorder. Also disclosed is a compound of the present disclosure or a pharmaceutically acceptable salt thereof for preventing a GLP-1R-mediated disease or disorder.

[0639] VIII. Examples

[0640] Many general references providing well-known chemical synthesis schemes and conditions that can be used to synthesize the disclosed compounds are available (see, for example, Smith, “March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure”, 7th Edition, Wiley-Interscience, 2013).

[0641] The 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 phase and reverse phase as well as ion resins. For example, the compounds disclosed in the present invention can be purified by silica gel and / or alumina chromatography. See, for example, “Introduction to Modern Liquid Chromatography”, 2nd Edition, L.R. Snyder and J.J. Kirkland, John Wiley and Sons, 1979; and “Thin Layer Chromatography”, edited by E. Stahl, Springer-Verlag, New York, 1969.

[0642] In any method for preparing a subject compound, it may be necessary to protect any sensitive or reactive groups on any molecule in the relevant molecule. This can be achieved with conventional protecting groups as described in standard works such as T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", 4th Edition, Wiley, New York, 2006. The protecting groups can be removed using methods known in the art at a convenient subsequent stage.

[0643] Exemplary chemical entities of methods useful for practicing embodiments will now be described by reference to illustrative synthetic schemes of general preparations herein and specific examples below. Those skilled in the art will recognize that, in order to obtain the various compounds herein, the starting materials may be appropriately selected such that the ultimately desired substituents will be carried through reaction schemes with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary to use a suitable group at the position of the ultimately desired substituent, which suitable group may be carried through a reaction scheme and optionally replaced with the desired substituent. In addition, those skilled in the art will recognize that the transformations shown in the following schemes may be carried out in any order compatible with the functionality of the side groups. Each reaction depicted in the general scheme can be run at a temperature of from about 0 °C to the reflux temperature of the organic solvent used.

[0644] 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 individual steps described herein may be combined. It should also be understood that separate batches of the compounds may be combined and then continued in the next synthetic step.

[0645] In the following example descriptions, specific embodiments are described. These embodiments are described in sufficient detail to enable those skilled in the art to practice certain embodiments of the disclosure. Other embodiments may be utilized and logical and other changes may be made without departing from the scope of the disclosure. The embodiments also relate to methods and intermediates for preparing the subject compounds or their pharmaceutically acceptable salts. Accordingly, the following description is not intended to limit the scope of the disclosure.

[0646] In some embodiments, the disclosure generally provides a particular enantiomer or diastereomer as the desired product, although the stereochemistry of the enantiomer or diastereomer is not determined in all cases. When the stereochemistry of a particular stereocenter in an enantiomer or diastereomer is not determined, the compound is drawn without showing any stereochemistry at that particular stereocenter, even though the compound may be substantially enantiomerically pure or diastereomerically pure.

[0647] Representative syntheses of the compounds of the disclosure are described in the following schemes and the following examples.

[0648] The compounds detailed in the examples were synthesized according to the general synthetic method described below. Unless otherwise specified, ChemDraw version 18.1.0.535 (PerkinElmer Informatics, Inc.) was used to name the compounds.

[0649] Abbreviations

[0650] Certain abbreviations and acronyms are used to describe experimental details. Although most of these may be understood by those skilled in the art, Table 1 contains a list of many of these abbreviations and acronyms.

[0651] Table 1. List of Abbreviations and Acronyms 。

[0652]

[0653]

[0654] A. Synthesis of Intermediates

[0655] Preparation of Intermediate I-1 :

[0656]

[0657] 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 / hexane) 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).

[0658] 4-(4-Bromobenzo[d][1,3]dioxol-2-yl)-3-fluorobenzonitrile: 4-(Dibromomethyl)-3-fluorobenzonitrile (744 mg, 2.54 mmol) and 3-bromobenzene-1,2-diol (400 mg, 2.12 mmol) were added to a 40 mL vial. 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 showed 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) δ 7.76 (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).

[0659] Preparation of Intermediate I-2 :

[0660]

[0661] 2-(4-Bromo-2-methylbenzo[d][1,3]dioxol-2-yl)-5-chloropyridine: 5-Chloro-2-ethynylpyridine (1 g, 7.27 mmol), 3-bromobenzene-1,2-diol (1.37 g, 7.27 mmol), and dodecacarbonyltriruthenium (139 mg, 0.218 mmol) were added to a 40 mL vial. 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 (rinsed with EtOAc), and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel chromatography (eluent: EtOAc / hexane) 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).

[0662] Preparation of Intermediate I-3 :

[0663]

[0664] 4-Bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxole: To a 250 mL RBF was added 1-(4-chloro-2-fluorophenyl)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 h. Subsequently, the mixture was cooled and then loaded onto silica gel dry. 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).

[0665] Preparation of Intermediate I-4 :

[0666]

[0667] 5-Bromo-3a-(4-chlorophenyl)-1,2,3,3a-tetrahydrobenzo[d]pyrrolo[2,1-b] oxazole: To a 40 mL vial was added 4-chloro-1-(4-chlorophenyl)butan-1-one (462 mg, 2.13 mmol) and 2-amino-6-bromophenol (400 mg, 2.13 mmol). The mixture was dissolved in pyridine (5 mL). The vial was sealed and stirred at 50 °C for 4 h and then 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).

[0668] Preparation of Intermediate I-5 :

[0669]

[0670] 5-Bromo-3a-(4-chlorophenyl)-3,3a-dihydrobenzo[d]pyrrolo[2,1-b] oxazol-1(2H)-one: 4-(4-Chlorophenyl)-4-oxobutyric 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 h. Subsequently, the mixture was cooled and then loaded onto silica gel dry. 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).

[0671] Preparation of Intermediate I-6 :

[0672]

[0673] Methyl 4-amino-3-(((1-(cyanomethyl)cyclopropyl)methyl)amino)benzoate: Diisopropylethylamine (3.1 mL, 17.6 mmol) and 2-(1-(aminomethyl)cyclopropyl)acetonitrile hydrochloride (567 mg, 3.87 mmol) were added to a solution of methyl 3-fluoro-4-nitrobenzoate (700 mg, 3.52 mmol) in THF (10 mL) and DMF (5 mL). The resulting solution was heated to 70 °C for 24 h. After completion, the solvent was removed and the resulting residue was dissolved in EtOAc (50 mL), washed with brine (10 mL), concentrated, and carried on 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), then 10% palladium on carbon (368 mg, 0.346 mmol) was added. The resulting suspension was stirred under a hydrogen balloon at room temperature for 16 h. 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 + ).

[0674] Preparation of Intermediate I-7

[0675]

[0676] Methyl 4-amino-3-(2-methoxyethylamino)benzoate: To a solution of methyl 3-fluoro-4-nitrobenzoate (50.0 g, 251 mmol) in THF (400 mL) was added diisopropylethylamine (70.0 mL, 402 mmol) and 2-methoxyethylamine (34.9 mL, 402 mmol). The resulting solution was heated to 55 °C for 6 hours. After completion, the solvent was removed and the resulting residue was dissolved in EtOAc (150 mL), washed with brine (30 mL), concentrated, and carried on without further purification. Then methyl 3-(2-methoxyethylamino)-4-nitrobenzoate (20.0 g, 78.7 mmol) was dissolved in EtOAc:EtOH (1:1, 140 mL), and then 10% palladium on carbon (5.02 g, 4.72 mmol) was added. The resulting suspension was stirred under a hydrogen balloon at room temperature for 16 hours. The reaction mixture was filtered through celite, washed with EtOAc (100 mL), and concentrated to give the desired product I-7 without further purification. ES / MS: 225.2 (M+H + )。

[0677] Preparation of Intermediate I-8

[0678]

[0679] 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)methylamine; 2,2,2-trifluoroacetic acid in place of 2-methoxyethylamine. ES / MS: 253.3 (M+H + )。

[0680] Preparation of Intermediate I-9

[0681]

[0682] 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 2-methoxyethylamine. ES / MS: 237.0 (M+H + )。

[0683] Preparation of Intermediate I-10 :

[0684]

[0685] Ethyl 3,5-difluoro-4-nitrobenzoate: Dissolve ethyl 4-amino-3,5-difluorobenzoate (5.00 g, 24.9 mmol) in acetic acid (50.0 mL). Add sulfuric acid (12.1 M, 2.05 mL, 24.9 mmol) and hydrogen peroxide (30% aqueous solution, 46.7 mL, 74.6 mmol) successively and heat the reaction to 100 °C for 1 hour. Thereafter, cool the reaction to room temperature and then slowly pour it into 300 mL of ice water while vortexing. Then dilute the mixture with EtOAc (200 mL), transfer it to a separatory funnel, and collect the organic phase. Extract the aqueous phase with 2 × 100 mL of EtOAc, and dry and concentrate the combined organic matter in vacuo. Purify the residue by column chromatography (EtOAc / hexane gradient) to obtain the product. 4 Dry over MgSO

[0686] (S)-Ethyl 3-fluoro-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoate: Dissolve ethyl 3,5-difluoro-4-nitrobenzoate (2.50 g, 10.8 mmol) and (S)-oxetan-2-ylmethanamine (989 mg, 11.4 mol) in tetrahydrofuran (12.0 mL) and N,N-dimethylformamide (6.0 mL), and add N,N-diisopropylethylamine (9.42 mL, 54.1 mmol). Heat the reaction to 50 °C for 16 hours. Thereafter, concentrate the reaction in vacuo and purify the residue by column chromatography (0 - 25% EtOAc / hexane) to obtain the product. ES / MS: 299.2 (M+H + )

[0687] (S)-Ethyl 4-amino-3-fluoro-5-((oxetan-2-ylmethyl)amino)benzoate (I-10): (S)-Ethyl 3-fluoro-4-nitro-5-((oxetan-2-ylmethyl)amino)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. Then palladium on carbon (10 wt% loading, 785 mg, 0.74 mmol) was added and bubbling was continued for 5 minutes. Then hydrogen was bubbled through the solution for one minute, and the reaction was then placed under a hydrogen atmosphere balloon for 21 hours. Thereafter, the reaction was stopped and the mixture was filtered through Celite. The filter was washed with EtOAc (2 × 20 mL) and methanol (2 × 10 mL), and the filtrate was concentrated in vacuo to give (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).

