GLP-1R modulating compounds

Abstract

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

Description

[0001] This application is a divisional application of Chinese invention patent application (filed on October 22, 2020, application number 202080074611.4, PCT application number PCT / US2020 / 056867, entitled "GLP-1R Modulating Compound").

[0002] Cross-references to related applications

[0003] This application claims priority to U.S. Provisional Application No. 62 / 926,270, filed October 25, 2019, and U.S. Provisional Application No. 63 / 028,187, filed May 21, 2020, both of which are incorporated herein by reference in their entirety for all purposes. Technical Field

[0004] This disclosure relates to compounds that bind to the glucagon-like peptide-1 receptor (GLP-1R) and act as its agonists or modulators, as well as compounds that act as agonists or modulators of GLP-1R. This disclosure also relates to the use of the compounds for the treatment and / or prevention of diseases and / or conditions. Background Technology

[0005] Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted by enteroendocrine cells in the gut in response to diet. GLP-1 is thought to play a role in postprandial blood glucose regulation by directly increasing diet-induced insulin secretion from pancreatic β-cells and by promoting satiety through delaying food transport through the intestines. GLP-1 mediates intracellular signaling via the GLP-1 receptor (GLP-1R), a member of the G protein-coupled receptor family located on the cell membrane, which, upon activation, leads to the accumulation of the second messenger cyclic adenosine monophosphate (cAMP). Nonalcoholic steatohepatitis (NASH) is associated with features of metabolic syndrome, including obesity, type 2 diabetes, insulin resistance, and cardiovascular disease.

[0006] GLP-1R agonists are currently being investigated in relation to diabetes, obesity, and NASH. GLP-1R agonists include peptides already approved for the treatment of type 2 diabetes, such as exenatide, liraglutide, and dulaglutide. These peptides are primarily administered via subcutaneous injection. Oral GLP-1 agonists are also being investigated for the treatment of type 2 diabetes. Some GLP-1R agonists, such as liraglutide, dulaglutide, and exenatide, are resistant to rapid degradation by dipeptidyl peptidase 4, resulting in a longer half-life for GLP-1 agonists than for endogenous GLP-1.

[0007] In the treatment of metabolic and related diseases, including but not limited to NASH, obesity and type 2 diabetes, there remains a need for compounds with the desired therapeutic properties, metabolic properties and / or ease of administration, such as GLP-1R agonists. Summary of the Invention

[0008] In one embodiment, this disclosure provides a compound of formula (IA-1):

[0009]

[0010] Or its pharmaceutically acceptable salt, wherein

[0011] R 1 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, -SR 1b -S(O)R 1b -S(O)(NH)R 1b -S(O)2R 1b -S(O)2N(R) 1b (R) 1c ), -S(O)(NR 1b )R 1c -C(O)N(R) 1b (R) 1c -C(O)R 1b or -C(O)OR 1c ,

[0012] The alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is optionally divided by one to four Z groups. 1 replace;

[0013] Ring A is C 6-10 aryl or heteroaryl, each of which is optionally bound by one to four Zn groups. 1a replace;

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

[0015] R 2 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, -CN, -OR 2a -SR 2a -S(O)R 2a -S(O)(NH)R 2a -S(O)2R 2a -S(O)2N(R) 2a (R) 2b ) or -S(O)(NR 2a )R 2b ,

[0016] The alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is each optionally divided by one to four Z groups. 1 replace;

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

[0018] R 3 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, -CN, -NO2, -OR 3a -C(O)R 3a -CH2C(O)OR 3a -C(O)OR 3a -C(O)N(R) 3a (R) 3b ), -N(R 3a )C(O)R 3b -N(R) 3a )C(O)OR 3b -N(R) 3a )C(O)N(R 3b )2、-C(O)NHS(O)2R 3a -C(O)NR 3a S(O)2R 3b -C(O)NR 3a S(O)2NR 3b R 3c -C(O)NR 3a -S(O)(=NR 3b )R 3c -S(O)2R 3a-S(O)2OR 3a -S(O)2N(R) 3a (R) 3b ), -N(R 3a )S(O)2R 3b -S(O)2NHC(O)R 3a -S(O)(=NR) 3a )R 3b -S(O)(=NR) 3a )NR 3b -S(=NR) 3a (=NR) 3b )R 3c -P(O)(OR) 3a (R) 3b -P(O)(OR) 3a (OR) 3b -B(OR) 3a (OR) 3b ) or -OC 1-6 Alkyl-C(O)OR 3a The alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally divided by one to four R groups. 3d replace;

[0019] Each R 3a R 3b and R 3c H and C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkoxyalkyl, -C 1-4 Alkyl-N(R) 9a (R) 9b -C 1-4 Alkyl-N(R) 9a )C(O)-OC 1-4 Alkyl-OP(O)(OR) 9c )2、-C 1-4 Alkyl-C(O)N(R) 9a (R) 9b -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-OC 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl-N(R) 9a (R) 9b -C 1-4 Alkyl-OC(O)-C 1-4Alkyl-OP(O)(OR) 9c )2、-C 1-4 Alkyl-C 3-8 cycloalkyl, -C 1-4 alkyl-heterocyclic, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, -CH2CH(N(R) 9a )2)C(O)OR 9b -P(O)(OR) 9c )2、-OP(O)(OR 9c )2、-CH2P(O)(OR 9c )2、-CH2OP(O)(OR 9c )2、-OCH2P(O)(OR 9c )2、-C(O)OCH2P(O)(OR 9c )2、-P(O)(R 9c (OR) 9d ), -OP(O)(R 9c (OR) 9d -CH2P(O)(R) 9c (OR) 9d ), -OCH2P(O)(R 9c (OR) 9d -C(O)OCH2P(O)(R 9c (OR) 9d ), -P(O)(N(R) 9c )2)2、-OP(O)(N(R 9c )2)2、-CH2P(O)(N(R 9c )2)2、-OCH2P(O)(N(R 9c )2)2、-C(O)OCH2P(O)(N(R 9c )2)2、-P(O)(N(R 9c )2)(OR 9d ), -OP(O)(N(R) 9c )2)(OR 9d -CH2P(O)(N(R) 9c )2)(OR 9d ), -OCH2P(O)(N(R) 9c )2)(OR 9d ), -C(O)OCH2P(O)(N(R) 9c )2)(OR 9d ), -P(O)(R 9c )(N(R 9d)2), -OP(O)(R 9c )(N(R 9d )2), -CH2P(O)(R 9c )(N(R 9d )2), -OCH2P(O)(R 9c )(N(R 9d )2), -C(O)OCH2P(O)(R 9c )(N(R 9d )2) or C 1-6 alkyl-heterocyclic groups;

[0020] The alkyl, alkenyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally surrounded by one to four Z groups. 1b replace,

[0021] Each R 4 Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 4a -C(O)R 4a -C(O)OR 4a -C(O)N(R) 4a (R) 4b ), -N(R 4a (R) 4b ), -N(R 4a )2(R 4b ) + -N(R) 4a )-C(O)R 4b -N(R) 4a )C(O)O(R 4b ), -N(R 4a )C(O)N(R 4b (R) 4c ), -N(R 4a )S(O)2(R 4b ), -N(R 4a )S(O)2-N(R 4b (R) 4c ), -N(R 4a )S(O)2O(R 4b -OC(O)R 4a -OC(O)OR 4a-OC(O)-N(R) 4a (R) 4b ), -SR 4a -S(O)R 4a -S(O)(NH)R 4a -S(O)2R 4a -S(O)2N(R) 4a (R) 4b ), -S(O)(NR 4a )R 4b or -Si(R) 4a )3;

[0022] The alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally divided by one to four Z groups. 1b replace;

[0023] Or two R atoms connected to adjacent ring atoms 4 Groups combine with the atoms they are attached to to form C 5-10 Cycloalkyl or heterocyclic group, each optionally surrounded by one to four Z groups. 1b replace;

[0024] R 5a and R 5b Each independently represents H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkoxyalkyl, halogen, C 3-10 Cycloalkyl, heterocyclic, -C 1-6 Alkyl-N(R) 9a (R) 9b -CN, -OR 5a1 or

[0025] -N(R 5a1 (R) 5a2 );

[0026] Or R 5a and R 5b They combine with the atoms they are attached to to form C 3-10 Cycloalkyl or heterocyclic group, each optionally surrounded by one to four R groups. 5a3 replace;

[0027] Each R 5a1 and R 5a2 H and C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, C 6-10aryl or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally surrounded by one to four R groups. 5a4 replace;

[0028] V is -C(O)-, -O-, -N(R)- 6a - or -C(R) 6b (R) 6c )-;

[0029] R 6a For H, C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, -S(O)2R 6a1 or -S(O)2N(R 6a1 (NR) 6a2 ), wherein the cycloalkyl or heterocyclic group is optionally C 1-6 Alkyl, F, or -CN substitution;

[0030] Each R 6b and R 6c H and C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkoxyalkyl, halogen, C 3-10 Cycloalkyl, heterocyclic, -C 1-6 Alkyl-N(R) 9a (R) 9b -CN, -OR 6c1 or -N(R) 6c2 (R) 6c3 ), wherein the alkyl, cycloalkyl, or heterocyclic group is optionally surrounded by one to four R groups. 6b1 replace;

[0031] Or R 6b and R 6c They combine with the atoms they are attached to to form C 3-10 Cycloalkyl or heterocyclic group, each optionally surrounded by one to four R groups. 6b1 replace;

[0032] Or R 6a Or R 6c With an R 4 Groups and the atoms they are attached to combine to form C 5-10 Cycloalkyl or heterocyclic group, each optionally surrounded by one to four R groups. 10 replace;

[0033] Y is -N(R) 7 )-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NH)- or -S(O)(=NR 7)-;

[0034] Each R 1a R 3d R 5a3 R 5a4 R 6b1 and R 10 Independently for C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-10 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, CO2R 3e -NO2 or -C(O)N(R) 2a (R) 2b ), wherein the heterocyclic or heteroaryl group is optionally C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; and

[0035] Each R 6a1 R 6a2 R 6c1 R 6c2 R 6c3 and R 7 H and C independently 1-6 Alkyl or C 3-10 cycloalkyl;

[0036] Each R 8 Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, CO2R 3e , -NO2, -NH2, -N3, -SH, -O(C 1-9 Alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 2-6 alkenyl), -O(C) 2-6 alkynyl group), -O(C 3-15 cycloalkyl), -O (heterocyclic), -O (C 6-10 aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8Halogenated alkyl), -NH(C) 2-6 alkenyl), -NH(C) 2-6 alkynyl group), -NH(C 3-15 cycloalkyl), -NH (heterocyclic), -NH (C 6-10 aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 1-8 (halogenated alkyl)2, -N(C) 2-6 alkenyl)2, -N(C 2-6 2, -N(C) 3-15 cycloalkyl)2, -N(heterocyclic)2, -N(C 6-10 aryl)2, -N(heteroaryl)2, -N(C 1-9 Alkyl)(C 1-8 Halogenated alkyl), -N(C) 1-9 Alkyl)(C 2-6 alkenyl), -N(C) 1-9 Alkyl)(C 2-6 alkynyl group), -N(C 1-9 Alkyl)(C 3-15 cycloalkyl), -N(C) 1-9 Alkyl (heterocyclic), -N(C) 1-9 Alkyl)(C 6-10 aryl), -N(C 1-9 Alkyl)(heteroaryl), -C(O)(C 1-9 Alkyl), -C(O)(C 1-8 Halogenated alkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 ynyl group), -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 Halogenated alkyl groups), -C(O)O(C 2-6 alkenyl), -C(O)O(C 2-6 alkynyl group), -C(O)O(C 3-15 cycloalkyl), -C(O)O (heterocyclic), -C(O)O (C 6-10 aryl), -C(O)O (heteroaryl), -C(O)NH2, -C(O)NH(C 1-9 Alkyl), -C(O)NH(C 1-8 Halogenated alkyl), -C(O)NH(C 2-6 alkenyl), -C(O)NH(C 2-6 ynyl group), -C(O)NH(C 3-15cycloalkyl), -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 (halogenated alkyl)2、-C(O)N(C 2-6 alkenyl)2, -C(O)N(C 2-6 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, -NHC(O)(C 1-9 Alkyl), -NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 ynyl group), -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (C 6-10 aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (C 6-10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -NHC(O)NH(C 1-8 (halogenated alkyl), -NHC(O)NH(C) 2-6 alkenyl), -NHC(O)NH(C 2-6 ), -NHC(O)NH(C 3-15 cycloalkyl), -NHC(O)NH (heterocyclic), -NHC(O)NH (C 6-10 aryl), -NHC(O)NH (heteroaryl), -NHS(O)(C 1-9 alkyl), -N(C) 1-9 Alkyl)(S(O)(C) 1-9 alkyl), -S(C 1-9 alkyl), -S(C 1-8 Halogenated alkyl), -S(C 2-6 alkenyl), -S(C 2-6 alkynyl group), -S(C 3-15cycloalkyl), -S (heterocyclic), -S (C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2、-S(O)(C 1-9 Alkyl), -S(O)(C 1-8 Halogenated alkyl groups), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 ynyl group), -S(O)(C 3-15 cycloalkyl), -S(O)(heterocyclic), -S(O)(C 6-10 aryl), -S(O) (heteroaryl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 2-6 alkenyl), -S(O)2(C 2-6 alkynyl group), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (C 6-10 aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2;

[0037] In each example, the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one to three C atoms. 1-9 Alkyl, C 1-8 Halogenated alkyl groups, halogens, -OH, -NH2, -CO2H, -O(C) 1-9 Alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 3-15 cycloalkyl), -O (heterocyclic), -O (aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 3-15 cycloalkyl), -NH (heterocyclic), -NH (aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 3-15 cycloalkyl)2、-NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (aryl), -NHC(O)O (heteroaryl), -NHC(O)NH(C 1-9 Alkyl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2-substituted;

[0038] Each R 9a and R 9b H and C independently 1-6 Alkyl or C 1-6 Halogenated alkyl, or R 9a and R 9b Together they form a 6-membered heterocyclic group;

[0039] Each Z 1 Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic,

[0040] C 6-10 aryl, heteroaryl, oxo, -NO2, -N3, -CN, -OR 12a -C(O)-R 12a -C(O)OR 12a ,

[0041] -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 ,

[0042] -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 ),

[0043] -NR 12a S(O)2N(R 12b (R) 12c -NR 12a S(O)₂O(R) 12b -OC(O)R 12a -OC(O)OR 12a ,

[0044] -OC(O)-N(R 12a (R) 12b ), -SR 12a -S(O)R 12a -S(O)(NH)R 12a -S(O)2R 12a ,

[0045] -S(O)2N(R 12a (R) 12b ), -S(O)(NR 12a )R 12b or -Si(R) 12a 3;

[0046] The alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally divided by one to four Z groups. 1a replace;

[0047] Each Z 1a Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 12a -C(O)R 12a ,

[0048] -C(O)OR 12a -C(O)N(R) 12a (R) 12b), -N(R 12a (R) 12b ), -N(R 12a )2(R 12b ) + ,

[0049] -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 ),

[0050] -N(R 12a )S(O)2(R 12b ), -N(R 12a )S(O)2-N(R 12b (R) 12c ), -N(R 12a )S(O)2O(R 12b ),

[0051] -OC(O)R 12a -OC(O)OR 12a -OC(O)-N(R) 12a (R) 12b ), -SR 12a ,

[0052] -S(O)R 12a -S(O)(NH)R 12a -S(O)2R 12a -S(O)2N(R) 12a (R) 12b ), -S(O)(NR 12a )R 12b or -Si(R) 12a )3;

[0053] The alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally divided by one to four Z groups. 1b replace;

[0054] Each Z 1b Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, CO2R 3e, -NO2, -NH2, -N3, -SH, -O(C 1-9 Alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 2-6 alkenyl), -O(C) 2-6 alkynyl group), -O(C 3-15 cycloalkyl), -O (heterocyclic), -O (C 6-10 aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 2-6 alkenyl), -NH(C) 2-6 alkynyl group), -NH(C 3-15 cycloalkyl), -NH (heterocyclic), -NH (C 6-10 aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 1-8 (halogenated alkyl)2, -N(C) 2-6 alkenyl)2, -N(C 2-6 2, -N(C) 3-15 cycloalkyl)2, -N(heterocyclic)2, -N(C 6-10 aryl)2, -N(heteroaryl)2, -N(C 1-9 Alkyl)(C 1-8 Halogenated alkyl), -N(C) 1-9 Alkyl)(C 2-6 alkenyl), -N(C) 1-9 Alkyl)(C 2-6 alkynyl group), -N(C 1-9 Alkyl)(C 3-15 cycloalkyl), -N(C) 1-9 Alkyl (heterocyclic), -N(C) 1-9 Alkyl)(C 6-10 aryl), -N(C 1-9 Alkyl)(heteroaryl), -C(O)(C 1-9 Alkyl), -C(O)(C 1-8 Halogenated alkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 ynyl group), -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 Halogenated alkyl groups), -C(O)O(C 2-6 alkenyl), -C(O)O(C 2-6 alkynyl group), -C(O)O(C3-15 cycloalkyl), -C(O)O (heterocyclic), -C(O)O (C 6-10 aryl), -C(O)O (heteroaryl), -C(O)NH2, -C(O)NH(C 1-9 Alkyl), -C(O)NH(C 1-8 Halogenated alkyl), -C(O)NH(C 2-6 alkenyl), -C(O)NH(C 2-6 ynyl group), -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 (halogenated alkyl)2、-C(O)N(C 2-6 alkenyl)2, -C(O)N(C 2-6 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, -NHC(O)(C 1-9 Alkyl), -NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 ynyl group), -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (C 6-10 aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (C 6-10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -NHC(O)NH(C 1-8 (halogenated alkyl), -NHC(O)NH(C) 2-6 alkenyl), -NHC(O)NH(C 2-6 ), -NHC(O)NH(C 3-15 cycloalkyl), -NHC(O)NH (heterocyclic), -NHC(O)NH (C6-10 aryl), -NHC(O)NH (heteroaryl), -NHS(O)(C 1-9 alkyl), -N(C) 1-9 Alkyl)(S(O)(C) 1-9 alkyl), -S(C 1-9 alkyl), -S(C 1-8 Halogenated alkyl), -S(C 2-6 alkenyl), -S(C 2-6 alkynyl group), -S(C 3-15 cycloalkyl), -S (heterocyclic), -S (C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2、-S(O)(C 1-9 Alkyl), -S(O)(C 1-8 Halogenated alkyl groups), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 ynyl group), -S(O)(C 3-15 cycloalkyl), -S(O)(heterocyclic), -S(O)(C 6-10 aryl), -S(O) (heteroaryl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 2-6 alkenyl), -S(O)2(C 2-6 alkynyl group), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (C 6-10 aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2;

[0055] In each example, the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one to three C atoms. 1-9 Alkyl, C 1-8 Halogenated alkyl groups, halogens, -OH, -NH2, -CO2H, -O(C) 1-9 Alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 3-15 cycloalkyl), -O (heterocyclic), -O (aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 3-15 cycloalkyl), -NH (heterocyclic), -NH (aryl), -NH (heteroaryl), -N (C1-9 Alkyl)2, -N(C 3-15 cycloalkyl)2、-NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (aryl), -NHC(O)O (heteroaryl), -NHC(O)NH(C 1-9 Alkyl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2-substituted;

[0056] 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 H and C independently 1-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, heterocyclic, C 6-10 aryl or heteroaryl, wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally divided by one to four Z-groups. 1b Replace; and

[0057] Each R 3e H and C independently 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-4 Alkyl-N(R) 9a (R)9b -C 1-4 Alkyl-C(O)N(R) 9a (R) 9b -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-OC 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl-N(R) 9a (R) 9b -C 1-4 Alkyl-C 3-8 cycloalkyl, -C 1-4 alkyl-heterocyclic, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, -P(O)(OR) 9c )2、-CH2P(O)(OR 9c )2、-OCH2P(O)(OR 9c )2、-C(O)OCH2P(O)(OR 9c )2、-P(O)(R 9c (OR) 9d ), -OP(O)(R 9c (OR) 9d -CH2P(O)(R) 9c (OR) 9d -C(O)OCH2P(O)(R 9c (OR) 9d ), -P(O)(N(R) 9c )2)2、-CH2P(O)(N(R 9c )2)2、-C(O)OCH2P(O)(N(R 9c )2)2、-P(O)(N(R 9c )2)(OR 9d -CH2P(O)(N(R) 9c )2)(OR 9d ), -C(O)OCH2P(O)(N(R) 9c )2)(OR 9d ), -P(O)(R 9c )(N(R 9d )2), -CH2P(O)(R 9c )(N(R 9d )2) or -C(O)OCH2P(O)(R 9c )(N(R 9d)2); wherein the alkyl, alkenyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is each optionally surrounded by one to four Z groups. 1b Substitution; wherein each heteroaryl group has 5 to 12 ring members and one to four heteroatoms, each independently N, O, or S; and

[0058] Each heterocyclic group has 3 to 12 ring members and one to four heteroatoms that are independently N, O or S.

[0059] This disclosure also provides pharmaceutical compositions, methods, and uses comprising compounds of formulas (I), (IA-1), (IA-2), or pharmaceutically acceptable salts thereof. For example, the compounds of this disclosure are commonly used in methods for treating GLP-1R-mediated diseases or conditions. Detailed Implementation

[0060] I. Definition

[0061] 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 beginning or end of chemical groups are for the purpose of indicating the point of connection with the parent part; chemical groups may be depicted without one or more dashes without losing their ordinary meaning. Prefixes such as "C" u-v "or "C u -C v "Indicates that the following groups have u to v carbon atoms, where u and v are integers. For example, "C 1-6 "alkyl" or "C1-C6 alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0062] "Alkyl" is a monovalent or divalent straight-chain or branched saturated hydrocarbon radical. For example, an alkyl group can have 1 to 10 carbon atoms (i.e., C64 ... 1-10 Alkyl groups or 1 to 8 carbon atoms (i.e., C464, C56, C6 ... 1-8 Alkyl groups or 1 to 6 carbon atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 1-6 Alkyl groups or 1 to 4 carbon atoms (i.e., C46) 1-4Alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, isopropyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, -CH(C H3)2CH3), 2-methyl-2-propyl (t-Bu, tert-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH 2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(C The alkyl groups can be unsubstituted or substituted.

[0063] "Alkoxy" refers to the -O-alkyl group, where alkyl is as defined above. For example, C 1-4 An alkoxy group is a -O-alkyl group having 1 to 4 carbon atoms. Alkoxy groups can be unsubstituted or substituted.

[0064] "Alkoxyalkyl" is an alkoxy group attached to an alkyl group as defined above, such that the alkyl group is divalent. For example, C 2-6 Alkoxyalkyl groups include -CH2-OMe, -CH2-O-iPr, -CH2-CH2-OMe, -CH2-CH2-O-CH2-CH3, and -CH2-CH2-O-tBu. The alkoxyalkyl group can be unsubstituted or substituted.

[0065] "Alkenyl" is a monovalent or divalent straight-chain or branched hydrocarbon radical having at least one carbon-carbon double bond. For example, an alkenyl group can have 2 to 8 carbon atoms (i.e., C2, C3, C4, C5, C6, C6, C7, C8, C9 ... 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 groups. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and -CH2-CH=CH-CH3. Alkenyl groups can be unsubstituted or substituted.

[0066] "Alynyl" is a monovalent or divalent straight-chain or branched hydrocarbon radical having at least one carbon-carbon triple bond. For example, an alkynyl group can have 2 to 8 carbon atoms (i.e., C64 ... 2-8 (alkynyl group) or 2 to 6 carbon atoms (i.e., C10, C20, C30, C40, C50, C6 ... 2-6 (alkynyl group) or 2 to 4 carbon atoms (i.e., C46) 2-4 (Alynyl group). Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), and -CH2-C≡C-CH3. The alkynyl group can be unsubstituted or substituted.

[0067] "Halogens" refer to fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I).

[0068] "Haloalkyl" is an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently substituted with a halogen (which may be the same or different), such that the alkyl group is divalent. The alkyl group and the halogen may be any of those described above. In some embodiments, the haloalkyl group defines the number of carbon atoms in the alkyl moiety, for example, C... 1-4 Alkyl halogens include CF3, CH2F, CHF2, CH2CF3, CH2CH2CF3, CCl2CH2CH2CH3, and C(CH3)2(CF2H). The alkyl halogen group can be unsubstituted or substituted.

[0069] "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 a halogen (which may be the same or different), such that the alkyl group is divalent. The alkoxy group and the halogen may be any of those described above. In some embodiments, the haloalkoxy group defines the number of carbon atoms in the alkyl moiety, for example, C... 1-4 Haloalkoxy groups include OCF3, OCH2F, OCH2CF3, OCH2CH2CF3, OCCl2CH2CH2CH3, and OC(CH3)2(CF2H). The haloalkoxy group can be unsubstituted or substituted.

[0070] "Cycloalkyl" is a monovalent or divalent single all-carbon ring or a polyfused all-carbon ring system, wherein the ring is, in each instance, a non-aromatic saturated or unsaturated ring. For example, in some embodiments, the cycloalkyl group has 3 to 12 carbon atoms, 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, 3 to 5 carbon atoms, or 3 to 4 carbon atoms. Exemplary 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., ring systems comprising 2 rings). When valence requirements permit, these rings in the polyfused ring system may be interconnected by fusion, spirocyclic, or bridging bonds. Exemplary polycyclic cycloalkyl groups include octahydrocyclopentadiene, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[2.2.2]oct-2-ene, and spiro[2.5]octane. The cycloalkyl groups may be unsubstituted or substituted.

[0071] "alkylcycloalkyl" means an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently substituted by a cycloalkyl group (which may be the same or different). The alkyl group and the cycloalkyl group may be any of those described above. In some embodiments, the number of carbon atoms in the alkyl and cycloalkyl moieties may be specified separately, for example, C... 1-6 Alkyl-C 3-12 Cycloalkyl. The alkylcycloalkyl group can be unsubstituted or substituted.

[0072] As used herein, “aryl” refers to a monovalent or divalent single all-carbon aromatic ring or a polyfused all-carbon ring system, wherein the ring is aromatic. For example, in some embodiments, the aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms. Aryl groups include phenyl radicals. Aryl groups also include polyfused ring systems having about 9 to 20 carbon atoms (e.g., ring systems comprising 2, 3, or 4 rings), wherein multiple rings are aromatic. When valence requirements permit, these rings in a polyfused ring system may be interconnected by fused bonds. It should also be understood that when referring to a range of atomic aryl groups (e.g., 6-10 aryl groups), the atomic range is the total number of ring atoms in the aryl group. For example, a 6-membered aryl group would include a phenyl group, and a 10-membered aryl group would include a naphthyl group. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, etc. Aryl groups can be unsubstituted or substituted.

[0073] "alkylaryl" means an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently substituted by an aryl group (which may be the same or different). The alkyl group and the aryl group may be either of those described above, such that the alkyl group is divalent. In some embodiments, the alkylaryl group has 7 to 24 carbon atoms, 7 to 16 carbon atoms, 7 to 13 carbon atoms, or 7 to 11 carbon atoms. 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, C7 alkylaryl refers to benzyl, while C7 alkylaryl refers to Benzyl. 11 Alkyl aryl groups include 1-methylnaphthyl and n-pentylphenyl. In some embodiments, the number of carbon atoms in the alkyl and aryl moieties can be specified separately, for example, C... 1-6 Alkyl-C 6-10 Aryl. Non-limiting examples of alkyl aryl groups include, but are not limited to, benzyl, 2,2-dimethylphenyl, n-pentylphenyl, 1-methylnaphthyl, 2-ethylnaphthyl, etc. Alkyl aryl groups may be unsubstituted or substituted.

[0074] As used herein, “heterocyclic group” or “heterocyclic alkyl group” refers to a single saturated or partially unsaturated non-aromatic ring or non-aromatic polycyclic system having at least one heteroatom (i.e., at least one cyclic heteroatom selected from oxygen, nitrogen, and sulfur). Unless otherwise specified, a heterocyclic group has 3 to about 20 cyclic atoms, for example 3 to 12 cyclic atoms, for example 4 to 12 cyclic atoms, 4 to 10 cyclic atoms, or 3 to 8 cyclic atoms, or 3 to 6 cyclic atoms, or 3 to 5 cyclic atoms, or 4 to 6 cyclic atoms, or 4 to 5 cyclic atoms. Thus, the term includes a single saturated or partially unsaturated ring (e.g., a 3, 4, 5, 6, or 7-membered ring) having about 1 to 6 cyclic carbon atoms and about 1 to 3 cyclic heteroatoms selected from oxygen, nitrogen, and sulfur. When valence requirements permit, these rings in a polyfused ring system (e.g., bicyclic heterocyclic groups) can be interconnected through fusion, spirocyclic, and bridging bonds. Heterocyclic rings include, but are not limited to, aziridine, imidazoline, morpholine, ethylene oxide (epoxide), oxacyclobutane, thiobutane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinine ring, 2-oxa-6-azaspiro[3.3]hept-6-yl, 6-oxa-1-azaspiro[3.3]hept-1-yl, 2- Thiophene-6-azaspiro[3.3]hept-6-yl, 2,6-diazaspiro[3.3]hept-2-yl, 2-azabicyclo[3.1.0]hex-2-yl, 3-azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.1.1]hexyl, 2-azabicyclo[2.2.1]hept-2-yl, 4-azaspiro[2.4]heptyl, 5-azaspiro[2.4]heptyl, etc. The heterocyclic group can be unsubstituted or substituted.

[0075] "alkyl heterocyclic group" means an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently substituted by a heterocyclic group (which may be the same or different). The alkyl group and the heterocyclic group can be any of those described above, such that the alkyl group is divalent. In some embodiments, the number of atoms in the alkyl and heterocyclic moieties may be specified separately, for example, having one to three heteroatoms, each independently N, O, or S. 1-6 Alkyl-3 to 12-membered heterocyclic groups. The alkyl heterocyclic group can be unsubstituted or substituted.

[0076] "Heteroaryl" refers to a monoaryl aromatic ring having at least one atom other than carbon, wherein the atom is selected from oxygen, nitrogen, and sulfur; "heteroaryl" also includes polyfused ring systems having at least one such aromatic ring, which will be further described below. Thus, "heteroaryl" includes a monoaryl aromatic ring having about 1 to 6 carbon atoms and about 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur. Sulfur and nitrogen atoms may also be present in oxidized forms, provided that the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridinyl, pyrimidinyl, oxazolyl, or furanyl. "Heteroaryl" also includes polyfused ring systems (e.g., ring systems comprising 2, 3, or 4 rings), wherein a heteroaryl group as defined above is fused with one or more rings selected from heteroaryl (to form, for example, 1,8-naphthidyl) and fused with an aryl group (to form, for example, benzimidazolyl or indazolyl), thereby forming a polyfused ring system. Therefore, a heteroaryl group (monoaromatic ring or polyfused ring system) may have about 1 to 20 carbon atoms and about 1 to 6 heteroatoms within the heteroaryl ring. For example, a tetrazolium group has 1 carbon atom and 4 nitrogen heteroatoms within the ring. These rings of the polyfused ring system may be interconnected by fused bonds when valence requirements permit. It should be understood that the individual rings of the polyfused ring system may be connected relative to each other in any order. It should be understood that the connection points of the heteroaryl group or the polyfused ring system may be located on any suitable atom of the heteroaryl group or the polyfused ring system, including carbon atoms and heteroatoms (e.g., nitrogen). It should also be understood that when referring to a certain atomic range of mono-heteroaryl groups (e.g., 5- to 10-membered heteroaryl groups), the atomic range is the total number of ring atoms of the heteroaryl group and includes carbon atoms and heteroatoms. It should also be understood that these rings in the polyfused ring system may include aryl rings (e.g., 3, 4, 5, 6, or 7-membered rings) fused with heterocycles having saturated or partially unsaturated bonds, having about 1 to 6 cyclic carbon atoms and about 1 to 3 cyclic heteroatoms selected from oxygen, nitrogen, and sulfur. For example, 5-membered heteroaryl groups include thiazolyl groups, and 10-membered heteroaryl groups include quinolinyl groups. Exemplary heteroaryl groups include, but are not limited to, pyridyl, pyrroloyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiophene, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, oxadiazolyl, thiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzooxazolyl, indazole, quinoxolinyl, quinazolinyl, benzofuranyl, benzimidazolyl, thiophene, pyrrolo[2,3-b]pyridyl, quinazolinyl-4(3H)-one, triazolyl, and tetrazolyl. The heteroaryl group may be unsubstituted or substituted.

[0077] "alkylheteroaryl" means an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently substituted by a heteroaryl group (which may be the same or different), such that the alkyl group is divalent. The alkyl group and the heteroaryl group may be any of those described above. In some embodiments, the number of atoms in the alkyl and heteroaryl moieties are specified separately, for example, C having one to four heteroatoms, each independently N, O, or S. 1-6 Alkyl-5 to 10-membered heteroaryl groups. The alkyl heteroaryl groups can be unsubstituted or substituted.

[0078] As used in this article, "oxo" refers to =O.

[0079] As used herein, “substitution” 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.

[0080] "Compounds of this disclosure" includes compounds disclosed herein, such as compounds of formula (I), (Ia), (Ib), (Ic), and (Id), including the compounds of the examples. In some embodiments, "compounds of this disclosure" includes compounds of formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and (Id).

[0081] "Pharmaceutical acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the U.S. Food and Drug Administration for use in humans or livestock.

[0082] As used herein, "therapeutic effective amount" or "effective amount" means an amount capable of effectively evoking the desired biological or medical response, including amounts of compounds that, when administered to a subject to treat a disease, are sufficient to affect such treatment of the disease. Effective amounts will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject being treated. Effective amounts may include a range of amounts. As understood in the art, an effective amount may be one or more doses; that is, a single dose or multiple doses may be required to achieve the desired therapeutic endpoint. Effective amounts may be considered in the case of administration of one or more therapeutic agents, and administration of a single agent may be considered in an effective amount if a desired or beneficial outcome can be achieved or attained when used in combination with one or more other agents. The appropriate dose of any co-administered compounds may optionally be reduced due to the combined effects of the compounds (e.g., additive or synergistic effects).

[0083] As used herein, “co-administration” means administering a unit dose of the compound disclosed herein before or after administration of a unit dose of one or more additional therapeutic agents, for example, administering the compound disclosed herein within seconds, minutes, or hours after administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of the compound disclosed herein 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 the compound disclosed herein within seconds or minutes. In some embodiments, a unit dose of the compound disclosed herein is administered first, followed by a unit dose of one or more additional therapeutic agents several hours later (e.g., 1 hour–12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of the compound disclosed herein several hours later (e.g., 1 hour–12 hours). Co-administration of the 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.

[0084] Pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms, and other substances that can be used to prepare pharmaceutical compositions suitable for veterinary or human use.

[0085] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts, or, where appropriate, as free bases. Pharmaceutically acceptable salts are non-toxic salts of compounds in their free base form, which possess the desired pharmacological activity of a free base. These salts can be derived from inorganic or organic acids or bases. For example, compounds containing basic nitrogen can be prepared as pharmaceutically acceptable salts by contacting them with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propargylates, oxalates, malonates, succinates, octanoates, sebacic acid salts, fumarates, maleates, etc. Alkyne-1,4-diacidate, hexyne-1,6-diacidate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methanesulfonate, 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, Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0086] Examples of pharmaceutically acceptable salts of the compounds disclosed herein also include those derived from suitable bases (such as alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium, and N(C1≡C4 alkyl)4). + Salts. Also includes base addition salts, such as sodium or potassium salts.

[0087] Also provided are compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, wherein one to n hydrogen atoms bonded to a carbon atom may be substituted with a deuterium atom or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds can increase resistance to metabolism and are therefore used to increase the half-life of compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, when administered to mammals. 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 substituted with deuterium.

[0088] Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 36 Cl、 123 I and 125 I. Using positron-emitting isotopes such as 11 C 18 F, 15 O and 13 Substitution of N can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. Isotopically labeled compounds of formula (IA-1) and / or (I) can generally be prepared using conventional techniques known to those skilled in the art, or by methods similar to those described in the examples listed below, using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent.

[0089] The compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts, may include one or more asymmetric centers, and thus may produce enantiomers, diastereomers, and other stereoisomers that can be defined by absolute stereochemistry as (R)- or (S)- or for amino acids as (D)- or (L)-. This disclosure is intended to include all such possible isomers as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain alkene double bonds or other geometrically asymmetric centers, and unless otherwise stated, it is intended that the compounds include E and Z geometric isomers. Similarly, all tautomers are also intended to be included. When compounds are represented in their chiral form, it should be understood that embodiments cover, but are not limited to, specific diastereomers or enantiomer-enriched forms. When chirality is not specified but is present, it should be understood that the embodiment relates to specific diastereomers or enantiomer-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 not equal to 1:1.

[0090] As used herein, a "stereoisomer" refers to a compound consisting of identical atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. This disclosure envisions various stereoisomers and mixtures thereof and includes "enantiomers," which are two stereoisomers whose molecules are mirror images of each other that cannot be superimposed.

[0091] As used herein, "tautomer" refers to 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.

[0092] As used herein, "solvent" refers to the result of the interaction between the solvent and the compound. Solvents of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0093] As used herein, “hydrate” means a compound of this disclosure that is chemically associated with one or more water molecules.

[0094] "Prevention" or "preventing" means any treatment that prevents the development of clinical symptoms of a disease or condition. In some implementations, the compound may be administered to subjects (including humans) who are at risk or have a family history of the disease or condition.

[0095] As used herein, a "prodrug" is a derivative of a drug that, when administered to the human body, is converted into the parent drug via some chemical or enzymatic pathway. In some implementations, a "prodrug" is a non-biologically active derivative of a drug that, when administered to the human body, is converted into the biologically active parent drug via some chemical or enzymatic pathway.

