GLP-1R Modulating Compounds

Abstract

The present application describes GLP-IR modulating compounds useful for treating GLP-IR mediated diseases or conditions.

Description

[Technical field]

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 63 / 268,622, filed February 28, 2022, U.S. Provisional Application No. 63 / 366,565, filed June 17, 2022, and U.S. Patent Application No. 18 / 056,836, filed November 18, 2022, all of which are incorporated by reference in their entireties herein.

[0002] This application relates generally to compounds that bind to and act as agonists or modulators of the glucagon-like peptide-1 receptor (GLP-1R), and the use of such compounds for the treatment and / or prevention of GLP-1R mediated diseases and conditions. [Background technology]

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

[0004] GLP-1R agonists are currently being investigated in relation to diabetes, obesity, and NASH. GLP-1R agonists include peptides approved for the treatment of type 2 diabetes, such as exenatide, liraglutide, and dulaglutide. Such peptides are primarily administered by subcutaneous injection. Oral GLP-1 agonists are also under investigation for the treatment of type 2 diabetes. Some GLP-1R agonists, such as liraglutide, dulaglutide, and exenatide, are resistant to rapid degradation by dipeptidyl peptidase 4, resulting in a longer half-life than endogenous GLP-1.

[0005] There remains a need for compounds, such as agonists of GLP-1R, that have desirable therapeutic properties, metabolic properties, and / or are easy to administer in the treatment of GLP-1R mediated diseases and conditions. Summary of the Invention

[0006] One aspect of the present application is a compound of formula IA-1 [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered 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 1cwherein each of alkyl, haloalkyl, cycloalkyl, aryl, 5- to 10-membered heteroaryl, and heterocyclyl is selected from 1 to 4 Z 1 and any two Z 1 are bonded to the atom to which they are attached, 3-10 Cycloalkyl or heterocyclyl or C 6-10 can form an aryl or a 5- to 10-membered heteroaryl; Ring A contains 1 to 4 Z 1a C optionally substituted with 3-10 Cycloalkyl, heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; Ring B is each 1 to 4 R 4 C optionally substituted with 3-10 Cycloalkyl, heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; Ring A and ring B each contain 0 to 3 double bonds; R 2 , H, C 1-6 Alkyl, -C 1-6 Alkyl-alkoxy, -C 1-6 Alkyl-cycloalkoxy, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered 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 alkyl, alkoxy, cycloalkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl, in each occurrence, is selected from 1 to 4 Z 1and any two Z 1 are bonded to the atom to which they are attached, 3-10 Cycloalkyl or heterocyclyl or C 6-10 can form an aryl or a 5- to 10-membered heteroaryl; X is independently -N=, -C(H)=, or -C(R 8 )= Each R 3 and R 3’ are independent of each other, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered 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 alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl, at each occurrence, is selected from 1 to 4 R 3d optionally replaced by Each R 3a , R 3b , and R 3c are independently H, C 1-6 Alkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 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)-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, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, -CHCH(N(R 9a )2)C(O)OR 9b , -P(O)(OR 9c ) 2、 -OP(O)(OR 9c ) 2、 -CH2P(O)(OR 9c ) 2、 -CH2OP(O)(OR 9c ) 2、 -OCH2P(O)(OR 9c )2, -C(O)OCH2P(O)(OR 9c ) 2、 -P(O)(R 9c )(OR 9d ), -OP(O)(R 9c )(OR 9d ), -CH2P(O)(R 9c )(OR 9d ), -OCH2P(O)(R 9c )(OR 9d ), -C(O)OCH2P(O)(R 9c )(OR 9d ), -P(O)(N(R 9c )2)2, -OP(O)(N(R 9c )2) 2、 -CH2P(O)(N(R 9c )2) 2、 -OCH2P(O)(N(R 9c )2) 2、 -C(O)OCH2P(O)(N(R 9c )2)2, -P(O)(N(R 9c )2)(OR 9d ), -OP(O)(N(R 9c )2)(OR 9d ), -CH2P(O)(N(R 9c )2)(OR 9d ), -OCH2P(O)(N(R 9c )2)(OR 9d ), -C(O)OCH2P(O)(N(R 9c )2)(OR 9d ), -P(O)(R 9c )(N(R 9d)2), -OP(O)(R 9c )(N(R 9d )2), -CH2P(O)(R 9c )(N(R 9d )2), -OCH2P(O)(R 9c )(N(R 9d )2), -C(O)OCH2P(O)(R 9c )(N(R 9d )2) C 1-6 Alkyl-heterocyclyl, C 1-6 Alkyl-aryl, or C 1-6 alkyl-(5-10 membered)heteroaryl, where alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl is, in each occurrence, one to four Z 1b optionally replaced by Each R 4 are independently H, -OH, CH2OH, C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered 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, in which alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl is, in each occurrence, represented by 1 to 4 Z 1b or two R attached to adjacent ring atoms 4 The groups each have 1 to 4 Z 1b C optionally substituted with 5-10 forming a cycloalkyl or heterocyclyl, Each R 5a and R 5b are independently H, C 1-6 Alkyl, C 1-6 Alkyloxy, C 1-6 Haloalkyl, C 2-6 Alkoxyalkyl, halogen, C 3-10 Cycloalkyl, heterocyclyl, -C 1-6 Alkyl-N(R 9a )(R 9b ), -CN, -OR 5a1 , or -N(R 5a1 )(R 5a2 ) or R 5a and R 5b are bonded to the atom to which they are attached, and each has 1 to 4 R 5a3 C optionally substituted with 3-10 forming a cycloalkyl or heterocyclyl, Or, R 5a Or R 5b Each of the substituents on ring A is bonded to one to four R 5a3 C optionally substituted with 5-10 can form a cycloalkyl or heterocyclyl, Each R 5a1 and R 5a2 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, where cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl are each independently selected from 1 to 4 R 5a4 optionally replaced by V is -C(O)-, -O-, -N(R 6a )-, or -C(R 6b )(R 6c )-and R 6a , H, C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclyl, -S(O)R 6a1 , or -S(O)2N(R 6a1 )(R 6a2 ) in which cycloalkyl or heterocyclyl is, in each case, C 1-6 optionally substituted with alkyl, F, or -CN; Each R 6b and R 6c are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkoxyalkyl, halogen, C 3-10 Cycloalkyl, heterocyclyl, -C 1-6 Alkyl-N(R 9a )(R 9b ), -CN, -OR 6c1 , or -N(R 6c2 )(R 6c3wherein alkyl, cycloalkyl, or heterocyclyl, in each occurrence, is selected from 1 to 4 R 6b1 or R 6b and R 6c are bonded to the atom to which they are attached, and each has 1 to 4 R 6b1 C optionally substituted with 3-10 forming a cycloalkyl or heterocyclyl, or R 6b Or R 6c is one R 4 1 to 4 R 10 C optionally substituted with 5-10 forming a cycloalkyl or heterocyclyl, Y is -N(R 7 )-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NH)-, or -S(O)(=NR 7 )-and Each R 3d , R 5a3 , R 5a4 , R 6b1 , and R 10 are independent of each other, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, oxo, -OH, -CN, COR 3e , -NO2, or -C(O)N(R 2a )(R 2b ), wherein heterocyclyl or 5- to 10-membered heteroaryl is, in each case, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with haloalkoxy; Each R 6a1 , R 6a2 , R6c1 , R 6c2 , R 6c3 , and R 7 are independently H, C 1-6 Alkyl or C 3-10 is cycloalkyl, Each R 8 is independently 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, oxo, -OH, -CN, COR 3e , -NO2, -NH2, -N3, -SH, -O(C 1-9 alkyl), -O(C 1-8 haloalkyl), -NH(C 1-9 alkyl), -NH(C 1-8 haloalkyl), -N(C 1-9 Alkyl)2, -N(C 1-8 haloalkyl)2, Each R 9a and R 9b are independent of each other, H, C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered 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(R12b )(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, or R 9a and R 9b Both are C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 Aryl, heteroaryl, oxo, -NO2, -CN, -N 3、 -OR 12a , -C(O)R 12a , -C(O)OR 12a , -C(O)N(R 12a )(R 12b ), -N(R 12a )(R 12b ), -N(R 12a )2(R 12b ) + , -N(R 12a )-C(O)R 12b , -N(R 12a )C(O)O(R 12b ), -N(R 12a )C(O)N(R12b )(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 ) forming an optionally substituted 3- to 10-membered heterocyclyl with 3; each Z 1 is independent, C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered 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(R12a )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, in which alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl is, in each occurrence, selected from 1 to 4 Z 1a optionally replaced by each Z 1a are independent of each other, H, C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered 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 alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl is, in each occurrence, selected from 1 to 4 Z 1b optionally replaced by each Z 1b are independent of each other, H, C 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, oxo, -OH, -CN, COR 3e , -NO2, -NH2, -N3, -SH, -O(C 1-9 alkyl), -O(C 1-8 haloalkyl), -O(C 2-6 alkenyl), -O(C 2-6 alkynyl), -O(C 3-15Cycloalkyl), -O(heterocyclyl), -O(C 6-10 aryl), -O(5-10 membered heteroaryl), -NH(C 1-9 alkyl), -NH(C 1-8 haloalkyl), -NH(C 2-6 alkenyl), -NH(C 2-6 alkynyl), -NH(C 3-15 Cycloalkyl), -NH(heterocyclyl), -NH(C 6-10 aryl), -NH(5-10 membered heteroaryl), -N(cyclo-alkyl), -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(5-10 membered heteroaryl)2, -N(C 1-9 Alkyl)(C 1-8 haloalkyl), -N(C 1-9 Alkyl)(C 2-6 alkenyl), -N(C 1-9 Alkyl)(C 2-6 alkynyl), -N(C 1-9 Alkyl)(C 3-15 Cycloalkyl), -N(C 1-9 alkyl)(heterocyclyl), -N(C 1-9 Alkyl)(C 6-10 Aryl), -N(C 1-9 alkyl)(5-10 membered 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)(5-10 membered heteroaryl), -C(O)O(C 1-9 alkyl), -C(O)O(C 1-8 haloalkyl), -C(O)O(C2-6 alkenyl), -C(O)O(C 2-6 alkynyl), -C(O)O(C 3-15 Cycloalkyl), -C(O)O(heterocyclyl), -C(O)O(C 6-10 aryl), -C(O)O(5-10 membered 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(5-10 membered 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(5-10 membered heteroaryl)2, -NHC(O)(C 1-9 alkyl), -NHC(O)(C 1-8 haloalkyl), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 alkynyl), -NHC(O)(C 3-15 Cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6-10 aryl), -NHC(O)(5-10 membered 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 6-10aryl), -NHC(O)O(5-10 membered 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(5-10 membered heteroaryl), -NHS(O)(C 1-9 alkyl), -N(C 1-9 Alkyl)(S(O)(C 1-9 alkyl), -S(C 1-9 alkyl), -S(C 1-8 haloalkyl), -S(C 2-6 alkenyl), -S(C 2-6 alkynyl), -S(C 3-15 Cycloalkyl), -S(heterocyclyl), -S(C 6-10 aryl), -S(5-10 membered heteroaryl), -S(O)N(C 1-9 alkyl)2, -S(O)(C 1-9 alkyl), -S(O)(C 1-8 haloalkyl), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 alkynyl), -S(O)(C 3-15 Cycloalkyl), -S(O)(heterocyclyl), -S(O)(C 6-10 aryl), -S(O)(5-10 membered heteroaryl), -S(O)2(C 1-9 alkyl), -S(O)2(C 1-8 haloalkyl), -S(O)2(C 2-6 alkenyl), -S(O)2(C 2-6 alkynyl), -S(O)2(C 3-15 Cycloalkyl), -S(O)2(Heterocyclyl), -S(O)2(C 6-10 aryl), -S(O)2(5-10 membered heteroaryl), -S(O)(NH)(C 1-9 alkyl), -S(O)2NH(C 1-9alkyl), or -S(O)2N(C 1-9 alkyl)2, where alkyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl is, in each case, 1 to 3 C 1-9 Alkyl, C 1-8 Haloalkyl, halogen, -OH, -NH2, CO2H, -O(C 1-9 alkyl), -O(C 1-8 haloalkyl), -O(C 3-15 Cycloalkyl), -O(heterocyclyl), -O(aryl), -O(5-10 membered heteroaryl), -NH(C 1-9 alkyl), -NH(C 1-8 haloalkyl), -NH(C 3-15 Cycloalkyl), -NH(heterocyclyl), -NH(aryl), -NH(5-10 membered 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)(5-10 membered 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(5-10 membered 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(5-10 membered heteroaryl), -S(O)(NH)(C 1-9 alkyl), -S(O)2NH(C 1-9 alkyl), or -S(O)2N(C 1-9 Optionally substituted with alkyl)2; Each R 1b , R 1c , R 2a , R 2b , R 4a , R 4b , R 4c , R 9c , R 9d , R 12a , R 12b , and R 12c are independently H, -OH, C 1-9 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, each of which is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and 5-10 membered heteroaryl, each of which is selected from the group consisting of 1-4 Z 1b optionally replaced by Each R 3e are independent of each other, 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)-OC 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl-N(R 9a )(R 9b ), -C 1-4 Alkyl-C 3-8 Cycloalkyl, -C 1-4 Alkyl-heterocyclyl, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered 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)(R9c )(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) in which alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl is, in each occurrence, represented by 1 to 4 Z 1b each 5-10 membered heteroaryl has 5-12 ring members and 1-4 heteroatoms which are each independently N, O, or S; and each heterocyclyl has 3-12 ring members and 1-4 heteroatoms which are each independently N, O, or S.

[0007] Another aspect of the present application relates to methods of treating a GLP-1R mediated disease or condition using the compounds of the present application.

[0008] Another aspect of the present application relates to methods of making the compounds of the present application. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] I. Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. A dash at the beginning or end of a chemical group is for convenience to indicate the point of attachment to the parent moiety, and a chemical group may be represented with or without one or more dashes without loss of ordinary meaning. u-v " or "C u -C v " indicates that the following group has u to v carbon atoms, where u and v are integers. For example, "C 1-6 "Alkyl" or "C1-C6 alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms.

[0010] "Alkyl" refers to a monovalent or divalent linear or branched saturated hydrocarbon group. For example, an alkyl group can be any group having 1 to 10 carbon atoms (i.e., C 1-10 alkyl) or 1 to 8 carbon atoms (i.e., C 1-8 alkyl) or 1 to 6 carbon atoms (i.e., C 1-6 alkyl) or 1 to 4 carbon atoms (i.e., C 1-4Examples of alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3). , 2-Methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl 1-butyl-2-methyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3) Examples of alkyl groups include, but are not limited to, 3-methyl-3-pentyl (-C(CH)(CHCH)), 2-methyl-3-pentyl (-CH(CHCH)CH(CH)), 2,3-dimethyl-2-butyl (-C(CH)CH(CH)), 3,3-dimethyl-2-butyl (-CH(CH)C(CH), and octyl (-(CH)CH). Alkyl groups can be unsubstituted or substituted.

[0011] "Alkoxy" refers to an -O-alkyl group, where alkyl is as defined above. For example, C 1-4 Alkoxy refers to an -O-alkyl group having 1 to 4 carbons. The alkoxy group can be unsubstituted or substituted.

[0012] An "alkoxyalkyl" is an alkoxy group attached to an alkyl, as defined above, such that the alkyl is divalent. For example, C 2-6 Alkoxyalkyl includes -CH2-OMe, -CH2-O-iPr, -CH2-CH2-OMe, -CH2-CH2-O-CH2-CH3, and -CH2-CH2-O-tBu. Alkoxyalkyl groups can be unsubstituted or substituted.

[0013] "Alkenyl" refers to a monovalent or divalent linear or branched hydrocarbon group having at least one carbon-carbon double bond. For example, an alkenyl group can be an alkyl group having 2 to 8 carbon atoms (i.e., C 2-8 alkenyl) or 2 to 6 carbon atoms (i.e., C 2-6 alkenyl) or 2 to 4 carbon atoms (i.e., C 2-4 Examples of alkenyl groups include, but are not limited to, ethenyl (-CH=CH2), allyl (-CH2CH=CH2), and -CH2-CH=CH-CH3. Alkenyl groups can be unsubstituted or substituted.

[0014] "Alkynyl" refers to a monovalent or divalent linear or branched hydrocarbon group having at least one carbon-carbon triple bond. For example, an alkynyl group can be an alkynyl group having 2 to 8 carbon atoms (i.e., C 2-8 alkynyl) or 2 to 6 carbon atoms (i.e., C 2-6 alkynyl) or 2 to 4 carbon atoms (i.e., C 2-4 Examples of alkynyl groups include, but are not limited to, acetylenyl (-C≡CH), propargyl (-CH2C≡CH), and -CH2-C≡C-CH3. Alkynyl groups can be unsubstituted or substituted.

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

[0016] "Haloalkyl" means an alkyl, as defined herein, where one or more hydrogen atoms of the alkyl are independently replaced by a halogen, which may be the same or different, such that the alkyl is divalent. The alkyl group and halogen may be any of those described above. In some embodiments, the haloalkyl defines the number of carbon atoms in the alkyl portion, e.g., C 1-4 Haloalkyl includes CF3, CH2F, CHF2, CH2CF3, CH2CH2CF3, CCl2CH2CH2CH3, and C(CH3)2(CF2H). Haloalkyl groups can be unsubstituted or substituted.

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

[0018] "Cycloalkyl" refers to a monovalent or divalent single all-carbocyclic ring or multiple condensed all-carbocyclic ring system, where the rings are, in each case, non-aromatic, saturated or unsaturated rings. For example, in some embodiments, the cycloalkyl group has 3 to 12 carbon atoms, 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, 3 to 5 carbon atoms, or 3 to 4 carbon atoms. Exemplary single-ring cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. Cycloalkyl also includes multiple condensed ring systems (e.g., ring systems containing two rings) having about 7 to 12 carbon atoms. The rings of multiple condensed ring systems can be connected to each other through fused, spiro, or bridged bonds, if permitted by valence requirements. Exemplary polycyclic cycloalkyl groups include octahydropentalene, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[2.2.2]oct-2-ene, and spiro[2.5]octane. Cycloalkyl groups can be unsubstituted or substituted.

[0019] "Alkylcycloalkyl" refers to an alkyl, as defined herein, where one or more hydrogen atoms of the alkyl are independently replaced by a cycloalkyl group, which may be the same or different. The alkyl and cycloalkyl groups 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 (e.g., C 1-6 Alkyl-C 3-12 Cycloalkyl). An alkylcycloalkyl group can be unsubstituted or substituted.

[0020] As used herein, "aryl" refers to a monovalent or divalent single all-carbon aromatic ring or multiple condensed all-carbon ring system, where the rings are aromatic. For example, in some embodiments, an aryl group has 6-20 carbon atoms, 6-14 carbon atoms, 6-12 carbon atoms, or 6-10 carbon atoms. Aryl includes phenyl groups. Aryl also includes multiple condensed ring systems (e.g., ring systems containing 2, 3, or 4 rings) having about 9-20 carbon atoms, where multiple rings are aromatic. The rings of a multiple condensed ring system can be bonded to each other through fused bonds, if permitted by valence requirements. It is also understood that when referring to a particular atom range of membered aryl (e.g., 6-10 membered aryl), the atom range is for all ring atoms of the aryl. For example, 6 membered aryl includes phenyl, and 10 membered aryl includes naphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like. Aryl groups can be unsubstituted or substituted.

[0021] "Alkylaryl" refers to an alkyl, as defined herein, where one or more hydrogen atoms of the alkyl are independently replaced by an aryl group, which may be the same or different. The alkyl and aryl groups may be any of those described above, such that the alkyl is divalent. In some embodiments, the alkylaryl group has 7-24 carbon atoms, 7-16 carbon atoms, 7-13 carbon atoms, or 7-11 carbon atoms. An alkylaryl group defined by the number of carbon atoms refers to the total number of carbon atoms present in the combination of the constituent alkyl and aryl groups. For example, C7 alkylaryl refers to benzyl, C 11 Alkylaryl includes 1-methylnaphthyl and n-pentylphenyl. In some embodiments, the number of carbon atoms in the alkyl and aryl moieties can be specified separately (e.g., C 1-6 Alkyl-C 6-10aryl). Non-limiting examples of alkylaryl groups include, but are not limited to, benzyl, 2,2-dimethylphenyl, n-pentylphenyl, 1-methylnaphthyl, 2-ethylnaphthyl, and the like. Alkylaryl groups can be unsubstituted or substituted.

[0022] As used herein, "heterocyclyl" or "heterocycle" or "heterocycloalkyl" refers to a single saturated or partially unsaturated non-aromatic ring or non-aromatic multiple ring system having at least one heteroatom in the ring (i.e., at least one cyclic (i.e., ring-shaped) heteroatom selected from oxygen, nitrogen, and sulfur). Unless otherwise specified, a heterocyclyl group has 3 to about 20 ring atoms, e.g., 3 to 12 ring atoms, e.g., 4 to 12 ring atoms, 4 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 3 to 5 ring atoms, or 4 to 6 ring atoms, or 4 to 5 ring atoms. Thus, the term includes a single saturated or partially unsaturated ring (e.g., a 3-, 4-, 5-, 6-, or 7-membered ring) having about 1 to 6 cyclic carbon atoms and about 1 to 3 cyclic heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. The rings of a multiple condensed ring (e.g., bicyclic heterocyclyl) system can be connected to each other through condensed bonds, spiro bonds, and bridge bonds, if permitted by valence requirements. Heterocycles include azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, thietane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, and the like. , 2-thia-6-azaspiro[3.3]heptan-6-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2-azabicyclo[3.1.0]hexan-2-yl, 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[2.1.1]hexanyl, 2-azabicyclo[2.2.1]heptan-2-yl, 4-azaspiro[2.4]heptanyl, 5-azaspiro[2.4]heptanyl, etc. Heterocyclyl groups can be unsubstituted or substituted.

[0023] "Alkylheterocyclyl" refers to an alkyl, as defined herein, where one or more hydrogen atoms of the alkyl are independently replaced by a heterocyclyl group, which may be the same or different. The alkyl and heterocyclyl groups may be any of those described above, such that the alkyl is divalent. In some embodiments, the number of atoms in the alkyl and heterocyclyl moieties may be specified separately (e.g., C 11 having 1-3 heteroatoms, each independently being N, O, or S). 1-6 Alkyl-3 to 12 membered heterocyclyl). The alkylheterocyclyl group may be unsubstituted or substituted.

[0024] "5-10 membered heteroaryl" refers to a single aromatic ring having at least one atom other than carbon in the ring, where the atom is selected from the group consisting of oxygen, nitrogen, and sulfur. "5-10 membered heteroaryl" also includes multiple condensed ring systems having at least one such aromatic ring, which are further described below. Thus, "5-10 membered heteroaryl" includes a single aromatic ring of about 1-6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The sulfur and nitrogen atoms may also be present in oxidized form, provided the ring is aromatic. Exemplary 5-10 membered heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. "5-10 membered heteroaryl" also includes multiple condensed ring systems (e.g., ring systems containing 2, 3, or 4 rings), where the 5-10 membered heteroaryl group defined above is fused with one or more rings selected from 5-10 membered heteroaryl (e.g., to form 1,8-naphthyridinyl) and aryl (e.g., to form benzimidazolyl or indazolyl) to form the multiple condensed ring system. Thus, a 5-10 membered heteroaryl (single aromatic ring or multiple condensed ring system) can have about 1-20 carbon atoms and about 1-6 heteroatoms in the 5-10 membered heteroaryl ring. For example, tetrazolyl has 1 carbon atom and 4 nitrogen heteroatoms in the ring. The rings of the multiple condensed ring system can be bonded to each other via fused bonds if permitted by valence requirements. It is understood that the individual rings of the multiple condensed ring system can be bonded to each other in any order. It is understood that the point of attachment of a 5-10 membered heteroaryl or 5-10 membered heteroaryl multiple condensed ring system can be at any suitable atom of the 5-10 membered heteroaryl or 5-10 membered heteroaryl multiple condensed ring system, including carbon atoms and heteroatoms (e.g., nitrogen). It is also understood that when referring to a particular range of atoms (e.g., a 5-10 membered heteroaryl), the range of atoms is for all ring atoms of the 5-10 membered heteroaryl, including carbon atoms and heteroatoms.It is also understood that rings of multiple condensed ring systems can include aryl rings fused to saturated or partially unsaturated heterocycles (e.g., 3-, 4-, 5-, 6-, or 7-membered rings) having about 1-6 annular carbon atoms and about 1-3 annular heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. For example, 5-10 membered heteroaryls include thiazolyl, and 5-10 membered heteroaryls include quinolinyl. Exemplary 5-10 membered heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, and tetrazolyl. The 5-10 membered heteroaryl groups may be unsubstituted or substituted.

[0025] "Alkylheteroaryl" refers to an alkyl, as defined herein, where one or more hydrogen atoms of the alkyl are independently replaced by a heteroaryl group, which can be the same or different, such that the alkyl is divalent. The alkyl and heteroaryl groups can be any of those described above. In some embodiments, the number of atoms in the alkyl and heteroaryl moieties are specified separately (e.g., C 11 having 1-4 heteroatoms, each independently being N, O, or S). 1-6 Alkyl-5 to 10 membered heteroaryl). The alkylheteroaryl group may be unsubstituted or substituted.

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

[0027] As used herein, "substituted" refers to one or more hydrogen atoms of a group being independently replaced with one or more substituents (eg, 1, 2, 3, or more), as indicated.

[0028] "Compounds of the present application" include compounds disclosed herein, for example, compounds of the present application include compounds of formula IA-1, including compounds of the Examples. In some embodiments, "compounds of the present application" include compounds of formula IA-1.

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

[0030] As used herein, a "therapeutically effective amount" or "effective amount" refers to an amount effective to induce a desired biological or medical response when administered to a subject to treat a disease, including an amount of a compound sufficient to affect such treatment of the disease. The effective amount will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated. An effective amount may include a variety of amounts. As is understood in the art, an effective amount may be one or more doses, i.e., a single dose or multiple doses may be required to achieve a desired therapeutic endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount when a desired or beneficial result can be or is achieved in combination with one or more other agents. The appropriate dosage of any co-administered compound may be reduced as necessary due to the combined effects (e.g., additive or synergistic effects) of the compounds.

[0031] As used herein, "co-administration" refers to administering a unit dose of a compound disclosed herein before or after administering a unit dose of one or more additional therapeutic agents, e.g., administering a compound disclosed herein within seconds, minutes, or hours of administering one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound of the present application is administered first, followed within seconds or minutes by a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed within seconds or minutes by a unit dose of a compound of the present application. In some embodiments, a unit dose of a compound of the present application is administered first, followed hours (e.g., 1-12 hours) later by a unit dose of one or more additional therapeutic agents. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed within hours (e.g., 1-12 hours) later by a unit dose of a compound of the present application. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents such that a therapeutically effective amount of each agent is present in the subject's body.

[0032] Pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein are also provided.

[0033] "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms and other substances useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0034] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts, or as free bases, if appropriate.Pharmaceutically acceptable salts are non-toxic salts of the free base form of compounds that have the desired pharmacological activity of the free base.These salts can be derived from inorganic or organic acids or bases.For example, compounds that contain basic nitrogen can be prepared as pharmaceutically acceptable salts by contacting the compounds with inorganic or organic acids. Non-limiting examples of pharma- ceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexaphosphate ... Examples of suitable pharmaceutically acceptable salts include syn-1,6-dioate, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott William and Wilkins, Philadelphia, Pa., 2006.

[0035] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include alkali metal (e.g., sodium, potassium), alkaline earth metal (e.g., magnesium), ammonium, and N(C1-C4 alkyl)4 salts. +Also included are salts derived from appropriate bases such as , and base addition salts such as sodium or potassium salts.

[0036] Also provided are compounds described herein, or pharma- ceutically acceptable salts, isomers, or mixtures thereof, in which 1 to n hydrogen atoms bonded to a carbon atom may be replaced by deuterium atoms or D, where n is the number of hydrogen atoms in the molecule. As known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such compounds may increase resistance to metabolism and thus may be useful in increasing the half-life of the compounds described herein, or their pharma- ceutically acceptable salts, isomers, or mixtures, when administered to a mammal. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol.Sci., 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0037] Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, e.g., 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 can also be mentioned. 11 C. 18 F, 15 O, and 13Substitution with positron emitting isotopes such as N can be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of formula IA-1 can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the examples below, substituting the appropriate isotopically labeled reagent for the non-labeled reagent previously used.

[0038] The compounds of the embodiments disclosed herein, or their pharma- ceutically acceptable salts, may contain one or more asymmetric centers and therefore may give rise to enantiomers, tautomers, diastereomers, and other stereoisomeric forms that may be defined in terms of absolute stereochemistry as (R)- or (S)- for amino acids, or as (D)- or (L)-, as well as deuterated analogs thereof. The chemical formulae depicted in this application are 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 / isolating individual enantiomers include chiral synthesis from appropriate optically pure precursors, or resolution of the racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are intended to be included. When compounds are represented in their chiral form, it is understood that the embodiments encompass, but are not limited to, the specific diastereomerically or enantiomerically enriched forms. When no chirality is specified, it is understood that the embodiments are directed to either the specific diastereomerically or enantiomerically enriched forms, or racemic or scalemic mixtures of such compound(s). As used herein, a "scalemic mixture" is a mixture of stereoisomers in a ratio other than 1:1.

[0039] As used herein, "stereoisomers" refer to compounds composed of the same atoms linked by the same bonds, but with different, incompatible three-dimensional structures. The present application contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0040] As used herein, "tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. In some embodiments, the present application includes tautomers of the above compounds.

[0041] As used herein, "solvate" refers to the result of the interaction of a solvent and a compound. Solvates of the salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0042] As used herein, "hydrate" refers to a compound of the present disclosure that is chemically associated with one or more water molecules.

[0043] "Prevention" or "preventing" refers to any treatment of a disease or condition that does not result in the development of clinical symptoms of the disease or condition. The compounds, in some embodiments, can be administered to subjects (including humans) at risk for or who have a family history of the disease or condition.