[0688] Preparation of Intermediate I-11 :

[0689]

[0690] Methyl 5-amino-6-(((1-(fluoromethyl)cyclopropyl)methyl)amino)picolinate: To a solution of methyl 6-chloro-5-nitropyridine-2-carboxylate (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. To the solution was added iron (2.4 g, 43.2 mmol) and ammonium chloride (3.3 g, 61.8 mmol). 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 I-11, which was used without further purification. ES / MS: 254.2 (M+H + ).

[0691] Preparation of Intermediate I-12 :

[0692]

[0693] 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. Upon 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 MgSO 4 and filtered and concentrated. The crude residue was purified by column chromatography (0-50% EtOAc / hexane) to give the title compound.

[0694] (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-ylmethanamine (0.12 mL, 1.2 mmol). The resulting solution was heated to 60 °C for 4 h. After 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 carried on without further purification. ES / MS: 327.9 (M+H + ).

[0695] (S)-tert-Butyl 4-amino-2-fluoro-3-((oxetan-2-ylmethyl)amino)benzoate: (S)-tert-Butyl 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. Then iron powder (323 mg, 5.79 mmol) was added to the reaction mixture and the reaction was heated to 60 °C. After 3 h, 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 MgSO 4 , filtered, and concentrated. Product I-12 was used without further purification. ES / MS: 298.0 (M+H + )

[0696] Preparation of Intermediate I-13 :

[0697]

[0698] 1-(tert-Butyl) 3-methyl 2-(5-bromo-3-fluoropyridin-2-yl)malonate: To a 40 mL vial was added tert-butyl methyl malonate (898 mg, 5.16 mmol) and DMF (10 mL). The solution was cooled to 0 °C, and NaH (60% in mineral oil, 237 mg, 6.19 mmol) was added. The reaction mixture was stirred at RT for 20 min, and gas evolution was observed. Then the reaction was 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 formation of the product. The mixture was partitioned between EtOAc (50 mL) and water (20 mL), and the organic layer was separated, dried over MgSO 4Dry and concentrate under reduced pressure to obtain 1-(tert-butyl) 3-methyl 2-(5-bromo-3-fluoropyridin-2-yl)malonate, which is directly carried forward in the next step. ES / MS: 348.5 (M+H + ).

[0699] Methyl 2-(5-bromo-3-fluoropyridin-2-yl)acetate: Add 1-(tert-butyl) 3-methyl 2-(5-bromo-3-fluoropyridin-2-yl)malonate (1.4 g, 4.02 mmol) to a 100 mL RBF, and add trifluoroacetic acid (10 mL) and CH 2 Cl 2 (10 mL). Stir the mixture overnight at RT. LCMS shows the formation of the product. Evaporate the solvent under reduced pressure to obtain the product as the TFA salt. ES / MS: 248.3 (M+H + )

[0700] 2-(5-Bromo-3-fluoro-2-pyridinyl)acetic acid (I-13): Add methyl 2-(5-bromo-3-fluoropyridin-2-yl)acetate (trifluoroacetate) (1.2 g, 3.31 mmol) to a 40 mL RBF. Add methanol (10 mL) and THF (5 mL), then add 1 M NaOH (6.63 mL, 6.63 mmol). Stir the reaction mixture overnight at 70 degrees. Concentrate the mixture under reduced pressure, and dissolve the residue in water and acidify with 1 N HCl. Extract the resulting mixture 3 times with a mixture of DCM and methanol. Dry the combined organic layers over MgSO 4 dry, filter and concentrate under reduced pressure. The crude I-13 can be carried forward without further purification.

[0701] ES / MS: 234.159 (M+H + )

[0702] Preparation of Intermediate I-14 :

[0703]

[0704] Methyl 4-[[2-(4-bromo-2-fluorophenyl)acetyl]amino]-3-(2-methoxyethylamino)benzoate: To a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (1.00 g, 4.29 mmol) in DMF (20.0 mL) was added methyl 4-amino-3-(2-methoxyethylamino)benzoate (I-7) (1.18 g, 5.28 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.96 g, 5.15 mmol), then N,N-diisopropylethylamine (3.74 mL, 21.5 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. The reaction was concentrated in vacuo, 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 on without further purification. ES / MS m / z: 583.5 (M+H + )

[0705] Methyl 2-[(4-bromo-2-fluorophenyl)methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate: The crude product methyl 4-[[2-(4-bromo-2-fluorophenyl)acetyl]amino]-3-(2-methoxyethylamino)benzoate (1.89 g, 4.29 mmol) from the previous step was dissolved in AcOH (40.0 mL) and the reaction mixture was heated to 60 °C for 2 h. Then the reaction mixture was concentrated in vacuo, the crude residue was dissolved in DCM and washed with saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with DCM (2X). The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by column chromatography (0 - 100% EtOAc / hexanes) to afford the title compound. ES / MS m / z: 421.9 (M+H + )

[0706] Methyl 2-[[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate: To a vial was added methyl 2-[(4-bromo-2-fluorophenyl)methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylate (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-dioxaborolane (145 mg, 0.570 mmol), (1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (33.6 mg, 0.0475 mmol) and potassium acetate (0.140 g, 1.42 mmol). 1,4-Di Alkane (4.80 mL) and the reaction was heated to 100 °C and maintained for 24 h. The reaction mixture was filtered through diatomaceous earth, 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 + )。

[0707] Preparation of Intermediate I-15 :

[0708]

[0709] 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 in the manner described for intermediate I-2 using 5-ethynylthiophene-2-carbonitrile instead of 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).

[0710] Preparation of Intermediate I-16 :

[0711]

[0712] 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 in the manner described for intermediate I-2 using 2-ethynyl-1-methyl-1H-benzo[d]imidazole instead of 5-chloro-2-ethynylpyridine. ES / MS: 346.2 (M+H + )。

[0713] Preparation of Intermediate I-17 :

[0714] 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 equiv). The mixture was heated at 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 afford 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).

[0715] 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-di ane (30 mL) together with potassium propionate (3.59 g, 0.0320 mol), bis(diphenylphosphino)ferrocene)palladium(II) dichloride (1.19 g, 0.00160 mol) and bis(pinacolato)diboron (3.52 g, 0.0139 mol). The mixture was capped and bubbled with nitrogen for five minutes. Then, the mixture was heated at 110 °C for 1 h. Thereafter, the reaction cap was opened and bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.594 g, 0.0008 mol) and 2 M aqueous sodium bicarbonate (10.7 mL, 0.0214 mol) 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 (5.5 g, 0.0160 mol) was added. Then, the mixture was capped and heated at 95 °C for 3 h. LCMS showed complete conversion of the boronate. The mixture was then cooled to room temperature, filtered through celite and concentrated in vacuo. The mixture was directly loaded onto a column and eluted with a slow gradient of 0-30% EtOAc / hexanes to afford an oil. LC-MS (ESI) m / z 449.0 (M+H).

[0716] 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-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]-2,6-difluorophenyl]acetate (1.50 g, 0.00334 mol) was dissolved in 15 mL of acetonitrile. Then, 0.3 M lithium hydroxide solution (0.0167 mol, 16.7 mL) was 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 addition of water and EtOAc. The mixture was extracted 3 times with EtOAc, dried over magnesium sulfate and concentrated under reduced pressure to give 2-[4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]-2,6-difluorophenyl]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).

[0717] Preparation of Intermediate I-18 :

[0718] 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+).

[0719] Preparation of Intermediate I-19 :

[0720] 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+).

[0721] Preparation of Intermediates I-20 and I-21 :

[0722] 2-(4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorophenyl)acetic acid I-17, as a mixture of two stereoisomers, was separated by chiral SFC (OJ-H column with 5% MeOH cosolvent) to give two different stereoisomers.

[0723] 2-(4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorophenyl)acetic acid: ES / MS: 436.1.

[0724] 2-(4-(2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,6-difluorophenyl)acetic acid: ES / MS: 436.1.

[0725] Preparation of Intermediate I-22 :

[0726] 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 and washed with 5% LiCl 2× and brine. The organic extract was dried over sodium sulfate to give the title product. ES / MS m / z: 222 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.26 (dd, J = 8.7, 1.7 Hz, 1H), 8.23 (s, 1H), 7.21 (d, J = 1.7 Hz, 1H), 6.89 (dt, J = 8.8, 1.5 Hz, 1H), 3.71 (dd, J = 5.6, 4.8 Hz, 2H), 3.51 (q, J = 5.2 Hz, 2H), 3.45 (d, J = 1.0 Hz, 3H).

[0727] 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 overnight at 110 °C. The mixture was diluted with EtOAc and washed with 5% LiCl 3 × 50 mL. The aqueous layer was extracted twice with 100 mL of EtOAc. The combined organic extracts were dried over sodium sulfate to give the title product as an oil. ES / MS m / z: 265.2 (M+H+); 1H NMR (400 MHz, MeOD) δ 8.32 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.35 (dd, J = 8.9, 1.8 Hz, 1H), 3.82–3.69 (m, 2H), 3.66 (t, J = 5.2 Hz, 2H), 3.46 (s, 3H), 3.01 (d, J = 0.5 Hz, 4H).

[0728] 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 overnight at room temperature under a hydrogen balloon. The mixture was filtered through a Celite plug 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+).

[0729] Preparation of Intermediate I-23 :

[0730] tert-Butyl 2-(6-chloro-2-methoxypyridin-3-yl)acetate: In a 40 mL reaction vial, a mixture of 3-bromo-6-chloro-2-methoxypyridine (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 3 times with Ar / vac. THF (10 mL) was added and degassed 3 times with Ar / vac. To this was added bromo-(2-tert-butoxy-2-oxo-ethyl)zinc (0.500 M, 13.5 mL, 6.74 mmol) and the mixture was heated at 65 °C for 3 h. The reaction was diluted with EtOAc and brine. The organic extract was dried over sodium sulfate and purified by flash chromatography (eluent: EtOAc / hexanes) to give the title compound. ES / MS m / z: 258.2 (M+H+); 1H NMR (400 MHz, CDCl3) δ 7.43 (dt, J = 7.6, 0.7 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 3.97 (s, 3H), 3.48 (s, 2H), 1.46 (s, 9H).