[0096] As used herein, “treatment” refers to a method for achieving a beneficial or desired outcome. For the purposes of this disclosure, beneficial or desired outcomes include, but are not limited to, the reduction of symptoms and / or the lessening of the severity of symptoms and / or the prevention of the worsening of symptoms associated with a disease or condition. In one embodiment, “treatment” includes one or more of the following: a) suppressing a disease or condition (e.g., reducing one or more symptoms caused by the disease or condition, and / or lessening the severity of the disease or condition); b) slowing or halting the development of one or more symptoms associated with a disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition); and c) alleviating a disease or condition, such as causing the disappearance of clinical symptoms, improving the disease state, delaying the progression of the disease, improving quality of life, and / or prolonging survival. As used herein, “individual at risk” means an individual at risk of developing a condition to be treated. An individual at risk may or may not have a detectable disease or condition and may or may not show a detectable disease prior to the treatment described herein. "At risk" means that an individual possesses one or more so-called risk factors that are associated with the development of a disease or condition and are measurable parameters known in the art. Individuals with one or more of these risk factors are more likely to develop a disease or condition than individuals without these risk factors.

[0097] II.Compounds

[0098] In some embodiments, the compounds disclosed herein are compounds of formula (IA-1):

[0099]

[0100] Or its pharmaceutically acceptable salt, wherein

[0101] R 1 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, -SR1b -S(O)R 1b -S(O)(NH)R 1b -S(O)2R 1b -S(O)2N(R) 1b (R) 1c ), -S(O)(NR 1b )R 1c -C(O)N(R) 1b (R) 1c -C(O)R 1b or -C(O)OR 1c ,

[0102] The alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is optionally divided by one to four Z groups. 1 replace;

[0103] Ring A is C 6-10 aryl or heteroaryl, each optionally separated by one to four Zn groups. 1a replace;

[0104] Ring B is C 6-10 aryl or heteroaryl, each optionally surrounded by one to four R 4 replace;

[0105] R 2 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, -CN, -OR 2a -SR 2a -S(O)R 2a -S(O)(NH)R 2a -S(O)2R 2a -S(O)2N(R) 2a (R) 2b ) or -S(O)(NR 2a )R 2b ,

[0106] The alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally divided by one to four Z groups. 1 replace;

[0107] X 1 X 2 and X 3 Each is independently -N=, -C(H)=, or -C(R)=. 8 = ;

[0108] R 3 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, -CN, -NO2, -OR 3a -C(O)R 3a -CH2C(O)OR 3a -C(O)OR 3a -C(O)N(R) 3a (R) 3b ), -N(R 3a )C(O)R 3b -N(R) 3a )C(O)OR 3b -N(R) 3a )C(O)N(R 3b )2、-C(O)NHS(O)2R 3a -C(O)NR 3a S(O)2R 3b -C(O)NR 3a S(O)2NR 3b R 3c -C(O)NR 3a -S(O)(=NR 3b )R 3c -S(O)2R 3a -S(O)2OR 3a -S(O)2N(R) 3a (R) 3b ), -N(R 3a )S(O)2R 3b -S(O)2NHC(O)R 3a -S(O)(=NR) 3a )R 3b -S(O)(=NR) 3a )NR 3b -S(=NR) 3a (=NR) 3b )R 3c -P(O)(OR) 3a (R) 3b -P(O)(OR) 3a (OR) 3b -B(OR) 3a (OR) 3b ) or -OC 1-6Alkyl-C(O)OR 3a The alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally divided by one to four R groups. 3d replace;

[0109] Each R 3a R 3b and R 3c H and C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkoxyalkyl, -C 1-4 Alkyl-N(R) 9a (R) 9b -C 1-4 Alkyl-N(R) 9a )C(O)-OC 1-4 Alkyl-OP(O)(OR) 9c )2、-C 1-4 Alkyl-C(O)N(R) 9a (R) 9b -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-OC 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl-N(R) 9a (R) 9b -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl-OP(O)(OR) 9c )2、-C 1-4 Alkyl-C 3-8 cycloalkyl, -C 1-4 alkyl-heterocyclic, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, -CH2CH(N(R) 9a )2)C(O)OR 9b -P(O)(OR) 9c )2、-OP(O)(OR 9c )2、-CH2P(O)(OR 9c )2、-CH2OP(O)(OR 9c )2、-OCH2P(O)(OR 9c )2、-C(O)OCH2P(O)(OR 9c )2、-P(O)(R 9c(OR) 9d ), -OP(O)(R 9c (OR) 9d -CH2P(O)(R) 9c (OR) 9d ), -OCH2P(O)(R 9c (OR) 9d -C(O)OCH2P(O)(R 9c (OR) 9d ), -P(O)(N(R) 9c )2)2、-OP(O)(N(R 9c )2)2、-CH2P(O)(N(R 9c )2)2、-OCH2P(O)(N(R 9c )2)2、-C(O)OCH2P(O)(N(R 9c )2)2、-P(O)(N(R 9c )2)(OR 9d ), -OP(O)(N(R) 9c )2)(OR 9d -CH2P(O)(N(R) 9c )2)(OR 9d ), -OCH2P(O)(N(R) 9c )2)(OR 9d ), -C(O)OCH2P(O)(N(R) 9c )2)(OR 9d ), -P(O)(R 9c )(N(R 9d )2), -OP(O)(R 9c )(N(R 9d )2), -CH2P(O)(R 9c )(N(R 9d )2), -OCH2P(O)(R 9c )(N(R 9d )2), -C(O)OCH2P(O)(R 9c )(N(R 9d )2) or C 1-6 alkyl-heterocyclic groups;

[0110] The alkyl, alkenyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally surrounded by one to four Z groups. 1b replace,

[0111] Each R 4 Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Halogenated alkoxy groups, C2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 4a -C(O)R 4a -C(O)OR 4a -C(O)N(R) 4a (R) 4b ), -N(R 4a (R) 4b ), -N(R 4a )2(R 4b ) + -N(R) 4a )-C(O)R 4b -N(R) 4a )C(O)O(R 4b ), -N(R 4a )C(O)N(R 4b (R) 4c ), -N(R 4a )S(O)2(R 4b ), -N(R 4a )S(O)2-N(R 4b (R) 4c ), -N(R 4a )S(O)2O(R 4b -OC(O)R 4a -OC(O)OR 4a -OC(O)-N(R) 4a (R) 4b ), -SR 4a -S(O)R 4a -S(O)(NH)R 4a -S(O)2R 4a -S(O)2N(R) 4a (R) 4b ), -S(O)(NR 4a )R 4b or -Si(R) 4a 3;

[0112] The alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally divided by one to four Z groups. 1b replace;

[0113] Or two R atoms connected to adjacent ring atoms 4 Groups combine with the atoms they are attached to to form C 5-10Cycloalkyl or heterocyclic group, each optionally surrounded by one to four Z groups. 1b replace;

[0114] R 5a and R 5b Each independently represents H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkoxyalkyl, halogen, C 3-10 Cycloalkyl, heterocyclic, -C 1-6 Alkyl-N(R) 9a (R) 9b -CN, -OR 5a1 or -N(R) 5a1 (R) 5a2 );

[0115] Or R 5a and R 5b They combine with the atoms they are attached to to form C 3-10 Cycloalkyl or heterocyclic group, each optionally surrounded by one to four R groups. 5a3 replace;

[0116] Each R 5a1 and R 5a2 H and C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally surrounded by one to four R groups. 5a4 replace;

[0117] V is -C(O)-, -O-, -N(R)- 6a - or -C(R) 6b (R) 6c )-;

[0118] R 6a For H, C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, -S(O)2R 6a1 or -S(O)2N(R) 6a1 (NR) 6a2 ), wherein the cycloalkyl or heterocyclic group is optionally C 1-6 Alkyl, F, or -CN substitution;

[0119] Each R 6b and R 6c H and C independently 1-6 Alkyl, C 1-6Haloalkyl, C 2-6 Alkoxyalkyl, halogen, C 3-10 Cycloalkyl, heterocyclic, -C 1-6 Alkyl-N(R) 9a (R) 9b -CN, -OR 6c1 or -N(R) 6c2 (R) 6c3 ), wherein the alkyl, cycloalkyl, or heterocyclic group is optionally surrounded by one to four R groups. 6b1 replace;

[0120] Or R 6b and R 6c They combine with the atoms they are attached to to form C 3-10 Cycloalkyl or heterocyclic group, each optionally surrounded by one to four R groups. 6b1 replace;

[0121] Or R 6a Or R 6c With an R 4 Groups and the atoms they are attached to combine to form C 5-10 Cycloalkyl or heterocyclic group, each optionally surrounded by one to four R groups. 10 replace;

[0122] Y is -N(R) 7 )-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NH)- or -S(O)(=NR 7 )-;

[0123] Each R 1a R 3d R 5a3 R 5a4 R 6b1 and R 10 Independently for C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-10 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, CO2R 3e -NO2 or

[0124] -C(O)N(R 2a (R) 2b ), wherein the heterocyclic or heteroaryl group is optionally C 1-6Alkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; and

[0125] Each R 6a1 R 6a2 R 6c1 R 6c2 R 6c3 and R 7 H and C independently 1-6 Alkyl or C 3-10 cycloalkyl;

[0126] Each R 8 Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, CO2R 3e , -NO2, -NH2, -N3, -SH, -O(C 1-9 Alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 2-6 alkenyl), -O(C) 2-6 alkynyl group), -O(C 3-15 cycloalkyl), -O (heterocyclic), -O (C 6-10 aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 2-6 alkenyl), -NH(C) 2-6 alkynyl group), -NH(C 3-15 cycloalkyl), -NH (heterocyclic), -NH (C 6-10 aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 1-8 (halogenated alkyl)2, -N(C) 2-6 alkenyl)2, -N(C 2-6 2, -N(C) 3-15 cycloalkyl)2, -N(heterocyclic)2, -N(C 6-10 aryl)2, -N(heteroaryl)2, -N(C 1-9 Alkyl)(C 1-8 Halogenated alkyl), -N(C) 1-9 Alkyl)(C 2-6 alkenyl), -N(C) 1-9 Alkyl)(C 2-6 alkynyl group), -N(C 1-9Alkyl)(C 3-15 cycloalkyl), -N(C) 1-9 Alkyl (heterocyclic), -N(C) 1-9 Alkyl)(C 6-10 aryl), -N(C 1-9 Alkyl)(heteroaryl), -C(O)(C 1-9 Alkyl), -C(O)(C 1-8 Halogenated alkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 ynyl group), -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 Halogenated alkyl groups), -C(O)O(C 2-6 alkenyl), -C(O)O(C 2-6 alkynyl group), -C(O)O(C 3-15 cycloalkyl), -C(O)O (heterocyclic), -C(O)O (C 6-10 aryl), -C(O)O (heteroaryl), -C(O)NH2, -C(O)NH(C 1-9 Alkyl), -C(O)NH(C 1-8 Halogenated alkyl), -C(O)NH(C 2-6 alkenyl), -C(O)NH(C 2-6 ynyl group), -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 (halogenated alkyl)2、-C(O)N(C 2-6 alkenyl)2, -C(O)N(C 2-6 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, -NHC(O)(C 1-9 Alkyl), -NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 ynyl group), -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (C6-10 aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (C 6-10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -NHC(O)NH(C 1-8 (halogenated alkyl), -NHC(O)NH(C) 2-6 alkenyl), -NHC(O)NH(C 2-6 ), -NHC(O)NH(C 3-15 cycloalkyl), -NHC(O)NH (heterocyclic), -NHC(O)NH (C 6-10 aryl), -NHC(O)NH (heteroaryl), -NHS(O)(C 1-9 alkyl), -N(C) 1-9 Alkyl)(S(O)(C) 1-9 alkyl), -S(C 1-9 alkyl), -S(C 1-8 Halogenated alkyl), -S(C 2-6 alkenyl), -S(C 2-6 alkynyl group), -S(C 3-15 cycloalkyl), -S (heterocyclic), -S (C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2、-S(O)(C 1-9 Alkyl), -S(O)(C 1-8 Halogenated alkyl groups), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 ynyl group), -S(O)(C 3-15 cycloalkyl), -S(O)(heterocyclic), -S(O)(C 6-10 aryl), -S(O) (heteroaryl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 2-6 alkenyl), -S(O)2(C 2-6 alkynyl group), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (C 6-10aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2;

[0127] In each example, the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one to three C atoms. 1-9 Alkyl, C 1-8 Halogenated alkyl groups, halogens, -OH, -NH2, -CO2H, -O(C) 1-9 Alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 3-15 cycloalkyl), -O (heterocyclic), -O (aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 3-15 cycloalkyl), -NH (heterocyclic), -NH (aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 3-15 cycloalkyl)2、-NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (aryl), -NHC(O)O (heteroaryl), -NHC(O)NH(C 1-9 Alkyl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2-substituted;

[0128] Each R 9a and R 9b H and C independently 1-6 Alkyl or C1-6 Halogenated alkyl, or R 9a and R 9b Together they form a 6-membered heterocyclic group;

[0129] Each Z 1 Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -NO2, -N3, -CN, -OR 12a -C(O)-R 12a -C(O)OR 12a -C(O)-N(R) 12a (R) 12b ), -N(R 12a (R) 12b ), -N(R 12a )2(R 12b ) + -N(R) 12a )C(O)-R 12b -N(R) 12a )C(O)OR 12b -N(R) 12a )C(O)N(R 12b (R) 12c ), -N(R 12a )S(O)2(R 12b -NR 12a S(O)2N(R 12b (R) 12c -NR 12a S(O)₂O(R) 12b -OC(O)R 12a -OC(O)OR 12a -OC(O)-N(R) 12a (R) 12b ), -SR 12a -S(O)R 12a -S(O)(NH)R 12a -S(O)2R 12a -S(O)2N(R) 12a (R) 12b ), -S(O)(NR 12a )R 12b or -Si(R)12a 3;

[0130] The alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally divided by one to four Z groups. 1a replace;

[0131] Each Z 1a Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 12a -C(O)R 12a -C(O)OR 12a -C(O)N(R) 12a (R) 12b ), -N(R 12a (R) 12b ), -N(R 12a )2(R 12b ) + -N(R) 12a )-C(O)R 12b -N(R) 12a )C(O)O(R 12b ), -N(R 12a )C(O)N(R 12b (R) 12c ), -N(R 12a )S(O)2(R 12b ), -N(R 12a )S(O)2-N(R 12b (R) 12c ), -N(R 12a )S(O)2O(R 12b -OC(O)R 12a -OC(O)OR 12a -OC(O)-N(R) 12a (R) 12b ), -SR 12a -S(O)R 12a -S(O)(NH)R 12a -S(O)2R 12a -S(O)2N(R) 12a (R) 12b), -S(O)(NR 12a )R 12b or -Si(R) 12a )3;

[0132] The alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally divided by one to four Z groups. 1b replace;

[0133] Each Z 1b Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, CO2R 3e , -NO2, -NH2, -N3, -SH, -O(C 1-9 Alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 2-6 alkenyl), -O(C) 2-6 alkynyl group), -O(C 3-15 cycloalkyl), -O (heterocyclic), -O (C 6-10 aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 2-6 alkenyl), -NH(C) 2-6 alkynyl group), -NH(C 3-15 cycloalkyl), -NH (heterocyclic), -NH (C 6-10 aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 1-8 (halogenated alkyl)2, -N(C) 2-6 alkenyl)2, -N(C 2-6 2, -N(C) 3-15 cycloalkyl)2, -N(heterocyclic)2, -N(C 6-10 aryl)2, -N(heteroaryl)2, -N(C 1-9 Alkyl)(C 1-8 Halogenated alkyl), -N(C) 1-9 Alkyl)(C 2-6 alkenyl), -N(C) 1-9 Alkyl)(C 2-6 alkynyl group), -N(C 1-9 Alkyl)(C 3-15 cycloalkyl), -N(C) 1-9 Alkyl (heterocyclic), -N(C)1-9 Alkyl)(C 6-10 aryl), -N(C 1-9 Alkyl)(heteroaryl), -C(O)(C 1-9 Alkyl), -C(O)(C 1-8 Halogenated alkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 ynyl group), -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 Halogenated alkyl groups), -C(O)O(C 2-6 alkenyl), -C(O)O(C 2-6 alkynyl group), -C(O)O(C 3-15 cycloalkyl), -C(O)O (heterocyclic), -C(O)O (C 6-10 aryl), -C(O)O (heteroaryl), -C(O)NH2, -C(O)NH(C 1-9 Alkyl), -C(O)NH(C 1-8 Halogenated alkyl), -C(O)NH(C 2-6 alkenyl), -C(O)NH(C 2-6 ynyl group), -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 (halogenated alkyl)2、-C(O)N(C 2-6 alkenyl)2, -C(O)N(C 2-6 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, -NHC(O)(C 1-9 Alkyl), -NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 ynyl group), -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (C 6-10 aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (C 6-10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -NHC(O)NH(C 1-8 (halogenated alkyl), -NHC(O)NH(C) 2-6 alkenyl), -NHC(O)NH(C 2-6 ), -NHC(O)NH(C 3-15 cycloalkyl), -NHC(O)NH (heterocyclic), -NHC(O)NH (C 6-10 aryl), -NHC(O)NH (heteroaryl), -NHS(O)(C 1-9 alkyl), -N(C) 1-9 Alkyl)(S(O)(C) 1-9 alkyl), -S(C 1-9 alkyl), -S(C 1-8 Halogenated alkyl), -S(C 2-6 alkenyl), -S(C 2-6 alkynyl group), -S(C 3-15 cycloalkyl), -S (heterocyclic), -S (C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2、-S(O)(C 1-9 Alkyl), -S(O)(C 1-8 Halogenated alkyl groups), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 ynyl group), -S(O)(C 3-15 cycloalkyl), -S(O)(heterocyclic), -S(O)(C 6-10 aryl), -S(O) (heteroaryl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 2-6 alkenyl), -S(O)2(C 2-6 alkynyl group), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (C 6-10 aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2;

[0134] In each example, the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one to three C atoms. 1-9 Alkyl, C 1-8 Halogenated alkyl groups, halogens, -OH, -NH2, -CO2H, -O(C) 1-9 Alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 3-15 cycloalkyl), -O (heterocyclic), -O (aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 3-15 cycloalkyl), -NH (heterocyclic), -NH (aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 3-15 cycloalkyl)2、-NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (aryl), -NHC(O)O (heteroaryl), -NHC(O)NH(C 1-9 Alkyl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2-substituted;

[0135] Each R 1b R 1c R 2a R 2b R 4a R 4b R 4c R 9cR 9d R 12a R 12b and R 12c H and C independently 1-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, heterocyclic, C 6-10 aryl or heteroaryl, wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally divided by one to four Z-groups. 1b Replace; and

[0136] Each R 3e H and C independently 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-4 Alkyl-N(R) 9a (R) 9b -C 1-4 Alkyl-C(O)N(R) 9a (R) 9b -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-OC 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl-N(R) 9a (R) 9b -C 1-4 Alkyl-C 3-8 cycloalkyl, -C 1-4 alkyl-heterocyclic, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, -P(O)(OR) 9c )2、-CH2P(O)(OR 9c )2、-OCH2P(O)(OR 9c )2、-C(O)OCH2P(O)(OR 9c )2、-P(O)(R 9c (OR) 9d ), -OP(O)(R 9c (OR) 9d -CH2P(O)(R) 9c (OR) 9d -C(O)OCH2P(O)(R 9c (OR) 9d ), -P(O)(N(R) 9c )2)2、-CH2P(O)(N(R 9c)2)2、-C(O)OCH2P(O)(N(R 9c )2)2、-P(O)(N(R 9c )2)(OR 9d -CH2P(O)(N(R) 9c )2)(OR 9d ), -C(O)OCH2P(O)(N(R) 9c )2)(OR 9d ), -P(O)(R 9c )(N(R 9d )2), -CH2P(O)(R 9c )(N(R 9d )2) or -C(O)OCH2P(O)(R 9c )(N(R 9d )2); wherein the alkyl, alkenyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is each optionally surrounded by one to four Z groups. 1b Substitution; wherein each heteroaryl group has 5 to 12 ring members and one to four heteroatoms, each independently N, O, or S; and

[0137] Each heterocyclic group has 3 to 12 ring members and one to four heteroatoms that are independently N, O or S.

[0138] In some embodiments, the compounds disclosed herein are compounds of formula (IA-1):

[0139]

[0140] Or its pharmaceutically acceptable salt, wherein

[0141] R 1 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, -SR 1b -S(O)R 1b -S(O)(NH)R 1b -S(O)2R 1b -S(O)2N(R) 1b (R) 1c ), -S(O)(NR 1b )R 1c -C(O)N(R) 1b (R) 1c -C(O)R 1b or -C(O)OR1c ,

[0142] The alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is optionally divided by one to four Z groups. 1 replace;

[0143] Ring A is C 6-10 aryl or heteroaryl, each of which is optionally bound by one to four Zn groups. 1a replace;

[0144] Ring B is C 6-10 aryl or heteroaryl, each optionally surrounded by one to four R 4 replace;

[0145] R 2 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, -CN, -OR 2a -SR 2a -S(O)R 2a -S(O)(NH)R 2a -S(O)2R 2a -S(O)2N(R) 2a (R) 2b ) or -S(O)(NR 2a )R 2b ,

[0146] The alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is each optionally divided by one to four Z groups. 1 replace;

[0147] X 1 X 2 and X 3 Each is independently -N=, -C(H)=, or -C(R)=. 8 = ;

[0148] R 3 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, -CN, -NO2, -OR 3a -C(O)R 3a -C(O)OR 3a-C(O)N(R) 3a (R) 3b ), -N(R 3a )C(O)R 3b -N(R) 3a )C(O)OR 3b -N(R) 3a )C(O)N(R 3b )2、-C(O)NHS(O)2R 3a -C(O)NR 3a S(O)2R 3b -C(O)NR 3a S(O)2NR 3b R 3c -C(O)NR 3a -S(O)(=NR 3b )R 3c -S(O)2R 3a -S(O)2OR 3a -S(O)2N(R) 3a (R) 3b ), -N(R 3a )S(O)2R 3b -S(O)2NHC(O)R 3a -S(O)(=NR) 3a )R 3b -S(O)(=NR) 3a )NR 3b -S(=NR) 3a (=NR) 3b )R 3c -P(O)(OR) 3a (R) 3b -P(O)(OR) 3a (OR) 3b ) or -B (OR 3a (OR) 3b ), wherein the alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally divided by one to four R groups. 3d replace;

[0149] Each R 3a R 3b and R 3c H and C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkoxyalkyl, -C 1-4 Alkyl-N(R) 9a (R) 9b -C 1-4 Alkyl-C(O)N(R)9a (R) 9b -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-OC 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl-N(R) 9a (R) 9b -C 1-4 Alkyl-C 3-8 cycloalkyl, -C 1-4 alkyl-heterocyclic, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, -P(O)(OR) 9c )2、-OP(O)(OR 9c )2、-CH2P(O)(OR 9c )2、-OCH2P(O)(OR 9c )2、-C(O)OCH2P(O)(OR 9c )2、-P(O)(R 9c (OR) 9d ), -OP(O)(R 9c (OR) 9d -CH2P(O)(R) 9c (OR) 9d ), -OCH2P(O)(R 9c (OR) 9d -C(O)OCH2P(O)(R 9c (OR) 9d ), -P(O)(N(R) 9c )2)2、-OP(O)(N(R 9c )2)2、-CH2P(O)(N(R 9c )2)2、-OCH2P(O)(N(R 9c )2)2、-C(O)OCH2P(O)(N(R 9c )2)2、-P(O)(N(R 9c )2)(OR 9d ), -OP(O)(N(R) 9c )2)(OR 9d -CH2P(O)(N(R) 9c )2)(OR 9d ), -OCH2P(O)(N(R) 9c )2)(OR 9d), -C(O)OCH2P(O)(N(R) 9c )2)(OR 9d ), -P(O)(R 9c )(N(R 9d )2), -OP(O)(R 9c )(N(R 9d )2), -CH2P(O)(R 9c )(N(R 9d )2), -OCH2P(O)(R 9c )(N(R 9d )2) or -C(O)OCH2P(O)(R 9c )(N(R 9d )2);

[0150] The alkyl, alkenyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally surrounded by one to four Z groups. 1b replace,

[0151] Each R 4 Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 4a -C(O)R 4a -C(O)OR 4a -C(O)N(R) 4a (R) 4b ), -N(R 4a (R) 4b ), -N(R 4a )2(R 4b ) + -N(R) 4a )-C(O)R 4b -N(R) 4a )C(O)O(R 4b ), -N(R 4a )C(O)N(R 4b (R) 4c ), -N(R 4a )S(O)2(R 4b ), -N(R 4a )S(O)2-N(R 4b (R) 4c ), -N(R4a )S(O)2O(R 4b -OC(O)R 4a -OC(O)OR 4a -OC(O)-N(R) 4a (R) 4b ), -SR 4a -S(O)R 4a -S(O)(NH)R 4a -S(O)2R 4a -S(O)2N(R) 4a (R) 4b ), -S(O)(NR 4a )R 4b or -Si(R) 4a )3;

[0152] The alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally divided by one to four Z groups. 1b replace;

[0153] Or two R atoms connected to adjacent ring atoms 4 Groups combine with the atoms they are attached to to form C 5-10 Cycloalkyl or heterocyclic group, each optionally surrounded by one to four Z groups. 1b replace;

[0154] R 5a and R 5b Each independently represents H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkoxyalkyl, halogen, C 3-10 Cycloalkyl, heterocyclic, -C 1-6 Alkyl-N(R) 9a (R) 9b -CN, -OR 5a1 or

[0155] -N(R 5a1 (R) 5a2 );

[0156] Or R 5a and R 5b They combine with the atoms they are attached to to form C 3-10 Cycloalkyl or heterocyclic group, each optionally surrounded by one to four R groups. 5a3 replace;

[0157] Each R 5a1 and R 5a2 H and C independently 1-6 Alkyl, C2-6 alkenyl, C 2-6 acetylinyl

[0158] C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally surrounded by one to four R groups. 5a4 replace;

[0159] V is -C(O)-, -O-, -N(R)- 6a - or -C(R) 6b (R) 6c )-;

[0160] R 6a For H, C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, -S(O)2R 6a1 or -S(O)2N(R) 6a1 (NR) 6a2 ), wherein the cycloalkyl or heterocyclic group is optionally C 1-6 Alkyl, F, or -CN substitution;

[0161] Each R 6b and R 6c H and C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkoxyalkyl, halogen, C 3-10 Cycloalkyl, heterocyclic, -C 1-6 Alkyl-N(R) 9a (R) 9b -CN, -OR 6c1 or -N(R) 6c2 (R) 6c3 ), wherein the alkyl, cycloalkyl, or heterocyclic group is optionally surrounded by one to four R groups. 6b1 replace;

[0162] Or R 6b and R 6c They combine with the atoms they are attached to to form C 3-10 Cycloalkyl or heterocyclic group, each optionally surrounded by one to four R groups. 6b1 replace;

[0163] Or R 6a Or R 6c With an R 4 Groups and the atoms they are attached to combine to form C 5-10 Cycloalkyl or heterocyclic group, each optionally surrounded by one to four R groups. 10 replace;

[0164] Y is -N(R) 7 )-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NH)- or -S(O)(=NR 7 )-;

[0165] Each R 1a R 3d R 5a3 R 5a4 R 6b1 and R 10 Independently for C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen

[0166] C 3-10 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, CO2R 3e ,

[0167] -NO2 or -C(O)N(R) 2a (R) 2b ),

[0168] The heterocyclic or heteroaryl group is optionally C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; and

[0169] Each R 6a1 R 6a2 R 6c1 R 6c2 R 6c3 and R 7 H and C independently 1-6 Alkyl or C 3-10 cycloalkyl;

[0170] Each R 8 Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, CO2R 3e , -NO2, -NH2, -N3, -SH, -O(C 1-9Alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 2-6 alkenyl), -O(C) 2-6 alkynyl group), -O(C 3-15 cycloalkyl), -O (heterocyclic), -O (C 6-10 aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 2-6 alkenyl), -NH(C) 2-6 alkynyl group), -NH(C 3-15 cycloalkyl), -NH (heterocyclic), -NH (C 6-10 aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 1-8 (halogenated alkyl)2, -N(C) 2-6 alkenyl)2, -N(C 2-6 2, -N(C) 3-15 cycloalkyl)2, -N(heterocyclic)2, -N(C 6-10 aryl)2, -N(heteroaryl)2, -N(C 1-9 Alkyl)(C 1-8 Halogenated alkyl), -N(C) 1-9 Alkyl)(C 2-6 alkenyl), -N(C) 1-9 Alkyl)(C 2-6 alkynyl group), -N(C 1-9 Alkyl)(C 3-15 cycloalkyl), -N(C) 1-9 Alkyl (heterocyclic), -N(C) 1-9 Alkyl)(C 6-10 aryl), -N(C 1-9 Alkyl)(heteroaryl), -C(O)(C 1-9 Alkyl), -C(O)(C 1-8 Halogenated alkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 ynyl group), -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 Halogenated alkyl groups), -C(O)O(C 2-6 alkenyl), -C(O)O(C 2-6 alkynyl group), -C(O)O(C 3-15 cycloalkyl), -C(O)O (heterocyclic), -C(O)O (C6-10 aryl), -C(O)O (heteroaryl), -C(O)NH2, -C(O)NH(C 1-9 Alkyl), -C(O)NH(C 1-8 Halogenated alkyl), -C(O)NH(C 2-6 alkenyl), -C(O)NH(C 2-6 ynyl group), -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 (halogenated alkyl)2、-C(O)N(C 2-6 alkenyl)2, -C(O)N(C 2-6 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, -NHC(O)(C 1-9 Alkyl), -NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 ynyl group), -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (C 6-10 aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (C 6-10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -NHC(O)NH(C 1-8 (halogenated alkyl), -NHC(O)NH(C) 2-6 alkenyl), -NHC(O)NH(C 2-6 ), -NHC(O)NH(C 3-15 cycloalkyl), -NHC(O)NH (heterocyclic), -NHC(O)NH (C 6-10 aryl), -NHC(O)NH (heteroaryl), -NHS(O)(C1-9 alkyl), -N(C) 1-9 Alkyl)(S(O)(C) 1-9 alkyl), -S(C 1-9 alkyl), -S(C 1-8 Halogenated alkyl), -S(C 2-6 alkenyl), -S(C 2-6 alkynyl group), -S(C 3-15 cycloalkyl), -S (heterocyclic), -S (C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2、-S(O)(C 1-9 Alkyl), -S(O)(C 1-8 Halogenated alkyl groups), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 ynyl group), -S(O)(C 3-15 cycloalkyl), -S(O)(heterocyclic), -S(O)(C 6-10 aryl), -S(O) (heteroaryl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 2-6 alkenyl), -S(O)2(C 2-6 alkynyl group), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (C 6-10 aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2;

[0171] In each example, the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one to three C atoms. 1-9 Alkyl, C 1-8 Halogenated alkyl groups, halogens, -OH, -NH2, -CO2H, -O(C) 1-9 Alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 3-15 cycloalkyl), -O (heterocyclic), -O (aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 3-15 cycloalkyl), -NH (heterocyclic), -NH (aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 3-15cycloalkyl)2、-NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (aryl), -NHC(O)O (heteroaryl), -NHC(O)NH(C 1-9 Alkyl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2-substituted;

[0172] Each R 9a and R 9b H and C independently 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0173] Each Z 1 Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -NO2, -N3, -CN, -OR 12a -C(O)-R 12a -C(O)OR 12a -C(O)-N(R) 12a (R) 12b ), -N(R 12a (R) 12b ), -N(R 12a )2(R 12b ) + -N(R)12a )C(O)-R 12b -N(R) 12a )C(O)OR 12b -N(R) 12a )C(O)N(R 12b (R) 12c ), -N(R 12a )S(O)2(R 12b -NR 12a S(O)2N(R 12b (R) 12c -NR 12a S(O)₂O(R) 12b -OC(O)R 12a -OC(O)OR 12a -OC(O)-N(R) 12a (R) 12b ), -SR 12a -S(O)R 12a -S(O)(NH)R 12a -S(O)2R 12a -S(O)2N(R) 12a (R) 12b ), -S(O)(NR 12a )R 12b or -Si(R) 12a 3;

[0174] The alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally divided by one to four Z groups. 1a replace;

[0175] Each Z 1a Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 12a -C(O)R 12a -C(O)OR 12a -C(O)N(R) 12a (R) 12b ), -N(R 12a (R) 12b ), -N(R 12a)2(R 12b ) + -N(R) 12a )-C(O)R 12b -N(R) 12a )C(O)O(R 12b ), -N(R 12a )C(O)N(R 12b (R) 12c ), -N(R 12a )S(O)2(R 12b ), -N(R 12a )S(O)2-N(R 12b (R) 12c ), -N(R 12a )S(O)2O(R 12b -OC(O)R 12a -OC(O)OR 12a -OC(O)-N(R) 12a (R) 12b ), -SR 12a -S(O)R 12a -S(O)(NH)R 12a -S(O)2R 12a -S(O)2N(R) 12a (R) 12b ), -S(O)(NR 12a )R 12b or -Si(R) 12a 3;

[0176] The alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally divided by one to four Z groups. 1b replace;

[0177] Each Z 1b Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, CO2R 3e , -NO2, -NH2, -N3, -SH, -O(C 1-9 Alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 2-6 alkenyl), -O(C) 2-6 alkynyl group), -O(C 3-15 cycloalkyl), -O (heterocyclic), -O (C 6-10aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 2-6 alkenyl), -NH(C) 2-6 alkynyl group), -NH(C 3-15 cycloalkyl), -NH (heterocyclic), -NH (C 6-10 aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 1-8 (halogenated alkyl)2, -N(C) 2-6 alkenyl)2, -N(C 2-6 2, -N(C) 3-15 cycloalkyl)2, -N(heterocyclic)2, -N(C 6-10 aryl)2, -N(heteroaryl)2, -N(C 1-9 Alkyl)(C 1-8 Halogenated alkyl), -N(C) 1-9 Alkyl)(C 2-6 alkenyl), -N(C) 1-9 Alkyl)(C 2-6 alkynyl group), -N(C 1-9 Alkyl)(C 3-15 cycloalkyl), -N(C) 1-9 Alkyl (heterocyclic), -N(C) 1-9 Alkyl)(C 6-10 aryl), -N(C 1-9 Alkyl)(heteroaryl), -C(O)(C 1-9 Alkyl), -C(O)(C 1-8 Halogenated alkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 ynyl group), -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 Halogenated alkyl groups), -C(O)O(C 2-6 alkenyl), -C(O)O(C 2-6 alkynyl group), -C(O)O(C 3-15 cycloalkyl), -C(O)O (heterocyclic), -C(O)O (C 6-10 aryl), -C(O)O (heteroaryl), -C(O)NH2, -C(O)NH(C 1-9 Alkyl), -C(O)NH(C 1-8 Halogenated alkyl), -C(O)NH(C 2-6alkenyl), -C(O)NH(C 2-6 ynyl group), -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 (halogenated alkyl)2、-C(O)N(C 2-6 alkenyl)2, -C(O)N(C 2-6 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, -NHC(O)(C 1-9 Alkyl), -NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 ynyl group), -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (C 6-10 aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (C 6-10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -NHC(O)NH(C 1-8 (halogenated alkyl), -NHC(O)NH(C) 2-6 alkenyl), -NHC(O)NH(C 2-6 ), -NHC(O)NH(C 3-15 cycloalkyl), -NHC(O)NH (heterocyclic), -NHC(O)NH (C 6-10 aryl), -NHC(O)NH (heteroaryl), -NHS(O)(C 1-9 alkyl), -N(C) 1-9 Alkyl)(S(O)(C) 1-9 alkyl), -S(C 1-9 alkyl), -S(C 1-8 Halogenated alkyl), -S(C2-6 alkenyl), -S(C 2-6 alkynyl group), -S(C 3-15 cycloalkyl), -S (heterocyclic), -S (C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2、-S(O)(C 1-9 Alkyl), -S(O)(C 1-8 Halogenated alkyl groups), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 ynyl group), -S(O)(C 3-15 cycloalkyl), -S(O)(heterocyclic), -S(O)(C 6-10 aryl), -S(O) (heteroaryl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 2-6 alkenyl), -S(O)2(C 2-6 alkynyl group), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (C 6-10 aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2;

[0178] In each example, the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one to three C atoms. 1-9 Alkyl, C 1-8 Halogenated alkyl groups, halogens, -OH, -NH2, -CO2H, -O(C) 1-9 Alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 3-15 cycloalkyl), -O (heterocyclic), -O (aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 3-15 cycloalkyl), -NH (heterocyclic), -NH (aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 3-15 cycloalkyl)2、-NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (aryl), -NHC(O) (heteroaryl), -NHC(O)O(C1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (aryl), -NHC(O)O (heteroaryl), -NHC(O)NH(C 1-9 Alkyl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2-substituted;

[0179] 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 H and C independently 1-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, heterocyclic, C 6-10 aryl or heteroaryl, wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally divided by one to four Z-groups. 1b Replace; and

[0180] Each R 3e H and C independently 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-4 Alkyl-N(R) 9a (R) 9b -C 1-4 Alkyl-C(O)N(R) 9a (R) 9b -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-OC 1-4Alkyl, -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl-N(R) 9a (R) 9b -C 1-4 Alkyl-C 3-8 cycloalkyl, -C 1-4 alkyl-heterocyclic, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, -P(O)(OR) 9c )2、-CH2P(O)(OR 9c )2、-OCH2P(O)(OR 9c 2.

[0181] -C(O)OCH2P(O)(OR 9c )2、-P(O)(R 9c (OR) 9d ), -OP(O)(R 9c (OR) 9d ),

[0182] -CH2P(O)(R 9c (OR) 9d -C(O)OCH2P(O)(R 9c (OR) 9d ),

[0183] -P(O)(N(R 9c )2)2、-CH2P(O)(N(R 9c )2)2、-C(O)OCH2P(O)(N(R 9c )2)2、

[0184] -P(O)(N(R 9c )2)(OR 9d -CH2P(O)(N(R) 9c )2)(OR 9d ), -C(O)OCH2P(O)(N(R) 9c )2)(OR 9d ), -P(O)(R 9c )(N(R 9d )2)

[0185] -CH2P(O)(R 9c )(N(R 9d )2) or -C(O)OCH2P(O)(R 9c )(N(R 9d )2); wherein the alkyl, alkenyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is each optionally surrounded by one to four Z groups.1b Substitution; wherein each heteroaryl group has 5 to 12 ring members and one to four heteroatoms, each independently N, O, or S; and

[0186] Each heterocyclic group has 3 to 12 ring members and one to four heteroatoms that are independently N, O or S.