[0044] As used herein, a "prodrug" refers to a derivative of a drug that, when administered to the human body, is converted to the parent drug by some chemical or enzymatic pathway. In some embodiments, a prodrug is a biologically inactive derivative of a drug that, when administered to the human body, is converted to the biologically active parent drug by some chemical or enzymatic pathway.

[0045] As used herein, "treatment" or "treat" or "treating" refers to an approach to obtain a beneficial or desired result. For purposes of this application, beneficial or desired results include, but are not limited to, alleviating symptoms and / or reducing the severity of symptoms and / or preventing the worsening of symptoms associated with a disease or condition. In one embodiment, "treatment" or "treating" includes one or more of: a) inhibiting a disease or condition (e.g., reducing one or more symptoms caused by a disease or condition and / or reducing the severity of the disease or condition); b) delaying or preventing the onset of one or more symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, slowing the worsening or progression of a disease or condition); and c) relieving a disease or condition (e.g., causing regression of clinical symptoms, ameliorating disease condition, slowing progression of a disease, improving quality of life, and / or prolonging survival). As used herein, "at risk individual" refers to an individual at risk of developing the condition being treated. An "at risk" individual may or may not have detectable disease or illness, and may or may not show detectable disease before treatment according to the methods described herein. "At risk" means that an individual has one or more so-called risk factors, which are measurable parameters that correlate with the development of a disease or illness, and are known in the art. Individuals who have one or more of these risk factors are more likely to develop a disease or illness than individuals who do not have these risk factor(s).

[0046] II. Compounds One aspect of the present application relates to compounds that bind to GLP-1R and act as agonists or modulators thereof. In some embodiments, the present application relates to compounds of formula IA-1 [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is C 1-6 Alkyl, C1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered 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 each of alkyl, haloalkyl, cycloalkyl, aryl, 5- to 10-membered heteroaryl, and heterocyclyl is selected from 1 to 4 Z 1 and any two Z 1 are bonded to the atom to which they are attached, 3-10 Cycloalkyl or heterocyclyl or C 6-10 can form an aryl or a 5- to 10-membered heteroaryl; Ring A contains 1 to 4 Z 1a C optionally substituted with 3-10 Cycloalkyl, heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; Ring B is each 1 to 4 R 4 C optionally substituted with 3-10 Cycloalkyl, heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; Ring A and ring B each contain 0 to 3 double bonds; R 2 , H, C 1-6 Alkyl, -C 1-6 Alkyl-alkoxy, -C 1-6 Alkyl-cycloalkoxy, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered 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 each of the alkyl, alkoxy, cycloalkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl, and 5- to 10-membered heteroaryl is selected from 1 to 4 Z 1 and any two Z 1 are bonded to the atom to which they are attached, 3-10 Cycloalkyl or heterocyclyl or C 6-10 can form an aryl or a 5- to 10-membered heteroaryl; X is independently -N=, -C(H)=, or -C(R 8 )= Each R 3 and R 3’ are independent of each other, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered 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)2R3a , -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 alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl, at each occurrence, is selected from 1 to 4 R 3d optionally replaced by Each R 3a , R 3b , and R 3c are independently H, C 1-6 Alkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 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 1-4Alkyl-OP(O)(OR 9c )2, -C 1-4 Alkyl-C(O)N(R 9a )(R 9b ), -C 1-4 Alkyl-OC(O)-OC 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl-N(R 9a )(R 9b ), -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl-OP(O)(OR 9c )2, -C 1-4 Alkyl-C 3-8 Cycloalkyl, -C 1-4 Alkyl-heterocyclyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, -CHCH(N(R 9a )2)C(O)OR 9b , -P(O)(OR 9c ) 2、 -OP(O)(OR 9c ) 2、 -CH2P(O)(OR 9c ) 2、 -CH2OP(O)(OR 9c ) 2、 -OCH2P(O)(OR 9c )2, -C(O)OCH2P(O)(OR 9c ) 2、 -P(O)(R 9c )(OR 9d ), -OP(O)(R 9c )(OR 9d ), -CH2P(O)(R 9c )(OR 9d ), -OCH2P(O)(R 9c )(OR 9d ), -C(O)OCH2P(O)(R 9c )(OR 9d ), -P(O)(N(R 9c )2)2, -OP(O)(N(R 9c )2) 2、 -CH2P(O)(N(R 9c )2)2、 -OCH2P(O)(N(R 9c )2) 2、 -C(O)OCH2P(O)(N(R 9c )2)2, -P(O)(N(R 9c )2)(OR 9d ), -OP(O)(N(R 9c )2)(OR 9d ), -CH2P(O)(N(R 9c )2)(OR 9d ), -OCH2P(O)(N(R 9c )2)(OR 9d ), -C(O)OCH2P(O)(N(R 9c )2)(OR 9d ), -P(O)(R 9c )(N(R 9d )2), -OP(O)(R 9c )(N(R 9d )2), -CH2P(O)(R 9c )(N(R 9d )2), -OCH2P(O)(R 9c )(N(R 9d )2), -C(O)OCH2P(O)(R 9c )(N(R 9d )2) C 1-6 Alkyl-heterocyclyl, C 1-6 Alkyl-aryl, or C 1-6 alkyl-(5-10 membered)heteroaryl, where alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl is, in each occurrence, one to four Z 1b optionally replaced by Each R 4 are independently H, -OH, CH2OH, C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered 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, in which alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl is, in each occurrence, represented by 1 to 4 Z 1b or two R attached to adjacent ring atoms 4 The groups each have 1 to 4 Z 1b C optionally substituted with 5-10 forming a cycloalkyl or heterocyclyl, Each R 5a and R 5b are independently H, C1-6 Alkyl, C 1-6 Alkyloxy, C 1-6 Haloalkyl, C 2-6 Alkoxyalkyl, halogen, C 3-10 Cycloalkyl, heterocyclyl, -C 1-6 Alkyl-N(R 9a )(R 9b ), -CN, -OR 5a1 , or -N(R 5a1 )(R 5a2 ) or R 5a and R 5b are bonded to the atom to which they are attached, and each has 1 to 4 R 5a3 C optionally substituted with 3-10 forming a cycloalkyl or heterocyclyl, or R 5a Or R 5b Each of the substituents on ring A is bonded to one to four R 5a3 C optionally substituted with 5-10 can form a cycloalkyl or heterocyclyl, Each R 5a1 and R 5a2 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, where cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl each have 1 to 4 R 5a4 optionally replaced by V is -C(O)-, -O-, -N(R 6a )-, or -C(R 6b )(R 6c )-and R 6a , H, C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclyl, -S(O)R 6a1 , or -S(O)2N(R 6a1 )(R 6a2) in which cycloalkyl or heterocyclyl is, in each case, C 1-6 optionally substituted with alkyl, F, or -CN; Each R 6b and R 6c are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkoxyalkyl, halogen, C 3-10 Cycloalkyl, heterocyclyl, -C 1-6 Alkyl-N(R 9a )(R 9b ), -CN, -OR 6c1 , or -N(R 6c2 )(R 6c3 wherein alkyl, cycloalkyl, or heterocyclyl, in each occurrence, is selected from 1 to 4 R 6b1 or R 6b and R 6c are bonded to the atom to which they are attached, and each has 1 to 4 R 6b1 C optionally substituted with 3-10 forming a cycloalkyl or heterocyclyl, or R 6b Or R 6c is one R 4 Each of the R groups and the atoms to which they are attached has 1 to 4 R 10 C optionally substituted with 5-10 forming a cycloalkyl or heterocyclyl, Y is -N(R 7 )-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NH)-, or -S(O)(=NR 7 )-and Each R 3d , R 5a3 , R 5a4 , R 6b1 , and R 10 are independent of each other, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6Alkenyl, C 2-6 Alkynyl, halogen, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, oxo, -OH, -CN, COR 3e , -NO2, or -C(O)N(R 2a )(R 2b ), wherein heterocyclyl or 5- to 10-membered heteroaryl is, in each case, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with haloalkoxy; Each R 6a1 , R 6a2 , R 6c1 , R 6c2 , R 6c3 , and R 7 are independently H, C 1-6 Alkyl or C 3-10 is cycloalkyl, Each R 8 is independently 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, oxo, -OH, -CN, COR 3e , -NO2, -NH2, -N3, -SH, -O(C 1-9 alkyl), -O(C 1-8 haloalkyl), -NH(C 1-9 alkyl), -NH(C 1-8 haloalkyl), -N(C 1-9 Alkyl)2, -N(C 1-8 haloalkyl)2, Each R 9a and R 9b are independent of each other, H, C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclyl, C6-10 Aryl, 5-10 membered 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, or R 9a and R 9b Both are C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclyl, C6-10 Aryl, 5-10 membered heteroaryl, oxo, -NO2, -CN, -N 3、 -OR 12a , -C(O)R 12a , -C(O)OR 12a , -C(O)N(R 12a )(R 12b ), -N(R 12a )(R 12b ), -N(R 12a )2(R 12b ) + , -N(R 12a )-C(O)R 12b , -N(R 12a )C(O)O(R 12b ), -N(R 12a )C(O)N(R 12b )(R 12c ), -N(R 12a )S(O)2(R 12b ), -N(R 12a )S(O)2-N(R 12b )(R 12c ), -N(R 12a )S(O)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 ) forming an optionally substituted 3- to 10-membered heterocyclyl with 3; each Z 1 is independent, C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C3-15 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered 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, in which alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl is, in each occurrence, selected from 1 to 4 Z 1a optionally replaced by each Z 1a are independent of each other, H, C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered 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, in which alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl is, in each occurrence, selected from 1 to 4 Z 1b optionally replaced by each Z 1b are independent of each other, H, C 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, oxo, -OH, -CN, COR 3e , -NO2, -NH2, -N3, -SH, -O(C 1-9 alkyl), -O(C 1-8 haloalkyl), -O(C 2-6 alkenyl), -O(C 2-6 alkynyl), -O(C 3-15 Cycloalkyl), -O(heterocyclyl), -O(C 6-10 aryl), -O(5-10 membered heteroaryl), -NH(C 1-9 alkyl), -NH(C 1-8 haloalkyl), -NH(C 2-6 alkenyl), -NH(C 2-6 alkynyl), -NH(C 3-15 Cycloalkyl), -NH(heterocyclyl), -NH(C 6-10 aryl), -NH(5-10 membered heteroaryl), -N(cyclo-alkyl), -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(5-10 membered heteroaryl)2, -N(C 1-9 Alkyl)(C 1-8 haloalkyl), -N(C 1-9 Alkyl)(C 2-6 alkenyl), -N(C 1-9 Alkyl)(C 2-6 alkynyl), -N(C 1-9 Alkyl)(C 3-15 Cycloalkyl), -N(C 1-9 alkyl)(heterocyclyl), -N(C1-9 Alkyl)(C 6-10 Aryl), -N(C 1-9 alkyl)(5-10 membered 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)(5-10 membered 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(5-10 membered 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(5-10 membered 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(5-10 membered heteroaryl)2, -NHC(O)(C 1-9 alkyl), -NHC(O)(C 1-8 haloalkyl), -NHC(O)(C 2-6alkenyl), -NHC(O)(C 2-6 alkynyl), -NHC(O)(C 3-15 Cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6-10 aryl), -NHC(O)(5-10 membered 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(5-10 membered 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(5-10 membered heteroaryl), -NHS(O)(C 1-9 alkyl), -N(C 1-9 Alkyl)(S(O)(C 1-9 alkyl), -S(C 1-9 alkyl), -S(C 1-8 haloalkyl), -S(C 2-6 alkenyl), -S(C 2-6 alkynyl), -S(C 3-15 Cycloalkyl), -S(heterocyclyl), -S(C 6-10 aryl), -S(5-10 membered heteroaryl), -S(O)N(C 1-9 alkyl)2, -S(O)(C 1-9 alkyl), -S(O)(C 1-8 haloalkyl), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 alkynyl), -S(O)(C 3-15Cycloalkyl), -S(O)(heterocyclyl), -S(O)(C 6-10 aryl), -S(O)(5-10 membered heteroaryl), -S(O)2(C 1-9 alkyl), -S(O)2(C 1-8 haloalkyl), -S(O)2(C 2-6 alkenyl), -S(O)2(C 2-6 alkynyl), -S(O)2(C 3-15 Cycloalkyl), -S(O)2(Heterocyclyl), -S(O)2(C 6-10 aryl), -S(O)2(5-10 membered heteroaryl), -S(O)(NH)(C 1-9 alkyl), -S(O)2NH(C 1-9 alkyl), or -S(O)2N(C 1-9 alkyl)2, where alkyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl, in each case, is selected from 1 to 3 C 1-9 Alkyl, C 1-8 Haloalkyl, halogen, -OH, -NH2, CO2H, -O(C 1-9 alkyl), -O(C 1-8 haloalkyl), -O(C 3-15 Cycloalkyl), -O(heterocyclyl), -O(aryl), -O(5-10 membered heteroaryl), -NH(C 1-9 alkyl), -NH(C 1-8 haloalkyl), -NH(C 3-15 Cycloalkyl), -NH(heterocyclyl), -NH(aryl), -NH(5-10 membered 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)(5-10 membered heteroaryl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 1-8 haloalkyl), -NHC(O)O(C 2-6 alkynyl), -NHC(O)O(C 3-15Cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(aryl), -NHC(O)O(5-10 membered 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(5-10 membered heteroaryl), -S(O)(NH)(C 1-9 alkyl), -S(O)2NH(C 1-9 alkyl), or -S(O)2N(C 1-9 Optionally substituted with alkyl)2; Each R 1b , R 1c , R 2a , R 2b , R 4a , R 4b , R 4c , R 9c , R 9d , R 12a , R 12b , and R 12c are independently H, -OH, C 1-9 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl each comprises 1-4 Z 1b optionally replaced by Each R 3e are independent of each other, 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)-OC 1-4 Alkyl, -C1-4 Alkyl-OC(O)-C 1-4 Alkyl-N(R 9a )(R 9b ), -C 1-4 Alkyl-C 3-8 Cycloalkyl, -C 1-4 Alkyl-heterocyclyl, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered 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) in which alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl is, in each occurrence, represented by 1 to 4 Z 1beach 5-10 membered heteroaryl has 5-12 ring members and 1-4 heteroatoms which are each independently N, O, or S; and each heterocyclyl has 3-12 ring members and 1-4 heteroatoms which are each independently N, O, or S.

[0047] In some embodiments, each Z in formula IA-1 or a pharma- ceutical acceptable salt thereof is 1 is independent, C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, oxo, -NO2, -N3, -CN, -OR 12a , -C(O)-R 12a , -C(O)OR 12a , -C(O)-N(R 12a )(R 12b ), or -N(R 12a )(R 12b ).

[0048] In some embodiments, each Z in formula IA-1 or a pharma- ceutical acceptable salt thereof is 1a are independently H, -OH, C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 It is an alkoxyalkyl, or a halogen.

[0049] In some embodiments, each Z in formula IA-1 or a pharma- ceutical acceptable salt thereof is 1b are independent of each other, H, C 1-9 Alkyl, C 1-8 It is haloalkyl, halogen, oxo, -OH, or -CN.

[0050] In some embodiments, each R in formula IA-1 or a pharma- ceutically acceptable salt thereof is 8 are independently H, oxo, OH, C 1-9 Alkyl, C 1-8 Haloalkyl, halogen, -O(C 1-3 alkyl), or -O(C 1-3 haloalkyl).

[0051] Another embodiment is a compound of formula IA-2 [ka] Or formula IA-3 [ka] or a pharma- ceutically acceptable salt thereof, wherein Ring C contains 1 to 4 Z 1 C optionally substituted with 3-10 Cycloalkyl, heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; Y1-V is N-CH2, N-CH(CH3), N-CF2, CH-CH2, CH-CF2, CH-NH, NS(O), NS(O)2, NC(O), CH-C(O) or cyclopropyl; Y2 is C, CH, or N; R 2 , H, C 1-6 Alkyl, -C 1-6 Alkyl-alkoxy, -C 1-6 Alkyl-cycloalkoxy, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered 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 alkyl, alkoxy, cycloalkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl, in each occurrence, is selected from 1 to 4 Z 1 and any two Z 1 are bonded to the atom to which they are attached, 3-10 Cycloalkyl or heterocyclyl or C 6-10 can form an aryl or a 5- to 10-membered heteroaryl; X is independently -N=, -C(H)=, or -C(R 8 )= Each R 3 and R 3’ are independent of each other, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered 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 alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl, at each occurrence, is selected from 1 to 4 R 3d optionally replaced by Each R 3a , R 3b , and R 3c are independently H, C 1-6 Alkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 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)-OC 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-C 1-4Alkyl-N(R 9a )(R 9b ), -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl-OP(O)(OR 9c )2, -C 1-4 Alkyl-C 3-8 Cycloalkyl, -C 1-4 Alkyl-heterocyclyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, -CHCH(N(R 9a )2)C(O)OR 9b , C 1-6 Alkyl-heterocyclyl, C 1-6 Alkyl-aryl or C 1-6 alkyl-(5-10 membered)heteroaryl, where alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl or 5-10 membered heteroaryl are each independently selected from 1 to 4 Z 1b optionally replaced by Each R 5a and R 5b are independently H, C 1-6 Alkyl, C 1-6 Alkyloxy, C 1-6 Haloalkyl, C 2-6 Alkoxyalkyl, halogen, C 3-10 Cycloalkyl, heterocyclyl, -C 1-6 Alkyl-N(R 9a )(R 9b ), -CN, -OR 5a1 , or -N(R 5a1 )(R 5a2 ) or R 5a and R 5b are bonded to the atom to which they are attached, and each has 1 to 4 R 5a3 C optionally substituted with 3-10 forming a cycloalkyl or heterocyclyl, Each R 5a1 and R 5a2 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, in which cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl are optionally substituted, in each case, with 1 to 4 halogen; Each R 3d and R 5a3 are independent of each other, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, oxo, -OH, -CN, COR 3e , -NO2, or -C(O)N(R 2a )(R 2b ), wherein heterocyclyl or 5-10 membered heteroaryl is C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with haloalkoxy; Each R 8 is independently 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, oxo, -OH, -CN, COR 3e , -NO2, -NH2, -N3, -SH, -O(C 1-9 alkyl), -O(C 1-8 haloalkyl), -NH(C 1-9 alkyl), -NH(C 1-8 haloalkyl), -N(C 1-9 Alkyl)2, -N(C 1-8 haloalkyl)2, Each R 9a and R 9b are independent of each other, H, C 1-9 Alkyl, C 1-8Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered 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, or R 9a and R 9b Both are C 1-9 Alkyl, C 1-8Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, oxo, -NO2, -CN, -N 3、 -OR 12a , -C(O)R 12a , -C(O)OR 12a , -C(O)N(R 12a )(R 12b ), -N(R 12a )(R 12b ), -N(R 12a )2(R 12b ) + , -N(R 12a )-C(O)R 12b , -N(R 12a )C(O)O(R 12b ), -N(R 12a )C(O)N(R 12b )(R 12c ), -N(R 12a )S(O)2(R 12b ), -N(R 12a )S(O)2-N(R 12b )(R 12c ), -N(R 12a )S(O)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 ) forming an optionally substituted 3- to 10-membered heterocyclyl with 3; each Z 1 is independent, C1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, oxo, -NO2, -N3, -CN, or -OR 12a wherein alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl, in each occurrence, is selected from 1 to 4 Z 1a optionally replaced by each Z 1a are independent of each other, H, C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered 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, in which alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl is, in each occurrence, selected from 1 to 4 Z 1b optionally replaced by each Z 1b are independent of each other, H, C 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, oxo, -OH, -CN, COR 3e , -NO2, -NH2, -N3, -SH, -O(C 1-9 alkyl), -O(C 1-8 haloalkyl), -O(C 2-6 alkenyl), -O(C 2-6 alkynyl), -O(C 3-15 Cycloalkyl), -O(heterocyclyl), -O(C 6-10 aryl), -O(5-10 membered heteroaryl), -NH(C 1-9 alkyl), -NH(C 1-8 haloalkyl), -NH(C 2-6 alkenyl), -NH(C 2-6 alkynyl), -NH(C 3-15Cycloalkyl), -NH(heterocyclyl), -NH(C 6-10 aryl), -NH(5-10 membered heteroaryl), -N(cyclo-alkyl), -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(5-10 membered heteroaryl)2, -N(C 1-9 Alkyl)(C 1-8 haloalkyl), -N(C 1-9 Alkyl)(C 2-6 alkenyl), -N(C 1-9 Alkyl)(C 2-6 alkynyl), -N(C 1-9 Alkyl)(C 3-15 Cycloalkyl), -N(C 1-9 alkyl)(heterocyclyl), -N(C 1-9 Alkyl)(C 6-10 Aryl), -N(C 1-9 alkyl)(5-10 membered 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)(5-10 membered 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(5-10 membered heteroaryl), -C(O)NH2, -C(O)NH(C 1-9 alkyl), -C(O)NH(C1-8 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(5-10 membered 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(5-10 membered heteroaryl)2, -NHC(O)(C 1-9 alkyl), -NHC(O)(C 1-8 haloalkyl), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 alkynyl), -NHC(O)(C 3-15 Cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6-10 aryl), -NHC(O)(5-10 membered 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(5-10 membered heteroaryl), -NHC(O)NH(C 1-9 alkyl), -NHC(O)NH(C 1-8 haloalkyl), -NHC(O)NH(C 2-6 alkenyl), -NHC(O)NH(C 2-6 alkynyl), -NHC(O)NH(C 3-15Cycloalkyl), -NHC(O)NH(heterocyclyl), -NHC(O)NH(C 6-10 aryl), or -NHC(O)NH(5- to 10-membered heteroaryl), where alkyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl, in each case, is selected from 1 to 3 C 1-9 Alkyl, C 1-8 Haloalkyl, halogen, -OH, -NH2, CO2H, -O(C 1-9 alkyl), -O(C 1-8 haloalkyl), -O(C 3-15 Cycloalkyl), -O(heterocyclyl), -O(aryl), -O(5-10 membered heteroaryl), -NH(C 1-9 alkyl), -NH(C 1-8 haloalkyl), -NH(C 3-15 Cycloalkyl), -NH(heterocyclyl), -NH(aryl), -NH(5-10 membered 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)(5-10 membered 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(5-10 membered heteroaryl), or -NHC(O)NH(C 1-9 alkyl), Each R 1b , R 1c , R 2a , R 2b , R 4c , R 9c , R 12a , R 12b , and R 12c are independently H, -OH, and C 1-9Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl is, in each occurrence, selected from 1 to 4 Z 1b optionally replaced by Each R 3e are independent of each other, 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)-OC 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl-N(R 9a )(R 9b ), -C 1-4 Alkyl-C 3-8 Cycloalkyl, -C 1-4 Alkyl-heterocyclyl, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, in which alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl are each independently selected from 1 to 4 Z 1b each 5-10 membered heteroaryl has 5-12 ring members and 1-4 heteroatoms which are each independently N, O, or S; and each heterocyclyl has 3-12 ring members and 1-4 heteroatoms which are each independently N, O, or S.

[0052] Another embodiment is a compound of formula IA-4 [ka] Or formula IA-5 [ka] or a pharma- ceutically acceptable salt thereof, wherein Ring C contains 1 to 4 Z 1 C optionally substituted with 3-10 Cycloalkyl, heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; Y1-V is N-CH2, N-CH(CH3), N-CF2, CH-CH2, CH-CF2, CH-NH, NS(O), NS(O)2, NC(O), CH-C(O) or cyclopropyl; Y2 is C, CH, or N; R 2 , H, C 1-6 Alkyl, -C 1-6 Alkyl-alkoxy, -C 1-6 Alkyl-cycloalkoxy, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered 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 alkyl, alkoxy, cycloalkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl, in each occurrence, is selected from 1 to 4 Z 1 and any two Z 1 are bonded to the atom to which they are attached, 3-10 Cycloalkyl or heterocyclyl or C 6-10 can form an aryl or a 5- to 10-membered heteroaryl; X is independently -N=, -C(H)=, or -C(R 8 )= Each R 3 and R 3’ are independent of each other, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered 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 alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl, at each occurrence, is selected from 1 to 4 R 3d optionally replaced by Each R 3a , R 3b , and R 3c are independently H, C 1-6 Alkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 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)-OC 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl-N(R 9a )(R 9b ), -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl-OP(O)(OR 9c )2, -C 1-4 Alkyl-C 3-8 Cycloalkyl, -C 1-4 Alkyl-heterocyclyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, -CHCH(N(R 9a )2)C(O)OR 9b , C 1-6Alkyl-heterocyclyl, C 1-6 Alkyl-aryl or C 1-6 alkyl-(5-10 membered)heteroaryl, where alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl or 5-10 membered heteroaryl are each independently selected from 1 to 4 Z 1b optionally replaced by Each R 5a are independently H, C 1-6 Alkyl, C 1-6 Alkyloxy, C 1-6 Haloalkyl, C 2-6 Alkoxyalkyl, halogen, C 3-10 Cycloalkyl, heterocyclyl, -C 1-6 Alkyl-N(R 9a )(R 9b ), -CN, -OR 5a1 , or -N(R 5a1 )(R 5a2 ) and Each R 5a1 and R 5a2 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, in which cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl are optionally substituted, in each case, with 1 to 4 halogen; R 3d are independent of each other, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, oxo, -OH, -CN, COR 3e , -NO2, or -C(O)N(R 2a)(R 2b ), wherein heterocyclyl or 5-10 membered heteroaryl is C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with haloalkoxy; Each R 8 is independently 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, oxo, -OH, -CN, COR 3e , -NO2, -NH2, -N3, -SH, -O(C 1-9 alkyl), -O(C 1-8 haloalkyl), -NH(C 1-9 alkyl), -NH(C 1-8 haloalkyl), -N(C 1-9 Alkyl)2, -N(C 1-8 haloalkyl)2, Each R 9a and R 9b are independent of each other, H, C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered 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, or R 9a and R 9b Both are C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, oxo, -NO2, -CN, -N 3、 -OR 12a , -C(O)R 12a , -C(O)OR 12a , -C(O)N(R 12a )(R 12b ), -N(R 12a )(R 12b ), -N(R 12a )2(R 12b ) + , -N(R 12a )-C(O)R 12b , -N(R 12a )C(O)O(R 12b ), -N(R12a )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 ) forming an optionally substituted 3- to 10-membered heterocyclyl with 3; each Z 1 is independent, C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, oxo, -NO2, -N3, -CN, or -OR 12a wherein alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl, in each occurrence, is selected from 1 to 4 Z 1a optionally replaced by each Z 1a are independent of each other, H, C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered 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, in which alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl is, in each occurrence, selected from 1 to 4 Z 1b optionally replaced by each Z1b are independent of each other, H, C 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, oxo, -OH, -CN, COR 3e , -NO2, -NH2, -N3, -SH, -O(C 1-9 alkyl), -O(C 1-8 haloalkyl), -O(C 2-6 alkenyl), -O(C 2-6 alkynyl), -O(C 3-15 Cycloalkyl), -O(heterocyclyl), -O(C 6-10 aryl), -O(5-10 membered heteroaryl), -NH(C 1-9 alkyl), -NH(C 1-8 haloalkyl), -NH(C 2-6 alkenyl), -NH(C 2-6 alkynyl), -NH(C 3-15 Cycloalkyl), -NH(heterocyclyl), -NH(C 6-10 aryl), -NH(5-10 membered heteroaryl), -N(cyclo-alkyl), -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(5-10 membered heteroaryl)2, -N(C 1-9 Alkyl)(C 1-8 haloalkyl), -N(C 1-9 Alkyl)(C 2-6 alkenyl), -N(C 1-9 Alkyl)(C 2-6 alkynyl), -N(C 1-9 Alkyl)(C 3-15 Cycloalkyl), -N(C 1-9 alkyl)(heterocyclyl), -N(C 1-9 Alkyl)(C6-10 Aryl), -N(C 1-9 alkyl)(5-10 membered 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)(5-10 membered 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(5-10 membered 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(5-10 membered 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(5-10 membered heteroaryl)2, -NHC(O)(C 1-9 alkyl), -NHC(O)(C 1-8 haloalkyl), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C2-6 alkynyl), -NHC(O)(C 3-15 Cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6-10 aryl), -NHC(O)(5-10 membered 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(5-10 membered 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), or -NHC(O)NH(5- to 10-membered heteroaryl), where alkyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl, in each case, is selected from 1 to 3 C 1-9 Alkyl, C 1-8 Haloalkyl, halogen, -OH, -NH2, CO2H, -O(C 1-9 alkyl), -O(C 1-8 haloalkyl), -O(C 3-15 Cycloalkyl), -O(heterocyclyl), -O(aryl), -O(5-10 membered heteroaryl), -NH(C 1-9 alkyl), -NH(C 1-8 haloalkyl), -NH(C 3-15 Cycloalkyl), -NH(heterocyclyl), -NH(aryl), -NH(5-10 membered heteroaryl), -N(C 1-9 Alkyl)2, -N(C 3-15 cycloalkyl)2, -NHC(O)(C 1-8haloalkyl), -NHC(O)(C 3-15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl), -NHC(O)(5-10 membered 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(5-10 membered heteroaryl), or -NHC(O)NH(C 1-9 alkyl), Each R 1b , R 1c , R 2a , R 2b , R 4c , R 9c , R 12a , R 12b , and R 12c are independently H, -OH, and C 1-9 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl is, in each occurrence, selected from 1 to 4 Z 1b optionally replaced by Each R 3e are independent of each other, 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)-OC 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl-N(R 9a )(R9b ), -C 1-4 Alkyl-C 3-8 Cycloalkyl, -C 1-4 Alkyl-heterocyclyl, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, in which alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl are each independently selected from 1 to 4 Z 1b each 5-10 membered heteroaryl has 5-12 ring members and 1-4 heteroatoms which are each independently N, O, or S; and each heterocyclyl has 3-12 ring members and 1-4 heteroatoms which are each independently N, O, or S.