[0731] 2-(6-Chloro-2-methoxypyridin-3-yl)acetic acid: To a solution of tert-butyl 2-(6-chloro-2-methoxy-3-pyridyl)acetate (250 mg, 0.970 mmol) in DCM (5 mL) was added TFA (0.750 mL). The reaction was stirred overnight at room temperature, concentrated to dryness, and used in the next step without further purification. ES / MS m / z: 202.2 (M+H+).

[0732] Methyl 4-(2-(6-chloro-2-methoxypyridin-3-yl)acetamido)-3-((2-methoxyethyl)amino)benzoate: To a solution of 2-(6-chloro-2-methoxypyridin-3-yl)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 reaction was stirred overnight at room temperature. The reaction was diluted with EtOAc and washed with 5% LiCl, saturated NaHCO 3 and brine. The organic extract was dried over sodium sulfate and concentrated. Assuming complete conversion, the crude residue was carried on without further purification. ES / MS m / z: 408.2 (M+H+).

[0733] Methyl 2-[(4-bromo-2,6-difluorophenyl)methyl]-3-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate (I-23): A solution of methyl 4-[[2-(6-chloro-2-methoxypyridin-3-yl)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 h. The mixture was concentrated and chromatographed (eluent: EtOAc / hexane) to afford the title compound. ES / MS m / z: 390.2 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.11 (dd, J = 1.6, 0.7 Hz, 1H), 7.99 (dd, J = 8.5, 1.6 Hz, 1H), 7.73 (dd, J = 8.5, 0.6 Hz, 1H), 7.46–7.38 (m, 1H), 6.87 (d, J = 7.7 Hz, 1H), 4.39 (t, J = 5.4 Hz, 2H), 4.30–4.25 (m, 2H), 4.00 (s, 3H), 3.97 (s, 3H), 3.65 (t, J = 5.4 Hz, 2H), 3.26 (s, 3H).

[0734] Preparation of Intermediate I-24 :

[0735] 2-Chloro-5,5-dimethoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulene: 3-(2-Chloro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ylidene)propan-2-one (1 g, 5.14 mmol), methanol (10 mL), HCl (2.5 M solution in methanol, 2.05 mL, 1.03 mmol) and trimethyl orthoformate (1.69 mL, 12.5 mmol) were added to a 100 mL vial. The solution was heated at 70 °C for 24 h. Subsequently, the mixture was cooled to room temperature and concentrated under reduced pressure. The crude material was diluted with diethyl ether (50 mL) and washed with 50% aqueous NaHCO 3 solution (1 × 20 mL). The aqueous layer was back-extracted with diethyl ether (1 × 50 mL) and the combined organic layers were dried over MgSO 4 and filtered and concentrated under reduced pressure to afford the desired product 2-chloro-5,5-dimethoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulene, which was carried on to the next step.

[0736] 4-Bromo-2'-chloro-6',7',8',9'-tetrahydrospiro[benzo[d][1,3]dioxole-2,5'-benzo[7]annulene]: 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) were added to a 100 mL vial. The mixture was dissolved in toluene (10 mL), and the solution was refluxed under Dean-Stark conditions overnight. Subsequently, the mixture was cooled, loaded onto silica gel dry, and purified by silica gel chromatography (eluent: EtOAc / hexane) to give the desired product I-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).

[0737] Preparation of Intermediate I-25 :

[0738] 4'-Bromo-8-chloro-3,4-dihydro-2H-spiro[benzo[b] heptalene-5,2'-benzo[d][1,3]dioxole] (I-25): 4'-Bromo-8-chloro-3,4-dihydro-2H-spiro[benzo[b] heptalene-5,2'-benzo[d][1,3]dioxole] was prepared in the same manner as for I-24 using 8-chloro-3,4-dihydrobenzo[b] heptalen-5(2H)-one in place of 3-2-chloro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-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).

[0739] Preparation of Intermediate I-26 :

[0740] 4'-Bromo-8-chloro-3,4-dihydro-2H-spiro[benzo[b] heptopyran-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 by replacing 3-2-chloro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one with 6-chloro-3,4-dihydronaphthalen-1(2H)-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).

[0741] Preparation of Intermediate I-27 :

[0742] 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 by replacing 3-2-chloro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one with 1-(4-chloro-2-fluorophenyl)propan-1-one.

[0743] Preparation of Intermediate I-28 :

[0744] 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 by replacing 1-(4-chloro-2-fluorophenyl)ethan-1-one with 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).

[0745] Preparation of Intermediate I-29 :

[0746] 4-Chloro-1-(diethoxyphosphorylmethyl)-2-fluoro-benzene: 1-(Bromomethyl)-4-chloro-2-fluoro-benzene (3.3 g, 14.8 mmol) and triethyl phosphite (2.53 mL, 14.8 mmol) (gas evolution) were added to a 40 mL vial (vented to the atmosphere). The mixture was heated at 100 °C for 3 h. The mixture was cooled and used directly in the next step.

[0747] (E)-1-Bromo-3-(4-chloro-2-fluorostyryl)-2-fluoro-benzene: THF (100 mL) was added to a 250 mL vial containing 4-chloro-1-(diethoxyphosphorylmethyl)-2-fluoro-benzene (4 g, 14.3 mmol), 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 min. 3-Bromo-2-fluoro-benzaldehyde (2.89 g, 14.3 mmol) was added, and the mixture was stirred at room temperature for 48 h. The mixture was diluted with EtOAc (100 mL) and washed with saturated NH 4 Cl aqueous solution (1 × 50 mL). The organic layer was dried over MgSO 4 and filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (eluent: EtOAc / hexane) 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).

[0748] 1-(3-Bromo-2-fluorophenyl)-2-(4-chloro-2-fluorophenyl)ethane-1,2-diol: tert-Butanol (12 mL), water (10 mL), acetone (10 mL), citric acid (50% aqueous solution, 2.3 mL), potassium osmate(IV) dihydrate (5.6 mg, 0.015 mmol), and 4-methylmorpholine N-oxide (390 mg, 3.3 mmol) were added to a 100 mL vial containing (E)-1-bromo-3-(4-chloro-2-fluorostyryl)-2-fluoro-benzene (1 g, 3.03 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 NH 4 Cl aqueous solution was added. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over MgSO 4Dry, filter, and concentrate under reduced pressure. Purify the crude material by silica gel chromatography (eluent: EtOAc / hexane) to obtain 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).

[0749] 1-Bromo-7-chloro-4b,9b-dihydrobenzofuro[3,2-b]benzofuran (I-29): Add THF (5 mL) 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), and cool the mixture to 0 °C under a nitrogen atmosphere. Add potassium tert-butoxide (1 M in THF, 0.825 mL, 0.825 mmol), stir the mixture for 1 hour, and warm to room temperature. Quench the mixture with water (2 mL) and dilute with EtOAc (20 mL). Separate the layers, and extract the aqueous layer with EtOAc (2 × 10 mL). Dry the combined organic layers over MgSO 4 Dry, filter, and concentrate under reduced pressure. Purify the crude material by silica gel chromatography (eluent: EtOAc / hexane) to obtain the desired product.

[0750] Preparation of Intermediate I-30 :

[0751] 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 similar manner to I-11 using 2-(1-(aminomethyl)cyclopropyl)acetonitrile hydrochloride instead of [1-(fluoromethyl)cyclopropyl]methylamine; 2,2,2-trifluoroacetic acid. ES / MS: 261.2 (M+H+).

[0752] Preparation of Intermediates I-31 and I-32 :

[0753] 2-(4-Bromo-2-methyl-1,3-benzodioxol-2-yl)-5-chloropyridine (I-31 and I-32): Separate 2-(4-bromo-2-methyl-1,3-benzodioxol-2-yl)-5-chloropyridine (I-2) by chiral SFC (AD-H column with 5% IPA-NH3 co-solvent) to obtain two different stereoisomers.

[0754] 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).

[0755] 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).

[0756] Preparation of Intermediate I-33 :

[0757] 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 in the same manner as described for I-6 by replacing 2-(1-(aminomethyl)cyclopropyl)acetonitrile hydrochloride with (4-ethyl-4H-1,2,4-triazol-3-yl)methylamine. ES / MS: 276.2 (M+H+).

[0758] Preparation of Intermediate I-34 :

[0759] 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 in the same manner as described for I-6 by replacing 2-(1-(aminomethyl)cyclopropyl)acetonitrile hydrochloride with (4-Ethyl-4H-1,2,4-triazol-3-yl)methylamine hydrochloride and ES / MS: 248.2 (M+H+).

[0760] Preparation of Intermediates I-35 and I-36 :

[0761] 4-Bromo-2-(4-chloro-2-fluorophenyl)isoindolin-1-one: Methyl 3-bromo-2-(bromomethyl)benzoate (216 mg, 0.70 mmol) was added to a solution of 4-chloro-2-fluoroaniline (100 g, 0.69 mmol) in acetic acid (1.37 mL). 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 2 column chromatography (eluent: EtOAc / hexane) to give 4-bromo-2-(4-chloro-2-fluorophenyl)isoindolin-1-one (I-35). ES / MS m / z: 341.954 (M + H+).

[0762] 4-Bromo-2-(4-chloro-2-fluorophenyl)isoindoline: Borane-tetrahydrofuran complex (1 M solution in THF, 1 mL, 1 mmol) was added to 4-bromo-2-(4-chloro-2-fluorophenyl)isoindolin-1-one (36 mg, 0.10 mmol). The resulting mixture was stirred at room temperature for 3 days, then diluted with methanol. The mixture was then concentrated to dryness, and the crude material was purified by SiO 2 column chromatography (eluent: EtOAc / hexane) to give 4-bromo-2-(4-chloro-2-fluorophenyl)isoindoline (I-36). ES / MS m / z: 326.019 (M + H+).