[0187] In some embodiments, the compounds disclosed herein are compounds of formula (I):

[0188]

[0189] Or its pharmaceutically acceptable salt, wherein

[0190] R 1 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, -SR 1b -S(O)R 1b -S(O)(NH)R 1b -S(O)2R 1b -S(O)2N(R) 1b (R) 1c ), -S(O)(NR 1b )R 1c -C(O)N(R) 1b (R) 1c -C(O)R 1b or -C(O)OR 1c ,

[0191] The alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is optionally divided by one to four Z groups. 1 replace;

[0192] Ring A is C 6-10 aryl or heteroaryl, each optionally separated by one to four Zn groups. 1a replace;

[0193] Ring B is C 6-10 aryl or heteroaryl, each optionally surrounded by one to four R 4 replace;

[0194] R 2 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, -CN, -OR 2a -SR 2a -S(O)R 2a -S(O)(NH)R 2a -S(O)2R 2a -S(O)2N(R) 2a (R) 2b ) or -S(O)(NR 2a )R 2b ,

[0195] The alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally divided by one to four Z groups. 1 replace;

[0196] X 1 X 2 and X 3 Each is independently -N=, -C(H)=, or -C(R)=. 8 = ;

[0197] R 3 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, -CN, -NO2, -OR 3a -C(O)R 3a -C(O)OR 3a -C(O)N(R) 3a (R) 3b ), -N(R 3a )C(O)R 3b -N(R) 3a )C(O)OR 3b -N(R) 3a )C(O)N(R 3b )2、-C(O)NHS(O)2R 3a -C(O)NR 3a S(O)2R 3b -C(O)NR 3a S(O)2NR 3b R 3c -C(O)NR 3a -S(O)(=NR 3b )R 3c -S(O)2R 3a-S(O)2OR 3a -S(O)2N(R) 3a (R) 3b ), -N(R 3a )S(O)2R 3b -S(O)2NHC(O)R 3a -S(O)(=NR) 3a )R 3b -S(O)(=NR) 3a )NR 3b -S(=NR) 3a (=NR) 3b )R 3c -P(O)(OR) 3a (R) 3b -P(O)(OR) 3a (OR) 3b ) or -B (OR 3a (OR) 3b ), wherein the alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally divided by one to four R groups. 3d replace;

[0198] Each R 3a R 3b and R 3c H and C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkoxyalkyl, -C 1-4 Alkyl-N(R) 9a (R) 9b -C 1-4 Alkyl-C(O)N(R) 9a (R) 9b -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-OC 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl-N(R) 9a (R) 9b -C 1-4 Alkyl-C 3-8 cycloalkyl, -C 1-4 alkyl-heterocyclic, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, -P(O)(OR) 9c)2、-OP(O)(OR 9c )2、-CH2P(O)(OR 9c )2、-OCH2P(O)(OR 9c )2、-C(O)OCH2P(O)(OR 9c )2、-P(O)(R 9c (OR) 9d ), -OP(O)(R 9c (OR) 9d -CH2P(O)(R) 9c (OR) 9d ), -OCH2P(O)(R 9c (OR) 9d -C(O)OCH2P(O)(R 9c (OR) 9d ), -P(O)(N(R) 9c )2)2、-OP(O)(N(R 9c )2)2、-CH2P(O)(N(R 9c )2)2、-OCH2P(O)(N(R 9c )2)2、-C(O)OCH2P(O)(N(R 9c )2)2、-P(O)(N(R 9c )2)(OR 9d ), -OP(O)(N(R) 9c )2)(OR 9d -CH2P(O)(N(R) 9c )2)(OR 9d ), -OCH2P(O)(N(R) 9c )2)(OR 9d ), -C(O)OCH2P(O)(N(R) 9c )2)(OR 9d ), -P(O)(R 9c )(N(R 9d )2), -OP(O)(R 9c )(N(R 9d )2), -CH2P(O)(R 9c )(N(R 9d )2), -OCH2P(O)(R 9c )(N(R 9d )2) or -C(O)OCH2P(O)(R 9c )(N(R 9d )2);

[0199] The alkyl, alkenyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups are each optionally surrounded by one to four Z groups.1b replace;

[0200] Each R 4 Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 4a -C(O)R 4a -C(O)OR 4a -C(O)N(R) 4a (R) 4b ), -N(R 4a (R) 4b ), -N(R 4a )2(R 4b ) + -N(R) 4a )-C(O)R 4b -N(R) 4a )C(O)O(R 4b ), -N(R 4a )C(O)N(R 4b (R) 4c ), -N(R 4a )S(O)2(R 4b ), -N(R 4a )S(O)2-N(R 4b (R) 4c ), -N(R 4a )S(O)2O(R 4b -OC(O)R 4a -OC(O)OR 4a -OC(O)-N(R) 4a (R) 4b ), -SR 4a -S(O)R 4a -S(O)(NH)R 4a -S(O)2R 4a -S(O)2N(R) 4a (R) 4b ), -S(O)(NR 4a )R 4b or -Si(R) 4a )3;

[0201] The alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally divided by one to four Z groups. 1b replace;

[0202] Or two R atoms connected to adjacent ring atoms 4 Groups combine with the atoms they are attached to to form C 5-10 Cycloalkyl or heterocyclic group, each optionally surrounded by one to four Z groups. 1b replace;

[0203] R 5a and R 5b Each independently represents H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkoxyalkyl, halogen, C 3-10 Cycloalkyl, heterocyclic, -CN, -OR 5a1 or -N(R) 5a1 (R) 5a2 );

[0204] Or R 5a and R 5b They combine with the atoms they are attached to to form C 3-10 Cycloalkyl or heterocyclic group, each optionally surrounded by one to four R groups. 5a3 replace;

[0205] Each R 5a1 and R 5a2 H and C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally surrounded by one to four R groups. 5a4 replace;

[0206] V is -C(O)-, -O-, -N(R)- 6a - or -C(R) 6b (R) 6c )-;

[0207] R 6a For H, C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, -S(O)2R 6a1 or -S(O)2N(R) 6a1 (NR) 6a2 ), wherein the cycloalkyl or heterocyclic group is optionally C 1-6 Alkyl, F, or -CN substitution;

[0208] Each R 6b and R 6c H and C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkoxyalkyl, halogen, C 3-10 Cycloalkyl, heterocyclic, -CN, -OR 6c1 or -N(R) 6c2 (R) 6c3 ), wherein the alkyl, cycloalkyl, or heterocyclic group is optionally surrounded by one to four R groups. 6b1 replace;

[0209] Or R 6b and R 6c They combine with the atoms they are attached to to form C 3-10 Cycloalkyl or heterocyclic group, each optionally surrounded by one to four R groups. 6b1 replace;

[0210] Or R 6a Or R 6c With an R 4 Groups and the atoms they are attached to combine to form C 5-10 Cycloalkyl or heterocyclic group, each optionally surrounded by one to four R groups. 10 replace;

[0211] Y is -N(R) 7 )-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NH)- or -S(O)(=NR 7 )-;

[0212] Each R 1a R 3d R 5a3 R 5a4 R 6b1 and R 10 Independently for C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -OH, -CN, -NO2 or

[0213] -C(O)N(R 2a (R) 2b), wherein the heterocyclic or heteroaryl group is optionally C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; and

[0214] Each R 6a1 R 6a2 R 6c1 R 6c2 R 6c3 and R 7 H and C independently 1-6 Alkyl or C 3-10 cycloalkyl;

[0215] Each R 9a and R 9b H and C independently 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0216] Each Z 1 Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -NO2, -N3, -CN, -OR 12a -C(O)-R 12a -C(O)OR 12a -C(O)-N(R) 12a (R) 12b ), -N(R 12a (R) 12b ), -N(R 12a )2(R 12b ) + -N(R) 12a )C(O)-R 12b -N(R) 12a )C(O)OR 12b -N(R) 12a )C(O)N(R 12b (R) 12c ), -N(R 12a )S(O)2(R 12b -NR 12a S(O)2N(R 12b (R) 12c -NR 12aS(O)₂O(R) 12b -OC(O)R 12a -OC(O)OR 12a -OC(O)-N(R) 12a (R) 12b ), -SR 12a -S(O)R 12a -S(O)(NH)R 12a -S(O)2R 12a -S(O)2N(R) 12a (R) 12b ), -S(O)(NR 12a )R 12b or -Si(R) 12a )3;

[0217] The alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally divided by one to four Z groups. 1a replace;

[0218] Each Z 1a Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 12a -C(O)R 12a -C(O)OR 12a -C(O)N(R) 12a (R) 12b ), -N(R 12a (R) 12b ), -N(R 12a )2(R 12b ) + -N(R) 12a )-C(O)R 12b -N(R) 12a )C(O)O(R 12b ), -N(R 12a )C(O)N(R 12b (R) 12c ), -N(R 12a )S(O)2(R 12b ), -N(R 12a )S(O)2-N(R12b (R) 12c ), -N(R 12a )S(O)2O(R 12b -OC(O)R 12a -OC(O)OR 12a -OC(O)-N(R) 12a (R) 12b ), -SR 12a -S(O)R 12a -S(O)(NH)R 12a -S(O)2R 12a -S(O)2N(R) 12a (R) 12b ), -S(O)(NR 12a )R 12b or -Si(R) 12a 3;

[0219] The alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally divided by one to four Z groups. 1b replace;

[0220] Each R 8 or Z 1b Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C) 1-9 Alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 2-6 alkenyl), -O(C) 2-6 alkynyl group), -O(C 3-15 cycloalkyl), -O (heterocyclic), -O (C 6-10 aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 2-6 alkenyl), -NH(C) 2-6 alkynyl group), -NH(C 3-15 cycloalkyl), -NH (heterocyclic), -NH (C 6-10 aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 1-8 (halogenated alkyl)2, -N(C) 2-6 alkenyl)2, -N(C2-6 2, -N(C) 3-15 cycloalkyl)2, -N(heterocyclic)2, -N(C 6-10 aryl)2, -N(heteroaryl)2, -N(C 1-9 Alkyl)(C 1-8 Halogenated alkyl), -N(C) 1-9 Alkyl)(C 2-6 alkenyl), -N(C) 1-9 Alkyl)(C 2-6 alkynyl group), -N(C 1-9 Alkyl)(C 3-15 cycloalkyl), -N(C) 1-9 Alkyl (heterocyclic), -N(C) 1-9 Alkyl)(C 6-10 aryl), -N(C 1-9 Alkyl)(heteroaryl), -C(O)(C 1-9 Alkyl), -C(O)(C 1-8 Halogenated alkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 ynyl group), -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 Halogenated alkyl groups), -C(O)O(C 2-6 alkenyl), -C(O)O(C 2-6 alkynyl group), -C(O)O(C 3-15 cycloalkyl), -C(O)O (heterocyclic), -C(O)O (C 6-10 aryl), -C(O)O (heteroaryl), -C(O)NH2, -C(O)NH(C 1-9 Alkyl), -C(O)NH(C 1-8 Halogenated alkyl), -C(O)NH(C 2-6 alkenyl), -C(O)NH(C 2-6 ynyl group), -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 (halogenated alkyl)2、-C(O)N(C 2-6 alkenyl)2, -C(O)N(C 2-6 2, -C(O)N(C) 3-15Cycloalkyl)2, -C(O)N(heterocyclic)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 Halogenated alkyl groups), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 ynyl group), -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (C 6-10 aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (C 6-10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -NHC(O)NH(C 1-8 (halogenated alkyl), -NHC(O)NH(C) 2-6 alkenyl), -NHC(O)NH(C 2-6 ), -NHC(O)NH(C 3-15 cycloalkyl), -NHC(O)NH (heterocyclic), -NHC(O)NH (C 6-10 aryl), -NHC(O)NH (heteroaryl), -NHS(O)(C 1-9 alkyl), -N(C) 1-9 Alkyl)(S(O)(C) 1-9 alkyl), -S(C 1-9 alkyl), -S(C 1-8 Halogenated alkyl), -S(C 2-6 alkenyl), -S(C 2-6 alkynyl group), -S(C 3-15 cycloalkyl), -S (heterocyclic), -S (C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2、-S(O)(C 1-9 Alkyl), -S(O)(C 1-8 Halogenated alkyl groups), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 ynyl group), -S(O)(C 3-15cycloalkyl), -S(O)(heterocyclic), -S(O)(C 6-10 aryl), -S(O) (heteroaryl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 2-6 alkenyl), -S(O)2(C 2-6 alkynyl group), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (C 6-10 aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2;

[0221] In each example, the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one to three C atoms. 1-9 Alkyl, C 1-8 Halogenated alkyl groups, halogens, -OH, -NH2, -O(C) 1-9 Alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 3-15 cycloalkyl), -O (heterocyclic), -O (aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 3-15 cycloalkyl), -NH (heterocyclic), -NH (aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 3-15 cycloalkyl)2、-NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (aryl), -NHC(O)O (heteroaryl), -NHC(O)NH(C 1-9 Alkyl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 3-15cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2-substituted;

[0222] and

[0223] 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 H and C independently 1-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, heterocyclic, C 6-10 aryl or heteroaryl, wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally divided by one to four Z-groups. 1b replace;

[0224] Each heteroaryl group has 5 to 12 ring members and one to four heteroatoms, each independently N, O, or S; and

[0225] Each heterocyclic group has 3 to 12 ring members and one to four heteroatoms that are independently N, O or S.

[0226] In some embodiments of compounds of formula (I), (IA-1) and / or other formulas described herein, or pharmaceutically acceptable salts thereof,

[0227] R 1 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl having one to three heteroatoms, each independently N, O, or S, or 3- to 12-membered heterocyclic group having one to three heteroatoms, each independently N, O, or S, wherein the cycloalkyl, aryl, heteroaryl, and heterocyclic group are each optionally surrounded by one to three Z-membered groups. 1 replace;

[0228] Ring A is C 6-10aryl, 5- to 10-membered heteroaryl having one to three heteroatoms, each independently N, O, or S, or 3- to 12-membered heterocyclic group having one to three heteroatoms, each independently N, O, or S, wherein the aryl, heteroaryl, and heterocyclic group are each optionally separated by one to four Zn groups. 1 replace;

[0229] Ring B is C 6-10 An aryl group or a 5- to 10-membered heteroaryl group having one to three heteroatoms, each independently N, O, or S, wherein the aryl group and the heteroaryl group are each optionally surrounded by one to four R atoms. 4 replace;

[0230] R 2 For H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 2-6 Alkoxyalkyl, C 3-10 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, C 1-6 Alkyl-C 3-10 cycloalkyl, C 1-6 alkyl-heterocyclic, 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-C 1-6 Alkyl, -CN, -C(O)R 2a -C(O)OR 2a -C(O)N(R) 2a (R) 2b -C(O)NR 2c S(O)2R 2a -S(O)2R 2a -S(O)2N(R) 2a (R) 2b ) or -S(O)2NR 2c C(O)R 2a Each heterocyclic group comprises 3 to 12 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; each heteroaryl group comprises 5 to 10 ring members and 1 to 3 heteroatoms, each independently being N, O, or S; and each of the cycloalkyl, aryl, heteroaryl, and heterocyclic groups is optionally separated by one to four Zn groups. 1b replace;

[0231] X 1 X 2 and X3 Each is independently -N = or -C(R) 8 = ;

[0232] R 3 For H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups, halogens, C 3-10 cycloalkyl, C 6-10 Aryl groups, 3- to 12-membered heterocyclic groups having one to three heteroatoms that are independently N, O, or S, 5- to 10-membered heteroaryl groups having one to four heteroatoms that are independently N, O, or S, -CN, -NO2, -C(O)R 3a -C(O)OR 3a -C(O)N(R) 3a (R) 3b ), -N(R 3a )C(O)R 3b -N(R) 3a )C(O)OR 3b -N(R) 3a )C(O)N(R 3b )2、-C(O)NHS(O)2R 3a -S(O)2R 3a -S(O)2OR 3a -S(O)2N(R) 3a (R) 3b ), -N(R 3a )S(O)2R 3b -S(O)2NHC(O)R 3a -S(O)(=NR) 3a )R 3b -S(O)(=NR) 3a )NR 3b -S(=NR) 3a (=NR) 3b )R 3c -P(O)(OR) 3a (R) 3b -P(O)(OR) 3a (OR) 3b ) or -B (OR 3a (OR) 3b ), wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is optionally surrounded by one to four R groups. 3d replace;

[0233] Each R 2a R 2b R2c R 3a R 3b and R 3c H and C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl, 3- to 12-membered heterocyclic groups having one to three heteroatoms that are each independently N, O, or S, or 5- to 10-membered heteroaryl groups having one to four heteroatoms that are each independently N, O, or S;

[0234] Each R 4 H and C independently 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, halogens, C 3-10 Cycloalkyl groups, 3- to 12-membered heterocyclic groups having one to three heteroatoms that are each independently N, O, or S, oxo groups, -OH, -CN, -NO2, -N3, C(O)OR 4a or C(O)N(R) 4a (R) 4b ), wherein the cycloalkyl group and the heterocyclic group are each optionally surrounded by one to four R 4c replace;

[0235] Each R 4a and R 4b H and C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl, 3- to 12-membered heterocyclic groups having one to three heteroatoms that are each independently N, O, or S, or 5- to 10-membered heteroaryl groups having one to four heteroatoms that are each independently N, O, or S;

[0236] Alternatively, two R atoms connected to adjacent ring atoms 4 Groups combine with the atoms they are attached to to form C 3-10 Cycloalkyl or a 3- to 12-membered heterocyclic group having one to three heteroatoms, each independently N, O, or S, wherein the cycloalkyl and heterocyclic group are each optionally surrounded by one to four R atoms. 4c replace;

[0237] R 5a and R 5b Each independently represents H and C. 1-6 Alkyl, halogen, C 3-10Cycloalkyl groups, 3- to 12-membered heterocyclic groups having one to three heteroatoms, each independently N, O, or S, -CN,

[0238] -OR 5a1 or -N(R) 5a1 (R) 5a2 ), wherein the cycloalkyl group and the heterocyclic group are each optionally surrounded by one to four R 5a3 replace;

[0239] Each R 5a1 R 5a1 and R 5a2 H and C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 aryl, a 3- to 12-membered heterocyclic group having one to three heteroatoms, each independently of N, O, or S, or a 5- to 10-membered heteroaryl group having one to three heteroatoms, each independently of N, O, or S, wherein the cycloalkyl, aryl, heteroaryl, and heterocyclic group are each optionally surrounded by one to four R... 5a4 replace;

[0240] V is -C(O)-, -O-, -N(R)- 6a )-、-C(R 6b (R) 6c )-;

[0241] R 6a For H, C 1-6 Alkyl, C 3-10 Cycloalkyl groups, 3- to 12-membered heterocyclic groups having one to three heteroatoms, each independently N, O, or S, -S(O)2R 6a1 or -S(O)2N(R) 6a1 (NR) 6a2 ), wherein the cycloalkyl group and the heterocyclic group are each optionally represented by F, CN or C. 1-6 Alkyl substitution;

[0242] Each R 6b and R 6c Independently H, halogen, -CN, C 1-6 Alkyl, C 3-10 Cycloalkyl groups, 3- to 12-membered heterocyclic groups having one to three heteroatoms, each independently N, O, or S, -OR 6c1 or -N(R) 6c2 (R) 6c3 ), wherein the alkyl, cycloalkyl, and heterocyclic groups are each optionally surrounded by one to four R groups. 6b1 replace;

[0243] Alternatively, R 6band R 6c They combine with the atoms they are attached to to form C 3-10 cycloalkyl group, which is optionally surrounded by one to four R groups 6b1 replace;

[0244] Alternatively, R 6c With an R 4 Groups and the atoms they are attached to combine to form C 3-10 Cycloalkyl or a 3- to 12-membered heterocyclic group having one to three heteroatoms, each independently N, O, or S, wherein the cycloalkyl and heterocyclic group are each optionally surrounded by one to four R atoms. 4c replace;

[0245] Y is -N(R) 7 -, -O-, -S-, -S(O)-, -S(=NH)- or -S(=NR)- 7 )-;

[0246] Each R 8 For H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups, halogens, C 3-10 cycloalkyl, C 6-10 Aryl, 3- to 12-membered heterocyclic groups having one to three heteroatoms that are independently N, O, or S, or 5- to 10-membered heteroaryl groups having one to four heteroatoms that are independently N, O, or S, -CN, -NO2, -C(O)R 3a -C(O)OR 3a -C(O)N(R) 3a (R) 3b ), -N(R 3a )C(O)R 3b -N(R) 3a )C(O)OR 3b -N(R) 3a )C(O)N(R 3b )2、-C(O)NHS(O)2R 3a -S(O)2R 3a -S(O)2OR 3a -S(O)2N(R) 3a (R) 3b ), -N(R 3a )S(O)2R 3b -S(O)2NHC(O)R 3a -S(O)(=NR) 3a )R 3b -S(O)(=NR) 3a )NR3b -S(=NR) 3a (=NR) 3b )R 3c -P(O)(OR) 3a (R) 3b -P(O)(OR) 3a (OR) 3b ) or -B (OR 3a (OR) 3b );

[0247] Each Z 1b R 3d R 4c R 5a3 R 5a4 and R 6b1 Independently for C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, halogens, C 3-10 Cycloalkyl groups, 3- to 12-membered heterocyclic groups having one to three heteroatoms, each independently N, O, or S; 5- to 10-membered heteroaryl groups, oxo groups, -OH, -CN, or -NO2 groups having one to three heteroatoms, each independently N, O, or S; and

[0248] Each R 6a1 R 6a2 R 6c1 R 6c2 R 6c3 and R 7 Independently for C 1-6 Alkyl or C 3-10 Cycloalkyl.

[0249] In some embodiments of compounds of formula (I), (IA-1) and / or other formulas described herein, R 1 C 6-10 aryl, heteroaryl, or heterocyclic, wherein the aryl, heteroaryl, or heterocyclic group is optionally surrounded by one to three Z groups. 1 Substitution. In some embodiments of compounds of formula (I), (IA-1) and / or other formulas described herein, R 1 C 6-10 aryl, heteroaryl, or heterocyclic, wherein the aryl, heteroaryl, or heterocyclic group is optionally surrounded by one to three R groups. 1a Substitution. In some embodiments of compounds of formula (I), (IA-1) and / or other formulas described herein, R 1 C 6-10An aryl group, a 5- to 10-membered heteroaryl group having one to three heteroatoms, each independently of O, N, or S, or a 4- to 12-membered heterocyclic group having one to three heteroatoms, each independently of O, N, or S, wherein the aryl, heteroaryl, or heterocyclic group is optionally surrounded by one to three R atoms. 1a Substitution. In some embodiments of compounds of formula (I), (IA-1) and / or other formulas described herein, R 1 Heterocyclic group, C 6-10 aryl or 6-membered heteroaryl, wherein the heterocyclic, aryl, or heteroaryl group is each optionally bound by one to three Z groups. 1 Replace, where Z 1 Independently for C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, oxo groups, -OH, -CN, or -NO2, C 3-10 Cycloalkyl, 3- to 12-membered heterocyclic groups having one to three heteroatoms, or 5- to 10-membered heteroaryl groups having one to three heteroatoms.

[0250] In some embodiments of compounds of formula (I), (IA-1) and / or other formulas described herein, or pharmaceutically acceptable salts thereof, each R 5a and R 5b H and C independently 1-6 Alkyl, F, Cl, -OR 5a1 -CN,C 3-10 Cycloalkyl or heterocyclic groups. In some embodiments of compounds of formula (I), (IA-1) and / or (IA-2) or their pharmaceutically acceptable salts, R 5a For H; and R 5b For H, C 1-6 Alkyl, F, Cl, -OR 5a1 -CN,C 3-10 Cycloalkyl or heterocyclic groups. In some embodiments, each R 5a and R 5b For H.

[0251] In some embodiments of compounds of formula (I), (IA-1) and / or other formulas described herein, or pharmaceutically acceptable salts thereof, Y is -O-.

[0252] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has the structure of formula (Ia):

[0253]

[0254] The subscript p is 1, 2 or 3.

[0255] In some embodiments of compounds of formula (I), (IA-1), (Ia) and / or other formulas described herein, or pharmaceutically acceptable salts thereof, ring A is C. 6-10 aryl or 5 to 10 heteroaryl groups, wherein the aryl or heteroaryl group is optionally surrounded by one to three Z groups. 1a Replace, where each Z 1a Independently for C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 3-10 cycloalkyl, C 6-10 Aryl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -C(O)N(R) 2a (R) 2b ), oxo groups, -OH, halogens, -CN, -NO2, -OR 12a C 3-10 Cycloalkyl, heterocyclic, heterocyclic-C 1-6 Alkyl, heterocyclic -C 1-6 Halogenated alkyl groups, heteroaryl groups, heteroaryl-C 1-6 Alkyl or heteroaryl-C 1-6 Halogenated alkyl groups, wherein each group is optionally Z-shaped. 1b Substitution. In some embodiments of compounds of formula (I), (IA-1), (Ia) and / or other formulas described herein, or pharmaceutically acceptable salts thereof, ring A is C. 6-10 An aryl group or a 5- to 10-membered heteroaryl group having one to three heteroatoms, each independently of O, N, or S, wherein the aryl group or heteroaryl group is optionally surrounded by one to three Z atoms. 1a Substitution. In some embodiments of compounds of formula (I), (IA-1), (Ia) and / or other formulas described herein, or pharmaceutically acceptable salts thereof, ring A is phenyl or a 5- to 6-membered heteroaryl group, wherein the phenyl or heteroaryl group is optionally surrounded by one to three Z-membered rings. 1a Substitution. In some embodiments of compounds of formula (I), (IA-1), (IA-2) and / or (Ia) or pharmaceutically acceptable salts thereof, ring A is a phenyl or a 5- to 6-membered heteroaryl group having one to three heteroatoms, each independently O, N, or S, wherein the phenyl or heteroaryl group is optionally surrounded by one to three Z... 1a Substitution. In some embodiments of compounds of formula (I), (IA-1), (Ia) and / or other formulas described herein, or pharmaceutically acceptable salts thereof, ring A is...

[0256]

[0257] Each ring is optionally divided by one or two Z. 1a replace.

[0258] In some embodiments of compounds of formula (I), (IA-1), (Ia), and / or other formulas described herein, or pharmaceutically acceptable salts thereof, ring A is

[0259]

[0260] Each ring is optionally divided by one or two Z. 1a replace.

[0261] In some embodiments of compounds of formula (I), (IA-1), (IA-2) and / or (Ia) or their pharmaceutically acceptable salts, ring A is

[0262]

[0263] Each ring is optionally replaced by one or two halogens.

[0264] In some embodiments, compounds of formula (I), (IA-1), and / or (Ia), or pharmaceutically acceptable salts thereof, have the structure of formula (Ib):

[0265]

[0266] Z 1a Halogen, C 1-4 Alkyl, -OR 12a Or -CN, where C 1-4 Alkyl groups are optionally Z 1b replace.

[0267] The subscript p is 1, 2, or 3; and

[0268] The subscript q is 0, 1, or 2.

[0269] In some embodiments, compounds of formula (I), (IA-1), and / or (Ia), or pharmaceutically acceptable salts thereof, have the structure of formula (Ib-1):

[0270]

[0271] in

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

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

[0274] In some embodiments of compounds of formula (IA-1), (I), (Ia), (Ib) and / or (Ib-1) or pharmaceutically acceptable salts thereof, ring B is a phenyl or a 5- to 6-membered heteroaryl group, wherein the phenyl or heteroaryl group is optionally surrounded by one to four R groups. 4 Substitution. In some embodiments of compounds of formula (IA-1), (I), (Ia), (Ib) and / or (Ib-1) or pharmaceutically acceptable salts thereof, ring B is a phenyl or a 5- to 6-membered heteroaryl group having one to three heteroatoms, each independently of O, N, or S, wherein the phenyl or heteroaryl group is optionally surrounded by one to four R... 4 Substitution. In some embodiments of compounds of formula (IA-1), (I), (Ia), (Ib) and / or (Ib-1) or their pharmaceutically acceptable salts, ring B is

[0275]

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

[0277] In some embodiments of compounds of formula (IA-1), (I), (Ia), (Ib) and / or (Ib-1) or their pharmaceutically acceptable salts, ring B is

[0278]

[0279] These groups are each optionally surrounded by one or two R groups. 4 replace.

[0280] In some embodiments of compounds of formula (IA-1), (I), (Ia), (Ib) and / or (Ib-1) or their pharmaceutically acceptable salts, ring B is

[0281]

[0282] This group is optionally surrounded by one or two R groups. 4 replace.

[0283] In some embodiments of compounds of formula (I), (IA-1), and / or other formulas described herein, or pharmaceutically acceptable salts thereof, ring B is substituted with one, two, or three halogens. In some embodiments of compounds of formula (I), (IA-1), and / or other formulas described herein, or pharmaceutically acceptable salts thereof, ring B is substituted with one, two, or three fluorines.

[0284] In some embodiments, compounds of formula (I), (IA-1) and / or (Ia) and / or other formulas described herein, or pharmaceutically acceptable salts thereof, have the formula:

[0285]

[0286] in

[0287] X A and X B Each can be independently represented as -CH= or -N=;

[0288] The subscript n is 0, 1, 2, or 3; and

[0289] The subscript p is 1, 2 or 3.

[0290] In some embodiments of compounds of formulas (I), (IA-1), (Ia), (Ib), (Ib-1) and / or (Ic) and / or other formulas described herein, or pharmaceutically acceptable salts thereof, X 1 X 2 and X 3 Each is independently -N=, -CH=, -C(F)=, -C(Cl=, -C(Br=) or -C(CN=). In some embodiments of compounds of formula (I), (IA-1) and / or other formulas described herein, or pharmaceutically acceptable salts thereof, X 1 X 2 and X 3 Each is independently -CH=, -C(F)=, -C(Cl)=, -C(Br)=, or -C(CN)=. In some embodiments of compounds of formula (I), (IA-1), and / or other formulas described herein, or pharmaceutically acceptable salts thereof, X 1 X 2 and X 3 Each can be independently -N=, -CH=, or -C(F)=. In some implementations, X 1 X 2 and X 3 In this context, two are represented by -CH=, and one by -N=. For example, X 1 It can be -N=, while X 2 and X 3 Each is -CH=. In some embodiments of compounds of formula (I), (IA-1) and / or other formulas described herein, or pharmaceutically acceptable salts thereof, X 1 X 2 and X 3 In this context, both are -CH=, and one is -C(F)=. In some implementations, X 1 X 2 and X 3 Each is -CH=.

[0291] In some embodiments of compounds of formula (I), (IA-1), (IA-2), (Ia), (Ib), (Ib-1) and / or (Ic) or their pharmaceutically acceptable salts, V is -O-, -NH- or -CH2-.

[0292] In some embodiments of compounds of formula (I), (IA-1), and / or other formulas described herein, or pharmaceutically acceptable salts thereof, V is -O-. In some embodiments, V is -CH2. In some embodiments of formula (I), (IA-1), (IA-2), and / or other formulas described herein, V is -CH2-, -CH(CH3)-, or -C(CH3)2-. In some embodiments, V is -CH2.

[0293] In some embodiments, compounds of formula (I), (IA-1), (Ia), and / or (Ic) and / or other formulas described herein, or pharmaceutically acceptable salts thereof, have the formula:

[0294]

[0295] in

[0296] X A and X B Each can be independently represented as -CH= or -N=;

[0297] The subscript n is 0, 1, 2, or 3; and

[0298] The subscript p is 1, 2 or 3.

[0299] In some embodiments of compounds of formula (Ic) and / or (Id) or their pharmaceutically acceptable salts, the subscript n is 0, 1, or 2. In some embodiments, the subscript n is 0. In some embodiments of compounds of formula (I) or other compounds described herein, the subscript n is 1. In some embodiments, the subscript n is 2.

[0300] In some embodiments of compounds of formula (Ia), (Ib), (Ib-1), (Ic), and / or (Id) or their pharmaceutically acceptable salts, the subscript p is 1 or 2. In some embodiments, the subscript p is 1. In some embodiments of compounds of formula (I) or other compounds described herein, the subscript p is 2.

[0301] In some embodiments of compounds of formula (Ib) and / or (Ib-1) or their pharmaceutically acceptable salts, the subscript q is 0 or 1. In some embodiments, the subscript q is 0. In some embodiments, the subscript q is 1.

[0302] In some embodiments of compounds of formula (Ic) and / or (Id) or their pharmaceutically acceptable salts, X A and X B One of them is -CH=, and the other is -N=. In some implementations, X A For -N=, X B For -CH=. In some implementations, X A For -CH=, X B For -N=.

[0303] In some embodiments of compounds of formulas (IA-1), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id) and / or other formulas described herein, or pharmaceutically acceptable salts thereof, each Z 1 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, C 3-10 Cycloalkyl, 3- to 12-membered heterocyclic groups having one to three heteroatoms, each independently N, O, or S, 5- to 10-membered heteroaryl groups having one to three heteroatoms, each independently N, O, or S, oxoyl groups, -OH, -CN, or -NO2. In some embodiments of compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id) or their pharmaceutically acceptable salts, each Z 1 Independent of halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -CN, or 5- to 6-membered heteroaryl. In some embodiments of compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id) or their pharmaceutically acceptable salts, each Z 1 Independent of halogen, C 1-6 Haloalkyl, C 1-6 A 5- to 6-membered heteroaryl group having one to three heteroatoms, each independently N, O, or S. In some embodiments of compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id) or their pharmaceutically acceptable salts, each Z 1 Independently for C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C2-6 Alkyne, halogen, C 3-10 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, heterocyclic -C 1-6 Alkyl, heterocyclic -C 1-6 Halogenated alkyl, heteroaryl-C 1-6 Alkyl, heteroaryl-C 1-6 Halogenated alkyl groups, oxo groups, -OH, -CN, -NO2, or -C(O)N(R) 12a (R) 12b ), wherein the heteroaryl or heterocyclic group is optionally bonded by one to four halogens, -CN, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 4- to 6-membered heterocyclic substituted groups. In some embodiments, each Z... 1 Independent of halogen, C 1-6 Haloalkyl, -CN, C 1-3 Alkoxy or C 3-10 Cycloalkyl. In some embodiments of compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id) or pharmaceutically acceptable salts thereof, each Z 1 Independently for C 1-6 Haloalkyl, C 1-6 Haloalkoxy, halogen, 5- to 6-membered heteroaryl groups or -CN having one to three heteroatoms, each independently N, O, or S. In some embodiments, each Z 1 Independent of halogen, C 1-6 Halogenated alkyl or -CN. In some embodiments of compounds of formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id) or their pharmaceutically acceptable salts, each Z 1 Independent of halogen, C 1-6 Haloalkyl, C 1-3 Alkoxy, C 3-10 Cycloalkyl or -CN. In some embodiments of compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id) or their pharmaceutically acceptable salts, each Z 1 Independent of halogen, C 1-3 Haloalkyl, C 1-3 Haloalkoxy or -CN. In some embodiments of compounds of formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id) or their pharmaceutically acceptable salts, each R 2d F and C independently 1-6Halogenated alkyl, -CN or C 3-10 Cycloalkyl. In some embodiments of compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id) or pharmaceutically acceptable salts thereof, each Z 1 Independently halogenated or -CN. In some embodiments of compounds of formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id) or their pharmaceutically acceptable salts, Z 1 Z is -CN. In some embodiments of compounds of formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id) or their pharmaceutically acceptable salts, Z 1 Halogens, such as F.