[0053] Another embodiment is a compound of formula IA-6 [ka] Or formula IA-7 [ka] or a pharma- ceutically acceptable salt thereof, wherein Ring C contains 1 to 4 Z 1 C optionally substituted with 3-10 Cycloalkyl, heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; V is CH2, CH(CH3), NH, C(O), S(O), S(O)2; n=0, 1, 2, 3, or 4; R 2 , H, C 1-6 Alkyl, -C 1-6 Alkyl-alkoxy, -C 1-6 Alkyl-cycloalkoxy, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, C 6-10Aryl, 5-10 membered 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 alkyl, alkoxy, cycloalkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl, in each occurrence, is selected from 1 to 4 Z 1 and any two Z 1 are bonded to the atom to which they are attached, 3-10 Cycloalkyl or heterocyclyl or C 6-10 can form an aryl or a 5- to 10-membered heteroaryl; X is independently -N=, -C(H)=, or -C(R 8 )= Each R 3 and R 3’ are independent of each other, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered 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)2R3b , -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 alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl, at each occurrence, is selected from 1 to 4 R 3d optionally replaced by Each R 3a , R 3b , and R 3c are independently H, C 1-6 Alkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 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 1-4Alkyl-C(O)N(R 9a )(R 9b ), -C 1-4 Alkyl-OC(O)-OC 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl-N(R 9a )(R 9b ), -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl-OP(O)(OR 9c )2, -C 1-4 Alkyl-C 3-8 Cycloalkyl, -C 1-4 Alkyl-heterocyclyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, -CHCH(N(R 9a )2)C(O)OR 9b , C 1-6 Alkyl-heterocyclyl, C 1-6 Alkyl-aryl or C 1-6 alkyl-(5-10 membered)heteroaryl, where alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl or 5-10 membered heteroaryl are each independently selected from 1 to 4 Z 1b optionally replaced by Each R 4 are independently H, -OH, CH2OH, C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, oxo, -NO2, -CN, -N3, -OR 4a , -C(O)R 4a , -C(O)OR 4a , -C(O)N(R 4a )(R 4b ), -N(R4a )(R 4b ), -N(R 4a )2(R 4b ) + , -N(R 4a )-C(O)R 4b , -N(R 4a )C(O)O(R 4b ), -N(R 4a )C(O)N(R 4b )(R 4c ), -N(R 4a )S(O)2(R 4b ), -N(R 4a )S(O)2-N(R 4b )(R 4c ), -N(R 4a )S(O)2O(R 4b ), -OC(O)R 4a , -OC(O)OR 4a、 -OC(O)-N(R 4a )(R 4b ), -SR 4a , -S(O)R 4a、 -S(O)(NH)R 4a , -S(O)2R 4a、 -S(O)2N(R 4a )(R 4b ), -S(O)(NR 4a )R 4b , or -Si(R 4a )3, in which alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl is, in each occurrence, represented by 1 to 4 Z 1b or two R attached to adjacent ring atoms 4 The groups each have 1 to 4 Z 1b C optionally substituted with 5-10 forming a cycloalkyl or heterocyclyl, Each R 5a and R 5b are independently H, C 1-6 Alkyl, C 1-6 Alkyloxy, C 1-6 Haloalkyl, C 2-6 Alkoxyalkyl, halogen, C3-10 Cycloalkyl, heterocyclyl, -C 1-6 Alkyl-N(R 9a )(R 9b ), -CN, -OR 5a1 , or -N(R 5a1 )(R 5a2 ) or R 5a and R 5b are bonded to the atom to which they are attached, and each has 1 to 4 R 5a3 C optionally substituted with 3-10 forming a cycloalkyl or heterocyclyl, Each R 5a1 and R 5a2 are independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, in which cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl are optionally substituted, in each case, with 1 to 4 halogen; Each R 3d and R 5a3 are independent of each other, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, oxo, -OH, -CN, COR 3e , -NO2, or -C(O)N(R 2a )(R 2b ), wherein heterocyclyl or 5- to 10-membered heteroaryl is, in each case, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 optionally substituted with haloalkoxy; Each R 8is independently 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, oxo, -OH, -CN, COR 3e , -NO2, -NH2, -N3, -SH, -O(C 1-9 alkyl), -O(C 1-8 haloalkyl), -NH(C 1-9 alkyl), -NH(C 1-8 haloalkyl), -N(C 1-9 Alkyl)2, -N(C 1-8 haloalkyl)2, Each R 9a and R 9b are independent of each other, H, C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, oxo, -NO2, -CN, -N3, -OR 12a , -C(O)R 12a、 -C(O)OR 12a , -C(O)N(R 12a )(R 12b ), -N(R 12a )(R 12b ), -N(R 12a )2(R 12b ) + , -N(R 12a )-C(O)R 12b , -N(R 12a )C(O)O(R 12b ), -N(R 12a )C(O)N(R 12b )(R 12c ), -N(R 12a )S(O)2(R 12b ), -N(R 12a )S(O)2-N(R 12b )(R 12c ), -N(R12a )S(O)2O(R 12b ), -OC(O)R 12a、 -OC(O)OR 12a , -OC(O)-N(R 12a )(R 12b ), -SR 12a , -S(O)R 12a , -S(O)(NH)R 12a , -S(O)2R 12a , -S(O)2N(R 12a )(R 12b ), -S(O)(NR 12a )R 12b , or -Si(R 12a )3, or R 9a and R 9b Both are C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, oxo, -NO2, -CN, -N 3、 -OR 12a , -C(O)R 12a , -C(O)OR 12a , -C(O)N(R 12a )(R 12b ), -N(R 12a )(R 12b ), -N(R 12a )2(R 12b ) + , -N(R 12a )-C(O)R 12b , -N(R 12a )C(O)O(R 12b ), -N(R 12a )C(O)N(R 12b )(R 12c ), -N(R 12a )S(O)2(R 12b ), -N(R 12a )S(O)2-N(R 12b )(R 12c), -N(R 12a )S(O)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 ) forming an optionally substituted 3- to 10-membered heterocyclyl with 3; each Z 1 is independent, C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, oxo, -NO2, -N3, -CN, -OR 12a wherein alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl, in each occurrence, is selected from 1 to 4 Z 1a optionally replaced by each Z 1a are independent of each other, H, C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, oxo, -NO2, -CN, -N3, -OR12a , -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, in which alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl is, in each occurrence, selected from 1 to 4 Z 1b optionally replaced by each Z 1b are independent of each other, H, C 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclyl, C 6-10Aryl, 5-10 membered heteroaryl, oxo, -OH, -CN, COR 3e , -NO2, -NH2, -N3, -SH, -O(C 1-9 alkyl), -O(C 1-8 haloalkyl), -O(C 2-6 alkenyl), -O(C 2-6 alkynyl), -O(C 3-15 Cycloalkyl), -O(heterocyclyl), -O(C 6-10 aryl), -O(5-10 membered heteroaryl), -NH(C 1-9 alkyl), -NH(C 1-8 haloalkyl), -NH(C 2-6 alkenyl), -NH(C 2-6 alkynyl), -NH(C 3-15 Cycloalkyl), -NH(heterocyclyl), -NH(C 6-10 aryl), -NH(5-10 membered heteroaryl), -N(cyclo-alkyl), -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(5-10 membered heteroaryl)2, -N(C 1-9 Alkyl)(C 1-8 haloalkyl), -N(C 1-9 Alkyl)(C 2-6 alkenyl), -N(C 1-9 Alkyl)(C 2-6 alkynyl), -N(C 1-9 Alkyl)(C 3-15 Cycloalkyl), -N(C 1-9 alkyl)(heterocyclyl), -N(C 1-9 Alkyl)(C 6-10 Aryl), -N(C 1-9 alkyl)(5-10 membered heteroaryl), -C(O)(C 1-9 alkyl), -C(O)(C 1-8 haloalkyl), -C(O)(C 2-6 alkenyl), -C(O)(C2-6 alkynyl), -C(O)(C 3-15 Cycloalkyl), -C(O)(heterocyclyl), -C(O)(C 6-10 aryl), -C(O)(5-10 membered 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(5-10 membered 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(5-10 membered 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(5-10 membered heteroaryl)2, -NHC(O)(C 1-9 alkyl), -NHC(O)(C 1-8 haloalkyl), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 alkynyl), -NHC(O)(C 3-15 Cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C 6-10 aryl), -NHC(O)(5-10 membered heteroaryl), -NHC(O)O(C 1-9alkyl), -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(5-10 membered 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), or -NHC(O)NH(5- to 10-membered heteroaryl), where alkyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl, in each case, is selected from 1 to 3 C 1-9 Alkyl, C 1-8 Haloalkyl, halogen, -OH, -NH2, CO2H, -O(C 1-9 alkyl), -O(C 1-8 haloalkyl), -O(C 3-15 Cycloalkyl), -O(heterocyclyl), -O(aryl), -O(5-10 membered heteroaryl), -NH(C 1-9 alkyl), -NH(C 1-8 haloalkyl), -NH(C 3-15 Cycloalkyl), -NH(heterocyclyl), -NH(aryl), -NH(5-10 membered 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)(5-10 membered heteroaryl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C1-8 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(5-10 membered heteroaryl), or -NHC(O)NH(C 1-9 alkyl), Each R 1b , R 1c , R 2a , R 2b , R 4a , R 4b , R 4c , R 9c , R 12a , R 12b , and R 12c are independently H, -OH, C 1-9 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl is selected from 1 to 4 Z 1b optionally replaced by Each R 3e are independent of each other, 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)-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 3-10Cycloalkyl, heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, in which alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl are each independently selected from 1 to 4 Z 1b each 5-10 membered heteroaryl has 5-12 ring members and 1-4 heteroatoms which are each independently N, O, or S; and each heterocyclyl has 3-12 ring members and 1-4 heteroatoms which are each independently N, O, or S.

[0054] In some embodiments of the compound of formula IA-2, IA-3, IA-5, IA-6, IA-7, or a pharma- ceutically acceptable salt thereof, each R 5 and R 5b are independently H, C 1-9 Alkyl, or C 2-6 and alkoxyalkyl, where each alkyl or alkoxyalkyl is optionally substituted with one or more halogens.

[0055] In some embodiments of the compound of formula IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, or a pharma- ceutically acceptable salt thereof, ring C is selected from the structures shown below: 6-10 aryl or 5-10 membered heteroaryl; [ka] These are H, OH, oxo, halogen, and C, respectively. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, -NO2, -N3, -CN, -OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-N(C0-6 Alkyl)(C 0-6 Alkyl) and -N(C 0-6 Alkyl)(C 0-6 alkyl), wherein each of the 1 to 4 substituents may be optionally substituted with one or more halogens.

[0056] In some embodiments of the compound of formula IA-1, or a pharma- ceutically acceptable salt thereof, ring A is one of the following: [ka] These are each 1 to 4 Z 1a is optionally replaced by

[0057] In some embodiments of the compound of formula IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, or a pharma- ceutically acceptable salt thereof, Z 1a are independently H, halogen, or C 1-9 Alkyl, C 1-6 Alkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-15 cycloalkyl, or heterocyclyl, each of which is optionally substituted with one or more halogens.

[0058] In some embodiments of the compound of formula IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, or a pharma- ceutically acceptable salt thereof, R 2 is C 1-6 Alkyl, -C 1-6 Alkyl-alkoxy, -C 1-6 Alkyl-cycloalkoxy, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, C 6-10aryl, or 5-10 membered heteroaryl, each of which is 1 Preferably, R 2 is one of the following: [ka] These are each 1 to 4 Z 1 is optionally replaced by

[0059] In some embodiments of the compound of formula IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, or a pharma- ceutically acceptable salt thereof, R 2’ is H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 alkyl or -cycloalkoxy, each of which is optionally substituted with one or more halogens.

[0060] In some embodiments of the compound of formula IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, or a pharma- ceutically acceptable salt thereof, each R 3 and R 3’ are independently H, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)R 3a , -CH2C(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)2N(R 3a )(R 3b ), -N(R 3a )S(O)2R 3b , -S(O)2NHC(O)R 3a , or -OC 1-6 Alkyl-C(O)OR 3a These are each 1 to 4 R 3d is optionally replaced by

[0061] Preferably, each R and R 3’ are independently H, C(O)NR 3a (CH2) m R 3b , C(O)NR 3a (CH2) m C(O)R 3b , N.R. 3a C(O)(CH2) m R 3b , N.R. 3a (CH2) m R 3b , N.R. 3a (CH2) m C(O)R 3b , C(O)NR 3a R 3b , or N.R. 3a C(O)R 3b These are each 1 to 4 R 3d and m=0, 1, 2, or 3. Preferably, each R 3 and R 3’ are independently H, C(O)NHR 3b , or NHC(O)R 3b It is.

[0062] In some embodiments of the compound of formula IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, or a pharma- ceutically acceptable salt thereof, R 3b are independent of each other, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkoxyalkyl, -C 1-4 Alkyl-N(R 9a )(R 9b), -C 1-4 Alkyl-C(O)N(R 9a )(R 9b ), -C 1-4 Alkyl-OC(O)-OC 1-4 Alkyl, -C 1-4 Alkyl-OC(O)-C 1-4 Alkyl-N(R 9a )(R 9b ), -C 1-4 Alkyl-C 3-8 Cycloalkyl, -C 1-4 Alkyl-heterocyclyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, -CHCH(N(R 9a )2)C(O)OR 9b , C 1-6 Alkyl-heterocyclyl, C 1-6 Alkyl-aryl or C 1-6 alkyl-(5-10 membered)heteroaryl, where alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl is, in each occurrence, one to four Z 1b is optionally replaced by

[0063] Preferably, R 3b is C 5-10 substituted aryl or substituted 5-10 membered heteroaryl, each of which is represented by 1 to 5 R 3f where each R 3f are independently H, OH, oxo, NH2, halogen, -NO2, -N3, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, -OC 1-6 Alkyl, -C(O)-C 1-6Alkyl, -C(O)-N(R 12a )(R 12b ), -N(R 12a )(R 12b ), C 6-10 aryl, or 5-10 membered heteroaryl; R 3f In each case, one or more halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, or C 1-6 Optionally substituted with haloalkoxy.

[0064] Preferably, R 3b is one of the following: [ka] These are 1 to 5 R 3f is optionally replaced by

[0065] In some embodiments of the compound of formula IA-1, or a pharma- ceutically acceptable salt thereof, R 4 are independently H, -OH, C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 3-15 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, oxo, -NO2, -CN, -N3, -OC 1-9 Alkyl, or -C(O)C 1-9 alkyl, each of which is selected from 1 to 4 Z 1b or two R attached to adjacent ring atoms 4 The groups each have 1 to 4 Z 1b C optionally substituted with 5-10 It forms a cycloalkyl or heterocyclyl.

[0066] Preferably, R 4 are independently H, halogen, or C 1-9 Alkyl, C 1-8 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-15 It is cycloalkyl.

[0067] In some embodiments, the compound of formula IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, or IA-7, or a pharma- ceutically acceptable salt thereof, has one of the structures listed below. [ka] TIFF2025508914000330.tif235170TIFF2025508914000331.tif235170TIFF2025508914000332.tif206170TIFF202 5508914000333.tif216170TIFF2025508914000334.tif237170TIFF2025508914000335.tif221170TIFF20255089140 00336.tif223170TIFF2025508914000337.tif223170TIFF2025508914000338.tif232170TIFF2025508914000339.t if241170TIFF2025508914000340.tif228170TIFF2025508914000341.tif236170TIFF2025508914000342.tif205170

[0068] III. Pharmaceutical Compositions Another aspect of the present application relates to a pharmaceutical composition comprising the compound of the present application. In some embodiments, the present application provides a pharmaceutical composition comprising the compound of the present application and one or more pharma- ceutically acceptable excipients.

[0069] In some embodiments, the pharmaceutical composition comprises a compound of formula IA-1 or a pharma- ceutically acceptable salt thereof.

[0070] In some embodiments, the pharmaceutical composition comprises a compound of formula IA-2, or a pharma- ceutically acceptable salt thereof.

[0071] In some embodiments, the pharmaceutical composition comprises a compound of formula IA-3, or a pharma- ceutically acceptable salt thereof.

[0072] In some embodiments, the pharmaceutical composition comprises a compound of formula IA-4, or a pharma- ceutically acceptable salt thereof.

[0073] In some embodiments, the pharmaceutical composition comprises a compound of formula IA-5, or a pharma- ceutically acceptable salt thereof.

[0074] In some embodiments, the pharmaceutical composition comprises a compound of formula IA-6, or a pharma- ceutically acceptable salt thereof.

[0075] In some embodiments, the pharmaceutical composition comprises a compound of formula IA-7, or a pharma- ceutically acceptable salt thereof.

[0076] In some embodiments, the pharmaceutical compositions of the present application further comprise one or more additional therapeutic agents. Examples of additional therapeutic agents include, but are not limited to, those listed in the combination therapy section of the present application.

[0077] The pharmaceutical compositions of the present application may be in any form suitable for the intended method of administration, in some embodiments the pharmaceutical composition is in the form of a tablet, sachet, troche, lozenge, aqueous or oily suspension, dispersible powder or granule, emulsion, hard or soft capsule, syrup, or elixir for oral administration.

[0078] In some embodiments, the pharmaceutical compositions of the present application are provided in 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 is a tablet.

[0079] Pharmaceutical compositions can be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient (e.g., the compound of the present application or a pharmaceutical salt thereof) with one or more pharma-ceutically acceptable excipients. In some embodiments, pharmaceutical compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid excipients or finely divided solid excipients or both, and then, if necessary, shaping the product. Techniques and formulations are generally described in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0080] Examples of the one or more excipients include, but are not limited to, fillers, binders, bulking agents, glidants, sweeteners, flavoring agents, coloring agents, and preservatives. In some embodiments, the pharmaceutical composition is in the form of a tablet and includes one or more pharma- ceutically acceptable excipients suitable for tablet manufacture. These excipients can be, for example, inert diluents such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate, granulating and disintegrating agents such as corn starch or alginic acid, binders such as cellulose, microcrystalline cellulose, starch, gelatin or acacia, and lubricants such as magnesium stearate, stearic acid or talc. The tablets can be uncoated or coated by known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate can be used alone or with a wax.

[0081] The amount of active ingredient that can be combined with the inactive ingredient to produce a dosage form may vary depending on the intended subject of treatment and the method of administration. For example, in some embodiments, a dosage form for oral administration to humans may contain about 1-1000 mg of active agent formulated with an appropriate and convenient amount of pharma-ceutically acceptable excipients. In some embodiments, the pharma-ceutically acceptable excipients vary from about 5% to about 95% of the total composition (weight:weight).

[0082] In some embodiments, the pharmaceutical composition of the present application does not contain an agent that affects the rate at which the active ingredient is metabolized. Thus, in one aspect, it is understood that the pharmaceutical composition that includes the compound of the present application does not contain an agent that affects (e.g., slows, prevents, or delays) the metabolism of the compound of the present application or any other active ingredient that is administered separately, sequentially, or simultaneously with the compound of the present application. It is also understood that none of the methods, kits, articles of manufacture, etc. detailed in one aspect of this specification contain an agent that affects (e.g., slows, prevents, or delays) the metabolism of the compound of the present application or any other active ingredient that is administered separately, sequentially, or simultaneously with the compound of the present application.

[0083] IV. Treatment method Another aspect of the present application relates to a method of preventing, treating or ameliorating a GLP-1R mediated disease or condition using the compounds of the present application, hi some embodiments, the method comprises administering to a subject in need of such treatment an effective amount of a compound of formula IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, or a pharma- ceutically acceptable salt thereof.

[0084] Examples of GLP-1R mediated diseases or conditions include the chronic intrahepatic or some forms of extrahepatic cholestatic conditions of the present application, hepatic fibrosis, acute intrahepatic cholestatic conditions, obstructive or chronic inflammatory diseases resulting from abnormalities in bile composition, gastrointestinal diseases in which the intake of dietary fat and fat-soluble dietary vitamins is reduced, inflammatory bowel diseases, lipid and lipoprotein disorders, type 2 diabetes and clinical complications of types 1 and 2 diabetes, chronic fatty degeneration of organs due to forced accumulation of lipids, especially triglycerides, followed by activation of profibrotic pathways. and diseases and disorders resulting from fibrotic degeneration, obesity and metabolic syndrome (a combined condition of dyslipidemia, diabetes mellitus and an abnormally high body mass index), acute myocardial infarction, acute stroke, thrombosis occurring as an end point in chronic obstructive atherosclerosis, persistent infection with intracellular bacteria or protozoan parasites, non-malignant hyperproliferative diseases, malignant hyperproliferative diseases such as colon adenocarcinoma and hepatocellular carcinoma, fatty liver and related syndromes, liver failure or dysfunction as a result of chronic liver disease or surgical liver resection, hepatitis B infection, Cholestatic and fibrotic effects associated with Hepatitis C infection and / or alcohol-induced cirrhosis or viral-mediated hepatitis, Type 1 diabetes, prediabetes, idiopathic type 1 diabetes, latent autoimmune diabetes, maturity-onset diabetes of the young, early-onset diabetes, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, obesity, eating disorders, sleep apnea, weight gain, sugar cravings Examples of conditions that may be affected include, but are not limited to, glaucoma, dyslipidemia, hyperinsulinemia, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial hyperlipidemia, metabolic acidosis, ketosis, arthritis, left ventricular hypertrophy, Parkinson's disease, peripheral arterial disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, angina pectoris, premenstrual syndrome, thrombosis, atherosclerosis, glucose metabolism disorders, or vascular restenosis.

[0085] In some embodiments, the GLP-1R mediated disease or condition is type 1 diabetes mellitus (T1D), type 2 diabetes mellitus (T2DM), prediabetes, idiopathic T1D, latent autoimmune diabetes in adults (LADA), early onset T2DM (EOD), atypical diabetes of the young (YOAD), maturity onset diabetes of the young (MODY), 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, sleep apnea, obesity, eating disorders, weight gain due to use of other medications, excessive sugar cravings, dyslipidemia, hyperinsulinemia, NAFLD, NASH, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance. , congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial hyperlipidemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis The present invention is directed to the prevention or treatment of chronic obstructive pulmonary disease, acute myocardial infarction, pulmonary embolism, pulmonary edema, pulmonary edema, and the treatment of chronic obstructive pulmonary disease (COPD), chronic obstructive pulmonary disease (COPD), and the treatment of addiction.

[0086] In some embodiments, the GLP-1R mediated disease or condition is a liver disease, e.g., liver fibrosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), cirrhosis, compensated liver fibrosis, decompensated liver fibrosis, hepatocellular carcinoma, primary biliary cirrhosis (PBC), or primary sclerosing cholangitis (PSC).

[0087] In some embodiments, the GLP-1R mediated disease or condition is a metabolic disease.

[0088] In some embodiments, the present application relates to a method for treating and / or preventing NAFLD, the method comprising administering to a subject in need of such treatment and / or prevention an effective amount of a compound of formula IA-1 or a pharma- ceutically acceptable salt thereof.

[0089] In some embodiments, the present application relates to a method for treating and / or preventing NASH, hi some embodiments, the method comprises administering to a subject in need of such treatment and / or prevention an effective amount of a compound of formula IA-1.

[0090] In some embodiments, the present application relates to the prophylactic and post-traumatic treatment of cardiovascular diseases, such as acute myocardial infarction, acute stroke, or thrombosis occurring as an endpoint of chronic obstructive atherosclerosis. In some embodiments, the method comprises administering to a subject in need of such prophylactic and post-traumatic treatment an effective amount of a compound of formula IA-1.

[0091] In some embodiments, the present application relates to a method for the treatment and / or prevention of obesity and related disorders such as metabolic syndrome (a combined condition of dyslipidemia, diabetes and abnormally high body mass index), which can be overcome by GLP1R-mediated reduction of serum triglycerides and blood glucose levels, increased insulin sensitivity, and GLP1R-mediated weight loss. In some embodiments, the method comprises administering to a subject in need of such treatment and / or prevention an effective amount of a compound of formula IA-1.

[0092] In some embodiments, the present application relates to a method for preventing and / or treating clinical complications of type 1 and type 2 diabetes. Examples of such complications include diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, or peripheral arterial occlusive disease (PAOD). Other clinical complications of diabetes are also encompassed by the present application. In some embodiments, the method comprises administering to a subject in need of such treatment and / or prevention an effective amount of a compound of formula IA-1.

[0093] Furthermore, diseases and disorders resulting from chronic fatty and fibrotic degeneration of organs due to forced accumulation of lipids and / or triglycerides and subsequent activation of profibrotic pathways can also be prevented and / or treated by administering the compounds or pharmaceutical compositions of the present application, including, but not limited to, NASH and chronic cholestatic conditions in the liver, glomerulosclerosis and diabetic nephropathy in the kidney, macular degeneration and diabetic retinopathy in the eye, neurodegenerative diseases such as Alzheimer's disease in the brain, or diabetic neuropathy in the peripheral nervous system.

[0094] In some embodiments, the present application relates to a method for treating and / or preventing diseases and disorders resulting from chronic fatty and fibrotic degeneration of organs due to forced accumulation of lipids and / or triglycerides and subsequent activation of profibrotic pathways, hi some embodiments, the method comprises administering to a subject in need of such treatment and / or prevention an effective amount of a compound of formula IA-1.

[0095] In some embodiments, the compounds of the present application are used in a prodrug or other suitably modified form that releases the active ingredient in vivo.

[0096] The compounds of the present application (also referred to herein as active ingredients) or pharmaceutical compositions of the present application can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intratumoral, intrathecal, and epidural), and the like. It will be understood that the preferred route may vary, for example, depending on the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0097] The compounds of the present application can be administered to an individual according to an effective dosing regimen for a desired period or duration, such as at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or more. In one variation, the compounds are administered daily or intermittently for the life of the individual.

[0098] The dosage or frequency of administration of a compound of the present application may be adjusted over the course of treatment, based on the judgment of the administering physician.

[0099] The compound can be administered to an individual (e.g., a human) in an effective amount. In some embodiments, the compound is administered once a day.

[0100] The compound can be administered by any useful route and means, such as oral or parenteral (e.g., intravenous) administration. The therapeutically effective amount of the compound can be about 0.00001 mg / kg body weight / day to about 10 mg / kg body weight / day, such as about 0.0001 mg / kg body weight / day to about 10 mg / kg body weight / day, or for example, about 0.001 mg / kg body weight / day to about 1 mg / kg body weight / day, or for example, about 0.01 mg / kg body weight / day to about 1 mg / kg body weight / day, or for example, about 0.05 mg / kg body weight / day to about 0.5 mg / kg body weight / day, or for example, about 0.3 mg to about 30 mg / day, or for example, about 30 mg to about 300 mg / day.

[0101] The compounds of the present application can be combined with one or more additional therapeutic agents at any dose of the compounds of the present application (e.g., 1 mg to 1000 mg of the compounds). Therapeutically effective amounts can include about 1 mg to about 1000 mg per dose, such as about 50 mg to about 500 mg per dose, or about 100 mg to about 400 mg per dose, or about 150 mg to about 350 mg per dose, or about 200 mg to about 300 mg per dose. Other therapeutically effective amounts of the compounds of the present application are about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or about 500 mg per dose. Other therapeutically effective amounts of the compounds of the present application are about 100 mg per dose, or about 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, or about 500 mg per dose. A single dose can be administered hourly, daily, or weekly. For example, a single dose can be administered once every 1, 2, 3, 4, 6, 8, 12, 16, or 24 hours. A single dose can also be administered once every 1, 2, 3, 4, 5, 6, or 7 days. A single dose can also be administered once every 1, 2, 3, or 4 weeks. In some embodiments, a single dose can be administered once every week. A single dose can also be administered once every month.

[0102] Also included in the present application are kits comprising a compound of the present application or a pharma- ceutically acceptable salt thereof. In one embodiment, the kit further comprises a label and / or instructions for use of the compound in treating an indication, such as a disease or condition described herein. In one embodiment, the kit comprises a compound of the present application or a pharma- ceutically acceptable salt thereof in combination with one or more (e.g., 1, 2, 3, 4, 1 or 2, or 1-3, or 1-4) additional therapeutic agents.

[0103] V. Combination Therapy Also provided herein is the use of the compounds of the present application in combination with one or more additional therapeutic agents that have a synergistic effect with the compounds of the present application.

[0104] In some embodiments, the one or more additional therapeutic agents comprise an apoptosis signal-regulating kinase (ASK-1) inhibitor, a farnesoid X receptor (FXR) agonist, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, fish oil, an acetyl-CoA carboxylase (ACC) inhibitor, or a TGFβ antagonist, or a combination thereof.