[0763] Preparation of Intermediate I-37 :

[0764] 7-Bromo-2-(4-chloro-2-fluorophenyl)isoindolin-1-one: Methyl 2-bromo-6-(bromomethyl)benzoate (270 mg, 0.88 mmol) was added to a solution of 4-chloro-2-fluoroaniline (106 g, 0.73 mmol) in acetic acid (1.5 mL). 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 2 column chromatography (eluent: EtOAc / hexane) to give 7-bromo-2-(4-chloro-2-fluorophenyl)isoindolin-1-one (I-37). ES / MS m / z: 342.074 (M + H+).

[0765] Preparation of Intermediate I-38 :

[0766] 2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-ol: p-Toluenesulfonic acid (190 mg, 1.0 mmol) was added 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). The resulting mixture was heated to reflux using a Dean–Stark water separator for 2.5 days. The resulting mixture was concentrated to dryness, and the crude material was then purified by SiO 2 column chromatography (eluent: EtOAc / hexane) to afford 2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-ol. 1H NMR (400 MHz, CDCl3) δ 7.61–7.52 (m, 1H), 7.20–7.10 (m, 2H), 6.73 (t, J = 8.1 Hz, 1H), 6.54–6.47 (m, 2H), 5.09 (s, 1H), 2.10 (d, J = 1.2 Hz, 3H).

[0767] 2-(4-Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl trifluoromethanesulfonate: Trifluoromethanesulfonic anhydride (1 M solution in CH 2 Cl 2 Cl 2 , 0.24 mL, 0.24 mmol) and triethylamine (0.06 mL, 0.43 mmol) were added 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) at -78 °C (external temperature, acetone / CO 2 Cl 2 bath). The resulting mixture was stirred at -78 °C for 20 minutes and slowly warmed to room temperature over 40 minutes. The resulting mixture was diluted with CH 2 Cl 2 and washed with aqueous sodium bicarbonate solution. The aqueous layer was back-extracted with CH 2 Cl and concentrated to dryness. The crude material was then purified by SiO 2 column chromatography (eluent: EtOAc / hexane) to afford 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).

[0768] Preparation of Intermediate I-39 :

[0769] 4-(1,1-Dimethoxyethyl)-3-fluorobenzonitrile: Trimethyl orthoformate (0.1 mL, 0.91 mmol) was added 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). The resulting mixture was heated to 50 °C for 24 h and then cooled to room temperature. The resulting mixture was diluted with diethyl ether and washed with dilute aqueous sodium bicarbonate solution. The aqueous layer was back-extracted, dried over magnesium sulfate, concentrated to dryness to give 4-(1,1-dimethoxyethyl)-3-fluorobenzonitrile. 1H NMR (400 MHz, CDCl3) δ 7.82 (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).

[0770] 4-(4-Bromo-2-methylbenzo[d][1,3]dioxol-2-yl)-3-fluorobenzonitrile: p-Toluenesulfonic acid (12 mg, 0.06 mmol) was added 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). The resulting mixture was heated to 75 °C for 4 days and concentrated to dryness. Then the crude material was purified by silica gel 2 column chromatography (eluent: EtOAc / hexane) to give 4-(4-bromo-2-methylbenzo[d][1,3]dioxol-2-yl)-3-fluorobenzonitrile (I-39). 1H NMR (400 MHz, MeOD) δ 7.81 (t, J = 7.7 Hz, 1H), 7.69 (dd, J = 10.6, 1.5 Hz, 1H), 7.63 (dd, J = 8.0, 1.6 Hz, 1H), 7.02 (dd, J = 8.2, 1.2 Hz, 1H), 6.87 (dd, J = 7.8, 1.2 Hz, 1H), 6.80 (t, J = 8.0 Hz, 1H), 2.13 (d, J = 1.1 Hz, 3H).

[0771] Preparation of Intermediate I-40 :

[0772] 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 (400 MHz, CDCl3) δ 8.10 (d, J = 1.6 Hz, 1H), 8.00 (dt, J = 8.5, 1.4 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.45 (dd, J = 9.4, 4.6 Hz, 1H), 6.98–6.88 (m, 1H), 4.40 (d, J = 3.2 Hz, 2H), 4.32 (t, J = 5.2 Hz, 2H), 3.97 (d, J = 1.1 Hz, 3H), 3.64 (t, J = 5.2 Hz, 2H), 3.25 (d, J = 1.8 Hz, 3H), 1.36 (s, 12H).

[0773] Preparation of Intermediate I-41 :

[0774] 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-fluorophenyl)-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-d ane (3.0 mL) and the solution was degassed by bubbling N 2 through it for 10 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (107 mg, 0.146 mmol) and NaHCO 3An aqueous solution (2.0 M, 2.18 mL, 4.37 mmol) was added to a flask and the mixture was heated to 90 °C for 1 h. The reaction was cooled to ambient temperature and diluted with EtOAc (5 mL) and water (2 mL), and the organic layer was separated. The aqueous layer was extracted with EtOAc (5 × 2 mL), and the organic layers were combined, washed with brine (5 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The product was purified by passing through a silica plug to remove residual palladium (hexane solution of 50% EtOAc). ES / MS: 445.0 (M+H+).

[0775] The residue was dissolved in ACN (5.0 mL) and an aqueous solution of LiOH (1.0 M, 2 mL) was added. The reaction was heated to 80 °C for 2 h. The reaction was cooled to ambient temperature and quenched with aqueous HCl (1 M) until slightly acidic as determined using pH 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+).

[0776] Preparation of Intermediate I-42 :

[0777] (S)-Methyl 4-amino-3-(((tetrahydrofuran-2-yl)methyl)amino)benzoate: (S)-Methyl 4-amino-3-(((tetrahydrofuran-2-yl)methyl)amino)benzoate (I-42) was prepared as described for I-7 using [(2S)-tetrahydrofuran-2-yl]methanamine instead of 2-methoxyethylamine. ES / MS m / z: 251.2 (M+H+).

[0778] B. Compound Examples

[0779] Procedure 1: Example 1 :

[0780]

[0781] Methyl 2-(4-bromo-2,6-difluorobenzyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate: To a solution of 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 h and then diluted with saturated aqueous ammonium chloride 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, separated 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 h. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (eluent: EtOAc / Hex) to afford the desired product. ES / MS: 474.0, 476.0 (M+H + ).

[0782] 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]dichloropalladium(II) (9.4 mg, 0.013 mmol) in 1,4-di The solution in alkane (1.0 mL) was degassed by bubbling argon for 60 seconds and then heated at 110 °C for 45 minutes in a sealed tube. 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 for 2 hours in a sealed tube. 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 + ).

[0783] 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 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 methyl ester (48.5 mg, 0.074 mmol) in MeCN (0.75 mL) was added 0.3M aqueous lithium hydroxide solution (0.49 mL, 0.15 mmol). The reaction mixture was heated at 100 °C for 2 minutes in a sealed tube. The cooled reaction mixture was purified by RP-HPLC (eluent: water / MeCN*0.1% TFA) to give the product Example 1 as the trifluoroacetate salt. ES / MS: 644.2 (M+H + ). 1H NMR (400 MHz, MeOD) δ 8.56 (dd, J = 1.4, 0.7 Hz, 1H), 8.14 (dd, J = 8.6, 1.4 Hz, 1H), 7.71 (dd, J = 8.5, 0.6 Hz, 1H), 7.64–7.53 (m, 3H), 7.31 (dd, J = 10.9, 2.0 Hz, 1H), 7.23 (ddd, J = 8.4, 2.0, 0.8 Hz, 1H), 7.20 (dd, J = 7.8, 1.5 Hz, 1H), 7.03–6.93 (m, 2H), 4.76 (s, 2H), 4.73 (s, 2H), 2.64 (s, 2H), 2.12 (d, J = 1.0 Hz, 3H), 1.03–0.96 (m, 2H), 0.96–0.88 (m, 2H).

[0784] Procedure 2, Example 2

[0785] 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):

[0786]

[0787] (S)-tert-Butyl 4-(2-(4-bromo-2,6-difluorophenyl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate: 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), then N,N-diisopropylethylamine (0.35 mL, 1.99 mmol) was added, 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 and filtered and concentrated in vacuo. The crude residue was carried on without further purification. ES / MS: 529.5 (M+H + ).

[0788] (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 min. The reaction mixture was concentrated in vacuo and the crude residue was dissolved in EtOAc (40 mL) and washed with saturated aqueous sodium bicarbonate (4 × 10 mL), then with water (10 mL) and brine (10 mL). The organic layer was dried over MgSO 4 and 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 + ).

[0789] 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]dichloropalladium(II) (15 mg, 0.020 mmol) and dioxane (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 an 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 (2 M 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 MgSO 4, 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 4 ) + .

[0790] 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 h. 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 4. The EtOAc was removed by rotary evaporation, the crude residue was dissolved in acetonitrile (20 mL) and concentrated to dryness twice, after which the residue was dissolved in acetonitrile:water (2:1, 20 mL), frozen and placed on a lyophilizer to obtain the final compound, Example 2. ES / MS: 639.6 (M+H + +). 1H NMR (400 MHz, DMSO-d6) δ 7.67–7.53 (m, 5H), 7.44–7.35 (m, 2H), 7.31 (dd, J = 8.0, 1.3 Hz, 1H), 7.07 (dd, 7.8, 1.3 Hz, 1H), 7.01 (t, J = 7.9 Hz, 1H), 5.18–5.10 (m, 1 Hz), 4.85 (dd, J = 15.6, 7.1 Hz, 1H), 4.69 (dd, J = 15.7, 2.8 Hz, 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).

[0791] Procedure 3: Example 3

[0792]

[0793] 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): To a mixture of 2-[[4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]-2,6-difluorophenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylic acid (Example 19) (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 addition of 50 μL TFA and the crude reaction mixture was purified directly by RP-HPLC (15 - 76.84% 0.1% TFA-ACN in 0.1% TFA water, 15 minute gradient, column: Gemini 5uM, NX-C18 110 Å, 250×21.2 mm) to afford the title compound Example 3 as a racemic mixture of trifluoroacetates. ES / MS m / z: 712.3 (M+H + ). 1 H NMR (400 MHz, methanol-d4) δ 8.41–8.37 (m,1H), 8.01 (dd, J = 8.6, 1.6 Hz, 1H), 7.76 (dd, J = 8.6, 0.7 Hz, 1H), 7.65–7.54 (m, 3H), 7.34 (dd, J = 11.0, 2.0 Hz, 1H), 7.29–7.24 (m, 1H), 7.21 (dd, J = 7.8, 1.5 Hz, 1H), 7.05–6.95 (m, 2H), 4.85 (s, 3H), 4.78 (t, J = 5.0 Hz, 2H), 4.73 (s, 2H), 3.87 (t, J = 4.9 Hz, 2H), 3.25–3.17 (m, 1H), 2.14 (s, 3H), 1.41–1.28 (m, 2H), 1.23–1.10 (m, 2H).