[0304] In some embodiments, compounds of formula (I), (IA-1), and / or other formulas described herein, or pharmaceutically acceptable salts thereof, have formula (IA-2):

[0305]

[0306] in

[0307] U is -CH= or -N=;

[0308] X B For -CH= or -N=;

[0309] R B C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, or -CN;

[0310] X 1 and X 2 Each is independently -N=, -C(H)=, or -C(R)=. 8 = ;

[0311] X 3 -C(H) = ;

[0312] Each R 4 Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10Aryl, oxo, -NO2, -N3, -OR 4a -C(O)R 4a -C(O)OR 4a -C(O)N(R) 4a (R) 4b ), -N(R 4a (R) 4b ), -N(R 4a )2(R 4b ) + -N(R) 4a )C(O)O(R 4b ), -N(R 4a )C(O)N(R 4b (R) 4c ), -N(R 4a )S(O)2-N(R 4b (R) 4c ), -N(R 4a )S(O)2O(R 4b -OC(O)R 4a -OC(O)OR 4a -OC(O)-N(R) 4a (R) 4b ), -SR 4a -S(O)R 4a -S(O)(NH)R 4a -S(O)2R 4a -S(O)2N(R) 4a (R) 4b ), -S(O)(NR 4a )R 4b or -Si(R) 4a )3;

[0313] The alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally divided by one to four Z groups. 1b replace;

[0314] Or two R atoms connected to adjacent ring atoms 4 Groups combine with the atoms they are attached to to form C 5-10 Cycloalkyl or heterocyclic group, each optionally surrounded by one to four Z groups. 1b replace;

[0315] V is -C(O)-, -O-, -N(R)- 6a - or -C(R) 6b (R) 6c )-;

[0316] R 6aFor H, C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, -S(O)2R 6a1 or -S(O)2N(R 6a1 (NR) 6a2 ), wherein the cycloalkyl or heterocyclic group is optionally C 1-6 Alkyl, F, or -CN substitution;

[0317] Each R 6b and R 6c Independently H or C 1-6 alkyl;

[0318] Each R 1a R 3d R 5a3 R 5a4 and R 10 Independently for C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-10 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, CO2R 3e -NO2 or -C(O)N(R) 2a (R) 2b ), wherein the heterocyclic or heteroaryl group is optionally C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; and

[0319] Each R 6a1 R 6a2 R 6c1 R 6c2 R 6c3 and R 7 H and C independently 1-6 Alkyl or C 3-10 cycloalkyl;

[0320] Each R 8 Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, CO2R 3e, -NO2, -NH2, -N3, -SH, -O(C 1-9 Alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 2-6 alkenyl), -O(C) 2-6 alkynyl group), -O(C 3-15 cycloalkyl), -O (heterocyclic), -O (C 6-10 aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 2-6 alkenyl), -NH(C) 2-6 alkynyl group), -NH(C 3-15 cycloalkyl), -NH (heterocyclic), -NH (C 6-10 aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 1-8 (halogenated alkyl)2, -N(C) 2-6 alkenyl)2, -N(C 2-6 2, -N(C) 3-15 cycloalkyl)2, -N(heterocyclic)2, -N(C 6-10 aryl)2, -N(heteroaryl)2, -N(C 1-9 Alkyl)(C 1-8 Halogenated alkyl), -N(C) 1-9 Alkyl)(C 2-6 alkenyl), -N(C) 1-9 Alkyl)(C 2-6 alkynyl group), -N(C 1-9 Alkyl)(C 3-15 cycloalkyl), -N(C) 1-9 Alkyl (heterocyclic), -N(C) 1-9 Alkyl)(C 6-10 aryl), -N(C 1-9 Alkyl)(heteroaryl), -C(O)(C 1-9 Alkyl), -C(O)(C 1-8 Halogenated alkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 ynyl group), -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 Halogenated alkyl groups), -C(O)O(C 2-6 alkenyl), -C(O)O(C 2-6 alkynyl group), -C(O)O(C3-15 cycloalkyl), -C(O)O (heterocyclic), -C(O)O (C 6-10 aryl), -C(O)O (heteroaryl), -C(O)NH2, -C(O)NH(C 1-9 Alkyl), -C(O)NH(C 1-8 Halogenated alkyl), -C(O)NH(C 2-6 alkenyl), -C(O)NH(C 2-6 ynyl group), -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 (halogenated alkyl)2、-C(O)N(C 2-6 alkenyl)2, -C(O)N(C 2-6 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, -NHC(O)(C 1-9 Alkyl), -NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 ynyl group), -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (C 6-10 aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (C 6-10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -NHC(O)NH(C 1-8 (halogenated alkyl), -NHC(O)NH(C) 2-6 alkenyl), -NHC(O)NH(C 2-6 ), -NHC(O)NH(C 3-15 cycloalkyl), -NHC(O)NH (heterocyclic), -NHC(O)NH (C6-10 aryl), -NHC(O)NH (heteroaryl), -NHS(O)(C 1-9 alkyl), -N(C) 1-9 Alkyl)(S(O)(C) 1-9 alkyl), -S(C 1-9 alkyl), -S(C 1-8 Halogenated alkyl), -S(C 2-6 alkenyl), -S(C 2-6 alkynyl group), -S(C 3-15 cycloalkyl), -S (heterocyclic), -S (C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2、-S(O)(C 1-9 Alkyl), -S(O)(C 1-8 Halogenated alkyl groups), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 ynyl group), -S(O)(C 3-15 cycloalkyl), -S(O)(heterocyclic), -S(O)(C 6-10 aryl), -S(O) (heteroaryl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 2-6 alkenyl), -S(O)2(C 2-6 alkynyl group), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (C 6-10 aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2;

[0321] In each example, the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one to three C atoms. 1-9 Alkyl, C 1-8 Halogenated alkyl groups, halogens, -OH, -NH2, -CO2H, -O(C) 1-9 Alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 3-15 cycloalkyl), -O (heterocyclic), -O (aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 3-15 cycloalkyl), -NH (heterocyclic), -NH (aryl), -NH (heteroaryl), -N (C1-9 Alkyl)2, -N(C 3-15 cycloalkyl)2、-NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (aryl), -NHC(O)O (heteroaryl), -NHC(O)NH(C 1-9 Alkyl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2-substituted; each R 9a and R 9b H and C independently 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0322] Each Z 1 Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -NO2, -N3, -CN, -OR 12a -C(O)-R 12a -C(O)OR 12a -C(O)-N(R) 12a (R) 12b ), -N(R 12a (R) 12b ), -N(R 12a )2(R 12b ) +-N(R) 12a )C(O)-R 12b -N(R) 12a )C(O)OR 12b -N(R) 12a )C(O)N(R 12b (R) 12c ), -N(R 12a )S(O)2(R 12b -NR 12a S(O)2N(R 12b (R) 12c -NR 12a S(O)₂O(R) 12b -OC(O)R 12a -OC(O)OR 12a -OC(O)-N(R) 12a (R) 12b ), -SR 12a -S(O)R 12a -S(O)(NH)R 12a -S(O)2R 12a -S(O)2N(R) 12a (R) 12b ), -S(O)(NR 12a )R 12b or -Si(R) 12a 3;

[0323] The alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally divided by one to four Z groups. 1a replace;

[0324] Each Z 1a Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 12a -C(O)R 12a -C(O)OR 12a -C(O)N(R) 12a (R) 12b ), -N(R 12a (R) 12b ), -N(R12a )2(R 12b ) + -N(R) 12a )-C(O)R 12b -N(R) 12a )C(O)O(R 12b ), -N(R 12a )C(O)N(R 12b (R) 12c ), -N(R 12a )S(O)2(R 12b ), -N(R 12a )S(O)2-N(R 12b (R) 12c ), -N(R 12a )S(O)2O(R 12b -OC(O)R 12a -OC(O)OR 12a -OC(O)-N(R) 12a (R) 12b ), -SR 12a -S(O)R 12a -S(O)(NH)R 12a -S(O)2R 12a -S(O)2N(R) 12a (R) 12b ), -S(O)(NR 12a )R 12b or -Si(R) 12a 3;

[0325] The alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally divided by one to four Z groups. 1b replace;

[0326] Each Z 1b Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, CO2R 3e , -NO2, -NH2, -N3, -SH, -O(C 1-9 Alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 2-6 alkenyl), -O(C) 2-6 alkynyl group), -O(C 3-15 cycloalkyl), -O (heterocyclic), -O (C6-10 aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 2-6 alkenyl), -NH(C) 2-6 alkynyl group), -NH(C 3-15 cycloalkyl), -NH (heterocyclic), -NH (C 6-10 aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 1-8 (halogenated alkyl)2, -N(C) 2-6 alkenyl)2, -N(C 2-6 2, -N(C) 3-15 cycloalkyl)2, -N(heterocyclic)2, -N(C 6-10 aryl)2, -N(heteroaryl)2, -N(C 1-9 Alkyl)(C 1-8 Halogenated alkyl), -N(C) 1-9 Alkyl)(C 2-6 alkenyl), -N(C) 1-9 Alkyl)(C 2-6 alkynyl group), -N(C 1-9 Alkyl)(C 3-15 cycloalkyl), -N(C) 1-9 Alkyl (heterocyclic), -N(C) 1-9 Alkyl)(C 6-10 aryl), -N(C 1-9 Alkyl)(heteroaryl), -C(O)(C 1-9 Alkyl), -C(O)(C 1-8 Halogenated alkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 ynyl group), -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 Halogenated alkyl groups), -C(O)O(C 2-6 alkenyl), -C(O)O(C 2-6 alkynyl group), -C(O)O(C 3-15 cycloalkyl), -C(O)O (heterocyclic), -C(O)O (C 6-10 aryl), -C(O)O (heteroaryl), -C(O)NH2, -C(O)NH(C 1-9 Alkyl), -C(O)NH(C 1-8 Halogenated alkyl), -C(O)NH(C2-6 alkenyl), -C(O)NH(C 2-6 ynyl group), -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 (halogenated alkyl)2、-C(O)N(C 2-6 alkenyl)2, -C(O)N(C 2-6 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, -NHC(O)(C 1-9 Alkyl), -NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 ynyl group), -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (C 6-10 aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (C 6-10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -NHC(O)NH(C 1-8 (halogenated alkyl), -NHC(O)NH(C) 2-6 alkenyl), -NHC(O)NH(C 2-6 ), -NHC(O)NH(C 3-15 cycloalkyl), -NHC(O)NH (heterocyclic), -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 1-8Halogenated alkyl), -S(C 2-6 alkenyl), -S(C 2-6 alkynyl group), -S(C 3-15 cycloalkyl), -S (heterocyclic), -S (C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2、-S(O)(C 1-9 Alkyl), -S(O)(C 1-8 Halogenated alkyl groups), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 ynyl group), -S(O)(C 3-15 cycloalkyl), -S(O)(heterocyclic), -S(O)(C 6-10 aryl), -S(O) (heteroaryl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 2-6 alkenyl), -S(O)2(C 2-6 alkynyl group), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (C 6-10 aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2;

[0327] In each example, the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one to three C atoms. 1-9 Alkyl, C 1-8 Halogenated alkyl groups, halogens, -OH, -NH2, -CO2H, -O(C) 1-9 Alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 3-15 cycloalkyl), -O (heterocyclic), -O (aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 3-15 cycloalkyl), -NH (heterocyclic), -NH (aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 3-15 cycloalkyl)2、-NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 3-15cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (aryl), -NHC(O)O (heteroaryl), -NHC(O)NH(C 1-9 Alkyl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2-substituted;

[0328] 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 H and C independently 1-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, heterocyclic, C 6-10 aryl or heteroaryl, wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally divided by one to four Z-groups. 1b Replace; and

[0329] Each R 3e H and C independently 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-4 Alkyl-N(R) 9a (R) 9b -C 1-4 Alkyl-C(O)N(R) 9a (R) 9b -C 1-4 Alkyl-OC(O)-C1-4 Alkyl, -C 1-4 Alkyl-OC(O)-OC 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl-N(R) 9a (R) 9b -C 1-4 Alkyl-C 3-8 cycloalkyl, -C 1-4 alkyl-heterocyclic, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl, heteroaryl, -P(O)(OR) 9c )2、-CH2P(O)(OR 9c )2、-OCH2P(O)(OR 9c )2、-C(O)OCH2P(O)(OR 9c )2、-P(O)(R 9c (OR) 9d ), -OP(O)(R 9c (OR) 9d -CH2P(O)(R) 9c (OR) 9d -C(O)OCH2P(O)(R 9c (OR) 9d ), -P(O)(N(R) 9c )2)2、-CH2P(O)(N(R 9c )2)2、-C(O)OCH2P(O)(N(R 9c )2)2、-P(O)(N(R 9c )2)(OR 9d -CH2P(O)(N(R) 9c )2)(OR 9d ), -C(O)OCH2P(O)(N(R) 9c )2)(OR 9d ), -P(O)(R 9c )(N(R 9d )2), -CH2P(O)(R 9c )(N(R 9d )2) or -C(O)OCH2P(O)(R 9c )(N(R 9d )2); wherein the alkyl, alkenyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is each optionally surrounded by one to four Z groups. 1b Substitution; wherein each heteroaryl group has 5 to 12 ring members and one to four heteroatoms, each independently N, O, or S; and

[0330] Unless otherwise stated, each heterocyclic group has 3 to 12 ring members and one to four heteroatoms, each independently N, O, or S; and

[0331] m can be 0, 1, or 2.

[0332] In some embodiments of compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id) or their pharmaceutically acceptable salts, R 2 For H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 2-6 Alkoxyalkyl, -CN, -C(O)R 2a -C(O)OR 2a -C(O)N(R) 2a (R) 2b -C(O)NR 2c S(O)2R 2a -S(O)2R 2a -S(O)2N(R) 2a (R) 2b -S(O)2NR 2c C(O)R 2a C 3-10 cycloalkyl, C 1-6 Alkyl-C 3-10 cycloalkyl, C 1-6 Alkyl-C 3-10 cycloalkyl-C 1-6 Alkyl, C 1-6 alkyl-heterocyclic-C 1-6 Alkyl, C 6-10 Aryl, C 1-6 Alkyl-C 6-10 Aryl, heterocyclic, C 1-6 alkyl-heterocyclic, heteroaryl, or C 1-6 Alkyl-heteroaryl, wherein the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups are each optionally separated by one or more Z. 1b Substitution. In some embodiments of compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id) or their pharmaceutically acceptable salts, R 2 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, C 1-6 Alkyl-C 3-10 cycloalkyl, C 1-6 alkyl-heterocyclic, 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-C 1-6 Alkyl, -CN, -C(O)R 2a -C(O)OR 2a -C(O)N(R) 2a (R) 2b -C(O)NR 2c S(O)2R 2a -S(O)2R 2a -S(O)2N(R) 2a (R) 2b ) or -S(O)2NR 2c C(O)R 2a The alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups are each optionally surrounded by one to four Zn groups. 1b Substitution. In some embodiments of compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id) or their pharmaceutically acceptable salts, R 2 For H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, C 1-6 Alkyl-C 3-10 cycloalkyl, C 1-6 alkyl-heterocyclic, 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-C 1-6 Alkyl, -CN, -C(O)R 2a -C(O)OR 2a -C(O)N(R) 2a (R)2b -C(O)NR 2c S(O)2R 2a -S(O)2R 2a -S(O)2N(R) 2a (R) 2b ) or -S(O)2NR 2c C(O)R 2a The alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups are each optionally surrounded by one to four Zn groups. 1b Replace, where each Z 1b Independently for C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 Alkoxyalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-10 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, heterocyclic -C 1-6 Alkyl, heterocyclic -C 1-6 Halogenated alkyl, heteroaryl-C 1-6 Alkyl, heteroaryl-C 1-6 Halogenated alkyl groups, oxo groups, -OH, -CN, -NO2, or -C(O)N(R) 12a (R) 12b In some embodiments of compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id) or their pharmaceutically acceptable salts, R 2 For H, C 1-6 Alkyl, C 2-6 Alkoxyalkyl, C 3-10 cycloalkyl, C 1-6 Alkyl-C 3-10 cycloalkyl, heterocyclic, C 1-6 alkyl-heterocyclic, heteroaryl, or C 1-6 Alkyl-heteroaryl, wherein each heterocyclic group comprises 3 to 12 ring members and 1 to 3 heteroatoms, each independently of N, O, or S, wherein each heteroaryl group comprises 5 to 10 ring members and 1 to 3 heteroatoms, each independently of N, O, or S, wherein the cycloalkyl, heterocyclic, and heteroaryl groups are each optionally separated by one to four Z-units. 1b Substitution. In some embodiments of compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id) or their pharmaceutically acceptable salts, R 2 C 1-6 Alkyl, C2-6 Alkoxyalkyl, C 3-10 cycloalkyl, C 1-6 Alkyl-C 3-10 cycloalkyl, C 1-6 alkyl-heteroaryl or C 1-6 An alkyl-heterocyclic group, wherein each heterocyclic group comprises 3 to 12 ring members and 1 to 3 heteroatoms, each independently of N, O, or S; wherein each heteroaryl group comprises 5 to 10 ring members and 1 to 3 heteroatoms, each independently of N, O, or S; and wherein the cycloalkyl, heterocyclic, and heteroaryl groups are each optionally separated by one or two Z-terminal groups. 1b Substitution. In some embodiments of compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id) or their pharmaceutically acceptable salts, R 2 C 1-6 Alkyl, C 3-10 cycloalkyl, C 1-6 Alkyl-C 3-10 cycloalkyl, C 1-6 Alkyl-C 3-10 cycloalkyl-C 1-6 Alkyl, C 1-6 alkyl-heterocyclic-C 1-6 Alkyl, heterocyclic, C 1-6 alkyl-heterocyclic, heteroaryl, or C 1-6 Alkyl-heteroaryl, wherein each group is optionally surrounded by one to four Z-shaped radicals. 1b Substitution. In some embodiments of compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id) or their pharmaceutically acceptable salts, R 2 C 1-6 Alkyl-C 3-10 cycloalkyl or C 1-6 Alkyl-C 3-10 cycloalkyl-C 1-6 Alkyl groups, these groups are optionally separated by one to four Z-groups. 1b replace.

[0333] In some embodiments of compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id) or their pharmaceutically acceptable salts, R 2 C 1-6 Alkyl group, which is optionally divided by one to four Z-units 1b Substitution. In some embodiments of compounds of formulas (IA-1), (IA-2), (I), and / or other formulas described herein, R 2 C 3-10Cycloalkyl or heterocyclic groups, wherein each group is optionally surrounded by one to four Z-shaped radicals. 1b Substitution. In some embodiments of compounds of formulas (IA-1), (IA-2), (I), and / or other formulas described herein, R 2 C 1-6 alkyl-heterocyclic-C 1-6 Alkyl or C 1-6 Alkyl-heterocyclic groups, wherein each group is optionally surrounded by one to four Z-shaped radicals. 1b replace.

[0334] In some embodiments of compounds of formulas (IA-1), (IA-2), (I), and / or other formulas described herein,

[0335] R 2 for

[0336]

[0337] In some embodiments of compounds of formula (IA-1), (IA-2) and / or other formulas described herein, or pharmaceutically acceptable salts thereof,

[0338] R 1 Heterocyclic group, C 6-10 Aryl or 6-membered heteroaryl groups, each of which is optionally bound by one to three carbon atoms. 1-6 Halogenated alkyl, halogenated or -CN substituted;

[0339] R B It can be methyl, halogen, -CN or -OCH3;

[0340]

[0341] R 3 -C(O)R 3a ;

[0342] R 3a For H, C 1-4 Alkyl-N(R) 9a (R) 9b -C 1-4 Alkyl-N(R) 9a )C(O)-OC 1-4 Alkyl-OP(O)(OR) 9c )2、-C 1-4 Alkyl-OC(O)-C 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-OC 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl-N(R)9a (R) 9b -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl-OP(O)(OR) 9c )2、-CH2CH(N(R 9a )2)C(O)OR 9b -P(O)(OR) 9c )2、-OP(O)(OR 9c )2、-CH2P(O)(OR 9c )2、-CH2OP(O)(OR 9c )2 or C 1-6 Alkyl-heterocyclic group, wherein each of the alkyl or heterocyclic group is optionally substituted with one to four halogens;

[0343] Each R 4 Independently, it can be F, an oxo group, or -CN;

[0344] R 5a and R 5b Each is H; and

[0345] Y is -O-; and

[0346] Each R 8 Independently H or halogen;

[0347] Each R 9a R 9b and R 9c Independently H or C 1-6 alkyl;

[0348] m is 0 or 1; and

[0349] n is 1 or 2.

[0350] In some embodiments of compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id) or their pharmaceutically acceptable salts, R 3 -C(O)OR 3a -C(O)N(R) 3a (R) 3b ), -N(R 3a )C(O)R 3b -N(R) 3a )C(O)OR 3b -N(R) 3a )C(O)N(R 3b (R) 3c -C(O)NHS(O)2R 3a -S(O)2R3a -S(O)2OR 3a -S(O)2N(R) 3a (R) 3b ), -N(R 3a )S(O)2R 3b -S(O)2NHC(O)R 3a -S(O)(=NR) 3a )R 3b -S(O)(=NR) 3a )NR 3b -S(=NR) 3a (=NR) 3b )R 3c -P(O)(OR) 3a (R) 3b -P(O)(OR) 3a (OR) 3b -B(OR) 3a (OR) 3b Or a 5- to 10-membered heteroaryl group having one to four heteroatoms, each independently N, O, or S. In some embodiments of compounds of formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id) or pharmaceutically acceptable salts thereof, R 3 It can be H, halogen, heteroaryl, -C(O)NH2, -C(O)OH, or -CH2C(O)OR. 3a -C(O)OR 3a -C(O)N(R) 3a )S(O)2(R 3b -S(O)2NHC(O)R 3a -P(O)(OR) 3a )2、-C(O)N(R 3a )S(O)2N(R 3b (R) 3c ) or -OC 1-6 Alkyl-C(O)OR 3a The heteroaryl group is optionally surrounded by one to four R groups. 3d Substitution. In some embodiments of compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id) or their pharmaceutically acceptable salts, R 3 -C(O)OH, -C(O)OR 3a -C(O)N(R) 3a )S(O)2(R 3b -S(O)2NHC(O)R 3a -C(O)NR3a S(O)2NR 3b R 3c Or a heteroaryl group, wherein the heteroaryl group is optionally surrounded by one to four R groups. 3d Substitution. In some embodiments of compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id) or their pharmaceutically acceptable salts, R 3 It is a 5- to 6-membered heteroaryl group, which is optionally divided by one to four R groups. 3d Replacement. In some implementations, R 3 -C(O)OR 3a In some embodiments of compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id) or their pharmaceutically acceptable salts, R 3 It is -C(O)OH.

[0351] In some embodiments of compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id) or their pharmaceutically acceptable salts,

[0352] R 3 for

[0353]

[0354]

[0355] In some embodiments of compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id) or their pharmaceutically acceptable salts, R 3a For H, C 1-4 Alkyl-N(R) 9a (R) 9b -C 1-4 Alkyl-N(R) 9a )C(O)-OC 1-4 Alkyl-OP(O)(OR) 9c 2. C 1-4 Alkyl-C(O)N(R) 9a (R) 9b -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-OC 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl-N(R)9a )(R 9b )、-C 1-4 alkyl - O - C(O) - C 1-4 alkyl - OP(O)(OR 9c )2、-CH2CH(N(R 9a )2)C(O)OR 9b 、-P(O)(OR 9c )2、-OP(O)(OR 9c )2、-CH2P(O)(OR 9c )2、-CH2OP(O)(OR 9c )2、-OCH2P(O)(OR 9c )2、-C(O)OCH2P(O)(OR 9c )2、-P(O)(R 9c )(OR 9d )、-OP(O)(R 9c )(OR 9d )、-CH2P(O)(R 9c )(OR 9d )、-OCH2P(O)(R 9c )(OR 9d )、-C(O)OCH2P(O)(R 9c )(OR 9d )、-P(O)(N(R 9c )2)2、-OP(O)(N(R 9c )2)2、-CH2P(O)(N(R 9c )2)2、-OCH2P(O)(N(R 9c )2)2、-C(O)OCH2P(O)(N(R 9c )2)2、-P(O)(N(R 9c )2)(OR 9d )、-OP(O)(N(R 9c )2)(OR 9d )、-CH2P(O)(N(R 9c )2)(OR 9d )、-OCH2P(O)(N(R 9c )2)(OR 9d )、-C(O)OCH2P(O)(N(R 9c )2)(OR 9d )、-P(O)(R 9c )(N(R 9d )2)、-OP(O)(R 9c )(N(R 9d )2)、-CH2P(O)(R9c )(N(R 9d )2), -OCH2P(O)(R 9c )(N(R 9d )2), -C(O)OCH2P(O)(R 9c )(N(R 9d )2) or C 1-6 Alkyl-heterocyclic group, wherein the alkyl or heterocyclic group is optionally substituted with one to four halogens.

[0356] In some embodiments of compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id) or their pharmaceutically acceptable salts, R 3 For H, -Br,

[0357]

[0358] In some embodiments of compounds of formulas (I), (IA-1), (IA-2), (Ia), (Ib), (Ic) and / or (Id) or their pharmaceutically acceptable salts, each R 3a R 3b and R 3c H and C independently 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-10 Cycloalkyl.

[0359] In some embodiments of compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id) or their pharmaceutically acceptable salts, each R 4 Independently for C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, halogen, oxo group, -CN or -OR 4a In some embodiments of compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id) or their pharmaceutically acceptable salts, each R 4 Independently for C 1-6 Alkyl, C 2-6 Alkoxyalkyl, C 1-6 Alkoxy, C 1-6Halogenated alkoxy groups, halogens, oxo groups, -OH, or -CN. In some embodiments of compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id) or their pharmaceutically acceptable salts, two R groups are attached to adjacent ring atoms. 4 Groups combine with the atoms they are attached to to form C 3-10 Cycloalkyl. In some embodiments of compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id) or pharmaceutically acceptable salts thereof, each R 4 Independently for C 1-6 Alkyl, halogen, oxo, -CN or -OR 4 In some embodiments of compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id) or their pharmaceutically acceptable salts, each R 4 It can be F, oxo group or -CN independently.

[0360] In some embodiments of compounds of formula (IA-1), (IA-2) and / or (I) or their pharmaceutically acceptable salts, each R 5a and R 5b H and C independently 1-6 Alkyl, F, Cl, C 3-10 Cycloalkyl groups, 3- to 12-membered heterocyclic groups having one to three heteroatoms, each independently of O, N, or S, or -CN.

[0361] In some embodiments of compounds of formula (IA-1), (IA-2) and / or (I) or their pharmaceutically acceptable salts, R 6a For H, C 1-6 Alkyl, C 3-10 Cycloalkyl or heterocyclic groups. In some embodiments, R 6a For H, C 1-6 Alkyl, C 3-10 Cycloalkyl or 3- to 12-membered heterocyclic groups having one to three heteroatoms, each independently of O, N, or S.

[0362] In some embodiments of compounds of formula (IA-1), (IA-2) and / or (I) or their pharmaceutically acceptable salts, each R 6b and R 6c Independently, H, F, Cl, C 1-3 Alkyl or -CN. In some embodiments, each R 6b and R 6c It can be H, F, Cl or -CN independently.

[0363] In some embodiments of compounds of formula (IA-1), (IA-2) and / or (I) or their pharmaceutically acceptable salts, R 6c With an R 4 Groups and the atoms they are attached to combine to form C 3-10 Cycloalkyl or a 3- to 12-membered heterocyclic group having one to three heteroatoms, each independently N, O, or S, wherein the cycloalkyl and heterocyclic group are each optionally surrounded by one to four R atoms. 4c replace.

[0364] In some embodiments of compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id) or their pharmaceutically acceptable salts, each R 8 Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C) 1-9 Alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 2-6 alkenyl), -O(C) 2-6 alkynyl group), -O(C 3-15 cycloalkyl), -O (heterocyclic), -O (C 6-10 aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 2-6 alkenyl), -NH(C) 2-6 alkynyl group), -NH(C 3-15 cycloalkyl), -NH (heterocyclic), -NH (C 6-10 aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 1-8 (halogenated alkyl)2, -N(C) 2-6 alkenyl)2, -N(C 2-6 2, -N(C) 3-15 cycloalkyl)2, -N(heterocyclic)2, -N(C 6-10 aryl)2, -N(heteroaryl)2, -N(C 1-9 Alkyl)(C 1-8 Halogenated alkyl), -N(C) 1-9 Alkyl)(C 2-6 alkenyl), -N(C) 1-9Alkyl)(C 2-6 alkynyl group), -N(C 1-9 Alkyl)(C 3-15 cycloalkyl), -N(C) 1-9 Alkyl (heterocyclic), -N(C) 1-9 Alkyl)(C 6-10 aryl), -N(C 1-9 Alkyl)(heteroaryl), -C(O)(C 1-9 Alkyl), -C(O)(C 1-8 Halogenated alkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 ynyl group), -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 Halogenated alkyl groups), -C(O)O(C 2-6 alkenyl), -C(O)O(C 2-6 alkynyl group), -C(O)O(C 3-15 cycloalkyl), -C(O)O (heterocyclic), -C(O)O (C 6-10 aryl), -C(O)O (heteroaryl), -C(O)NH2, -C(O)NH(C 1-9 Alkyl), -C(O)NH(C 1-8 Halogenated alkyl), -C(O)NH(C 2-6 alkenyl), -C(O)NH(C 2-6 ynyl group), -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 (halogenated alkyl)2、-C(O)N(C 2-6 alkenyl)2, -C(O)N(C 2-6 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, -NHC(O)(C 1-9 Alkyl), -NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 ynyl group), -NHC(O)(C3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (C 6-10 aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (C 6-10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -NHC(O)NH(C 1-8 (halogenated alkyl), -NHC(O)NH(C) 2-6 alkenyl), -NHC(O)NH(C 2-6 ), -NHC(O)NH(C 3-15 cycloalkyl), -NHC(O)NH (heterocyclic), -NHC(O)NH (C 6-10 aryl), -NHC(O)NH (heteroaryl), -NHS(O)(C 1-9 alkyl), -N(C) 1-9 Alkyl)(S(O)(C) 1-9 alkyl), -S(C 1-9 alkyl), -S(C 1-8 Halogenated alkyl), -S(C 2-6 alkenyl), -S(C 2-6 alkynyl group), -S(C 3-15 cycloalkyl), -S (heterocyclic), -S (C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2、-S(O)(C 1-9 Alkyl), -S(O)(C 1-8 Halogenated alkyl groups), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 ynyl group), -S(O)(C 3-15 cycloalkyl), -S(O)(heterocyclic), -S(O)(C 6-10 aryl), -S(O) (heteroaryl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 2-6 alkenyl), -S(O)2(C 2-6 alkynyl group), -S(O)2(C 3-15cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (C 6-10 aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2. In some embodiments, each R 8 Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C) 1-9 Alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 2-6 alkenyl), -O(C) 2-6 alkynyl group), -O(C 3-15 cycloalkyl), -O (heterocyclic), -O (C 6-10 aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 2-6 alkenyl), -NH(C) 2-6 alkynyl group), -NH(C 3-15 cycloalkyl), -NH (heterocyclic), -NH (C 6-10 aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 1-8 (halogenated alkyl)2, -N(C) 2-6 alkenyl)2, -N(C 2-6 2, -N(C) 3-15 cycloalkyl)2, -N(heterocyclic)2, -N(C 6-10 aryl)2, -N(heteroaryl)2, -N(C 1-9 Alkyl)(C 1-8 Halogenated alkyl), -N(C) 1-9 Alkyl)(C 2-6 alkenyl), -N(C) 1-9 Alkyl)(C 2-6 alkynyl group), -N(C 1-9 Alkyl)(C 3-15 cycloalkyl), -N(C) 1-9 Alkyl (heterocyclic), -N(C) 1-9 Alkyl)(C 6-10 aryl), -N(C 1-9Alkyl)(heteroaryl), -C(O)(C 1-9 Alkyl), -C(O)(C 1-8 Halogenated alkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 ynyl group), -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 Halogenated alkyl groups), -C(O)O(C 2-6 alkenyl), -C(O)O(C 2-6 alkynyl group), -C(O)O(C 3-15 cycloalkyl), -C(O)O (heterocyclic), -C(O)O (C 6-10 Aryl) or -C(O)O (heteroaryl). In some embodiments, each R 8 Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, -NO2, or -NH2. In some embodiments, each R 8 Independently for C 1-3 Alkyl, C 1-3 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-7 Cycloalkyl, oxo, -OH, -CN, or -NH2. In some embodiments of compounds of formula (I), (IA-1), and / or (IA-2) or their pharmaceutically acceptable salts, each R 8 Independently for C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, halogens, C 3-7 Cycloalkyl, oxo, -OH, -CN, or -NH2. In some embodiments, each R 8 Independently for C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, halogens, C 3-7 Cycloalkyl, oxo, or -CN. In compounds of formula (I), (IA-1), and / or (IA-2), or their pharmaceutically acceptable salts, R 8 C 1-9 Alkyl, halogen or -O(C) 1-9Alkyl). In some embodiments of compounds of formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id) or pharmaceutically acceptable salts thereof, each Z 1b Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C) 1-9 Alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 2-6 alkenyl), -O(C) 2-6 alkynyl group), -O(C 3-15 cycloalkyl), -O (heterocyclic), -O (C 6-10 aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 2-6 alkenyl), -NH(C) 2-6 alkynyl group), -NH(C 3-15 cycloalkyl), -NH (heterocyclic), -NH (C 6-10 aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 1-8 (halogenated alkyl)2, -N(C) 2-6 alkenyl)2, -N(C 2-6 2, -N(C) 3-15 cycloalkyl)2, -N(heterocyclic)2, -N(C 6-10 aryl)2, -N(heteroaryl)2, -N(C 1-9 Alkyl)(C 1-8 Halogenated alkyl), -N(C) 1-9 Alkyl)(C 2-6 alkenyl), -N(C) 1-9 Alkyl)(C 2-6 alkynyl group), -N(C 1-9 Alkyl)(C 3-15 cycloalkyl), -N(C) 1-9 Alkyl (heterocyclic), -N(C) 1-9 Alkyl)(C 6-10 aryl), -N(C 1-9 Alkyl)(heteroaryl), -C(O)(C 1-9 Alkyl), -C(O)(C 1-8 Halogenated alkyl), -C(O)(C2-6 alkenyl), -C(O)(C 2-6 ynyl group), -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 Halogenated alkyl groups), -C(O)O(C 2-6 alkenyl), -C(O)O(C 2-6 alkynyl group), -C(O)O(C 3-15 cycloalkyl), -C(O)O (heterocyclic), -C(O)O (C 6-10 aryl), -C(O)O (heteroaryl), -C(O)NH2, -C(O)NH(C 1-9 Alkyl), -C(O)NH(C 1-8 Halogenated alkyl), -C(O)NH(C 2-6 alkenyl), -C(O)NH(C 2-6 ynyl group), -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 (halogenated alkyl)2、-C(O)N(C 2-6 alkenyl)2, -C(O)N(C 2-6 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, -NHC(O)(C 1-9 Alkyl), -NHC(O)(C 1-8 Halogenated alkyl groups), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 ynyl group), -NHC(O)(C 3-15 cycloalkyl), -NHC(O) (heterocyclic), -NHC(O) (C 6-10 aryl), -NHC(O) (heteroaryl), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 1-8 Halogenated alkyl groups), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15cycloalkyl), -NHC(O)O (heterocyclic), -NHC(O)O (C 6-10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -NHC(O)NH(C 1-8 (halogenated alkyl), -NHC(O)NH(C) 2-6 alkenyl), -NHC(O)NH(C 2-6 ), -NHC(O)NH(C 3-15 cycloalkyl), -NHC(O)NH (heterocyclic), -NHC(O)NH (C 6-10 aryl), -NHC(O)NH (heteroaryl), -NHS(O)(C 1-9 alkyl), -N(C) 1-9 Alkyl)(S(O)(C) 1-9 alkyl), -S(C 1-9 alkyl), -S(C 1-8 Halogenated alkyl), -S(C 2-6 alkenyl), -S(C 2-6 alkynyl group), -S(C 3-15 cycloalkyl), -S (heterocyclic), -S (C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2、-S(O)(C 1-9 Alkyl), -S(O)(C 1-8 Halogenated alkyl groups), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 ynyl group), -S(O)(C 3-15 cycloalkyl), -S(O)(heterocyclic), -S(O)(C 6-10 aryl), -S(O) (heteroaryl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Halogenated alkyl groups), -S(O)2(C 2-6 alkenyl), -S(O)2(C 2-6 alkynyl group), -S(O)2(C 3-15 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (C 6-10 aryl), -S(O)2 (heteroaryl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9Alkyl)2. In some embodiments of compounds of formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id) or their pharmaceutically acceptable salts, each Z 1b Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, -SH, -O(C) 1-9 Alkyl), -O(C) 1-8 Halogenated alkyl), -O(C) 2-6 alkenyl), -O(C) 2-6 alkynyl group), -O(C 3-15 cycloalkyl), -O (heterocyclic), -O (C 6-10 aryl), -O (heteroaryl), -NH (C 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -NH(C) 2-6 alkenyl), -NH(C) 2-6 alkynyl group), -NH(C 3-15 cycloalkyl), -NH (heterocyclic), -NH (C 6-10 aryl), -NH (heteroaryl), -N (C 1-9 Alkyl)2, -N(C 1-8 (halogenated alkyl)2, -N(C) 2-6 alkenyl)2, -N(C 2-6 2, -N(C) 3-15 cycloalkyl)2, -N(heterocyclic)2, -N(C 6-10 aryl)2, -N(heteroaryl)2, -N(C 1-9 Alkyl)(C 1-8 Halogenated alkyl), -N(C) 1-9 Alkyl)(C 2-6 alkenyl), -N(C) 1-9 Alkyl)(C 2-6 alkynyl group), -N(C 1-9 Alkyl)(C 3-15 cycloalkyl), -N(C) 1-9 Alkyl (heterocyclic), -N(C) 1-9 Alkyl)(C 6-10 aryl), -N(C 1-9 Alkyl)(heteroaryl), -C(O)(C 1-9 Alkyl), -C(O)(C 1-8Halogenated alkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 ynyl group), -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 Halogenated alkyl groups), -C(O)O(C 2-6 alkenyl), -C(O)O(C 2-6 alkynyl group), -C(O)O(C 3-15 cycloalkyl), -C(O)O (heterocyclic), -C(O)O (C 6-10 Aryl) or -C(O)O (heteroaryl). In some embodiments of compounds of formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id) or their pharmaceutically acceptable salts, each Z 1b Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-15 cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, -NO2, or -NH2. In some embodiments of compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id) or their pharmaceutically acceptable salts, each Z 1b Independently for C 1-3 Alkyl, C 1-3 Haloalkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 3-7 Cycloalkyl, oxo, -OH, -CN, or -NH2. In some embodiments of compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id) or their pharmaceutically acceptable salts, each Z 1b Independently for C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, halogens, C 3-7 Cycloalkyl, oxo, -OH, -CN, or -NH2. In some embodiments of compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id) or their pharmaceutically acceptable salts, each Z 1b Independently for C1-3 Alkyl, C 1-3 Halogenated alkyl groups, halogens, C 3-7 Cycloalkyl, oxo, or -CN.

[0365] In some embodiments, compounds of formulas (I), (IA-1), (IA-2), (Ia), (Ib), (Ic) and / or (Id), or pharmaceutically acceptable salts thereof, have the formula:

[0366]

[0367]

[0368]

[0369]

[0370]

[0371] In some embodiments, the compounds disclosed herein have the following structures:

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

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

[0433]

[0434] This document also discloses in vivo metabolites of the compounds described herein, which are novel to some extent and not significantly superior to existing technologies. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc., of the applied compound, primarily due to enzymatic processes. Therefore, methods including the generation of novel and non-obvious compounds by means of exposing the compound to mammals for a period sufficient to produce its metabolites are also included. Such products are typically generated by preparing radiolabeled (e.g., 14 C or 3 To identify compounds (H), the radiolabeled compound is administered parenterally to animals, such as rats, mice, guinea pigs, monkeys, or humans, at a detectable dose (e.g., greater than about 0.5 mg / kg), allowing sufficient time for metabolism (typically about 30 seconds to 30 hours), and its metabolites are isolated from urine, blood, or other biological samples. These products can be readily separated due to labeling (other products are separated using antibodies capable of binding to viable epitopes in the metabolites). The metabolite structure is determined in a conventional manner, such as by MS or NMR analysis. Typically, the analysis of metabolites can be performed in the same manner as routine drug metabolism studies well known to those skilled in the art. The metabolites can be used for diagnostic determination of the therapeutic dose of the compound, provided they are not otherwise detected in vivo, even if they do not possess GLP-1R activity themselves.