[0105] In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of ACE inhibitors, 2-acylglycerol O-acyltransferase 2 (DGAT2) inhibitors, acetaldehyde dehydrogenase inhibitors, acetyl-CoA carboxylase inhibitors, adrenergic receptor agonists, Alström syndrome protein 1 (ALMS1) / PKCα protein interaction inhibitors, apelin receptor agonists, diacylglycerol O-acyltransferase 2 inhibitors, adenosine A3 receptor agonists, adenosine A3 receptor antagonists, adiponectin receptor agonists, aldehyde dehydrogenase 2 stimulators, AKT protein kinase inhibitors, AMP-activated protein kinase (AMPK), AMP kinase activators, ATP citrate lyase inhibitors, AMP-activated protein kinase stimulators, endothelial nitric oxide synthase stimulators, NAD-dependent deacetylase sirtuin-1 stimulators, androgen receptor agonists, amylin receptor agonists, angiotensin II AT-1 receptor antagonists, autophagy protein regulators, autotaxin inhibitors, Axl tyrosine kinase receptor inhibitors, Bax protein stimulators, β-catenin inhibitors, bioactive lipids, alcitonin agonists, cannabinoid receptor regulators, caspase inhibitors, caspase-3 stimulators, cathepsin inhibitors, caveolin-1 inhibitors, CCK receptor antagonists, CCL26 gene inhibitors, CCR2 chemokine antagonists, CCR2 chemokine antagonists, angiotensin IIAT-1 receptor antagonists, CCR3 chemokine antagonists, CCR5 chemokine antagonists, CD3 antagonists, CDGSH iron-sulfur domain protein modulators, chitinase inhibitors, chloride channel stimulators, chitotriosidase 1 inhibitors, CNR1 inhibitors, connective tissue growth factor ligand inhibitors, cyclin D1 inhibitors, cytochrome P4507A1 inhibitors, DGAT1 / 2 inhibitors, diacylglycerol O-acyltransferase 1 (DGAT1) inhibitors, cytochrome P4502E1 (CYP2E1) inhibitors, CXCR4 chemokine antagonists, dihydroceramide delta 4 desaturase inhibitors, dihydroorotate dehydrogenase inhibitors, dipeptidyl peptidase IV inhibitors, endosialin modulators, eotaxin ligand inhibitors toxic agents, extracellular matrix protein regulators, farnesoid X receptor agonists, fatty acid synthase inhibitors, FGF1 receptor agonists, fibroblast growth factor (FGF-15, FGF-19, FGF-21) ligands, fibroblast activation protein inhibitors, free fatty acid receptor 1 agonists, galectin-3 inhibitors, GDNF family receptor α-like agonists, glucagon receptor agonists, glucagon-like peptide 1 agonists, glucocorticoid receptor antagonists, glucose 6-phosphate 1-dehydrogenase inhibitors, G protein-coupled bile acid receptor 1 agonists, G protein-coupled receptor-119 agonists, G protein-coupled receptor 84 antagonists, hedgehog (Hh) regulators, hepatitis C virus NS3 protease inhibitors, hepatocyte nuclear factor 4 α (HNF4A) regulators, hepatocyte growth factor regulators, histone deacetylase inhibitors, STAT-3 regulators, HMG CoA reductase inhibitors, HSD17B13 gene inhibitors, 5-HT 2a receptor antagonists, hydrolase inhibitors, hypoxia inducible factor-2 α inhibitors, IL-10 agonists, IL-17 antagonists, IL-22 agonists, ileal sodium bile acid cotransporter inhibitors, insulin sensitizers, insulin ligand agonists, insulin receptor agonists, integrin regulators, integrin antagonists, integrin α-V / β-1 antagonists, integrin α-V / β-6 antagonists, interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors, IL-6 receptor agonists, interleukin-17 ligand inhibitors, Jak2 tyrosine kinase inhibitors, JunN-terminal kinase 1 inhibitors, Kelch-like ECH-associated protein 1 regulators, Ketohexokinase (KHK) inhibitors, Klotho-beta stimulators, Leukotriene A4 hydrolase inhibitors, 5-lipoxygenase inhibitors, Lipoprotein lipase inhibitors, Liver X receptor, LPL gene stimulators, Lysophosphatidic acid 1 receptor antagonists, Lysyl oxidase homolog 2 inhibitors, LXR inverse agonists, Macrophage mannose receptor 1 regulators, Matrix metalloproteinase (MMP) inhibitors, MEKK-5 protein kinase inhibitors, MCH receptor-1 antagonists, Membrane copper amine oxidase (VAP-1) inhibitors, Methionine aminopeptidase-2 inhibitors, Methyl CpG-binding protein 2 regulators, MicroRNA-132 (miR-132) antagonists, MicroRNA-21 (miR-21) inhibitors, Mitochondrial uncouplers, Mixed lineage kinase 3 inhibitors, Motile sperm domain protein 2 inhibitors, Myelin basic protein stimulators, NACHT LRR PYD domain protein 3 (NLRP3) inhibitors, NAD-dependent deacetylase sirtuin stimulators, NADPH oxidase (NOX) inhibitors, NFE2L2 gene inhibitors, nicotinic acid receptor 1 agonists, opioid receptor μ antagonists, P2Y13 purinergic receptor stimulators, nuclear erythroid 2-related factor 2 stimulators, nuclear receptor modulators, P2X7 purinergic receptor modulators, PACAPType I receptor agonists, PDE3 inhibitors, PDE4 inhibitors, PDE5 inhibitors, PDGF receptor beta modulators, phenylalanine hydroxylase stimulators, phospholipase C inhibitors, phosphodiester hydrolase inhibitors, PPARα agonists, PPARδ agonists, PPARγ agonists, peptidyl prolyl cis-trans isomerase A inhibitors, PNPLA3 gene inhibitors, PPARγ modulators, protease-activated receptor 2 antagonists, protein kinase modulators, protein NOV homolog modulators, PTGS2 gene inhibitors, renin inhibitors, resistin / CAP1 (adenylyl cyclase-associated protein 1) interaction inhibitors, Rho-associated protein kinase inhibitors, S-nitrosoglutathione reductase (GSNOR) enzyme inhibitors, sodium glucose transporter-2 inhibitors, sphingolipid delta the inhibitor is selected from the group consisting of 4 desaturase DES1 inhibitors, SREBP transcription factor inhibitors, STAT-1 inhibitors, stearoyl-CoA desaturase-1 inhibitors, STK25 inhibitors, suppressor of cytokine signaling-1 stimulators, suppressor of cytokine signaling-3 stimulators, telomerase stimulators, TERT gene regulators, TGFβ (TGFB1) ligand inhibitors, TNF antagonists, transforming growth factor beta (TGF-β), transforming growth factor beta activated kinase 1 (TAK1), thyroid hormone receptor beta agonists, TLR-4 antagonists, transglutaminase inhibitors, tyrosine kinase receptor modulators, GPCR modulators, nuclear hormone receptor modulators, TLR-9 antagonists, VDR agonists, WNT modulators, YAP / TAZ modulators, and zonulin inhibitors.

[0106] Non-limiting examples of the one or more additional therapeutic agents include: -ACE inhibitors such as enalapril, -acetaldehyde dehydrogenase inhibitors, such as ADX-629; -Acetyl-CoA carboxylase (ACC) inhibitors such as NDI-010976 (firsocostat), DRM-01, gemcabene, GS-834356, PF-05175157, QLT-091382, PF-05221304, -Acetyl-CoA carboxylase / diacylglycerol O-acyltransferase 2 inhibitors, such as PF-07055341; - Adenosine receptor agonists such as CF-102 (namodenoson), CF-101, CF-502, and CGS21680; -Adenosine A3 receptor antagonists such as FM-101, -Adiponectin receptor agonists such as ADP-355 and ADP-399, -Adrenergic receptor antagonists such as bromocriptine, phentermine, and VI-0521, -Aldehyde dehydrogenase 2 stimulators such as FP-045, - alpha-glucosidase inhibitors (e.g., voglibose, acarbose, or miglitol), - amylin / calcitonin receptor agonists such as KBP-042, KBP-089, -AMP-activated protein kinase stimulators such as C-455, PXL-770, and O-304, -AMP kinase activators / ATP citrate lyase inhibitors such as bempedoic acid (ETC-1002, ESP-55016), -AMP-activated protein kinase / endothelial nitric oxide synthase / NAD-dependent deacetylase sirtuin-1 stimulators such as NS-0200 (leucine + metformin + sildenafil), -Androgen receptor agonists such as LPCN-1144, LPCN-1148, testosterone prodrugs, -Angiotensin II AT-1 receptor antagonists such as irbesartan, angiopoietin-related protein 3 inhibitors such as bupanorsen (IONIS-ANGPTL3-LRx), -Apelin receptor agonists such as CB-5064 and MBT-2, -Autophagy protein regulators such as A-2906, - Autotaxin (ectonucleotide pyrophosphatase / phosphodiesterase 2 (NPP2 or ENPP2)) inhibitors such as FP10.47, PAT-505, PAT-048, GLPG-1690, X-165, PF-8380, TJC-0265, TJC-0316, AM-063, BBT-877, -Axl tyrosine kinase receptor inhibitors, such as bencetinib (BGB-324, R-428), - Bax protein stimulators such as CBL-514, -Bioactive lipids such as DS-102, -Cannabinoid receptor modulators such as namacizumab (nimasimab), GWP-42004, REV-200, CRB-4001, INV-101, and SCN-002; -Caspase inhibitors such as emricasan, - pan-cathepsin B inhibitors, such as VBY-376; - pan-cathepsin inhibitors, such as VBY-825; -CCK receptor antagonists such as proglumide, - CCL26 gene inhibitors such as mosedipimod and KDDF-201410-10, -CCR2 / CCR5 chemokine antagonists such as BMS-687681, cenicriviroc, maraviroc, CCX-872, leronlimab, and WXSH-0213; -CCR2 / CCR5 chemokine antagonists and FXR agonists, such as LJC-242 (tropifexor + cenicriviroc), -CCR2 chemokine antagonists such as propagermanium, -CCR2 chemokine / angiotensin II AT-1 receptor antagonists such as DMX-200, DMX-250, -CCR3 chemokine antagonists such as bertilimumab, -CD3 antagonists such as NI-0401 (foralumab), - CDGSH iron-sulfur domain protein modulators, such as EYP-002, -chitinase inhibitors such as OATD-01, - Chitotriosidase 1 inhibitors, such as OAT-2068, -Chloride channel stimulants such as cobiprostone and lubiprostone, - Casein kinase-1 (CK1) delta / epsilon inhibitors, such as PF-05006739; -Connective tissue growth factor ligand inhibitors, such as PBI-4050, -CXCR4 chemokine antagonists such as AD-214, -Diglyceride acyltransferase 2 (DGAT2) inhibitors, such as IONIS-DGAT2Rx and PF-06865571; -Diglyceride acyltransferase 1 (DGAT1) inhibitors, such as GSK-3008356; -Diacylglycerol O-acyltransferase 1 (DGAT1) / cytochrome P4502E1 (CYP2E1) inhibitors, such as SNP-610; -Dihydroorotate dehydrogenase inhibitors such as bidofludimus, -Dipeptidyl peptidase IV inhibitors such as linagliptin and evogliptin, -Eotaxin ligand inhibitors such as bertilimumab and CM-101, -Extracellular matrix protein modulators, such as CNX-024, -AGN-242266, AGN-242256, ASC-42, EDP-297 (EP-024297), RDX-023, BWL-200, AKN-083, EDP-305, GNF-5120, cilofexor tromethamine (GS-9674), HPG-1860, IOT-022, LMB-763, obeticholic acid, P farnesoid X receptor (FXR) agonists such as x-102, Px-103, M790, M780, M450, M-480, MET-409, MET-642, PX20606, SYHA-1805, bonafexor (EYP-001), TERN-101, TC-100, INT-2228, TQA-3526, and ZG-5266; -Farnesoid X receptor (FXR) / G protein-coupled bile acid receptor 1 (TGR5) agonists, such as INT-767; -Fatty acid synthase inhibitors such as TVB-2640 and FT-8225, -fibroblast growth factor 19 (rhFGF19) / cytochrome P450 (CYP) 7A1 inhibitors, such as aldafermin (NGM-282); - Fibroblast growth factor 21 (FGF-21) ligand modulators such as AP-025, BMS-986171, B-1654, BIO89-100, and BOS-580; -Peg Belfermin (BMS-986036), B-1344, - Fibroblast growth factor 21 (FGF-21) / glucagon-like peptide 1 (GLP-1) agonists such as YH-25723 (YH-25724, YH-22241) and efluxfermin (AKR-001); -FGF receptor agonists / Klotho-β stimulants such as BFKB-8488A (RG-7992); -Free fatty acid receptor 1 agonists, such as SCO-267, -Galectin-3 inhibitors such as Bellapectin (GR-MD-02), GB-1107 (Gal-300), and GB-1211 (Gal-400); -GDNF family receptor alpha agonists such as NGM-395, - Glucagon-like peptide 1 (GLP1R) agonists such as ALT-801, AC-3174, liraglutide, cotadutide (MEDI-0382), SAR-425899, LY-3305677, HM-15211, YH-25723, YH-GLP1, RPC-8844, PB-718, PF-06882961, and semaglutide; -Glucagon-like peptide 1 receptor agonists, oxyntomodulin ligands, glucagon receptor agonists (e.g., efinopeglutide), -Gastric inhibitory polypeptide / glucagon-like peptide-1 (GIP / GLP-1) receptor coagonists, such as tirzepatide (LY-3298176); -PEGylated long-acting glucagon-like peptide-1 / glucagon (GLP-1R / GCGR) receptor dual agonists, such as DD-01; -glucagon / GLP1 receptor agonists, such as BI-456906; -Glucocorticoid receptor antagonists, such as CORT-118335 (myricolant), -glucose 6-phosphate 1-dehydrogenase inhibitors, such as ST001; -Glucokinase stimulators such as dorzagliatin and sinogliatin (RO-5305552), -G protein-coupled bile acid receptor 1 (TGR5) agonists, such as RDX-009, INT-777, and HY-209; -G protein-coupled receptor 84 antagonists, such as PBI-4547, -G protein-coupled receptor-119 agonists, such as DA-1241, -Heat shock protein 47 (HSP47) inhibitors, such as ND-L02-s0201; - Hedgehog protein and / or TGFβ ligand inhibitors, such as Oxy-210; -histone deacetylase inhibitors / STAT-3 modulators such as SFX-01, -HMG CoA reductase inhibitors such as atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin, -HSD17B13 gene inhibitors such as ALN-HSD and ARO-HSD, -Hydrolytic enzyme inhibitors such as ABD-X, - Hypoxia-inducible factor-2 alpha inhibitors such as PT-2567, -IL-10 agonists such as peg-ilodecaquine, - ileal sodium bile acid cotransporter inhibitors such as odebixibat (A-4250), borixibat potassium ethanolate hydrate (SHP-262), GSK2330672, CJ-14199, and elobixibat (A-3309); - insulin sensitizers such as KBP-042, azemiglitazone potassium (MSDC-0602K), ION-224, MSDC-5514, Px-102, RG-125 (AZD4076), trimidone, VVP-100X, CB-4211, ETI-101, and pioglitazone; -Insulin ligands / ds insulin receptor agonists such as ORMD-0801, -Integrin antagonists such as IDL-2965, -IL-6 receptor agonists such as KM-2702, - dual integrin α-V / β-6 and α-V / β-1 inhibitors such as PLN-74809; -Interleukin-17 ligand inhibitors, such as netakimab, -Jak1 / 2 tyrosine kinase inhibitors such as baricitinib, - Jun N-terminal kinase-1 inhibitors such as CC-90001, -Kelch-like ECH-associated protein 1 modulators, such as α-cyclodextrin-stabilized sulforaphane, -Ketohexokinase (KHK) inhibitors such as PF-06835919 and LY-3478045; -β-Klotho (KLB)-FGF1c agonists, such as MK-3655 (NGM-313); - leukotriene A4 hydrolase inhibitors, such as LYS-006; - 5-lipoxygenase inhibitors such as tipelukast (MN-001), epeleutone (DS-102, (AF-102), - lipoprotein lipase inhibitors such as CAT-2003, -LPL gene stimulators such as alipogene tiparvovec, -Liver X receptor (LXR) inhibitors, such as PX-665, PX-L603, PX-L493, BMS-852927, T-0901317, GW-3965, and SR-9238; - Lysophosphatidic acid-1 receptor antagonists such as BMT-053011, UD-009 (CP-2090), AR-479, ITMN-10534, BMS-986020, and KI-16198; - lysyl oxidase homolog 2 inhibitors such as simtuzumab, PXS-5382A (PXS-5338), - macrophage mannose receptor 1 modulators such as tilmanocept-Cy3 (technetium Tc 99m tilmanocept), -Matrix metalloproteinase inhibitors such as ALS-L1023, -Membrane copper amine oxidase (VAP-1) inhibitors such as TERN-201, TT-01025, -MEKK-5 protein kinase (ASK-1) inhibitors such as CJ-16871, CS-17919, selonsertib (GS-4997), SRT-015, GS-444217, GST-HG-151, TERN-301, -MCH receptor 1 antagonists, such as CSTI-100 (ALB-127158); - semicarbazide-sensitive amine oxidase / vascular adhesion protein-1 (SSAO / VAP-1) inhibitors, such as PXS-4728A (BI-1467335); -Methionine aminopeptidase-2 inhibitors such as ZGN-1061, ZGN-839, ZN-1345, -Methyl-CpG binding protein 2 modulators such as mercaptamines, -Mineralocorticoid receptor antagonists (MCRAs), such as MT-3995 (Aparalenone); -Mitochondrial uncouplers such as 2,4-dinitrophenol, HU6, and Mito-99-0053, -mixed lineage kinase-3 inhibitors, such as URMC-099-C, -Motile sperm domain protein 2 inhibitors, such as VB-601; -Myelin basic protein stimulators such as olesoxime, -Myeloperoxidase inhibitors such as PF-06667272, AZM-198, -NADPH oxidase inhibitors such as GKT-831, GenKyoTex, APX-311, and setanaxib, - Nicotinic acid receptor 1 agonists, such as ARI-3037MO, - NACHTLRR PYD domain protein 3 (NLRP3) inhibitors such as KDDF-201406-03, NBC-6, IFM-514, and JT-194 (JT-349); -NFE2L2 gene inhibitors such as GeRP-amiR-144, - Nuclear receptor modulators such as DUR-928 (Dv-928), -Opioid receptor μ antagonists such as methylnaltrexone, - P2X7 purinergic receptor modulators, such as SGM-1019, - P2Y13 purinergic receptor stimulants, such as CER-209, -PDE3 / 4 inhibitors such as tipelukast (MN-001), -PDE5 inhibitors, such as MSTM-102, -PDGF receptor beta modulators such as BOT-191, BOT-509, - peptidyl prolyl cis-trans isomerase inhibitors, such as CRV-431 (CPI-432-32), NVP-018, and NV-556 (NVP-025); -Phenylalanine hydroxylase stimulators such as HepaStem, - phosphodiester hydrolase inhibitors such as ZSP-1601, - PNPLA3 gene inhibitors, such as AZD-2693, -Tiglitazar, Elafibranor (GFT-505), Seradelparridine (MBX-8025), Deuterated Pioglitazone R-enantiomer, Pioglitazone, PXL-065 (DRX-065), PPAR agonists such as saroglitazar, lanifibranor (IVA-337), CHS-131, pemafibrate (K-877), ZG-0588, ZSP-0678, and ZSYM-008; -Protease-activated receptor-2 antagonists, such as PZ-235, - protein kinase modulators, such as CNX-014; - protein NOV homologue regulators, such as BLR-200, -PTGS2 gene inhibitors such as STP-705 and STP-707, -renin inhibitors such as PRO-20, - resistin / CAP1 (adenylyl cyclase-associated protein 1) interaction inhibitors, such as DWJ-211; -Rev protein modulators such as ABX-464, -Rho-associated protein kinase (ROCK) inhibitors such as REDX-10178 (REDX-10325), KD-025, RXC-007, and TDI-01; -S-nitrosoglutathione reductase (GSNOR) enzyme inhibitors, such as SL-891; - Sodium glucose transporter-2 (SGLT2) inhibitors such as ipragliflozin, remogliflozin etabonate, ertugliflozin, dapagliflozin, tofogliflozin, and sotagliflozin; - Sodium glucose transporter-1 / 2 (SGLT 1 / 2) inhibitors, such as licogliflozin bis(prophosphate) (LIK-066); - SREBP transcription factor inhibitors such as CAT-2003, HPN-01, and MDV-4463, -Stearoyl CoA desaturase-1 inhibitors such as aramchol, -Thyroid hormone receptor beta agonists, such as ALG-009, ASC-41, CNPT-101101, CNPT-101207, CS-27186, KY-41111, resmetirom (MGL-3196), MGL-3745, TERN-501, and VK-2809; -TLR-2 / TLR-4 antagonists such as VB-201 (CI-201); -TLR-4 antagonists such as JKB-121, JKB-122, and naltrexone, - tyrosine kinase receptor modulators such as CNX-025, GFE-2137 (repurposed nitazoxanide), -TLR-9 antagonists such as GNKS-356, -TNF antagonists such as ALF-421, -GPCR modulators such as CNX-023, -Nuclear hormone receptor modulators such as Px-102, -VDR agonists such as CK-15, -xanthine oxidase inhibitors, such as ACQT-1127, xanthine oxidase / urate anion exchanger 1 (URAT1) inhibitors, such as RLBN-1001 and RLBN-1127, as well as -Zonulin inhibitors such as lorazotide acetate (INN-202).

[0107] In some embodiments, the one or more additional therapeutic agents are A-4250, AC-3174, acetylsalicylic acid, AK-20, alipogen tiparvovec, AMX-342, AN-3015, anti-TAGE antibodies, aramchol, ARI-3037MO, ASP-8232, AZD-2693, bertilimumab, betaine anhydrous, BI-1467335, BMS-986036, BMS-986171, BMT-053011, BOT-191, BTT-1023, budesonide, BX-003, CAT-2003, cenicriviroc, CBW-511, CER -209, CF-102, CGS21680, CNX-014, CNX-023, CNX-024, CNX-025, cobiprostone, colesevelam, dabigatran etexilate mesylate, dapagliflozin, DCR-LIV1, deuterated pioglitazone R-enantiomer, 2,4-dinitrophenol, DRX-065, DS-102, DUR-928, EDP-305, elafibranor (GFT-505), emricasan, enalapril, ertugliflozin, evogliptin, F-351, fluasterone (ST-002), FT-41 01, GDD-3898, GH-509, GKT-831, GNF-5120, GRI-0621, GR-MD-02, GS-300, GS-4997, GS-9674, HEC-96719, HTD-1801, HS-10356, HSG-4112, HST-202, HST-201, HU-6, hydrochlorothiazide, icosabtate (PRC-4016), icosapentaenoic acid ethyl ester, IMM-124-E, INT-767, INV-240, IONIS-DGAT2Rx, ipragliflozin, irbesarta, propagermanium, IVA -337, J2H-1702, JKB-121, KB-GE-001, KBLP-004, KBLP-009, KBP-042, KD-025, M790, M780, M450, metformin, sildenafil, LB-700, LC-280126, linagliptin, liraglutide, (LJN-452) (Tropifexor), LM-011, LM-002 (CVI-LM-002), LMB-763, LYN-100, MB-N-008, MBX-8025, MDV-4463, mercaptamine, MGL-3196, MGL-3745, MP-301,MSDC-0602K, Namacizumab, NC-101, NDI-010976, ND-L02-s0201 (BMS-986263), NGM-282, NGM-313, NGM-386, NGM-395, NP-011, NP-135, NP-160, Norursodeoxycholic acid, NV-422, NVP-022, O-304, Obeticholic acid (OCA), 25HC3S, Olesoxime, PAT-505, PAT-048, PBI-4547 , peg-ilodecaquin, pioglitazone, pirfenidone, PRI-724, PX20606, Px-102, PX-L603, PX-L493, PXS-4728A, PZ-235, PZH-2109, RCYM-001, RDX-009, remogliflozin etabonate, RG-125 (AZD4076), RPI-500, S-723595, saroglitazar, SBP-301, semaglutide, SH-2442, SHC-028, SHC- 023, simtuzumab, solithromycin, sotagliflozin, statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), symbiotic, TCM-606F, TEV-45478, TQA-3526, TQA-3563, tipelukast (MN-001), TLY-012, TRX-318, TVB-2640, TXR-612, TS-20004, UD-009, UN-0 3, selected from ursodeoxycholic acid, VBY-376, VBY-825, VK-2809, vismodegib, borixib potassium ethanolate hydrate (SHP-626), VVP-100X, WAV-301, WNT-974, WXSH-0038, WXSH-0078, XEN-103, XRx-117, XTYW-003, XW-003, XW-004, ZGN-839, ZG-5216, ZSYM-008, and ZYSM-007.

[0108] In some embodiments, the compounds of the present application are useful as anti-obesity agents, peptide YY and its analogs, neuropeptide Y receptor type 2 (NPYR2) agonists, NPYR1 agonists, NPYR5 antagonists, cannabinoid receptor type 1 (CB1 R antagonists, lipase inhibitors (e.g., orlistat), human islet forming peptide (HIP), melanocortin receptor 4 agonists (e.g., setomelanotide), melanin-concentrating hormone receptor 1 antagonists, phagocytosis signal-regulating kinase (ASK-1) inhibitors, zonisamide, phentermine (alone or in combination with topiramate), norepinephrine / dopamine reuptake inhibitors (e.g., bupropion), opioid receptor antagonists (e.g., naltrexone), combinations of norepinephrine / dopamine reuptake inhibitors and opioid receptor antagonists (e.g., bupropion and naltrexone), GDF-15 analogs, sibutramine, cholecystokinin agonists, amylin and its analogs (e.g., praxonamide ... murintide), leptin and its analogs (e.g., metroleptin), serotonergic agents (e.g., lorcaserin), methionine aminopeptidase 2 (MetAP2) inhibitors (e.g., beloranib or ZGN-1061), phendimetrazine, diethylpropion, benzphetamine, SGLT2 inhibitors (e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, or ertugliflozin), SGLTL1 inhibitors, SGLT2 / SGLT1 dual inhibitors, fibroblast growth factor receptor (FGFR) modulators, AMP-activated protein kinase (AMPK) activators, biotin, MAS receptor modulators, glucagon receptor agonists (alone or with other GLP-1R agonists (e.g., in combination with liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, or semaglutide), insulin sensitizers such as thiazolidinediones (TZDs), peroxisome proliferator-activated receptor alpha (PPARα) agonists, fish oil, acetyl-CoA carboxylase (ACC) inhibitors, transforming growth factor beta (TGFβ) antagonists, GDNF family receptor alpha-like (GFRAL) agonists, and melanocortin-4 receptor (MC4R) agonists. EXAMPLES

[0109] synthesis The compounds of the present disclosure can be prepared using the methods disclosed herein and the routine modifications thereof that become apparent in light of the disclosure of the present specification and methods well known in the art.In addition to the teachings of the present specification, conventional well-known synthetic methods can be used.The synthesis of the exemplary compound of formula IA-1 or its pharma-ceutically acceptable salt (e.g., the compound having the structure described in one or more of formula IA-1 or other formulas, or the compound disclosed herein) can be achieved as illustrated in the following examples.

[0110] General Synthesis Exemplary embodiments of the compounds according to the present application can be synthesized using the general reaction schemes and / or examples described below. In view of the description herein, it will be apparent that the general schemes can be modified by replacing the starting materials with other materials having similar structures to obtain different products accordingly. The synthetic description provides numerous examples of how the starting materials can be varied to obtain the corresponding products. The starting materials are typically obtained from commercial sources or are synthesized using published methods for synthesizing the compounds that are embodiments of the present application, and the identity of each substituent is obtained by inspecting the structure of the compound to be synthesized. In view of the examples herein, the identity of the final product will generally reveal the identity of the necessary starting materials by a simple inspection process. The group labels (e.g., R1, R2) used in the reaction schemes herein are for illustrative purposes only and do not necessarily correspond in name or function to the labels used elsewhere to describe the compounds of formula IA-1 or aspects or fragments thereof, unless otherwise specified.

[0111] Synthesis reaction parameters The compounds of the present disclosure can be prepared, for example, from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, it will be understood that other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0112] Moreover, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, numerous protecting groups are described in TW Greene and GM Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York and references cited therein.

[0113] In addition, the compounds of the present application may contain one or more chiral centers. Thus, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. Unless otherwise indicated, all such stereoisomers (and enriched mixtures) are included within the scope of the present disclosure. Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral resolving agents, and the like.

[0114] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). Others can be prepared by procedures described in standard references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplemental (Elsevier Science Publishers, 1989) organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989) or obvious modifications thereof.

[0115] The terms "solvent", "inert organic solvent" or "inert solvent" refer to a solvent that is inert under the conditions of the reaction described therein, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), N,N-dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine, and the like. Unless otherwise specified, the solvents used in the reactions of this application are inert organic solvents and the reactions are carried out under an inert gas, preferably nitrogen.

[0116] The term "qs" means adding a quantity sufficient to achieve a stated function, for example, a quantity sufficient to bring a solution to the desired volume (ie, 100%).

[0117] The compounds provided herein can be synthesized according to the general schemes shown below. In the schemes below, it should be understood that each compound shown therein may have protecting groups at any step, as necessary. Standard protecting groups are well within the knowledge of one of ordinary skill in the art.

[0118] Example 1: Synthesis of compound of formula IA-1 In another aspect, the present invention provides methods for preparing a compound of formula IA-1, a pharma- ceutically acceptable salt, ester, or stereoisomer thereof, the methods including six general routes (Route 1, Route 2, Route 3, Route 4, Route 5, and Route 6). Route 1: [ka] Route 2: [ka] Route 3: [ka] Route 4: [ka] Route 5: [ka] Route 6: [ka]

[0119] Preparation of intermediates The intermediate can be synthesized via the following five routes: Route 1 [ka] Route 2 [ka] Route 3 [ka] Route 4 [ka] Route 5 [ka]

[0120] Preparation of 3,7-dimethyl-1H-indazol-5-amine (Intermediate A) [ka] NIS (N-iodosuccinimide) (29.0 g, 1.1 equiv.) was added to a solution of 5-bromo-7-methyl-1H-indazole (25.0 g) in DCE (1,2-dichloroethane) (200 ml) at room temperature (RT), and the mixture was stirred at 80° C. for 12 h. After cooling to room temperature, the reaction mixture was diluted with THF (tetrahydrofuran), washed with Na2S2SO3 (aq.) and brine, dried over anhydrous Na2SO4, and concentrated to give the desired product intermediate A-2 as a yellow solid, which was further purified by washing with PE (petroleum ether) (35.0 g, yield: 87.7%).

[0121] NaH (11.5 g, 2.5 equiv.) was added to a stirred solution of intermediate A-2 (40 g) and SemCl (40 g, 2.1 equiv.) in THF (250 ml) at 0° C. The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was quenched with HO, extracted with EA (ethyl acetate) and the organic phase was concentrated in vacuo to give intermediate A-3 (45.4 g, yield: 81.9%).

[0122] Pd2(dppf)Cl2 (0.9 g), K3PO4 (11.04 g, 2.7 equiv.), and CH3B(OH)2 (1.96 g, 1.7 equiv.) were added to a solution of intermediate A-3 (9.0 g) in dioxane with stirring at 25° C. The mixture was stirred at 95° C. for 3 h. After the mixture was cooled, the solid was filtered, and then the filtrate was concentrated under vacuum to obtain intermediate A-4, and the residue was purified by silica gel column chromatogram (EA / PE) to obtain the title compound as a colored solid (5.4 g, 78.9% yield).