[0794] Procedure 4: Example 4

[0795]

[0796] 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 manner similar to the first step of Procedure 1) (60 mg, 0.142 mmol), bis(neopentyl glycol)diboron (64.3 mg, 0.285 mmol), Pd(dppf)Cl 2 (16 mg, 0.0214 mmol), and potassium propionate (48 mg, 0.43 mmol). 1,4-Dioxane (1.0 mL) was added, 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 conversion of the starting aryl bromide to the intermediate boronic acid. Pd(dppf)Cl was added (8 mg, 0.012 mmol) and 4-(4-bromobenzo[d][1,3]dioxol-2-yl)-3-fluorobenzonitrile (I-1) (41 mg, 0.128 mmol), and sodium carbonate (2 M 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 onto a loading column, and the crude material was purified by silica gel chromatography (eluent: EtOAc / hexanes) to afford the desired product. ES / MS: 582.4 (M+H 2 ). + ).

[0797] 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) was added. To the mixture was added LiOH H 2O (3.3 mg, 0.06 mmol), and the mixture was stirred at 55 °C for 3 h. 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 the trifluoroacetate salt. ES / MS: 568.5 (M+H + ). 1H NMR (400 MHz, methanol-d4) δ 8.53 (d, J = 1.4 Hz, 1H), 8.20 (dd, J = 8.6, 1.5 Hz, 1H), 7.85–7.78 (m, 1H), 7.78–7.63 (m, 4H), 7.49 (t, J = 8.0 Hz, 1H), 7.46 (s, 1H), 7.23 (dd, J = 8.0, 1.3 Hz, 1H), 7.06 (t, J = 7.9 Hz, 1H), 6.99 (dd, J = 7.8, 1.2 Hz, 1H), 4.78 (t, J = 5.0 Hz, 2H), 4.73 (s, 2H), 3.85–3.73 (m, 2H), 3.30 (s, 3H).

[0798] Procedure 5: Example 5

[0799]

[0800] Methyl 2-(4-(2-(4-cyano-2-fluorophenyl)-1,3-benzodioxol-4-yl)-2,6-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate: To a vial was added bromo(1,3-benzodioxol-2-yl)-3-fluorobenzonitrile (I-1) (65 mg, 0.203 mmol), bis(neopentyl glycol) diboron (60 mg, 0.264 mmol), Pd(dppf)Cl 2 (22.6 mg, 0.03 mmol) and potassium propionate (68 mg, 0.609 mmol). 1,4-Di ane (1.0 mL) was added and the mixture was degassed with argon for 30 s. The vial was sealed and the mixture was heated at 120 °C for 30 min. The vial was cooled and LCMS showed conversion of the starting aryl bromide to the intermediate boronic acid. Pd(dppf)Cl 2(12 mg, 0.018 mmol) and methyl 2-(4-bromo-2,6-difluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (prepared in a similar manner to the first step of Procedure 1) (93 mg, 0.212 mmol), and sodium carbonate (2 M aqueous solution, 0.2 mL, 0.406 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 room temperature. The organic layer was directly transferred to a 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 + ).

[0801] 2-(4-(2-(4-Cyan-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-cyan-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) was added. To the mixture was added LiOH H 2 O (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 the trifluoroacetate salt. ES / MS: 586.291 (M+H + ). 1H NMR (400 MHz, methanol-d4) δ 8.54 (d, J = 1.5 Hz, 1H), 8.21 (dd, J = 8.5, 1.6 Hz, 1H), 7.86–7.62 (m, 4H), 7.51–7.40 (m, 2H), 7.35 (dd, J = 10.0, 6.2 Hz, 1H), 7.12–6.98 (m, 3H), 4.80 (t, J = 5.0 Hz, 2H), 4.74 (s, 2H), 3.83 (t, J = 4.9 Hz, 2H), 3.30 (s, 3H).

[0802] Procedure 6: Example 32

[0803]

[0804] Methyl 2-(2-fluoro-4-(2-phenylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate: 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)Cl 2 (23.8 mg, 0.024 mmol), 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) (100 mg, 0.214 mmol), DME (1 mL), and sodium carbonate (2 M aqueous solution, 0.21 mL, 0.427 mmol) were added to a vial. The flask was degassed with argon for 30 seconds, 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 a loading column, and the crude material was purified by silica gel chromatography (eluent: EtOAc / hexane) to give the desired product. ES / MS: 539.568 (M+H + ).

[0805] 2-(2-fluoro-4-(2-phenylbenzo[d][1,3]dioxol-4-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid: 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) was added to a 40 mL vial, and acetonitrile (2 mL) was added. LiOH (11.1 mg, 0.464 mmol) dissolved in water (0.5 mL) was added to the mixture, 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 the trifluoroacetate salt. ES / MS: 525.581 (M+H +)。1H NMR (400 MHz, methanol-d4) δ 8.55 (s, 1H), 8.23 (dd, J = 8.6, 1.4 Hz, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.74–7.64 (m, 2H), 7.60 (dd, J = 7.4, 2.4 Hz, 2H), 7.56–7.42 (m, 4H), 7.19 (d, J = 8.1 Hz, 1H), 7.13 (s, 1H), 7.01 (t, J = 7.9 Hz, 1H), 6.94 (d, J = 7.7 Hz, 1H), 4.81 (t, J = 5.0 Hz, 2H), 4.76 (s, 2H), 3.80 (t, J = 4.9 Hz, 2H), 3.30 (s, 3H).

[0806] Procedure 7: Example 7

[0807]

[0808] 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 added slowly. The resulting mixture was slowly warmed to RT with rapid stirring over 16 h. H 2 O (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 MgSO 4 4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: EtOAc / hexane). ES / MS: 245.2 (M + H + +).

[0809] Methyl 2-(3-bromo-2-((tert-butyldimethylsilyl)oxy)phenyl)acetate: Imidazole (720 mg, 10.5 mmol) and tert-butyldimethylsilyl chloride (1.20 g, 7.90 mmol) were added to a solution of methyl 2-(3-bromo-2-hydroxyphenyl)acetate (1.29 g, 5.26 mmol) in DCM (10 mL) at RT. The mixture was stirred at room temperature for 1.5 h and then diluted with H 2 2O (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 × 50 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4 Dry, filter, and concentrate in vacuo. Purify the residue by silica gel chromatography (eluent: EtOAc / hexanes). 1H NMR (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).

[0810] 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 dropwise diisobutylaluminum hydride (1 M solution in hexanes) (1.04 mL, 1.04 mmol). The solution was warmed to RT over 1 h with rapid stirring and then quenched with saturated aqueous potassium sodium tartrate (50 mL) and diluted with EtOAc (50 mL). The resulting slurry was filtered through a pad of Celite and the 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 4 Dry, filter, and concentrate in vacuo.

[0811] Dissolve the crude mixture in DCM (10 mL). Add NaHCO 3 (76 mg, 1.25 mmol) and Dess-Martin periodinane (270 mg) at RT. Stir the mixture at RT for 1 h, then filter through Celite and wash the cake with DCM (20 mL). Concentrate the filtrate in vacuo and purify by silica gel chromatography (eluent: EtOAc / hexanes). 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).

[0812] 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) at 0 °C was added dropwise phenylmagnesium bromide (1 M solution in THF) (0.46 mL, 0.46 mmol). The resulting mixture was stirred at 0 °C for 1 h and then, with rapid stirring, quenched with saturated NH4 The Cl aqueous solution (10 mL) was quenched 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 × 20 mL), and the combined organic extracts were washed with brine (50 mL), dried over MgSO 4 and filtered, and concentrated in vacuo.

[0813] The crude mixture was redissolved in THF (5 mL). Tetrabutylammonium fluoride (1 M solution in THF) (0.46 mL, 0.46 mmol) was added dropwise at RT, and the resulting mixture was stirred for 1 h, then diluted with EtOAc (20 mL) and saturated NaHCO 3 aqueous solution (20 mL). The mixture was poured into a separatory funnel and the layers were separated. The aqueous phase was extracted with EtOAc (2 × 20 mL), and the combined organic extracts were washed with brine (50 mL), dried over MgSO 4 and filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: EtOAc / hexane). 1H NMR (400 MHz, chloroform-d) δ 9.29 (s, 1H), 7.37–7.26 (m, 5H), 7.25–7.19 (m, 1H), 6.82 (dd, J = 7.5, 1.6 Hz, 1H), 6.62 (t, J = 7.7 Hz, 1H), 5.49 (s, 1H), 5.10 (dd, J = 8.2, 3.1 Hz, 1H), 3.14 (dd, J = 14.4, 8.2 Hz, 1H), 3.02 (dd, J = 14.4, 3.1 Hz, 1H).

[0814] 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) at RT were added triphenylphosphine (52 mg, 0.20 mmol) and diisopropyl azodicarboxylate (50 mg, 0.25 mmol) separately. 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).