[0435] Formulations and methods for determining the stability of compounds in alternative gastrointestinal secretions are known. Compounds are defined herein as stable in the gastrointestinal tract, wherein less than about 50 mol% of the protecting group is deprotected in alternative intestinal or gastric juices after incubation at 37°C for 1 hour. The fact that compounds are stable in the gastrointestinal tract does not mean they cannot be hydrolyzed in vivo. Prodrugs are generally stable in the digestive system but can be hydrolyzed substantially to the parent drug in the digestive lumen, liver, lungs, or other metabolic organs, or generally intracellularly. As used herein, a prodrug is understood to be a compound chemically engineered to efficiently release the parent drug after overcoming the biological barriers of oral delivery.

[0436] III. Methods for preparing compounds

[0437] The compounds disclosed herein can be prepared by any method known in the art. The following exemplary general methods illustrate a route that can be used to obtain the compounds disclosed herein.

[0438] Option 1

[0439]

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

[0441] Option 2

[0442]

[0443] Compounds of formula (IA-1), (IA-2), and / or formula (I) having the structure of a compound of formula 2.9 can be synthesized by first combining intermediate 2.1 (where X) via metal-mediated cross-coupling using a suitable base (e.g., DIPEA, KOtBu, etc.) or a suitable palladium catalyst. 21 and X 22 Intermediate 2.2 (where Y = O, NH, or S) is coupled with a leaving group, such as a halogen (e.g., Cl or Br), to obtain intermediate 2.3 (Scheme 2). Intermediate 2.4 (where M = Li, MgBr, MgCl, or MgI, commercially available or obtained by metallization of the corresponding halide) can be combined with intermediate 2.3 using a suitable palladium catalyst to provide intermediate 2.5. After conversion to acidic intermediate 2.6 using standard conditions (e.g., LiOH, LiI, and pyridine), intermediate 1.3 can be added using standard amide bond forming conditions (e.g., DIPEA and HATU) to obtain intermediate 2.7, which can then be converted to the corresponding benzimidazole intermediate 2.8 under the influence of an acid catalyst (e.g., HCl, AcOH, etc.). This intermediate can be converted to compounds of formula (IA-1), (IA-2), and / or formula (I) using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine).

[0444] Although Scheme 2 above uses intermediate 2.1 as a dihalopyridine for illustration, any dihalogenated A-ring starting material can be used to obtain similar compounds of formula (IA-1), (IA-2) and / or formula (I).

[0445] Option 3

[0446]

[0447] In some embodiments, compounds of formula (IA-1), (IA-2), and / or formula (I) having the structure of a compound of formula 2.9 can be combined in the following manner: firstly, intermediate 3.1 (where X) is formed under standard amide bond formation conditions (e.g., DIPEA and HATU, etc.). 31 A combination of intermediate 1.3 (where R = alkyl, alkylaryl, or aryl) and intermediate 3.3 (where R = alkyl, alkylaryl, or aryl) (Scheme 3); treatment with a suitable acid catalyst (e.g., HCl, AcOH, etc.) can provide intermediate 3.3; -X 31 Halogen metal exchange to -M can be achieved by transition metal coupling using suitable reagents (e.g., iPrMgBr, etc.) or by using suitable palladium catalysts and metal sources (e.g., B2Pin2, Bu6Sn2, etc.) to obtain intermediate 2.8, which can be converted into compounds of formula (IA-1), (IA-2) and / or formula (I) using standard ester hydrolysis conditions (e.g., LiOH, LiI and pyridine, etc.).

[0448] Option 4

[0449]

[0450] In some embodiments, the compound of formula 2.9 can be formed by first converting intermediate 2.3 into the metallized variant intermediate 4.1 using a suitable palladium catalyst and a metal source (e.g., B2Pin2, Bu6Sn2, etc.) (Scheme 4); intermediate 4.1 can be coupled with intermediate 3.3 using a suitable palladium catalyst to provide intermediate 2.8, and then intermediate 2.8 can be converted into the compound of formula (IA-1), (IA-2) and / or formula (I) using standard ester hydrolysis conditions (e.g., LiOH, LiI and pyridine, etc.).

[0451] Option 5

[0452]

[0453] Compounds of formula (IA-1), (IA-2) and / or formula (I) having the structure of a compound of formula 5.3 can be combined in the following manner: firstly, intermediate 5.2 is provided by coupling a suitable coupling coupler and a palladium catalyst to a halogen-X (where X is Cl, Br or I) of intermediate 5.2, which can be converted into a compound of formula 5.3 using standard ester hydrolysis conditions (e.g., LiOH, LiI and pyridine, etc.) (Scheme 5).

[0454] Option 6

[0455]

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

[0457] Option 7

[0458]

[0459] Compounds of formula (IA-1), (IA-2) and / or formula (I) having the structure of a compound of formula 7.3 can be combined in the following manner: firstly, intermediate 7.2 is provided by coupling a suitable coupling coupler and a palladium catalyst to the halogen-X of intermediate 7.1, and intermediate 7.2 can be converted into a compound of formula 7.3 (scheme 7) using standard ester hydrolysis conditions (e.g., LiOH, LiI and pyridine).

[0460] Option 8

[0461]

[0462] Compounds of formula (IA-1), (IA-2), and / or formula (I) having the structure of a compound of formula 2.9 can be combined as follows: first, intermediate 3.4 is cross-coupled with intermediate 2.1 using a suitable transition metal catalyst (e.g., palladium, etc.) (Scheme 8); then, intermediate 8.1 is coupled with intermediate 2.2 containing heteroatoms (where Y = O, N, or S) via metal-mediated cross-coupling using a suitable base (e.g., DIPEA, KOtBu, etc.) or a suitable palladium catalyst to obtain intermediate 2.8; intermediate 2.8 can be converted into compounds of formula (IA-1), (IA-2), and / or formula (I) having the structure of a compound of formula 2.9 using standard ester hydrolysis conditions (e.g., LiOH, LiI, and pyridine, etc.).

[0463] IV. Pharmaceutical Preparations

[0464] In some embodiments, this disclosure provides a pharmaceutical composition comprising a compound of the disclosure (e.g., a compound of formula (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic) and / or (Id)) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

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

[0466] Pharmaceutical compositions comprising the compounds disclosed herein or their pharmaceutically acceptable salts may be prepared using one or more pharmaceutically acceptable excipients, which may be selected according to conventional practices. Tablets may contain excipients, including gliding agents, fillers, binders, etc. Aqueous compositions may be prepared aseptically and are typically isotonic when intended for delivery by non-oral administration. In some embodiments, the composition may contain excipients such as those described in Rowe et al., “Handbook of Pharmaceutical Excipients,” 6th edition, American Pharmacists Association, 2009. Excipients may include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, etc. In some embodiments, the composition is provided as a solid dosage form, including solid oral dosage forms.

[0467] The compositions comprise those suitable for various routes of administration, including oral administration. The compositions may be present in unit dosage forms and may be prepared by any of the methods well known in the pharmaceutical field. Such methods include the steps of associating an active ingredient (e.g., a compound of this disclosure or a pharmaceutically acceptable salt thereof) with one or more pharmaceutically acceptable excipients. The compositions may be prepared by homogeneously and tightly associating the active ingredient with a liquid excipient or a fractionated solid excipient, or both, and then, if desired, shaping the product. Techniques and formulations are commonly found in “Remington: The Science and Practice of Pharmacy,” 21st edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0468] The compositions described herein suitable for oral administration may exist as discrete units (unit dosage forms), including but not limited to capsules, sachets, or tablets each containing a predetermined amount of the active ingredient. In one embodiment, the pharmaceutical composition disclosed herein is a tablet.

[0469] 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 optional other therapeutic agents. Pharmaceutical compositions containing an active ingredient may be in any form suitable for the intended method of administration. When intended for oral use, they may be prepared, for example, tablets, lozenges, tablets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more excipients, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable formulation. Tablets containing an active ingredient mixed with a non-toxic, pharmaceutically acceptable excipient suitable for manufacturing tablets are acceptable. These excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, polyvinylpyrrolidone, calcium phosphate or sodium phosphate; granulating and disintegrants such as corn starch or alginate; binders such as cellulose, microcrystalline cellulose, starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or coated using known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby providing sustained action over a longer period. For example, delaying agents such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with waxes.

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

[0471] In some embodiments, in one variation, compositions comprising compounds of the present disclosure or pharmaceutically acceptable salts thereof do not contain agents that affect the metabolic rate of the active ingredient. Therefore, it should be understood that, in one aspect, compositions comprising compounds of the present disclosure do not contain agents that would affect (e.g., slow down, inhibit, or delay) the metabolism of the compounds of the present disclosure or any other active ingredient applied separately, sequentially, or simultaneously with the compounds of the present disclosure. It should also be understood that, in one aspect, any of the methods, kits, articles, etc., detailed herein do not contain agents that would affect (e.g., slow down, inhibit, or delay) the metabolism of the compounds of the present disclosure or any other active ingredient applied separately, sequentially, or simultaneously with the compounds of the present disclosure.

[0472] In some embodiments, the above-described pharmaceutical composition is used in humans or animals.

[0473] This disclosure also includes compounds of the disclosure applied as a single active ingredient in a pharmaceutically acceptable composition, the active ingredient being prepared by conventional methods known in the art, for example by binding the active ingredient to a pharmaceutically acceptable, therapeutically inert organic and / or inorganic carrier or excipient, or by mixing the active ingredient with them.

[0474] In one aspect, this document provides for the use of the compounds of this disclosure as a second or other active ingredient that has a synergistic effect with other active ingredients in known pharmaceutical products, or for the administration of the compounds of this disclosure together with such pharmaceutical products.

[0475] The compounds disclosed herein can also be used as prodrugs or other suitable modified forms that release the active ingredient in vivo.

[0476] V. Route of application

[0477] The compounds disclosed herein (also referred to herein as the active ingredients) may be administered via 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, intrathecal, and epidural). It should be understood that preferred routes may vary depending on, for example, the recipient's condition. An advantage of some of the compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0478] The compounds disclosed herein can be administered to an individual for the required period of time or duration according to an effective dosing regimen, such as at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. In one variant, the compounds are administered on a daily or intermittent schedule for the duration of an individual's life.

[0479] The dosage or frequency of administration of the compounds disclosed herein can be adjusted during treatment based on the judgment of the administering physician.

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

[0481] The compound may be administered by any available route and method, such as by oral or parenteral (e.g., intravenous) administration. Therapeuticly effective amounts of the compound may 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.

[0482] The compounds disclosed herein may be combined with one or more additional therapeutic agents at any dose of the disclosed compounds (e.g., 1 mg to 1000 mg of the compound). Therapeuticly effective doses may include about 1 mg / dose to about 1000 mg / dose, such as about 50 mg / dose to about 500 mg / dose, or such as about 100 mg / dose to about 400 mg / dose, or such as about 150 mg / dose to about 350 mg / dose, or such as about 200 mg / dose to about 300 mg / dose. Other therapeutically effective doses of the compounds disclosed herein 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 disclosed herein are about 100 mg / dose, or about 125 mg / dose, about 150 mg / dose, about 175 mg / dose, about 200 mg / dose, about 225 mg / dose, about 250 mg / dose, about 275 mg / dose, about 300 mg / dose, about 350 mg / dose, about 400 mg / dose, about 450 mg / dose, or about 500 mg / dose. A single dose may be administered hourly, daily, or weekly. For example, a single dose may be administered every 1, 2, 3, 4, 6, 8, 12, or 16 hours, or every 24 hours. A single dose may also be administered every 1, 2, 3, 4, 5, or 6 days, or every 7 days. A single dose may also be administered every 1, 2, or 3 weeks, or every 4 weeks. In some embodiments, a single dose may be administered weekly. A single dose may also be administered monthly.

[0483] This disclosure also includes kits comprising 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 comprises a label and / or instructions for use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogue thereof, and the compound described herein in a therapeutic indication (such as the disease or condition described herein). In one embodiment, kits are provided comprising 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.

[0484] This document also provides articles in suitable containers, including compounds of the present disclosure, or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs thereof. Containers may be vials, wide-mouth bottles, ampoules, pre-loaded syringes, and intravenous bags.

[0485] VI. Combination Therapy

[0486] In some embodiments, the compounds of this disclosure or pharmaceutically acceptable salts thereof may be combined with therapeutically effective amounts of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) adjunctive therapeutic agents. In some embodiments, the adjunctive therapeutic agents include apoptosis signal-regulated kinase-1 (ASK-1) inhibitors, farnesoid X receptor (FXR) agonists, peroxisome proliferation-activated receptor α (PPARα) agonists, fish oil, acetyl-CoA carboxylase (ACC) inhibitors, or TGFβ antagonists, or combinations thereof.

[0487] In some implementations, the therapeutic agent or combination of therapeutic agents includes ACE inhibitors, 2-acylglycerol O-acyltransferase 2 (DGAT2), aldehyde dehydrogenase inhibitors, acetyl-CoA carboxylase inhibitors, adrenergic receptor agonists, Alstrom syndrome protein 1 (ALMS1) / PKCα protein interaction inhibitors, apralin peptide receptor agonists, diacylglycerol O-acyltransferase 2 inhibitors, adenosine A3 receptor agonists, adenosine A3 receptor antagonists, adiponectin receptor agonists, aldehyde dehydrogenase 2 stimulators, AKT protein kinase inhibitors, AMP-activated protein kinase (AMPK), AMP kinase activators, ATP citrate lyase inhibitors, AMP-activated protein kinase stimulators, endothelial nitric oxide synthase stimulators, NAD-dependent deacetylase Sirtuin-1 stimulators, adrenergic receptor antagonists, androgen receptor agonists, pancreatic amyloid peptide receptor agonists, and angiotensin II. AT-1 receptor antagonists, autophagy protein modulators, autocrine motor factor inhibitors, Axl tyrosine kinase receptor inhibitors, Bax protein stimulators, β-catenin inhibitors, bioactive lipids, calcitonin agonists, cannabinoid receptor modulators, caspase inhibitors, caspase-3 stimulators, cathepsin inhibitors, caveolin 1 inhibitors, CCK receptor antagonists, CCL26 gene inhibitors, CCR2 chemokine antagonists, angiotensin II AT-1 receptor antagonists, CCR3 chemokine antagonists, CCR5 chemokine antagonists, CD3 antagonists, CDGSH iron-sulfur domain protein modulators, chitosanase inhibitors, chloride channel stimulators, chitosan trisaccharidase 1 inhibitors, CNR1 inhibitors, connective tissue growth factor ligand inhibitors, cyclin D1 inhibitors, cytochrome P450. 7A1 inhibitors, DGAT1 / 2 inhibitors, diacylglycerol O-acyltransferase 1 inhibitors (DGAT1), cytochrome P450CYP2E1 inhibitors, CXCR4 chemokine antagonists, dihydroceramide δ4 desaturase inhibitors, dihydroorotate dehydrogenase inhibitors, dipeptidyl peptidase IV inhibitors, endothelial sialic acid protein modulators, eosinophil activation chemokine ligand inhibitors, extracellular matrix protein modulators, farnesoid X receptor agonists, fatty acid synthase inhibitors, FGF1 receptor agonists, fibroblast growth factor (FGF-15, FGF-19, FGF-21) ligands, fibroblast activation protein inhibitors, free fatty acid receptor 1 agonists, galactolectin-3 inhibitors, GDNF family Glucagon receptor alpha-like agonists, glucagon receptor agonists, glucagon-like peptide-1 agonists, glucocorticoid receptor antagonists, glucose-6-phosphate 1-dehydrogenase inhibitors, G protein-coupled bile acid receptor 1 agonists, G protein-coupled receptor-119 agonists, G protein-coupled receptor 84 antagonists, hedgehog (Hh) modulators, hepatitis C virus NS3 protease inhibitors, hepatocyte nuclear factor 4α modulators (HNF4A), hepatocyte growth factor modulators, histone deacetylase inhibitors, STAT-3 modulators, HMG coenzyme A reductase inhibitors, HSD17B13 gene inhibitors, 5-HT 2α receptor antagonists, hydrolase inhibitors, hypoxia-inducible factor-2α inhibitors, IL-10 agonists, IL-17 antagonists, IL-22 agonists, ileal bile acid sodium cotransporter inhibitors, insulin sensitizers, insulin ligand agonists, insulin receptor agonists, integrin modulators, integrin antagonists, integrin α-V / β-1 antagonists, integrin α-V / β-6 antagonists, interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors, IL-6 receptor agonists, interleukin-17 ligand inhibitors, Jak2 tyrosine kinase inhibitors, Jun N-terminal kinase-1 inhibitors, Kelch-like ECH-associated protein 1 modulators, ketohexokinase (KHK) inhibitors, Klothoβ stimulants, leukotriene A4 hydrolase inhibitors, 5-lipoxygenase inhibitors, lipoprotein lipase inhibitors, liver X receptor, LPL gene stimulants, lysophosphatidic acid-1 receptor antagonists, lysyl oxidase homologue 2 inhibitors, LXR anti-agonists, macrophage mannose receptor 1 modulators, matrix metalloproteinase (MMP) inhibitors, MEKK-5 protein kinase inhibitors, MCH receptor-1 antagonists, membrane copper amine oxidase (VAP-1) inhibitors, methionine aminopeptidase-2 inhibitors, methyl CpG binding protein 2 modulators, microRNA-132 (miR-132) antagonists, microRNA-21 (miR-21) inhibitors, mitochondrial uncoupling agents, mixed lineage kinase 3 inhibitors, motile sperm domain protein 2 inhibitors, myelin basic protein stimulants, NACHT LRRPYD domain protein 3 (NLRP3) inhibitors, NAD-dependent deacetylase Sirtuin stimulants, NADPH oxidase inhibitors (NOX), NFE2L2 gene inhibitors, niacin receptor 1 agonists, opioid receptor μ antagonists, P2Y13 purine receptor stimulants, nucleoerythrocyte 2-associated factor 2 stimulants, nuclear receptor modulators, P2X7 purine receptor modulators, PACAP Type I receptor agonists, PDE3 inhibitors, PDE4 inhibitors, PDE5 inhibitors, PDGF receptor β modulators, phenylalanine hydroxylase stimulators, phospholipase C inhibitors, phosphodiesterase inhibitors, PPARα agonists, PPARδ agonists, PPARγ agonists, peptidylprolyl cis-trans isomerase A inhibitors, PNPLA3 gene inhibitors, PPARγ modulators, protease-activated receptor-2 antagonists, protein kinase modulators, protein NOV homologue modulators, PTGS2 gene inhibitors, renin inhibitors, resistin / CAP1 (adenylate cyclase-associated protein 1) interaction inhibitors, Rho-associated protein kinase inhibitors, S-nitrosoglutathione reductase (GSNOR) inhibitors, sodium glucose transporter-2 inhibitors, sphingolipid δ4 Desaturase DES1 inhibitors, SREBP transcription factor inhibitors, STAT-1 inhibitors, stearoyl-CoA desaturase-1 inhibitors, STK25 inhibitors, cytokine signaling inhibitor-1 stimulators, cytokine signaling inhibitor-3 stimulators, telomerase stimulators, TERT gene regulators, TGFβ (TGFB1) ligand inhibitors, TNF antagonists, transforming growth factor β (TGF-β), transforming growth factor β-activated kinase 1 (TAK1), thyroid hormone receptor β agonists, TLR-4 antagonists, transglutaminase inhibitors, tyrosine kinase receptor modulators, GPCR modulators, nuclear hormone receptor modulators, TLR-9 antagonists, VDR agonists, WNT modulators or YAP / TAZ modulators, and ligand inhibitors.

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

[0489] -ACE inhibitors, such as enalapril;

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

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

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

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

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

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

[0496] -Adrenergic receptor antagonists, such as bromoergot, phenylbutyramine, and VI-0521;

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

[0498] -α-glucosidase inhibitors (e.g., voglibose, acarbose, or miglitol);

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

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

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

[0502] - AMP-activated protein kinase / endothelial nitric oxide synthase / NAD-dependent deacetylase Sirtuin-1 stimulators, such as NS-0200 (leucine + metformin + sildenafil); - androgen receptor agonists, such as LPCN-1144, LPCN-1148, and testosterone prodrugs.

[0503] -Angiotensin II AT-1 receptor antagonists, such as irbesartan;

[0504] - Angiopoietin-associated protein-3 inhibitors, such as vupanorsen (IONIS-ANGPTL3-LRx);

[0505] - Apalin peptide receptor agonists, such as CB-5064 and MBT-2;

[0506] - Autophagy protein regulators, such as A-2906;

[0507] - Inhibitors of autocrine motor factors (exonucleic acid pyrophosphatase / phosphodiesterase 2 (NPP2 or ENPP2)), such as FP10.47, PAT-505, PAT-048, GLPG-1690, X-165, PF-8380, TJC-0265, TJC-0316, AM-063, BBT-877;

[0508] -Axl tyrosine kinase receptor inhibitors, such as besentinib (BGB-324, R-428);

[0509] -Bax protein stimulants, such as CBL-514;

[0510] -Bioactive lipids, such as DS-102;

[0511] - Cannabinoid receptor modulators, such as namacizumab, GWP-42004, REV-200, CRB-4001, INV-101, SCN-002;

[0512] - Cysteine ​​protease inhibitors, such as enricazone;

[0513] -Pan cathepsin B inhibitors, such as VBY-376;

[0514] -Pan cathepsin inhibitors, such as VBY-825;

[0515] -CCK receptor antagonists, such as propargylamine;

[0516] - CCL26 gene inhibitors, such as mosedipimod and KDDF-201410-10;

[0517] -CCR2 / CCR5 chemokine antagonists, such as BMS-687681, sinivirol, maraviro, CCX-872, leronlimab, WXSH-0213;

[0518] - CCR2 / CCR5 chemokine antagonists and FXR agonists, such as LJC-242 (zopifexoline + linagliptin (cenivriviroc));

[0519] -CCR2 chemokine antagonists, such as propargyl germanium;

[0520] -CCR2 chemokine / angiotensin II AT-1 receptor antagonists, such as DMX-200 and DMX-250;

[0521] -CCR3 chemokine antagonists, such as bertilimab;

[0522] -CD3 antagonists, such as NI-0401 (formeluzumab);

[0523] -CDGSH iron-sulfur domain protein regulators, such as EYP-002;

[0524] - Chitosan polysaccharide inhibitors, such as OATD-01;

[0525] - Chitotriosidase 1 inhibitors, such as OAT-2068;

[0526] - Chloride channel stimulants, such as coprostaglandin and lubiprostaglandin;

[0527] - Casein kinase-1 (CK1) δ / ε inhibitors, such as PF-05006739;

[0528] - Connective tissue growth factor ligand inhibitors, such as PBI-4050;

[0529] -CXCR4 chemokine antagonists, such as AD-214;

[0530] - Diglyceride acyltransferase 2 (DGAT2) inhibitors, such as IONIS-DGAT2Rx and PF-06865571;

[0531] - Diglyceride acyltransferase 1 (DGAT1) inhibitors, such as GSK-3008356;

[0532] - Diacylglycerol O-acyltransferase 1 (DGAT1) / cytochrome P450 2E1 inhibitor (CYP2E1), such as SNP-610;

[0533] - Dihydroorotate dehydrogenase inhibitors, such as vidofluradimo;

[0534] - Dipeptidyl peptidase IV inhibitors, such as linagliptin and etagliptin;

[0535] - Inhibitors of eosinophil activation chemokine ligands, such as bertilimab and CM-101;

[0536] - Extracellular matrix protein modulators, such as CNX-024;

[0537] - Farnesoid X receptor (FXR) agonists, such as AGN-242266, AGN-242256, ASC-42, EDP-297 (EP-024297), RDX-023, BWL-200, AKN-083, EDP-305, GNF-5120, cilofexor Tromethamine (GS-9674), HPG-1860, IOT-022, LMB-763, Obeticholic Acid, Px-102, Px-103, M790, M780, M450, M-480, MET-409, MET-642, PX20606, SYHA-1805, Viloribumab (EYP-001), TERN-101, TC-100, INT-2228, TQA-3526, ZG-5266;

[0538] - Farnesoid X receptor (FXR) / G protein-coupled bile acid receptor 1 (TGR5) agonists, such as INT-767;

[0539] - Fatty acid synthase inhibitors, such as TVB-2640 and FT-8225;

[0540] - Fibroblast growth factor 19 (rhFGF19) / cytochrome P450 (CYP) 7A1 inhibitors, such as odavmin (NGM-282);

[0541] - Fibroblast growth factor 21 (FGF-21) ligand modulators, such as AP-025, BMS-986171, B-1654, BIO89-100, and BOS-580;

[0542] -Pegbelfermin(BMS-986036), B-1344;

[0543] - Fibroblast growth factor 21 (FGF-21) / glucagon-like peptide 1 (GLP-1) agonists, such as YH-25723 (YH-25724, YH-22241) and efruxifermin (AKR-001);

[0544] -FGF receptor agonists / Klothoβ stimulators, such as BFKB-8488A (RG-7992);

[0545] - Free fatty acid receptor 1 agonists, such as SCO-267;

[0546] -Galactolectin-3 inhibitors, such as belapectin (GR-MD-02), GB-1107 (Gal-300), and GB-1211 (Gal-400);

[0547] -GDNF family receptor alpha-like agonists, such as NGM-395;

[0548] - Glucagon-like peptide-1 receptor (GLP1R) agonists, such as ALT-801, AC-3174, liraglutide, cotodextrin (MEDI-0382), SAR-425899, LY-3305677, HM-15211, YH-25723, YH-GLP1, RPC-8844, PB-718, PF-06882961, and smegglutide;

[0549] - Glucagon-like peptide-1 receptor agonists; gastric acid regulator ligands; glucagon receptor agonists, such as enopedus peptide;

[0550] - Glucagon / glucagon-like peptide-1 (GIP / GLP-1) receptor co-agonists, such as telposide (LY-3298176);

[0551] - Pegylated long-acting glucagon-like peptide-1 / glucagon (GLP-1R / GCGR) receptor dual agonists, such as DD-01;

[0552] - Glucagon / GLP1 receptor agonists, such as BI-456906;

[0553] - Glucocorticoid receptor antagonists, such as CORT-118335 (Milicorice);

[0554] - Glucose 6-phosphate 1-dehydrogenase inhibitors, such as ST001;

[0555] - Glucokinase stimulants, such as doggliatin and sinogliatin (RO-5305552);

[0556] -G protein-coupled bile acid receptor 1 (TGR5) agonists, such as RDX-009, INT-777, and HY-209;

[0557] -G protein-coupled receptor 84 antagonists, such as PBI-4547;

[0558] -G protein-coupled receptor-119 agonists, such as DA-1241;

[0559] - Heat shock protein 47 (HSP47) inhibitors, such as ND-L02-s0201;

[0560] - Hedgehog protein and / or TGFβ ligand inhibitors, such as Oxy-210;

[0561] -Histone deacetylase inhibitors / STAT-3 regulators, such as SFX-01;

[0562] -HMG coenzyme A reductase inhibitors, such as atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin;

[0563] -HSD17B13 gene inhibitors, such as ALN-HSD and ARO-HSD;

[0564] - Hydrolytic enzyme inhibitors, such as ABD-X;

[0565] - Hypoxia-inducible factor-2α inhibitors, such as PT-2567;

[0566] -IL-10 agonists, such as pegylated interleukin;

[0567] - Inhibitors of sodium ileoside cotransporter, such as ovacitabine (A-4250), vocitabine potassium ethanol hydrate (SHP-262), GSK2330672, CJ-14199, and elocitabine (A-3309).

[0568] - Insulin sensitizers, such as KBP-042, azemiglitazone potassium (MSDC-0602K), ION-224, MSDC-5514, Px-102, RG-125 (AZD4076), torimidone, VVP-100X, CB-4211, ETI-101, pioglitazone;

[0569] -Insulin ligands / ds insulin receptor agonists, such as ORMD-0801;

[0570] -Integrin antagonists, such as IDL-2965;

[0571] -IL-6 receptor agonists, such as KM-2702;

[0572] - Dual inhibitors of integrin α-V / β-6 and α-V / β-1, such as PLN-74809;

[0573] - Interleukin-17 ligand inhibitors, such as nittazimab;

[0574] -Jak1 / 2 tyrosine kinase inhibitors, such as baricitinib;

[0575] -Jun N-terminal kinase-1 inhibitors, such as CC-90001;

[0576] -Kelch-like ECH-associated protein 1 regulators, such as α-cyclodextrin-stabilized sulforaphane;

[0577] - Ketohexokinase (KHK) inhibitors, such as PF-06835919 and LY-3478045;

[0578] -βKlotho(KLB)-FGF1c agonists, such as MK-3655 (NGM-313);

[0579] - Leukotriene A4 hydrolase inhibitors, such as LYS-006;

[0580] -5-lipoxygenase inhibitors, such as tylutrascine (MN-001) and acetonitrile (DS-102, AF-102);

[0581] - Lipoprotein lipase inhibitors, such as CAT-2003;

[0582] -LPL gene stimulants, such as aliprine;

[0583] - Hepatic receptor X (LXR) inhibitors, such as PX-665, PX-L603, PX-L493, BMS-852927, T-0901317, GW-3965, SR-9238;

[0584] - Lysophosphatidylcholine-1 receptor antagonists, such as BMT-053011, UD-009 (CP-2090), AR-479, ITMN-10534, BMS-986020, KI-16198;

[0585] - Lysyl oxidase homologue 2 inhibitors, such as sintuzumab, PXS-5382A (PXS-5338);

[0586] - Macrophage mannose receptor 1 modulators, such as temannoxetine-Cy3 (Tc 99m temannoxetine);

[0587] - Matrix metalloproteinase inhibitors, such as ALS-L1023;

[0588] - Inhibitors of membrane copper amine oxidase (VAP-1), such as TERN-201 and TT-01025;

[0589] -MEKK-5 protein kinase (ASK-1) inhibitors, such as CJ-16871, CS-17919, selosenoside (GS-4997), SRT-015, GS-444217, GST-HG-151, TERN-301;

[0590] -MCH receptor-1 antagonists, such as CSTI-100 (ALB-127158);

[0591] -Inhibitors of aminourea-sensitive amine oxidase / vascular adhesion protein-1 (SSAO / VAP-1), such as PXS-4728A (BI-1467335);

[0592] -Methionine aminopeptidase-2 inhibitors, such as ZGN-1061, ZGN-839, and ZN-1345;

[0593] β-methylCpG-binding protein 2 regulators, such as mercaptoethylamine;

[0594] - Mineralocorticoid receptor antagonists (MCRAs), such as MT-3995 (aparidone);

[0595] - Mitochondrial uncoupling agents, such as 2,4-dinitrophenol, HU6, Mito-99-0053;

[0596] - Mixed lineage kinase-3 inhibitors, such as URMC-099-C;

[0597] - Inhibitors of active sperm domain protein 2, such as VB-601;

[0598] - Myelin basic protein stimulants, such as orlisoxi;

[0599] - Green peroxidase inhibitors, such as PF-06667272 and AZM-198;

[0600] - NADPH oxidase inhibitors, such as GKT-831, GenKyoTex, APX-311, and celtanazine;

[0601] - Nicotinic acid receptor 1 agonists, such as ARI-3037MO;

[0602] -NACHT LRR PYD domain protein 3 (NLRP3) inhibitors, such as KDDF-201406-03, NBC-6, IFM-514, JT-194 (JT-349);

[0603] -NFE2L2 gene inhibitors, such as GeRP-amiR-144;

[0604] - Nuclear receptor modulators, such as DUR-928 (DV-928);

[0605] -Opioid receptor μ antagonists, such as methylnaltrexone;

[0606] -P2X7 purine receptor modulators, such as SGM-1019;

[0607] -P2Y13 purine receptor stimulators, such as CER-209;

[0608] -PDE 3 / 4 inhibitors, such as tylucast (MN-001);

[0609] -PDE 5 inhibitors, such as sildenafil and MSTM-102;

[0610] -PDGF receptor β modulators, such as BOT-191 and BOT-509;

[0611] - Peptidyl prolyl cis-trans isomerase inhibitors, such as CRV-431 (CPI-432-32), NVP-018, and NV-556 (NVP-025);

[0612] -Phenylanase hydroxylase stimulants, such as HepaStem;

[0613] - Phosphodiesterase inhibitors, such as ZSP-1601;

[0614] - PNPLA3 gene inhibitors, such as AZD-2693;

[0615] -PPAR agonists, such as selafinranor, elafinranor (GFT-505), seladelparlysine (MBX-8025), deuterated pioglitazone R-enantiomer, pioglitazone, PXL-065 (DRX-065), salrogleeza, ranirino (IVA-337), CHS-131, pemafidate (K-877), ZG-0588, ZSP-0678, ZSYM-008;

[0616] -Protein-activating receptor-2 antagonists, such as PZ-235;

[0617] - Protein kinase modulators, such as CNX-014;

[0618] - Protein NOV homologue regulators, such as BLR-200;

[0619] -PTGS2 gene inhibitors, such as STP-705 and STP-707;

[0620] - Renin inhibitors, such as PRO-20;

[0621] - Inhibitors of the resistin / CAP1 (adenylate cyclase-associated protein 1) interaction, such as DWJ-211;

[0622] -Rev protein modulators, such as ABX-464;

[0623] -Rho-associated protein kinase (ROCK) inhibitors, such as REDX-10178 (REDX-10325), KD-025, RXC-007, and TDI-01;

[0624] -S-nitrosoglutathione reductase (GSNOR) enzyme inhibitors, such as SL-891;

[0625] - Sodium glucose transporter-2 (SGLT2) inhibitors, such as etagliflozin, regaggliflozin etopolate, etagliflozin, dapagliflozin, toggliflozin, and soggliflozin;

[0626] - Sodium glucose transporter-1 / 2 (SGLT1 / 2) inhibitors, such as licogliflozinbis (prolinate) (LIK-066);

[0627] -SREBP transcription factor inhibitors, such as CAT-2003, HPN-01, MDV-4463;

[0628] - Stearoyl-CoA desaturase-1 inhibitors, such as eicosanoylaminocholanoic acid;

[0629] - Thyroid hormone receptor beta agonists, such as ALG-009, ASC-41, CNPT-101101, CNPT-101207, CS-27186, KY-41111, Resmetiro (MGL-3196), MGL-3745, TERN-501, VK-2809;

[0630] -TLR-2 / TLR-4 antagonists, such as VB-201 (CI-201);

[0631] -TLR-4 antagonists, such as JKB-121, JKB-122, and naltrexone;

[0632] - Tyrosine kinase receptor modulators, such as CNX-025 and GFE-2137 (recycled nitrozonide);

[0633] -TLR-9 antagonists, such as GNKS-356;

[0634] -TNF antagonists, such as ALF-421;

[0635] -GPCR modulators, such as CNX-023;

[0636] - Nuclear hormone receptor modulators, such as Px-102;

[0637] -VDR agonists, such as CK-15;

[0638] - Xanthine oxidase inhibitors, such as ACQT-1127;

[0639] - Xanthine oxidase / uric acid anion exchanger 1 (URAT1) inhibitors, such as RLBN-1001, RLBN-1127; and

[0640] - Linalool inhibitors, such as larizoline acetate (INN-202).

[0641] In some implementations, one or more adjunctive therapeutic agents are selected from A-4250, AC-3174, acetylsalicylic acid, AK-20, aripiprazole, AMX-342, AN-3015, anti-TAGE antibody, eicosanoylaminocholanic acid, ARI-3037MO, ASP-8232, AZD-2693, bertilimab, anhydrous betaine, BI-1467335, BMS-986036, BMS-986171, BMT-053011, BOT-191, BTT-1023, budesonide, BX-003, CAT-2003, sinivirol, CBW-511, CER-209, CF-102, CGS21680, C NX-014, CNX-023, CNX-024, CNX-025, Cobiprostone, Colesvelam, Dabigatran Mesylate, Dapagliflozin, DCR-LIV1, Deuterated Pioglitazone R-enantiomer, 2,4-Dinitrophenol, DRX-065, DS-102, DUR-928, EDP-305, elafibranor (GFT-505), Enricafen, Enalapril, Egliflozin, Igglitin, F-351, Fluasterone (ST-002), FT-4101, GDD-3898, GH-509, GKT-831, GNF-5120, GRI-0621, GR-MD-02, GS-30 0, GS-4997, GS-9674, HEC-96719, HTD-1801, HS-10356, HSG-4112, HST-202, HST-201, HU-6, Hydrochlorothiazide, Icobut (PRC-4016), Ethyl eicosapentaenoic acid, IMM-124-E, INT-767, INV-240, IONIS-DGAT2Rx, Epagliflozin, Irbesartan, Propadegerm, IVA-337, J2H-1702, JKB-121, KB-GE-001, KBLP-004, KBLP-009, KBP-042, KD-025, M790, M780, M450, Metformin, Sildenafil Naflipin, LB-700, LC-280126, Linagliptin, Liraglutide, (LJN-452) (Zopifexox), LM-011, LM-002 (CVI-LM-002), LMB-763, LYN-100, MB-N-008, MBX-8025, MDV-4463, Mercaptoethylamine, MGL-3196, MGL-3745, MP-301, MSDC-0602K, Namacizumab, NC-101, NDI-010976, ND-L02-s0201 (BMS-986263), NGM-282, NGM-313, NGM-386, NGM-395, NP-011NP-135, NP-160, Norursodeoxycholic Acid, NV-422, NVP-022, O-304, Obeticholic Acid (OCA), 25HC3S, Olisozoprolol, PAT-505, PAT-048, PBI-4547, Polyethylene Glycol Interleukin, Pioglitazone, Pirfenidone, PRI-724, PX20606, Px-102, PX-L603, PX-L493, PXS- 4728A, PZ-235, PZH-2109, RCYM-001, RDX-009, Repaglinide Esophanic Acid, RG-125 (AZD4076), RPI-500, S-723595, Sarogligaza, SBP-301, Smegglutide, SH-2442, SHC-028, SHC-023, Simtuzumab, Sophormycin, Sopaglinide, Stardine (Atorvastatin, Fluvastatin) Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin), Symbiotic, TCM-606F, TEV-45478, TQA-3526, TQA-3563, Tipelukast (MN-001), TLY-012, TRX-318, TVB-2640, TXR-612, TS-20004, UD-009, UN-03, Ursodeoxycholic acid, VBY-376, VBY- 825, VK-2809, Vimodil, Vocibart potassium ethoxide hydrate (SHP-626), VVP-100X, WAV-301, WNT-974, WXSH-0038, WXSH-0078, XEN-103, XRx-117, XTYW-003, XW-003, XW-004, ZGN-839, ZG-5216, ZSYM-008, ZYSM-007.