[0123] NH2Boc (5.2 g, 4 equiv.), Cs2CO3 (14.4 g, 4 equiv.), Pd2(dba)3 (1.2 g, 0.15 equiv.), and X-phos (1.8 g, 0.3 equiv.) were added to a solution of intermediate A-4 (4.0 g) in dioxane (100 ml) at room temperature, and the mixture was stirred at 100 °C under N2 for 4 h. After cooling the reaction, the mixture was quenched with water (100 ml) and extracted with EA (100 ml x 2). The residue was purified by silica gel column chromatogram (EA / PE = 1 / 40 to 1 / 10) to give intermediate A-5 (3.6 g, 81.7% yield).

[0124] To a solution of intermediate A-5 (3.6 g) in MeOH (5 ml), HCl / EA (2 M, 10 ml) was added and the mixture was stirred for 4 h at 40° C. A white solid was precipitated and filtered to give intermediate A (1.4 g, yield: 94.5%). 1 H NMR (500 MHz, chloroform-d) δ 11.40 (s, 1H), 6.85 (d, J = 2.2 Hz, 1H), 6.68 (d, J = 2.0 Hz, 1H), 4.35 (d, J = 5.1 Hz, 1H), 4.33 (d, J = 5.1 Hz, 1H), 2.95 (s, 3H), 2.65 (s, 3H).

[0125] Preparation of 7-fluoro-3-methyl-1H-indazol-5-amine (Intermediate B) [ka] Intermediate B-1 (5.0 g) and hydrazinium hydroxide solution (98%, 2.7 g, 2.5 eq.) were added to NMP (N-methylpyrrolidone) (15 ml). The mixture was stirred under N2 at 150° C. for 4 h. After cooling the reaction, a white solid was precipitated and filtered to give Intermediate B-2 (3.8 g, 78.0%).

[0126] The next reaction sequence can be followed for the preparation of intermediate A to give 7-fluoro-3-methyl-1H-indazol-5-amine.

[0127] Preparation of 3,7-dimethyl-1H-indazole-5-carboxylic acid (intermediate C) [ka] Intermediate C-1 (2.0 g), trimethylamine (2.24 g, 2.5 equiv.), 2,2'-bis(diphenylphosphino)-1,10-binaphthyl (0.55 g, 0.1 equiv.), and PdCl2 (0.31 g, 0.2 equiv.) were added to methanol (20 ml) and acetonitrile (20 ml). The mixture was placed under carbon monoxide atmosphere (40 bar), vigorously stirred at 100°C for 18 h, cooled and exposed to air. The cooled reaction mixture was filtered through Celite and the solvent was removed in vacuo. NaOH (4M, 5 ml) was added to the filtrate and stirred for 30 min. HCl (2M) was then added to the mixture until pH 6 was reached. A white solid was precipitated and filtered to give intermediate C (0.7 g, yield: 41.4%). 1 H NMR (500 MHz, chloroform-d) δ 8.44 (d, J = 2.2 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 2.97 (s, 3H), 2.66 (s, 3H).

[0128] Preparation of 3-cyclopropyl-7-methyl-1H-indazol-5-amine (Intermediate D) [ka] A solution of 2-isopropylaniline (Intermediate D-1, 2.14 g, 0.02 mol) in 1,2-dichloroethane (10 ml) was added to a solution of boron trichloride (20 ml, 0.02 mol, 1M in toluene) in dichloromethane at 0° C. with stirring. Aluminum chloride (2.96 g, 0.022 mol) and cyclopropanecarbonitrile (2.01 g, 0.03 mol) were then added to the mixture. The reaction mixture was refluxed at 80° C. for 20 hours. The reaction mixture was then cooled to 0° C., followed by the addition of 2N HCl (10 ml). The reaction mixture was heated to 80° C. and stirred for an additional 30 minutes. The reaction mixture was then cooled to room temperature and extracted with dichloromethane. The organic layer was washed with 1N NaOH (10 ml) and brine and dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography to give the title compound, intermediate D-2 (2.1 g, 60%) as a yellow solid.

[0129] KNO3 (1.38 g, 13.7 mmol) was slowly added to a stirred solution of intermediate D-2 (2.0 g, 11.4 mmol) in H2SO4 (98%, 8 ml) at 0°C and stirred for 2 hours. The mixture was slowly added to ice water (50 ml) and extracted with ethyl acetate (50 ml) to produce an organic layer. The organic layer was removed under reduced pressure to give intermediate D-3 (1.9 g, 76%) as a yellow solid.

[0130] To a solution of intermediate D-3 (1.9 g, 8.6 mmol) and hydroxylamine hydrochloride (1.8 g, 25.8 mmol) in water (2 ml) and ethanol (8 ml) was added sodium hydroxide (2.7 g, 68.8 mmol) under nitrogen atmosphere with stirring at 0 °C. After addition, the mixture was refluxed at 80 °C for 1 h. The mixture was concentrated and the residue was dissolved in water (14 ml) and extracted with ethyl acetate (20 ml x 2) to obtain the organic layer, which was concentrated in vacuum. The residue was dissolved in dichloromethane (10 ml). Triethylamine (1.74 g, 17.2 mmol) was added slowly and the reaction mixture was stirred at room temperature for 15 min and then cooled to 0-5 °C in an ice / water bath. Methanesulfonyl chloride (1.25 g, 10.9 mmol) was added to 30 mL of dichloromethane and the resulting solution was cooled to 0-5 °C. A cold solution of methanesulfonyl chloride was added dropwise to the mixture. The resulting solution was stirred at 0-5 °C for 1.5 h. Silica gel was added and the green / brown solution was concentrated by rotary evaporation. The residue was purified by flash column chromatography to give the title compound, intermediate D-4 (1.65 g, 88%) as a yellow solid.

[0131] Intermediate D-4 (1.65 g, 7.6 mmol) and Pd / C (0.16 g, 10% w / w, 30% water) were added to methanol (10 ml) in a 50 ml one-neck round-bottom flask. The flask was fitted with a hydrogen balloon and stirred for 4 h until the yellow color disappeared. After filtration, the filtrate was concentrated in vacuo to give Intermediate D (1.25 g, 88%) as a brown oil. LCMS (ESI): Calcd for C11H13N3; [M+H] + : 188.1, Actual value: 188.1. 1 H NMR (500 MHz, chloroform-d) δ 7.15 (d, J = 2.2 Hz, 1H), 6.84 (d, J = 2.2 Hz, 1H), 4.42-4.32 (m, 2H), 2.66 (s, 3H), 2.24-2.19 (m, 1H), 1.03-0.87 (m, 4H).

[0132] Preparation of 7-fluoro-3-methyl-1H-indazole-5-carboxylic acid (Intermediate E) [ka] A solution of methyl 4-amino-3-fluorobenzoate (intermediate E-1, 3.38 g, 0.20 mol) in 1,2-dichloroethane (10 mL) was added to a solution of boron trichloride (20 ml, 20 mmol, 1M in toluene) in dichloromethane with stirring at 0° C. To the mixture was added aluminum chloride (2.94 g, 22 mol) and acetonitrile (1.2 g, 30 mmol). The reaction mixture was refluxed at 80° C. for 20 hours. After cooling, 2N HCl (10 ml) was added. The reaction mixture was then heated to 80° C. and stirred for an additional 30 minutes. The reaction mixture was then cooled to room temperature and extracted with dichloromethane. The organic layer was washed with 1N NaOH (10 ml) and brine and dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography to give the title compound (Intermediate E-2) (2.98 g, 70.65%) as a yellow solid.

[0133] To a solution of intermediate E-2 (2 g, 9.5 mmol) and hydroxylamine hydrochloride (1.97 g, 28.5 mmol) in water (2 ml) and ethanol (8 mL) was added sodium hydroxide (2.3 g, 57.6 mmol) under nitrogen with stirring at 0 °C. After addition, the mixture was refluxed at 80 °C for 1 h. The mixture was concentrated and the residue was dissolved in water (14 ml) and extracted with ethyl acetate (20 ml x 2) to produce an organic layer, which was concentrated in vacuo. The residue was dissolved in dichloromethane (10 ml). Triethylamine (1.6 g, 14.8 mmol) was added slowly and the reaction mixture was stirred at room temperature for 15 min and then cooled to 0-5 °C in an ice / water bath. Methanesulfonyl chloride (1.08 g, 9.5 mmol) was added to 30 ml of dichloromethane and the resulting solution was cooled to 0-5 °C. A cold solution of methanesulfonyl chloride was added dropwise to the mixture. The resulting solution was stirred at 0-5 °C for 1.5 h. Silica gel was added and the green / brown solution was concentrated by rotary evaporation. The residue was purified by flash column chromatography to give the title compound, Intermediate E-3 (1.43 g, 73%) as a yellow solid.

[0134] Intermediate E-3 (1.43 g, 6.87 mmol) and NaOH (1.1 g, 27.5 mmol) were added to methanol (10 ml) and water (5 ml) and stirred at 60° C. for 1 h. After cooling, the mixture reaction was concentrated in vacuum. The residue was dissolved in water (10 ml) and 1N HCl was added to adjust the pH to 7. Then, ethyl acetate (20 ml×2) was added for extraction to obtain an organic layer. The solvent was removed under reduced pressure to obtain intermediate E (1.25 g, 94%) as a white solid. LCMS (ESI): calculated for C9H7FN2O2; [M+H] + :195.0,Actual value:195.0. 1 H NMR (500 MHz, chloroform-d) δ 11.22 (s, 1H), 8.36 (d, J = 2.2 Hz, 1H), 7.705 (dd, J = 7.9, 2.0 Hz, 1H), 2.95 (s, 3H).

[0135] Preparation of tert-butyl (2-(chloromethyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamate (Intermediate F) [ka] Di-tert-butyl dicarbonate (30.88 g, 141.66 mmol) was added portionwise to a solution of intermediate F-1 (17.0 g, 108.97 mmol) in tert-butanol (250 ml). The reaction mixture was stirred at 55° C. for 8 h. The resulting mixture was concentrated in vacuo. The residue was triturated with petroleum ether (300 ml) at 0° C. to give intermediate F-2 as an off-white solid (26 g, 93.2%). LCMS m / z 257.2 [M+H]+.

[0136] 1-(1-Ethyl-1H-imidazol-5-yl)methanamine dihydrochloride (2.18 g, 11 mmol) and K2CO3 (6.95 g, 50 mmol) were added to a solution of intermediate F-2 (2.56 g, 10 mmol) in DMF (N,N-dimethylformamide) (30 ml). The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was poured into water (300 ml) and then extracted with EtOAc (400 ml x 2). The combined organic extracts were washed with brine (200 ml x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (0-5% MeOH / DCM (dichloromethane)) to give intermediate F-3 (2.2 g, 61%) as a pale red solid. LCMS m / z 362.40 [M+H]+.

[0137] Intermediate F-3 (181 mg, 0.501 mmol) was suspended in MeOH (150 ml) and treated with 10% palladium on carbon (20 mg) and the mixture was stirred at room temperature under 50 psi of H2 for 1 h. The mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure to give Intermediate F-4 (154 mg, 93%) as a light brown solid, which was used directly in the next step. LCMS m / z 332.20 [M+H+].

[0138] 2-Chloro-1,1,1-trimethoxyethane (143 mg, 0.93 mmol) and pyridin-1-ium 4-methylbenzenesulfonate (23.2 mg, 0.093 mmol) were added to a solution of intermediate F-4 (123 mg, 0.37 mmol) in MeCN (5 ml). The mixture was heated to 70° C. for 1 h. The reaction was cooled to room temperature and concentrated under reduced pressure. The resulting crude product was triturated in 50% EtOAc / heptane. The solid was collected by filtration to give intermediate F (102 mg, 70%) as a brown solid. LCMS m / z 390.10 [M+H+].

[0139] Preparation of 2-bromo-6-((4-chloro-2-fluorobenzyl)oxy)pyridine (Intermediate G) [ka] t-BuOK (21.0 g, 187 mmol) was added to a solution of intermediate G-1 (20.0 g, 124.6 mmol) in THF (150 ml). The reaction mixture was stirred at 10-15 °C for 45 min. Intermediate G-2 (20 g, 104 mmol) was then added to the mixture and stirred at room temperature overnight. H2O (500 ml) was added and filtered to obtain intermediate G (22.0 g, yield: 79.7%).

[0140] Preparation of tert-butyl (2-(5-fluoro-2-(hydroxymethyl)-4-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamate (Intermediate H) [ka] Intermediate H-1 (1.0 g, 2.88 mmol), Intermediate H-2 (0.93 g, 3.17 mmol), and HATU (1.44 g, 3.45 mmol) were dissolved in N,N-dimethylformamide (10 ml) and N,N-diisopropylethylamine (2.5 ml, 14.4 mmol) was added. The mixture was stirred at room temperature for 1 h, then diluted with saturated aqueous NH4Cl (10 ml) and extracted with EtOAc (10 ml x 3). The combined organics were dried over MgSO4 and concentrated in vacuo. The resulting residue was dissolved in acetic acid (25 ml) and the mixture was heated to 100 °C for 1 h. The mixture was then cooled to room temperature, concentrated in vacuo, and the material was purified by normal phase column chromatography (eluent: EtOAc / PE) to give the product Intermediate H-3 (1.2 g, yield: 66.9%).

[0141] Intermediate H-3 (1.0 g, 1.92 mmol), bis(pinacolato)diboron (512.4 mg, 2.02 mmol), AcOK (282.3 mg, 2.88 mmol), and Pd(dppf)Cl2 (139 mg, 0.2 mmol) were placed in dioxane (10 ml) and stirred at 90-95 °C for 2 h under N2. After cooling, water (10 ml) was added and extracted with EtOAc (10 ml x 3). The combined organics were dried over MgSO4 and concentrated in vacuo. The resulting residue was purified by crystallization with EtOH (3 ml) to give intermediate H (0.85 g, yield: 78%). LCMS (ESI): C 30 H 39 Calculated for BFN3O6; [M+H] + :568.3,Actual value:568.3.

[0142] Preparation of (S)-tert-butyl (2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-yl)carbamate (Intermediate I) [ka] (Boc)2O (42.0 g, 192 mmol) was added to a stirred solution of 4-fluoro-3-nitroaniline (15.0 g, 96.0 mmol) in t-BuOH (150 ml) at 25° C. The reaction mixture was stirred at 40° C. for 12 h. The mixture was concentrated in vacuo and the crude product was slurried with PE to give tert-butyl (4-fluoro-3-nitrophenyl)carbamate (21.6 g, 88% yield) as a yellow solid. LCMS (ESI): calculated for C11H13FN2O4; [M+H]+: 256.2, found: 256.2.

[0143] N-Ethyl-N-isopropyl-propan-2-amine (26.5 g, 205.1 mmol) was added to a stirred solution of [(2S)-oxetan-2-yl]methanamine (9.3 g, 106.5 mmol) and compound 2 (21.0 g, 81.9 mmol) in THF (150 ml) at 25° C. The reaction mixture was stirred at 60° C. for 12 h. The mixture was diluted with EtOAc (100 ml) and H2O (200 ml). The layers were separated and the aqueous layer was extracted with EtOAc (100 ml×2). The combined organic phase was washed with brine (200 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was slurried with methyl tert-butyl ether to give (S)-tert-butyl(3-nitro-4-((oxetan-2-ylmethyl)amino)phenyl)carbamate (23.6 g, 89.1% yield) as a yellow solid. LCMS (ESI): C 15 H 21 Calculated for N3O5; [M+H] + : 323.3, Actual value: 323.3.

[0144] 10% Pd / C (4.6 g) was added to a stirred solution of compound intermediate I-3 (23.0 g, 71.1 mmol) in 1:1 EtOAc:MeOH (200 ml) at 25° C. The reaction mixture was stirred under hydrogen at 25° C. for 12 h. The mixture was filtered and the filter cake was washed with EtOAc (100 ml×2). The combined organic phase was concentrated in vacuo to give tert-butyl (S)-(3-amino-4-((oxetan-2-ylmethyl)amino)phenyl)carbamate (18.8 g, 90% yield) as a brown solid. LCMS (ESI): C 15 H 23 Calculated for N3O3; [M+H] + :293.4,Actual value:293.4.

[0145] 2-Chloro-1,1,1-trimethoxyethane (11.4 g, 73.6 mmol) and pyridinium p-toluenesulfonate (1.23 g, 4.9 mmol) were added to a stirred solution of (S)-(3-amino-4-((oxetan-2-ylmethyl)amino)phenyl)carbamate (18.0 g, 61.4 mmol) in CH3CN (150 ml) at room temperature. The reaction mixture was stirred at 70° C. for 2 h and upon completion of the reaction, EtOAc (100 ml) and H2O (200 ml) were added to the mixture. The organic layer was separated and the aqueous layer was extracted with EtOAc (100 ml×2). The combined organic phase was washed with brine (200 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (petroleum ether / ethyl acetate 3:1) to give intermediate I, (S)-(2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-yl)tert-butylcarbamate (18.0 g, 83% yield) as a yellow solid. LCMS (ESI): C 17 H 22 Calculated for ClN3O3; [M+H] + : 352.1, Actual value: 352.1.

[0146] Preparation of (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carboxylate (Intermediate J) [ka] N-Ethyl-N-isopropyl-propan-2-amine (25.9 g, 200.8 mmol) was added to a stirred solution of [(2S)-oxetan-2-yl]methanamine (10.9 g, 125.5 mmol) and methyl 4-fluoro-3-nitrobenzoate (20.0 g, 100.5 mmol) in THF (100 ml) at 25° C. The reaction mixture was stirred at 60° C. for 4 h. The mixture was diluted with EtOAc (100 ml) and H2O (200 ml). The layers were separated and the aqueous layer was extracted with EtOAc (100 ml×2). The combined organic phase was washed with brine (200 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was slurried with methyl tert-butyl ether to give compound intermediate J-3, methyl (S)-3-nitro-4-((oxetan-2-ylmethyl)amino)benzoate (24.6 g, 92.3% yield) as a yellow solid. LCMS (ESI): C 12 H 14 Calculated for N2O5; [M+H] + : 266.2, Actual value: 267.2.

[0147] 10% Pd / C (5.0 g) was added to a stirred solution of compound intermediate J-3 (24.0 g, 90.1 mmol) in 1:1 EtOAc:MeOH (200 ml) at 25° C. The reaction mixture was stirred under hydrogen at 25° C. for 12 h. The mixture was filtered and the filter cake was washed with EtOAc (100 ml×2). The combined organic phase was concentrated in vacuo to give compound intermediate J-4, methyl (S)-3-amino-4-((oxetan-2-ylmethyl)amino)benzoate (18.8 g, 88.1% yield, 93% purity) as a brown solid. LCMS (ESI): C 12 H 16 Calculated for N2O3; [M+H] + : 236.2, Actual value: 237.2.

[0148] 2-Chloro-1,1,1-trimethoxyethane (14.1 g, 91.4 mmol) and 4-methylbenzenesulfonic acid (1.3 g, 7.62 mmol) were added to a stirred solution of compound intermediate J-4, (S)-3-amino-4-((oxetan-2-ylmethyl)amino)methylbenzoate (18.0 g, 76.2 mmol) in CH3CN (150 ml) at room temperature. The reaction mixture was stirred at 70° C. for 2 h. To the mixture was added EtOAc (100 ml) and H2O (200 ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (100 ml×2). The combined organic phase was washed with brine (200 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was purified by flash column chromatography (petroleum ether / ethyl acetate 3:1) to give compound intermediate J, methyl (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carboxylate (18.0 g, 80% yield) as a yellow solid. LCMS (ESI): C 14 H 15 Calculated for ClN2O3; [M+H] + :294.7, Actual value:295.7

[0149] Preparation of 6-((4-chloro-2-fluorobenzyl)oxy)-1',2',3',6'-tetrahydro-2,4'-bipyridine (Intermediate K) and 2-((4-chloro-2-fluorobenzyl)oxy)-6-(piperidin-4-yl)pyridine (Intermediate L) [ka] In a 500 ml round bottom flask, tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (27.3 g, 88.2 mmol, 1.2 equiv), K2CO3 (20.3 g, 147 mmol, 2.0 equiv), Pd(dppf)Cl2·DCM (5.7 g, 6.3 mmol, 0.085 equiv), and H2O (40 ml) were added. A solution of compound intermediate G (20.0 g, 73.5 mmol, 1.0 equiv) in dioxane (200 ml) was added. The final mixture was kept under N2 atmosphere and stirred at 90 °C for 3.5 h. After that, the reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with EA (100 ml). The filtrate was added with brine (200 ml) and separated, the aqueous phase was extracted with EA (100 ml x 2), and the combined organic phase was concentrated under vacuum. The residue was purified by recrystallization from PE:EA=1:1 to give the crude compound, which was then decolorized with activated charcoal at room temperature for 2 h. The mixture was filtered through a Celite pad, the filter cake was washed with EA, and then concentrated under vacuum to give the crude compound. The crude compound intermediate K-2 was purified by recrystallization with EtOH / H2O=6 / 1 to give the desired product tert-butyl 6-((4-chloro-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (20.1 g, 65% yield) as a pale yellow solid. LCMS (ESI): C 22 H 24 Calculated for ClFN2O3; [M+H] + : 418.8, Actual value: 419.1

[0150] A solution of compound intermediate K-2 (20.0 g, 47.8 mmol) in DCM (100 ml) was added to a 500 ml round bottom flask, then TFA (trifluoroacetic acid) (20 ml) was added and the reaction mixture was stirred at 25° C. for 2 hours. The reaction mixture was diluted with DCM, and the reaction mixture was washed successively with aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude compound 2-12 was purified by recrystallization from CH3CN to give the desired product intermediate K, 6-((4-chloro-2-fluorobenzyl)oxy)-1',2',3',6'-tetrahydro-2,4'-bipyridine (13.5 g, 88% yield) as a white solid. LCMS (ESI): C 17 H 16 Calculated for ClFNO [M+H] + : 318.8, Actual value: 319.1

[0151] 10% Pd / C (3.9 g) was added to a stirred solution of compound intermediate K (13.0 g, 40.8 mmol) in 100 ml of EtOAc:MeOH at 25° C. The reaction mixture was stirred under hydrogen at 25° C. for 6 h. The mixture was filtered and the filter cake was washed with EtOAc (100 ml×2). The combined organic phase was concentrated in vacuo to give compound intermediate L, 2-((4-chloro-2-fluorobenzyl)oxy)-6-(piperidin-4-yl)pyridine (12.0 g, 91% yield) as a white solid. LCMS (ESI): C 17 H 18 Calculated for ClFNO [M+H] + : 320.8, Actual value: 321.1

[0152] Preparation of 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-1,2,3,6-tetrahydropyridine (Intermediate M) [ka] Under a N2 atmosphere, a mixture of 5-chloro-2-ethynylpyridine (1.80 g, 13.1 mmol), 3-bromobenzene-1,2-diol (2.47 g, 13.1 mmol), and triruthenium dodecacarbonyl (167 mg, 0.261 mmol) was added to toluene (25 ml) and heated at 100° C. for 16 h. The reaction mixture was diluted with ethyl acetate (30 ml), filtered through a pad of diatomaceous earth, and the filtrate was concentrated in vacuo and purified using silica gel chromatography (gradient: 0% to 1% ethyl acetate in petroleum ether) to give intermediate M-2 as a yellow oil (1.5 g, 37.5%).

[0153] tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.17 g, 8.8 mmol, 1.2 equiv), K2CO3 (1.6 g, 11.7 mmol, 2.0 equiv), Pd(dppf)Cl2·DCM (0.4 g, 0.50 mmol, 0.085 equiv), and H2O (4 ml) were added to a solution of intermediate compound M-2 (2.0 g, 5.84 mmol, 1.0 equiv) in dioxane (20 ml), and the final mixture was poured under N2 atmosphere and stirred at 90 °C for 3.5 h. Then, the reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with EA (20 ml). The filtrate was added with brine (20 ml) and separated, the aqueous phase was extracted with EA (20 ml x 2), and the combined organic phase was concentrated under vacuum. The residue was purified by recrystallization from PE:EA=1:1 to give compound intermediate M-3 (2.1 g, 80.9%) as a pale yellow solid. LCMS (ESI): C 24 H 25 Calculated for ClFNO4; [M+H] + : 446.15, Actual value: 446.15

[0154] Compound intermediate M-3 (2.0 g, 4.5 mmol) and DCM (10 ml) were added to a 50 ml round bottom flask, followed by the addition of TFA (2 ml) and the reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with DCM and the reaction mixture was washed successively with aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude compound was purified by recrystallization from CH3CN to give the desired product intermediate M (1.3 g, 83.8% yield) as a white solid. LCMS (ESI): C 19 H 17 Calculated for ClFNO2 [M+H] + :346.1,Actual value:346.1

[0155] procedure Procedure 1. Preparation of 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)benzyl)-N-(4-hydroxyphenethyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-5-carboxamide (1) [ka] Refer to the following reaction scheme (Route 1). Potassium tert-butoxide (14.7 g, 0.13 mol, 2.4 eq.) was added to THF (200 ml) in a 500 ml round bottom flask and stirred for 5 min, then 3-fluoro-4-(hydroxymethyl)benzonitrile (14 g, 0.092 mol, 1.7 eq.) was added and stirred at 15° C. for 45 min. 2,6-dichloropyridine (8.07 g, 0.055 mol, 1.0 eq.) was added to the mixture and stirred at 15° C. for 18 h. Saturated aqueous ammonium chloride solution (18 eq.) and EA (100 ml) were added for reaction work-up. The reaction mixture was filtered. The filtrate was extracted with EA (200 ml×2), the combined organic phase was washed with brine (200 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by recrystallization with PE / EA=8 / 1 to give crude compound 1-3. The crude compound 1-3 was purified by recrystallization with EtOH / H2O=1 / 1 to give the desired product (10.3 g, 70% yield) as a pale yellow solid. LCMS (ESI): 13 Calculated for H8ClFN2O; [M+H] + :262.6, Actual value:263.6

[0156] A solution of compound 1-3 (10.0 g, 0.038 mol, 1.0 equiv) in dioxane (100 ml, 10V) was added to a 250 ml round bottom flask, followed by ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (14.4 g, 0.050 mol, 1.3 equiv), K2CO3 (10.8 g, 0.760 mol, 2.0 equiv), Pd(dppf)Cl2·DCM (2.5 g, 0.003 mmol, 0.085 equiv), and H2O (20 ml) were added to the flask. The final mixture was kept under N2 atmosphere and stirred at 90 °C for 3.5 h. Afterwards, the reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with EA (100 ml). The filtrate was added with brine (100 ml) and separated, the aqueous phase was extracted with EA (100 ml x 2), and the combined organic phase was concentrated under vacuum. The residue was purified by recrystallization from PE:EA = 1:1 to give compound 1-5. Crude compound 1-5 was decolorized with activated charcoal at room temperature for 2 h. The mixture was filtered through a Celite pad, the filter cake was washed with EA, then concentrated under vacuum and purified by recrystallization with EtOH / H2O = 6 / 1 to give the desired product 1-5 (8.8 g, 65% yield) as a pale yellow solid. LCMS (ESI): C 23 H 19 Calculated for FN2O3; [M+H] + :390.4, Actual value:391.4

[0157] A solution of compound 1-5 (8.0 g, 20.49 mmol) in THF (20.0 ml), CH3CN (20.0 ml), water (20.0 ml) and lithium hydroxide (982 mg, 41 mmol) were added to a 250 ml round bottom flask at 25° C., and the reaction mixture was stirred at 25° C. for 12 h. It was then concentrated to remove the organic solvent, and the aqueous residue was adjusted to pH 6 by adding 1 M hydrochloric acid. The resulting mixture was extracted with EA (60 ml×3), and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuum to give the crude product. Crude compound 1-6 was purified by recrystallization with EtOH to give the desired product (6.5 g, 87% yield) as a pale yellow solid. LCMS (ESI): C 21 H 15 Calculated for FN2O3; [M+H]+ :362.3, Actual value:363.3

[0158] A solution of compound 1-6 (6.0 g, 16.56 mmol), compound 1-7 (3.71 g, 16.56 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 9.45 g, 33.12 mmol) in N,N-dimethylformamide (60 ml) was stirred at 25° C. for 30 minutes, after which triethylamine (6.7 g, 66.23 mmol) was added and stirring was continued at 25° C. for 12 hours. The reaction mixture was then poured into water (300 ml) and extracted with ethyl acetate (200 ml×3). The combined organic layer was washed with saturated aqueous sodium chloride solution (200 ml×3), dried over sodium sulfate, filtered, and concentrated in vacuum. Silica gel chromatography (eluent: 1:1 petroleum ether / ethyl acetate) afforded compound 1-8 as a brown solid (7.8 g, 83% yield), which was used directly in the next step. LCMS (ESI): 32 Calculated for H29FN4O5; [M+H] + :568.6, Actual value:569.6

[0159] A solution of compound 1-8 (7.5 g, 13.19 mmol) in acetic acid (50 ml) was stirred at 75° C. for 12 h, after which it was concentrated in vacuo to give the crude product as a brown solid. The residue was purified by recrystallization with CH3CN to give the desired product compound 1-9 (6.1 g, 85% yield) as a yellow solid. LCMS (ESI): 32 H 27 Calculated for FN4O4; [M+H] + :550.6, Actual value:551.6

[0160] A solution of compound 1-9 (6.0 g, 10.9 mmol) in THF (20.0 ml) was added to a 250 ml round bottom flask at 0° C., followed by the addition of CH3CN (20.0 ml), water (20.0 ml) and lithium hydroxide (522 mg, 21.8 mmol), and the reaction mixture was stirred at 25° C. for 12 h. It was then concentrated to remove the organic solvent, and the aqueous residue was adjusted to pH 6 by adding 1 M hydrochloric acid. The resulting mixture was extracted with EA (60 ml×3), and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuum to give the crude product. The crude compound 1-10 was purified by recrystallization with CH3CN to give the desired product compound 1-10 (5.1 g, 87% yield) as a yellow solid. LCMS (ESI): C 31 H 25 Calculated for FN4O4; [M+H] + :536.5, Actual value:537.6

[0161] A solution of compound 1-10 (100 mg, 1.86 mmol), N-hydroxybenzotrizole (HOBT, 37.78 mg, 2.79 mmol), and N-(3-dimethylaminopropyl)-n''-ethylcarbodiimide hydrochloride (EDCI, 9.45 g, 33.12 mmol) in N,N-dimethylformamide (2 ml) was stirred at 25° C. for 30 min, after which N,N-diisopropylethylamine (48.18 mg, 3.73 mmol) and 4-(2-aminoethyl)phenol (37.8 mg, 1.86 mmol) were added and stirring was continued at 25° C. for 12 h. The reaction mixture was then poured into water (10 ml) and extracted with ethyl acetate (10 ml×3). The combined organic layer was washed with saturated aqueous sodium chloride solution (10 ml×3), dried over sodium sulfate, filtered, and concentrated in vacuum. The crude product was purified by preparative liquid phase chromatography to give compound 1 (67 mg, yield: 54.9%). LCMS (ESI): 39 H 34 Calculated for FN5O4 [M+H] + :655.73, Actual value:656.2

[0162] Step 2. Preparation of (2S,4R)-1-((2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-5-carbonyl)glycyl)-4-hydroxypyrrolidine-2-carboxylic acid (2) [ka] See the following reaction scheme (pathway 2).