[0815] Methyl 2-(2-fluoro-4-(2-phenyl-2,3-dihydrobenzofuran-7-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate: Charge a 5 mL microwave vial 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). Add dioxane (3 mL) and Na 2CO 2 3 (1.5 M aqueous H 3 2O solution) (0.22 mL, 0.33 mmol), and purge the resulting mixture with argon for 2 minutes. Heat the mixture to 85 °C and stir for 2 h, then cool to RT. After dilution with H 2 2O (20 mL) and EtOAc (20 mL), pour the mixture into a separatory funnel. Separate the layers, and extract the aqueous phase with EtOAc (2 × 20 mL). Wash the combined organic extracts with brine (50 mL), dry over MgSO 2 4, filter, and concentrate in vacuo. Purify the residue by silica gel chromatography (eluent: EtOAc / hexanes). ES / MS: 537.20 (M+H 4 +). + )

[0816] 2-(2-fluoro-4-(2-phenyl-2,3-dihydrobenzofuran-7-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid: Dissolve 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) in acetonitrile (0.9 mL), then add LiOH (2 M aqueous H 2 2O solution) (0.2 mL, 0.40 mmol) and stir the resulting mixture at 50 °C for 3 h. Adjust the reaction mixture to pH 2 with citric acid (1 M aqueous H 2 2O solution) (1 mL) and extract with EtOAc (2 × 10 mL). Concentrate the combined organics and purify by RP-HPLC (eluent: H 2 2O / MeCN 0.1% TFA) to give the product as the trifluoroacetate salt (Example 7). ES / MS: 523.2 (M+H +)。1H NMR(400 MHz, DMSO-d6) δ 8.31 (d, J = 1.5 Hz, 1H), 7.89 (dd, J = 8.5, 1.5 Hz, 1H), 7.67 (d, J = 8.5 Hz, 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, 1.3 Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H), 5.92 (dd, J = 9.4, 8.1 Hz, 1H), 4.64 (t, J = 5.2 Hz, 2H), 4.51 (s, 2H), 3.75 (dd, J = 15.9, 9.4 Hz, 1H), 3.66 (t, J = 5.0 Hz, 2H), 3.25–3.14 (m, 4H)。

[0817] Procedure 8: Example 8

[0818]

[0819] 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-thienyl]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) in dichloro The suspension in alkane (2 mL) 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 (400 MHz, CDCl3) δ 7.58 (t, J = 8.3 Hz, 1H), 7.48 (d, J = 3.7 Hz, 1H), 7.18 (dd, J = 10.5, 2.0 Hz, 1H), 7.13 (ddd, J = 8.4, 2.0, 0.8 Hz, 1H), 7.09 (dd, J = 8.1, 1.2 Hz, 1H), 6.98 (dd, J = 3.7, 1.0 Hz, 1H), 6.84 (t, J = 7.9 Hz, 1H), 6.75 (dd, J = 7.7, 1.1 Hz, 1H), 3.89 (d, J = 0.9 Hz, 2H), 3.78 (s, 3H), 2.15 (d, J = 1.1 Hz, 3H).

[0820] 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-thienyl]acetate (69.0 mg, 0.165 mmol) and lithium hydroxide monohydrate (19.3 mg, 0.461 mmol) in CH 3 CN (3 mL) and water (1 mL) was stirred overnight at RT. 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 afford the desired product. ES / MS: 405.0 (M + ).

[0821] Methyl 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-carboxylate: To a solution of 2-[5-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]-2-thienyl]acetic acid (66.7 mg, 0.165 mmol), methyl 4-amino-3-(2-methoxyethylamino)benzoate I-7 (44.3 mg, 0.198 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (106 mg, 0.279 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine (0.135 mL, 0.776 mmol). The mixture was stirred overnight at RT. 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 give the crude product, which was carried on to the next step.

[0822] A solution of methyl 4-[[2-[5-[2-(4-chloro-2-fluorophenyl)-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 h. The reaction mixture was concentrated and purified by silica gel chromatography (eluent: EtOAc / hexane). ES / MS: 593.2 (M + +). Multipeak reported 1H NMR (400 MHz, CDCl3) δ 8.11 (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 (dd, J = 8.1, 1.1 Hz, 1H), 6.96 (d, J = 3.6 Hz, 1H), 6.82 (t, J = 7.9 Hz, 1H), 6.74 (dd, J = 7.8, 1.2 Hz, 1H), 4.67 (s, 2H), 4.40 (t, J = 5.3 Hz, 2H), 3.98 (s, 3H), 3.66 (t, J = 5.3 Hz, 2H), 3.29 (s, 3H), 2.13 (d, J = 1.0 Hz, 3H).

[0823] 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: In a 40 mL reaction vial, methyl 2-[[5-[2-(4-chloro-2-fluoro-phenyl)-2-methyl-1,3-benzodioxol-4-yl]-2-thienyl]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 CH 3 CN (1 mL) were heated at 90 °C for 15 minutes. 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: H 2 O / MeCN 0.1% TFA) to give the product as the trifluoroacetate (Example 8). ES / MS: 593.2 (M + ). Multiplex reported 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).

[0824] Procedure 9: Example 9 and Example 13

[0825]

[0826] 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 (0.49 mL, 0.15 mmol). The reaction mixture was heated in a sealed tube at 70 °C for 2 h. The cooled reaction mixture was purified by RP-HPLC (eluent: water / MeCN * 0.1% TFA) to afford the products Example 9 and Example 13 as trifluoroacetates.

[0827] Example 9: ES / MS: 680.0 (M+H + )。1H NMR (400 MHz, methanol-d4) δ 8.24 (d, J = 1.2 Hz, 1H), 7.70–7.55 (m, 2H), 7.51 (d, J = 9.0 Hz, 2H), 7.33 (dd, J = 10.9, 2.0 Hz, 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 = 1.0 Hz, 3H), 0.96–0.80 (m, 1H).

[0828] Example 13: ES / MS: 662.2 (M+H + )。1H NMR (400 MHz, methanol-d4) δ 8.24 (d, J = 1.2 Hz, 1H), 7.73–7.57 (m, 2H), 7.57–7.46 (m, 2H), 7.32 (dd, J = 10.9, 2.0 Hz, 1H), 7.28–7.15 (m, 2H), 7.06–6.81 (m, 2H), 4.66 (s, 2H), 4.55 (s, 2H), 2.61 (s, 2H), 2.13 (d, J = 1.0 Hz, 3H), 0.98–0.79 (m, 4H).

[0829] Procedure 10: Example 10 and Example 17

[0830]

[0831] 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 a solution of 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 methyl ester (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 trifluoroacetates.

[0832] Example 10: ES / MS: 648.2 (M + )。1H NMR (400 MHz, methanol-d4) δ 8.54 (t, J = 1.0 Hz, 1H), 8.21 (dd, J = 8.6, 1.4 Hz, 1H), 8.08–8.00 (m, 2H), 7.76 (d, J = 8.6 Hz, 1H), 7.57–7.50 (m, 2H), 7.41–7.33 (m, 2H), 7.33–7.21 (m, 2H), 7.00 (t, J = 7.8 Hz, 1H), 4.85–4.81 (m, 2H), 4.78 (s, 2H), 3.88–3.81 (m, 2H), 3.47 (t, J = 6.4 Hz, 2H), 3.32 (s, 3H), 2.94 (t, J = 6.4 Hz, 2H).

[0833] Example 17: ES / MS: 630.2 (M +)。1H NMR (400 MHz, methanol-d4) δ 8.58 (s, 1H), 8.28–8.22 (m, 1H), 8.12–8.01 (m, 2H), 7.78 (d, J = 8.6 Hz, 1H), 7.71 (t, J = 8.6 Hz, 4H), 7.59–7.44 (m, 3H), 4.86–4.83 (m, 4H), 3.87 (t, J = 4.9 Hz, 2H), 3.74 (t, J = 6.6 Hz, 2H), 3.46 (t, J = 6.5 Hz, 2H), 3.32 (s, 3H).

[0834] 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 (Examples 33 and 34):

[0835]

[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: 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, which is a mixture of two stereoisomers (Example 4 obtained as described in Procedure 4), was separated by chiral SFC (CELL-2 column with 30% EtOH-TFA co-solvent) to give two different stereoisomers.

[0837] 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 (400 MHz, methanol-d4) δ 8.41 (s, 1H), 8.13–8.06 (m, 1H), 7.84–7.77 (m, 1H), 7.77–7.59 (m, 5H), 7.43 (d, J = 14.0 Hz, 2H), 7.25–7.17 (m, 1H), 7.04 (t, J = 7.9 Hz, 1H), 6.97 (dd, J = 7.6, 1.1 Hz, 1H), 4.67 (t, J = 5.0 Hz, 2H), 4.62 (s, 2H), 3.75 (t, J = 4.9 Hz, 2H), 3.28 (s, 3H).

[0838] 2-(4-(2-(4-Cyano-2-fluorophenyl)-1,3-benzodioxol-4-yl)-2-fluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 34). ES / MS: 568.4 (M+H + )。1H NMR (400 MHz, methanol-d4) δ 8.41 (s, 1H), 8.11 (dd, J = 8.6, 1.5 Hz, 1H), 7.80 (t, J = 7.5 Hz, 1H), 7.77–7.57 (m, 5H), 7.43 (d, J = 12.3 Hz, 2H), 7.22 (dd, J = 8.0, 1.2 Hz, 1H), 7.04 (t, J = 7.9 Hz, 1H), 6.97 (dd, J = 7.8, 1.2 Hz, 1H), 4.67 (t, J = 5.0 Hz, 2H), 4.63 (s, 2H), 3.75 (t, J = 5.0 Hz, 2H), 3.28 (s, 3H).

[0839] Procedure 12: 2-(2-Fluoro-4-(2-phenyl-1,3-benzodioxol-4-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Examples 35 and 36):

[0840]

[0841] 2-(2-Fluoro-4-(2-phenyl-1,3-benzodioxol-4-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid: 2-(2-Fluoro-4-(2-phenyl-1,3-benzodioxol-4-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid, obtained as a mixture of two stereoisomers (Example 32 obtained as described in Procedure 6), was separated by chiral SFC (AD-H column with 30% MeOH cosolvent) to give two different stereoisomers.

[0842] 2-(2-Fluoro-4-(2-phenyl-1,3-benzodioxol-4-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 35): ES / MS: 525.3 (M+H +)。1H NMR (400 MHz, methanol-d4) δ 8.52–8.48 (m, 1H), 8.19 (dd, J = 8.6, 1.4 Hz, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.72–7.64 (m, 2H), 7.64–7.56 (m, 2H), 7.52–7.42 (m, 4H), 7.19 (dd, J = 8.1, 1.2 Hz, 1H), 7.13 (s, 1H), 7.01 (t, J = 7.9 Hz, 1H), 6.93 (dd, J = 7.7, 1.2 Hz, 1H), 4.76 (t, J = 5.0 Hz, 2H), 4.71 (s, 2H), 3.79 (t, J = 4.9 Hz, 2H), 3.29 (s, 3H).