[0642] In some embodiments, the compounds of this disclosure are combined with one or more therapeutic agents selected from anti-obesity agents, including but not limited to peptide YY or analogues thereof, neuropeptide Y receptor type 2 (NPYR2) agonists, NPYR1 agonists, NPYR5 antagonists, cannabinoid receptor type 1 (CB1R) antagonists, lipase inhibitors (e.g., orlistat), human islet peptide (HIP), melanocortin receptor 4 agonists (e.g., sermelatide), melanin condensing hormone receptor 1 antagonists, farnesoid X receptor (FXR) agonists (e.g., obeticholic acid), apoptosis signal-regulated kinase (ASK-1) inhibitors, zonisamide, phentermine (alone or in combination with topiramate), norepinephrine / dopamine reuptake inhibitors (e.g., bupropion), opioid receptor antagonists (e.g., naltrexone), norepinephrine, etc. Combinations of dopamine / reuptake inhibitors and opioid receptor antagonists (e.g., bupropion and naltrexone), GDF-15 analogs, cholecystokinin agonists, amylin and its analogs (e.g., pramlintide), leptin and its analogs (e.g., metroleptin), serotonergic agents (e.g., lorcaserin), methionine aminopeptidase 2 (MetAP2) inhibitors (e.g., beloranil or ZGN-1061), benzomorpholine, diethylamine acetone, benzphenamine, SGLT 2. Inhibitors (e.g., empagliflozin, canagliflozin, dapagliflozin, ioggliflozin, tolagliflozin, seragliflozin ecaponicate, repaggliflozin ecaponicate, or etagliflozin), 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). Glutide, abiglutide, lixilatide or semaglutide), insulin sensitizers such as thiazolidinediones (TZDs), peroxisome proliferator-activated receptor α (PPARα) agonists, fish oil, acetyl-CoA carboxylase (ACC) inhibitors, transforming growth factor β (TGFβ) antagonists, GDNF family receptor α-like (GFRAL) agonists, melanocortin-4 receptor (MC4R) agonists, including pharmaceutically acceptable salts of the specifically named reagents and pharmaceutically acceptable solvates of said reagents and salts.

[0643] In some embodiments, the method and composition comprise a therapeutically effective amount of a compound of formula (IA-1), (IA-2), and / or formula (I) and a therapeutically effective amount of a farnesoid X receptor (FXR) agonist. In some embodiments, the FXR agonist is a compound of formula (II) or (III):

[0644]

[0645]

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

[0647] In some embodiments, the method and composition comprise a therapeutically effective amount of a compound of formula (IA-1), (IA-2), and / or formula (I) and a therapeutically effective amount of an ASK1 inhibitor. In some embodiments, the ASK1 inhibitor is a compound of formula (IV):

[0648]

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

[0650] In some embodiments, the methods and compositions comprise a therapeutically effective amount of a compound of formula (IA-1), (IA-2), and / or formula (I) and a therapeutically effective amount of an acetyl-CoA carboxylase (ACC) inhibitor. In some embodiments, the ACC inhibitor is a compound of formula (V):

[0651]

[0652] Or its pharmaceutically acceptable salt.

[0653] In some embodiments, the method and composition comprise a therapeutically effective amount of a compound of formula (IA-1), (IA-2), and / or formula (I) and a therapeutically effective amount of a thyroid hormone receptor (THR) β agonist. In some embodiments, the THRβ agonist is a compound of formula (VI):

[0654]

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

[0656] VII. Treatment Methods

[0657] In some embodiments, compounds of formulas (IA-1), (IA-2), (I), (Ia), (Ib), (Ib-1), (Ic), and / or (Id), or pharmaceutically acceptable salts thereof, may be used in methods for treating and / or preventing GLP-1R-mediated diseases or conditions. In some embodiments, methods for treating and / or preventing GLP-1R-mediated diseases or conditions include administering a pharmaceutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject in need.

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

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

[0660] In some embodiments, this disclosure relates to the use of compounds of formula (I), (IA-1), (IA-2), or pharmaceutically acceptable salts thereof in the preparation of medicaments for the prevention and / or treatment of GLP-1R-mediated diseases or conditions, such as liver disease or metabolic diseases. For example, some embodiments provide a compound of formula (I), (IA-1), and / or (IA-2) or a pharmaceutically acceptable salt thereof, or their use, for the treatment and / or prevention of chronic intrahepatic or some forms of extrahepatic cholestasis, liver fibrosis, acute gastrointestinal cholestasis, obstructive or chronic inflammatory conditions caused by improper bile composition, gastrointestinal conditions with reduced dietary fat intake and fat-soluble dietary vitamins, inflammatory bowel disease, lipid and lipoprotein disorders, type II diabetes and clinical complications of type I and type II diabetes, due to forced lipid and, in particular, glycerol The accumulation of triglycerides and subsequent activation of pro-fibrotic pathways lead to chronic fatty degeneration and fibrotic degeneration of organs, resulting in various symptoms and diseases, including obesity and metabolic syndrome (a combination of dyslipidemia, diabetes, and abnormally high body mass index), acute myocardial infarction, acute stroke, thrombosis as an endpoint of chronic obstructive atherosclerosis, persistent infections caused by intracellular bacteria or parasitic protozoa, non-malignant hyperproliferative diseases, malignant hyperproliferative diseases (e.g., colonic adenocarcinoma and hepatocellular carcinoma), hepatic steatosis and related syndromes, and liver failure as a result of chronic liver disease or surgical hepatectomy. Hepatic dysfunction or liver failure, hepatitis B infection, hepatitis C infection and / or cholestasis and fibrosis associated with alcohol-induced cirrhosis or viral hepatitis, type 1 diabetes, prediabetes, idiopathic type 1 diabetes, occult autoimmune diabetes, adolescent-onset adult-onset diabetes, 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, glucose cravings, dyslipidemia, hyperinsulinemia, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, left ventricular hypertrophy, Parkinson's disease, peripheral artery disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, angina pectoris, premenstrual syndrome, thrombosis, atherosclerosis, impaired glucose metabolism, or restenosis.

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

[0662] This disclosure also relates to compounds of formula (IA-1), (IA-2), and / or formula (I), or pharmaceutical compositions comprising said compounds, for the preventive and post-traumatic treatment of cardiovascular diseases such as acute myocardial infarction, acute stroke, or thrombosis that occurs as an endpoint of chronic obstructive atherosclerosis. In some embodiments, methods of treating and / or preventing cardiovascular diseases include administering a compound of formula (IA-1), (IA-2), and / or formula (I) to a subject in need.

[0663] This disclosure also relates to compounds or pharmaceutical compositions for the treatment and / or prevention of obesity and related diseases, such as metabolic syndrome (a syndrome of dyslipidemia, diabetes, and abnormally high body mass index), which can be overcome by GLP1R-mediated reduction of serum triglycerides, blood glucose, and insulin sensitivity, as well as GLP1R-mediated weight loss. In some embodiments, a method of treating and / or preventing metabolic diseases includes administering a compound of formula (I) to a subject in need. In some embodiments, a method of treating and / or preventing metabolic diseases includes administering compounds of formulas (IA-1) and / or (IA-2) to a subject in need.

[0664] In another embodiment, the compounds or pharmaceutical compositions of this disclosure can be used to prevent and / or treat clinical complications of type 1 and type 2 diabetes. Examples of such complications include diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, or peripheral artery occlusive disease (PAOD). This disclosure also covers other clinical complications of diabetes. In some embodiments, a method of treating and / or preventing complications of type 1 and type 2 diabetes includes administering a compound of formula (I) to a subject in need. In some embodiments, a method of treating and / or preventing complications of type 1 and type 2 diabetes includes administering compounds of formulas (IA-1) and / or (IA-2) to a subject in need.

[0665] Furthermore, the application of the compounds or pharmaceutical compositions disclosed herein can also prevent and / or treat conditions and diseases resulting from chronic fatty degeneration and fibrotic degeneration of organs due to forced accumulation of lipids and / or triglycerides and subsequent activation of profibrotic pathways. Such conditions and diseases may include NASH and chronic cholestasis in the liver, glomerulosclerosis and diabetic nephropathy in the kidneys, macular degeneration and diabetic retinopathy in the eyes, and neurodegenerative diseases such as Alzheimer's disease in the brain or diabetic neuropathy in the peripheral nervous system. In some embodiments, a method of treating and / or preventing conditions and diseases resulting from chronic fatty degeneration and fibrotic degeneration of organs due to forced accumulation of lipids and / or triglycerides and subsequent activation of profibrotic pathways comprises administering a compound of formula (I) to a subject in need. In some embodiments, methods for treating and / or preventing symptoms and diseases resulting from chronic fatty degeneration and fibrotic degeneration of organs due to forced accumulation of lipids and / or triglycerides and subsequent activation of profibrotic pathways include administering compounds of formula (IA-1) and / or (IA-2) to a subject in need. In some embodiments, methods for treating and / or preventing NASH include administering a compound of formula (I) to a subject in need. In some embodiments, methods for treating and / or preventing NASH include administering compounds of formula (IA-1) and / or (IA-2) to a subject in need.

[0666] This document also provides a pharmaceutical composition for treating the GLP-1R-mediated diseases or conditions described herein, the pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0667] This disclosure also describes the use of a medicament for treating GLP-1R-mediated diseases or conditions, the medicament comprising a compound of this disclosure or a pharmaceutically acceptable salt thereof. The medicaments mentioned herein can be prepared by conventional methods, including combinations of compounds according to this disclosure and pharmaceutically acceptable carriers.

[0668] The present disclosure also discloses compounds or pharmaceutically acceptable salts thereof for the treatment of GLP-1R-mediated diseases or conditions. The present disclosure also discloses compounds or pharmaceutically acceptable salts thereof for the prevention of GLP-1R-mediated diseases or conditions.

[0669] VIII. Examples

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

[0671] The compounds 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, rapid column chromatography, and ion-exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases, as well as ion exchange resins. For example, the compounds disclosed in this invention can be purified by silica gel and / or alumina chromatography. See, for example, “Introduction to Modern Liquid Chromatography,” 2nd edition, L.S. Nyder and J.J. Kirkland, John Wiley and Sons, 1979; and “Thin Layer Chromatography,” edited by E. Stahl, Springer-Verlag, New York, 1969.

[0672] In any method for preparing the subject compound, it may be necessary to protect any sensitive or reactive groups on any molecules in the relevant molecule. This can be achieved using conventional protecting groups as described in standard literature, such as TWGreene and PGMWuts, “Protective Groups in Organic Synthesis,” 4th edition, Wiley, New York, 2006. Protecting groups can be removed at a convenient subsequent stage using methods known in the art.

[0673] Exemplary chemical entities that can be used to implement the methods will now be described with reference to the general preparation described herein and the illustrative synthetic schemes of specific examples below. Those skilled in the art will recognize that, in order to obtain the various compounds described herein, the starting material can be suitably selected such that the ultimately desired substituent will be carried by a reaction scheme, whether protected or unprotected, to produce the desired product. Alternatively, it may be necessary to use a suitable group at the position of the ultimately desired substituent, which can be carried by the reaction scheme and, if appropriate, replaced by the desired substituent. Furthermore, those skilled in the art will recognize that the transformations shown in the following schemes can be performed in any order compatible with the functionality of the side groups. Each reaction depicted in the general scheme can be operated at a temperature from about 0°C to the reflux temperature of the organic solvent used.

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

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

[0676] In some embodiments, this disclosure typically provides a specific 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 specific stereocenter in the enantiomer or diastereomer is not determined, the compound is drawn without any stereochemistry showing at that specific stereocenter, even if the compound may be substantially enantiomerically pure or diastereomerically pure.

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

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

[0679] abbreviation

[0680] Certain abbreviations and acronyms are used to describe experimental details. While most of these are understandable to those skilled in the art, Table 1 contains a list of acronyms and acronyms that have many of these abbreviations and acronyms.

[0681] Table 1. List of Abbreviations and Acronyms

[0682]

[0683]

[0684]

[0685] A. Synthesis of intermediates

[0686] Intermediate I-1

[0687]

[0688] Methyl 4-amino-3-(2-methoxyethylamino)benzoate (I-1): Diisopropylethylamine (70.0 mL, 402 mmol) and 2-methoxyethylamine (34.9 mL, 402 mmol) were added to a solution of methyl 3-fluoro-4-nitro-benzoate (50.0 g, 251 mmol) in THF (400 mL). 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 allowed to proceed without further purification. Then, methyl 3-(2-methoxyethylamino)-4-nitro-benzoate (20.0 g, 78.7 mmol) was dissolved in EtOAc:EtOH (1:1, 140 mL), and then 10% carbon-supported palladium (5.02 g, 4.72 mmol) was added. The resulting suspension was stirred for 16 hours at room temperature under a hydrogen balloon. The reaction mixture was filtered through a Celite filter, washed with EtOAc (100 mL), and concentrated to give the desired compound without further purification: ES / MS: 225.2 (M+H). + ).

[0689] Intermediates I-2 and I-3

[0690]

[0691] 4-(((6-bromo-5-methylpyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (I-2) and 4-(((6-chloro-3-methylpyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (I-3): Potassium tert-butoxide (0.736 g, 6.56 mmol) was added to a mixture of 3-fluoro-4-(hydroxymethyl)benzonitrile (0.659 g, 4.36 mmol) and 2-bromo-6-chloro-3-methyl-pyridine (750 mg, 3.63 mmol) in THF (36.0 mL), and the reaction mixture was stirred at room temperature for 16 hours. The reactants were quenched by adding saturated aqueous ammonium chloride solution, and the mixture was extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude residue was purified by column chromatography (0%–10% EtOAc / hexane, followed by 1% MeOH / DCM) to give the title compound (an inseparable mixture, approximately 2:1 ratio): ES / MS m / z: 321.2, 208.0 (M+H) + ).

[0692] Intermediate I-4

[0693]

[0694] 4-(((2-chloropyrimidin-4-yl)oxy)methyl)-3-fluorobenzonitrile (I-4): Potassium tert-butoxide (237 mg, 2.11 mmol) was added to a solution of 3-fluoro-4-(hydroxymethyl)benzonitrile (609 mg, 4.03 mmol) in tetrahydrofuran (1.00 mL), and the mixture was stirred at room temperature for 5 minutes. This solution was then added to a frozen solution of 2,4-dichloropyrimidin (300 mg, 2.01 mmol) in N,N-dimethylformamide (1.50 mL), cooled to -78 °C, and the reaction mixture was slowly warmed to room temperature and stirred for 1 hour. The mixture was poured into 50 mL of water and stirred for 5 minutes. The precipitate was separated to give the title compound, which can be used directly without further purification: ES / MS m / z: 264.1 (M+H + ); 1 H NMR (400MHz, CDCl3) δ8.39 (d, J = 5.7Hz, 1H), 7.66 (t, J = 7.4Hz, 1H), 7.53 (dd, J = 8 .0,1.5Hz,1H),7.44(dd,J=9.2,1.5Hz,1H),6.78(d,J=5.7Hz,1H),5.57(s,2H).

[0695] Intermediate I-5

[0696]

[0697] Methyl 4-{[2-(4-bromo-2-fluoro-phenyl)acetyl]amino}-3-(2-methoxyethylamino)benzoate: methyl 4-amino-3-(2-methoxyethylamino)benzoate (1.18 g, 5.28 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.96 g, 5.15 mmol) were added to a solution of 2-(4-bromo-2-fluoro-phenyl)acetic acid (1.00 g, 4.29 mmol) in DMF (20.0 mL), followed by the addition of N,N-diisopropylethylamine (3.74 mL, 21.5 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reactants were concentrated under vacuum, and the residue was dissolved in EtOAc and washed with water (1×) and brine (1×). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. Assuming complete conversion, the crude residue can be proceeded without further purification: ES / MS m / z: 583.5 (M+H) + ).

[0698] Methyl 2-[(4-bromo-2-fluoro-phenyl)methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylic acid: The crude product methyl 4-{[2-(4-bromo-2-fluoro-phenyl)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 hours. The reaction mixture was concentrated under vacuum, and the crude residue was dissolved in DCM and washed with saturated sodium bicarbonate aqueous solution. The layers were separated, and the aqueous layer was extracted with DCM (2×). The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude residue was purified by column chromatography (0%–100% EtOAc / hexane) to give the title compound: ES / MS m / z: 421.9 (M+H + ).

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

[0700] Intermediate I-6

[0701]

[0702] 4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluorobenzonitrile (I-6): 3-fluoro-4-(hydroxymethyl)benzonitrile (2 g, 13.2 mmol) was added to 100 mL of dry RBF. The substance was dissolved in anhydrous THF (20 mL) at 0 °C under a nitrogen atmosphere. Sodium hydride (60% dispersion in mineral oil, 0.507 g, 13.2 mmol) was added in one step, and the mixture was stirred at 0 °C under N2 for 30 minutes. Then 2,6-dibromopyridine (3.13 g, 13.2 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The mixture was diluted with EtOAc (100 mL) and water (20 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (eluent: EtOAc / hexane) to obtain intermediate I-6: ES / MS: 307.058 (M+H) + ); 1 ¹H NMR (400MHz, chloroform-d) δ 7.72–7.63 (m, 1H), 7.52–7.46 (m, 2H), 7.41 (dd, J = 9.2, 1.5Hz, 1H), 7.14 (dd, J = 7.5, 0.7Hz, 1H), 6.79 (dd, J = 8.2, 0.7Hz, 1H), 5.50 (t, J = 0.9Hz, 2H).

[0703] Intermediate I-7

[0704]

[0705] 3-Fluoro-4-[(6-tributyltinyl-2-pyridinyl)oxymethyl]benzonitrile (I-7): 4-[(6-bromo-2-pyridinyl)oxymethyl]-3-fluorobenzonitrile (I-6) (400 mg, 1.3 mmol), tetrakis(triphenylphosphine)palladium (0) (151 mg, 0.13 mmol), and tributyl(tributyltinyl)stanane (907 mg, 1.56 mmol) were added to a 40 mL vial. Toluene (8 mL) was added, and the mixture was degassed with argon for 2 min. The vial was sealed and stirred overnight at 100 °C. LC-MS showed clear product formation, and the vial was cooled to room temperature. The mixture was dried, loaded onto silica gel, and purified by silica gel chromatography (elution: hexane, then EtOAc / hexane) to give intermediate I-7: ES / MS: 517.402 (M+H + ).

[0706] Intermediate I-8

[0707]

[0708] 2-(2-bromopyrimidin-5-yl)acetic acid (I-8): Ethyl 2-(2-bromopyrimidin-5-yl)acetate (250 mg, 1.02 mmol), acetonitrile (3 mL), and THF (3 mL) were added to a 40 mL vial. Lithium hydroxide (49 mg, 2.04 mmol) was dissolved in water (0.75 mL), and the mixture was stirred at 65 °C for 1 hour. LC-MS showed clear product formation, and the mixture was diluted with EtOAc (60 mL) and acidified with 1 M HCl. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give the product, which was ready for use without further purification: ES / MS: 217.006 (M+H + ).

[0709] Intermediate I-9

[0710]

[0711] 6-Bromoisocyanate-1-carboxylic acid (I-9): Add 2-(3-bromophenyl)ethanol (500 mg, 2.49 mmol) and glyoxylic acid monohydrate (458 mg, 4.97 mmol) to a 40 mL vial. Add trifluoroacetic acid (2 mL) and stir the mixture overnight at 70 °C. Concentrate the mixture under reduced pressure and partition the crude residue between EtOAc (75 mL) and water (50 mL), alkalizing with 1 M NaOH. Separate the layers and wash the aqueous layer again with EtOAc (50 mL). Acidify the aqueous layer with 1 M HCl (pH < 4) and extract with EtOAc (3 × 75 mL). Dry the combined organic layers over MgSO4, filter, and concentrate under reduced pressure. Intermediate I-9 can be used without further purification.

[0712] Intermediate I-10

[0713]

[0714] 7-Bromochromatin-4-carboxylic acid (I-10): Zinc(II) iodide (85 mg, 0.264 mmol) was added to a suspension of 7-bromochromatin-4-one (1 g, 4.4 mmol) in THF (5 mL), followed by dropwise addition of trimethylsilylformonitrile (1.65 mL, 13.2 mmol) using a syringe. The reaction mixture was stirred overnight at room temperature, then diluted with EtOAc (50 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The crude mixture was then dissolved in acetic acid (15 mL) and concentrated hydrochloric acid (15 mL), and stannous chloride (3.32 g, 17.5 mmol) was added. The reaction mixture was refluxed and heated for 24 hours. The mixture was cooled, diluted with dichloromethane (50 mL), and washed with water (50 mL) and brine (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated. Once the substance is determined to have sufficient purity, further purification can proceed: 1 H NMR (400MHz, CDCl3) δ7.21–7.15(m,1H),7.09–7.00(m,2H),4.33–4.23(m,2H),3.79(dd,J=6.1,3.8Hz,1H),2.46–2.30(m,1H),2.21–2.13(m,1H).

[0715] Intermediate I-11

[0716]

[0717] Methyl 2-(4-bromo-2-hydroxyphenyl)acetic acid: Concentrated sulfuric acid (0.1 mL) was added to a solution of 2-(4-bromo-2-hydroxyphenyl)acetic acid (250 mg, 1.08 mmol) in methanol (10 mL). The mixture was heated at 60 °C for 2 hours, and then concentrated under reduced pressure. The residue was dissolved in water (10 mL), and the mixture was extracted with EtOAc (2 × 30 mL). The combined organic phases were dried over MgSO4. The product was concentrated under reduced pressure, which could be further purified without further purification. 1 H NMR (400MHz, CDCl3) δ7.14 (d, J = 2.0 Hz, 1H), 7.04 (dd, J = 8.1, 2.0 Hz, 1H), 6.97 (d, J = 8.1 Hz, 1H), 3.79 (s, 3H), 3.66 (s, 2H).

[0718] Methyl 2-(4-bromo-2-(difluoromethoxy)phenyl)acetate: At -78 °C, difluoroacetophenone (972 mg, 5.1 mmol) was added to a mixture of methyl 2-(4-bromo-2-hydroxyphenyl)acetate (250 mg, 1.02 mmol), KOH aqueous solution (30 wt%, 4 mL), and acetonitrile (5 mL). The reaction mixture was heated to room temperature and then to 80 °C overnight. The mixture was diluted with water (10 mL) and extracted with Et2O (3 × 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution: EtOAc / hexane) to give the product: 1 HNMR (400MHz, CDCl3) δ7.40–7.33(m,2H),7.19(d,J=8.1Hz,1H),6.50(t,J=73.4Hz,1H),3.73(s,3H),3.67(s,2H).

[0719] 2-[4-Bromo-2-(difluoromethoxy)phenyl]acetic acid (I-11): Methyl 2-(4-bromo-2-(difluoromethoxy)phenyl)acetate (154 mg, 0.522 mmol), THF (4 mL), and acetonitrile (4 mL) were added to 25 mL of RBF. Lithium hydroxide (1 M aqueous solution, 2.61 mL, 2.61 mmol) was added, and the mixture was stirred overnight at 70 °C. The mixture was acidified with 1 M HCl and partitioned between water (20 mL) and EtOAc (50 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material could be proceeded without further purification.

[0720] Intermediate I-12

[0721]

[0722] 4-Amino-3-(((1-methylcyclopropyl)methyl)amino)benzoate (I-12): 4-Amino-3-(((1-methylcyclopropyl)methyl)amino)benzoate was prepared in the same manner as described for intermediate I-1, using (1-methylcyclopropyl)methylamine hydrochloride instead of methoxyethylamine: ES / MS: 235.1 (M+H) + ).

[0723] Intermediate I-13

[0724]

[0725] 4-Amino-3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)benzoate (I-13): As described for intermediate I-1, 4-amino-3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)benzoate was prepared by replacing methoxyethylamine with (1-(fluoromethyl)cyclopropyl)methylamine 2,2,2-trifluoroacetic acid: ES / MS: 253.3 (M+H) + ).

[0726] Intermediate I-14

[0727]

[0728] 4-Amino-3-((3-fluoro-2,2-dimethylpropyl)amino)methyl benzoate (I-14): As described for intermediate I-1, 4-amino-3-((3-fluoro-2,2-dimethylpropyl)amino)methyl benzoate was prepared by replacing methoxyethylamine with 3-fluoro-2,2-dimethyl-propane-1-amine hydrochloride: ES / MS: 255.4 (M+H) + ).

[0729] Intermediate I-15

[0730]

[0731] 4-Amino-3-((3,3-difluoro-2,2-dimethylpropyl)amino)methyl benzoate (I-15): As described for intermediate I-1, 4-amino-3-((3,3-difluoro-2,2-dimethylpropyl)amino)methyl benzoate was prepared by replacing methoxyethylamine with 3,3-difluoro-2,2-dimethyl-propane-1-amine hydrochloride: ES / MS: 273.2 (M+H) + ).

[0732] Intermediate I-16

[0733]

[0734] 4-Amino-3-(((1-cyanocyclopropyl)methyl)amino)benzoate (I-16): 4-Amino-3-(((1-cyanocyclopropyl)methyl)amino)benzoate was prepared in the same manner as described for intermediate I-1, using 1-(aminomethyl)cyclopropaneformonitrile hydrochloride instead of methoxyethylamine: ES / MS: 246.3 (M+H) + ).

[0735] Intermediate I-17

[0736]

[0737] 4-Amino-3-((2-cyano-methylpropyl)amino)methyl benzoate (I-17): As described for intermediate I-1, 4-amino-3-(((1-cyanocyclopropyl)methyl)amino)methyl benzoate was prepared by replacing methoxyethylamine with 3-amino-2,2-dimethylpropionitrile: ES / MS: 248.4 (M+H) + ).

[0738] Intermediate I-18

[0739]

[0740] 4-Amino-3-((3-cyano-2,2-dimethylpropyl)amino)methyl benzoate (I-18): As described for intermediate I-1, 4-amino-3-((3-cyano-2,2-dimethylpropyl)amino)methyl benzoate was prepared by replacing methoxyethylamine with 4-amino-3,3-dimethylbutyronitrile: ES / MS: 262.5 (M+H) + ).

[0741] Intermediate I-19

[0742]

[0743] 4-Amino-3-((oxetane-2-ylmethyl)amino)methyl benzoate (I-19): As described for intermediate I-1, 4-amino-3-((oxetane-2-ylmethyl)amino)methyl benzoate was prepared by replacing methoxyethylamine with oxetane-2-ylmethylamine: ES / MS: 237.0 (M+H) + ).

[0744] Intermediate I-20

[0745]

[0746] 4-(((6-chloropyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile: 3-fluoro-4-(hydroxymethyl)benzonitrile (5.64 g, 37.3 mmol) was added to a suspension of reagent-grade 95% potassium tert-butoxide (6.3 g, 56.14 mmol) in THF (80 mL) at 10-15 °C. The black solution was stirred for 45 minutes, then 2,6-dichloropyridine (4.6 g, 31.08 mmol) was added and stirred for 18 hours. The mixture was poured into a saturated NH4Cl (20 mL) solution. EtOAc (20 mL) was added, and the mixture was stirred for 15 minutes. The resulting mixture was filtered through a Celite filter to separate the organic layer, and the aqueous layer was extracted with EtOAc (2 × 120 mL). The combined organic extracts were washed with brine (100 mL) and dried over sodium sulfate to obtain the crude product. The crude product was purified by silica gel chromatography (elution buffer: EtOAc / hexane): ES / MS: 263.2 (M+H) + ); 1 H NMR (400MHz, CDCl3) δ7.68 (t, J=7.5Hz, 1H), 7.60 (dd, J=8.2, 7.5Hz, 1H), 7.50 (dd, J=7.9, 1.6Hz, 1H), 7.4 2(dd,J=9.2,1.6Hz,1H), 6.99(dd,J=7.5,0.7Hz,1H), 6.77(dd,J=8.2,0.7Hz,1H), 5.51(t,J=0.9Hz,2H).

[0747] Intermediate I-21

[0748]

[0749] 1-(tert-butyl)-3-methyl-2-(5-bromo-3-fluoropyridin-2-yl)malonate: 898 mg (5.16 mmol) of tert-butylmalonate and 10 mL of DMF were added to a 40 mL vial. The solution was cooled to 0 °C, and NaH (60% mineral oil, 237 mg, 6.19 mmol) was added. The reaction mixture was stirred at room temperature for 20 minutes, and gas escaping was observed. The reaction mixture was then cooled to 0 °C, and 1.0 g (5.16 mmol) of 5-bromo-2,3-difluoropyridine was added. The reaction mixture was stirred overnight. LC-MS showed product formation. The mixture was partitioned between EtOAc (50 mL) and water (20 mL), and the organic layer was separated, dried over MgSO4, and concentrated under reduced pressure to give 1-(tert-butyl)-3-methyl-2-(5-bromo-3-fluoropyridin-2-yl)malonate, which was directly carried out in the next step: ES / MS: 348.470 (M+H) + ).

[0750] 2-(5-bromo-3-fluoropyridin-2-yl)methyl acetate: 1-(tert-butyl)-3-methyl-2-(5-bromo-3-fluoropyridin-2-yl)malonate (1.4 g, 4.02 mmol), trifluoroacetic acid (10 mL), and CH₂Cl₂ (10 mL) were added to 100 mL of RBF. The mixture was stirred overnight at room temperature. LC / MS showed the formation of the product. The solvent was evaporated under reduced pressure to give the product as the trifluoroacetate salt: ES / MS: 248.347 (M+H) + ).

[0751] 2-(5-Bromo-3-fluoro-2-pyridyl)acetic acid (I-21): Methyl 2-(5-bromo-3-fluoropyridyl-2-yl)acetate (trifluoroacetate) (1.2 g, 3.31 mmol) was added to 40 mL of RBF. Methanol (10 mL) and THF (5 mL) were added, followed by 1 M NaOH (6.63 mL, 6.63 mmol). The reaction mixture was stirred overnight at 70 °C. The mixture was concentrated under reduced pressure, and the residue was dissolved in water and acidified with 1 N HCl. The resulting mixture was extracted three times with a mixture of DCM and methanol. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was allowed to proceed without further purification: ES / MS: 234.159 (M+H) + ).

[0752] Intermediate I-22

[0753]

[0754] 4-Amino-3-(((1,1-dioxothiophen-2-yl)methyl)amino)benzoate (I-22): 4-Amino-3-(((1,1-dioxothiophen-2-yl)methyl)amino)benzoate was prepared in the same manner as described for intermediate I-1, using (1,1-dioxothiophen-2-yl)methylamine hydrochloride instead of methoxyethylamine: ES / MS: 285.2 (M+H) + ).

[0755] Intermediate I-23

[0756]

[0757] 4-Amino-3-(((1-(cyanomethyl)cyclopropyl)methyl)amino)benzoate (I-23): The same as described for intermediate I-1, 4-amino-3-(((1-(cyanomethyl)cyclopropyl)methyl)amino)benzoate was prepared by replacing methoxyethylamine with 2-[1-(aminomethyl)cyclopropyl]acetonitrile hydrochloride: ES / MS: 260.2 (M+H) + ).

[0758] Intermediate I-24

[0759]

[0760] 5-Amino-6-(((1-methylcyclopropyl)methyl)amino)pyridinecarboxylate (I-24): Same as described for intermediate I-1, but with (1-methylcyclopropyl)methylamine hydrochloride instead of methoxyethylamine and methyl 6-chloro-5-nitro-pyridine-2-carboxylate instead of methyl 3-fluoro-4-nitro-benzoate to prepare methyl 4-amino-3-((oxetanebut-2-ylmethyl)amino)benzoate: ES / MS: 236.3 (M+H) + ).

[0761] Intermediate I-25

[0762]

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

[0764] 4-Bromo-2-chlorothiazol (250 mg, 1.26 mmol), 3-fluoro-4-(hydroxymethyl)benzonitrile (0.209 g, 1.39 mmol), cesium carbonate (0.821 g, 2.52 mmol), and acetonitrile (4 mL) were added to a vial, and the reaction mixture was heated to 60 °C for 16 hours. The reaction mixture was poured into water, and the precipitate was filtered off, washed with water, and dried under vacuum to give the title compound: ES / MS m / z: 314.3 (M+H) + ); 1 H NMR (400MHz, CDCl3) δ7.66(t,J=7.5Hz,1H),7.56–7.50(m,1H),7.44(dd,J=9.1,1.6Hz,1H),6.68(s,1H),5.60(s,2H).

[0765] Intermediate I-26

[0766]

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

[0768] 3-Bromo-5-fluorophenol (300 mg, 1.57 mmol), 4-(bromomethyl)-3-fluorobenzonitrile (370 mg, 1.73 mmol), and cesium carbonate (930 mg, 2.86 mmol) were added to a vial, followed by acetonitrile (5.00 mL). The reaction mixture was stirred at 60 °C for 16 hours. The reaction mixture was poured into water, and the precipitate was filtered off, washed with water, and dried under vacuum to give the title compound: 1 HNMR (400MHz, CDCl3) δ7.67(t,J=7.5Hz,1H),7.56–7.52(m,1H),7.44(dd,J=9.3,1.6Hz,1H),6.99–6.92(m,2H),6.70–6.64(m,1H),5.17(s,2H).

[0769] Intermediate I-27

[0770]

[0771] 4-((3-bromo-4-fluorophenoxy)methyl)-3-fluorobenzonitrile (I-27): The title compound was prepared by replacing 3-bromo-5-fluorophenol with 3-bromo-4-fluorophenol according to the procedure described for intermediate I-26. 1 HNMR (400MHz, CDCl3) δ7.68 (t, J=7.5Hz, 1H), 7.54 (dd, J=8.0, 1.6Hz, 1H), 7.43 (dd, J=9.3, 1.5Hz,1H),7.21–7.17(m,1H),7.09(dd,J=9.0,8.0Hz,1H),6.93–6.87(m,1H),5.15(s,2H).

[0772] Intermediate I-28

[0773]

[0774] 4-((3-bromo-5-cyanophenoxy)methyl)-3-fluorobenzonitrile (I-28): The title compound was prepared by replacing 3-bromo-5-fluorophenol with 3-bromo-5-hydroxybenzonitrile according to the procedure described for intermediate I-26. 1 H NMR (400MHz, CDCl3) δ7.66 (t, J = 7.5Hz, 1H), 7.58–7.53 (m, 1H), 7.49–7.44 (m, 2H), 7.42–7.39 (m, 1H), 7.22–7.18 (m, 1H), 5.21 (s, 2H).

[0775] Intermediate I-29

[0776]

[0777] 4-((3-bromo-5-methoxyphenoxy)methyl)-3-fluorobenzonitrile (I-29): The title compound was prepared by replacing 3-bromo-5-fluorophenol with 3-bromo-5-methoxyphenol according to the procedure described for intermediate I-26: 1 H NMR (400MHz, CDCl3) δ7.71–7.64(m,1H),7.56–7.51(m,1H),7.45–7.40(m,1H),6.79–6.72(m,2H),6.47(t,J=2.3Hz,1H),5.16(s,2H),3.80(s,3H).

[0778] Intermediate I-30

[0779]

[0780] 4-(((6-bromo-4-methylpyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (I-30): Potassium tert-butoxide (0.982 g, 8.75 mmol) was added to a solution of 3-fluoro-4-(hydroxymethyl)benzonitrile (0.878 g, 5.81 mmol) in THF cooled to 0 °C, and the reaction mixture was stirred for 10 min. Then 2-bromo-6-chloro-4-methylpyridine (1.00 g, 4.84 mmol) was added, and the reaction mixture was stirred at 0 °C for 1 h, followed by heating to 50 °C for 3 h. The reaction mixture was cooled to room temperature, poured into water, and the precipitate was filtered off and dried under vacuum to give the title compound as a mixture of Br / Cl isomers: ES / MS m / z: 321.1 (M+H + ),277.1(M+H + ).

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

[0782]

[0783] 4-Nitro-3-((2,3-dimethoxy-3-oxopropyl)amino)tert-butyl benzoate: 3-Amino-2-methoxy-propionate (355 mg, 2.3 mmol) was suspended in DCM / methanol (5 mL, 3:1), and TMS diazomethane (2.0 M, 1.1 mL, 2.3 mmol) was added until a pale yellow color persisted. The reactants were concentrated to dryness by adding AcOH (approximately 1 drop), dissolved in MeTHF (3 mL), and concentrated to dryness again. The resulting crude amino ester dissolved in MeTHF (3 mL) was added to 3-fluoro-4-nitro-benzoate tert-butyl ester (500 mg, 2.1 mmol) and DIPEA (1.1 mL, 6.2 mmol). The mixture was stirred overnight at 80 °C. The reactants were then cooled, diluted with EtOAc, washed with aqueous NH4Cl solution, dried over Na2SO4, filtered, and concentrated: ES / MS: 355.1 (M+H) + ).

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

[0785] 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenyl]methyl]-3-(2,3-dimethoxy-3-oxopropyl)benzimidazole-5-carboxylic acid tert-butyl ester (I-32): 2-[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenyl]acetic acid (I-128, 240 mg, 0.63 mmol), 4-amino-3-[(2,3-dimethoxy-3-oxopropyl)amino]benzoate tert-butyl ester (I-31, 235 mg, 0.73 mmol), HATU (360 mg, 0.95 mmol), and DIPEA (0.55 mL, 3.2 mmol) were mixed in DCE / DMF (2:1, 3 mL) and stirred at 50 °C for 15 minutes. The reactants were cooled, diluted with EtOAc, and washed with aqueous NH4Cl, aqueous NaHCO3, and brine. The organic fraction was dried over Na2SO4, filtered, and concentrated. The crude solid was dissolved in AcOH (2 mL) and stirred at 70 °C for 20 min, then at 85 °C for 35 min, and finally at 90 °C for 40 min. The reactants were then cooled to room temperature, concentrated to dryness, and purified by column chromatography (40%–85% EtOAc / hexane) to give the title compound. ES / MS: 669.4 (M+H) + ); 1 H NMR (400MHz, chloroform-d) δ8.22–8.06(m,1H),7.97(d,J=8.5Hz,1H),7.78(d,J=8.4Hz,1H),7.76–7.63(m,4H),7.47(dd,J=7.9,1.5Hz,1H),7.42(dd,J=9.3 ,1.6Hz,1H),7.36(d,J=7.4Hz,1H),6.82(d,J=8.2Hz,1H),5.62(s,2H),4. 64–4.36(m,4H),4.13–4.09(m,1H),3.83(s,3H),3.32(s,3H),1.66(s,9H). 19 F NMR (376MHz, chloroform-d) δ -115.30–-115.58 (m), -117.61.