[0163] Compound intermediate J (12.2 g, 41.2 mmol) was added to a stirred solution of compound intermediate L (12.0 g, 37.4 mmol) in acetonitrile (120 ml), followed by potassium carbonate (15.5 g, 112 mmol). The reaction mixture was stirred at 75° C. for 3 h. The reaction mixture was filtered, washed with EA (100 ml), the filtrate was concentrated in vacuum, and the crude product was purified by slurry (PE:EA=5:1) to give compound 2-14, (S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carboxylate (17.5 g, 82% yield) as a yellow solid. LCMS (ESI): C 31 H 32 Calculated for ClFN4O4; [M+H] + :579.1, Actual value:579.2

[0164] A solution of compound 2-14 (16.0 g, 10.9 mmol) in MeOH (80.0 ml), water (80.0 ml) and sodium hydroxide (5.5 g, 138.0 mmol) were added to a 250 ml round-bottom flask at 0° C., and the reaction mixture was stirred at 50° C. for 2 h. It was then concentrated to remove the organic solvent, and the aqueous residue was adjusted to pH 6 by adding 1 M hydrochloric acid. The resulting mixture was extracted with EA (100 ml×3), and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude product. The crude product was purified by slurrying in CH3CN to give the desired product, compound 2-15, (S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carboxylic acid (13.5 g, 84% yield) as a yellow solid. LCMS (ESI): C 30 H 30 Calculated for ClFN4O4; [M+H] + :565.1, Actual value:565.2

[0165] A solution of the above compound 2-15 (100 mg, 0.177 mmol), N-hydroxybenzotrizole (HOBT, 35.8 mg, 0.265 mmol), and N-(3-dimethylaminopropyl)-n''-ethylcarbodiimide hydrochloride (EDCI, 50.9 mg, 0.265 mmol) in N,N-dimethylformamide (2 mL) was stirred at 25° C. for 30 minutes, after which N,N-diisopropylethylamine (58.0 mg, 0.442 mmol) and compound 2-16, (2S,4R)-1-glycyl-4-hydroxypyrrolidine-2-carboxylate methyl (40.0 mg, 0.195 mmol), were added and stirring was continued at 25° C. for 12 hours. The reaction mixture was then poured into water (10 ml) and extracted with ethyl acetate (10 ml×3). The combined organic layers were washed with saturated aqueous sodium chloride solution (10 ml×2), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by preparative liquid phase chromatography to give compound 2-17, (2S,4R)-1-((2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-5-carbonyl)glycyl)-4-hydroxypyrrolidine-2-carboxylate (67 mg, yield: 51%) as a white solid. LCMS (ESI): C 38 H 42 Calculated for ClFN6O7; [M+H]+: 749.2, Found: 749.2.

[0166] A solution of compound 2-17 (60.0 mg, 0.08 mmol) in MeOH (1.0 ml), water (1.0 ml) and sodium hydroxide (16 mg, 0.40 mmol) were added to a 25 ml round-bottom flask at 0° C., and the reaction mixture was stirred at 50° C. for 1.5 h. It was then concentrated to remove the organic solvent, and the aqueous residue was adjusted to pH 6 by adding 1 M hydrochloric acid. The resulting mixture was extracted with EA (10 ml×3), and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude product. The crude product was purified by preparative liquid phase chromatography to give the desired product, compound 2, (2S,4R)-1-((2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-5-carbonyl)glycyl)-4-hydroxypyrrolidine-2-carboxylic acid (35 mg, yield: 60%) as a white solid. LCMS (ESI): C 37 H 40 Calculated for ClFN6O7; [M+H] + :735.2, Actual value:735.2 1 H NMR (400MHz, DMSO-d6).

[0167] Step 3. Preparation of (S)-2-((6-((4-chloro-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)methyl)-N-(3-methyl-1H-indazol-5-yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carboxamide (3) [ka] Refer to the following reaction scheme (Route 3). Compound intermediate J (10.2 g, 34 mmol) was added to a solution of compound intermediate K (10.0 g, 31.3 mmol) in acetonitrile (100 ml) with stirring, followed by potassium carbonate (10.8 g, 78.4 mmol). The reaction mixture was stirred at 75° C. for 3 hours. The reaction mixture was filtered, washed with EA (100 ml), the filtrate was concentrated in vacuum, and the crude product was purified by slurry (PE:EA=5:1) to obtain compound 3-1, methyl (S)-2-((6-((4-chloro-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carboxylate (14.5 g, 80% yield) as a yellow solid. LCMS(ESI):C 31 H 30 Calculated for ClFN4O4; [M+H] + :577.1,Actual value:577.1.

[0168] A solution of compound 3-1 (14.0 g, 24.3 mmol) in MeOH (70.0 ml), water (70.0 ml) and lithium hydroxide (4.85 g, 121.3 mmol) were added to a 250 ml round bottom flask at 0° C., and the reaction mixture was stirred at 50° C. for 2 h. It was then concentrated to remove the organic solvent, and the aqueous residue was adjusted to pH 6 by adding 1 M hydrochloric acid. The resulting mixture was extracted with EA (100 ml×3), and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude product. The crude compound 3-2 was purified by slurrying in CH3CN to give the desired product (S)-2-((6-((4-chloro-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carboxylic acid (11.7 g, 86% yield) as a yellow solid. LCMS (ESI): C 30 H 28 Calculated for ClFN4O4; [M+H] + :563.0,Actual value:563.1

[0169] A solution of compound 3-2 (100 mg, 0.177 mmol), N-hydroxybenzotrizole (HOBT, 35. mg, 0.265 mmol), and N-(3-dimethylaminopropyl)-n''-ethylcarbodiimide hydrochloride (EDCI, 50.9 mg, 0.265 mmol) in N,N-dimethylformamide (2 ml) was stirred at 25° C. for 30 min, after which N,N-diisopropylethylamine (58.0 mg, 0.442 mmol) and 3-methyl-1H-indazol-5-amine (28.8 mg, 0.195 mmol) were added and stirring was continued at 25° C. for 12 h. The reaction mixture was then poured into water (10 ml) and extracted with ethyl acetate (10 ml×3). The combined organic layer was washed with saturated aqueous sodium chloride solution (10 ml×2), dried over sodium sulfate, filtered, and concentrated in vacuum. The crude product was purified by preparative liquid phase chromatography to obtain compound 3, (S)-2-((6-((4-chloro-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-N-(3-methyl-1H-indazol-5-yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-5-carboxamide (64 mg, yield: 52%) as a white solid. LCMS (ESI): C 38 H 35 Calculated for ClFN7O3; [M+H] + :692.1, Actual value:692.2 1 H NMR (400MHz, DMSO-d6).

[0170] Step 4. Preparation of (S)-N-(2-((6-((4-chloro-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-yl)-3-methyl-1H-indazole-5-carboxamide (4) [ka] See the following reaction scheme (pathway 4).

[0171] Compound intermediate K (17.0 g, 48.3 mmol) was added to a stirred solution of compound intermediate I (14.0 g, 43.9 mmol) in acetonitrile (100 ml), followed by potassium carbonate (15.2 g, 109.8 mmol). The reaction mixture was stirred at 75° C. for 3 hours. The reaction mixture was filtered and washed with EA (100 ml), the filtrate was concentrated in vacuo, and the crude product was purified by slurry (PE:EA=6:1) to give compound 4-6, (S)-(2-((6-((4-chloro-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-yl)tert-butylcarbamate (22.5 g, 80.6% yield) as an off-white solid. LCMS (ESI): C 34 H 37 Calculated for ClFN5O4; [M+H] + :634.1, Actual value:634.2

[0172] A solution of compound 4-6 (20.0 g, 31.5 mmol) in DCM (100.0 ml) was added to a 500 ml round bottom flask, then TFA (20 ml) was added to the flask, and the reaction mixture was stirred at 25° C. for 2 h. The mixture was diluted with DCM, and the reaction mixture was washed successively with aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by recrystallization with PE:EA=5:1 to give the desired product compound 4-7, (S)-2-((6-((4-chloro-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-amine (13.5 g, 80% yield) as an off-white solid. LCMS (ESI): C 29 H 29 Calculated for ClFN5O2; [M+H] + :534.1, Actual value:534.2

[0173] A solution of compound 4-8 (40 mg, 0.227 mmol), N-hydroxybenzotrizole (HOBT, 46.0 mg, 0.340 mmol), and N-(3-dimethylaminopropyl)-n''-ethylcarbodiimide hydrochloride (EDCI, 65.1 mg, 0.340 mmol) in N,N-dimethylformamide (2 ml) was stirred at 25° C. for 30 min, after which N,N-diisopropylethylamine (58.0 mg, 0.442 mmol) and compound 4-7 (121.1 mg, 0.227 mmol) were added and stirred at 25° C. for 12 h. The reaction mixture was then poured into water (10 ml) and extracted with ethyl acetate (10 ml×3). The combined organic layer was washed with saturated aqueous sodium chloride solution (10 ml×2), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by preparative liquid phase chromatography to obtain compound 4, (S)-N-(2-((6-((4-chloro-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-5-yl)-3-methyl-1H-indazole-5-carboxamide (81 mg, yield: 51.9%) as a white solid. LCMS (ESI): C 38 H 35 Calculated for ClFN7O3; [M+H] + :692.1, Actual value:692.2

[0174] Procedure 5. Preparation of 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-N-(3-methyl-1H-indazol-5-yl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-5-carboxamide (5) [ka] See the following reaction scheme (pathway 5).

[0175] Compound intermediate J (1.0 g, 3.48 mmol) was added to a stirred solution of compound intermediate M (1.0 g, 2.9 mmol) in acetonitrile (10 ml), followed by potassium carbonate (10.5 g, 7.25 mmol) and the reaction mixture was stirred at 75° C. for 3 h. The reaction mixture was filtered and washed with EA (20 ml), the filtrate was concentrated in vacuo and the crude product was purified by slurry (PE:EA=5:1) to give compound 5-5 (1.5 g, 85.8% yield) as a yellow solid. LCMS (ESI): C 33 H 31 Calculated for ClFN3O5; [M+H] + :604.2,Actual value:604.2

[0176] Compound 5-5 (1.4 g, 2.3 mmol), MeOH (7.0 ml), water (7.0 ml) and sodium hydroxide (0.46 g, 11.5 mmol) were added to a 25 ml round bottom flask at 0° C., the reaction mixture was stirred at 50° C. for 2 h, then concentrated to remove the organic solvent. 1 M hydrochloric acid was added to the aqueous residue to adjust the pH to 6. The resulting mixture was extracted with EA (10 ml×3), and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude product. The crude compound 5-6 was purified by slurrying in CH3CN to give the desired product (1.2 g, 87.8% yield) as a yellow solid. LCMS (ESI): C 32 H 29 Calculated for ClFN3O5; [M+H] + :590.2, Actual value:590.2

[0177] A solution of compound 5-6 (100 mg, 0.17 mmol), N-hydroxybenzotrizole (HOBT, 35.8 mg, 0.265 mmol), and N-(3-dimethylaminopropyl)-n''-ethylcarbodiimide hydrochloride (EDCI, 50.9 mg, 0.265 mmol) in N,N-dimethylformamide (2 ml) was stirred at 25° C. for 30 min, after which N,N-diisopropylethylamine (58.0 mg, 0.442 mmol) and 3-methyl-1H-indazol-5-amine (28.8 mg, 0.195 mmol) were added and stirring was continued at 25° C. for 12 h. The reaction mixture was then poured into water (10 ml) and extracted with ethyl acetate (10 ml×3). The combined organic layer was washed with saturated aqueous sodium chloride solution (10 ml×2), dried over sodium sulfate, filtered, and concentrated in vacuum. The crude product was purified by preparative liquid phase chromatography to give a mixture of diastereomeric products 5-7. Separation of the two products was carried out by SFC (supercritical fluid chromatography) [column: Chiral Technologies ChiralCel OD, 5 pm, mobile phase: 55:45 carbon dioxide / (methanol with 0.1% ammonium hydroxide)] to give two chiral compounds, namely, compound 5 (23 mg) (LCMS (ESI): C 40 H 36 Calculated for ClFN6O4; [M+H] + : 719.3, measured value: 719.3) and compound 5' (19 mg) (LCMS (ESI): C 40 H 36 Calculated for ClFN6O4; [M+H] + : 719.3, actual value: 719.3) was obtained.

[0178] Procedure 6. Preparation of 2-(6-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-6-azaspiro[2.5]octan-1-yl)-1-(2-methoxyethyl)-N-(3-methyl-1H-indazol-5-yl)-1H-benzo[d]imidazole-5-carboxamide (6) [ka] A mixture of compound 1-3 (2.0 g, 7.61 mmol), methyl 6-azaspiro[2.5]octane-1-carboxylate (1.42 g, 8.38 mmol), Cs2CO3 (4.97 g, 15.2 mmol), Pd2(dba)3 (696 mg, 0.77 mmol) and X-Phose (734 mg, 1.54 mmol) in dioxane (20 ml) was prepared under a N2 atmosphere and heated at 100 °C for 4 h. The reaction mixture was diluted with ethyl acetate (30 ml), filtered through a pad of diatomaceous earth, and the filtrate was concentrated in vacuo and purified using silica gel chromatography (gradient: 0% to 5% MeOH in dichloromethane) to give compound 6-2 as a yellow oil (1.5 g, 49%).

[0179] The next reaction sequence can follow procedure 1. Compound 6 was obtained through hydrolysis, condensation reaction, cyclization, hydrolysis, and condensation.

[0180] The following compounds were prepared according to the procedures described herein (and shown in the procedures in Table 1) using the appropriate starting material(s) and, where necessary, appropriate protecting group chemistry. [Table 1] 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[0181] Example 2: Evaluation of in vitro biological activity A. GLP-1R cAMP Assay

[0182] 1.Material (1) Reagents cAMP detection kit, Cisbio (catalog number 62AM4PEJ) 1M HEPES, Invitrogen (catalog number 15630-106) 1X HBSS, Invitrogen (Cat. No. 14025) BSA, Sigma (catalog number B2064-100G) IBMX, Sigma (Cat. No. I5879) GLP-1(7-37), Hao Yuan(HY-P0055)

[0183] (2) Culture medium The cell line was constructed by WuXi, and the detailed information is shown below. [Table 2]

[0184] (3) Equipment OptiPlate-384, white, PerkinElmer (cat. no. 6007290); 384-well plate for Echo, Labcyte (Cat. No. P-05525); EnVision, PerkinElmer, Vi-Cell Counter, Beckman (Cat. No. Vi-CELL™ XR Cell Viability Analyzer)

[0185] 2. Method a) Preparation of compound source plate: Reference 7-37 was diluted 10-fold 4-fold from 500 nM in DMSO using a Bravo. Compounds were diluted 10-fold 3-fold from 10 million nM in DMSO using a Bravo. b) Compound transfer: 1) Using the Echo, transfer 100 nL of compound to the OptiPlate-384 plate. 2) Spin the plate at 1000 rpm for 5 seconds. c) Preparation of cell suspension: 1) Rapidly thaw one vial of GLP-1 cells in a 37° C. water bath. 2) Transfer the cell suspension to 10 ml of HBSS in a 15 ml conical tube. 3) Centrifuge the cells at 1000 rpm for 5 minutes at room temperature to pellet the cells. 4) Gently aspirate the supernatant, being careful not to aspirate the cells. 5) Gently tap the pellet to release the cells and resuspend the cell pellet in 10 ml of HBSS. Pipette up and down using a sterile pipette to remove clumps. 6) Count cells for concentration and determine cell viability on Vi-cell. 7) Resuspend GLP-1 cells in assay buffer at a concentration of 1.0×E5 / mL cells. 8) Transfer 10 μL of GLP-1 cells to the OptiPlate-384 plate. d) HTRF cAMP Assay for Agonists: 1) Incubate the plate at room temperature for 30 minutes and then add the detection reagent. 2) Using an electronic multichannel pipette, add 10 μL of each detection reagent. 3) Cover the 384 plate with TopSeal-A film and incubate at room temperature for 60 minutes. Remove TopSeal-A and read on EnVision.

[0186] 3. Data Analysis A. Standard curve Create a new log(Inhibitor) vs response-Variable slope mode in Prism 5.0 software, input the standard curve concentrations (x) and their corresponding 665 / 615 data (y) into the model, transform the standard curve concentrations (abscissa) by x = log(x), and create a standard curve through the transformed xy.

[0187] B. cAMP Level Shift: Convert the 665 / 615 data for the entire plate into columns of data, substitute the standard curve concentrations (x) and the 665 / 615 data (y) into the table of y, copy the x that corresponds to the automatic conversion by the software (interpolated x) into the table, convert to cAMP levels with the formula x=10^(x), and reset the data to the 384 distribution.

[0188] C.% activity %Activity=(cAMP level-LC) / (HC-LC)*100% Z factor: 1-3*(STD_HC+STD_HC) / (HC-LC) Assay window: HC / LC LC:Average cAMP levels in DMSO-added wells HC: average cAMP levels when the highest concentration of reference compound wells was added.

[0189] D. Sample curve: In Prism 5.0 software, the log(slope) vs response-variable agonist mode was created, sample concentrations (x) and their corresponding % activity data (y) were substituted into the model, the standard curve concentrations (abscissa) were transformed into x = log(x), and the sample curve was created through the transformed xy.

[0190] Table 2 shows the biological activity of the compounds in the GLP-1R agonist cAMP stimulation assay. [Table 3] TIFF2025508914000601.tif254170TIFF2025508914000602.tif255169TIFF2025508914000603.tif234170

[0191] B. Tag-lite binding assay 1.Material (1) Reagents [Table 4] DMEM, Gibco (catalog number 11965-092); FBS, Excell (catalog number FSP500), Penicillin / Streptomycin (100x), 10,000 units / ml, Hyclone-SV30010, G418, Gibco (catalog number 10131-027), DPBS, Corning (catalog number 21-031-CVC); TE, Gibco (Cat. No. 25300-062),

[0192] (2) Culture medium The cell line was constructed by Wu Xi. [Table 5]

[0193] (3) Equipment Vi-Cell Counter, Beckman (Cat. No. Vi-CELL™ XR Cell Viability Analyzer); Incubator, Thermo (1153447), Microplate, 384-well, PS, F-bottom, small volume, high base, medium binding, white, Greiner (Cat. No. 784075); EnVision, PerkinElmer (651436), Bravo V11, Agilent (337076), ECHO 655, Labcyte(2474218),

[0194] 2. Method Day 1: Cell seeding 1) Remove the culture medium by aspiration. 2) Rinse the cells with DPBS and remove by aspiration. 3) Add 3 ml of trypsin-EDTA (0.05%). 4) Incubate at 37°C for 1 minute. Check the progress of enzyme digestion using an inverted phase contrast microscope. 5) Gently tap the culture dish to detach the cells from the bottom of the dish. Add 10 ml of growth medium and thoroughly suspend the cells by pipetting to wash away any remaining cells on the bottom of the dish. 6) Centrifuge the cells at 1000 rpm for 5 minutes at room temperature. 7) Gently pour off or aspirate the supernatant, being careful not to aspirate the cells. 8) Resuspend the cell pellet in growth medium by pipetting up and down using a sterile pipette to remove clumps. 9) Count cells using Vi-CELL™ to determine cell viability and cell concentration. Prepare cell suspension in plating medium / well. 10) Dispense cells into cell plates (1.8 M cells / well in 2 ml medium in a 6-well plate, 4 wells total). 11) Place the plate in a 37°C / 5% CO2 incubator for 16-20 hours. Day 2: Tag-lite binding assay 1) Thaw a 5ml vial of Tag-lite buffer (TLB 5x). Dilute Tag-lite 1:5. 2) Using the 100 μM stock solution, dilute a vial of Tag-lite SNAP-Lumi4-Tb solution by making a 1:1000 dilution. 3) Remove the cell culture medium from the 6-well plate and then gently add 1 mL of Tag-lite SNAP-Lumi4-Tb diluted in Tag-lite labeling medium to the cells. 4) Incubate the cells at 37°C + 5% CO2 for 1 hour. 5) Wash the cells twice with 1 mL of Tag-lite buffer. 6) Trypsinize the cells and disperse them at 1x10 in 1X TLB. 6 Suspend cells / mL. 7) Serially dilute test and reference compounds 3-fold, 10 points using Echo, then transfer 100 nL of compound to the assay plate. 8) Add labeled cells to each well according to the plate map at 10000 cells / 10uL / well. Centrifuge the plate at 1000rpm for 1 minute. 9) Incubate the plate at 23°C for 30 minutes. 10) Using the Echo, add 50 nL of red agonist (final concentration: 4.917 nM) to the destination plate. 11) Incubate the plate at 23°C for 2 hours. 12) Read the plate in an HTRF® compatible reader (665 nm and 620 nm).

[0195] 3. Data Analysis a) % Inhibition: %inhibition=100%-(ratio-LC) / (HC-LC)*100% Z factor: 1-3*(STD_HC+STD_HC) / (HC-LC) Assay window: HC / LC HC:Average ratio when DMSO wells were added LC: Average ratio when highest concentration of reference compound well was added

[0196] b) The dose-response curves of each sample were fitted using the "log(inhibitor) vs. response-Variable slope" model in GraphPad Prism 5.0. Sample concentrations (x) and their corresponding % inhibition data (y) were entered into the model. Sample concentrations (abscissa) were transformed to x = log(x). The transformed xy was used as the sample curve to obtain the IC50.

[0197] c) Calculate the sample Ki according to the sample IC50 and the red agonist Kd, where S is the concentration of the red agonist actually used.

number

[0198] Table 3 shows the biological activity of compounds in the GLP-1R agonist Tag-lite binding assay.