[0843] 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 (400 MHz, methanol-d4) δ 8.50 (t, J = 1.0 Hz, 1H), 8.18 (dd, J = 8.6, 1.4 Hz, 1H), 7.75 (d, J = 8.6 Hz, 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, 1.2 Hz, 1H), 7.13 (s, 1H), 7.01 (t, J = 7.9 Hz, 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).

[0844] 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 (Examples 37 and 38):

[0845]

[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: 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, which is a mixture of two stereoisomers (Example 5 obtained as described in Procedure 5), was separated by chiral SFC (AD-H column with 40% MeOH co-solvent) to obtain two different stereoisomers.

[0847] 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).

[0848] 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 (400 MHz, methanol-d4) δ 8.45 (s, 1H), 8.14 (dd, J = 8.4, 1.5 Hz, 1H), 7.81 (t, J = 7.5 Hz, 1H), 7.76–7.70 (m, 2H), 7.67 (dd, J = 8.0, 1.6 Hz, 1H), 7.48–7.37 (m, 2H), 7.28 (dd, J = 10.1, 6.2 Hz, 1H), 7.12–6.97 (m, 3H), 4.73 (t, J = 5.0 Hz, 2H), 4.66 (s, 2H), 3.79 (t, J = 4.9 Hz, 2H), 3.29 (s, 3H).

[0849] 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 (Examples 39 and 40):

[0850]

[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: 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, which is a mixture of two stereoisomers (Example 31 obtained as described in Procedure 1), was separated by chiral SFC (CELL-2 column with 45% MeOH cosolvent) to obtain two different stereoisomers.

[0852] 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 (400 MHz, methanol-d4) δ 8.50 (s, 1H), 8.18 (dd, J = 8.6, 1.6 Hz, 1H), 7.82 (t, J = 7.5 Hz, 1H), 7.78–7.64 (m, 3H), 7.49–7.40 (m, 2H), 7.31 (dd, J = 10.1, 6.2 Hz, 1H), 7.10–6.98 (m, 3H), 4.77 (t, J = 5.0 Hz, 2H), 4.70 (s, 2H), 3.81 (t, J = 5.0 Hz, 2H), 3.30 (s, 3H).

[0853] 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).

[0854] 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 (Examples 41 and 42):

[0855]

[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: 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, obtained as a mixture of two stereoisomers (Example 30 obtained as described in Procedure 1), was separated by chiral SFC (IG column with 50% MeOH co-solvent) to give two different stereoisomers.

[0857] 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 (400 MHz, methanol-d4) δ 8.44 (s, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.82 (t, J = 7.4 Hz, 1H), 7.72 (dd, J = 24.1, 9.1 Hz, 3H), 7.55 (d, J = 8.9 Hz, 2H), 7.49 (s, 1H), 7.26 (d, J = 7.8 Hz, 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 = 9.4 Hz, 1H), 2.61–2.47 (m, 1H).

[0858] 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 (400 MHz, methanol-d4) δ 8.47 (s, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.82 (t, J = 7.5 Hz, 1H), 7.77–7.67 (m, 3H), 7.55 (d, J = 8.9 Hz, 2H), 7.48 (s, 1H), 7.26 (d, J = 7.9 Hz, 1H), 7.11–6.98 (m, 2H), 5.26 (qd, J = 7.3, 2.4 Hz, 1H), 4.84–4.62 (m, 5H), 4.50 (dt, J = 9.1, 6.0 Hz, 1H), 2.85 (dq, J = 14.6, 7.7 Hz, 1H), 2.64–2.50 (m, 1H).

[0859] 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 (Examples 43 and 44):

[0860]

[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: 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, which is a mixture of two stereoisomers (Example 28 obtained as described in Procedure 1), was separated by chiral SFC (AZ-H column with 25% IPA-NH3 co-solvent) to give two different stereoisomers.

[0862] 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) δ 8.32 (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, 6.9 Hz, 1H), 4.69–4.56 (m, 3H), 4.55–4.40 (m, 2H), 2.79 (dq, J = 16.7, 7.8, 5.9 Hz, 1H), 2.58–2.41 (m, 1H), 2.06 (s, 3H).

[0863] 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(400 MHz, methanol-d4) δ 8.31 (dd, J = 1.5, 0.7 Hz, 1H), 7.99 (dd, J = 8.5, 1.5 Hz, 1H), 7.67 (dd, J = 8.5, 0.6 Hz, 1H), 7.61 (t, J = 8.3 Hz, 1H), 7.40–7.26 (m, 2H), 7.26–7.15 (m, 2H), 7.02–6.87 (m, 3H), 5.19 (qd, J = 7.0, 2.6 Hz, 1H), 4.78–4.39 (m, 7H), 2.80 (dtd, J = 11.4, 8.2, 6.1 Hz, 1H), 2.49 (ddt, J = 11.4, 9.2, 7.2 Hz, 1H), 2.06 (d, J = 1.1 Hz, 3H).

[0864] 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 (Examples 45 and 46):

[0865]

[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: 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, obtained as a mixture of two stereoisomers (Example 29 obtained as described in Procedure 1), was separated by chiral SFC (AD-H column with 35% MeOH-DEA co-solvent) to give two different stereoisomers.

[0867] 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 (400 MHz, methanol-d4) δ 8.63 (dd, J = 2.4, 0.7 Hz, 1H), 8.52 (t, J = 1.0 Hz, 1H), 8.17 (dd, J = 8.6, 1.4 Hz, 1H), 7.92 (dd, J = 8.5, 2.4 Hz, 1H), 7.76 (dd, J = 8.6, 0.7 Hz, 1H), 7.71 (dd, J = 8.5, 0.7 Hz, 1H), 7.44 (dd, J = 10.0, 6.0 Hz, 1H), 7.33 (dd, J = 10.0, 6.2 Hz, 1H), 7.04–6.92 (m, 3H), 5.25 (qd, J = 7.4, 2.4 Hz, 1H), 4.99–4.64 (m, 5H), 4.52 (dt, J = 9.1, 5.9 Hz, 1H), 2.95–2.77 (m, 1H), 2.63–2.44 (m, 1H), 2.07 (s, 3H).

[0868] 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 (400 MHz, methanol-d4) δ 8.63 (dd, J = 2.5, 0.7 Hz, 1H), 8.54–8.46 (m, 1H), 8.15 (dd, J = 8.5, 1.4 Hz, 1H), 7.92 (dd, J = 8.5, 2.4 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.71 (dd, J = 8.5, 0.7 Hz, 1H), 7.43 (dd, J = 10.0, 6.0 Hz, 1H), 7.31 (dd, J = 10.0, 6.1 Hz, 1H), 7.04–6.93 (m, 3H), 5.23 (dd, J = 8.1, 5.8 Hz, 1H), 4.86–4.64 (m, 5H), 4.51 (dt, J = 9.2, 6.0 Hz, 1H), 2.93–2.76 (m, 1H), 2.64–2.44 (m, 1H), 2.07 (s, 3H).

[0869] 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 (Examples 47 and 48):

[0870]

[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: 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, which is a mixture of two stereoisomers (Example 22 obtained as described in Procedure 1), was separated by chiral SFC (AD-H column with 25% IPA-NH3 co-solvent) to give two different stereoisomers.

[0872] 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 (400 MHz, DMSO) δ 12.79 (s, 1H), 8.26 (d, J = 1.6 Hz, 1H), 7.78 (dd, J = 8.4, 1.6 Hz, 1H), 7.67–7.47 (m, 5H), 7.39 (dd, J = 8.4, 2.1 Hz, 1H), 7.31 (dd, J = 7.9, 1.4 Hz, 1H), 7.10–6.95 (m, 2H), 5.12 (qd, J = 6.9, 2.7 Hz, 1H), 4.81 (dd, J = 15.6, 6.8 Hz, 1H), 4.68 (dd, J = 15.6, 2.7 Hz, 1H), 4.61–4.39 (m, 3H), 4.35 (dt, J = 9.1, 5.9 Hz, 1H), 2.82–2.71 (m, 1H), 2.44–2.36 (m, 1H), 2.12 (s, 3H).

[0873] 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)。

[0874] 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 (Examples 49 and 50):

[0875]

[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: 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, which was obtained as a mixture of two stereoisomers (Example 27 obtained as described in Procedure 1), was separated by chiral SFC (AD-H column with 35% EtOH co-solvent) to give two different stereoisomers.

[0877] 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 (400 MHz, DMSO) δ 12.81 (s, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.27 (d, J = 1.5 Hz, 1H), 8.04 (dd, J = 8.5, 2.5 Hz, 1H), 7.78 (dd, J = 8.5, 1.6 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.57 (dd, J = 10.5, 8.5 Hz, 4H), 7.29 (dd, J = 7.4, 1.9 Hz, 1H), 7.22–6.91 (m, 3H), 5.11 (tt, J = 7.1, 3.7 Hz, 1H), 4.81 (dd, J = 15.6, 6.8 Hz, 1H), 4.68 (dd, J = 15.5, 2.7 Hz, 1H), 4.60–4.38 (m, 4H), 4.35 (dt, J = 9.1, 5.9 Hz, 1H), 2.74 (dq, J = 11.1, 7.6 Hz, 1H), 2.45–2.35 (m, 1H), 2.12 (s, 4H).

[0878] 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 (400 MHz, DMSO) δ 12.79 (s, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.26 (d, J = 1.5 Hz, 1H), 8.04 (dd, J = 8.5, 2.5 Hz, 1H), 7.78 (dd, J = 8.5, 1.6 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.56 (t, J = 8.9 Hz, 4H), 7.29 (dd, J = 7.4, 2.0 Hz, 1H), 7.16–6.92 (m, 2H), 5.12 (qd, J = 6.9, 2.7 Hz, 1H), 4.81 (dd, J = 15.6, 6.8 Hz, 1H), 4.67 (dd, J = 15.6, 2.7 Hz, 1H), 4.61–4.40 (m, 4H), 4.35 (dt, J = 9.0, 5.9 Hz, 1H), 2.97–2.62 (m, 1H), 2.39 (ddt, J = 11.3, 9.1, 6.9 Hz, 1H), 2.12 (s, 4H).