[0786] I-33 and I-34: Isomers 1 and 2 of 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenyl]methyl]-3-(2,3-dimethoxy-3-oxo-propyl)benzimidazole-5-carboxylic acid tert-butyl ester. The mixture of the two stereoisomers of 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenyl]methyl]-3-(2,3-dimethoxy-3-oxo-propyl)benzimidazole-5-carboxylic acid tert-butyl ester was separated by chiral SFC (IG column with 45% EtOH cosolvent) to give two distinct stereoisomers (I-33 and I-34).

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

[0788]

[0789] Enantiomer 1 of 3-(6-(tert-butoxycarbonyl)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-1H-benzimidazole-1-yl)-2-methoxypropionic acid (I-35): 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridinyl]-2-fluoro-phenyl]methyl]-3-(2,3-dimethoxy-3-oxopropyl)benzimidazole-5-carboxylic acid tert-butyl ester (I-33, peak 1) (151 mg, 0.23 mmol) was mixed with lithium hydroxide monohydrate (28 mg, 0.67 mmol) in THF (2 mL) and water (0.3 mL) and stirred at 30 °C. After 45 minutes, the reaction mixture was diluted with EtOAc (5 mL) and HCl aqueous solution (1 M, 2 mL). The organic layer was separated, washed with brine, dried over MgSO4, filtered, and concentrated to give the title compound: ES / MS: 655.2 (M+H + ).

[0790] Enantiomer 2 (I-36) of 3-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-1H-benzimidazole-1-yl)-2-methoxypropionic acid: hydrolyzed using a similar procedure with peak 2: ES / MS: 655.2 (M+H) + ).

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

[0792]

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

[0794] Methyl 4-amino-3-[[3-(tert-butoxycarbonylamino)-2-methoxy-propyl]amino]benzoate (I-38): Methyl 3-[[3-(tert-butoxycarbonylamino)-2-methoxy-propyl]amino]-4-nitro-benzoate (I-37, 1.8 g, 4.7 mmol) was mixed with iron powder (1.05 g, 18.8 mmol) and saturated NH4Cl aqueous solution (4.7 mL) in ethanol (20 mL). The mixture was stirred at 60 °C for 10 min, then cooled to RT, diluted with EtOAc (100 mL), filtered through a Celite filter and washed twice with brine. The organic fraction was dried over Na2SO4, filtered and concentrated to give the title compound: ES / MS: 354.1 (M+H + ).

[0795] 3-[3-(tert-butoxycarbonylamino)-2-methoxy-propyl]-2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenyl]methyl]benzimidazole-5-carboxylic acid methyl ester (I-39): Methyl 4-amino-3-[[3-(tert-butoxycarbonylamino)-2-methoxy-propyl]amino]benzoate (I-38, 500 mg, 1.4 mmol), 2-[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenyl]acetic acid (I-128, 460 mg, 1.2 mmol), HATU (689 mg, 1.81 mmol), and DIPEA (1.05 mL, 6.05 mmol) were mixed with DCE / DMF (2:1, 6 mL) and stirred at 50 °C for 45 minutes. The reactants were cooled, diluted with EtOAc, and washed with aqueous NH4Cl, aqueous NaHCO3, and brine. The organic fraction was dried over Na2SO4, filtered, and concentrated. The crude solid was dissolved in DCE / AcOH (1:2, 5 mL) and stirred at 80 °C for 30 min, then cooled to room temperature, concentrated to dryness, and purified by column chromatography (40%–85% EtOAc / hexane) to give the title compound: ES / MS: 698.3 (M+H + ); 1 H NMR(400MHz, chloroform-d)δ8.13(s,1H),8.05(d,J=8.5Hz,1H),7.85(s,1H),7.78–7.63(m, 4H),7.48(dd,J=7.9,1.6Hz,1H),7.42(dd,J=9.2,1.5Hz,1H),7.37(d,J=7.5Hz,1H), 6.83(d,J=8.2Hz,1H),5.62(s,2H),4.89(t,J=6.0Hz,1H),4.56(s,1H),4.30(s,2H), 3.98(s,3H),3.67–3.56(m,1H),3.42(s,2H),3.12(s,3H),2.12(s,1H),1.49(s,9H).

[0796] Enantiomers 1 and 2 (I-40 and I-41) of methyl 1-(3-amino-2-methoxypropyl)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-1H-benzimidazole-6-carboxylic acid ester: methyl 3-[3-(tert-butoxycarbonylamino)-2-methoxy-propyl]-2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridinyl]-2-fluoro-phenyl]methyl]benzimidazole-5-carboxylic acid ester, obtained as a mixture of two stereoisomers, were separated by chiral SFC (IG column with 40% EtOH cosolvent) to give two different stereoisomers. The separated enantiomers were treated with TFA (65 equivalents) at RT for 5 min each. The reactants were diluted with water, quenched to pH 7 with 1M NaOH, and extracted three times with DCM. The combined organic fractions were washed with aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated to give the title compound. ES / MS: 598.5 (M+H) + ).

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

[0798]

[0799] Methyl 4-[[2-(4-bromo-2,6-difluoro-phenyl)acetyl]amino]-3-(2-methoxyethylamino)benzoate: Methyl 4-amino-3-(2-methoxyethylamino)benzoate was added to a solution of 2-(4-bromo-2,6-difluoro-phenyl)acetic acid (3.67 g, 0.0146 mol), methyl 4-amino-3-(2-methoxyethylamino)benzoate (3.00 g, 0.0134 mol), and 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate (HATU) (99%, 3.78 g, 0.00993 mol) in DMF (35 mL). The mixture was stirred overnight at RT. The reactants were diluted with EtOAc and washed with 5% LiCl, saturated NaHCO3, and brine. The organic extract was dried over sodium sulfate and concentrated. The crude residue could be further purified without further purification. ES / MS m / z: 457.0, 459.0 (M+H) + )

[0800] Methyl 2-[(4-bromo-2,6-difluoro-phenyl)methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylic acid (I-42): A solution of methyl 4-[[2-(4-bromo-2,6-difluoro-phenyl)acetyl]amino]-3-(2-methoxyethylamino)benzoate (6.12 g, 0.0134 mol) in AcOH (24 mL) and DCE (24 mL) was heated at 60 °C for 7 hours. The mixture was concentrated and separated by chromatography (elution: EtOAc / hexane) to give the title compound. ES / MS m / z: 439.0, 441.0 (M+H) + ); 1 H NMR (400MHz, CDCl3) δ8.09(dd,J=1.5,0.7Hz,1H),7.96(dd,J=8.5,1.6Hz,1H),7.74(d,J=8.5Hz,1H),7. 16(d,J=6.8Hz,2H), 4.46(t,J=5.2Hz,2H), 4.36(s,2H), 3.97(s,3H), 3.74(t,J=5.1Hz,2H), 3.31(s,3H).

[0801] 2-[[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylic acid methyl ester (I-43): In a 200 mL round-bottom flask, 2-[(4-bromo-2,6-difluoro-phenyl)methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylic acid methyl ester (1000 mg, 2.28 mmol), A mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,3,2-dioxaborhecyclopentanane (695 mg, 2.74 mmol), (1,1'-bis(diphenylphosphine)ferrocene)-palladium(II) dichloride (81.5 mg, 0.115 mmol), and potassium acetate (671 mg, 6.84 mmol) was purged three times with Ar / vacuum. Dioxane (24 mL) was added, and the mixture was degassed with Ar for 5 min. The mixture was heated at 100 °C for 3.5 h. The mixture was filtered through a Celite stopper, diluted with EtOAc, and washed with brine. The organic extract was dried over sodium sulfate and separated chromatographically (eluent: EtOAc / hexane). The resulting compound was diluted with EtOAc, washed twice with saturated NaHCO3, and dried over magnesium sulfate. The organic extract was filtered and concentrated, then treated with Et₂O (2 mL) and sonicated to obtain a precipitate. Hexane was added to the precipitate, and the mixture was filtered and washed with hexane to give the title compound. ES / MS m / z: 487.2 (M+H)+ ); 1 HNMR (400MHz, CDCl3) δ8.17–8.07(m,1H),7.97(d,J=8.5Hz,1H),7.75(d,J=8.4Hz,1H),7.37(d,J= 7.3Hz, 2H), 4.45 (t, J = 5.2Hz, 4H), 3.97 (s, 3H), 3.71 (t, J = 5.2Hz, 2H), 3.30 (s, 3H), 1.35 (s, 12H).

[0802] Intermediate I-44 :

[0803]

[0804] 3-(2-Methoxyethylamino)-4-nitrobenzonitrile: A solution of 3-fluoro-4-nitrobenzonitrile (2 g, 12.04 mmol), 2-methoxyethylamine (1.25 mL, 14.79 mmol), and N,N-diisopropylethylamine (3.2 mL, 18.37 mmol) in DMF was stirred at RT for two days. The mixture was diluted with EtOAc and washed twice with 5% LiCl and brine. The organic extract was dried over sodium sulfate to give the title compound. ES / MS m / z: 222 (M+H + ); 1 H NMR(400MHz, CDCl3)δ8.26(dd,J=8.7,1.7Hz,1H),8.23(s,1H),7.21(d,J=1.7Hz,1H),6.89(dt ,J=8.8,1.5Hz,1H),3.71(dd,J=5.6,4.8Hz,2H),3.51(q,J=5.2Hz,2H),3.45(d,J=1.0Hz,3H).

[0805] N-(2-Methoxyethyl)-2-nitro-5-(2H-tetrazole-5-yl)aniline: In a 200 mL round-bottom flask, a suspension of 3-(2-methoxyethylamino)-4-nitrobenzonitrile (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 with EtOAc (2 × 100 mL). The combined organic extracts were dried over sodium sulfate to give the title compound. ES / MS m / z: 265.2 (M+H + ); 1H NMR (400MHz, MeOD) δ8.32(d,J=8.8Hz,1H),7.77(d,J=1.8Hz,1H),7.35(dd,J=8.9,1. 8Hz, 1H), 3.82–3.69 (m, 2H), 3.66 (t, J = 5.2Hz, 2H), 3.46 (s, 3H), 3.01 (d, J = 0.5Hz, 4H.

[0806] N-2-(2-methoxyethyl)-4-(2H-tetrazol-5-yl)phenyl-1,2-diamine (I-44): A solution of N-(2-methoxyethyl)-2-nitro-5-(2H-tetrazol-5-yl)aniline (93 mg, 352 μmol) in EtOH (25 mL) was degassed three times under vacuum with Ar. Pd / C (10%, 37.7 mg, 0.0354 mmol) was added, and the mixture was stirred overnight at RT under a hydrogen balloon. The mixture was filtered through a Celite stopper, washed with EtOAc, and concentrated to give the title product, which can be used for subsequent steps without further purification. ES / MS m / z: 235.2 (M+H + )

[0807] Intermediate I-45 :

[0808]

[0809] 4-(hydroxymethyl)-3-methoxybenzonitrile: In a 500 mL round-bottom flask, 3.46 g of 4-formyl-3-methoxybenzonitrile (0.0215 mol) was dissolved in 115 mL of MeOH and 115 mL of THF. The mixture was cooled to 0 °C, and sodium borohydride (0.813 g, 0.0215 mol) was added in portions. The mixture was stirred at 0 °C for 2 hours under a nitrogen atmosphere. EtOAc (175 mL) was added, followed by the slow addition of water (50 mL) and NH4Cl (50 mL, gas evaporation). Brine was added and the mixture was partitioned. The organic extract was dried over MgSO4 and concentrated, then redissolved with EtOAc and dried over sodium sulfate to obtain a crude residue. The crude residue was diluted with 200 mL of EtOAc and stirred with a saturated Rochelle salt solution for 2 hours. The layers were separated, and the organic extract was dried over sodium sulfate and concentrated to obtain the title compound, which could be proceeded without further purification. 1 HNMR (400MHz, MeOD) δ7.59(dd,J=7.7,1.0Hz,1H),7.35(dd,J=7.8,1.5Hz,1H),7.29(d,J=1.4Hz,1H),4.68(s,2H),3.90(s,3H).

[0810] 4-[(4-bromopyrimidin-2-yl)oxymethyl]-3-methoxybenzonitrile (I-45): A solution of 4-(hydroxymethyl)-3-methoxybenzonitrile (0.918 g, 0.00563 mol) in 15 mL of THF was cooled to 0 °C in 100 mL of RBF. Potassium tert-butoxide (1.00 M THF solution, 5.10 mL, 0.00510 mol) was added, and the mixture was stirred at 0 °C for 15 minutes.

[0811] A solution of 4-bromo-2-methylsulfonylpyrimidine (1.20 g, 0.00506 mol) in 15 mL of THF was cooled to -78 °C in a separate 100 mL RBF container. A solution of benzyl alcohol and KOtBu mixture was added via syringe over 5 minutes, and the mixture was stirred at -78 °C for 1 hour. The mixture was diluted with 60 mL of EtOAc and 30 mL of water. The organic extract was dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (elution: EtOAc / hexane) to give the title compound. ES / MS m / z: 321.91 (M+H) + ); 1 H NMR (400MHz, CDCl3) δ8.32(d,J=5.1Hz,1H),7.62(d,J=7.8Hz,1H),7.31(dd,J=7.8, 1.4Hz, 1H), 7.21 (d, J = 5.2Hz, 1H), 7.14 (d, J = 1.4Hz, 1H), 5.52 (s, 2H), 3.92 (s, 3H).

[0812] Intermediate I-46 :

[0813]

[0814] 3-Fluoro-4-[(3-iodo-2-pyridyl)oxymethyl]benzonitrile (I-46): A suspension of 3-fluoro-4-(hydroxymethyl)benzonitrile (0.757 g, 5.01 mmol), 2-chloro-3-iodopyridine (1.00 g, 4.18 mmol), and cesium carbonate (2.45 g, 7.52 mmol) in THF (15 mL) was heated at 80 °C until the starting material was consumed. The mixture was diluted with EtOAc and washed with brine. The organic extract was dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent: EtOAc / hexane) to give the title compound.

[0815] 1H NMR (400MHz, CDCl3) δ8.16–8.07(m,2H),7.79(dd,J=8.0,7.1Hz,1H),7.52(dd,J=7.9,1. 5Hz, 1H), 7.41 (dd, J = 9.3, 1.5Hz, 1H), 6.74 (dd, J = 7.6, 4.9Hz, 1H), 5.57 (d, J = 1.1Hz, 2H).

[0816] Intermediate I-47 :

[0817]

[0818] N-(6-bromo-2-pyridyl)-4-cyano-2-fluorobenzoamide (I-47): Pyridine (0.1 mL, 1.24 mmol) was added to a suspension of 6-bromopyridin-2-amine (1050 mg, 0.578 mmol) and 4-cyano-2-fluorobenzoyl chloride (138 mg, 0.751 mmol) in DCM (5 mL). The mixture was stirred overnight at RT. The mixture was diluted with EtOAc and washed with NH4Cl and brine. The organic extract was dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (elution: EtOAc / hexane) to give the title compound. ES / MS m / z: 320.0, 322.0 (M+H + ); 1 H NMR (400MHz, CDCl3) δ8.95(d,J=11.9Hz,1H),8.35(dd,J=8.2,0.7Hz,1H),8.27(t,J=7.8Hz,1H ), 7.66 (ddd, J = 8.0, 4.7, 3.2Hz, 2H), 7.57 (dd, J = 10.9, 1.5Hz, 1H), 7.34 (dd, J = 7.7, 0.7Hz, 1H).

[0819] Intermediate I-48 :

[0820]

[0821] N-(6-bromo-2-pyridyl)benzamide (I-48): The title compound was prepared by replacing 4-cyano-2-fluoro-benzoyl chloride with benzoyl chloride in the manner described for I-47: ES / MS m / z: 277.0, 279.0 (M+H) + ); 1H NMR (400MHz, CDCl3) δ8.59 (s, 1H), 8.39 (dd, J = 8.2, 0.7Hz, 1H), 8.07–7.87 (m, 2H), 7.70–7.57 (m, 2H), 7.57–7.47 (m, 2H), 7.41–7.19 (m, 1H).

[0822] Intermediate I-49 :

[0823]

[0824] 4-[(3-iodo-2-pyridyl)oxymethyl]-3-methoxybenzonitrile (I-49): A suspension of 3-fluoro-4-(hydroxymethyl)benzonitrile (0.128 g, 0.784 mmol), 2-fluoro-3-iodo-pyridine (0.150 g, 0.673 mmol), and cesium carbonate (0.400 g, 1.23 mmol) in THF (3 mL) was heated overnight at 80 °C. The mixture was diluted with EtOAc and washed with brine. The organic extract was dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent: EtOAc / hexane) to give the title compound. ES / MS: 366.9 (M+H) + );

[0825] 1 H NMR (400MHz, CDCl3) δ8.15(dd,J=4.9,1.7Hz,1H),8.11(dd,J=7.5,1.7Hz,1H),7.73(d,J=7.8Hz,1H),7.35(d d,J=7.8,1.4Hz,1H),7.13(d,J=1.4Hz,1H),6.73(dd,J=7.6,4.9Hz,1H),5.51(d,J=1.1Hz,2H),3.93(s,3H).

[0826] Intermediate I-50 :

[0827]

[0828] 4-[(6-bromo-3-chloro-2-pyridyl)oxymethyl]-3-fluorobenzonitrile (I-50): A suspension of 3-fluoro-4-(hydroxymethyl)benzonitrile (0.237 g, 1.57 mmol), 6-bromo-3-chloro-2-fluoropyridine (0.300 g, 1.43 mmol), and potassium carbonate (0.591 g, 4.28 mmol) in NMP (5 mL) was heated overnight at 100 °C. The mixture was diluted with EtOAc and washed with 5% LiCl solution (3×). The organic extract was dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent: EtOAc / hexane) to give the title compound. 1 H NMR (400MHz, CDCl3) δ7.74(t,J=7.5Hz,1H),7.59–7.47(m,2H),7.43(dd,J=9.3,1.5Hz,1H),7.11(d,J=7.9Hz,1H),5.57(s,2H); 19 F NMR(376MHz, CDCl3)δ-112.14–-116.85(m).

[0829] Intermediate I-51 :

[0830]

[0831] 3-Fluoro-4-[(6-Fluoro-2-pyridyl)oxymethyl]benzonitrile (I-51): A suspension of 2,6-difluoropyridine (0.39 mL, 4.34 mmol), 3-fluoro-4-(hydroxymethyl)benzonitrile (0.72 g, 4.78 mmol), and potassium carbonate (1.8 g, 13.03 mmol) in NMP (10 mL) was heated overnight at 100 °C. The mixture was diluted with EtOAc and washed with 5% LiCl aqueous solution (3×). The organic extract was dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (elution: EtOAc / hexane) to give the title product. ES / MS: 247.0 (M+H) + ); 1 H NMR (400MHz, chloroform-d) δ7.73(q,J=8.0Hz,1H),7.67(t,J=7.5Hz,1H),7.50(dd,J=7.9,1.6Hz,1H),7.41(d d,J=9.3,1.6Hz,1H),6.73(dd,J=8.0,1.6Hz,1H),6.56(dd,J=7.8,2.4Hz,1H),5.48(d,J=1.2Hz,2H); 19F NMR (376MHz, chloroform-d) δ -70.47 (d, J = 8.7Hz), -112.50–-117.78 (m).

[0832] Intermediate I-52

[0833]

[0834] 2-Bromo-6-((4-(trifluoromethyl)benzyl)oxy)pyridine (I-52): 1-(bromomethyl)-4-(trifluoromethyl)benzene (239 mg, 1 mmol) was added to acetonitrile (4 mL) containing 6-bromopyridin-2-ol (190 mg, 1.1 mmol) and cesium carbonate (360 mg, 1.1 mmol). The mixture was stirred overnight at ambient temperature. The mixture was filtered through a Celite filter and concentrated by rotary evaporation. The product was ready for use without further purification, yielding the title compound. 1 ¹H NMR (400MHz, chloroform-d) δ 7.66 (d, J = 8.2Hz, 2H), 7.60 (d, J = 8.1Hz, 2H), 7.48 (t, J = 7.8Hz, 1H), 7.13 (d, J = 7.4Hz, 1H), 6.79 (d, J = 8.1Hz, 1H), 5.45 (s, 2H).

[0835] Intermediate I-53

[0836]

[0837] Methyl 4-amino-3-(((1-ethyl-2-methyl-1H-imidazol-5-yl)methyl)amino)benzoate (I-53): Methyl 4-amino-3-(((1-ethyl-2-methyl-1H-imidazol-5-yl)methyl)amino)benzoate was prepared by replacing methoxyethylamine with chloro-[(3-ethyl-2-methyl-imidazol-4-yl)methyl]-imino-λ5-chloroane in the manner described with respect to I-1. ES / MS: 289.3 (M+H) + ).

[0838] Intermediate I-54

[0839]

[0840] 4-Amino-3-(((1-ethyl-1H-pyrazol-5-yl)methyl)amino)tert-butyl benzoate (I-54): Same as described for I-1, but with (1-ethyl-1H-pyrazol-5-yl)methylamine instead of methoxyethylamine to prepare 4-amino-3-(((1-ethyl-1H-pyrazol-5-yl)methyl)amino)tert-butyl benzoate ES / MS: 317.4 (M+H)+ ).

[0841] Intermediate I-55

[0842]

[0843] 4-Amino-3-(((1-(2-methoxyethyl)-1H-imidazol-5-yl)methyl)amino)benzoate (I-55): Methyl 4-amino-3-(((1-(2-methoxyethyl)-1H-imidazol-5-yl)methylamine was prepared in place of methoxyethylamine, as described for I-1: ES / MS: 305.4 (M+H) + ).

[0844] Intermediate I-56

[0845]

[0846] Methyl 4-amino-3-((pyrimidin-5-ylmethyl)amino)benzoate (I-56): As described with respect to I-1, methyl 4-amino-3-((pyrimidin-5-ylmethyl)amino)benzoate was prepared by replacing methoxyethylamine with pyrimidin-5-ylmethylamine. ES / MS: 259.3 (M+H) + ).

[0847] Intermediate I-57

[0848]

[0849] Methyl 4-amino-3-(((3-ethylpyridin-4-yl)methyl)amino)benzoate (I-57): As described for I-1, methyl 4-amino-3-(((3-ethylpyridin-4-yl)methyl)amino)benzoate was prepared by replacing methoxyethylamine with (3-ethyl-4-pyridinyl)methylamine: ES / MS: 286.3 (M+H) + ).

[0850] Intermediate I-58

[0851]

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

[0853] Intermediate I-59

[0854]

[0855] 4-(((6-bromopyridin-2-yl)oxy)methyl)benzonitrile (I-59): As described with respect to I-51, 4-(((6-bromopyridin-2-yl)oxy)methyl)benzonitrile is prepared by replacing 1-(bromomethyl)-4-(trifluoromethyl)benzene with 4-(bromomethyl)benzonitrile. 1 ¹H NMR (400MHz, chloroform-d) δ 7.79–7.64 (m, 2H), 7.59 (d, J = 8.1 Hz, 2H), 7.49 (dd, J = 8.1, 7.5 Hz, 1H), 7.19–7.05 (m, 1H), 6.80 (dd, J = 8.1, 0.6 Hz, 1H), 5.45 (s, 2H).

[0856] Intermediate I-60

[0857]

[0858] 2-(4-Bromo-2-cyano-6-fluorobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazolium-6-carboxylic acid tert-butyl ester (I-60): As described for intermediate I-5, 2-(4-bromo-2-cyano-6-fluorophenyl)acetic acid was prepared instead of 2-(4-bromo-2-fluorophenyl)acetic acid. ES / MS: 488.7 (M+H) + ).

[0859] Intermediate I-61

[0860]

[0861] 2-(1-(4-chloro-2-fluorophenyl)ethoxy)-3-iodopyridine (I-61): 3-fluoro-4-(hydroxymethyl)benzonitrile (0.875 g, 5.01 mmol) and 2-chloro-3-iodopyridine (1.00 g, 4.18 mmol) were dissolved in 1,4-dioxane (8.0 mL), and potassium tert-butoxide (0.703 g, 6.26 mmol) was added fractionally. After addition, the mixture was sealed and heated to 110 °C for 8 hours. After completion, the mixture was cooled to RT and diluted with EtOAc (100 mL) and water (100 mL). The organic phase was collected, and the aqueous phase was extracted with EtOAc (2 × 50 mL). The combined organic matter was dried over MgSO4, filtered, and concentrated under vacuum. The residue was then purified by normal-phase column chromatography (elution: EtOAc / hexane gradient) to give the title compound.

[0862] Intermediate I-62

[0863]

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

[0865] Ethyl (S)-3-fluoro-4-nitro-5-((oxetane-2-ylmethyl)amino)benzoate: Ethyl 3,5-difluoro-4-nitro-benzoate (2.50 g, 10.8 mmol) and (S)-oxetane-2-ylmethylamine (989 mg, 11.4 mol) were dissolved in tetrahydrofuran (12.0 mL) and N,N-dimethylformamide (6.0 mL), and N,N-diisopropylethylamine (9.42 mL, 54.1 mmol) was added. The mixture was heated to 50 °C for 16 hours. The mixture was then concentrated under vacuum, and the residue was purified by column chromatography (elution: 0%-25% EtOAc / hexane) to give the product. ES / MS: 299.2 (M+H) + ).

[0866] Ethyl (S)-4-amino-3-fluoro-5-((oxetanebut-2-ylmethyl)amino)benzoate (I-62): Ethyl (S)-3-fluoro-4-nitro-5-((oxetanebut-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 under nitrogen for 5 min. Then, carbon-supported palladium (10 wt%, 785 mg, 0.74 mmol) was added and bubbling continued for 5 min. Hydrogen was then bubbled through the solution for one minute, and the mixture was then placed in a hydrogen atmosphere balloon for 21 h. Afterward, the reaction was stopped and the mixture was filtered through a Celite filter. The filter was washed with EtOAc (2 × 20 mL) and methanol (2 × 10 mL), and the filtrate was concentrated under vacuum to give ethyl (S)-4-amino-3-fluoro-5-((oxetanebut-2-ylmethyl)amino)benzoate (I-62). ES / MS: 269.2 (M+H) + ); 1 ¹H NMR (400MHz, chloroform) δ 7.44–7.30 (m, 2H), 5.13 (qd, J = 7.1, 3.4 Hz, 1H), 4.72 (ddd, J = 8.7, 7.4, 6.0 Hz, 1H), 4.62 (dt, J = 9.1, 6.1 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.58–3.30 (m, 2H), 2.76 (dtd, J = 11.4, 8.0, 6.1 Hz, 1H), 2.56 (ddt, J = 11.3, 9.0, 7.1 Hz, 1H), 1.37 (t, J = 7.1 Hz, 3H).

[0867] Intermediate I-63

[0868]

[0869] Methyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluorobenzyl)-1H-benzo[d]imidazolium-6-carboxylate (I-63): Methyl 2-(4-(6-((4-cyano-2-fluoro-phenyl)methoxy)-2-pyridinyl)-2-fluoro-phenyl)acetic acid was prepared by replacing 2-(3'-((4-cyano-2-fluorobenzyl)oxy)-3,4'-difluoro-(1,1'-biphenyl)-4-yl)acetic acid: ES / MS: 511.2 (M+H) + ).

[0870] Intermediate I-64

[0871]

[0872] Methyl 2-(4-bromo-3-nitrobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazolium-6-carboxylic acid: 2-(4-bromo-3-nitrophenyl)acetic acid (1000 mg, 3.85 mmol), methyl 4-amino-3-(2-methoxyethylamino)benzoate (I-1) (862 mg, 3.85 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (2485 mg, 5.77 mmol) were dissolved in DMF (8 mL), and N,N-diisopropylethylamine (3.35 mL, 19.2 mmol) was added. The mixture was stirred at room temperature for 30 minutes. Afterward, the mixture was diluted with EtOAc (200 mL) and water (200 mL). The organic phase was collected, and the aqueous phase was extracted with EtOAc (2 × 50 mL). The combined organic phases were dried over Na₂SO₄ and concentrated under vacuum. The resulting residue was dissolved in acetic acid (20 mL) and heated to 75 °C. After 7 hours, the mixture was concentrated under vacuum and diluted with EtOAc (50 mL). The organic phase was washed with saturated NaHCO₃ aqueous solution (20 mL) and the aqueous phase was extracted with EtOAc (2 × 50 mL). The combined organic phases were dried over Na₂SO₄ and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (eluent: 20%-100% hexane / EtOAc): ES / MS: 448.1 (M+H) + ).

[0873] Methyl 2-(4-(6-(((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3-nitrobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazol-6-carboxylic acid: Add methyl 2-(4-bromo-3-nitrobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazol-6-carboxylic acid (0.350 g, 0.781 mmol), bis(pinacol)diboron (300 mg, 1.17 mmol), Pd(dppf)Cl2 (54 mg, 0.078 mmol), and potassium propionate (263 mg, 2.34 mmol) to a vial. Add DMF (10 mL) and degas the mixture with argon for 2 minutes. Seal the vial and heat the mixture at 100 °C for 1 hour. Subsequently, LC / MS showed that the aryl bromide was converted to the intermediate boric acid, and the mixture was cooled to room temperature. At this point, an aqueous sodium carbonate solution (1.5 M, 1.56 mL, 2.34 mmol) was added, followed by Pd(dppf)Cl2 (54 mg, 0.078 mmol) and 4-[(6-bromo-2-pyridyl)oxymethyl]-3-fluorobenzonitrile (I-6, 360 mg, 1.17 mmol). The vial was resealed and heated to 90 °C for 3 hours. The mixture was then cooled to room temperature and diluted with EtOAc (50 mL) and water (50 mL). The organic phase was collected, and the aqueous phase was extracted with EtOAc (2 × 50 mL). The combined organic phases were dried over Na2SO4 and concentrated under vacuum. The crude material was purified by silica gel chromatography (elution: 20%–80% EtOAc / hexane) to give the desired product: ES / MS: 596.2 (M+H). + ).

[0874] Methyl 2-(3-amino-4-(6-(((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazolium-6-carboxylate (I-64): Methyl 2-(4-(6-(((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3-nitrobenzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazolium-6-carboxylate (40 mg, 0.0675 mmol) was dissolved in ethanol (0.50 mL), and water (0.15 mL) and acetic acid (0.15 mL) were added. Iron powder (38 mg, 0.675 mmol) was then added to the mixture, and the mixture was heated to 70 °C. After 2 hours, the mixture was cooled to room temperature and filtered through a Celite filter. The residue was diluted with EtOAc (10 mL) and water (10 mL). The organic phase was collected, and the aqueous phase was extracted with EtOAc (2 × 10 mL). The combined organic phases were dried over Na₂SO₄ and concentrated under vacuum. The crude material was purified by silica gel chromatography (elution buffer: 20%-80% EtOAc / hexane) to obtain the desired product. ES / MS: 566.3 (M+H) + ).

[0875] Intermediate I-65

[0876]

[0877] Methyl 2-(2-amino-4-(6-(((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazolium-6-carboxylate (I-65): As described with respect to I-64, methyl 2-(2-amino-4-(6-(((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazolium-6-carboxylate was prepared by replacing 2-(4-bromo-2-nitrophenyl)acetic acid with 2-(4-bromo-3-nitrophenyl)acetic acid. ES / MS: 566.2 (M+H) + ).

[0878] Intermediate I-66

[0879]

[0880] 2-(3-Bromo-4-(6-(((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester (I-66): 2-(3-amino-4-(6-(((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester (I-64, 26 mg, 0.0460 mmol) and copper bromide (I) (20 mg, 0.140 mmol) were suspended in EtOAc (1.0 mL) and MeCN (1.0 mL). After stirring for 5 minutes, tBuONO was added, and the mixture was stirred at RT for 3 hours. The residue was then diluted with EtOAc (20 mL) and washed with saturated NH4Cl aqueous solution (5 × 5 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum. The crude substance was purified by silica gel chromatography (eluent: EtOAc / hexane) to obtain the desired product. ES / MS: 631.0 (M+H) + ).

[0881] Intermediate I-67

[0882]

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

[0884] Intermediate I-68

[0885]

[0886] 3-((2-methoxyethyl)amino)-4-nitrobenzene tert-butyl ester: 10 g (41.5 mmol) of 3-fluoro-4-nitrobenzene tert-butyl ester was added to 500 mL of RBF. The substance was dissolved in THF (150 mL), and 2-methoxyethylamine (7.2 mL, 82.9 mmol) and N,N-diisopropylethylamine (21.7 mL, 124 mmol) were added. The mixture was stirred overnight at 50 °C. The mixture was then concentrated to remove most of the THF, and the crude substance was dissolved in EtOAc (400 mL). The organic matter was washed with 50% NH4Cl (2 × 100 mL) and brine (1 × 50 mL). The organic matter was then dried over MgSO4, filtered, and concentrated under reduced pressure. The crude substance was allowed to proceed without further purification: ES / MS: 297.1 (M+H) + ); 1 ¹H NMR (400MHz, chloroform-d) δ 8.21 (d, J = 8.9 Hz, 1H), 7.55 (d, J = 1.7 Hz, 1H), 7.20 (dd, J = 8.9, 1.7 Hz, 1H), 3.72 (dd, J = 5.8, 4.8 Hz, 2H), 3.57 (q, J = 5.2 Hz, 2H), 3.46 (s, 3H), 1.62 (s, 9H).

[0887] 4-Amino-3-((2-methoxyethyl)amino)benzoate tert-butyl ester (I-68): 1 L of RBF was added to tert-butyl 3-((2-methoxyethyl)amino)-4-nitrobenzoate (13 g, 43.9 mmol), ethanol (100 mL), and EtOAc (50 mL). The mixture was stirred and sonicated until all substances were dissolved. Nitrogen was bubbled through the mixture for 5 minutes, and then carbon-supported palladium (10 wt%, 2.33 g, 2.19 mmol) was added. Hydrogen was bubbled through the mixture for 5 minutes, and the mixture was stirred overnight under a hydrogen balloon. Nitrogen was then bubbled through the flask for 10 minutes, and the mixture was filtered through a Celite filter to remove the catalyst. The filtrate was concentrated under reduced pressure and was ready for use without further purification: ES / MS: 267.2 (M+H). + ).

[0888] Intermediate I-69

[0889]

[0890] 5-Bromo-2-((6-(methoxycarbonyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)methyl)benzoic acid: 7-bromoisocyanate-1,3-dione (1.18 g, 4.91 mmol), methyl 4-amino-3-(2-methoxyethylamino)benzoate (I-1, 1 g, 4.46 mmol), and THF (20 mL) were added to 100 mL of RBF. After stirring the mixture at 55 °C for 16 h, AcOH (6 mL) was added, and the mixture was stirred at 60 °C for 24 h. LCMS analysis showed conversion to the desired product. The evaporator was evaporated, and the crude mixture was ground with Et2O (20 mL). The resulting solid was dried under vacuum and further processing was carried out: ES / MS: 447.6 (M+).

[0891] Methyl 2-(4-bromo-2-(hydroxymethyl)benzyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (I-69): 5-bromo-2-((6-(methoxycarbonyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazolium-2-yl)methyl)benzoic acid (300 mg, 0.67 mmol) was dissolved in anhydrous THF (20 mL) in 100 mL RBF under a nitrogen atmosphere, and the solution was cooled to 0 °C. Borane dimethyl sulfide (0.083 mL, 0.87 mmol) was added dropwise using a syringe, and the mixture was stirred at 0 °C and then slowly heated to room temperature. Methanol (2 mL) was slowly added to quench the reaction, followed by water (10 mL) and EtOAc (50 mL). The layers were separated, and the aqueous layer was extracted once with EtOAc (20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (eluent: EtOAc / hexane) to give I-69. ES / MS: 433.1 (M+).

[0892] Intermediate I-70

[0893]

[0894] 2-(4-Bromo-2-(methoxymethyl)benzyl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylic acid methyl ester (I-70): 2-[[4-bromo-2-(hydroxymethyl)phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylic acid methyl ester (I-69) (100 mg, 0.23 mmol) and THF (2 mL) were added to a 40 mL vial. The solution was cooled to 0 °C, and NaH (60% mineral dispersion, 18 mg, 0.46 mmol) was added under a nitrogen atmosphere. The mixture was stirred at 0 °C for 15 min, methyl iodoforme (0.073 mL, 1.15 mmol) was added, and the mixture was stirred overnight at room temperature. The mixture was quenched with 3 drops of water, and the crude mixture was added directly to a silica-loaded column. The crude substance was purified by silica column chromatography (elution: EtOAc / hexane) to give I-70. ES / MS: 447.1 (M+).

[0895] Intermediate I-71

[0896]

[0897] 2-(4-Bromo-2-(fluoromethyl)benzyl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylic acid methyl ester (I-71): 2-[[4-bromo-2-(hydroxymethyl)phenyl]methyl]-3-(2-methoxyethyl)benzimidazole-5-carboxylic acid methyl ester (I-69) (100 mg, 0.23 mmol) and dichloromethane (5 mL) were added to a 40 mL vial. The solution was placed under a nitrogen atmosphere and cooled to 0 °C. Diethylaminosulfur trifluoride (0.03 mL, 0.23 mmol) was added via syringe, and the mixture was stirred at 0 °C for 30 min. The mixture was diluted with CH2Cl2 (10 mL) and washed once with water (5 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica column chromatography (eluent: EtOAc / hexane) to obtain I-71. ES / MS: 435.1 (M+).

[0898] Intermediate I-72

[0899]

[0900] 2-((4-bromo-5-fluoro-2-oxopyridin-1(2H)-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester (I-72): 2-(chloromethyl)-3-(2-methoxyethyl)benzimidazole-5-carboxylic acid methyl ester hydrochloride (416 mg, 1.3 mmol), 4-bromo-5-fluoro-1H-pyridin-2-one (250 mg, 1.3 mmol), potassium carbonate (900 mg, 6.51 mmol), and DMF (4 mL) were added to a 20 mL vial. N,N-diisopropylethylamine (0.45 mL, 2.6 mmol) was added, and the mixture was stirred at 60 °C for 1 hour. LCMS showed a mixture of two products (O-alkylation and N-alkylation), favoring the more polar product (N-alkylation). The mixture was diluted with EtOAc (50 mL) and washed with water (15 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica chromatography (eluent: EtOAc / hexane) to give I-72. ES / MS: 438.1 (M+).