Table 6

Claims

1. Formula I-A-1 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, wherein R1 is C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -S-R1b, -S(O)R1b, -S(O)(NH)R1b, -S(O)2R1b, -S(O)2N(R1b)(R1c), -S(O)(NR1b)R1c, -C(O)N(R1b)(R1c), -C(O)R 1b, or -C(O)OR1c, wherein said alkyl, haloalkyl, cycloalkyl, aryl, 5- to 10-membered heteroaryl, or heterocyclyl are each optionally substituted with 1-4 Z1, and any two Z1 can be combined with the atoms to which they are attached to form a C3-10 cycloalkyl or heterocyclyl, or a C6-10 aryl or 5- to 10-membered heteroaryl; Ring A is a C cycloalkyl, heterocyclyl, C aryl or 5-10 membered heteroaryl, each optionally substituted with 1 to 4 Z; Ring B is a C cycloalkyl, heterocyclyl, C aryl or 5-10 membered heteroaryl, each optionally substituted with 1-4 R; Ring A and Ring B each contain 0 to 3 double bonds; R2 is H, C1-6 alkyl, -C1-6 alkyl-alkoxy, -C1-6 alkyl-cycloalkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -CN, -OR2a, -S-R2a, -S(O)R2a, -S(O)(NH)R2a, -S(O)2R2a, -S(O)2N(R2a)(R2b), or -S(O) (NR2a)R2b, wherein said alkyl, alkoxy, cycloalkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl, at each occurrence, is optionally substituted with 1 to 4 Z1, and any two Z1 can be combined with the atoms to which they are attached to form a C3-10 cycloalkyl or heterocyclyl, or a C6-10 aryl or 5-10 membered heteroaryl; Each X is independently -N=, -C(H)=, or -C(R8)=; Each R3 and R3' is independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -CN, -NO2. -OR3a, -C(O)R3a, -CH2C(O)OR3a, -C(O)OR3a, -C(O)N(R3a)(R3b), -N(R3 a) C(O)R3b, -N(R3a)C(O)OR3b, -N(R3a)C(O)N(R3b)2, -C(O)NHS(O)2R3a , -C(O)NR3aS(O)2R3b, -C(O)NR3aS(O)2NR3bR3c, -C(O)NR3a-S(O)(=NR3 b) R3c, -S(O)2R3a, -S(O)2OR3a, -S(O)2N(R3a)(R3b), -N(R3a)S(O)2R3b , -S(O)NHC(O)R3a, -S(O)(=NR3a)R3b, -S(O)(=NR3a)NR3b, -S(=NR3a)(=NR3b)R3c, -P(O)(OR3a)(R3b), -P(O)(OR3a)(OR3b), -B(OR3a)(OR3b), or -O-C1-6alkyl-C(O)OR3a, where alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl are optionally substituted at each occurrence by 1 to 4 R3d; Each R3a, R3b, and R3c is independently H, C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, C1-6 haloalkyl, C2-8 alkoxyalkyl, -C1-4 alkyl-N(R9a)(R9b), -C1-4 alkyl-N(R9a)C(O)-O-C1-4 alkyl-OP(O)(OR9c)2, -C1-4 alkyl-C(O)N(R9a)(R9b), -C1-4 alkyl-O-C(O)-O-C1-4 alkyl, -C1-4 alkyl-O-C(O)-C1-4 alkyl-N(R9a)(R9b), -C1-4 alkyl-O -C(O)-C1-4 alkyl-OP(O)(OR9c)2, -C1-4 alkyl-C3-8 cycloalkyl, -C1-4 alkyl-heterocyclyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, -CH2CH(N(R9a)2)C(O)OR9b, -P(O)(OR9c)2, -OP(O)(OR9c)2, -CH2P(O)(OR9c)2, -CH2OP(O)(OR9c)2, -OCH2P(O)(OR9c)2, -C(O)OCHP(O)(OR9c)2, -P(O)(R9c)(OR9d), -O P(O)(R9c)(OR9d), -CH2P(O)(R9c)(OR9d), -OCH2P(O)(R9c)(OR9d), -C(O) OCH2P(O)(R9c)(OR9d), -P(O)(N(R9c)2)2, -OP(O)(N(R9c)2)2, -CH2P(O)(N (R9c)2)2, -OCH2P(O)(N(R9c)2)2, -C(O)OCH2P(O)(N(R9c)2)2, -P(O)(N(R 9c)2) (OR9d), -OP(O)(N(R9c)2)(OR9d), -CH2P(O)(N(R9c)2)(OR9d), -OCH2 P(O)(N(R9c)2)(OR9d), -C(O)OCHP(O)(N(R9c)2)(OR9d), -P(O)(R9c)(N(R9d)2), -OP(O)(R9c)(N(R9d)2), -CHP(O)(R9c)(N(R9d)2), -OCHP(O)(R9c)(N(R9d)2), -C(O)OCHP(O)(R9c)(N(R9d)2), Calkyl-heterocyclyl, Calkyl-aryl, or Calkyl-(5-10 membered)heteroaryl, wherein said alkyl, alkenyl, cycloalkyl,heterocyclyl, aryl, or 5- to 10-membered heteroaryl, at each occurrence, are optionally substituted by 1 to 4 Z1b; Each R4 is independently H, -OH, CH2OH, C1-9 alkyl, C1-8 haloalkyl, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, oxo, -NO2, -CN, -N3, -O-R4a, -C(O )R4a, -C(O)O-R4a, -C(O)N(R4a)(R4b), -N(R4a)(R4b), -N(R4a)2(R4b)+, -N(R4a)-C(O)R4b, -N(R4 a) C(O)O(R4b), -N(R4a)C(O)N(R4b)(R4c), -N(R4a)S(O)2(R4b), -N(R4a)S(O)2-N(R4b)(R4c), -N(R 4a) S(O)2O(R4b), -OC(O)R4a, -OC(O)OR4a, -OC(O)-N(R4a)(R4b), -S-R4a, -S(O)R4a, -S(O)(NH)R4a, -S(O)2R4a, -S(O)2N(R4a)(R4b), -S(O)(NR4a)R4b, or -Si(R4a)3, in which alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl is optionally substituted with 1 to 4 Z1b in each occurrence, or two R4 groups attached to adjacent ring atoms combine with the atoms to which they are attached to form a C5-10 cycloalkyl or heterocyclyl, each optionally substituted with 1 to 4 Z1b; each R5a and R5b is independently H, C1-6 alkyl, C1-6 alkyloxy, C1-6 haloalkyl, C2-6 alkoxyalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, -C1-6 alkyl-N(R9a)(R9b), -CN, -OR5a1, or -N(R5a1)(R5a2); or R5a and R5b can combine with the atom to which they are attached to form a C3-10 cycloalkyl or heterocyclyl, each optionally substituted with 1 to 4 R5a3; or R5a or R5b can combine with the substituents on Ring A to form a C5-10 cycloalkyl or heterocyclyl, each optionally substituted with 1 to 4 R5a3; each R5a1 and R5a2 is independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, or 5-10 membered heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl, at each occurrence, is optionally substituted with 1 to 4 R5a4; V is —C(O)—, —O—, —N(R6a)—, or —C(R6b)(R6c)—; R6a is H, C1-6 alkyl, C3-10 cycloalkyl, heterocyclyl, -S(O)2R6a1, or -S(O)2N(R6a1)(R6a2), said cycloalkyl or heterocyclyl, at each occurrence, optionally substituted with C1-6 alkyl, F, or -CN; each R6b and R6c is independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkoxyalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, -C1-6 alkyl-N(R9a)(R9b), -CN, -OR6c1, or -N(R6c2)(R6c3), wherein said alkyl, cycloalkyl, or heterocyclyl, at each occurrence, is optionally substituted with 1 to 4 R6b1; or R6b and R6c combine with the atom to which they are attached to form a C3-10 cycloalkyl or heterocyclyl, each optionally substituted with 1 to 4 R6b1; or R6b or R6c combine with one R4 group and the atom to which they are attached to form a C5-10 cycloalkyl or heterocyclyl, each optionally substituted with 1 to 4 R10; Y is -N(R7)-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)(=NH)-, or -S(O)(=NR7)-; each R3d, R5a3, R5a4, R6b1, and R10 is independently H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, oxo, -OH, -CN, CO2R3e, -NO2, or -C(O)N(R2a)(R2b), wherein said heterocyclyl or 5-10 membered heteroaryl, at each occurrence, is optionally substituted with C1-6 alkyl, C1-6 haloalkyl, or C1-6 haloalkoxy; each R6a1, R6a2, R6c1, R6c2, R6c3, and R7 is independently H, C1-6 alkyl, or C3-10 cycloalkyl; each R8 is independently C1-9 alkyl, C1-8 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, oxo, -OH, -CN, CO2R3e, -NO2, -NH2, -N3, -SH, -O(C1-9 alkyl), -O(C1-8 haloalkyl), -NH(C1-9 alkyl), -NH(C1-8 haloalkyl), -N(C1-9 alkyl)2, -N(C1-8 haloalkyl)2; Each R9a and R9b is independently H, C1-9 alkyl, C1-8 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, oxo, -NO2, -CN, -N3, -O-R12a, -C(O)R12a, -C(O)O-R12a, -C(O)N(R12a)(R12b), -N(R12a)(R12b), -N(R12a)2(R12b)+, -N(R12a)-C(O)R12b , -N(R12a)C(O)O(R12b), -N(R12a)C(O)N(R12b)(R12c), -N(R12a)S(O)2(R12 b), -N(R12a)S(O)2-N(R12b)(R12c), -N(R12a)S(O)2O(R12b), -OC(O)R12a, -O C(O)OR12a, -OC(O)-N(R12a)(R12b), -S-R12a, -S(O)R12a, -S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b), -S(O)(NR12a)R12b, or -Si(R12a)3; Or, R9a and R9b are both C1-9 alkyl, C1-8 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -NO2, -CN, -N3, -O-R12a, -C(O)R12a, -C(O)O-R12a, -C(O)N(R12a)(R12b), -N(R12a)(R12b), -N(R12a)2(R12b)+, -N(R12a)-C(O)R12b, -N(R12a)C(O)O (R12b), -N(R12a)C(O)N(R12b)(R12c), -N(R12a)S(O)2(R12b), -N(R12a)S(O)2 -N(R12b)(R12c), -N(R12a)S(O)2O(R12b), -OC(O)R12a, -OC(O)OR12a, -OC(O)-N forming a 3- to 10-membered heterocyclyl optionally substituted by (R12a)(R12b), -S-R12a, -S(O)R12a, -S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b), -S(O)(NR12a)R12b, or -Si(R12a)3; Each Z1 is independently C1-9 alkyl, C1-8 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, oxo, -NO2, -N3, -C N, -O-R12a, -C(O)-R12a, -C(O)O-R12a, -C(O)-N(R12a)(R12b), -N(R12a)(R12b), -N(R12a )2(R12b)+, -N(R12a)C(O)-R12b, -N(R12a)C(O)O-R12b, -N(R12a)C(O)N(R12b)(R12c), -N (R12a)S(O)2(R12b), -NR12aS(O)2N(R12b)(R12c), -NR12aS(O)2O(R12b), -OC(O)R12a, - OC(O)OR12a, -OC(O)-N(R12a)(R12b), -S-R12a, -S(O)R12a, -S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b), -S(O)(NR12a)R12b, or -Si(R12a)3, wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl, at each occurrence, is optionally substituted with 1 to 4 Z1a; Each Z1a is independently H, -OH, C1-9 alkyl, C1-8 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, oxo, -NO2, -C N, -N3, -O-R12a, -C(O)R12a, -C(O)O-R12a, -C(O)N(R12a)(R12b), -N(R12a)(R12b), -N(R12 a) 2(R12b)+, -N(R12a)-C(O)R12b, -N(R12a)C(O)O(R12b), -N(R12a)C(O)N(R12b)(R12c), - N(R12a)S(O)2(R12b), -N(R12a)S(O)2-N(R12b)(R12c), -N(R12a)S(O)2O(R12b), -OC(O)R1 2a, -OC(O)OR12a, -OC(O)-N(R12a)(R12b), -S-R12a, -S(O)R12a, -S(O)(NH)R12a, -S(O)2R1 2a, -S(O)2N(R12a)(R12b), -S(O)(NR12a)R12b, or -Si(R12a)3, wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl, at each occurrence, is optionally substituted by 1 to 4 Z1b; Each Z1b is independently H, C1-9 alkyl, C1-8 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, oxo, -OH, -CN, CO2R3e, -NO2, -NH2, -N3, -SH, -O(C1-9 alkyl), -O(C1-8 haloalkyl), -O(C2-6 alkenyl), -O(C2-6 alkynyl), -O(C3-15 cycloalkyl), -O(heterocyclyl), -O(C6-10 aryl), -O(5-10 membered heteroaryl), - -NH(C1-9 alkyl), -NH(C1-8 haloalkyl), -NH(C2-6 alkenyl), -NH(C2-6 alkynyl), -NH(C3-15 cycloalkyl), -NH(heterocyclyl), -NH(C6-10 aryl), -NH(5-10 membered heteroaryl), -N(cyclo-alkyl), -N(C1-9 alkyl)2, -N(C1-8 haloalkyl)2, -N(C2-6 alkenyl)2, -N(C2-6 alkynyl)2, -N(C3-15 cycloalkyl)2, -N(heterocyclyl)2, -N(C6-10 aryl -N(5-10 membered heteroaryl)2, -N(C1-9 alkyl)(C1-8 haloalkyl), -N(C1-9 alkyl)(C2-6 alkenyl), -N(C1-9 alkyl)(C2-6 alkynyl), -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9 alkyl)(heterocyclyl), -N(C1-9 alkyl)(C6-10 aryl), -N(C1-9 alkyl)(5-10 membered heteroaryl), -C(O)(C1-9 alkyl), -C(O)(C1-8 haloalkyl), -C(O)(C2-6 alkenyl). , —C(O)(C2-6 alkynyl), —C(O)(C3-15 cycloalkyl), —C(O)(heterocyclyl), —C(O)(C6-10 aryl), —C(O)(5-10 membered heteroaryl), —C(O)O(C1-9 alkyl), —C(O)O(C1-8 haloalkyl), —C(O)O(C2-6 alkenyl), —C(O)O(C2-6 alkynyl), —C(O)O(C3-15 cycloalkyl), —C(O)O(heterocyclyl), —C(O)O(C6-10 aryl), —C(O)O(5-10 membered heteroaryl), —C(O)NH2,-C(O)NH(C1-9 alkyl), -C(O)NH(C1-8 haloalkyl), -C(O)NH(C2-6 alkenyl), -C(O)NH(C2-6 alkynyl), -C(O)NH(C3-15 cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(C6-10 aryl), C(O)NH(5-10 membered heteroaryl), -C(O)N(C1-9 alkyl)2, -C(O)N(C1-8 haloalkyl)2, -C(O)N(C2-6 alkenyl)2, -C(O)N(C2-6 alkynyl)2, -C(O)N(C3-15 cycloalkyl). -NHC(O)(C6-10 aryl), -NHC(O)(5-10 membered heteroaryl), -NHC(O)(C1-9 alkyl), -NHC(O)(C1-8 haloalkyl), -NHC(O)(C2-6 alkenyl), -NHC(O)(C2-6 alkynyl), -NHC(O)(C3-15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C6-10 aryl), -NHC(O)(5-10 membered heteroaryl), -NHC(O)O(C1-9 alkyl), -NHC(O)O(C1-8 haloalkyl), -NHC(O)O(C2-6 alkenyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(C6-10 aryl), -NHC(O)O(5-10 membered heteroaryl), -NHC(O)NH(C1-9 alkyl), -NHC(O)NH(C1-8 haloalkyl), -NHC(O)NH(C2-6 alkenyl), -NHC(O)NH(C2-6 alkynyl), -NHC(O)NH(C3-15 cycloalkyl), -NHC(O)NH( heterocyclyl), -NHC(O)NH(C6-10 aryl), -NHC(O)NH(5-10 membered heteroaryl), -NHS(O)(C1-9 alkyl), -N(C1-9 alkyl)(S(O)(C1-9 alkyl), -S(C1-9 alkyl), -S(C1-8 haloalkyl), -S(C2-6 alkenyl), -S(C2-6 alkynyl), -S(C3-15 cycloalkyl), -S(heterocyclyl), -S(C6-10 aryl), -S(5-10 membered heteroaryl), -S(O)N(C1-9 alkyl)2, -S(O)(C1-9 alkyl),-S(O)(C1-8 haloalkyl), -S(O)(C2-6 alkenyl), -S(O)(C2-6 alkynyl), -S(O)(C3-15 cycloalkyl), -S(O)(heterocyclyl), -S(O)(C6-10 aryl), -S(O)(5-10 membered heteroaryl), -S(O)2(C1-9 alkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(C2-6 alkenyl), -S(O)2(C2-6 alkynyl), -S(O)2(C3-15 cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(C6-10 aryl), -S(O)2(5-10 membered heteroaryl), -S(O)(NH)(C1-9 alkyl), -S(O)2NH(C1-9 alkyl), or -S(O)2N(C1-9 alkyl), wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl, at each occurrence, is selected from one to three of C1-9 alkyl, C1-8 haloalkyl, halogen, -OH, -NH2, CO2H, -O(C1-9 alkyl), -O(C1-8 haloalkyl), -O(C3-15 cycloalkyl), -O(heteroaryl), -S(O)2(NH)(C1-9 alkyl), -S(O)2NH(C1-9 alkyl), or -S(O)2N(C1-9 alkyl), cyclyl), -O(aryl), -O(5-10 membered heteroaryl), -NH(C1-9 alkyl), -NH(C1-8 haloalkyl), -NH(C3-15 cycloalkyl), -NH(heterocyclyl), -NH(aryl), -NH(5-10 membered heteroaryl), -N(C1-9 alkyl)2, -N(C3-15 cycloalkyl)2, -NHC(O)(C1-8 haloalkyl), -NHC(O)(C3-15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl), -NHC(O)(5-10 membered heteroaryl ), —NHC(O)O(C1-9 alkyl), —NHC(O)O(C1-8 haloalkyl), —NHC(O)O(C2-6 alkynyl), —NHC(O)O(C3-15 cycloalkyl), —NHC(O)O(heterocyclyl), —NHC(O)O(aryl), —NHC(O)O(5-10 membered heteroaryl), —NHC(O)NH(C1-9 alkyl), S(O)2(C1-9 alkyl), —S(O)2(C1-8 haloalkyl), —S(O)2(C3-15 cycloalkyl), —S(O)2(heterocyclyl), —S(O)2(aryl),optionally substituted with -S(O)2(5-10 membered heteroaryl), -S(O)(NH)(C1-9 alkyl), -S(O)2NH(C1-9 alkyl), or -S(O)2N(C1-9 alkyl); each R1b, R1c, R2a, R2b, R4a, R4b, R4c, R9c, R9d, R12a, R12b, and R12c is independently H, -OH, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, or 5-10 membered heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl is optionally substituted at each occurrence with 1 to 4 Z1b; Each R3e is independently selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, —C1-4 alkyl-N(R9a)(R9b), —C1-4 alkyl-C(O)N(R9a)(R9b), —C1-4 alkyl-O—C(O)—O—C1-4 alkyl, —C1-4 alkyl-O—C(O)—C1-4 alkyl-N(R9a)(R9b), —C1-4 alkyl-C3-8 cycloalkyl, —C1-4 alkyl-heterocyclyl, C3-10 cycloalkyl, heterocyclyl. Kryl, C6-10 aryl, 5-10 membered heteroaryl, -P(O)(OR9c)2, -CH2P(O)(OR9c)2, -OCH2P(O)(OR9c)2, -C(O)OCH2P(O)(OR9c)2, -P(O)(R9 c) (OR9d), -OP(O)(R9c)(OR9d), -CH2P(O)(R9c)(OR9d), -C(O)OCH2P(O)(R9c)(OR9d), -P(O)(N(R9c)2)2, -CH2P(O)(N(R9c) )2)2, -C(O)OCHP(O)(N(R9c)2), -P(O)(N(R9c)2)(OR9d), -CHP(O)(N(R9c)2)(OR9d), -C(O)OCHP(O)(N(R9c)2)(OR9d), -P(O)(R9c)(N(R9d)2), -CHP(O)(R9c)(N(R9d)2), or -C(O)OCHP(O)(R9c)(N(R9d)2), wherein said alkyl, alkenyl, cycloalkyl, or a pharma- ceutically acceptable salt thereof; or a compound of formula I-A-1, wherein heterocyclyl, aryl, or 5-10 membered heteroaryl, at each occurrence, is optionally substituted with 1-4 Z1b, each 5-10 membered heteroaryl has 5-12 ring members and has 1-4 heteroatoms which are each independently N, O, or S, and each heterocyclyl has 3-12 ring members and has 1-4 heteroatoms which are each independently N, O, or S.

2. The compound has the formula IA-2 【Chemistry 2】 Or formula IA-3 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof, wherein Ring C is a C cycloalkyl, heterocyclyl, C aryl or 5-10 membered heteroaryl, each optionally substituted with 1-4 Z; Y1-V is N-CH2, N-CH(CH3), N-CF2, CH-CH2, CH-CF2, CH-NH, N-S(O), N-S(O)2, N-C(O), CH-C(O) or cyclopropyl; Y2 is C, CH, or N; R2 is H, C1-6 alkyl, C1-6 alkyl-alkoxy, -C1-6 alkyl-cycloalkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -CN, -OR2a, -S-R2a, -S(O)R2a, -S(O)(NH)R2a, -S(O)2R2a, -S(O)2N(R2a)(R2b), or -S(O)( NR2a) R2b, wherein said alkyl, alkoxy, cycloalkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl, at each occurrence, is optionally substituted with 1 to 4 Z1, and any two Z1 can be combined with the atoms to which they are attached to form a C3-10 cycloalkyl or heterocyclyl, or a C6-10 aryl or 5-10 membered heteroaryl; Each X is independently -N=, -C(H)=, or -C(R8)=; Each R3 and R3' is independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -CN, -NO2. -OR3a, -C(O)R3a, -CH2C(O)OR3a, -C(O)OR3a, -C(O)N(R3a)(R3b), -N(R3 a) C(O)R3b, -N(R3a)C(O)OR3b, -N(R3a)C(O)N(R3b)2, -C(O)NHS(O)2R3a , -C(O)NR3aS(O)2R3b, -C(O)NR3aS(O)2NR3bR3c, -C(O)NR3a-S(O)(=NR3 b) R3c, -S(O)2R3a, -S(O)2OR3a, -S(O)2N(R3a)(R3b), -N(R3a)S(O)2R3b , -S(O)NHC(O)R3a, -S(O)(=NR3a)R3b, -S(O)(=NR3a)NR3b, -S(=NR3a)(=NR3b)R3c, -P(O)(OR3a)(R3b), -P(O)(OR3a)(OR3b), -B(OR3a)(OR3b), or -O-C1-6alkyl-C(O)OR3a, where alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl are optionally substituted at each occurrence by 1 to 4 R3d; Each R3a, R3b, and R3c is independently H, C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, C1-6 haloalkyl, C2-8 alkoxyalkyl, -C1-4 alkyl-N(R9a)(R9b), -C1-4 alkyl-N(R9a)C(O)-O-C1-4 alkyl-OP(O)(OR9c)2, -C1-4 alkyl-C(O)N(R9a)(R9b), -C1-4 alkyl-O-C(O)-O-C1-4 alkyl, -C1-4 alkyl-O-C(O)-C1-4 alkyl-N(R9a)(R9b), -C1-4 alkyl-O-C(O)-C1-4 alkoxy alkyl-OP(O)(OR9c)2, -C1-4alkyl-C3-8cycloalkyl, -C1-4alkyl-heterocyclyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, -CH2CH(N(R9a)2)C(O)OR9b, C1-6alkyl-heterocyclyl, C1-6alkyl-aryl or C1-6alkyl-(5-10 membered)heteroaryl, wherein said alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl or 5-10 membered heteroaryl is optionally substituted at each occurrence by 1 to 4 Z1b; Each R5a and R5b is independently H, C1-6 alkyl, C1-6 alkyloxy, C1-6 haloalkyl, C2-6 alkoxyalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, -C1-6 alkyl-N(R9a)(R9b), -CN, -OR5a1, or -N(R5a1)(R5a2); or R5a and R5b, together with the atom to which they are attached, are each optionally substituted with 1 to 4 R5a3. each R5a1 and R5a2 is independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, or 5-10 membered heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl, at each occurrence, is optionally substituted with 1 to 4 halogen; each R3d and R5a3 is independently H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, oxo, -OH, -CN, CO2R3e, -NO2, or -C(O)N(R2a)(R2b), wherein said heterocyclyl or 5-10 membered heteroaryl, at each occurrence, is optionally substituted with C1-6 alkyl, C1-6 haloalkyl, or C1-6 haloalkoxy; each R8 is independently C1-9 alkyl, C1-8 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, oxo, -OH, -CN, CO2R3e, -NO2, -NH2, -N3, -SH, -O(C1-9 alkyl), -O(C1-8 haloalkyl), -NH(C1-9 alkyl), -NH(C1-8 haloalkyl), -N(C1-9 alkyl)2, -N(C1-8 haloalkyl)2; Each R9a and R9b is independently selected from H, C1-9 alkyl, C1-8 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, oxo, -NO2, -CN, -N3, -O-R12a, -C(O)R12a, -C(O)O-R12a, -C(O)N(R12a)(R12b), -N(R12a)(R12b), -N(R12a)2(R12b)+, -N(R12a ) -C(O)R12b, -N(R12a)C(O)O(R12b), -N(R12a)C(O)N(R12b)(R12c), -N(R1 2a) S(O)2(R12b), -N(R12a)S(O)2-N(R12b)(R12c), -N(R12a)S(O)2O(R12b ), -OC(O)R12a, -OC(O)OR12a, -OC(O)-N(R12a)(R12b), -S-R12a, -S(O)R12 a, -S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b), -S(O)(NR12a)R12 b, or -Si(R12a)3, or R9a and R9b together are C1-9 alkyl, C1-8 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -NO2, -CN, -N3, -O-R12a, -C(O)R12a, -C(O)O-R12a, -C(O)N(R12a)(R12b), -N(R12a)(R12b), -N(R12a)2 (R12b)+, -N(R12a)-C(O)R12b, -N(R12a)C(O)O(R12b), -N(R12a)C(O)N(R1 2b) (R12c), -N(R12a)S(O)2(R12b), -N(R12a)S(O)2-N(R12b)(R12c), -N(R 12a) S(O)2O(R12b), -OC(O)R12a, -OC(O)OR12a, -OC(O)-N(R12a)(R12b), - S-R12a, -S(O)R12a, -S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b),forming a 3- to 10-membered heterocyclyl optionally substituted with -S(O)(NR12a)R12b or -Si(R12a)3; each Z1 is independently C1-9 alkyl, C1-8 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, oxo, -NO2, -N3, -CN, -O-R12a, where alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl, at each occurrence, is optionally substituted with 1 to 4 Z1a; Each Z1a is independently H, C1-9 alkyl, C1-8 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, oxo, -NO2, -CN, - N3, -O-R12a, -C(O)R12a, -C(O)O-R12a, -C(O)N(R12a)(R12b), -N(R12a)(R12b), -N(R12a) 2(R12b)+, -N(R12a)-C(O)R12b, -N(R12a)C(O)O(R12b), -N(R12a)C(O)N(R12b)(R12c), -N( R12a) S(O)2(R12b), -N(R12a)S(O)2-N(R12b)(R12c), -N(R12a)S(O)2O(R12b), -OC(O)R12 a, -OC(O)OR12a, -OC(O)-N(R12a)(R12b), -S-R12a, -S(O)R12a, -S(O)(NH)R12a, -S(O)2R12 a, -S(O)2N(R12a)(R12b), -S(O)(NR12a)R12b, or -Si(R12a)3, wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl, at each occurrence, is optionally substituted by 1 to 4 Z1b; Each Z1b is independently H, C1-9 alkyl, C1-8 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, oxo, -OH, -CN, CO2R3e, -NO2, -NH2, -N3, -SH, -O(C1-9 alkyl), -O(C1-8 haloalkyl), -O(C2-6 alkenyl), -O(C2-6 alkynyl), -O(C3-15 cycloalkyl), -O(heterocyclyl), -O(C6-10 aryl), -O(5-10 membered heteroaryl), - -NH(C1-9 alkyl), -NH(C1-8 haloalkyl), -NH(C2-6 alkenyl), -NH(C2-6 alkynyl), -NH(C3-15 cycloalkyl), -NH(heterocyclyl), -NH(C6-10 aryl), -NH(5-10 membered heteroaryl), -N(cyclo-alkyl), -N(C1-9 alkyl)2, -N(C1-8 haloalkyl)2, -N(C2-6 alkenyl)2, -N(C2-6 alkynyl)2, -N(C3-15 cycloalkyl)2, -N(heterocyclyl)2, -N(C6-10 aryl -N(5-10 membered heteroaryl)2, -N(C1-9 alkyl)(C1-8 haloalkyl), -N(C1-9 alkyl)(C2-6 alkenyl), -N(C1-9 alkyl)(C2-6 alkynyl), -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9 alkyl)(heterocyclyl), -N(C1-9 alkyl)(C6-10 aryl), -N(C1-9 alkyl)(5-10 membered heteroaryl), -C(O)(C1-9 alkyl), -C(O)(C1-8 haloalkyl), -C(O)(C2-6 alkenyl). , —C(O)(C2-6 alkynyl), —C(O)(C3-15 cycloalkyl), —C(O)(heterocyclyl), —C(O)(C6-10 aryl), —C(O)(5-10 membered heteroaryl), —C(O)O(C1-9 alkyl), —C(O)O(C1-8 haloalkyl), —C(O)O(C2-6 alkenyl), —C(O)O(C2-6 alkynyl), —C(O)O(C3-15 cycloalkyl), —C(O)O(heterocyclyl), —C(O)O(C6-10 aryl), —C(O)O(5-10 membered heteroaryl), —C(O)NH2,-C(O)NH(C1-9 alkyl), -C(O)NH(C1-8 haloalkyl), -C(O)NH(C2-6 alkenyl), -C(O)NH(C2-6 alkynyl), -C(O)NH(C3-15 cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(C6-10 aryl), -C(O)NH(5-10 membered heteroaryl), -C(O)N(C1-9 alkyl)2, -C(O)N(C1-8 haloalkyl)2, -C(O)N(C2-6 alkenyl)2, -C(O)N(C2-6 alkynyl)2, -C(O)N(C3-15 cycloalkyl). alkyl), -C(O)N(heterocyclyl), -C(O)N(C6-10 aryl), -C(O)N(5-10 membered heteroaryl), -NHC(O)(C1-9 alkyl), -NHC(O)(C1-8 haloalkyl), -NHC(O)(C2-6 alkenyl), -NHC(O)(C2-6 alkynyl), -NHC(O)(C3-15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C6-10 aryl), -NHC(O)(5-10 membered heteroaryl), -NHC(O)O(C1-9 alkyl), -NHC(O)O(C1 -8 haloalkyl), -NHC(O)O(C2-6 alkenyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(C6-10 aryl), -NHC(O)O(5-10 membered heteroaryl), -NHC(O)NH(C1-9 alkyl), -NHC(O)NH(C1-8 haloalkyl), -NHC(O)NH(C2-6 alkenyl), -NHC(O)NH(C2-6 alkynyl), -NHC(O)NH(C3-15 cycloalkyl), -NHC(O). NH(heterocyclyl), -NHC(O)NH(C6-10 aryl), or -NHC(O)NH(5-10 membered heteroaryl), wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl, at each occurrence, is selected from one to three of C1-9 alkyl, C1-8 haloalkyl, halogen, -OH, -NH2, CO2H, -O(C1-9 alkyl), -O(C1-8 haloalkyl), -O(C3-15 cycloalkyl), -O(heterocyclyl), -O(aryl), -O(5-10 membered heteroaryl);-NH(C1-9 alkyl), -NH(C1-8 haloalkyl), -NH(C3-15 cycloalkyl), -NH(heterocyclyl), -NH(aryl), -NH(5-10 membered heteroaryl), -N(C1-9 alkyl)2, -N(C3-15 cycloalkyl)2, -NHC(O)(C1-8 haloalkyl), -NHC(O)(C3-15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl) , optionally substituted with -NHC(O)(5-10 membered heteroaryl), -NHC(O)O(C1-9 alkyl), -NHC(O)O(C1-8 haloalkyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(aryl), -NHC(O)O(5-10 membered heteroaryl), or -NHC(O)NH(C1-9 alkyl); each R1b, R1c, R2a, R2b, R4c, R9c, R12a, R12b, and R12c is independently H, -OH, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, or 5-10 membered heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl, at each occurrence, is optionally substituted with 1 to 4 Z1b; Each R3e is independently H, C1-6 alkyl, C1-6 haloalkyl, -C1-4 alkyl-N(R9a)(R9b), -C1-4 alkyl-C(O)N(R9a)(R9b), -C1-4 alkyl-O-C(O)-O-C1-4 alkyl, -C1-4 alkyl-O-C(O)-C1-4 alkyl-N(R9a)(R9b), -C1-4 alkyl-C3-8 cycloalkyl, -C1-4 alkyl-heterocyclyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, or a 5- to 10-membered alkyl group.

2. The compound of claim 1, wherein said alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl, at each occurrence, is optionally substituted with 1 to 4 Z1b, each 5-10 membered heteroaryl having 5 to 12 ring members and having 1 to 4 heteroatoms which are each independently N, O, or S, and each heterocyclyl having 3 to 12 ring members and having 1 to 4 heteroatoms which are each independently N, O, or S.