[0879] Procedure 20: Example 82

[0880] Methyl 2-[[4-[6-[(4-cyano-2-fluorophenyl)methoxy]-2-pyridinyl]-2-fluorophenyl]methyl]-3-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxylate: To a solution of 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), methyl 4-amino-3-((2-(methylsulfonyl)ethyl)amino)benzoate I-18 (46.5 mg, 0.154 mmol) and O-(7-azabenzotriazol-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 overnight at RT. 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 give the crude product. Then, acetic acid was added to the intermediate and the mixture was heat...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein R 1 is C 6-10 aryl or heteroaryl, wherein each of said aryl or heteroaryl is optionally substituted with one to four Z 1 substituted; Ring A is a phenyl ring, wherein U 1 , U 2 , U 3 each is -C(H)=; Ring B is phenyl or a 5- or 6-membered heteroaryl, each optionally substituted by one to four R 4 substituents; R 2 is C 1-6 alkyl wherein said alkyl is optionally substituted by one to four Z 1 substituted; X 1 , X 2 and X 3 are independently -N=, -C(H)= or -C(R 8 )=; Y 1 and Y 2 each is -C(R y1 )(R y2 )-, -N(R y1 )-, -O-, or -S-; W is -C(R 5 )- or -N-, wherein when W is -N, Y 1 and Y 2 one of which is -C(R y1 )(R y2 )- or -C(O)- and Y 1 and Y 2 the other of which is -C(R y1 )(R y2 )-, -C(O)- or -S(O) 2 -; R 3 is -C(O)OH, -C(O)NHS(O) 2 R 3a or tetrazole, wherein R 3a is cyclopropyl; Each R 4 is independently C 1-9 alkyl, C 1-8 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, halogen, =O, -CN or -O-R 4a ; wherein each of said alkyl or haloalkyl is optionally substituted with one to four Z 1b substituted; R 5 is H, cyclopropyl or C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted by one, two or three groups selected from halogen, -OH, -OCH 3 , -CN, =O and -N(R x1 )(R x2 ); or R 5 and R y1 combine with the atoms to which they are attached to form a cycloalkyl or heterocyclic group optionally substituted by =O 3-10 ring alkyl or heterocyclic group; R x1 and R x2 each independently is H, C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclic group, -S(O) 2 R 6a1 or -S(O) 2 N(R 6a1 )(NR 6a2 ), wherein the C 1-6 alkyl, cycloalkyl or heterocyclic group is each optionally substituted by F, -CN, =O or C 3-6 cycloalkyl; or R x1 and R x2 combine with the atoms to which they are attached to form a heterocyclic group, which heterocyclic group is optionally substituted with one to four R 6b1 substituents; V is -CH 2 -; Each R y1 and R y2 are each independently H, a halogen group, C 1-6 alkyl, C 1-6 haloalkyl, where the alkyl and haloalkyl are each optionally substituted with ═O; Each R 6b1 is independently C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 3-10 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, =O, -OH, -CN, -NO 2 or -C(O)N(R 2a )(R 2b ), wherein the heterocyclic group or heteroaryl is optionally substituted by C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 haloalkoxy; and Each R 6a1 and R 6a2 are independently H, C 1-6 alkyl or C 3-10 cycloalkyl; Each Z 1 is independently C 1-8 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, halogen, C 3-15 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl, -CN, -C(O)-N(R 12a )(R 12b ) or -S(O) 2 R 12a ; wherein the cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted by one to four Z 1a substituted; Each Z 1a is independently C 1-9 alkyl, C 1-8 haloalkyl, halogen, C 3-15 cycloalkyl, heterocycloalkyl, C 6-10 aryl, heteroaryl, -CN, -C(O)R 12a , -C(O)O-R 12a or -C(O)N(R 12a )(R 12b ); wherein the alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted by one to four Z 1b substituted; Each R 8 is independently halogen or -CN; Each Z 1b is independently halogen, -CN or -C(O)NH 2 ; and Each R 2a , R 2b , R 4a , R 12a , and R 12b is independently H, C 1-9 alkyl, C 3-15 cycloalkyl, heterocyclic group, C 6-10 aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted by one to four Z 1b substituents; each heteroaryl has 5 to 12 ring members and has one to four heteroatoms each independently being N, O, or S; and each heterocyclic group has 3 to 12 ring members and has one to four heteroatoms each independently being N, O, or S.

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

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 is a 6 - aryl or 5 - or 6 - heteroaryl, wherein the aryl or heteroaryl is substituted by one, two or three Z 1 , and the Z 1 are independently selected from C 1-8 haloalkyl, halogen, C 1-6 alkoxy, - CN and - C(O) - N(R 12a )(R 12b ).

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

5. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 5 is hydrogen or methyl.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein Y 1 and Y 2 are both -O-.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 1, the compound having the structure of formula (Ia) or (Ib): wherein: subscript p is 1, 2, or 3; and subscript q is 0, 1, or 2.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein Each Z 1a is independently C 1-6 alkyl, halogen, C 3-10 cycloalkyl, heterocyclic group, C 6-10 aryl, heteroaryl or -C(O)N(R 12a )(R 12b ), where each is optionally substituted by Z 1b .

9. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein Ring B is phenyl or pyridyl, wherein the phenyl or pyridyl is optionally substituted with one to four Rs 4 substituted.

10. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein Each ring B is optionally substituted by one to three Rs 4 substitutions.

11. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring B is Each of them is optionally substituted by one or two Rs 4 substituted.

12. The compound or a pharmaceutically acceptable salt thereof according to claim 1, the compound having the structure of formula (Ic) or (Id): wherein subscript n is 0, 1, 2, or 3; and subscript p is 1, 2, or 3.

13. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein X 1 、 X 2 and X 3 are each independently -CH=, -C(F)=, -C(Cl)=, -C(Br)= or -C(CN)=.

14. The compound or a pharmaceutically acceptable salt thereof according to claim 1, the compound having the structure of formula (Ie) or (If): wherein subscript n is 0, 1, 2, or 3; and subscript p is 1, 2, or 3.

15. The compound or a pharmaceutically acceptable salt thereof according to claim 1, the compound having the structure of formula (Ig): wherein subscript n is 0, 1, 2, or 3; and subscript p is 1, 2, or 3.

16. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein Each Z 1 is independently C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, halogen, heterocyclic group, heteroaryl or -S(O) 2 R 12a , wherein each of said heteroaryl or heterocyclic group is optionally substituted by one to four halogens, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic group or -CN.

17. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein Each Z 1 is independently C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, a 3- to 12-membered heterocyclic group having one to three heteroatoms, or a 5- to 10-membered heteroaryl group having one to three heteroatoms.

18. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein Each Z 1 is independently C 1-6 haloalkoxy, halogen or a 5- to 6-membered heteroaryl having one to three heteroatoms.

19. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein Each Z 1 is independently a halogen or a C 1-3 alkoxy group.

20. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 is C 1-6 alkyl, wherein said alkyl is optionally substituted with one Z 1 substituent where each Z 1 is independently C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, halogen, C 3-15 cycloalkyl, heterocycloalkyl, C 6-10 aryl, heteroaryl or -S(O) 2 R 12a .

21. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is:

22. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is:

23. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 3 is -C(O)OH.

24. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein Each R 4 is independently C 1-6 alkyl, C 1-6 haloalkoxy, C 2-6 alkoxyalkyl, halogen, =O, -CN or -OR 4a .

25. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein Each R 4 is independently C 1-6 alkyl, halogen, =O, -CN or -OR 4a .

26. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein Each R 4 is independently C 1-6 alkyl, halogen, =O, -OH or -CN.

27. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein Each R 4 is independently F, =O or -CN.

28. The compound or a pharmaceutically acceptable salt thereof according to claim 12, wherein the subscript n is 0, 1 or 2.

29. The compound or a pharmaceutically acceptable salt thereof according to claim 12, wherein the subscript p is 1 or 2.

30. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has a structure selected from the following:

31. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 30, and a pharmaceutically acceptable carrier or excipient.

32. The pharmaceutical composition according to claim 31, which further comprises one or more additional therapeutic agents.

33. The pharmaceutical composition according to claim 31, which is used for treating a disease or disorder mediated by the glucagon-like peptide 1 receptor (GLP-1R).

34. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 30 in the manufacture of a medicament for use in a method of treating a GLP-1R-mediated disease or disorder in a subject in need thereof.

35. The use according to claim 34, wherein the disease or disorder is a liver disease.

36. The use according to claim 35, wherein the disease or disorder is liver fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cirrhosis, hepatocellular carcinoma, primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC).

37. The use according to claim 36, wherein the disease or disorder is non-alcoholic fatty liver disease (NAFLD).

38. The use according to claim 36, wherein the disease or disorder is non-alcoholic steatohepatitis (NASH).

39. The use according to claim 34, wherein the disease or disorder is a metabolic disease.

40. The use according to claim 39, wherein the disease or disorder is type 1 diabetes, type 2 diabetes, prediabetes, latent autoimmune diabetes, maturity-onset diabetes of the young, early-onset diabetes, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, impaired glucose tolerance, diabetic neuropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, obesity, eating disorder, sleep apnea, weight gain, sugar craving, dyslipidemia, hyperinsulinemia, congestive heart failure, myocardial infarction, 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, cataract, metabolic syndrome, angina, premenstrual syndrome, thrombosis, atherosclerosis, impaired glucose metabolism or restenosis.

41. The use according to claim 34, wherein the compound or a pharmaceutically acceptable salt thereof is administered in combination with an additional therapeutic agent.

42. The pharmaceutical composition according to claim 32, wherein the additional therapeutic agent is an apoptosis signal-regulating kinase (ASK-1) inhibitor, a farnesoid X receptor (FXR) agonist, a peroxisome proliferator-activated receptor α (PPARα) agonist, fish oil, an acetyl-CoA carboxylase (ACC) inhibitor, or a TGFβ antagonist.

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