[0901] Intermediate I-73

[0902]

[0903] 2-Bromo-6-((4-chloro-2-fluorobenzyl)oxy)pyridine (I-73): As described for I-6, 2-bromo-6-((4-chloro-2-fluorobenzyl)oxy)pyridine was prepared by replacing 3-fluoro-4-(hydroxymethyl)benzonitrile with (4-chloro-2-fluorophenyl)methanol. ES / MS: 317.8 (M+H) + ); 1 ¹H NMR (400MHz, chloroform-d) δ 7.52–7.45 (m, 2H), 7.19–7.02 (m, 3H), 6.75 (d, J = 8.2 Hz, 1H), 5.43–5.38 (m, 2H).

[0904] Intermediate I-74

[0905]

[0906] 2-Bromo-6-((4-chloro-2-methoxybenzyl)oxy)pyridine (I-74): As described for I-6, 2-bromo-6-((4-chloro-2-methoxybenzyl)oxy)pyridine was prepared by replacing 3-fluoro-4-(hydroxymethyl)benzonitrile with (4-chloro-2-methoxyphenyl)methanol. ES / MS: 329.9 (M+H) + ); 1¹H NMR (400MHz, chloroform-d) δ 7.49–7.39 (m, 2H), 7.09 (d, J = 7.4 Hz, 1H), 6.97 (dd, J = 8.1, 2.0 Hz, 1H), 6.91 (d, J = 1.9 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 5.37 (s, 2H), 3.88 (s, 3H).

[0907] Intermediate I-75

[0908]

[0909] 4-(((6-bromopyridin-2-yl)oxy)methyl)-3-methoxybenzonitrile (I-75): 6-bromopyridin-2-ol (231 mg, 1.33 mmol), 4-(bromomethyl)-3-methoxybenzonitrile (300 mg, 1.33 mmol), silver(II) carbonate (1.1 g, 3.98 mmol), and toluene (10 mL) were added to a 20 mL vial. The mixture was heated at 100 °C for 1 hour. The mixture was then cooled and filtered through a Celite filter to remove the solid precipitate, followed by washing with EtOAc. The filtrate was concentrated, and the crude residue was purified by silica chromatography (eluent: EtOAc / hexane) to give I-75. ES / MS: 319.1 (M+).

[0910] Intermediate I-76

[0911]

[0912] 4-(((4-bromopyrimidin-2-yl)oxy)methyl)-3-fluorobenzonitrile (I-76): As described for I-45, 4-(((4-bromopyrimidin-2-yl)oxy)methyl)-3-fluorobenzonitrile was prepared by replacing 4-(hydroxymethyl)-3-methoxy-benzonitrile with 3-fluoro-4-(hydroxymethyl)benzonitrile. ES / MS: 319.9 (M+); 1 ¹H NMR (400MHz, chloroform-d) δ 8.32 (d, J = 5.2Hz, 1H), 7.62 (d, J = 7.8Hz, 1H), 7.31 (dd, J = 7.8, 1.4Hz, 1H), 7.21 (d, J = 5.1Hz, 1H), 7.14 (d, J = 1.4Hz, 1H), 5.55–5.48 (m, 2H), 3.93 (s, 3H).

[0913] Intermediate I-77

[0914]

[0915] 4-Bromo-2-((4-chloro-2-fluorobenzyl)oxy)pyrimidine (I-77): As described for I-45, 4-bromo-2-((4-chloro-2-fluorobenzyl)oxy)pyrimidine was prepared by replacing 4-(hydroxymethyl)-3-methoxybenzonitrile with (4-chloro-2-fluorophenyl)methanol. ES / MS: 318.9 (M+H) + ); 1 ¹H NMR (400MHz, chloroform-d) δ 8.31 (d, J = 5.1Hz, 1H), 7.51 (t, J = 8.1Hz, 1H), 7.21 (d, J = 5.2Hz, 1H), 7.19–7.13 (m, 2H), 5.51–5.46 (m, 2H).

[0916] Intermediate I-78

[0917]

[0918] 4-Bromo-2-((4-chloro-2-methoxybenzyl)oxy)pyrimidine (I-78): As described for I-45, 4-bromo-2-((4-chloro-2-methoxybenzyl)oxy)pyrimidine was prepared by replacing 4-(hydroxymethyl)-3-methoxybenzonitrile with (4-chloro-2-methoxyphenyl)methanol. ES / MS: 318.9 (M+H) + ); 1 ¹H NMR (400MHz, chloroform-d) δ 8.31 (d, J = 5.1Hz, 1H), 7.51 (t, J = 8.1Hz, 1H), 7.21 (d, J = 5.2Hz, 1H), 7.19–7.13 (m, 2H), 5.51–5.46 (m, 2H).

[0919] Intermediate I-79

[0920]

[0921] 2-((5-chloro-2-fluorobenzyl)oxy)-3-iodopyridine (I-79): 2-chloro-3-iodopyridine (300 mg, 1.25 mmol), (5-chloro-2-fluorophenyl)methanol (302 mg, 1.88 mmol), Cs₂CO₃ (816 mg, 2.51 mmol), N,N-diisopropylethylamine (0.44 mL, 2.51 mmol), and NMP (1.5 mL) were added to a vial. The mixture was heated overnight at 120 °C. The mixture was then cooled and dissolved in EtOAc (30 mL). The organic matter was washed with water (2 × 10 mL), and the organic layer was dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude residue was purified by silica chromatography (eluent: EtOAc / hexane) to give I-79. ES / MS: 318.9 (M+H) + ); 1 ¹H NMR (400MHz, chloroform-d) δ 8.31 (d, J = 5.1Hz, 1H), 7.51 (t, J = 8.1Hz, 1H), 7.21 (d, J = 5.2Hz, 1H), 7.19–7.13 (m, 2H), 5.51–5.46 (m, 2H).

[0922] Intermediate I-80

[0923]

[0924] 2-((4-bromo-6-methyl-2-oxopyridin-1(2H)-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester (I-80): As described with respect to I-72, 2-((4-bromo-6-methyl-2-oxopyridin-1(2H)-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester was prepared by replacing 4-bromo-5-fluoro-1H-pyridin-2-one with 4-bromo-6-methylpyridin-2(1H)-one: ES / MS: 434.3 (M+); 1 HNMR (400MHz, chloroform-d) δ8.08(d,J=1.5Hz,1H),7.94(dd,J=8.5,1.6Hz,1H),7.69(d,J=8.5Hz,1H),6.70(d,J=2.1Hz,1H),6.3 3(dd,J=2.2,0.9Hz,1H),5.46(s,2H),4.66(t,J=5.0Hz,2H),3.95(s,3H),3.72(t,J=5.0Hz,2H),3.28(s,3H),2.62(s,3H).

[0925] Intermediate I-81

[0926]

[0927] Methyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorophenyl)acetate: A suspension of methyl 2-(4-bromo-2,5-difluorophenyl)acetate (10.5 g, 39.6 mmol), bis(neopentylethylene glycol)diboron (17.9 g, 79.2 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride, PdCl2 (dppf) (2.94 g, 3.96 mmol), and potassium propionate (15.6 g, 139 mmol) in dioxane (50 mL) was degassed with Ar for 20 min. The mixture was sealed and heated at 100 °C for 2 h. Sodium carbonate (2.0 M, 39.6 mL, 79.2 mmol) was added, and the mixture was stirred at RT for 10 min. Add [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride, PdCl2 (dppf) (1.47 g, 1.98 mmol), and I-6 (14 g, 45.6 mmol), degas the mixture with Ar for 10 min, then seal and heat at 100 °C for 1 h. Dilute the mixture with EtOAc and wash with brine. Dry the organic extract with sodium sulfate and separate by chromatography (eluent: EtOAc / hexane) to give the title product: ES / MS: 413.2 (M+H) + ).

[0928] 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorophenyl)acetic acid (I-81). A solution of methyl 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorophenyl)acetic acid (12.5 g, 30.3 mmol) and lithium hydroxide (0.2 M, 19.7 mL, 39.4 mmol) in CH3CN (50 mL) was heated at 50 °C for 2 hours. The mixture was acidified to pH 6-7 with 1 N hydrochloride. The precipitate was filtered through a filter funnel. The solid was washed with water and dried overnight to give the product: ES / MS: 399.2 (M+H + ); 1 ¹H NMR (400MHz, methanol-d⁴) δ 7.83–7.77 (m, 1H), 7.78–7.65 (m, 2H), 7.64–7.59 (m, 2H), 7.58–7.51 (m, 1H), 7.26–7.14 (m, 1H), 6.91 (d, J = 8.2 Hz, 1H), 5.63 (s, 2H), 3.73 (d, J = 1.2 Hz, 2H).

[0929] Intermediate I-82

[0930]

[0931] 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorophenyl)acetic acid (I-82). 2-(4-(6-(((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3-fluorophenyl)acetic acid (I-82) was prepared in the same manner as for I-81, using methyl 2-(4-bromo-3-fluorophenyl)acetate instead of methyl 2-(4-bromo-2,5-difluorophenyl)acetate. ES / MS: 381.2 (M+H) + ); 1 ¹H NMR (400MHz, methanol-d⁴) δ 7.92 (t, J = 8.2 Hz, 1H), 7.76 (dt, J = 14.4, 7.6 Hz, 2H), 7.66–7.55 (m, 2H), 7.49 (dd, J = 7.3, 1.8 Hz, 1H), 7.27–7.12 (m, 2H), 6.88 (d, J = 8.1 Hz, 1H), 5.63 (s, 2H), 3.70 (s, 2H).

[0932] Intermediate I-83

[0933]

[0934] 2-(4-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3-fluorophenyl)acetic acid (I-83): 2-(4-(2-(((4-bromopyrimidin-2-yl)oxy)methyl)-3-fluorobenzonitrile (I-76) was prepared in the same manner as for I-82, by replacing 4-(((6-bromopyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (I-6). ES / MS: 382.2 (M+H) + ); 1 H NMR (400 MHz, methanol-d4) δ 8.65 (d, J = 5.3 Hz, 1H), 8.11 (t, J = 8.1 Hz, 1H), 7.81 (t, J = 7.5 Hz, 1H), 7.69–7.59 (m, 3H), 7.36–7.22 (m, 2H), 5.70 (s, 2H), 3.74 (s, 2H).

[0935] Intermediate I-84

[0936]

[0937] 4-(((2-chloro-5-fluoropyrimidin-4-yl)oxy)methyl)-3-fluorobenzonitrile (I-84): 4-(((2-chloro-5-fluoropyrimidin-4-yl)oxy)methyl)-3-fluorobenzonitrile was prepared by replacing 4-bromo-2-chloro-thiazole with 2,4-dichloro-5-fluoropyrimidin. ES / MS: 282.2 [M+H] + .

[0938] Intermediate I-85

[0939]

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

[0941] 1,4-Dioxane (1.0 mL) was added to a vial containing methyl 2-(4-bromo-2,5-difluorobenzyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (30.0 mg, 0.063 mmol) (synthesized in a manner similar to I-96), bis(pinacol)diboron (20.8 mg, 0.082 mmol), Pd(dppf)Cl2 (7.0 mg, 0.0095 mmol), and potassium propionate (21.2 mg, 0.19 mmol). The suspension was degassed by purging with argon for 60 seconds, and the vial was then sealed and heated at 115 °C for 45 minutes. 2,4-Dichloro-5-fluoropyrimidine (10.5 mg, 0.063 mmol), Pd(dppf)Cl2 (3.5 mg, 0.0047 mmol), and sodium carbonate aqueous solution (2 M, 63 μL, 0.13 mmol) were added to the cooled mixture. The mixture was degassed by purging with argon for 60 seconds, then the vial was sealed and heated at 90 °C for 4 hours. The cooled mixture was filtered through a Celite pad (elution: EtOAc), concentrated, and purified by silica gel chromatography (elution: EtOAc / hexane) to obtain the desired product. ES / MS: 527.0 [M+H] + .

[0942] Intermediate I-86

[0943]

[0944] 4-[[(6-chloro-2-pyridyl)amino]methyl]-3-fluorobenzonitrile (I-86): 4-(aminomethyl)-3-fluorobenzonitrile hydrochloride (277 mg, 1.49 mmol), 2,6-dichloropyridine (200 mg, 1.35 mmol), N,N-diisopropylethylamine (0.942 mL, 5.41 mmol), and DMF were added to a microwave-safe vial. The solution was heated to 120 °C for 12 hours. The crude solution was concentrated under reduced pressure and purified by silica column chromatography (50%–100% EtOAc / hexane) to give the title compound. ES / MS: 262.2 (M+H) + ).

[0945] Intermediate I-87

[0946]

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

[0948] Intermediate I-88

[0949]

[0950] 3-Fluoro-4-[(3-iodo-2-pyridyl)oxymethyl]benzonitrile (I-88): 3-Fluoro-4-(hydroxymethyl)benzonitrile (114 mg, 0.75 mmol), 2-chloro-3-iodopyridine (150 mg, 0.63 mmol), cesium carbonate (367 mg, 1.13 mmol), and 5 mL THF were added to a microwave-safe vial. The vial was sealed, and the mixture was heated to 80 °C for 16 hours. The mixture was cooled to RT, concentrated, and purified by silica gel column chromatography (35%–100% EtOAc / hexane) to give the title compound: ES / MS: 354.9 (M+H). + ).

[0951] Intermediate I-89 :

[0952]

[0953] 2-[(2-fluorophenyl)methoxy]-3-iodopyridine (I-89): (4-chloro-2-fluorophenyl)methanol (121 mg, 0.75 mmol), 2-chloro-3-iodopyridine (120 mg, 0.50 mmol), cesium carbonate (294 mg, 0.90 mmol), and 5 mL THF were added to a microwave-safe vial. The vial was sealed, and the mixture was heated to 80 °C for 16 hours. The mixture was cooled to RT, concentrated, and purified by silica gel column chromatography (35%–100% EtOAc / hexane) to give the title compound. ES / MS: 363.8 (M+H) + ).

[0954] Intermediate I-90

[0955]

[0956] 4-[(3-bromopyrazin-2-yl)oxymethyl]-3-fluorobenzonitrile (I-90): 3-fluoro-4-(hydroxymethyl)benzonitrile (335 mg, 2.22 mmol), 2,3-dibromopyrazine (440 mg, 1.85 mmol), cesium carbonate (1.08 g, 3.33 mmol), and THF (10 mL) were added to a microwave-safe vial. The vial was sealed, and the mixture was heated to 80 °C for 16 hours. The mixture was cooled to RT, concentrated, and purified on a silica gel column (35%–100% EtOAc / hexane) to give the title compound: ES / MS: 308.1 (M+).

[0957] Intermediate I-91

[0958]

[0959] 2-[(2-fluorophenyl)methoxy]-3-iodopyridine (I-91): 3-fluoro-4-(hydroxymethyl)benzonitrile (94.8 mg, 0.75 mmol), 2-chloro-3-iodopyridine (120 mg, 0.50 mmol), cesium carbonate (294 mg, 0.90 mmol), and 5 mL THF were added to a microwave-safe vial. The vial was sealed, and the mixture was heated to 80 °C for 16 hours. The mixture was cooled to RT, concentrated, and purified by silica gel column chromatography (35%–100% EtOAc / hexane) to give the title compound: ES / MS: 329.9 (M+H). + ).

[0960] Intermediate I-92

[0961]

[0962] 3-Fluoro-4-[(5-iodopyrimidin-4-yl)oxymethyl]benzonitrile (I-92): 3-Fluoro-4-[(5-iodopyrimidin-4-yl)oxymethyl]benzonitrile was prepared according to procedure I-88, but with 2...

Claims

1. A compound of formula (IA-1): or a pharmaceutically acceptable salt thereof, wherein R 1 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, -SR 1b 、-S(O)R 1b 、-S(O)(NH)R 1b 、-S(O)2R 1b 、-S(O)2N(R 1b )(R 1c )、-S(O)(NR 1b )R 1c 、-C(O)N(R 1b )(R 1c )、-C(O)R 1b or-C(O)OR 1c , wherein the alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl groups are each optionally substituted by one to four Z 1 replace; Ring A is C 6-10 aryl or heteroaryl, each of which is optionally substituted by one to four Z 1a replace; Ring B is C 6-10 aryl or heteroaryl, each of which is optionally substituted by one to four R 4 replace; R 2 H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, -CN, -OR 2a 、-SR 2a 、-S(O)R 2a 、-S(O)(NH)R 2a 、-S(O)2R 2a 、-S(O)2N(R 2a )(R 2b ) or -S(O)(NR 2a )R 2b , wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1 replace; X 1 , X 2 and X 3 are independently -N=, -C(H)= or -C(R 8 )=; R 3 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, -NO2, -OR 3a 、-C(O)R 3a 、-CH2C(O)OR 3a 、-C(O)OR 3a 、-C(O)N(R 3a )(R 3b )、-N(R 3a )C(O)R 3b 、-N(R 3a )C(O)OR 3b 、-N(R 3a )C(O)N(R 3b )2、-C(O)NHS(O)2R 3a 、-C(O)NR 3a S(O)2R 3b 、-C(O)NR 3a S(O)2NR 3b R 3c 、-C(O)NR 3a -S(O)(=NR 3b )R 3c 、-S(O)2R 3a 、-S(O)2OR 3a 、-S(O)2N(R 3a )(R 3b )、-N(R 3a )S(O)2R 3b 、-S(O)2NHC(O)R 3a 、-S(O)(=NR 3a )R 3b 、-S(O)(=NR 3a )NR 3b 、-S(=NR 3a )(=NR 3b )R 3c 、-P(O)(OR 3a )(R 3b )、-P(O)(OR 3a )(OR 3b )、-B(OR 3a )(OR 3b ) or -OC 1-6 Alkyl-C(O)OR 3a wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four R 3d replace; Each R 3a , R 3b and R 3c Independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkoxyalkyl, -C 1-4 Alkyl-N(R 9a )(R 9b ),-C 1-4 Alkyl-N(R 9a )C(O)-OC 1-4 Alkyl-OP(O)(OR 9c 2. -C 1-4 Alkyl-C(O)N(R 9a )(R 9b ),-C 1-4 Alkyl-OC(O)-C 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-OC 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl-N(R 9a )(R 9b ),-C 1-4 Alkyl-OC(O)-C 1-4 Alkyl-OP(O)(OR 9c 2. -C 1-4 Alkyl-C 3-8 Cycloalkyl, -C 1-4 Alkyl-heterocyclyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, -CH2CH(N(R 9a )2)C(O)OR 9b 、-P(O)(OR 9c )2.-OP(O)(OR 9c )2、-CH2P(O)(OR 9c )2、-CH2OP(O)(OR 9c )2、-OCH2P(O)(OR 9c )2、-C(O)OCH2P(O)(OR 9c )2、-P(O)(R 9c )(OR 9d )、-OP(O)(R 9c )(OR 9d )、-CH2P(O)(R 9c )(OR 9d )、 -OCH2P(O)(R 9c )(OR 9d )、 -C(O)OCH2P(O)(R 9c )(OR 9d )、 -P(O)(N(R 9c )2)2、 -OP(O)(N(R 9c )2)2、 -CH2P(O)(N(R 9c )2)2、 -OCH2P(O)(N(R 9c )2)2、 -C(O)OCH2P(O)(N(R 9c )2)2、 -P(O)(N(R 9c )2)(OR 9d )、 -OP(O)(N(R 9c )2)(OR 9d )、 -CH2P(O)(N(R 9c )2)(OR 9d )、 -OCH2P(O)(N(R 9c )2)(OR 9d )、 -C(O)OCH2P(O)(N(R 9c )2)(OR 9d )、 -P(O)(R 9c )(N(R 9d )2)、 -OP(O)(R 9c )(N(R 9d )2)、 -CH2P(O)(R 9c )(N(R 9d )2)、 -OCH2P(O)(R 9c )(N(R 9d )2)、 -C(O)OCH2P(O)(R 9c )(N(R 9d )2) or C 1-6 alkyl - heterocyclic group; wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace, Each R 4 Independently for C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -NO2, -CN, -N3, -OR 4a 、-C(O)R 4a 、-C(O)OR 4a 、-C(O)N(R 4a )(R 4b )、-N(R 4a )(R 4b )、-N(R 4a )2(R 4b ) + 、-N(R 4a )-C(O)R 4b 、-N(R 4a )C(O)O(R 4b )、-N(R 4a )C(O)N(R 4b )(R 4c )、-N(R 4a )S(O)2(R 4b )、-N(R 4a )S(O)2-N(R 4b )(R 4c )、-N(R 4a )S(O)2O(R 4b )、-OC(O)R 4a 、-OC(O)OR 4a 、-OC(O)-N(R 4a )(R 4b ),-SR 4a 、-S(O)R 4a 、-S(O)(NH)R 4a 、-S(O)2R 4a 、-S(O)2N(R 4a )(R 4b )、-S(O)(NR 4a )R 4b or -Si(R 4a )3; wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace; or two R attached to adjacent ring atoms 4 The groups combine with the atoms to which they are attached to form C 5-10 Cycloalkyl or heterocyclic group, each of which is optionally substituted by one to four Z 1b replace; R 5a and R 5b Each independently is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkoxyalkyl, halogen, C 3-10 Cycloalkyl, heterocyclic, -C 1-6 Alkyl-N(R 9a )(R 9b )、-CN、-OR 5a1 or -N(R 5a1 )(R 5a2 ); or R 5a and R 5b Combine with the atoms to which they are attached to form C 3-10 Cycloalkyl or heterocyclic group, each of which is optionally substituted by one to four R 5a3 replace; Each R 5a1 and R 5a2 Independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclic, C 6-10 aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four R 5a4 replace; V is -C(O)-, -O-, -N(R 6a )-or-C(R 6b )(R 6c )-; R 6a H, C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclic, -S(O)2R 6a1 or -S(O)2N(R 6a1 )(NR 6a2 ), wherein the cycloalkyl or heterocyclyl is each optionally replaced by C 1-6 Alkyl, F or -CN substitution; Each R 6b and R 6c Independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkoxyalkyl, halogen, C 3-10 Cycloalkyl, heterocyclic, -C 1-6 Alkyl-N(R 9a )(R 9b )、-CN、-OR 6c1 or -N(R 6c2 )(R 6c3 ), wherein the alkyl, cycloalkyl or heterocyclyl groups are each optionally substituted by one to four R 6b1 replace; or R 6b and R 6c Combine with the atoms to which they are attached to form C 3-10 Cycloalkyl or heterocyclic group, each of which is optionally substituted by one to four R 6b1 replace; or R 6a or R 6c With an R 4 The groups and the atoms to which they are attached combine to form C 5-10 Cycloalkyl or heterocyclic group, each of which is optionally substituted by one to four R 10 replace; Y is -N(R 7 )-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NH)- or -S(O)(=NR 7 )-; Each R 1a , R 3d , R 5a3 , R 5a4 , R 6b1 and R 10 Independently for C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-10 Cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, CO2R 3e , -NO2 or -C(O)N(R 2a )(R 2b ), wherein the heterocyclic or heteroaryl is optionally replaced by C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 haloalkoxy substituted; and Each R 6a1 , R 6a2 , R 6c1 , R 6c2 , R 6c3 and R 7 Independently H, C 1-6 Alkyl or C 3-10 Cycloalkyl; Each R 8 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, CO2R 3e , -NO2, -NH2, -N3, -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(C 6-10 aryl), -NH(heteroaryl), -N(C 1-9 Alkyl)2, -N(C 1-8 Haloalkyl)2, -N(C 2-6 Alkenyl)2, -N(C 2-6 Alkynyl)2, -N(C 3-15 Cycloalkyl)2, -N(heterocyclyl)2, -N(C 6-10 Aryl)2, -N(heteroaryl)2, -N(C 1-9 Alkyl)(C 1-8 Haloalkyl), -N(C 1-9 Alkyl)(C 2-6 alkenyl), -N(C 1-9 Alkyl)(C 2-6 Alkynyl), -N(C 1-9 Alkyl)(C 3-15 Cycloalkyl), -N(C 1-9 alkyl)(heterocyclic), -N(C 1-9 Alkyl)(C 6-10 Aryl), -N(C 1-9 alkyl)(heteroaryl), -C(O)(C 1-9 alkyl), -C(O)(C 1-8 Haloalkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 Alkynyl), -C(O)(C 3-15 Cycloalkyl), -C(O)(heterocyclyl), -C(O)(C 6-10 aryl), -C(O)(heteroaryl), -C(O)O(C 1-9 alkyl), -C(O)O(C 1-8 haloalkyl), -C(O)O(C 2-6 alkenyl), -C(O)O(C 2-6 Alkynyl), -C(O)O(C 3-15 Cycloalkyl), -C(O)O(heterocyclyl), -C(O)O(C 6-10 aryl), -C(O)O(heteroaryl), -C(O)NH2, -C(O)NH(C 1-9 alkyl), -C(O)NH(C 1-8 haloalkyl), -C(O)NH(C 2-6 alkenyl), -C(O)NH(C 2-6 Alkynyl), -C(O)NH(C 3-15 Cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(C 6-10 aryl), -C(O)NH(heteroaryl), -C(O)N(C 1-9 Alkyl)2, -C(O)N(C 1-8 Haloalkyl)2, -C(O)N(C 2-6 Alkenyl)2, -C(O)N(C 2-6 Alkynyl)2, -C(O)N(C 3-15 Cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C 6-10 Aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C 1-9 Alkyl), -NHC(O)(C 1-8 Haloalkyl), -NHC(O)(C 2-6 -NHC(O)(C 2-6 Alkynyl), -NHC(O)(C 3-15 Cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6-10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 1-8 Haloalkyl), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C 2-6 Alkynyl), -NHC(O)O(C 3-15 Cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(C 6-10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -NHC(O)NH(C 1-8 haloalkyl), -NHC(O)NH(C 2-6 alkenyl), -NHC(O)NH(C 2-6 Alkynyl), -NHC(O)NH(C 3-15 Cycloalkyl), -NHC(O)NH(heterocyclyl), -NHC(O)NH(C 6-10 aryl), -NHC(O)NH(heteroaryl), -NHS(O)(C 1-9 Alkyl), -N(C 1-9 Alkyl)(S(O)(C 1-9 Alkyl), -S(C 1-9 Alkyl), -S(C 1-8 Haloalkyl), -S(C 2-6 -S(C 2-6 Alkynyl), -S(C 3-15 Cycloalkyl), -S(heterocyclyl), -S(C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2, -S(O)(C 1-9 Alkyl), -S(O)(C 1-8 Haloalkyl), -S(O)(C 2-6 -S(O)(C 2-6 Alkynyl), -S(O)(C 3-15 Cycloalkyl), -S(O)(heterocyclyl), -S(O)(C 6-10 aryl), -S(O)(heteroaryl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Haloalkyl), -S(O)2(C 2-6 -S(O)2(C 2-6 Alkynyl), -S(O)2(C 3-15 Cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(C 6-10 aryl), -S(O)2(heteroaryl), -S(O)(NH)(C 1-9 alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2; wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl radicals are optionally substituted by one to three C 1-9 Alkyl, C 1-8 Haloalkyl, halogen, -OH, -NH2, -CO2H, -O(C 1-9 Alkyl), -O(C 1-8 Haloalkyl), -O(C 3-15 Cycloalkyl), -O(heterocyclyl), -O(aryl), -O(heteroaryl), -NH(C 1-9 Alkyl), -NH(C 1-8 Haloalkyl), -NH(C 3-15 Cycloalkyl), -NH(heterocyclyl), -NH(aryl), -NH(heteroaryl), -N(C 1-9 Alkyl)2, -N(C 3-15 Cycloalkyl)2, -NHC(O)(C 1-8 Haloalkyl), -NHC(O)(C 3-15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 1-8 Haloalkyl), -NHC(O)O(C 2-6 Alkynyl), -NHC(O)O(C 3-15 Cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 Alkyl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Haloalkyl), -S(O)2(C 3-15 Cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)(NH)(C 1-9 alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2 substituted; Each R 9a and R 9b Independently H, C 1-6 Alkyl or C 1-6 A haloalkyl group, or R 9a and R 9b Together they form a 6-membered heterocyclic group; Each Z 1 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, -NO2, -N3, -CN, -OR 12a 、-C(O)-R 12a 、-C(O)OR 12a 、-C(O)-N(R 12a )(R 12b )、-N(R 12a )(R 12b )、-N(R 12a )2(R 12b ) + 、-N(R 12a )C(O)-R 12b 、-N(R 12a )C(O)OR 12b 、-N(R 12a )C(O)N(R 12b )(R 12c )、-N(R 12a )S(O)2(R 12b ),-NR 12a S(O)2N(R 12b )(R 12c ),-NR 12a S(O)2O(R 12b )、-OC(O)R 12a 、-OC(O)OR 12a 、-OC(O)-N(R 12a )(R 12b ),-SR 12a 、-S(O)R 12a 、-S(O)(NH)R 12a 、-S(O)2R 12a 、-S(O)2N(R 12a )(R 12b )、-S(O)(NR 12a )R 12b or -Si(R 12a )3; wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1a replace; Each Z 1a Independently 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, -NO2, -CN, -N3, -OR 12a 、-C(O)R 12a 、-C(O)OR 12a 、-C(O)N(R 12a )(R 12b )、-N(R 12a )(R 12b )、-N(R 12a )2(R 12b ) + 、-N(R 12a )-C(O)R 12b 、-N(R 12a )C(O)O(R 12b )、-N(R 12a )C(O)N(R 12b )(R 12c )、-N(R 12a )S(O)2(R 12b )、-N(R 12a )S(O)2-N(R 12b )(R 12c )、-N(R 12a )S(O)2O(R 12b )、-OC(O)R 12a 、-OC(O)OR 12a 、-OC(O)-N(R 12a )(R 12b ),-SR 12a 、-S(O)R 12a 、-S(O)(NH)R 12a 、-S(O)2R 12a 、-S(O)2N(R 12a )(R 12b )、-S(O)(NR 12a )R 12b or -Si(R 12a )3; wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace; Each 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, CO2R 3e , -NO2, -NH2, -N3, -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(C 6-10 aryl), -NH(heteroaryl), -N(C 1-9 Alkyl)2, -N(C 1-8 Haloalkyl)2, -N(C 2-6 Alkenyl)2, -N(C 2-6 Alkynyl)2, -N(C 3-15 Cycloalkyl)2, -N(heterocyclyl)2, -N(C 6-10 Aryl)2, -N(heteroaryl)2, -N(C 1-9 Alkyl)(C 1-8 Haloalkyl), -N(C 1-9 Alkyl)(C 2-6 alkenyl), -N(C 1-9 Alkyl)(C 2-6 Alkynyl), -N(C 1-9 Alkyl)(C 3-15 Cycloalkyl), -N(C 1-9 alkyl)(heterocyclic), -N(C 1-9 Alkyl)(C 6-10 Aryl), -N(C 1-9 alkyl)(heteroaryl), -C(O)(C 1-9 alkyl), -C(O)(C 1-8 Haloalkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 Alkynyl), -C(O)(C 3-15 Cycloalkyl), -C(O)(heterocyclyl), -C(O)(C 6-10 aryl), -C(O)(heteroaryl), -C(O)O(C 1-9 alkyl), -C(O)O(C 1-8 haloalkyl), -C(O)O(C 2-6 alkenyl), -C(O)O(C 2-6 Alkynyl), -C(O)O(C 3-15 Cycloalkyl), -C(O)O(heterocyclyl), -C(O)O(C 6-10 aryl), -C(O)O(heteroaryl), -C(O)NH2, -C(O)NH(C 1-9 alkyl), -C(O)NH(C 1-8 haloalkyl), -C(O)NH(C 2-6 alkenyl), -C(O)NH(C 2-6 Alkynyl), -C(O)NH(C 3-15 Cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(C 6-10 aryl), -C(O)NH(heteroaryl), -C(O)N(C 1-9 Alkyl)2, -C(O)N(C 1-8 Haloalkyl)2, -C(O)N(C 2-6 Alkenyl)2, -C(O)N(C 2-6 Alkynyl)2, -C(O)N(C 3-15 Cycloalkyl)2, -C(O)N(heterocyclyl)2, -C(O)N(C 6-10 Aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C 1-9 Alkyl), -NHC(O)(C 1-8 Haloalkyl), -NHC(O)(C 2-6 -NHC(O)(C 2-6 Alkynyl), -NHC(O)(C 3-15 Cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6-10 aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 1-8 Haloalkyl), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C 2-6 Alkynyl), -NHC(O)O(C 3-15 Cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(C 6-10 aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 alkyl), -NHC(O)NH(C 1-8 haloalkyl), -NHC(O)NH(C 2-6 alkenyl), -NHC(O)NH(C 2-6 Alkynyl), -NHC(O)NH(C 3-15 Cycloalkyl), -NHC(O)NH(heterocyclyl), -NHC(O)NH(C 6-10 aryl), -NHC(O)NH(heteroaryl), -NHS(O)(C 1-9 Alkyl), -N(C 1-9 Alkyl)(S(O)(C 1-9 Alkyl), -S(C 1-9 Alkyl), -S(C 1-8 Haloalkyl), -S(C 2-6 -S(C 2-6 Alkynyl), -S(C 3-15 Cycloalkyl), -S(heterocyclyl), -S(C 6-10 aryl), -S(heteroaryl), -S(O)N(C 1-9 Alkyl)2, -S(O)(C 1-9 Alkyl), -S(O)(C 1-8 Haloalkyl), -S(O)(C 2-6 -S(O)(C 2-6 Alkynyl), -S(O)(C 3-15 Cycloalkyl), -S(O)(heterocyclyl), -S(O)(C 6-10 aryl), -S(O)(heteroaryl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Haloalkyl), -S(O)2(C 2-6 -S(O)2(C 2-6 Alkynyl), -S(O)2(C 3-15 Cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(C 6-10 aryl), -S(O)2(heteroaryl), -S(O)(NH)(C 1-9 alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2; wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl radicals are optionally substituted by one to three C 1-9 Alkyl, C 1-8 Haloalkyl, halogen, -OH, -NH2, -CO2H, -O(C 1-9 Alkyl), -O(C 1-8 Haloalkyl), -O(C 3-15 Cycloalkyl), -O(heterocyclyl), -O(aryl), -O(heteroaryl), -NH(C 1-9 Alkyl), -NH(C 1-8 Haloalkyl), -NH(C 3-15 Cycloalkyl), -NH(heterocyclyl), -NH(aryl), -NH(heteroaryl), -N(C 1-9 Alkyl)2, -N(C 3-15 Cycloalkyl)2, -NHC(O)(C 1-8 Haloalkyl), -NHC(O)(C 3-15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 1-8 Haloalkyl), -NHC(O)O(C 2-6 Alkynyl), -NHC(O)O(C 3-15 Cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)NH(C 1-9 Alkyl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 1-8 Haloalkyl), -S(O)2(C 3-15 Cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)(NH)(C 1-9 alkyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2 substituted; Each R 1b , R 1c , R 2a , R 2b , R 4a , R 4b , R 4c , R 9c , R 9d , R 12a , R 12b and R 12c Independently H, C 1-9 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-15 Cycloalkyl, heterocyclic, C 6-10 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one to four Z 1b replace; and Each R 3e Independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-4 Alkyl-N(R 9a )(R 9b ),-C 1-4 Alkyl-C(O)N(R 9a )(R 9b ),-C 1-4 Alkyl-OC(O)-C 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-OC 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl-N(R 9a )(R 9b ),-C 1-4 Alkyl-C 3-8 Cycloalkyl, -C 1-4 Alkyl-heterocyclyl, C 3-10 Cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, -P(O)(OR 9c )2、-CH2P(O)(OR 9c )2、-OCH2P(O)(OR 9c )2、-C(O)OCH2P(O)(OR 9c )2、-P(O)(R 9c )(OR 9d )、-OP(O)(R 9c )(OR 9d )、-CH2P(O)(R 9c )(OR 9d )、-C(O)OCH2P(O)(R 9c )(OR 9d )、-P(O)(N(R 9c )2)2、-CH2P(O)(N(R 9c )2)2、-C(O)OCH2P(O)(N(R 9c )2)2、-P(O)(N(R 9c )2)(OR 9d )、-CH2P(O)(N(R 9c )2)(OR 9d )、-C(O)OCH2P(O)(N(R 9c )2)(OR 9d )、-P(O)(R 9c )(N(R 9d )2)、-CH2P(O)(R 9c )(N(R 9d )2) or -C(O)OCH2P(O)(R 9c )(N(R 9d ) 2); wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted by one to four Z 1b substituted; wherein each heteroaryl has 5 to 12 ring members and has one to four heteroatoms each independently being N, O or S; and wherein each heterocyclyl has 3 to 12 ring members and has one to four heteroatoms each independently being N, O or S.

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

3. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 1 is a heterocyclic group, C 6-10 aryl or 6-membered heteroaryl, each of which is optionally substituted by one to three Z 1 replace, Where Z 1 Independently for C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, oxo, -OH, -CN or -NO2, C 3-10 Cycloalkyl, 3- to 12-membered heterocyclyl having one to three heteroatoms, or 5- to 10-membered heteroaryl having one to three heteroatoms.

4. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 5a is H; and R 5b H, C 1-6 Alkyl, F, Cl, -OR 5a1 、-CN、C 3-10 Cycloalkyl or heterocyclic.

5. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 5a and R 5b Each is H.

6. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Y is -O-.

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

8. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring A is C 6-10 aryl or 5 to 10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one to three Z 1a replace, Each Z 1a Independently for C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-10 Cycloalkyl, heterocyclic, C 6-10 Aryl, heteroaryl, oxo, -OH, -CN, -NO2, -OR 12a 、-C(O)N(R 12a )(R 12b ), each of which is optionally replaced by Z 1b replace.

9. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl or 5- to 6-membered heteroaryl, wherein the phenyl or heteroaryl is optionally substituted by one to three Z 1a replace.

10. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring A is Each ring is optionally replaced by one or two Z 1a replace.

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