3. The compound is of formula I-A-4 【Chemistry 4】 Or formula IA-5 【Chemistry 5】 or a pharma- ceutically acceptable salt thereof, wherein Ring C is a C cycloalkyl, heterocyclyl, C aryl or 5-10 membered heteroaryl, each optionally substituted with 1-4 Z; Y1-V is N-CH2, N-CH(CH3), N-CF2, CH-CH2, CH-CF2, CH-NH, N-S(O), N-S(O)2, N-C(O), CH-C(O) or cyclopropyl; Y2 is C, CH, or N; R2 is H, C1-6 alkyl, C1-6 alkyl-alkoxy, C1-6 alkyl-cycloalkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -CN, -OR2a, -S-R2a, -S(O)R2a, -S(O)(NH)R2a, -S(O)2R2a, -S(O)2N(R2a)(R2b), or -S (O)(NR2a)R2b, wherein said alkyl, alkoxy, cycloalkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl are each optionally substituted with 1-4 Z1, and any two Z1 can be combined with the atoms to which they are attached to form a C3-10 cycloalkyl or heterocyclyl, or a C6-10 aryl or 5-10 membered heteroaryl; Each X is independently -N=, -C(H)=, or -C(R8)=; Each R3 and R3' is independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -CN, -NO2. -OR3a, -C(O)R3a, -CH2C(O)OR3a, -C(O)OR3a, -C(O)N(R3a)(R3b), -N(R3 a) C(O)R3b, -N(R3a)C(O)OR3b, -N(R3a)C(O)N(R3b)2, -C(O)NHS(O)2R3a , -C(O)NR3aS(O)2R3b, -C(O)NR3aS(O)2NR3bR3c, -C(O)NR3a-S(O)(=NR3 b) R3c, -S(O)2R3a, -S(O)2OR3a, -S(O)2N(R3a)(R3b), -N(R3a)S(O)2R3b , -S(O)NHC(O)R3a, -S(O)(=NR3a)R3b, -S(O)(=NR3a)NR3b, -S(=NR3a)(=NR3b)R3c, -P(O)(OR3a)(R3b), -P(O)(OR3a)(OR3b), -B(OR3a)(OR3b), or -O-C1-6alkyl-C(O)OR3a, where alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl are optionally substituted at each occurrence by 1 to 4 R3d; Each R3a, R3b, and R3c is independently H, C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, C1-6 haloalkyl, C2-8 alkoxyalkyl, -C1-4 alkyl-N(R9a)(R9b), -C1-4 alkyl-N(R9a)C(O)-O-C1-4 alkyl-OP(O)(OR9c)2, -C1-4 alkyl-C(O)N(R9a)(R9b), -C1-4 alkyl-O-C(O)-O-C1-4 alkyl, -C1-4 alkyl-O-C(O)-C1-4 alkyl-N(R9a)(R9b), -C1-4 alkyl-O-C(O)-C1-4 alkyl alkyl-OP(O)(OR9c)2, -C1-4alkyl-C3-8cycloalkyl, -C1-4alkyl-heterocyclyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, -CH2CH(N(R9a)2)C(O)OR9b, C1-6alkyl-heterocyclyl, C1-6alkyl-aryl or C1-6alkyl-(5-10 membered)heteroaryl, wherein alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl or 5-10 membered heteroaryl are optionally substituted at each occurrence by 1 to 4 Z1b; each R5a is independently H, C1-6 alkyl, C1-6 alkyloxy, C1-6 haloalkyl, C2-6 alkoxyalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, -C1-6 alkyl-N(R9a)(R9b), -CN, -OR5a1, or -N(R5a1)(R5a2); each R5a1 and R5a2 is independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, or 5-10 membered heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl, at each occurrence, is optionally substituted with 1 to 4 halogen; each R3d is independently H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, oxo, -OH, -CN, CO2R3e, -NO2, or -C(O)N(R2a)(R2b), wherein said heterocyclyl or 5-10 membered heteroaryl is optionally substituted with C1-6 alkyl, C1-6 haloalkyl, or C1-6 haloalkoxy; each R8 is independently C1-9 alkyl, C1-8 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, oxo, -OH, -CN, CO2R3e, -NO2, -NH2, -N3, -SH, -O(C1-9 alkyl), -O(C1-8 haloalkyl), -NH(C1-9 alkyl), -NH(C1-8 haloalkyl), -N(C1-9 alkyl)2, -N(C1-8 haloalkyl)2; Each R9a and R9b is independently selected from H, C1-9 alkyl, C1-8 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, oxo, -NO2, -CN, -N3, -O-R12a, -C(O)R12a, -C(O)O-R12a, -C(O)N(R12a)(R12b), -N(R12a)(R12b), -N(R12a)2(R12b)+, -N(R12a ) -C(O)R12b, -N(R12a)C(O)O(R12b), -N(R12a)C(O)N(R12b)(R12c), -N(R1 2a) S(O)2(R12b), -N(R12a)S(O)2-N(R12b)(R12c), -N(R12a)S(O)2O(R12b ), -OC(O)R12a, -OC(O)OR12a, -OC(O)-N(R12a)(R12b), -S-R12a, -S(O)R12 a, -S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b), -S(O)(NR12a)R12 b, or -Si(R12a)3, or R9a and R9b together are C1-9 alkyl, C1-8 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -NO2, -CN, -N3, -O-R12a, -C(O)R12a, -C(O)O-R12a, -C(O)N(R12a)(R12b), -N(R12a)(R12b), -N(R12a)2 (R12b)+, -N(R12a)-C(O)R12b, -N(R12a)C(O)O(R12b), -N(R12a)C(O)N(R1 2b) (R12c), -N(R12a)S(O)2(R12b), -N(R12a)S(O)2-N(R12b)(R12c), -N(R 12a) S(O)2O(R12b), -OC(O)R12a, -OC(O)OR12a, -OC(O)-N(R12a)(R12b), - S-R12a, -S(O)R12a, -S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b),forming a 3- to 10-membered heterocyclyl optionally substituted with -S(O)(NR12a)R12b or -Si(R12a)3; each Z1 is independently C1-9 alkyl, C1-8 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, oxo, -NO2, -N3, -CN, or -O-R12a, wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl, at each occurrence, is optionally substituted with 1 to 4 Z1a; Each Z1a is independently H, C1-9 alkyl, C1-8 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, oxo, -NO2, -CN, - N3, -O-R12a, -C(O)R12a, -C(O)O-R12a, -C(O)N(R12a)(R12b), -N(R12a)(R12b), -N(R12a) 2(R12b)+, -N(R12a)-C(O)R12b, -N(R12a)C(O)O(R12b), -N(R12a)C(O)N(R12b)(R12c), -N( R12a) S(O)2(R12b), -N(R12a)S(O)2-N(R12b)(R12c), -N(R12a)S(O)2O(R12b), -OC(O)R12 a, -OC(O)OR12a, -OC(O)-N(R12a)(R12b), -S-R12a, -S(O)R12a, -S(O)(NH)R12a, -S(O)2R12 a, -S(O)2N(R12a)(R12b), -S(O)(NR12a)R12b, or -Si(R12a)3, wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl, at each occurrence, is optionally substituted by 1 to 4 Z1b; Each Z1b is independently H, C1-9 alkyl, C1-8 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, oxo, -OH, -CN, CO2R3e, -NO2, -NH2, -N3, -SH, -O(C1-9 alkyl), -O(C1-8 haloalkyl), -O(C2-6 alkenyl), -O(C2-6 alkynyl), -O(C3-15 cycloalkyl), -O(heterocyclyl), -O(C6-10 aryl), -O(5-10 membered heteroaryl), - -NH(C1-9 alkyl), -NH(C1-8 haloalkyl), -NH(C2-6 alkenyl), -NH(C2-6 alkynyl), -NH(C3-15 cycloalkyl), -NH(heterocyclyl), -NH(C6-10 aryl), -NH(5-10 membered heteroaryl), -N(cyclo-alkyl), -N(C1-9 alkyl)2, -N(C1-8 haloalkyl)2, -N(C2-6 alkenyl)2, -N(C2-6 alkynyl)2, -N(C3-15 cycloalkyl)2, -N(heterocyclyl)2, -N(C6-10 aryl -N(5-10 membered heteroaryl)2, -N(C1-9 alkyl)(C1-8 haloalkyl), -N(C1-9 alkyl)(C2-6 alkenyl), -N(C1-9 alkyl)(C2-6 alkynyl), -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9 alkyl)(heterocyclyl), -N(C1-9 alkyl)(C6-10 aryl), -N(C1-9 alkyl)(5-10 membered heteroaryl), -C(O)(C1-9 alkyl), -C(O)(C1-8 haloalkyl), -C(O)(C2-6 alkenyl). , —C(O)(C2-6 alkynyl), —C(O)(C3-15 cycloalkyl), —C(O)(heterocyclyl), —C(O)(C6-10 aryl), —C(O)(5-10 membered heteroaryl), —C(O)O(C1-9 alkyl), —C(O)O(C1-8 haloalkyl), —C(O)O(C2-6 alkenyl), —C(O)O(C2-6 alkynyl), —C(O)O(C3-15 cycloalkyl), —C(O)O(heterocyclyl), —C(O)O(C6-10 aryl), —C(O)O(5-10 membered heteroaryl), —C(O)NH2,-C(O)NH(C1-9 alkyl), -C(O)NH(C1-8 haloalkyl), -C(O)NH(C2-6 alkenyl), -C(O)NH(C2-6 alkynyl), -C(O)NH(C3-15 cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(C6-10 aryl), -C(O)NH(5-10 membered heteroaryl), -C(O)N(C1-9 alkyl)2, -C(O)N(C1-8 haloalkyl)2, -C(O)N(C2-6 alkenyl)2, -C(O)N(C2-6 alkynyl)2, -C(O)N(C3-15 cycloalkyl). alkyl), -C(O)N(heterocyclyl), -C(O)N(C6-10 aryl), -C(O)N(5-10 membered heteroaryl), -NHC(O)(C1-9 alkyl), -NHC(O)(C1-8 haloalkyl), -NHC(O)(C2-6 alkenyl), -NHC(O)(C2-6 alkynyl), -NHC(O)(C3-15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C6-10 aryl), -NHC(O)(5-10 membered heteroaryl), -NHC(O)O(C1-9 alkyl), -NHC(O)O(C1 -8 haloalkyl), -NHC(O)O(C2-6 alkenyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(C6-10 aryl), -NHC(O)O(5-10 membered heteroaryl), -NHC(O)NH(C1-9 alkyl), -NHC(O)NH(C1-8 haloalkyl), -NHC(O)NH(C2-6 alkenyl), -NHC(O)NH(C2-6 alkynyl), -NHC(O)NH(C3-15 cycloalkyl), -NHC(O). NH(heterocyclyl), -NHC(O)NH(C6-10 aryl), or -NHC(O)NH(5-10 membered heteroaryl), wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl, at each occurrence, is selected from one to three of C1-9 alkyl, C1-8 haloalkyl, halogen, -OH, -NH2, CO2H, -O(C1-9 alkyl), -O(C1-8 haloalkyl), -O(C3-15 cycloalkyl), -O(heterocyclyl), -O(aryl), -O(5-10 membered heteroaryl);-NH(C1-9 alkyl), -NH(C1-8 haloalkyl), -NH(C3-15 cycloalkyl), -NH(heterocyclyl), -NH(aryl), -NH(5-10 membered heteroaryl), -N(C1-9 alkyl)2, -N(C3-15 cycloalkyl)2, -NHC(O)(C1-8 haloalkyl), -NHC(O)(C3-15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl) , optionally substituted with -NHC(O)(5-10 membered heteroaryl), -NHC(O)O(C1-9 alkyl), -NHC(O)O(C1-8 haloalkyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(aryl), -NHC(O)O(5-10 membered heteroaryl), or -NHC(O)NH(C1-9 alkyl); each R1b, R1c, R2a, R2b, R4c, R9c, R12a, R12b, and R12c is independently H, -OH, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, or 5-10 membered heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl, at each occurrence, is optionally substituted with 1 to 4 Z1b; Each R3e is independently H, C1-6 alkyl, C1-6 haloalkyl, -C1-4 alkyl-N(R9a)(R9b), -C1-4 alkyl-C(O)N(R9a)(R9b), -C1-4 alkyl-O-C(O)-O-C1-4 alkyl, -C1-4 alkyl-O-C(O)-C1-4 alkyl-N(R9a)(R9b), -C1-4 alkyl-C3-8 cycloalkyl, -C1-4 alkyl-heterocyclyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, or a 5- to 10-membered alkyl group.

2. The compound of claim 1, wherein said alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl, at each occurrence, is optionally substituted with 1 to 4 Z1b, each 5-10 membered heteroaryl having 5 to 12 ring members and having 1 to 4 heteroatoms which are each independently N, O, or S, and each heterocyclyl having 3 to 12 ring members and having 1 to 4 heteroatoms which are each independently N, O, or S.

4. The compound is represented by formula IA-6 【Chemistry 6】 Or formula I-A-7 【Chemistry 7】 or a pharma- ceutically acceptable salt thereof, wherein Ring C is a C cycloalkyl, heterocyclyl, C aryl or 5-10 membered heteroaryl, each optionally substituted with 1-4 Z; V is CH2, CH(CH3), NH, C(O), S(O), S(O)2; n=0, 1, 2, 3, or 4; R2 is H, C1-6 alkyl, -C1-6 alkyl-alkoxy, -C1-6 alkyl-cycloalkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -CN, -OR2a, -S-R2a, -S(O)R2a, -S(O)(NH)R2a, -S(O)2R2a, -S(O)2N(R2a)(R2b), or -S(O) (NR2a)R2b, wherein said alkyl, alkoxy, cycloalkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl, at each occurrence, is optionally substituted with 1 to 4 Z1, and any two Z1 can be combined with the atoms to which they are attached to form a C3-10 cycloalkyl or heterocyclyl, or a C6-10 aryl or 5-10 membered heteroaryl; Each X is independently -N=, -C(H)=, or -C(R8)=; Each R3 and R3' is independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -CN, -NO2. -OR3a, -C(O)R3a, -CH2C(O)OR3a, -C(O)OR3a, -C(O)N(R3a)(R3b), -N(R3 a) C(O)R3b, -N(R3a)C(O)OR3b, -N(R3a)C(O)N(R3b)2, -C(O)NHS(O)2R3a , -C(O)NR3aS(O)2R3b, -C(O)NR3aS(O)2NR3bR3c, -C(O)NR3a-S(O)(=NR3 b) R3c, -S(O)2R3a, -S(O)2OR3a, -S(O)2N(R3a)(R3b), -N(R3a)S(O)2R3b , -S(O)NHC(O)R3a, -S(O)(=NR3a)R3b, -S(O)(=NR3a)NR3b, -S(=NR3a)(=NR3b)R3c, -P(O)(OR3a)(R3b), -P(O)(OR3a)(OR3b), -B(OR3a)(OR3b), or -O-C1-6alkyl-C(O)OR3a, where alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl are optionally substituted at each occurrence by 1 to 4 R3d; Each R3a, R3b, and R3c is independently H, C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, C1-6 haloalkyl, C2-8 alkoxyalkyl, -C1-4 alkyl-N(R9a)(R9b), -C1-4 alkyl-N(R9a)C(O)-O-C1-4 alkyl-OP(O)(OR9c)2, -C1-4 alkyl-C(O)N(R9a)(R9b), -C1-4 alkyl-O-C(O)-O-C1-4 alkyl, -C1-4 alkyl-O-C(O)-C1-4 alkyl-N(R9a)(R9b), -C1-4 alkyl-O-C(O)-C1-4 alkoxy alkyl-OP(O)(OR9c)2, -C1-4alkyl-C3-8cycloalkyl, -C1-4alkyl-heterocyclyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, heterocyclyl, -CH2CH(N(R9a)2)C(O)OR9b, C1-6alkyl-heterocyclyl, C1-6alkyl-aryl or C1-6alkyl-(5-10 membered)heteroaryl, wherein said alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl or 5-10 membered heteroaryl is optionally substituted at each occurrence by 1 to 4 Z1b; Each R4 is independently H, CH2OH, -OH, C1-9 alkyl, C1-8 haloalkyl, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, oxo, -NO2, -CN, -N3, -O-R4a, -C(O )R4a, -C(O)O-R4a, -C(O)N(R4a)(R4b), -N(R4a)(R4b), -N(R4a)2(R4b)+, -N(R4a)-C(O)R4b, -N(R4a )C(O)O(R4b), -N(R4a)C(O)N(R4b)(R4c), -N(R4a)S(O)2(R4b), -N(R4a)S(O)2-N(R4b)(R4c), -N(R4 a) S(O)2O(R4b), -OC(O)R4a, -OC(O)OR4a, -OC(O)-N(R4a)(R4b), -S-R4a, -S(O)R4a, -S(O)(NH)R4a, -S(O)2R4a, -S(O)2N(R4a)(R4b), -S(O)(NR4a)R4b, or -Si(R4a)3, wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl is optionally substituted with 1 to 4 Z1b at each occurrence, or two R4 groups attached to adjacent ring atoms combine with the atoms to which they are attached to form a C5-10 cycloalkyl or heterocyclyl, each optionally substituted with 1 to 4 Z1b; each R5a and R5b is independently H, C1-6 alkyl, C1-6 alkyloxy, C1-6 haloalkyl, C2-6 alkoxyalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, -C1-6 alkyl-N(R9a)(R9b), -CN, -OR5a1, or -N(R5a1)(R5a2); or R5a and R5b combine with the atom to which they are attached to form a C3-10 cycloalkyl or heterocyclyl, each optionally substituted with 1 to 4 R5a3; each R5a1 and R5a2 is independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, or 5-10 membered heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl, at each occurrence, is optionally substituted with 1 to 4 halogen; each R3d and R5a3 is independently H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, oxo, -OH, -CN, CO2R3e, -NO2, or -C(O)N(R2a)(R2b), wherein said heterocyclyl or 5-10 membered heteroaryl, at each occurrence, is optionally substituted with C1-6 alkyl, C1-6 haloalkyl, or C1-6 haloalkoxy; each R8 is independently C1-9 alkyl, C1-8 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, oxo, -OH, -CN, CO2R3e, -NO2, -NH2, -N3, -SH, -O(C1-9 alkyl), -O(C1-8 haloalkyl), -NH(C1-9 alkyl), -NH(C1-8 haloalkyl), -N(C1-9 alkyl)2, -N(C1-8 haloalkyl)2; Each R9a and R9b is independently H, C1-9 alkyl, C1-8 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, oxo, -NO2, -CN, -N3, -O-R12a, -C(O)R12a, -C(O)O-R12a, -C(O)N(R12a)(R12b), -N(R12a)(R12b), -N(R12a)2(R12b)+, -N(R12a). -C(O)R12b, -N(R12a)C(O)O(R12b), -N(R12a)C(O)N(R12b)(R12c), -N(R12 a) S(O)2(R12b), -N(R12a)S(O)2-N(R12b)(R12c), -N(R12a)S(O)2O(R12b) , -OC(O)R12a, -OC(O)OR12a, -OC(O)-N(R12a)(R12b), -S-R12a, -S(O)R12a , -S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b), -S(O)(NR12a)R12b, or -Si(R12a)3, or R9a and R9b together are C1-9 alkyl, C1-8 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, oxo, -NO2, -CN, -N3, -O-R12a, -C(O)R12a, -C(O)O-R12a, -C(O)N(R12a)(R12b), -N(R12a)(R12b), -N(R12a) 2(R12b)+, -N(R12a)-C(O)R12b, -N(R12a)C(O)O(R12b), -N(R12a)C(O)N(R 12b) (R12c), -N(R12a)S(O)2(R12b), -N(R12a)S(O)2-N(R12b)(R12c), -N( R12a) S(O)2O(R12b), -OC(O)R12a, -OC(O)OR12a, -OC(O)-N(R12a)(R12b), -S-R12a, -S(O)R12a, -S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b),forming a 3- to 10-membered heterocyclyl optionally substituted with -S(O)(NR12a)R12b or -Si(R12a)3; each Z1 is independently C1-9 alkyl, C1-8 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, oxo, -NO2, -N3, -CN, or -O-R12a, wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl, at each occurrence, is optionally substituted with 1 to 4 Z1a; Each Z1a is independently H, C1-9 alkyl, C1-8 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, oxo, -NO2, -CN, - N3, -O-R12a, -C(O)R12a, -C(O)O-R12a, -C(O)N(R12a)(R12b), -N(R12a)(R12b), -N(R12a) 2(R12b)+, -N(R12a)-C(O)R12b, -N(R12a)C(O)O(R12b), -N(R12a)C(O)N(R12b)(R12c), -N( R12a) S(O)2(R12b), -N(R12a)S(O)2-N(R12b)(R12c), -N(R12a)S(O)2O(R12b), -OC(O)R12 a, -OC(O)OR12a, -OC(O)-N(R12a)(R12b), -S-R12a, -S(O)R12a, -S(O)(NH)R12a, -S(O)2R12 a, -S(O)2N(R12a)(R12b), -S(O)(NR12a)R12b, or -Si(R12a)3, wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5- to 10-membered heteroaryl, at each occurrence, is optionally substituted by 1 to 4 Z1b; Each Z1b is independently H, C1-9 alkyl, C1-8 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, oxo, -OH, -CN, CO2R3e, -NO2, -NH2, -N3, -SH, -O(C1-9 alkyl), -O(C1-8 haloalkyl), -O(C2-6 alkenyl), -O(C2-6 alkynyl), -O(C3-15 cycloalkyl), -O(heterocyclyl), -O(C6-10 aryl), -O(5-10 membered heteroaryl), - -NH(C1-9 alkyl), -NH(C1-8 haloalkyl), -NH(C2-6 alkenyl), -NH(C2-6 alkynyl), -NH(C3-15 cycloalkyl), -NH(heterocyclyl), -NH(C6-10 aryl), -NH(5-10 membered heteroaryl), -N(cyclo-alkyl), -N(C1-9 alkyl)2, -N(C1-8 haloalkyl)2, -N(C2-6 alkenyl)2, -N(C2-6 alkynyl)2, -N(C3-15 cycloalkyl)2, -N(heterocyclyl)2, -N(C6-10 aryl -N(5-10 membered heteroaryl)2, -N(C1-9 alkyl)(C1-8 haloalkyl), -N(C1-9 alkyl)(C2-6 alkenyl), -N(C1-9 alkyl)(C2-6 alkynyl), -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9 alkyl)(heterocyclyl), -N(C1-9 alkyl)(C6-10 aryl), -N(C1-9 alkyl)(5-10 membered heteroaryl), -C(O)(C1-9 alkyl), -C(O)(C1-8 haloalkyl), -C(O)(C2-6 alkenyl). , —C(O)(C2-6 alkynyl), —C(O)(C3-15 cycloalkyl), —C(O)(heterocyclyl), —C(O)(C6-10 aryl), —C(O)(5-10 membered heteroaryl), —C(O)O(C1-9 alkyl), —C(O)O(C1-8 haloalkyl), —C(O)O(C2-6 alkenyl), —C(O)O(C2-6 alkynyl), —C(O)O(C3-15 cycloalkyl), —C(O)O(heterocyclyl), —C(O)O(C6-10 aryl), —C(O)O(5-10 membered heteroaryl), —C(O)NH2,-C(O)NH(C1-9 alkyl), -C(O)NH(C1-8 haloalkyl), -C(O)NH(C2-6 alkenyl), -C(O)NH(C2-6 alkynyl), -C(O)NH(C3-15 cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(C6-10 aryl), -C(O)NH(5-10 membered heteroaryl), -C(O)N(C1-9 alkyl)2, -C(O)N(C1-8 haloalkyl)2, -C(O)N(C2-6 alkenyl)2, -C(O)N(C2-6 alkynyl)2, -C(O)N(C3-15 cycloalkyl). alkyl), -C(O)N(heterocyclyl), -C(O)N(C6-10 aryl), -C(O)N(5-10 membered heteroaryl), -NHC(O)(C1-9 alkyl), -NHC(O)(C1-8 haloalkyl), -NHC(O)(C2-6 alkenyl), -NHC(O)(C2-6 alkynyl), -NHC(O)(C3-15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C6-10 aryl), -NHC(O)(5-10 membered heteroaryl), -NHC(O)O(C1-9 alkyl), -NHC(O)O(C1 -8 haloalkyl), -NHC(O)O(C2-6 alkenyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(C6-10 aryl), -NHC(O)O(5-10 membered heteroaryl), -NHC(O)NH(C1-9 alkyl), -NHC(O)NH(C1-8 haloalkyl), -NHC(O)NH(C2-6 alkenyl), -NHC(O)NH(C2-6 alkynyl), -NHC(O)NH(C3-15 cycloalkyl), -NHC(O). NH(heterocyclyl), -NHC(O)NH(C6-10 aryl), or -NHC(O)NH(5-10 membered heteroaryl), wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl, at each occurrence, is selected from one to three of C1-9 alkyl, C1-8 haloalkyl, halogen, -OH, -NH2, CO2H, -O(C1-9 alkyl), -O(C1-8 haloalkyl), -O(C3-15 cycloalkyl), -O(heterocyclyl), -O(aryl), -O(5-10 membered heteroaryl);-NH(C1-9 alkyl), -NH(C1-8 haloalkyl), -NH(C3-15 cycloalkyl), -NH(heterocyclyl), -NH(aryl), -NH(5-10 membered heteroaryl), -N(C1-9 alkyl)2, -N(C3-15 cycloalkyl)2, -NHC(O)(C1-8 haloalkyl), -NHC(O)(C3-15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl) , optionally substituted with -NHC(O)(5-10 membered heteroaryl), -NHC(O)O(C1-9 alkyl), -NHC(O)O(C1-8 haloalkyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(aryl), -NHC(O)O(5-10 membered heteroaryl), or -NHC(O)NH(C1-9 alkyl); each R1b, R1c, R2a, R2b, R4a, R4b, R4c, R9c, R12a, R12b, and R12c is independently H, -OH, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, or 5-10 membered heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl is optionally substituted at each occurrence with 1 to 4 Z1b; each R3e is independently H, C1-6 alkyl, C1-6 haloalkyl, -C1-4 alkyl-N(R9a)(R9b), -C1-4 alkyl-C(O)N(R9a)(R9b), -C1-4 alkyl-O-C(O)-O-C1-4 alkyl, -C1-4 alkyl-O-C(O)-C1-4 alkyl-N(R9a)(R9b), -C1-4 alkyl-C3-8 cycloalkyl, -C1-4 alkyl-heterocyclyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, or 5-10 membered heteroaryl, wherein said alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl, at each occurrence, is optionally substituted with 1 to 4 Z1b; each 5-10 membered heteroaryl has 5 to 12 ring members and 1 to 4 heteroatoms which are each independently N, O, or S; The compound of claim 1, wherein each heterocyclyl has 3 to 12 ring members and 1 to 4 heteroatoms which are each independently N, O, or S.

5. Each R5a and R5b, if present, is independently H, C1-9 alkyl or C2-6 alkoxyalkyl, wherein said C1-9 alkyl or C2-6 alkoxyalkyl, in each occurrence, is optionally substituted with one or more halogens. The compound of any one of claims 2 to 4, or a pharma- ceutically acceptable salt thereof.

6. Ring C is a C aryl or 5-10 membered heteroaryl selected from the group consisting of: 【Chemistry 8】 each of which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of H, OH, oxo, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, -NO2, -N3, -CN, -O-C1-6 alkyl, -C(O)-C1-6 alkyl, -C(O)-N(C0-6 alkyl)(C0-6 alkyl) and -N(C0-6 alkyl)(C0-6 alkyl); 5. The compound according to any one of claims 2 to 4, or a pharma- ceutically acceptable salt thereof, wherein said one to four substituents, in each occurrence, are optionally substituted with one or more halogen.

7. Ring A is selected from the group consisting of: 【Chemistry 9】 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, each of which is optionally substituted with 1 to 4 Z1a.

8. 8. The compound of claim 7, wherein each of the one to four Z1a is independently H, halogen, C1-9 alkyl, C1-6 alkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, or heterocyclyl, each of which is optionally substituted with one or more halogens.

9. R2 is C1-6 alkyl, C1-6 alkyl-alkoxy, C1-6 alkyl-cycloalkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, or 5-10 membered heteroaryl, each of which is optionally substituted with 1 to 4 Z1. The compound of any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof.

10. R2 is selected from the group consisting of: 【Chemistry 10】 10. The compound of claim 9, or a pharma- ceutically acceptable salt thereof, each of which is optionally substituted with 1 to 4 Z1.

11. 11. The compound of claim 10, or a pharma- ceutically acceptable salt thereof, wherein R2' is H, C1-6 alkyl, C1-6 haloalkyl, or -C1-6 alkyl-cycloalkoxy, each of which is optionally substituted with one or more halogens.

12. Each R3 and R3' is independently selected from H, C6-10 aryl, 5- to 10-membered heteroaryl, -C(O)R3a, -CH2C(O)OR3a, -C(O)N(R3a)(R3b), -N(R3a)C(O)R3b, -N(R3a)C(O)OR3b, -N(R3a)C(O)N(R3b)2, -C(O)NHS(O)2R3a, -C(O)NR3aS(O)2R3b, -C(O)NR3aS(O 5. The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein: R is selected from the group consisting of -NR3bR3c, -C(O)NR3a-S(O)(=NR3b)R3c, -S(O)2N(R3a)(R3b), -N(R3a)S(O)2R3b, -S(O)2NHC(O)R3a, and -O-C1-6alkyl-C(O)OR3a, each of which is optionally substituted with 1 to 4 R3d.

13. 13. The compound of claim 12, or a pharma- ceutically acceptable salt thereof, wherein each R and R' is independently H, C(O)NR(CH2)mR, C(O)NR(CH2)mC(O)R, NRC(O)(CH2)mR, NR(CH2)mR, NR(CH2)mC(O)R, C(O)NRR, or NRC(O)R, each of which is optionally substituted with 1 to 4 R and m=0, 1, 2, or 3.

14. 14. The compound of claim 13, or a pharma- ceutically acceptable salt thereof, wherein each R3 and R3' is independently H, C(O)NHR3b, or NHC(O)R3b.

15. Each R3b is independently H, C1-6 alkyl, C1-6 haloalkyl, C2-8 alkoxyalkyl, -C1-4 alkyl-N(R9a)(R9b), -C1-4 alkyl-C(O)N(R9a)(R9b), -C1-4 alkyl-O-C(O)-O-C1-4 alkyl, -C1-4 alkyl-O-C(O)-C1-4 alkyl-N(R9a)(R9b), -C1-4 alkyl-C3-8 cycloalkyl, -C1-4 alkyl-heterocyclyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkenyl, 15. The compound of claim 14, or a pharma- ceutically acceptable salt thereof, wherein said alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, or 5-10 membered heteroaryl is optionally substituted with 1 to 4 Z1b.

16. Each R3b is independently C6-10 aryl or 5-10 membered heteroaryl, at each occurrence optionally substituted with 1 to 5 R3f, where R3f is H, OH, oxo, NH2, halogen, -NO2, -N3, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocyclyl, -O 16. The compound of claim 15, or a pharma- ceutically acceptable salt thereof, wherein R3f, at each occurrence, is optionally substituted with one or more halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy.

17. The aryl or 5- to 10-membered heteroaryl in R3b is selected from the group consisting of: 【Chemistry 11】 、 17. The compound of claim 16, or a pharma- ceutically acceptable salt thereof, each of which is optionally substituted with 1 to 5 R3f.

18. each R4 is independently H, -OH, -CH2OH, C1-9 alkyl, C1-8 haloalkyl, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, oxo, -NO2, -CN, -N3, -O-C1-9 alkyl, or -C(O)C1-9 alkyl, each of which is optionally substituted with 1 to 4 Z1b; The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein two R groups attached to adjacent ring atoms can combine with the atoms to which they are attached to form a C5-10 cycloalkyl or heterocyclyl, each optionally substituted with 1 to 4 Z1b.

19. 19. The compound of claim 18, or a pharma- ceutically acceptable salt thereof, wherein each R4 is independently H, halogen, -CH2OH, C1-9 alkyl, C1-8 haloalkyl, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, or C3-15 cycloalkyl.

20. Each Z1 is independently C1-9 alkyl, C1-8 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, oxo, -NO2, -N3, -CN, -O-R12a, -C(O)-R12a, -C(O)O-R12a, -C(O)-N(R12a)(R12b), or -N(R12a)(R12b), or a pharma- ceutically acceptable salt thereof.

21. The compound according to any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof, wherein each Z1a is independently H, -OH, C1-9 alkyl, C1-8 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, or halogen.

22. The compound according to any one of claims 1 to 21, wherein each Z1b is independently H, C1-9 alkyl, C1-8 haloalkyl, halogen, oxo, -OH, or -CN, or a pharma- ceutically acceptable salt thereof.

23. 23. The compound of any one of claims 1 to 22, or a pharma- ceutically acceptable salt thereof, wherein each R8 is independently H, oxo, OH, C1-9 alkyl, C1-8 haloalkyl, halogen, -O(C1-3 alkyl), or -O(C1-3 haloalkyl).

24. 2. The compound of claim 1, having a structure selected from the group consisting of: 【Chemistry 12】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】

25. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

26. 1. A method of treating a GLP-1R mediated disease or condition, comprising: The present invention relates to a method for treating a GLP-1R mediated disease or condition, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 25 or a pharma- ceutically acceptable salt thereof ... GLP-1R mediated disease or condition being selected from the group consisting of T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, 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, sleep apnea, obesity, eating disorders, weight gain due to use of other medications, excessive sugar cravings, dyslipidemia, hyperinsulinemia, NAFLD, NASH, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, vascular compliance, Disorders of the brain, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial hyperlipidemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina, thrombosis, atherosclerosis, the condition being selected from the group consisting of chronic arteriosclerosis, transient ischemic attack, vascular restenosis, glucose metabolism disorders, impaired fasting glucose conditions, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcers, ulcerative colitis, hyperapo B lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome, and drug addiction.

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